Application of self-efficacy theory in dental clinical practice.

PubMed

Kakudate, N; Morita, M; Fukuhara, S; Sugai, M; Nagayama, M; Kawanami, M; Chiba, I

2010-11-01

In clinical practice, self-efficacy refers to how certain a patient feels about his or her ability to take the necessary action to improve the indicators and maintenance of health. It is assumed that the prognosis for patient behaviour can be improved by assessing the proficiency of their self-efficacy through providing psychoeducational instructions adapted for individual patients, and promoting behavioural change for self-care. Therefore, accurate assessment of self-efficacy is an important key in daily clinical preventive care. The previous research showed that the self-efficacy scale scores predicted patient behaviour in periodontal patients and mother's behaviour in paediatric dental practice. Self-efficacy belief is constructed from four principal sources of information: enactive mastery experience, vicarious experience, verbal persuasion, and physiological and affective states. Thus, self-efficacy can be enhanced by the intervention exploiting these sources. The previous studies revealed that behavioural interventions to enhance self-efficacy improved oral-care behaviour of patients. Therefore, assessment and enhancement of oral-care specific self-efficacy is important to promote behaviour modification in clinical dental practice. However, more researches are needed to evaluate the suitability of the intervention method. © 2010 John Wiley & Sons A/S.

In Silico Screening Based on Predictive Algorithms as a Design Tool for Exon Skipping Oligonucleotides in Duchenne Muscular Dystrophy

PubMed Central

Echigoya, Yusuke; Mouly, Vincent; Garcia, Luis; Yokota, Toshifumi; Duddy, William

2015-01-01

The use of antisense ‘splice-switching’ oligonucleotides to induce exon skipping represents a potential therapeutic approach to various human genetic diseases. It has achieved greatest maturity in exon skipping of the dystrophin transcript in Duchenne muscular dystrophy (DMD), for which several clinical trials are completed or ongoing, and a large body of data exists describing tested oligonucleotides and their efficacy. The rational design of an exon skipping oligonucleotide involves the choice of an antisense sequence, usually between 15 and 32 nucleotides, targeting the exon that is to be skipped. Although parameters describing the target site can be computationally estimated and several have been identified to correlate with efficacy, methods to predict efficacy are limited. Here, an in silico pre-screening approach is proposed, based on predictive statistical modelling. Previous DMD data were compiled together and, for each oligonucleotide, some 60 descriptors were considered. Statistical modelling approaches were applied to derive algorithms that predict exon skipping for a given target site. We confirmed (1) the binding energetics of the oligonucleotide to the RNA, and (2) the distance in bases of the target site from the splice acceptor site, as the two most predictive parameters, and we included these and several other parameters (while discounting many) into an in silico screening process, based on their capacity to predict high or low efficacy in either phosphorodiamidate morpholino oligomers (89% correctly predicted) and/or 2’O Methyl RNA oligonucleotides (76% correctly predicted). Predictions correlated strongly with in vitro testing for sixteen de novo PMO sequences targeting various positions on DMD exons 44 (R2 0.89) and 53 (R2 0.89), one of which represents a potential novel candidate for clinical trials. We provide these algorithms together with a computational tool that facilitates screening to predict exon skipping efficacy at each position of a target exon. PMID:25816009

The job self-efficacy and job involvement of clinical nursing teachers.

PubMed

Yang, Hui-Ling; Kao, Yu-Hsiu; Huang, Yi-Ching

2006-09-01

This paper explored the present status of self-efficacy and job involvement of clinical nursing teachers and investigated the predictive power of teachers' personal background variables on such, as well as the relationship between self-efficacy and job involvement. A total of 419 participants in the survey sample were chosen among clinical nursing teachers at 19 public and private institutes of technology and junior colleges in Taiwan in 2004. The self-developed structural questionnaire was categorized into three sections, including personal background data, job self-efficacy related to the clinical teaching inventory and job involvement related to clinical teaching inventory. Of the total 419 questionnaires distributed for this cross-sectional survey, 266 valid copies were registered, at a recovery rate of 63%. Findings indicated that both the job self-efficacy and job involvement of clinical nursing teachers are at a medium to high level and that significant differences exist in job self-efficacy and job involvement based on differences in age, marital status, teaching seniority, teacher qualifications, and job satisfaction. Second, samples have significantly different performance in self-efficacy due to differences in education level attained and the medical institution to which nursing teachers had been assigned. Self-efficacy and job involvement are significantly positively correlated. These results can serve as a reference for the cultivation of nursing teachers and reform of clinical nursing education in the future.

Predictive validity of behavioural animal models for chronic pain

PubMed Central

Berge, Odd-Geir

2011-01-01

Rodent models of chronic pain may elucidate pathophysiological mechanisms and identify potential drug targets, but whether they predict clinical efficacy of novel compounds is controversial. Several potential analgesics have failed in clinical trials, in spite of strong animal modelling support for efficacy, but there are also examples of successful modelling. Significant differences in how methods are implemented and results are reported means that a literature-based comparison between preclinical data and clinical trials will not reveal whether a particular model is generally predictive. Limited reports on negative outcomes prevents reliable estimate of specificity of any model. Animal models tend to be validated with standard analgesics and may be biased towards tractable pain mechanisms. But preclinical publications rarely contain drug exposure data, and drugs are usually given in high doses and as a single administration, which may lead to drug distribution and exposure deviating significantly from clinical conditions. The greatest challenge for predictive modelling is, however, the heterogeneity of the target patient populations, in terms of both symptoms and pharmacology, probably reflecting differences in pathophysiology. In well-controlled clinical trials, a majority of patients shows less than 50% reduction in pain. A model that responds well to current analgesics should therefore predict efficacy only in a subset of patients within a diagnostic group. It follows that successful translation requires several models for each indication, reflecting critical pathophysiological processes, combined with data linking exposure levels with effect on target. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21371010

Predictive Value of Parkinsonian Primates in Pharmacologic Studies: A Comparison between the Macaque, Marmoset, and Squirrel Monkey.

PubMed

Veyres, Nicolas; Hamadjida, Adjia; Huot, Philippe

2018-05-01

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate is the gold-standard animal model of Parkinson disease (PD) and has been used to assess the effectiveness of experimental drugs on dyskinesia, parkinsonism, and psychosis. Three species have been used in most studies-the macaque, marmoset, and squirrel monkey-the last much less so than the first two species; however, the predictive value of each species at forecasting clinical efficacy, or lack thereof, is poorly documented. Here, we have reviewed all the published literature detailing pharmacologic studies that assessed the effects of experimental drugs on dyskinesia, parkinsonism, and psychosis in each of these species and have calculated their predictive value of success and failure at the clinical level. We found that, for dyskinesia, the macaque has a positive predictive value of 87.5% and a false-positive rate of 38.1%, whereas the marmoset has a positive predictive value of 76.9% and a false-positive rate of 15.6%. For parkinsonism, the macaque has a positive predictive value of 68.2% and a false-positive rate of 44.4%, whereas the marmoset has a positive predictive value of 86.9% and a false-positive rate of 41.7%. No drug that alleviates psychosis in the clinic has shown efficacy at doing so in the macaque, whereas the marmoset has 100% positive predictive value. The small number of studies conducted in the squirrel monkey precluded us from calculating its predictive efficacy. We hope our results will help in the design of pharmacologic experiments and will facilitate the drug discovery and development process in PD. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Self-efficacy: a means of identifying problems in nursing education and career progress.

PubMed

Harvey, V; McMurray, N

1994-10-01

Two nursing self-efficacy scales (academic and clinical) were developed and refined for use in identifying problems in progress in undergraduate nurses. Emergent factors within each scale contained items representing important aspects of nursing education. Both measures showed good internal consistency, test-retest reliability, and construct validity. Sensitivity to content and focus of tuition at time of completion was shown with some changes in factor structure over samples of first year nursing students. Academic self-efficacy (but not clinical self-efficacy) was predictive of course withdrawal. Applications to nursing education, progress in pursuing a nursing career and attrition are discussed.

Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle.

PubMed

Miller, Miles A; Gadde, Suresh; Pfirschke, Christina; Engblom, Camilla; Sprachman, Melissa M; Kohler, Rainer H; Yang, Katherine S; Laughney, Ashley M; Wojtkiewicz, Gregory; Kamaly, Nazila; Bhonagiri, Sushma; Pittet, Mikael J; Farokhzad, Omid C; Weissleder, Ralph

2015-11-18

Therapeutic nanoparticles (TNPs) have shown heterogeneous responses in human clinical trials, raising questions of whether imaging should be used to identify patients with a higher likelihood of NP accumulation and thus therapeutic response. Despite extensive debate about the enhanced permeability and retention (EPR) effect in tumors, it is increasingly clear that EPR is extremely variable; yet, little experimental data exist to predict the clinical utility of EPR and its influence on TNP efficacy. We hypothesized that a 30-nm magnetic NP (MNP) in clinical use could predict colocalization of TNPs by magnetic resonance imaging (MRI). To this end, we performed single-cell resolution imaging of fluorescently labeled MNPs and TNPs and studied their intratumoral distribution in mice. MNPs circulated in the tumor microvasculature and demonstrated sustained uptake into cells of the tumor microenvironment within minutes. MNPs could predictably demonstrate areas of colocalization for a model TNP, poly(d,l-lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG), within the tumor microenvironment with >85% accuracy and circulating within the microvasculature with >95% accuracy, despite their markedly different sizes and compositions. Computational analysis of NP transport enabled predictive modeling of TNP distribution based on imaging data and identified key parameters governing intratumoral NP accumulation and macrophage uptake. Finally, MRI accurately predicted initial treatment response and drug accumulation in a preclinical efficacy study using a paclitaxel-encapsulated NP in tumor-bearing mice. These approaches yield valuable insight into the in vivo kinetics of NP distribution and suggest that clinically relevant imaging modalities and agents can be used to select patients with high EPR for treatment with TNPs. Copyright © 2015, American Association for the Advancement of Science.

Endovascular Treatment of Malignant Superior Vena Cava Syndrome: Results and Predictive Factors of Clinical Efficacy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fagedet, Dorothee, E-mail: DFagedet@chu-grenoble.fr; Thony, Frederic, E-mail: FThony@chu-grenoble.fr; Timsit, Jean-Francois, E-mail: JFTimsit@chu-grenoble.fr

To demonstrate the effectiveness of endovascular treatment (EVT) with self-expandable bare stents for malignant superior vena cava syndrome (SVCS) and to analyze predictive factors of EVT efficacy. Retrospective review of the 164 patients with malignant SVCS treated with EVT in our hospital from August 1992 to December 2007 and followed until February 2009. Endovascular treatment includes angioplasty before and after stent placement. We used self-expandable bare stents. We studied results of this treatment and looked for predictive factors of clinical efficacy, recurrence, and complications by statistical analysis. Endovascular treatment was clinically successful in 95% of cases, with an acceptable ratemore » of early mortality (2.4%). Thrombosis of the superior vena cava was the only independent factor for EVT failure. The use of stents over 16 mm in diameter was a predictive factor for complications (P = 0.008). Twenty-one complications (12.8%) occurred during the follow-up period. Relapse occurred in 36 patients (21.9%), with effective restenting in 75% of cases. Recurrence of SVCS was significantly increased in cases of occlusion (P = 0.01), initial associated thrombosis (P = 0.006), or use of steel stents (P = 0.004). Long-term anticoagulant therapy did not influence the risk of recurrence or complications. In malignancy, EVT with self-expandable bare stents is an effective SVCS therapy. These results prompt us to propose treatment with stents earlier in the clinical course of patients with SVCS and to avoid dilatation greater than 16 mm.« less

Dose-specific efficacy of Haemophilus influenzae type b conjugate vaccines: a systematic review and meta-analysis of controlled clinical trials

PubMed Central

GRIFFITHS, U. K.; CLARK, A.; GESSNER, B.; MINERS, A.; SANDERSON, C.; SEDYANINGSIH, E. R.; MULHOLLAND, K. E.

2012-01-01

SUMMARY Global coverage of infant Haemophilus influenzae type b (Hib) vaccination has increased considerably during the past decade, partly due to GAVI Alliance donations of the vaccine to low-income countries. In settings where large numbers of children receive only one or two vaccine doses rather than the recommended three doses, dose-specific efficacy estimates are needed to predict impact. The objective of this meta-analysis is to determine Hib vaccine efficacy against different clinical outcomes after receiving one, two or three doses of vaccine. Studies were eligible for inclusion if a prospective, controlled design had been used to evaluate commercially available Hib conjugate vaccines. Eight studies were included. Pooled vaccine efficacies against invasive Hib disease after one, two or three doses of vaccine were 59%, 92% and 93%, respectively. The meta-analysis provides robust estimates for use in decision-analytical models designed to predict the impact of Hib vaccine. PMID:22583474

[Immunological surrogate endpoints to evaluate vaccine efficacy].

PubMed

Jin, Pengfei; Li, Jingxin; Zhou, Yang; Zhu, Fengcai

2015-12-01

An immunological surrogate endpoints is a vaccine-induced immune response (either humoral or cellular immune) that predicts protection against clinical endpoints (infection or disease), and can be used to evaluate vaccine efficacy in clinical vaccine trials. Compared with field efficacy trials observing clinical endpoints, immunological vaccine trials could reduce the sample size or shorten the duration of a trial, which promote the license and development of new candidate vaccines. For these reasons, establishing immunological surrogate endpoints is one of 14 Grand Challenges of Global Health of the National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation. From two parts of definition and statistical methods for evaluation of surrogate endpoints, this review provides a more comprehensive description.

Parkinson's Disease Gene Therapy: Success by Design Meets Failure by Efficacy

PubMed Central

Bartus, Raymond T; Weinberg, Marc S; Samulski, R. Jude

2014-01-01

Over the past decade, nine gene therapy clinical trials for Parkinson's disease (PD) have been initiated and completed. Starting with considerable optimism at the initiation of each trial, none of the programs has yet borne sufficiently robust clinical efficacy or found a clear path toward regulatory approval. Despite the immediately disappointing nature of the efficacy outcomes in these trials, the clinical data garnered from the individual studies nonetheless represent tangible and significant progress for the gene therapy field. Collectively, the clinical trials demonstrate that we have overcome the major safety hurdles previously suppressing central nervous system (CNS) gene therapy, for none produced any evidence of untoward risk or harm after administration of various vector-delivery systems. More importantly, these studies also demonstrated controlled, highly persistent generation of biologically active proteins targeted to structures deep in the human brain. Therefore, a renewed, focused emphasis must be placed on advancing clinical efficacy by improving clinical trial design, patient selection and outcome measures, developing more predictive animal models to support clinical testing, carefully performing retrospective analyses, and most importantly moving forward—beyond our past limits. PMID:24356252

RAPA: a novel in vitro method to evaluate anti-bacterial skin cleansing products.

PubMed

Ansari, S A; Gafur, R B; Jones, K; Espada, L A; Polefka, T G

2010-04-01

Development of efficacious anti-bacterial skin cleansing products has been limited by the availability of a pre-clinical (in vitro) method to predict clinical efficacy adequately. We report a simple and rapid method, designated as rapid agar plate assay (RAPA), that uses the bacteriological agar surface as a surrogate substrate for skin and combines elements of two widely used in vivo (clinical) methods (Agar Patch and Cup Scrub). To simulate the washing of the human hand or forearm skin with the test product, trypticase soy agar plates were directly washed with the test product and rinsed under running tap water. After air-drying the washed plates, test bacteria (Staphylococcus aureus or Escherichia coli) were applied and the plates were incubated at 37 degrees C for 18-24 h. Using S. aureus as the test organism, anti-bacterial bar soap containing triclocarbanilide showed a strong linear relationship (R(2) = 0.97) between bacterial dose and their per cent reduction. A similar dose-response relationship (R(2) = 0.96) was observed for anti-bacterial liquid hand soap against E. coli. RAPA was able to distinguish between anti-bacterial products based on the nature and level of actives in them. In limited comparative tests, results obtained by RAPA were comparable with the results obtained by clinical agar patch and clinical cup scrub methods. In conclusion, RAPA provides a simple, rugged and reproducible in vitro method for testing the relative efficacy of anti-bacterial skin cleansing products with a likelihood of comparable clinical efficacy. Further testing is warranted to improve the clinical predictability of this method.

Predictors of treatment efficacy in a clinical trial of three psychosocial treatments for adolescent depression.

PubMed

Brent, D A; Kolko, D J; Birmaher, B; Baugher, M; Bridge, J; Roth, C; Holder, D

1998-09-01

To assess the predictors of treatment outcome across treatments, as well as those associated with differential treatment response. One hundred seven adolescent outpatients, aged 13 to 18 years, with DSM-III-R major depression were randomly assigned to one of three manual-based, brief (12 to 16 sessions) psychosocial treatments: cognitive-behavioral therapy (CBT), systemic-behavioral family therapy, or nondirective supportive therapy. Those with good and poor outcomes were compared. Continued depression was predicted by clinical referral (versus via advertisement) and was in part mediated by hopelessness. Other predictors of depression were comorbid anxiety disorder and higher levels of cognitive distortion and hopelessness at intake. Achievement of clinical remission was predicted by a higher level of self-reported depression. Poorer functional status was predicted by a higher level of initial interviewer-rated depression. Comorbid anxiety and maternal depressive symptoms predicted differential treatment efficacy. CBT's performance continued to be robust with respect to nondirective supportive therapy, even in the presence of the above-noted adverse predictors. Predictors of poor outcome may give clues as to how to boost treatment response. Subjects who come to treatment for clinical trials via advertisement (versus clinical referral) may show more favorable treatment responses. CBT is likely to be a robust intervention even in more complex and difficult-to-treat patients.

Self-efficacy, pain, and quadriceps capacity at baseline predict changes in mobility performance over 2 years in women with knee osteoarthritis.

PubMed

Brisson, Nicholas M; Gatti, Anthony A; Stratford, Paul W; Maly, Monica R

2018-02-01

This study examined the extent to which baseline measures of quadriceps strength, quadriceps power, knee pain and self-efficacy for functional tasks, and their interactions, predicted 2-year changes in mobility performance (walking, stair ascent, stair descent) in women with knee osteoarthritis. We hypothesized that lesser strength, power and self-efficacy, and higher pain at baseline would each be independently associated with reduced mobility over 2 years, and each of pain and self-efficacy would interact with strength and power in predicting 2-year change in stair-climbing performance. This was a longitudinal, observational study of women with clinical knee osteoarthritis. At baseline and follow-up, mobility was assessed with the Six-Minute Walk Test, and stair ascent and descent tasks. Quadriceps strength and power, knee pain, and self-efficacy for functional tasks were also collected at baseline. Multiple linear regression examined the extent to which 2-year changes in mobility performances were predicted by baseline strength, power, pain, and self-efficacy, after adjusting for covariates. Data were analyzed for 37 women with knee osteoarthritis over 2 years. Lower baseline self-efficacy predicted decreased walking (β = 1.783; p = 0.030) and stair ascent (β = -0.054; p < 0.001) performances over 2 years. Higher baseline pain intensity/frequency predicted decreased walking performance (β = 1.526; p = 0.002). Lower quadriceps strength (β = 0.051; p = 0.015) and power (β = 0.022; p = 0.022) interacted with lesser self-efficacy to predict worsening stair ascent performance. Strategies to sustain or improve mobility in women with knee osteoarthritis must focus on controlling pain and boosting self-efficacy. In those with worse self-efficacy, developing knee muscle capacity is an important target.

Predictors of chemotherapy efficacy in non-small-cell lung cancer: a challenging landscape.

PubMed

Olaussen, K A; Postel-Vinay, S

2016-11-01

Conventional cytotoxic chemotherapy (CCC) is the backbone of non-small-cell lung cancer (NSCLC) treatment since decades and still represents a key element of the therapeutic armamentarium. Contrary to molecularly targeted therapies and immune therapies, for which predictive biomarkers of activity have been actively looked for and developed in parallel to the drug development process ('companion biomarkers'), no patient selection biomarker is currently available for CCC, precluding customizing treatment. We reviewed preclinical and clinical studies that assessed potential predictive biomarkers of CCC used in NSCLC (platinum, antimetabolites, topoisomerase inhibitors, and spindle poisons). Biomarker evaluation method, analytical validity, and robustness are described and challenged for each biomarker. The best-validated predictive biomarkers for efficacy are currently ERCC1, RRM1, and TS for platinum agents, gemcitabine and pemetrexed, respectively. Other potential biomarkers include hENT1 for gemcitabine, class III β-tubulin for spindle poisons, TOP2A expression and CEP17 duplication (mostly studied for predicting anthracyclines efficacy) whose applicability concerning etoposide would deserve further evaluation. However, none of these biomarkers has till now been validated prospectively in an appropriately designed and powered randomised trial, and none of them is currently ready for implementation in routine clinical practice. The search for predictive biomarkers to CCC has been proven challenging. If a plethora of biomarkers have been evaluated either in the preclinical or in the clinical setting, none of them is ready for clinical implementation yet. Considering that most mechanisms of resistance or sensitivity to CCC are multifactorial, a combinatorial approach might be relevant and further efforts are required. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Parent Caregiver Self-Efficacy and Child Reactions to Pediatric Cancer Treatment Procedures

PubMed Central

Peterson, Amy M.; Harper, Felicity W. K.; Albrecht, Terrance L.; Taub, Jeffrey W.; Orom, Heather; Phipps, Sean; Penner, Louis A.

2014-01-01

This study examined how parents’ sense of self-efficacy specific to caregiving for their child during cancer treatment procedures affected children’s distress and cooperation during procedures. Potential correlates of caregiver self-efficacy (ie, demographics, child clinical characteristics, parent dispositional attributes, and social support) were also examined. Participants were 119 children undergoing cancer treatment procedures and their parents. Parents’ self-efficacy about 6 procedure-specific caregiver tasks was measured. Parents, children, nurses, and observers rated child distress and parents, nurses and observers rated child cooperation during procedures. Higher parent self-efficacy about keeping children calm during procedures predicted lower child distress and higher child cooperation during procedures. Parent dispositional attributes (eg, enduring positive mood, empathy) and social support predicted self-efficacy. Parent caregiver self-efficacy influences child distress and cooperation during procedures and is associated with certain parent attributes. Findings suggest the utility of identifying parents who would benefit from targeted interventions to increase self-efficacy about caregiving during treatment procedures. PMID:24378818

Prediction of the Efficacy of Antihistamines in Chronic Spontaneous Urticaria Based on Initial Suppression of the Histamine- Induced Wheal.

PubMed

Sánchez, J; Zakzuk, J; Cardona, R

2016-01-01

Antihistamines are the first line of treatment for chronic spontaneous urticaria. However, there is no effective method to predict whether an antihistamine will have a beneficial clinical effect or not. To assess whether the change in histamine-induced wheal and flare measurements 24 hours after administration of antihistamine can predict the efficacy of treatment. We performed a multicenter, triple-blind, randomized study. Patients received a daily oral dose of cetirizine, fexofenadine, bilastine, desloratadine, or ebastine over 8 weeks. After 4 weeks, a higher dose of antihistamine was administered to patients who did not experience a clinical response. A histamine skin prick test was carried out at baseline and 24 hours after the first dose of antihistamine. Disease severity (Urticaria Activity Score [UAS]), response to the histamine skin prick test, and impact on the patient's quality of life (Dermatology Life Quality Index [DLQI]) were determined every 2 weeks. The study population comprised 150 patients (30 per group) and 30 controls. Twenty-four hours after administration of antihistamine, inhibition of the histamine wheal by >75% was significantly associated with better UAS and DLQI scores. The safety and efficacy of the 5 antihistamines were similar. After updosing, rates of disease control (DLQI score <5) increased from 58.7% to 76.7%. Measurement of the histamine-induced wheal can predict which patients will have a strong clinical response to antihistamines but has limited utility for identifying nonresponders. The clinical significance of these data could be relevant in the search for new urticaria treatment regimens.

Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension.

PubMed

Schuster, Cornelia; Eikesdal, Hans P; Puntervoll, Hanne; Geisler, Jürgen; Geisler, Stephanie; Heinrich, Daniel; Molven, Anders; Lønning, Per E; Akslen, Lars A; Straume, Oddbjørn

2012-01-01

VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12-49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab. ClinicalTrials.gov NCT00139360.

Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development

PubMed Central

Savonenko, Alena V; Melnikova, Tatiana; Hiatt, Andrew; Li, Tong; Worley, Paul F; Troncoso, Juan C; Wong, Phil C; Price, Don L

2012-01-01

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation—from how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Aβ immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development. PMID:21937983

Persistent grief in the aftermath of mass violence: the predictive roles of posttraumatic stress symptoms, self-efficacy, and disrupted worldview.

PubMed

Smith, Andrew J; Abeyta, Andrew A; Hughes, Michael; Jones, Russell T

2015-03-01

This study tested a conceptual model merging anxiety buffer disruption and social-cognitive theories to predict persistent grief severity among students who lost a close friend, significant other, and/or professor/teacher in tragic university campus shootings. A regression-based path model tested posttraumatic stress (PTS) symptom severity 3 to 4 months postshooting (Time 1) as a predictor of grief severity 1 year postshootings (Time 2), both directly and indirectly through cognitive processes (self-efficacy and disrupted worldview). Results revealed a model that predicted 61% of the variance in Time 2 grief severity. Hypotheses were supported, demonstrating that Time 1 PTS severity indirectly, positively predicted Time 2 grief severity through undermining self-efficacy and more severely disrupting worldview. Findings and theoretical interpretation yield important insights for future research and clinical application. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

Mathematical modeling of efficacy and safety for anticancer drugs clinical development.

PubMed

Lavezzi, Silvia Maria; Borella, Elisa; Carrara, Letizia; De Nicolao, Giuseppe; Magni, Paolo; Poggesi, Italo

2018-01-01

Drug attrition in oncology clinical development is higher than in other therapeutic areas. In this context, pharmacometric modeling represents a useful tool to explore drug efficacy in earlier phases of clinical development, anticipating overall survival using quantitative model-based metrics. Furthermore, modeling approaches can be used to characterize earlier the safety and tolerability profile of drug candidates, and, thus, the risk-benefit ratio and the therapeutic index, supporting the design of optimal treatment regimens and accelerating the whole process of clinical drug development. Areas covered: Herein, the most relevant mathematical models used in clinical anticancer drug development during the last decade are described. Less recent models were considered in the review if they represent a standard for the analysis of certain types of efficacy or safety measures. Expert opinion: Several mathematical models have been proposed to predict overall survival from earlier endpoints and validate their surrogacy in demonstrating drug efficacy in place of overall survival. An increasing number of mathematical models have also been developed to describe the safety findings. Modeling has been extensively used in anticancer drug development to individualize dosing strategies based on patient characteristics, and design optimal dosing regimens balancing efficacy and safety.

Self Efficacy in Depression: Bridging the Gap Between Competence and Real World Functioning.

PubMed

Milanovic, Melissa; Ayukawa, Emma; Usyatynsky, Aleksandra; Holshausen, Katherine; Bowie, Christopher R

2018-05-01

We investigated the discrepancy between competence and real-world performance in major depressive disorder (MDD) for adaptive and interpersonal behaviors, determining whether self-efficacy significantly predicts this discrepancy, after considering depressive symptoms. Forty-two participants (Mage = 37.64, 66.67% female) with MDD were recruited from mental health clinics. Competence, self-efficacy, and real-world functioning were evaluated in adaptive and interpersonal domains; depressive symptoms were assessed with the Beck Depression Inventory II. Hierarchical regression analysis identified predictors of functional disability and the discrepancy between competence and real-world functioning. Self-efficacy significantly predicted functioning in the adaptive and interpersonal domains over and above depressive symptoms. Interpersonal self-efficacy accounted for significant variance in the discrepancy between interpersonal competence and functioning beyond symptoms. Using a multilevel, multidimensional approach, we provide the first data regarding relationships among competence, functioning, and self-efficacy in MDD. Self-efficacy plays an important role in deployment of functional skills in everyday life for individuals with MDD.

Quantifying the Impact of Natural Immunity on Rotavirus Vaccine Efficacy Estimates: A Clinical Trial in Dhaka, Bangladesh (PROVIDE) and a Simulation Study.

PubMed

Rogawski, Elizabeth T; Platts-Mills, James A; Colgate, E Ross; Haque, Rashidul; Zaman, K; Petri, William A; Kirkpatrick, Beth D

2018-03-05

The low efficacy of rotavirus vaccines in clinical trials performed in low-resource settings may be partially explained by acquired immunity from natural exposure, especially in settings with high disease incidence. In a clinical trial of monovalent rotavirus vaccine in Bangladesh, we compared the original per-protocol efficacy estimate to efficacy derived from a recurrent events survival model in which children were considered naturally exposed and potentially immune after their first rotavirus diarrhea (RVD) episode. We then simulated trial cohorts to estimate the expected impact of prior exposure on efficacy estimates for varying rotavirus incidence rates and vaccine efficacies. Accounting for natural immunity increased the per-protocol vaccine efficacy estimate against severe RVD from 63.1% (95% confidence interval [CI], 33.0%-79.7%) to 70.2% (95% CI, 44.5%-84.0%) in the postvaccination period, and original year 2 efficacy was underestimated by 14%. The simulations demonstrated that this expected impact increases linearly with RVD incidence, will be greatest for vaccine efficacies near 50%, and can reach 20% in settings with high incidence and low efficacy. High rotavirus incidence leads to predictably lower vaccine efficacy estimates due to the acquisition of natural immunity in unvaccinated children, and this phenomenon should be considered when comparing efficacy estimates across settings. NCT01375647.

Hybrid stochastic framework predicts efficacy of prophylaxis against HIV: An example with different dolutegravir prophylaxis schemes.

PubMed

Duwal, Sulav; Dickinson, Laura; Khoo, Saye; von Kleist, Max

2018-06-01

To achieve the 90-90-90 goals set by UNAIDS, the number of new HIV infections needs to decrease to approximately 500,000 by 2020. One of the 'five pillars' to achieve this goal is pre-exposure prophylaxis (PrEP). Truvada (emtricitabine-tenofovir) is currently the only medication approved for PrEP. Despite its advantages, Truvada is costly and requires individuals to adhere to the once-daily regimen. To improve PrEP, many next-generation regimen, including long-acting formulations, are currently investigated. However, pre-clinical testing may not guide candidate selection, since it often fails to translate into clinical efficacy. On the other hand, quantifying prophylactic efficacy in the clinic is ethically problematic and requires to conduct long (years) and large (N>1000 individuals) trials, precluding systematic evaluation of candidates and deployment strategies. To prioritize- and help design PrEP regimen, tools are urgently needed that integrate pharmacological-, viral- and host factors determining prophylactic efficacy. Integrating the aforementioned factors, we developed an efficient and exact stochastic simulation approach to predict prophylactic efficacy, as an example for dolutegravir (DTG). Combining the population pharmacokinetics of DTG with the stochastic framework, we predicted that plasma concentrations of 145.18 and 722.23nM prevent 50- and 90% sexual transmissions respectively. We then predicted the reduction in HIV infection when DTG was used in PrEP, PrEP 'on demand' and post-exposure prophylaxis (PEP) before/after virus exposure. Once daily PrEP with 50mg oral DTG prevented 99-100% infections, and 85% of infections when 50% of dosing events were missed. PrEP 'on demand' prevented 79-84% infections and PEP >80% when initiated within 6 hours after virus exposure and continued for as long as possible. While the simulation framework can easily be adapted to other PrEP candidates, our simulations indicated that oral 50mg DTG is non-inferior to Truvada. Moreover, the predicted 90% preventive concentrations can guide release kinetics of currently developed DTG nano-formulations.

A new approach to estimate vaccine efficacy based on immunogenicity data applied to influenza vaccines administered by the intradermal or intramuscular routes.

PubMed

Coudeville, Laurent; Andre, Philippe; Bailleux, Fabrice; Weber, Françoise; Plotkin, Stanley

2010-10-01

Despite their pivotal role in the assessment of influenza vaccines, limited attempts have been made to use haemagglutination inhibition (HI) titers for predicting vaccine efficacy against laboratory-confirmed influenza. We present here the second step of a two-step approach allowing performing such predictions and use it to compare a new trivalent inactivated influenza vaccine administered by the intradermal (ID) route (INTANZA® /IDFlu®) with the vaccine administered by the classical intramuscular (IM) route. The first step corresponding to the estimation of the level of protection against laboratory-confirmed influenza that can be linked to each HI titer, referred to as the HI protection curve, was achieved by using a meta-analytical approach based on published information. Vaccine efficacy and differences in vaccine efficacy are predicted in a second step using this HI protection curve alongside the results of two randomized clinical trials providing comparative information on the immunogenicity of trivalent inactivated influenza vaccines administered ID or IM in 3503 & 1645 elderly participants, respectively. Pooling all available immunogenicity data, the predicted vaccine efficacy was 63.3% [CI: 58.1; 68.7] for ID route and 54.4% [CI: 49.4; 59.2] for IM route. The corresponding relative increase in efficacy that is of 16.5% [CI: 12.7; 20.1]. Predicted vaccine efficacies decreased with age for both vaccines, but the decrease was less marked by ID route: the relative increase in efficacy for subjects aged 70 years and above is of 18.0% [CI:12;24]. The analysis performed confirmed that the superior immune response provided by the vaccine using the ID route should translate into a higher vaccine efficacy against laboratory-confirmed influenza.

Vigabatrin pediatric dosing information for refractory complex partial seizures: results from a population dose-response analysis.

PubMed

Nielsen, Jace C; Tolbert, Dwain; Patel, Mahlaqa; Kowalski, Kenneth G; Wesche, David L

2014-12-01

We predicted vigabatrin dosages for adjunctive therapy for pediatric patients with refractory complex partial seizures (rCPS) that would produce efficacy comparable to that observed for approved adult dosages. A dose-response model related seizure-count data to vigabatrin dosage to identify dosages for pediatric rCPS patients. Seizure-count data were obtained from three pediatric and two adult rCPS clinical trials. Dosages were predicted for oral solution and tablet formulations. Predicted oral solution dosages to achieve efficacy comparable to that of a 1 g/day adult dosage were 350 and 450 mg/day for patients with body weight ranges 10-15 and >15-20 kg, respectively. Predicted oral solution dosages for efficacy comparable to a 3 g/day adult dosage were 1,050 and 1,300 mg/day for weight ranges 10-15 and >15-20 kg, respectively. Predicted tablet dosage for efficacy comparable to a 1 g/day adult dosage was 500 mg/day for weight ranges 25-60 kg. Predicted tablet dosage for efficacy comparable to a 3 g/day adult dosage was 2,000 mg for weight ranges 25-60 kg. Vigabatrin dosages were identified for pediatric rCPS patients with body weights ≥10 kg. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

The utility of Bayesian predictive probabilities for interim monitoring of clinical trials

PubMed Central

Connor, Jason T.; Ayers, Gregory D; Alvarez, JoAnn

2014-01-01

Background Bayesian predictive probabilities can be used for interim monitoring of clinical trials to estimate the probability of observing a statistically significant treatment effect if the trial were to continue to its predefined maximum sample size. Purpose We explore settings in which Bayesian predictive probabilities are advantageous for interim monitoring compared to Bayesian posterior probabilities, p-values, conditional power, or group sequential methods. Results For interim analyses that address prediction hypotheses, such as futility monitoring and efficacy monitoring with lagged outcomes, only predictive probabilities properly account for the amount of data remaining to be observed in a clinical trial and have the flexibility to incorporate additional information via auxiliary variables. Limitations Computational burdens limit the feasibility of predictive probabilities in many clinical trial settings. The specification of prior distributions brings additional challenges for regulatory approval. Conclusions The use of Bayesian predictive probabilities enables the choice of logical interim stopping rules that closely align with the clinical decision making process. PMID:24872363

Predictive biomarkers of sorafenib efficacy in advanced hepatocellular carcinoma: Are we getting there?

PubMed Central

Shao, Yu-Yun; Hsu, Chih-Hung; Cheng, Ann-Lii

2015-01-01

Sorafenib is the current standard treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is modest with low response rates and short response duration. Predictive biomarkers for sorafenib efficacy are necessary. However, efforts to determine biomarkers for sorafenib have led only to potential candidates rather than clinically useful predictors. Studies based on patient cohorts identified the potential of blood levels of angiopoietin-2, hepatocyte growth factor, insulin-like growth factor-1, and transforming growth factor-β1 for predicting sorafenib efficacy. Alpha-fetoprotein response, dynamic contrast-enhanced magnetic resonance imaging, and treatment-related side effects may serve as early surrogate markers. Novel approaches based on super-responders or experimental mouse models may provide new directions in biomarker research. These studies identified tumor amplification of FGF3/FGF4 or VEGFA and tumor expression of phospho-Mapk14 and phospho-Atf2 as possible predictive markers that await validation. A group effort that considers various prognostic factors and proper collection of tumor tissues before treatment is imperative for the success of future biomarker research in advanced HCC. PMID:26420960

Predictive biomarkers of sorafenib efficacy in advanced hepatocellular carcinoma: Are we getting there?

PubMed

Shao, Yu-Yun; Hsu, Chih-Hung; Cheng, Ann-Lii

2015-09-28

Sorafenib is the current standard treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is modest with low response rates and short response duration. Predictive biomarkers for sorafenib efficacy are necessary. However, efforts to determine biomarkers for sorafenib have led only to potential candidates rather than clinically useful predictors. Studies based on patient cohorts identified the potential of blood levels of angiopoietin-2, hepatocyte growth factor, insulin-like growth factor-1, and transforming growth factor-β1 for predicting sorafenib efficacy. Alpha-fetoprotein response, dynamic contrast-enhanced magnetic resonance imaging, and treatment-related side effects may serve as early surrogate markers. Novel approaches based on super-responders or experimental mouse models may provide new directions in biomarker research. These studies identified tumor amplification of FGF3/FGF4 or VEGFA and tumor expression of phospho-Mapk14 and phospho-Atf2 as possible predictive markers that await validation. A group effort that considers various prognostic factors and proper collection of tumor tissues before treatment is imperative for the success of future biomarker research in advanced HCC.

A dynamical systems model for combinatorial cancer therapy enhances oncolytic adenovirus efficacy by MEK-inhibition.

PubMed

Bagheri, Neda; Shiina, Marisa; Lauffenburger, Douglas A; Korn, W Michael

2011-02-01

Oncolytic adenoviruses, such as ONYX-015, have been tested in clinical trials for currently untreatable tumors, but have yet to demonstrate adequate therapeutic efficacy. The extent to which viruses infect targeted cells determines the efficacy of this approach but many tumors down-regulate the Coxsackievirus and Adenovirus Receptor (CAR), rendering them less susceptible to infection. Disrupting MAPK pathway signaling by pharmacological inhibition of MEK up-regulates CAR expression, offering possible enhanced adenovirus infection. MEK inhibition, however, interferes with adenovirus replication due to resulting G1-phase cell cycle arrest. Therefore, enhanced efficacy will depend on treatment protocols that productively balance these competing effects. Predictive understanding of how to attain and enhance therapeutic efficacy of combinatorial treatment is difficult since the effects of MEK inhibitors, in conjunction with adenovirus/cell interactions, are complex nonlinear dynamic processes. We investigated combinatorial treatment strategies using a mathematical model that predicts the impact of MEK inhibition on tumor cell proliferation, ONYX-015 infection, and oncolysis. Specifically, we fit a nonlinear differential equation system to dedicated experimental data and analyzed the resulting simulations for favorable treatment strategies. Simulations predicted enhanced combinatorial therapy when both treatments were applied simultaneously; we successfully validated these predictions in an ensuing explicit test study. Further analysis revealed that a CAR-independent mechanism may be responsible for amplified virus production and cell death. We conclude that integrated computational and experimental analysis of combinatorial therapy provides a useful means to identify treatment/infection protocols that yield clinically significant oncolysis. Enhanced oncolytic therapy has the potential to dramatically improve non-surgical cancer treatment, especially in locally advanced or metastatic cases where treatment options remain limited.

Clinical Efficacy and Safety of Bevacizumab Monotherapy in Patients with Metastatic Melanoma: Predictive Importance of Induced Early Hypertension

PubMed Central

Schuster, Cornelia; Eikesdal, Hans P.; Puntervoll, Hanne; Geisler, Jürgen; Geisler, Stephanie; Heinrich, Daniel; Molven, Anders; Lønning, Per E.; Akslen, Lars A.; Straume, Oddbjørn

2012-01-01

Background VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. Methods and Findings Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12–49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). Conclusion Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab. Trial Registration ClinicalTrials.gov NCT00139360. PMID:22719881

Four-hour quantitative real-time polymerase chain reaction-based comprehensive chromosome screening and accumulating evidence of accuracy, safety, predictive value, and clinical efficacy.

PubMed

Treff, Nathan R; Scott, Richard T

2013-03-15

Embryonic comprehensive chromosomal euploidy may represent a powerful biomarker to improve the success of IVF. However, there are a number of aneuploidy screening strategies to consider, including different technologic platforms with which to interrogate the embryonic DNA, and different embryonic developmental stages from which DNA can be analyzed. Although there are advantages and disadvantages associated with each strategy, a series of experiments producing evidence of accuracy, safety, clinical predictive value, and clinical efficacy indicate that trophectoderm biopsy and quantitative real-time polymerase chain reaction (qPCR)-based comprehensive chromosome screening (CCS) may represent a useful strategy to improve the success of IVF. This Biomarkers in Reproductive Medicine special issue review summarizes the accumulated experience with the development and clinical application of a 4-hour blastocyst qPCR-based CCS technology. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Influence of self-efficacy and coping on quality of life and social participation after acquired brain injury: a 1-year follow-up study.

PubMed

Brands, Ingrid; Köhler, Sebastian; Stapert, Sven; Wade, Derick; van Heugten, Caroline

2014-12-01

To investigate the relations linking self-efficacy and coping to quality of life (QOL) and social participation and what effect self-efficacy, changes in self-efficacy, and coping style have on long-term QOL and social participation. Prospective clinical cohort study. General hospitals, rehabilitation centers. Patients with newly acquired brain injury (ABI) (N=148) were assessed at baseline (start outpatient rehabilitation or discharge hospital/inpatient rehabilitation; mean time since injury, 15wk) and 1 year later (mean time since injury, 67wk). Not applicable. QOL was measured with the EuroQuol 5D (the EQ-5D index and the EQ-5D visual analog scale [EQ VAS]) and the 9-item Life Satisfaction Questionnaire (LiSat-9), social participation with the modified Frenchay Activities Index, coping with the Coping Inventory for Stressful Situations, and self-efficacy with the Traumatic Brain Injury Self-efficacy Questionnaire. At baseline, self-efficacy moderated the effect of emotion-oriented coping on the EQ-5D index and of avoidance coping on the EQ VAS. Self-efficacy mediated the relation between emotion-oriented coping and LiSat-9. An increase in self-efficacy over time predicted better scores on the EQ-5D index (β=.30), the EQ VAS (β=.49), and LiSat-9 (β=.44) at follow-up. In addition, higher initial self-efficacy (β=.40) predicted higher LiSat-9 scores at follow-up; higher initial emotion-oriented coping (β=-.23) predicted lower EQ VAS scores at follow-up. Higher modified Frenchay Activities Index scores at follow-up were predicted by higher self-efficacy (β=.19) and higher task-oriented coping (β=.14) at baseline (combined R(2)=5.1%). Self-efficacy and coping predict long-term QOL but seem less important in long-term social participation. High self-efficacy protects against the negative effect of emotion-oriented coping. Enhancing self-efficacy in the early stage after ABI may have beneficial long-term effects. Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

A Feedback-Controlled Mandibular Positioner Identifies Individuals With Sleep Apnea Who Will Respond to Oral Appliance Therapy.

PubMed

Remmers, John E; Topor, Zbigniew; Grosse, Joshua; Vranjes, Nikola; Mosca, Erin V; Brant, Rollin; Bruehlmann, Sabina; Charkhandeh, Shouresh; Zareian Jahromi, Seyed Abdolali

2017-07-15

Mandibular protruding oral appliances represent a potentially important therapy for obstructive sleep apnea (OSA). However, their clinical utility is limited by a less-than-ideal efficacy rate and uncertainty regarding an efficacious mandibular position, pointing to the need for a tool to assist in delivery of the therapy. The current study assesses the ability to prospectively identify therapeutic responders and determine an efficacious mandibular position. Individuals (n = 202) with OSA participated in a blinded, 2-part investigation. A system for identifying therapeutic responders was developed in part 1 (n = 149); the predictive accuracy of this system was prospectively evaluated on a new population in part 2 (n = 53). Each participant underwent a 2-night, in-home feedback-controlled mandibular positioner (FCMP) test, followed by treatment with a custom oral appliance and an outcome study with the oral appliance in place. A machine learning classification system was trained to predict therapeutic outcome on data obtained from FCMP studies on part 1 participants. The accuracy of this trained system was then evaluated on part 2 participants by examining the agreement between prospectively predicted outcome and observed outcome. A predicted efficacious mandibular position was derived from each FCMP study. Predictive accuracy was as follows: sensitivity 85%; specificity 93%; positive predictive value 97%; and negative predictive value 72%. Of participants correctly predicted to respond to therapy, the predicted mandibular protrusive position proved efficacious in 86% of cases. An unattended, in-home FCMP test prospectively identifies individuals with OSA who will respond to oral appliance therapy and provides an efficacious mandibular position. The trial that this study reports on is registered on www.clinicaltrials.gov, ID NCT03011762, study name: Feasibility and Predictive Accuracy of an In-Home Computer Controlled Mandibular Positioner in Identifying Favourable Candidates for Oral Appliance Therapy. © 2017 American Academy of Sleep Medicine

Examining the moderating effect of depressive symptoms on the relation between exercise and self-efficacy during the initiation of regular exercise.

PubMed

Kangas, Julie L; Baldwin, Austin S; Rosenfield, David; Smits, Jasper A J; Rethorst, Chad D

2015-05-01

People with depressive symptoms report lower levels of exercise self-efficacy and are more likely to discontinue regular exercise than others, but it is unclear how depressive symptoms affect the relation between exercise and self-efficacy. We sought to clarify whether depressive symptoms moderate the relations between exercise and same-day self-efficacy, and between self-efficacy and next-day exercise. Participants (n = 116) were physically inactive adults (35% reported clinically significant depressive symptoms) who initiated regular exercise and completed daily assessments for 4 weeks. Mixed linear models were used to test whether (a) self-efficacy differed on days when exercise did and did not occur, (b) self-efficacy predicted next-day exercise, and (c) these relations were moderated by depressive symptoms. First, self-efficacy was lower on days when no exercise occurred, but this difference was larger for people with high depressive symptoms (p < .001). They had lower self-efficacy than people with low depressive symptoms on days when no exercise occurred (p = .03), but self-efficacy did not differ on days when exercise occurred (p = .34). Second, self-efficacy predicted greater odds of next-day exercise, OR = 1.12, 95% [1.04, 1.21], but depressive symptoms did not moderate this relation, OR = 1.00, 95% CI [.99, 1.01]. During exercise initiation, daily self-efficacy is more strongly related to exercise occurrence for people with high depressive symptoms than those with low depressive symptoms, but self-efficacy predicts next-day exercise regardless of depressive symptoms. The findings specify how depressive symptoms affect the relations between exercise and self-efficacy and underscore the importance of targeting self-efficacy in exercise interventions, particularly among people with depressive symptoms. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

A linear programming computational framework integrates phosphor-proteomics and prior knowledge to predict drug efficacy.

PubMed

Ji, Zhiwei; Wang, Bing; Yan, Ke; Dong, Ligang; Meng, Guanmin; Shi, Lei

2017-12-21

In recent years, the integration of 'omics' technologies, high performance computation, and mathematical modeling of biological processes marks that the systems biology has started to fundamentally impact the way of approaching drug discovery. The LINCS public data warehouse provides detailed information about cell responses with various genetic and environmental stressors. It can be greatly helpful in developing new drugs and therapeutics, as well as improving the situations of lacking effective drugs, drug resistance and relapse in cancer therapies, etc. In this study, we developed a Ternary status based Integer Linear Programming (TILP) method to infer cell-specific signaling pathway network and predict compounds' treatment efficacy. The novelty of our study is that phosphor-proteomic data and prior knowledge are combined for modeling and optimizing the signaling network. To test the power of our approach, a generic pathway network was constructed for a human breast cancer cell line MCF7; and the TILP model was used to infer MCF7-specific pathways with a set of phosphor-proteomic data collected from ten representative small molecule chemical compounds (most of them were studied in breast cancer treatment). Cross-validation indicated that the MCF7-specific pathway network inferred by TILP were reliable predicting a compound's efficacy. Finally, we applied TILP to re-optimize the inferred cell-specific pathways and predict the outcomes of five small compounds (carmustine, doxorubicin, GW-8510, daunorubicin, and verapamil), which were rarely used in clinic for breast cancer. In the simulation, the proposed approach facilitates us to identify a compound's treatment efficacy qualitatively and quantitatively, and the cross validation analysis indicated good accuracy in predicting effects of five compounds. In summary, the TILP model is useful for discovering new drugs for clinic use, and also elucidating the potential mechanisms of a compound to targets.

Use Of Clinical Decision Analysis In Predicting The Efficacy Of Newer Radiological Imaging Modalities: Radioscintigraphy Versus Single Photon Transverse Section Emission Computed Tomography

NASA Astrophysics Data System (ADS)

Prince, John R.

1982-12-01

Sensitivity, specificity, and predictive accuracy have been shown to be useful measures of the clinical efficacy of diagnostic tests and can be used to predict the potential improvement in diagnostic certitude resulting from the introduction of a competing technology. This communication demonstrates how the informal use of clinical decision analysis may guide health planners in the allocation of resources, purchasing decisions, and implementation of high technology. For didactic purposes the focus is on a comparison between conventional planar radioscintigraphy (RS) and single photon transverse section emission conputed tomography (SPECT). For example, positive predictive accuracy (PPA) for brain RS in a specialist hospital with a 50% disease prevalance is about 95%. SPECT should increase this predicted accuracy to 96%. In a primary care hospital with only a 15% disease prevalance the PPA is only 77% and SPECT may increase this accuracy to about 79%. Similar calculations based on published data show that marginal improvements are expected with SPECT in the liver. It is concluded that: a) The decision to purchase a high technology imaging modality such as SPECT for clinical purposes should be analyzed on an individual organ system and institutional basis. High technology may be justified in specialist hospitals but not necessarily in primary care hospitals. This is more dependent on disease prevalance than procedure volume; b) It is questionable whether SPECT imaging will be competitive with standard RS procedures. Research should concentrate on the development of different medical applications.

Multiscale systems pharmacological analysis of everolimus action in hepatocellular carcinoma.

PubMed

Ande, Anusha; Chaar, Maher; Ait-Oudhia, Sihem

2018-05-03

Dysregulation of mTOR pathway is common in hepatocellular carcinoma (HCC). A translational quantitative systems pharmacology (QSP), pharmacokinetic (PK), and pharmacodynamic (PD) model dissecting the circuitry of this pathway was developed to predict HCC patients' response to everolimus, an mTOR inhibitor. The time course of key signaling proteins in the mTOR pathway, HCC cells viability, tumor volume (TV) and everolimus plasma and tumor concentrations in xenograft mice, clinical PK of everolimus and progression free survival (PFS) in placebo and everolimus-treated patients were extracted from literature. A comprehensive and multiscale QSP/PK/PD model was developed, qualified, and translated to clinical settings. Model fittings and simulations were performed using Monolix software. The S6-kinase protein was identified as critical in the mTOR signaling pathway for describing everolimus lack of efficacy in HCC patients. The net growth rate constant (kg) of HCC cells was estimated at 0.02 h -1 (2.88%RSE). The partition coefficient of everolimus into the tumor (kp) was determined at 0.06 (12.98%RSE). The kg in patients was calculated from the doubling time of TV in naturally progressing HCC patients, and was determined at 0.004 day -1 . Model-predicted and observed PFS were in good agreement for placebo and everolimus-treated patients. In conclusion, a multiscale QSP/PK/PD model elucidating everolimus lack of efficacy in HCC patients was successfully developed and predicted PFS reasonably well compared to observed clinical findings. This model may provide insights into clinical response to everolimus-based therapy and serve as a valuable tool for the clinical translation of efficacy for novel mTOR inhibitors.

Associations Between Changes in Depressive Symptoms and Social Support and Diabetes Management Among Low-Income, Predominantly Hispanic Patients in Patient-Centered Care.

PubMed

Oh, Hyunsung; Ell, Kathleen

2018-03-27

This study examined whether changes in depressive symptoms and social support prospectively predicted diabetes management among Hispanic patients with probable depression in patient-centered medical homes at safety-net clinics in East Los Angeles, CA. Data were collected from 251 patients enrolled in a randomized clinical trial testing the effectiveness of a promotora-assisted self-management intervention. Cross-lagged analyses examined associations between changes in depression symptoms and social support between baseline and 6-month follow-up and self-efficacy and adherence to diabetes management at the 6- and 12-month follow-ups. Changes in depressive symptoms predicted self-efficacy and level of adherence at the 6- and 12-month follow-ups. Changes in total social support and emotional social support were correlated only with self-efficacy regarding diabetes management at 6-month follow-up. Decline in depressive symptoms is a reliable predictor of improvement in self-efficacy and adherence to diabetes management. Further studies are recommended to study psychosocial mechanisms related to social relationships other than social support that affect diabetes management. © 2018 by the American Diabetes Association.

The impact of self-efficacy, expectations, and readiness on hearing aid outcomes.

PubMed

Ferguson, Melanie A; Woolley, Annie; Munro, Kevin J

2016-07-01

To examine the impact of self-efficacy and expectations for hearing aids, and readiness to improve hearing, on hearing aid outcome measures in first-time adult hearing aid users Design: A prospective, single centre design. Predictor variables measured at the hearing assessment included measures of self-efficacy, expectations and readiness to improve hearing. Outcome measures obtained at six-week follow-up were the Glasgow Hearing Aid Benefit Profile and Satisfaction with Amplification in Daily Life. A sample of 30 first-time adult hearing aid users were recruited through a public-sector funded audiology clinic. When measured prior to hearing aid fitting, self-efficacy for hearing aids predicted satisfaction with hearing aids but was not related to other hearing aid outcomes. Expectations of hearing aids, in particular positive expectations, and readiness to improve hearing predicted outcomes for hearing aid satisfaction and benefit, although not hearing aid use. Hearing sensitivity was not correlated with hearing aid outcomes. These results suggest that assessment of expectations of hearing aids, and readiness to improve hearing, may be useful to help identify individuals attending audiology clinics who would most likely benefit from hearing aid provision.

Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.

PubMed

Yarnitsky, David; Granot, Michal; Nahman-Averbuch, Hadas; Khamaisi, Mogher; Granovsky, Yelena

2012-06-01

This study aims to individualize the selection of drugs for neuropathic pain by examining the potential coupling of a given drug's mechanism of action with the patient's pain modulation pattern. The latter is assessed by the conditioned pain modulation (CPM) and temporal summation (TS) protocols. We hypothesized that patients with a malfunctioning pain modulation pattern, such as less efficient CPM, would benefit more from drugs augmenting descending inhibitory pain control than would patients with a normal modulation pattern of efficient CPM. Thirty patients with painful diabetic neuropathy received 1 week of placebo, 1 week of 30 mg/d duloxetine, and 4 weeks of 60 mg/d duloxetine. Pain modulation was assessed psychophysically, both before and at the end of treatment. Patient assessment of drug efficacy, assessed weekly, was the study's primary outcome. Baseline CPM was found to be correlated with duloxetine efficacy (r=0.628, P<.001, efficient CPM is marked negative), such that less efficient CPM predicted efficacious use of duloxetine. Regression analysis (R(2)=0.673; P=.012) showed that drug efficacy was predicted only by CPM (P=.001) and not by pretreatment pain levels, neuropathy severity, depression level, or patient assessment of improvement by placebo. Furthermore, beyond its predictive value, the treatment-induced improvement in CPM was correlated with drug efficacy (r=-0.411, P=.033). However, this improvement occurred only in patients with less efficient CPM (16.8±16.0 to -1.1±15.5, P<.050). No predictive role was found for TS. In conclusion, the coupling of CPM and duloxetine efficacy highlights the importance of pain pathophysiology in the clinical decision-making process. This evaluative approach promotes personalized pain therapy. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Association of serum anti-rotavirus immunoglobulin A antibody seropositivity and protection against severe rotavirus gastroenteritis: analysis of clinical trials of human rotavirus vaccine.

PubMed

Cheuvart, Brigitte; Neuzil, Kathleen M; Steele, A Duncan; Cunliffe, Nigel; Madhi, Shabir A; Karkada, Naveen; Han, Htay Htay; Vinals, Carla

2014-01-01

Clinical trials of the human rotavirus vaccine Rotarix™ (RV1) have demonstrated significant reductions in severe rotavirus gastroenteritis (RVGE) in children worldwide. However, no correlate of vaccine efficacy (VE) has yet been established. This paper presents 2 analyses which aimed to investigate whether serum anti-RV IgA measured by ELISA 1 or 2 mo post-vaccination can serve as a correlate of efficacy against RVGE: (1) In a large Phase III efficacy trial (Rota-037), the Prentice criteria for surrogate endpoints was applied to anti-RV IgA seropositivity 1 mo post-vaccination. These criteria determine whether a significant vaccine group effect can be predicted from the surrogate, namely seropositivity (anti-RV IgA concentration>20 U/mL); (2) Among other GSK-sponsored RV1 VE studies, 8 studies which assessed immunogenicity at 1 or 2 mo post-vaccination in all or a sub-cohort of enrolled subjects and had at least 10 RVGE episodes were included in a meta-analysis to measure the regression between clinical VE and VE predicted from immunogenicity (VE1). In Rota-037, anti-RV IgA seropositivity post-vaccination was associated with a lower incidence of any or severe RVGE, however, the proportion of vaccine group effect explained by seropositivity was only 43.6% and 32.7% respectively. This low proportion was due to the vaccine group effect observed in seronegative subjects. In the meta-analysis, the slope of the regression between clinical VE and VE1 was statistically significant. These two independent analyses support the hypothesis that post-vaccination anti-RV IgA seropositivity (antibody concentration ≥20 U/mL) may serve as a useful correlate of efficacy in clinical trials of RV1 vaccines.

Adolescent and parent diabetes distress in type 1 diabetes: the role of self-efficacy, perceived consequences, family responsibility and adolescent-parent discrepancies.

PubMed

Law, G Urquhart; Walsh, Jennifer; Queralt, Victoria; Nouwen, Arie

2013-04-01

To examine the association of adolescent and parent diabetes distress with perceived consequences, dietary self-efficacy, and discrepancies in diabetes family responsibility, in type 1 diabetes (T1D). 203 adolescents with T1D, aged 12-18, and their parents completed self-report questionnaires cross-sectionally. Higher HbA1c, greater perceived negative consequences of diabetes, and reduced self-efficacy predicted adolescent diabetes distress. Higher HbA1c predicted parental diabetes distress, as did diabetes family responsibility disagreements when both family members claimed responsibility, and parents' perception of reduced adolescent self-efficacy. Dietary self-efficacy and perceived negative consequences of diabetes are important factors to consider in assessing and managing adolescent diabetes distress. Perceptions of family responsibility for self-care tasks and parental confidence in adolescents' self-management have implications for parental diabetes distress. Clinical implications support long-held recommendations of taking a family-perspective of T1D care. Copyright © 2012 Elsevier Inc. All rights reserved.

Predicting Refractive Surgery Outcome: Machine Learning Approach With Big Data.

PubMed

Achiron, Asaf; Gur, Zvi; Aviv, Uri; Hilely, Assaf; Mimouni, Michael; Karmona, Lily; Rokach, Lior; Kaiserman, Igor

2017-09-01

To develop a decision forest for prediction of laser refractive surgery outcome. Data from consecutive cases of patients who underwent LASIK or photorefractive surgeries during a 12-year period in a single center were assembled into a single dataset. Training of machine-learning classifiers and testing were performed with a statistical classifier algorithm. The decision forest was created by feature vectors extracted from 17,592 cases and 38 clinical parameters for each patient. A 10-fold cross-validation procedure was applied to estimate the predictive value of the decision forest when applied to new patients. Analysis included patients younger than 40 years who were not treated for monovision. Efficacy of 0.7 or greater and 0.8 or greater was achieved in 16,198 (92.0%) and 14,945 (84.9%) eyes, respectively. Efficacy of less than 0.4 and less than 0.5 was achieved in 322 (1.8%) and 506 (2.9%) eyes, respectively. Patients in the low efficacy group (< 0.4) had statistically significant differences compared with the high efficacy group (≥ 0.8), yet were clinically similar (mean differences between groups of 0.7 years, of 0.43 mm in pupil size, of 0.11 D in cylinder, of 0.22 logMAR in preoperative CDVA, of 0.11 mm in optical zone size, of 1.03 D in actual sphere treatment, and of 0.64 D in actual cylinder treatment). The preoperative subjective CDVA had the highest gain (most important to the model). Correlations analysis revealed significantly decreased efficacy with increased age (r = -0.67, P < .001), central corneal thickness (r = -0.40, P < .001), mean keratometry (r = -0.33, P < .001), and preoperative CDVA (r = -0.47, P < .001). Efficacy increased with pupil size (r = 0.20, P < .001). This model could support clinical decision making and may lead to better individual risk assessment. Expanding the role of machine learning in analyzing big data from refractive surgeries may be of interest. [J Refract Surg. 2017;33(9):592-597.]. Copyright 2017, SLACK Incorporated.

Circulating complexes between tumour necrosis factor-alpha and etanercept predict long-term efficacy of etanercept in juvenile idiopathic arthritis.

PubMed

Kahn, Robin; Berthold, Elisabet; Gullstrand, Birgitta; Schmidt, Tobias; Kahn, Fredrik; Geborek, Pierre; Saxne, Tore; Bengtsson, Anders A; Månsson, Bengt

2016-04-01

The relationship between tumour necrosis factor-alpha (TNF-α) and drug survival had not been studied in juvenile idiopathic arthritis (JIA), and there were no laboratory tests to predict the long-term efficacy of biological drugs for JIA. We studied whether serum levels of TNF-α, free or bound to etanercept, could predict long-term efficacy of etanercept in children with JIA. We included 41 biologic-naïve patients with JIA who started treatment with etanercept at Skåne University Hospital between 1999 and 2010. Serum taken at the start of treatment and at the six-week follow-up were analysed for TNF-α and the long-term efficacy of etanercept was assessed using the drug survival time. Levels of TNF-α increased significantly at the six-week follow-up, and this was almost exclusively comprised of TNF-α in complex with etanercept. The increase in TNF-α showed a dose-dependent correlation to long-term drug survival (p < 0.01). Increasing levels of circulating TNF-α at treatment initiation predicted long-term efficacy of etanercept in children with JIA, which may have been due to different pathophysiological mechanisms of inflammation. Our result may provide a helpful clinical tool, as high levels of circulating TNF-α/etanercept complexes could be used as a marker for the long-term efficacy of etanercept. ©2015 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.

Effects of Gait Self-Efficacy and Lower-Extremity Physical Function on Dual-Task Performance in Older Adults

PubMed Central

Banducci, Sarah E.; Daugherty, Ana M.; Fanning, Jason; Awick, Elizabeth A.; Porter, Gwenndolyn C.; Burzynska, Agnieszka; Shen, Sa; Kramer, Arthur F.; McAuley, Edward

2017-01-01

Objectives. Despite evidence of self-efficacy and physical function's influences on functional limitations in older adults, few studies have examined relationships in the context of complex, real-world tasks. The present study tested the roles of self-efficacy and physical function in predicting older adults' street-crossing performance in single- and dual-task simulations. Methods. Lower-extremity physical function, gait self-efficacy, and street-crossing success ratio were assessed in 195 older adults (60–79 years old) at baseline of a randomized exercise trial. During the street-crossing task, participants walked on a self-propelled treadmill in a virtual reality environment. Participants crossed the street without distraction (single-task trials) and conversed on a cell phone (dual-task trials). Structural equation modeling was used to test hypothesized associations independent of demographic and clinical covariates. Results. Street-crossing performance was better on single-task trials when compared with dual-task trials. Direct effects of self-efficacy and physical function on success ratio were observed in dual-task trials only. The total effect of self-efficacy was significant in both conditions. The indirect path through physical function was evident in the dual-task condition only. Conclusion. Physical function can predict older adults' performance on high fidelity simulations of complex, real-world tasks. Perceptions of function (i.e., self-efficacy) may play an even greater role. The trial is registered with United States National Institutes of Health ClinicalTrials.gov (ID: NCT01472744; Fit & Active Seniors Trial). PMID:28255557

Efficacy of Atopy Patch Testing in Directed Dietary Therapy of Eosinophilic Esophagitis: A Pilot Study.

PubMed

Eckmann, Jason D; Ravi, Karthik; Katzka, David A; Davis, Dawn R; See, Jacalyn A; Geno, Debra R; Kryzer, Lori A; Alexander, Jeffrey A

2018-03-01

Atopy patch testing (APT) has shown potential for predicting dietary food triggers in studies of children and adolescents with eosinophilic esophagitis (EoE). To assess the efficacy of APT in adults with EoE. We conducted a prospective open-label pilot study of patients ≥ 18 years old with diagnosis of EoE at Mayo Clinic in Rochester, Minnesota, from November 2014 to January 2016. All patients underwent patch testing using intact food products, followed by a six food elimination diet and stepwise food reintroduction. Response to elimination diet was assessed with serial endoscopy with biopsies as well as clinical symptoms. APT results were directly compared to elimination diet results for assessment of efficacy. Correlation between clinical symptoms, endoscopic score, and histology was also qualitatively evaluated. Fifty percent of the patients had a positive APT, while only 16% had an APT result confirmed histologically during food reintroduction. Sensitivity of APT was calculated to be 5.9%, with specificity of 92.0%. Furthermore, we found significant qualitative inter-patient heterogeneity in the correlation between clinical symptoms, EREFS score, and histology. APT does not reliably predict food triggers identified by food elimination diet in adult patients with EoE. As a result, APT does not have a clear role in the evaluation of patients with EoE.

Oxytocin receptor gene variations predict neural and behavioral response to oxytocin in autism

PubMed Central

Watanabe, Takamitsu; Otowa, Takeshi; Abe, Osamu; Kuwabara, Hitoshi; Aoki, Yuta; Natsubori, Tatsunobu; Takao, Hidemasa; Kakiuchi, Chihiro; Kondo, Kenji; Ikeda, Masashi; Iwata, Nakao; Kasai, Kiyoto; Sasaki, Tsukasa

2017-01-01

Abstract Oxytocin appears beneficial for autism spectrum disorder (ASD), and more than 20 single-nucleotide polymorphisms (SNPs) in oxytocin receptor (OXTR) are relevant to ASD. However, neither biological functions of OXTR SNPs in ASD nor critical OXTR SNPs that determine oxytocin’s effects on ASD remains known. Here, using a machine-learning algorithm that was designed to evaluate collective effects of multiple SNPs and automatically identify most informative SNPs, we examined relationships between 27 representative OXTR SNPs and six types of behavioral/neural response to oxytocin in ASD individuals. The oxytocin effects were extracted from our previous placebo-controlled within-participant clinical trial administering single-dose intranasal oxytocin to 38 high-functioning adult Japanese ASD males. Consequently, we identified six different SNP sets that could accurately predict the six different oxytocin efficacies, and confirmed the robustness of these SNP selections against variations of the datasets and analysis parameters. Moreover, major alleles of several prominent OXTR SNPs—including rs53576 and rs2254298—were found to have dissociable effects on the oxytocin efficacies. These findings suggest biological functions of the OXTR SNP variants on autistic oxytocin responses, and implied that clinical oxytocin efficacy may be genetically predicted before its actual administration, which would contribute to establishment of future precision medicines for ASD. PMID:27798253

[Usefulness of clinical prediction rules for ruling out deep vein thrombosis in a hospital emergency department].

PubMed

Rosa-Jiménez, Francisco; Rosa-Jiménez, Ascensión; Lozano-Rodríguez, Aquiles; Santoro-Martínez, María Del Carmen; Duro-López, María Del Carmen; Carreras-Álvarez de Cienfuegos, Amelia

2015-01-01

To compare the efficacy of the most familiar clinical prediction rules in combination with D-dimer testing to rule out a diagnosis of deep vein thrombosis (DVT) in a hospital emergency department. Retrospective cross-sectional analysis of the case records of all patients attending a hospital emergency department with suspected lower-limb DVT between 1998 and 2002. Ten clinical prediction scores were calculated and D-dimer levels were available for all patients. The gold standard was ultrasound diagnosis of DVT by an independent radiologist who was blinded to clinical records. For each prediction rule, we analyzed the effectiveness of the prediction strategy defined by "low clinical probability and negative D-dimer level" against the ultrasound diagnosis. A total of 861 case records were reviewed and 577 cases were selected; the mean (SD) age was 66.7 (14.2) years. DVT was diagnosed in 145 patients (25.1%). Only the Wells clinical prediction rule and 4 other models had a false negative rate under 2%. The Wells criteria and the score published by Johanning and colleagues identified higher percentages of cases (15.6% and 11.6%, respectively). This study shows that several clinical prediction rules can be safely used in the emergency department, although none of them have proven more effective than the Wells criteria.

Revisiting Bevacizumab + Cytotoxics Scheduling Using Mathematical Modeling: Proof of Concept Study in Experimental Non-Small Cell Lung Carcinoma.

PubMed

Imbs, Diane-Charlotte; El Cheikh, Raouf; Boyer, Arnaud; Ciccolini, Joseph; Mascaux, Céline; Lacarelle, Bruno; Barlesi, Fabrice; Barbolosi, Dominique; Benzekry, Sébastien

2018-01-01

Concomitant administration of bevacizumab and pemetrexed-cisplatin is a common treatment for advanced nonsquamous non-small cell lung cancer (NSCLC). Vascular normalization following bevacizumab administration may transiently enhance drug delivery, suggesting improved efficacy with sequential administration. To investigate optimal scheduling, we conducted a study in NSCLC-bearing mice. First, experiments demonstrated improved efficacy when using sequential vs. concomitant scheduling of bevacizumab and chemotherapy. Combining this data with a mathematical model of tumor growth under therapy accounting for the normalization effect, we predicted an optimal delay of 2.8 days between bevacizumab and chemotherapy. This prediction was confirmed experimentally, with reduced tumor growth of 38% as compared to concomitant scheduling, and prolonged survival (74 vs. 70 days). Alternate sequencing of 8 days failed in achieving a similar increase in efficacy, thus emphasizing the utility of modeling support to identify optimal scheduling. The model could also be a useful tool in the clinic to personally tailor regimen sequences. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Characterization of recent and minimally passaged Brazilian dengue viruses inducing robust infection in rhesus macaques.

PubMed

Borges, Maria Beatriz; Marchevsky, Renato Sergio; Mendes, Ygara S; Mendes, Luiz Gustavo; Duarte, Ana Claudia; Cruz, Michael; de Filippis, Ana Maria Bispo; Vasconcelos, Pedro Fernando C; Freire, Marcos; Homma, Akira; Mossman, Sally; Lepine, Edith; Vanloubbeeck, Yannick; Lorin, Clarisse; Malice, Marie-Pierre; Caride, Elena; Warter, Lucile

2018-01-01

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model's predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans.

Characterization of recent and minimally passaged Brazilian dengue viruses inducing robust infection in rhesus macaques

PubMed Central

Borges, Maria Beatriz; Marchevsky, Renato Sergio; Mendes, Ygara S.; Mendes, Luiz Gustavo; Duarte, Ana Claudia; Cruz, Michael; de Filippis, Ana Maria Bispo; Vasconcelos, Pedro Fernando C.; Freire, Marcos; Homma, Akira; Mossman, Sally; Lepine, Edith; Vanloubbeeck, Yannick; Lorin, Clarisse; Malice, Marie-Pierre; Caride, Elena

2018-01-01

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model’s predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans. PMID:29694440

War and disaster in Sri Lanka: Implications for widows' family adjustment and perception of self-efficacy in caring for one's family.

PubMed

Witting, Alyssa Banford; Lambert, Jessica; Wickrama, Thulitha

2016-12-12

The data for this study were collected in 2014 from widows in Eastern Sri Lanka whose spouses died in the civil war, tsunami, or from health-related problems. Conservation of resources (COR) theory was used as a lens to examine the extent to which war and tsunami-related damages and family problems predict variation in social support, family adjustment and a perception of self-efficacy in caring for one's family as reported by widowed women. We also investigated whether social support from the community and social support from family and friends mediated those relationships. Results of a path model fit to the data suggested variation in family adjustment to be negatively predicted by war-related family problems and positively predicted by the social support of friends and family. Additionally, a sense of self-efficacy in caring for one's family was found to be inversely predicted by war-related family problems and tsunami damages. Clinical, social and theoretical implications are discussed as well as directions for further research. © 2016 International Union of Psychological Science.

Predictive factors of clinical response in steroid-refractory ulcerative colitis treated with granulocyte-monocyte apheresis

PubMed Central

D'Ovidio, Valeria; Meo, Donatella; Viscido, Angelo; Bresci, Giampaolo; Vernia, Piero; Caprilli, Renzo

2011-01-01

AIM: To identify factors predicting the clinical response of ulcerative colitis patients to granulocyte-monocyte apheresis (GMA). METHODS: Sixty-nine ulcerative colitis patients (39 F, 30 M) dependent upon/refractory to steroids were treated with GMA. Steroid dependency, clinical activity index (CAI), C reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), values at baseline, use of immunosuppressant, duration of disease, and age and extent of disease were considered for statistical analysis as predictive factors of clinical response. Univariate and multivariate logistic regression models were used. RESULTS: In the univariate analysis, CAI (P = 0.039) and ESR (P = 0.017) levels at baseline were singled out as predictive of clinical remission. In the multivariate analysis steroid dependency [Odds ratio (OR) = 0.390, 95% Confidence interval (CI): 0.176-0.865, Wald 5.361, P = 0.0160] and low CAI levels at baseline (4 < CAI < 7) (OR = 0.770, 95% CI: 0.425-1.394, Wald 3.747, P = 0.028) proved to be effective as factors predicting clinical response. CONCLUSION: GMA may be a valid therapeutic option for steroid-dependent ulcerative colitis patients with mild-moderate disease and its clinical efficacy seems to persist for 12 mo. PMID:21528055

Development and validation of a preoperative prediction model for colorectal cancer T-staging based on MDCT images and clinical information.

PubMed

Sa, Sha; Li, Jing; Li, Xiaodong; Li, Yongrui; Liu, Xiaoming; Wang, Defeng; Zhang, Huimao; Fu, Yu

2017-08-15

This study aimed to establish and evaluate the efficacy of a prediction model for colorectal cancer T-staging. T-staging was positively correlated with the level of carcinoembryonic antigen (CEA), expression of carbohydrate antigen 19-9 (CA19-9), wall deformity, blurred outer edges, fat infiltration, infiltration into the surrounding tissue, tumor size and wall thickness. Age, location, enhancement rate and enhancement homogeneity were negatively correlated with T-staging. The predictive results of the model were consistent with the pathological gold standard, and the kappa value was 0.805. The total accuracy of staging improved from 51.04% to 86.98% with the proposed model. The clinical, imaging and pathological data of 611 patients with colorectal cancer (419 patients in the training group and 192 patients in the validation group) were collected. A spearman correlation analysis was used to validate the relationship among these factors and pathological T-staging. A prediction model was trained with the random forest algorithm. T staging of the patients in the validation group was predicted by both prediction model and traditional method. The consistency, accuracy, sensitivity, specificity and area under the curve (AUC) were used to compare the efficacy of the two methods. The newly established comprehensive model can improve the predictive efficiency of preoperative colorectal cancer T-staging.

Informatics Approaches for Predicting, Understanding, and Testing Cancer Drug Combinations.

PubMed

Tang, Jing

2017-01-01

Making cancer treatment more effective is one of the grand challenges in our health care system. However, many drugs have entered clinical trials but so far showed limited efficacy or induced rapid development of resistance. We urgently need multi-targeted drug combinations, which shall selectively inhibit the cancer cells and block the emergence of drug resistance. The book chapter focuses on mathematical and computational tools to facilitate the discovery of the most promising drug combinations to improve efficacy and prevent resistance. Data integration approaches that leverage drug-target interactions, cancer molecular features, and signaling pathways for predicting, understanding, and testing drug combinations are critically reviewed.

Predicting the clinical efficacy and potential adverse effects of a humanized anticocaine monoclonal antibody

PubMed Central

Norman, Andrew B; Ball, William J

2012-01-01

The effects of a humanized monoclonal antibody (mAb) having high affinity and specificity for cocaine in animal models are reviewed. The mAb reduced the concentration of cocaine in the brain of mice after intravenous injection of cocaine. In addition, the mAb increased the concentration of cocaine required to reinstate cocaine self-administration. These effects may predict clinical efficacy of a passive immunotherapy for reducing the probability of cocaine-induced relapse. However, in the presence of the mAb, once cocaine self-administration was reinstated, the consumption rate of cocaine was increased. This effect is hypothesized to result from a pharmacokinetic/pharmacodynamic interaction. A humanized mAb should minimize adverse events related to the immunogenicity of the mAb protein, and the specificity for cocaine should avoid adverse events related to interactions with physiologically relevant endogenous proteins. PMID:22401638

Psychometric testing of the breastfeeding self-efficacy scale-short form among adolescents.

PubMed

Dennis, Cindy-Lee; Heaman, Maureen; Mossman, Marion

2011-09-01

This study aimed to (a) psychometrically assess the Breastfeeding Self-Efficacy Scale-Short Form (BSES-SF) antenatally and postnatally among adolescents, and (b) examine the relationship between breast-feeding self-efficacy and adolescent demographic variables. The BSES-SF is used internationally but has not been psychometrically tested with an adolescent population. A methodological study was conducted in which 103 pregnant adolescents were recruited from two prenatal clinics at a tertiary care setting in western Canada. The BSES-SF was administered at 34 weeks' gestation and again at 1 and 4 weeks postpartum. The Cronbach's alpha coefficient was .84 for the antenatal assessment and .93 for the postnatal assessment. Antenatal BSES-SF scores significantly predicted breast-feeding initiation, whereas antenatal and postnatal scores predicted duration and exclusivity to 4 weeks postpartum. Other reliability and validity results are consistent with previous research with adult samples. Study findings indicate prenatal classes and professional support may be particularly important sources of information to increase adolescent breast-feeding self-efficacy. Results provide evidence that the scale may be a valid and reliable measure of breast-feeding self-efficacy among adolescents, predicting breast-feeding initiation, duration, and exclusivity. Copyright © 2011 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Effectiveness of low-dose pasireotide in a patient with Cushing’s disease: antiproliferative effect and predictivity of a short pasireotide suppression test

PubMed Central

Grossrubatscher, Erika; Zampetti, Benedetta; Dalino Ciaramella, Paolo; Doneda, Paola; Loli, Paola

2015-01-01

Key Clinical Message This case shows efficacy of low-dose pasireotide in biochemical and clinical control of severe hypercortisolism and in tumor volume reduction in a patient with an ACTH-secreting macroadenoma. The drug may be an option for long-term treatment in some patients where control of tumor mass is an important clinical endpoint. PMID:26331021

New and Accurate Predictive Model for the Efficacy of Extracorporeal Shock Wave Therapy in Managing Patients With Chronic Plantar Fasciitis.

PubMed

Yin, Mengchen; Chen, Ni; Huang, Quan; Marla, Anastasia Sulindro; Ma, Junming; Ye, Jie; Mo, Wen

2017-12-01

To identify factors for the outcome of a minimum clinically successful therapy and to establish a predictive model of extracorporeal shock wave therapy (ESWT) in managing patients with chronic plantar fasciitis. Randomized, controlled, prospective study. Outpatient of local medical center settings. Patients treated for symptomatic chronic plantar fasciitis between 2014 and 2016 (N=278). ESWT was performed by the principal authors to treat chronic plantar fasciitis. ESWT was administered in 3 sessions, with an interval of 2 weeks (±4d). In the low-, moderate-, and high-intensity groups, 2400 impulses total of ESWT with an energy flux density of 0.2, 0.4, and 0.6mJ/mm 2 , respectively (a rate of 8 impulses per second), were applied. The independent variables were patient age, sex, body mass index, affected side, duration of symptoms, Roles and Maudsley score, visual analog scale (VAS) score when taking first steps in the morning, edema, bone spurs, and intensity grade of ESWT. A minimal reduction of 50% in the VAS score was considered as minimum clinically successful therapy. The correlations between the achievement of minimum clinically successful therapy and independent variables were analyzed. The statistically significant factors identified were further analyzed by multivariate logistic regression, and the predictive model was established. The success rate of ESWT was 66.9%. Univariate analysis found that VAS score when taking first steps in the morning, edema, and the presence of heel spur in radiograph significantly affected the outcome of the treatment. Logistic regression drew the equation: minimum clinically successful therapy=(1+e [.011+42.807×heel spur+.109×edema+5.395×VAS score] ) -1 .The sensitivity of the predictive factors was 96.77%, 87.63%, and 86.02%, respectively. The specificity of the predictive factors was 45.65%, 42.39%, and 85.87%, respectively. The area under the curve of the predictive factors was .751, .650, and .859, respectively. The Youden index was .4243, .3003, and .7189, respectively. The Hosmer-Lemeshow test showed a good fitting of the predictive model, with an overall accuracy of 89.6%. This study establishes a new and accurate predictive model for the efficacy of ESWT in managing patients with chronic plantar fasciitis. The use of these parameters, in the form of a predictive model for ESWT efficacy, has the potential to improve decision-making in the application of ESWT. Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Top-down and bottom-up modeling in system pharmacology to understand clinical efficacy: An example with NRTIs of HIV-1.

PubMed

Duwal, Sulav; von Kleist, Max

2016-10-30

A major aim of Systems Pharmacology is to understand clinically relevant mechanisms of action (MOA) of drugs and to use this knowledge in order to optimize therapy. To enable this mission it is necessary to obtain knowledge on how in vitro testable insights translate into clinical efficacy. Mathematical modeling and data integration are essential components to achieve this goal. Two modeling philosophies are prevalent, each of which in isolation is not sufficient to achieve the above described: In a 'top-down' approach, a minimal pharmacokinetic-pharmacodynamic (PK-PD) model is derived from- and fitted to available clinical data. This model may lack interpretability in terms of mechanisms and may only be predictive for scenarios already covered by the data used to derive it. A 'bottom-up' approach builds on mechanistic insights derived from in vitro/ex vivo experiments, which can be conducted under controlled conditions, but may not be fully representative for the in vivo/clinical situation. In this work, we employ both approaches side-by-side to predict the clinical potency (IC 50 values) of the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine, emtricitabine and tenofovir. In the 'top-down' approach, this requires to establish the dynamic link between the intracellularly active NRTI-triphosphates (which exert the effect) and plasma prodrug PK and to subsequently link this composite PK model to viral kinetics. The 'bottom-up' approach assesses inhibition of reverse transcriptase-mediated viral DNA polymerization by the intracellular, active NRTI-triphosphates, which has to be brought into the context of target cell infection. By using entirely disparate sets of data to derive and parameterize the respective models, our approach serves as a means to assess the clinical relevance of the 'bottom-up' approach. We obtain very good qualitative and quantitative agreement between 'top-down' vs. 'bottom-up' predicted IC 50 values, arguing for the validity of the 'bottom-up' approach. We noted, however, that the 'top-down' approach is strongly dependent on the sparse and noisy intracellular pharmacokinetic data. All in all, our work provides confidence that we can translate in vitro parameters into measures of clinical efficacy using the 'bottom-up' approach. This may allow to infer the potency of various NRTIs in inhibiting e.g. mutant viruses, to distinguish sources of interaction of NRTI combinations and to assess the efficacy of different NRTIs for repurposing, e.g. for pre-exposure prophylaxis. Copyright © 2016 Elsevier B.V. All rights reserved.

A physiologically based pharmacokinetic (PBPK) model for predicting the efficacy of drug overdose treatment with liposomes in man.

PubMed

Howell, Brett A; Chauhan, Anuj

2010-08-01

Physiologically based pharmacokinetic (PBPK) models were developed for design and optimization of liposome therapy for treatment of overdoses of tricyclic antidepressants and local anesthetics. In vitro drug-binding data for pegylated, anionic liposomes and published mechanistic equations for partition coefficients were used to develop the models. The models were proven reliable through comparisons to intravenous data. The liposomes were predicted to be highly effective at treating amitriptyline overdoses, with reductions in the area under the concentration versus time curves (AUC) of 64% for the heart and brain. Peak heart and brain drug concentrations were predicted to drop by 20%. Bupivacaine AUC and peak concentration reductions were lower at 15.4% and 17.3%, respectively, for the heart and brain. The predicted pharmacokinetic profiles following liposome administration agreed well with data from clinical studies where protein fragments were administered to patients for overdose treatment. Published data on local cardiac function were used to relate the predicted concentrations in the body to local pharmacodynamic effects in the heart. While the results offer encouragement for future liposome therapies geared toward overdose, it is imperative to point out that animal experiments and phase I clinical trials are the next steps to ensuring the efficacy of the treatment. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association

Predicting the preferences for involvement in medical decision making among patients with mental disorders

PubMed Central

Michaelis, Svea; Kriston, Levente; Härter, Martin; Watzke, Birgit; Schulz, Holger; Melchior, Hanne

2017-01-01

Background The involvement of patients in medical decision making has been investigated widely in somatic diseases. However, little is known about the preferences for involvement and variables that could predict these preferences in patients with mental disorders. Objective This study aims to determine what roles mentally ill patients actually want to assume when making medical decisions and to identify the variables that could predict this role, including patients’ self-efficacy. Method Demographic and clinical data of 798 patients with mental disorders from three psychotherapeutic units in Germany were elicited using self-report questionnaires. Control preference was measured using the Control Preferences Scale, and patients’ perceived self-efficacy was assessed using the Self-Efficacy Scale. Bivariate and multivariate regression analyses were conducted to investigate the associations between patient variables and control preference. Results Most patients preferred a collaborative role (57.5%), followed by a semi passive (21.2%), a partly autonomous (16.2%), an autonomous (2.8%) and a fully passive (2.3%) role when making medical decisions. Age, sex, diagnosis, employment status, medical pretreatment and perceived self-efficacy were associated with the preference for involvement in the multivariate logistic model. Conclusion Our results confirm the preferences for involvement in medical decisions of mentally ill patients. We reconfirmed previous findings that older patients prefer a shared role over an autonomous role and that subjects with a high qualification prefer a more autonomous role over a shared role. The knowledge about predictors may help strengthen treatment effectiveness because matching the preferred and actual role preferences has been shown to improve clinical outcome. PMID:28837621

Predicting the preferences for involvement in medical decision making among patients with mental disorders.

PubMed

Michaelis, Svea; Kriston, Levente; Härter, Martin; Watzke, Birgit; Schulz, Holger; Melchior, Hanne

2017-01-01

The involvement of patients in medical decision making has been investigated widely in somatic diseases. However, little is known about the preferences for involvement and variables that could predict these preferences in patients with mental disorders. This study aims to determine what roles mentally ill patients actually want to assume when making medical decisions and to identify the variables that could predict this role, including patients' self-efficacy. Demographic and clinical data of 798 patients with mental disorders from three psychotherapeutic units in Germany were elicited using self-report questionnaires. Control preference was measured using the Control Preferences Scale, and patients' perceived self-efficacy was assessed using the Self-Efficacy Scale. Bivariate and multivariate regression analyses were conducted to investigate the associations between patient variables and control preference. Most patients preferred a collaborative role (57.5%), followed by a semi passive (21.2%), a partly autonomous (16.2%), an autonomous (2.8%) and a fully passive (2.3%) role when making medical decisions. Age, sex, diagnosis, employment status, medical pretreatment and perceived self-efficacy were associated with the preference for involvement in the multivariate logistic model. Our results confirm the preferences for involvement in medical decisions of mentally ill patients. We reconfirmed previous findings that older patients prefer a shared role over an autonomous role and that subjects with a high qualification prefer a more autonomous role over a shared role. The knowledge about predictors may help strengthen treatment effectiveness because matching the preferred and actual role preferences has been shown to improve clinical outcome.

Immunogenicity of therapeutics: a matter of efficacy and safety.

PubMed

Nechansky, Andreas; Kircheis, Ralf

2010-11-01

The unwanted immunogenicity of therapeutic proteins is a major concern regarding patient safety. Furthermore, pharmacokinetic, pharmacodynamic and clinical efficacy can be seriously affected by the immunogenicity of therapeutic proteins. Authorities have fully recognized this issue and demand appropriate and well-characterized assays to detect anti-drug antibodies (ADAs). We provide an overview of the immunogenicity topic in general, the regulatory background and insight into underlying immunological mechanisms and the limited ability to predict clinical immunogenicity a priori. Furthermore, we comment on the analytical testing approach and the status-quo of appropriate method validation. The review provides insight regarding the analytical approach that is expected by regulatory authorities overseeing immunogenicity testing requirements. Additionally, the factors influencing immunogenicity are summarized and key references regarding immunogenicity testing approaches and method validation are discussed. The unwanted immunogenicity of protein therapeutics is of major concern because of its potential to affect patient safety and drug efficacy. Analytical testing is sophisticated and requires more than one assay. Because immunogenicity in humans is hardly predictable, assay development has to start in a timely fashion and for clinical studies immunogenicity assay validation is mandatory prior to analyzing patient serum samples. Regarding ADAs, the question remains as to when such antibodies are regarded of clinical relevance and what levels are, if at all, acceptable. In summary, the detection of ADAs should raise the awareness of the physician concerning patient safety and of the sponsor/manufacture concerning the immunogenic potential of the drug product.

Prediction of Short- and Medium-term Efficacy of Biosimilar Infliximab Therapy. Do Trough Levels and Antidrug Antibody Levels or Clinical And Biochemical Markers Play the More Important Role?

PubMed

Gonczi, Lorant; Vegh, Zsuzsanna; Golovics, Petra Anna; Rutka, Mariann; Gecse, Krisztina Barbara; Bor, Renata; Farkas, Klaudia; Szamosi, Tamás; Bene, László; Gasztonyi, Beáta; Kristóf, Tünde; Lakatos, László; Miheller, Pál; Palatka, Károly; Papp, Mária; Patai, Árpád; Salamon, Ágnes; Tóth, Gábor Tamás; Vincze, Áron; Biro, Edina; Lovasz, Barbara Dorottya; Kurti, Zsuzsanna; Szepes, Zoltan; Molnár, Tamás; Lakatos, Péter L

2017-06-01

Biosimilar infliximab CT-P13 received European Medicines Agency [EMA] approval in June 2013 for all indications of the originator product. In the present study, we aimed to evaluate the predictors of short- and medium-term clinical outcome in patients treated with the biosimilar infliximab at the participating inflammatory bowel disease [IBD] centres in Hungary. Demographic data were collected and a harmonised monitoring strategy was applied. Clinical and biochemical activities were evaluated at Weeks 14, 30, and 54. Trough level [TL] and anti-drug antibody [ADA] concentrations were measured by enzyme-linked immunosorbent assay [ELISA] [LT-005, Theradiag, France] at baseline at 14, 30 and 54 weeks and in two centres at Weeks 2 and 6. A total of 291 consecutive IBD patients (184 Crohn's disease [CD] and 107 ulcerative colitis [UC]) were included. In UC, TLs at Week 2 predicted both clinical response and remission at Weeks 14 and 30 (clinical response/remission at Week 14: area under the curve [AUC] = 0.81, p < 0.001, cut-off: 11.5 μg/ml/AUC = 0.79, p < 0.001, cut-off: 15.3μg/ml; clinical response/remission at Week 30: AUC = 0.79, p = 0.002, cut-off: 11.5 μg/ml/AUC = 0.74, p = 0.006, cut-off: 14.5 μg/ml), whereas ADA positivity at Week 14 was inversely associated with clinical response at Week 30 [58.3% vs 84.8% ,p = 0.04]. Previous anti-tumour necrosis factor [TNF] exposure was inversely associated with short-term clinical remission [Week 2: 18.8% vs 47.8%, p = 0.03, at Week 6: 38.9% vs 69.7%, p = 0.013, at Week 14: 37.5% vs 2.5%, p = 0.06]. In CD, TLs at Week 2 predicted short-term [Week 14 response/remission, AUCTLweek2 = 0.715-0.721, p = 0.05/0.005] but not medium-term clinical efficacy. In addition, early ADA status by Week 14 [p = 0.04-0.05 for Weeks 14 and 30], early clinical response [p < 0.001 for Weeks 30/54] and normal C-reactive protein [CRP] at Week 14 [p = 0.005-0.0001] and previous anti-TNF exposure [p = 0.03-0.0001 for Weeks 14, 30, and 54] were associated with short-and medium-term clinical response and remission. In UC, early TLs were predictive for short- and medium-term clinical efficacy, whereas in CD, Week 2 TLs were associated only with short-term clinical outcomes. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

CorVue algorithm efficacy to predict heart failure in real life: Unnecessary and potentially misleading information?

PubMed

Palfy, Julia Anna; Benezet-Mazuecos, Juan; Milla, Juan Martinez; Iglesias, Jose Antonio; de la Vieja, Juan Jose; Sanchez-Borque, Pepa; Miracle, Angel; Rubio, Jose Manuel

2018-06-01

Heart failure (HF) hospitalizations have a negative impact on quality of life and imply important costs. Intrathoracic impedance (ITI) variations detected by cardiac devices have been hypothesized to predict HF hospitalizations. Although Optivol™ algorithm (Medtronic) has been widely studied, CorVue™ algorithm (St. Jude Medical) long term efficacy has not been systematically evaluated in a "real life" cohort. CorVue™ was activated in ICD/CRT-D patients to store information about ITI measures. Clinical events (new episodes of HF requiring treatment and hospitalizations) and CorVue™ data were recorded every three months. Appropriate CorVue™ detection for HF was considered if it occurred in the four prior weeks to the clinical event. 53 ICD/CRT-D (26 ICD and 27 CRT-D) patients (67±1 years-old, 79% male) were included. Device position was subcutaneous in 28 patients. At inclusion, mean LVEF was 25±7% and 27 patients (51%) were in NYHA class I, 18 (34%) class II and 8 (15%) class III. After a mean follow-up of 17±9 months, 105 ITI drops alarms were detected in 32 patients (60%). Only six alarms were appropriate (true positive) and required hospitalization. Eighteen patients (34%) presented 25 clinical episodes (12 hospitalizations and 13 ER/ambulatory treatment modifications). Nineteen of these clinical episodes (76%) remained undetected by the CorVue™ (false negative). Sensitivity of CorVue™ resulted in 24%, specificity was 70%, positive predictive value of 6% and negative predictive value of 93%. CorVue™ showed a low sensitivity to predict HF events. Therefore, routinely activation of this algorithm could generate misleading information. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The art and science of choosing efficacy endpoints for rare disease clinical trials.

PubMed

Cox, Gerald F

2018-04-01

An important challenge in rare disease clinical trials is to demonstrate a clinically meaningful and statistically significant response to treatment. Selecting the most appropriate and sensitive efficacy endpoints for a treatment trial is part art and part science. The types of endpoints should align with the stage of development (e.g., proof of concept vs. confirmation of clinical efficacy). The patient characteristics and disease stage should reflect the treatment goal of improving disease manifestations or preventing disease progression. For rare diseases, regulatory approval requires demonstration of clinical benefit, defined as how a patient, feels, functions, or survives, in at least one adequate and well-controlled pivotal study conducted according to Good Clinical Practice. In some cases, full regulatory approval can occur using a validated surrogate biomarker, while accelerated, or provisional, approval can occur using a biomarker that is likely to predict clinical benefit. Rare disease studies are small by necessity and require the use of endpoints with large effect sizes to demonstrate statistical significance. Understanding the quantitative factors that determine effect size and its impact on powering the study with an adequate sample size is key to the successful choice of endpoints. Interpreting the clinical meaningfulness of an observed change in an efficacy endpoint can be justified by statistical methods, regulatory precedence, and clinical context. Heterogeneous diseases that affect multiple organ systems may be better accommodated by endpoints that assess mean change across multiple endpoints within the same patient rather than mean change in an individual endpoint across all patients. © 2018 Wiley Periodicals, Inc.

Osteoporosis: the emperor has no clothes

PubMed Central

Järvinen, T L N; Michaëlsson, K; Aspenberg, P; Sievänen, H

2015-01-01

Current prevention strategies for low-trauma fractures amongst older persons depend on the notions that fractures are mainly caused by osteoporosis (pathophysiology), that patients at high risk can be identified (screening) and that the risk is amenable to bone-targeted pharmacotherapy (treatment). However, all these three notions can be disputed. Pathophysiology Most fracture patients have fallen, but actually do not have osteoporosis. A high likelihood of falling, in turn, is attributable to an ageing-related decline in physical functioning and general frailty. Screening Currently available fracture risk prediction strategies including bone densitometry and multifactorial prediction tools are unable to identify a large proportion of patients who will sustain a fracture, whereas many of those with a high fracture risk score will not sustain a fracture. Treatment The evidence for the viability of bone-targeted pharmacotherapy in preventing hip fracture and other clinical fragility fractures is mainly limited to women aged 65–80 years with osteoporosis, whereas the proof of hip fracture-preventing efficacy in women over 80 years of age and in men at all ages is meagre or absent. Further, the antihip fracture efficacy shown in clinical trials is absent in real-life studies. Many drugs for the treatment of osteoporosis have also been associated with increased risks of serious adverse events. There are also considerable uncertainties related to the efficacy of drug therapy in preventing clinical vertebral fractures, whereas the efficacy for preventing other fractures (relative risk reductions of 20–25%) remains moderate, particularly in terms of the low absolute risk reduction in fractures with this treatment. PMID:25809279

Comparative testing of disinfectant efficacy on planktonic bacteria and bacterial biofilms using a new assay based on kinetic analysis of metabolic activity.

PubMed

Günther, F; Scherrer, M; Kaiser, S J; DeRosa, A; Mutters, N T

2017-03-01

The aim of our study was to develop a new reproducible method for disinfectant efficacy testing on bacterial biofilms and to evaluate the efficacy of different disinfectants against biofilms. Clinical multidrug-resistant strains were chosen as test isolates to ensure practical relevance. We compared the standard qualitative suspension assay for disinfectant testing, which does not take into account biofilm formation, to the new biofilm viability assay that uses kinetic analysis of metabolic activity in biofilms after disinfectant exposure to evaluate disinfectant efficacy. In addition, the efficacy of four standard disinfectants to clinical isolates was tested using both methods. All tested disinfectants were effective against test isolates when in planktonic state using the standard qualitative suspension assay, while disinfectants were only weakly effective against bacteria in biofilms. Disinfectant efficacy testing on planktonic organisms ignores biofilms and overestimates disinfectant susceptibility of bacteria. However, biofilm forming, e.g. on medical devices or hospital surfaces, is the natural state of bacterial living and needs to be considered in disinfectant testing. Although bacterial biofilms are the predominant manner of bacterial colonization, most standard procedures for antimicrobial susceptibility testing and efficacy testing of disinfectants are adapted for application to planktonic bacteria. To our knowledge, this is the first study to use a newly developed microplate-based biofilm test system that uses kinetic analysis of the metabolic activity in biofilms, after disinfectant exposure, to evaluate disinfectant efficacy. Our study shows that findings obtained from disinfectant efficacy testing on planktonic bacteria cannot be extrapolated to predict disinfectant efficacy on bacterial biofilms of clinically relevant multidrug-resistant organisms. © 2016 The Society for Applied Microbiology.

An acute rat in vivo screening model to predict compounds that alter blood glucose and/or insulin regulation.

PubMed

Brott, David A; Diamond, Melody; Campbell, Pam; Zuvich, Andy; Cheatham, Letitia; Bentley, Patricia; Gorko, Mary Ann; Fikes, James; Saye, JoAnne

2013-01-01

Drug-induced glucose dysregulation and insulin resistance have been associated with weight gain and potential induction and/or exacerbation of diabetes mellitus in the clinic suggesting they may be safety biomarkers when developing antipsychotics. Glucose and insulin have also been suggested as potential efficacy biomarkers for some oncology compounds. The objective of this study was to qualify a medium throughput rat in vivo acute Intravenous Glucose Tolerance Test (IVGTT) for predicting compounds that will induce altered blood glucose and/or insulin levels. Acute and sub-chronic studies were performed to qualify an acute IVGTT model. Double cannulated male rats (Han-Wistar and Sprague-Dawley) were administered vehicle, olanzapine, aripiprazole or other compounds at t=-44min for acute studies and at time=-44min on the last day of dosing for sub-chronic studies, treated with dextrose (time=0min; i.v.) and blood collected using an automated Culex® system for glucose and insulin analysis (time=-45, -1, 2, 10, 15, 30, 45, 60, 75, 90, 120, 150 and 180min). Olanzapine significantly increased glucose and insulin area under the curve (AUC) values while aripiprazole AUC values were similar to control, in both acute and sub-chronic studies. All atypical antipsychotics evaluated were consistent with literature references of clinical weight gain. As efficacy biomarkers, insulin AUC but not glucose AUC values were increased with a compound known to have insulin growth factor-1 (IGF-1) activity, compared to control treatment. These studies qualified the medium throughput acute IVGTT model to more quickly screen compounds for 1) safety - the potential to elicit glucose dysregulation and/or insulin resistance and 2) efficacy - as a surrogate for compounds affecting the glucose and/or insulin regulatory pathways. These data demonstrate that the same in vivo rat model and assays can be used to predict both clinical safety and efficacy of compounds. © 2013.

Do self-efficacy and depression predict oral impacts on daily performances across time? A 2-yr follow-up of students in Tanzania.

PubMed

Åstrøm, Anne N; Lie, Stein A; Mbawalla, Hawa

2016-08-01

This study aimed to assess the longitudinal validity of the oral impacts on daily performance (OIDP) and to identify psychosocial determinants, in terms of self-efficacy and depressive symptoms, of the OIDP across time. Following conceptual frameworks of oral health, it was hypothesized that sociodemographic, clinical, and psychosocial factors predict oral impacts across time at both population- averaged and person-specific levels. Whether the effects of sociodemographic and clinical factors were accounted for, totally or in part, by psychosocial factors were also investigated. Self administered questionnaires and oral clinical examinations at baseline (2009) and follow-up (2011) were completed by 1,714 and 727 secondary school students, respectively. Generalized equalized equations and a random intercept model were used to account for the dependency in repeated observations. Mean OIDP change scores were negative (worsened) among those who reported worsened self-reported oral health. Psychosocial, clinical, and sociodemographic factors were independently associated with oral impacts at the population-averaged and person-specific levels. Mediation of sociodemographic and clinical variables according to psychosocial variables was not observed. Satisfactory longitudinal evaluative properties of the OIDP, and independent effects of psychosocial factors on oral impacts across time, were confirmed among secondary school students in Tanzania. © 2016 Eur J Oral Sci.

Bridging the Gap Between Science and Clinical Efficacy: Physiology, Imaging, and Modeling of Aerosols in the Lung.

PubMed

Darquenne, Chantal; Fleming, John S; Katz, Ira; Martin, Andrew R; Schroeter, Jeffry; Usmani, Omar S; Venegas, Jose; Schmid, Otmar

2016-04-01

Development of a new drug for the treatment of lung disease is a complex and time consuming process involving numerous disciplines of basic and applied sciences. During the 2015 Congress of the International Society for Aerosols in Medicine, a group of experts including aerosol scientists, physiologists, modelers, imagers, and clinicians participated in a workshop aiming at bridging the gap between basic research and clinical efficacy of inhaled drugs. This publication summarizes the current consensus on the topic. It begins with a short description of basic concepts of aerosol transport and a discussion on targeting strategies of inhaled aerosols to the lungs. It is followed by a description of both computational and biological lung models, and the use of imaging techniques to determine aerosol deposition distribution (ADD) in the lung. Finally, the importance of ADD to clinical efficacy is discussed. Several gaps were identified between basic science and clinical efficacy. One gap between scientific research aimed at predicting, controlling, and measuring ADD and the clinical use of inhaled aerosols is the considerable challenge of obtaining, in a single study, accurate information describing the optimal lung regions to be targeted, the effectiveness of targeting determined from ADD, and some measure of the drug's effectiveness. Other identified gaps were the language and methodology barriers that exist among disciplines, along with the significant regulatory hurdles that need to be overcome for novel drugs and/or therapies to reach the marketplace and benefit the patient. Despite these gaps, much progress has been made in recent years to improve clinical efficacy of inhaled drugs. Also, the recent efforts by many funding agencies and industry to support multidisciplinary networks including basic science researchers, R&D scientists, and clinicians will go a long way to further reduce the gap between science and clinical efficacy.

Bridging the Gap Between Science and Clinical Efficacy: Physiology, Imaging, and Modeling of Aerosols in the Lung

PubMed Central

Fleming, John S.; Katz, Ira; Martin, Andrew R.; Schroeter, Jeffry; Usmani, Omar S.; Venegas, Jose

2016-01-01

Abstract Development of a new drug for the treatment of lung disease is a complex and time consuming process involving numerous disciplines of basic and applied sciences. During the 2015 Congress of the International Society for Aerosols in Medicine, a group of experts including aerosol scientists, physiologists, modelers, imagers, and clinicians participated in a workshop aiming at bridging the gap between basic research and clinical efficacy of inhaled drugs. This publication summarizes the current consensus on the topic. It begins with a short description of basic concepts of aerosol transport and a discussion on targeting strategies of inhaled aerosols to the lungs. It is followed by a description of both computational and biological lung models, and the use of imaging techniques to determine aerosol deposition distribution (ADD) in the lung. Finally, the importance of ADD to clinical efficacy is discussed. Several gaps were identified between basic science and clinical efficacy. One gap between scientific research aimed at predicting, controlling, and measuring ADD and the clinical use of inhaled aerosols is the considerable challenge of obtaining, in a single study, accurate information describing the optimal lung regions to be targeted, the effectiveness of targeting determined from ADD, and some measure of the drug's effectiveness. Other identified gaps were the language and methodology barriers that exist among disciplines, along with the significant regulatory hurdles that need to be overcome for novel drugs and/or therapies to reach the marketplace and benefit the patient. Despite these gaps, much progress has been made in recent years to improve clinical efficacy of inhaled drugs. Also, the recent efforts by many funding agencies and industry to support multidisciplinary networks including basic science researchers, R&D scientists, and clinicians will go a long way to further reduce the gap between science and clinical efficacy. PMID:26829187

A low-density cDNA microarray with a unique reference RNA: pattern recognition analysis for IFN efficacy prediction to HCV as a model.

PubMed

Daiba, Akito; Inaba, Niro; Ando, Satoshi; Kajiyama, Naoki; Yatsuhashi, Hiroshi; Terasaki, Hiroshi; Ito, Atsushi; Ogasawara, Masanori; Abe, Aki; Yoshioka, Junichi; Hayashida, Kazuhiro; Kaneko, Shuichi; Kohara, Michinori; Ito, Satoru

2004-03-19

We have designed and established a low-density (295 genes) cDNA microarray for the prediction of IFN efficacy in hepatitis C patients. To obtain a precise and consistent microarray data, we collected a data set from three spots for each gene (mRNA) and using three different scanning conditions. We also established an artificial reference RNA representing pseudo-inflammatory conditions from established hepatocyte cell lines supplemented with synthetic RNAs to 48 inflammatory genes. We also developed a novel algorithm that replaces the standard hierarchical-clustering method and allows handling of the large data set with ease. This algorithm utilizes a standard space database (SSDB) as a key scale to calculate the Mahalanobis distance (MD) from the center of gravity in the SSDB. We further utilized sMD (divided by parameter k: MD/k) to reduce MD number as a predictive value. The efficacy prediction of conventional IFN mono-therapy was 100% for non-responder (NR) vs. transient responder (TR)/sustained responder (SR) (P < 0.0005). Finally, we show that this method is acceptable for clinical application.

Type D personality, self-efficacy, and medication adherence in patients with heart failure-A mediation analysis.

PubMed

Wu, Jia-Rong; Song, Eun Kyeung; Moser, Debra K

2015-01-01

Type D personality is associated with medication non-adherence. Both Type D personality and non-adherence are predictors of poor outcomes. Self-efficacy, which is modifiable, is also associated with medication adherence. To determine the relationships among Type D personality, self-efficacy, and medication adherence in 84 heart failure patients. Self-efficacy, Type D personality, medication adherence, demographic and clinical data were collected. Hierarchical linear regression was used. Type D patients were more likely to have lower self-efficacy (p = .023) and medication non-adherence (p = .027) than non-Type D patients. Low self-efficacy was associated with medication non-adherence (p < .001). Type D personality didn't predict medication adherence after entering self-efficacy in the model (p = .422), demonstrating mediation. Self-efficacy mediates the relationship between Type D personality and medication adherence. Developing and applying interventions to enhance self-efficacy may help to sever the link between Type D personality and poor outcomes. Copyright © 2015 Elsevier Inc. All rights reserved.

Predicting Return of Fear Following Exposure Therapy With an Implicit Measure of Attitudes

PubMed Central

Vasey, Michael W.; Harbaugh, Casaundra N.; Buffington, Adam G.; Jones, Christopher R.; Fazio, Russell H.

2012-01-01

We sought to advance understanding of the processes underlying the efficacy of exposure therapy and particularly the phenomenon of return of fear (ROF) following treatment by drawing on a social psychological view of phobias as attitudes. Specifically, a dual process theory of attitude-related behavior predicts that a positive response to exposure therapy may reflect change in either the automatic (the attitude representation itself) or controlled (skills and confidence at coping with the fear) responses to the phobic stimulus, or both. However, if the attitude representation remains negative following treatment, ROF should be more likely. We tested this hypothesis in a clinical sample of individuals with public speaking phobia using a single-session exposure therapy protocol previously shown to be efficacious but also associated with some ROF. Consistent with predictions, a post-treatment implicit measure of attitudes toward public speaking (the Personalized Implicit Association Test [PIAT]) predicted ROF at 1-month follow-up. These results suggest that change in the automatically activated attitude toward the phobic stimulus is an important goal of exposure therapy and that an implicit measure like the PIAT can provide a useful measure of such change by which to gauge the adequacy of exposure treatment and predict its long-term efficacy. PMID:23085186

The use of pharmacokinetic/pharmacodynamic principles to predict clinical outcome in paediatric acute otitis media.

PubMed

Dagan, Ron

2007-12-01

Double tympanocentesis studies of children with acute otitis media, carried out over an 11-year period, were used to confirm that pharmacokinetic (PK) and pharmacodynamic (PD) parameters can be used as predictors of the bacteriological and clinical efficacy of antimicrobial agents. Predicted susceptibilities of common respiratory pathogens, such as Streptococcus pneumoniae and Haemophilus influenzae, were compared with the bacteriological outcome of treatment in which the high-dose formulation of amoxicillin/clavulanate (90mg/kg/day) given twice daily achieved the greatest bacteriological eradication rates for an oral agent. Further analysis of the data has indicated that failure to eradicate bacteria from the middle ear fluid is strongly correlated with clinical failure.

Genomic and Histopathological Tissue Biomarkers That Predict Radiotherapy Response in Localised Prostate Cancer

PubMed Central

Wilkins, Anna; Dearnaley, David; Somaiah, Navita

2015-01-01

Localised prostate cancer, in particular, intermediate risk disease, has varied survival outcomes that cannot be predicted accurately using current clinical risk factors. External beam radiotherapy (EBRT) is one of the standard curative treatment options for localised disease and its efficacy is related to wide ranging aspects of tumour biology. Histopathological techniques including immunohistochemistry and a variety of genomic assays have been used to identify biomarkers of tumour proliferation, cell cycle checkpoints, hypoxia, DNA repair, apoptosis, and androgen synthesis, which predict response to radiotherapy. Global measures of genomic instability also show exciting capacity to predict survival outcomes following EBRT. There is also an urgent clinical need for biomarkers to predict the radiotherapy fraction sensitivity of different prostate tumours and preclinical studies point to possible candidates. Finally, the increased resolution of next generation sequencing (NGS) is likely to enable yet more precise molecular predictions of radiotherapy response and fraction sensitivity. PMID:26504789

Genomic variants in the ASS1 gene, involved in the nitric oxide biosynthesis and signaling pathway, predict hydroxyurea treatment efficacy in compound sickle cell disease/β-thalassemia patients.

PubMed

Chalikiopoulou, Constantina; Tavianatou, Anastasia-Gerasimoula; Sgourou, Argyro; Kourakli, Alexandra; Kelepouri, Dimitra; Chrysanthakopoulou, Maria; Kanelaki, Vasiliki-Kaliopi; Mourdoukoutas, Evangelos; Siamoglou, Stavroula; John, Anne; Symeonidis, Argyris; Ali, Bassam R; Katsila, Theodora; Papachatzopoulou, Adamantia; Patrinos, George P

2016-03-01

Hemoglobinopathies exhibit a remarkable phenotypic diversity that restricts any safe association between molecular pathology and clinical outcomes. Herein, we explored the role of genes involved in the nitric oxide biosynthesis and signaling pathway, implicated in the increase of fetal hemoglobin levels and response to hydroxyurea treatment, in 119 Hellenic patients with β-type hemoglobinopathies. We show that two ASS1 genomic variants (namely, rs10901080 and rs10793902) can serve as pharmacogenomic biomarkers to predict hydroxyurea treatment efficacy in sickle cell disease/β-thalassemia compound heterozygous patients. These markers may exert their effect by inducing nitric oxide biosynthesis, either via altering splicing and/or miRNA binding, as predicted by in silico analysis, and ultimately, increase γ-globin levels, via guanylyl cyclase targeting.

Effectiveness of low-dose pasireotide in a patient with Cushing's disease: antiproliferative effect and predictivity of a short pasireotide suppression test.

PubMed

Grossrubatscher, Erika; Zampetti, Benedetta; Dalino Ciaramella, Paolo; Doneda, Paola; Loli, Paola

2015-08-01

This case shows efficacy of low-dose pasireotide in biochemical and clinical control of severe hypercortisolism and in tumor volume reduction in a patient with an ACTH-secreting macroadenoma. The drug may be an option for long-term treatment in some patients where control of tumor mass is an important clinical endpoint.

Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure.

PubMed

Fox, Susan H; Lang, Anthony E; Brotchie, Jonathan M

2006-10-01

Studies in MPTP-lesioned nonhuman primates have demonstrated the potential of nondopaminergic drugs in reducing the problems of levodopa-induced dyskinesia (LID). Here we review the process of translating findings from the monkey to man. Agents targeting glutamate, adensosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed for antidyskinetic potential in human studies. Eleven nondopaminergic drugs with antidyskinetic efficacy in the MPTP primate have been advanced to proof-of-concept phase IIa trials in PD patients (amantadine, istradefylline, idazoxan, fipamezole, sarizotan, quetiapine, clozapine, nabilone, rimonabant, naloxone, and naltrexone). For all six nondopaminergic transmitter systems reviewed, the MPTP-lesioned primate correctly predicted phase II efficacy of at least one drug. Of the 11 specific molecules tested in both monkeys and humans, 8 showed clear antidyskinetic properties in both human and monkey. In the instances where the primate studies did not, or did not consistently, predict the outcome of the human studies, the discrepancy may reflect limitations in the validity of the model or limitations in the design of either the clinical or the preclinical studies. We find that the major determinant of success in predicting efficacy is to ensure that primate studies are conducted in a statistically rigorous way and incorporate designs and outcome measures with clinical applicability. On the other hand, phase IIa trials should strive to replicate the preclinical study, especially in terms of protocol, drug dose equivalence, and outcome measure, so as to test the same hypothesis. Failure to meet these criteria carries the risk of false negative conclusions in phase IIa trials.

A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management.

PubMed

Oberg, Kjell; Krenning, Eric; Sundin, Anders; Bodei, Lisa; Kidd, Mark; Tesselaar, Margot; Ambrosini, Valentina; Baum, Richard P; Kulke, Matthew; Pavel, Marianne; Cwikla, Jaroslaw; Drozdov, Ignat; Falconi, Massimo; Fazio, Nicola; Frilling, Andrea; Jensen, Robert; Koopmans, Klaus; Korse, Tiny; Kwekkeboom, Dik; Maecke, Helmut; Paganelli, Giovanni; Salazar, Ramon; Severi, Stefano; Strosberg, Jonathan; Prasad, Vikas; Scarpa, Aldo; Grossman, Ashley; Walenkamp, Annemeik; Cives, Mauro; Virgolini, Irene; Kjaer, Andreas; Modlin, Irvin M

2016-09-01

The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy. © 2016 The authors.

Tools for outcome prediction in patients with community acquired pneumonia.

PubMed

Khan, Faheem; Owens, Mark B; Restrepo, Marcos; Povoa, Pedro; Martin-Loeches, Ignacio

2017-02-01

Community-acquired pneumonia (CAP) is one of the most common causes of mortality world-wide. The mortality rate of patients with CAP is influenced by the severity of the disease, treatment failure and the requirement for hospitalization and/or intensive care unit (ICU) management, all of which may be predicted by biomarkers and clinical scoring systems. Areas covered: We review the recent literature examining the efficacy of established and newly-developed clinical scores, biological and inflammatory markers such as C-Reactive protein (CRP), procalcitonin (PCT) and Interleukin-6 (IL-6), whether used alone or in conjunction with clinical severity scores to assess the severity of CAP, predict treatment failure, guide acute in-hospital or ICU admission and predict mortality. Expert commentary: The early prediction of treatment failure using clinical scores and biomarkers plays a developing role in improving survival of patients with CAP by identifying high-risk patients requiring hospitalization or ICU admission; and may enable more efficient allocation of resources. However, it is likely that combinations of scoring systems and biomarkers will be of greater use than individual markers. Further larger studies are needed to corroborate the additive value of these markers to clinical prediction scores to provide a safer and more effective assessment tool for clinicians.

[Accuracy of three methods for the rapid diagnosis of oral candidiasis].

PubMed

Lyu, X; Zhao, C; Yan, Z M; Hua, H

2016-10-09

Objective: To explore a simple, rapid and efficient method for the diagnosis of oral candidiasis in clinical practice. Methods: Totally 124 consecutive patients with suspected oral candidiasis were enrolled from Department of Oral Medicine, Peking University School and Hospital of Stomatology, Beijing, China. Exfoliated cells of oral mucosa and saliva or concentrated oral rinse) obtained from all participants were tested by three rapid smear methods(10% KOH smear, gram-stained smear, Congo red stained smear). The diagnostic efficacy(sensitivity, specificity, Youden's index, likelihood ratio, consistency, predictive value and area under curve(AUC) of each of the above mentioned three methods was assessed by comparing the results with the gold standard(combination of clinical diagnosis, laboratory diagnosis and expert opinion). Results: Gram-stained smear of saliva(or concentrated oral rinse) demonstrated highest sensitivity(82.3%). Test of 10%KOH smear of exfoliated cells showed highest specificity(93.5%). Congo red stained smear of saliva(or concentrated oral rinse) displayed highest diagnostic efficacy(79.0% sensitivity, 80.6% specificity, 0.60 Youden's index, 4.08 positive likelihood ratio, 0.26 negative likelihood ratio, 80% consistency, 80.3% positive predictive value, 79.4% negative predictive value and 0.80 AUC). Conclusions: Test of Congo red stained smear of saliva(or concentrated oral rinse) could be used as a point-of-care tool for the rapid diagnosis of oral candidiasis in clinical practice. Trial registration: Chinese Clinical Trial Registry, ChiCTR-DDD-16008118.

Predicting analysis time in events-driven clinical trials using accumulating time-to-event surrogate information.

PubMed

Wang, Jianming; Ke, Chunlei; Yu, Zhinuan; Fu, Lei; Dornseif, Bruce

2016-05-01

For clinical trials with time-to-event endpoints, predicting the accrual of the events of interest with precision is critical in determining the timing of interim and final analyses. For example, overall survival (OS) is often chosen as the primary efficacy endpoint in oncology studies, with planned interim and final analyses at a pre-specified number of deaths. Often, correlated surrogate information, such as time-to-progression (TTP) and progression-free survival, are also collected as secondary efficacy endpoints. It would be appealing to borrow strength from the surrogate information to improve the precision of the analysis time prediction. Currently available methods in the literature for predicting analysis timings do not consider utilizing the surrogate information. In this article, using OS and TTP as an example, a general parametric model for OS and TTP is proposed, with the assumption that disease progression could change the course of the overall survival. Progression-free survival, related both to OS and TTP, will be handled separately, as it can be derived from OS and TTP. The authors seek to develop a prediction procedure using a Bayesian method and provide detailed implementation strategies under certain assumptions. Simulations are performed to evaluate the performance of the proposed method. An application to a real study is also provided. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Postdose 3 G1 serum neutralizing antibody as correlate of protection for pentavalent rotavirus vaccine.

PubMed

Liu, G Frank; Hille, Darcy; Kaplan, Susan S; Goveia, Michelle G

2017-10-03

Although clinical trials of the pentavalent rotavirus vaccine (RotaTeq®, RV5) have demonstrated efficacy against RV gastroenteritis (RGE) in low and high-income settings, a clear correlate of protection or a measure of immune response that could predict efficacy has yet to be identified. This is the first time that immunogenicity data with both serum neutralized antibody (SNA) titers and anti-RV IgA titers from several clinical efficacy trials were pooled to provide a unique context for evaluating the correlation between immunogenicity and RGE risk or efficacy of RV5. The correlation between immunogenicity and RGE risk is evaluated with data at the individual subject level. The analyses show that higher Postdose 3 (PD3) G1 SNA titers are associated with lower odds of contracting any RGE. The correlation between immunogenicity and efficacy is assessed using aggregated population level data, which shows higher efficacy associated with higher PD3 G1 SNA geometric mean titer (GMT) ratio (between RV5 and placebo) and PD3 serum anti-RV IgA GMT ratio. Among high-income countries, efficacy plateaus over the range of PD3 G1 SNA GMT ratios and PD3 serum anti-RV IgA GMT ratios. From both individual- and population-level analyses, PD3 G1 SNA titers correlated most closely with the RGE risk or efficacy for RV5.

Self-Efficacy and Health-Related Quality of Life Among Heart Failure Patients in Singapore: A Descriptive Correlational Study.

PubMed

Suresh, Rajasekaram; Wang, Wenru; Koh, Karen W L; Shorey, Shefaly; Lopez, Violeta

2018-07-01

Heart failure (HF) accounts for 30% of all global deaths and Asians are likely to suffer from HF 10 years earlier than their Western counterparts. Low self-efficacy and poor health-related quality of life (HRQoL) have been reported in patients with HF. A descriptive correlational design was adopted to investigate the associations between self-efficacy and HRQoL in 91 patients with HF in Singapore. Patients with HF demonstrated moderately good self-efficacy ( M = 3.05, SD = 0.61) and HRQoL ( M = 22.48, SD = 18.99). Significant differences were found between total self-efficacy scores and education levels ( p = .05), and between overall HRQoL and smoking status ( p < .05). Self-efficacy was not significantly correlated to HRQoL. Smoking status, HF classification, and self-efficacy in maintaining function predicted HRQoL. Health care professionals should assess each patient's demographics, smoking status, and clinical condition before delivering individualized education to enhance their self-efficacy and, in turn, overall HRQoL.

A behavior-analytic critique of Bandura's self-efficacy theory

PubMed Central

Biglan, Anthony

1987-01-01

A behavior-analytic critique of self-efficacy theory is presented. Self-efficacy theory asserts that efficacy expectations determine approach behavior and physiological arousal of phobics as well as numerous other clinically important behaviors. Evidence which is purported to support this assertion is reviewed. The evidence consists of correlations between self-efficacy ratings and other behaviors. Such response-response relationships do not unequivocally establish that one response causes another. A behavior-analytic alternative to self-efficacy theory explains these relationships in terms of environmental events. Correlations between self-efficacy rating behavior and other behavior may be due to the contingencies of reinforcement that establish a correspondence between such verbal predictions and the behavior to which they refer. Such a behavior-analytic account does not deny any of the empirical relationships presented in support of self-efficacy theory, but it points to environmental variables that could account for those relationships and that could be manipulated in the interest of developing more effective treatment procedures. PMID:22477956

The germline BIM deletion polymorphism is not associated with the treatment efficacy of sorafenib in patients with advanced hepatocellular carcinoma.

PubMed

Shao, Yu-Yun; Chang, Yung-Lin; Huang, Chung-Yi; Hsu, Chih-Hung; Cheng, Ann-Lii

2013-01-01

A germline BIM deletion polymorphism has been proposed to predict a poor treatment efficacy of certain kinase inhibitors. The current study aimed to explore whether the BIM deletion polymorphism predicts the treatment efficacy of sorafenib for advanced hepatocellular carcinoma (HCC). All patients who were enrolled in clinical trials to receive sorafenib-containing regimens as first-line therapy for advanced HCC and consented to providing peripheral blood samples were included. Polymerase chain reaction followed by gel electrophoresis was used to detect the germline BIM deletion polymorphism. A total of 89 patients were enrolled; 69 (77%) patients had chronic hepatitis B infection, and 18 (20%) had chronic hepatitis C infection. The heterozygous BIM deletion polymorphism was identified in 9 (10%) patients. Patients with and without the BIM deletion polymorphism had similar response rates (11 vs. 6%) and disease control rates (56 vs. 61%). The time to progression, progression-free survival, and overall survival were similar between patients with and without the BIM deletion polymorphism. After adjusting for basic clinicopathologic variables and treatment regimens, the BIM polymorphism still could not predict treatment outcomes. The BIM deletion polymorphism was not associated with the treatment efficacy of sorafenib for advanced HCC. © 2013 S. Karger AG, Basel.

The relationship between internalized stigma, negative symptoms and social functioning in schizophrenia: the mediating role of self-efficacy.

PubMed

Hill, Kimberley; Startup, Mike

2013-04-30

The broad aim of the present study was to gain a greater understanding of the processes that contribute to negative symptoms and social functioning in schizophrenia. More specifically, a theoretical model was proposed predicting that self-efficacy would mediate the relationship between internalized stigma and both negative symptoms and social functioning in schizophrenia. Initial analyses revealed that all variables were correlated. Specifically, internalized stigma was strongly correlated with negative symptoms, social functioning and self-efficacy. Furthermore, self-efficacy was strongly related to negative symptoms and moderately associated with social functioning. Further analyses however did not support the mediational role of self-efficacy. The theoretical and clinical implications of the findings, together with recommendations for future research, are outlined. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Drug screening in 3D in vitro tumor models: overcoming current pitfalls of efficacy read-outs.

PubMed

Santo, Vítor E; Rebelo, Sofia P; Estrada, Marta F; Alves, Paula M; Boghaert, Erwin; Brito, Catarina

2017-01-01

There is cumulating evidence that in vitro 3D tumor models with increased physiological relevance can improve the predictive value of pre-clinical research and ultimately contribute to achieve decisions earlier during the development of cancer-targeted therapies. Due to the role of tumor microenvironment in the response of tumor cells to therapeutics, the incorporation of different elements of the tumor niche on cell model design is expected to contribute to the establishment of more predictive in vitro tumor models. This review is focused on the several challenges and adjustments that the field of oncology research is facing to translate these advanced tumor cells models to drug discovery, taking advantage of the progress on culture technologies, imaging platforms, high throughput and automated systems. The choice of 3D cell model, the experimental design, choice of read-outs and interpretation of data obtained from 3D cell models are critical aspects when considering their implementation in drug discovery. In this review, we foresee some of these aspects and depict the potential directions of pre-clinical oncology drug discovery towards improved prediction of drug efficacy. Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Application of PBPK Modeling and Virtual Clinical Study Approaches to Predict the Outcomes of CYP2D6 Genotype-Guided Dosing of Tamoxifen.

PubMed

Nakamura, Toshimichi; Toshimoto, Kota; Lee, Wooin; Imamura, Chiyo K; Tanigawara, Yusuke; Sugiyama, Yuichi

2018-06-19

The Tamoxifen Response by CYP2D6 Genotype-based Treatment-1 (TARGET-1) study (n = 180) was conducted from 2012-2017 in Japan to determine the efficacy of tamoxifen dosing guided by cytochrome P450 2D6 (CYP2D6) genotypes. To predict its outcomes prior to completion, we constructed the comprehensive physiologically based pharmacokinetic (PBPK) models of tamoxifen and its metabolites and performed virtual TARGET-1 studies. Our analyses indicated that the expected probability to achieve the end point (demonstrating the superior efficacy of the escalated tamoxifen dose over the standard dose in patients carrying CYP2D6 variants) was 0.469 on average. As the population size of this virtual clinical study (VCS) increased, the expected probability was substantially increased (0.674 for n = 260). Our analyses also informed that the probability to achieve the end point in the TARGET-1 study was negatively impacted by a large variability in endoxifen levels. Our current efforts demonstrate the promising utility of the PBPK modeling and VCS approaches in prospectively designing effective clinical trials. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

A Comparison of the Pathogenesis of Marburg Virus Disease in Humans and Nonhuman Primates and Evaluation of the Suitability of These Animal Models for Predicting Clinical Efficacy under the 'Animal Rule'.

PubMed

Glaze, Elizabeth R; Roy, Michael J; Dalrymple, Lonnie W; Lanning, Lynda L

2015-06-01

Marburg virus outbreaks are sporadic, infrequent, brief, and relatively small in terms of numbers of subjects affected. In addition, outbreaks most likely will occur in remote regions where clinical trials are not feasible; therefore, definitive, well-controlled human efficacy studies to test the effectiveness of a drug or biologic product are not feasible. Healthy human volunteers cannot ethically be deliberately exposed to a lethal agent such as Marburg virus in order to test the efficacy of a therapy or preventive prior to licensure. When human efficacy studies are neither ethical nor feasible, the US Food and Drug Administration may grant marketing approval of a drug or biologic product under the 'Animal Rule,' through which demonstration of the efficacy of a product can be 'based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is reasonably likely to produce clinical benefit in humans.' This process requires that the pathogenic determinants of the disease in the animal model are similar to those that have been identified in humans. After reviewing primarily English-language, peer-reviewed journal articles, we here summarize the clinical manifestations of Marburg virus disease and the results of studies in NHP showing the characteristics and progression of the disease. We also include a detailed comparison of the characteristics of the human disease relative to those for NHP. This review reveals that the disease characteristics of Marburg virus disease are generally similar for humans and 3 NHP species: cynomolgus macaques (Macaca fascicularis), rhesus macaques (Macaca mulatta), and African green monkeys (Chlorocebus aethiops).

A Comparison of the Pathogenesis of Marburg Virus Disease in Humans and Nonhuman Primates and Evaluation of the Suitability of These Animal Models for Predicting Clinical Efficacy under the ‘Animal Rule’

PubMed Central

Glaze, Elizabeth R; Roy, Michael J; Dalrymple, Lonnie W; Lanning, Lynda L

2015-01-01

Marburg virus outbreaks are sporadic, infrequent, brief, and relatively small in terms of numbers of subjects affected. In addition, outbreaks most likely will occur in remote regions where clinical trials are not feasible; therefore, definitive, well-controlled human efficacy studies to test the effectiveness of a drug or biologic product are not feasible. Healthy human volunteers cannot ethically be deliberately exposed to a lethal agent such as Marburg virus in order to test the efficacy of a therapy or preventive prior to licensure. When human efficacy studies are neither ethical nor feasible, the US Food and Drug Administration may grant marketing approval of a drug or biologic product under the ‘Animal Rule,’ through which demonstration of the efficacy of a product can be ‘based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is reasonably likely to produce clinical benefit in humans.’ This process requires that the pathogenic determinants of the disease in the animal model are similar to those that have been identified in humans. After reviewing primarily English-language, peer-reviewed journal articles, we here summarize the clinical manifestations of Marburg virus disease and the results of studies in NHP showing the characteristics and progression of the disease. We also include a detailed comparison of the characteristics of the human disease relative to those for NHP. This review reveals that the disease characteristics of Marburg virus disease are generally similar for humans and 3 NHP species: cynomolgus macaques (Macaca fascicularis), rhesus macaques (Macaca mulatta), and African green monkeys (Chlorocebus aethiops). PMID:26141449

Mesenchymal stromal cell-based therapy: Regulatory and translational aspects in gastroenterology.

PubMed

Dothel, Giovanni; Raschi, Emanuel; Rimondini, Roberto; De Ponti, Fabrizio

2016-11-07

The past decade has witnessed an outstanding scientific production focused towards the possible clinical applications of mesenchymal stromal cells (MSCs) in autoimmune and chronic inflammatory diseases. This raised the need of novel standards to adequately address quality, efficacy and safety issues of this advanced therapy. The development of a streamlined regulation is currently hampered by the complexity of analyzing dynamic biological entities rather than chemicals. Although numerous pieces of evidence show efficacy in reducing intestinal inflammation, some inconsistencies between the mechanisms of action of rodent vs human MSCs suggest caution before assigning translational value to preclinical studies. Preliminary evidence from clinical trials showed efficacy of MSCs in the treatment of fistulizing Crohn's disease (CD), and preparations of heterologous MSCs for CD treatment are currently tested in ongoing clinical trials. However, safety issues, especially in long-term treatment, still require solid clinical data. In this regard, standardized guidelines for appropriate dosing and methods of infusion could enhance the likelihood to predict more accurately the number of responders and the duration of remission periods. In addition, elucidating MSC mechanisms of action could lead to novel and more reliable formulations such as those derived from the MSCs themselves ( e.g ., supernatants).

Oncology biomarkers: discovery, validation, and clinical use.

PubMed

Heckman-Stoddard, Brandy M

2012-05-01

To discuss the discovery, validation, and clinical use of multiple types of biomarkers. Medical literature and published guidelines. Formal validation of biomarkers should include both retrospective analyses of well-characterized samples as well as a prospective clinical trial in which the biomarker is tested for its ability to predict the presence of disease or the efficacy of a cancer therapy. Biomarker development is complicated, with very few biomarker discoveries leading to clinically useful tests. Nurses should understand how a biomarker was developed, including the sensitivity and specificity before applying new biomarkers in the clinical setting. Copyright © 2012. Published by Elsevier Inc.

The potential predictive value of circulating immune cell ratio and tumor marker in atezolizumab treated advanced non-small cell lung cancer patients.

PubMed

Zhuo, Minglei; Chen, Hanxiao; Zhang, Tianzhuo; Yang, Xue; Zhong, Jia; Wang, Yuyan; An, Tongtong; Wu, Meina; Wang, Ziping; Huang, Jing; Zhao, Jun

2018-05-04

The PD-L1 antibody atezolizumab has shown promising efficacy in patients with advanced non-small cell lung cancer. But the predictive marker of clinical benefit has not been identified. This study aimed to search for potential predictive factors in circulating blood of patients receiving atezolizumab. Ten patients diagnosed with advanced non-small cell lung cancer were enrolled in this open-label observing study. Circulating immune cells and plasma tumor markers were examined in peripheral blood from these patients before and after atezolizumab treatment respectively. Relation between changes in circulating factors and anti-tumor efficacy were analyzed. Blood routine test showed that atezolizumab therapy induced slightly elevation of white blood cells count generally. The lymphocyte ratio was increased slightly in disease controlled patients but decreased prominently in disease progressed patients in response to atezolizumab therapy. Flow cytometric analysis revealed changes in percentage of various immune cell types, including CD4+ T cell, CD8+ T cell, myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also altered after anti-PD-L1 therapy. In comparison with baseline, the disease progressed patients showed sharp increase in tumor marker levels, while those disease controlled patients were seen with decreased regulatory T cell and myeloid-derived suppressor cell ratios. The circulating immune cell ratios and plasma tumor marker levels were related with clinical efficacy of atezolizumab therapy. These factors could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.

Global measurement of coagulation in plasma from normal and haemophilia dogs using a novel modified thrombin generation test – Demonstrated in vitro and ex vivo

PubMed Central

Madsen, Daniel Elenius; Nichols, Timothy C.; Merricks, Elizabeth P.; Waters, Emily K.; Wiinberg, Bo

2017-01-01

Introduction Canine models of severe haemophilia resemble their human equivalents both regarding clinical bleeding phenotype and response to treatment. Therefore pre-clinical studies in haemophilia dogs have allowed researchers to make valuable translational predictions regarding the potency and efficacy of new anti-haemophilia drugs (AHDs) in humans. To refine in vivo experiments and reduce number of animals, such translational studies are ideally preceded by in vitro prediction of compound efficacy using a plasma based global coagulation method. One such widely used method is the thrombin generation test (TGT). Unfortunately, commercially available TGTs are incapable of distinguishing between normal and haemophilia canine plasma, and therefore in vitro prediction using TGT has so far not been possible in canine plasma material. Aim Establish a modified TGT capable of: 1) distinguishing between normal and haemophilia canine plasma, 2) monitoring correlation between canine plasma levels of coagulation factor VIII (FVIII) and IX (FIX) and thrombin generation, 3) assessing for agreement between compound activity and thrombin generation in ex vivo samples. Methods A modified TGT assay was established where coagulation was triggered using a commercially available activated partial thromboplastin time reagent. Results With the modified TGT a significant difference was observed in thrombin generation between normal and haemophilia canine plasma. A dose dependent thrombin generation was observed when assessing haemophilia A and B plasma spiked with dilution series of FVIII and FIX, respectively. Correlation between FVIII activity and thrombin generation was observed when analyzing samples from haemophilia A dogs dosed with canine FVIII. Limit of detection was 0.1% (v/v) FVIII or FIX. Conclusion A novel modified TGT suitable for monitoring and prediction of replacement therapy efficacy in plasma from haemophilia A and B dogs was established. PMID:28384182

Hemodynamic Measurements for the Selection of Patients With Renal Artery Stenosis: A Systematic Review.

PubMed

van Brussel, Peter M; van de Hoef, Tim P; de Winter, Robbert J; Vogt, Liffert; van den Born, Bert-Jan

2017-05-22

Interventions targeting renal artery stenoses have been shown to lower blood pressure and preserve renal function. In recent studies, the efficacy of catheter-based percutaneous transluminal renal angioplasty with stent placement has been called into question. In the identification of functional coronary lesions, hyperemic measurements have earned a place in daily practice for clinical decision making, allowing discrimination between solitary coronary lesions and diffuse microvascular disease. Next to differences in clinical characteristics, the selection of renal arteries suitable for intervention is currently on the basis of anatomic grading of the stenosis by angiography rather than functional assessment under hyperemia. It is conceivable that, like the coronary circulation, functional measurements may better predict therapeutic efficacy of percutaneous transluminal renal angioplasty with stent placement. In this systematic review, the authors evaluate the available clinical evidence on the optimal hyperemic agents to induce intrarenal hyperemia, their association with anatomic grading, and their predictive value for treatment effects. In addition, the potential value of combined pressure and flow measurements to discriminate macrovascular from microvascular disease is discussed. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Predictive value of EGFR overexpression and gene amplification on icotinib efficacy in patients with advanced esophageal squamous cell carcinoma

PubMed Central

Fan, Qingxia; Lu, Ping; Ma, Changwu; Liu, Wei; Liu, Ying; Li, Weiwei; Hu, Shaoxuan; Ling, Yun; Guo, Lei; Ying, Jianming; Huang, Jing

2016-01-01

This study aimed to search for a molecular marker for targeted epithelial growth factor receptor (EGFR) inhibitor Icotinib by analyzing protein expression and amplification of EGFR proto-oncogene in esophageal squamous cell carcinoma (ESCC) patients. Immunohistochemistry and fluorescence in situ hybridization (FISH) was used to assess EGFR expression and gene amplification status in 193 patients with ESCC. We also examined the association between EGFR overexpression and the efficacy of a novel EGFR TKI, icotinib, in 62 ESCC patients. Of the 193 patients, 95 (49.2%) patients showed EGFR overexpression (3+), and 47(24.4%) patients harbored EGFR FISH positivity. EGFR overexpression was significantly correlated with clinical stage and lymph node metastasis (p<0.05). In addition, EGFR overexpression was significantly correlated with EGFR FISH positivity (p<0.001). Among the 62 patients who received icotinib, the response rate was 17.6% for patients with high EGFR-expressing tumors, which was markedly higher than the rate (0%) for patients with low to moderate EGFR-expressing tumors (p=0.341). Furthermore, all cases responded to icotinib showed EGFR overexpression. In conclusion, our study suggests that EGFR overexpression might potentially be used in predicting the efficacy in patients treated with Icotinib. These data have implications for both clinical trial design and therapeutic strategies. PMID:27013591

Predictive value of EGFR overexpression and gene amplification on icotinib efficacy in patients with advanced esophageal squamous cell carcinoma.

PubMed

Wang, Xi; Niu, Haitao; Fan, Qingxia; Lu, Ping; Ma, Changwu; Liu, Wei; Liu, Ying; Li, Weiwei; Hu, Shaoxuan; Ling, Yun; Guo, Lei; Ying, Jianming; Huang, Jing

2016-04-26

This study aimed to search for a molecular marker for targeted epithelial growth factor receptor (EGFR) inhibitor Icotinib by analyzing protein expression and amplification of EGFR proto-oncogene in esophageal squamous cell carcinoma (ESCC) patients.Immunohistochemistry and fluorescence in situ hybridization (FISH) was used to assess EGFR expression and gene amplification status in 193 patients with ESCC. We also examined the association between EGFR overexpression and the efficacy of a novel EGFR TKI, icotinib, in 62 ESCC patients.Of the 193 patients, 95 (49.2%) patients showed EGFR overexpression (3+), and 47(24.4%) patients harbored EGFR FISH positivity. EGFR overexpression was significantly correlated with clinical stage and lymph node metastasis (p<0.05). In addition, EGFR overexpression was significantly correlated with EGFR FISH positivity (p<0.001). Among the 62 patients who received icotinib, the response rate was 17.6% for patients with high EGFR-expressing tumors, which was markedly higher than the rate (0%) for patients with low to moderate EGFR-expressing tumors (p=0.341). Furthermore, all cases responded to icotinib showed EGFR overexpression.In conclusion, our study suggests that EGFR overexpression might potentially be used in predicting the efficacy in patients treated with Icotinib. These data have implications for both clinical trial design and therapeutic strategies.

Pharmacokinetics and Drug Interactions Determine Optimum Combination Strategies in Computational Models of Cancer Evolution.

PubMed

Chakrabarti, Shaon; Michor, Franziska

2017-07-15

The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression, a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multiscale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting nonintuitive strategies for combination therapies. We applied our approach to an ongoing phase Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the MTD are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction, and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials. Cancer Res; 77(14); 3908-21. ©2017 AACR . ©2017 American Association for Cancer Research.

The relationship between self-efficacy for behaviors that promote healthy weight and clinical indicators of adiposity in a sample of early adolescents.

PubMed

Steele, Michael M; Daratha, Kenn B; Bindler, Ruth C; Power, Thomas G

2011-12-01

Examine the relationship between self-efficacy and various measures of adiposity in a sample of teens. A total of 132 teens were selected from schools participating in an existing research study titled Teen Eating and Activity Mentoring in Schools (TEAMS). Teens completed demographic questionnaires and healthy eating-specific and physical activity-specific measures of self-efficacy. Waist circumference (WC), triceps skinfold thickness (TSF), and body mass index (BMI) percentile scores were also obtained. Regression analyses indicated that healthy eating-specific and physical activity-specific measures of self-efficacy predicted WC and TSF. ANOVA revealed significant differences in healthy eating-specific self-efficacy levels between students of recommended weight and overweight/obese status. Supplemental analyses showed significant negative relationships between a student's ideal BMI ratio and self-efficacy. Because self-efficacy may be amenable to change, these findings could inform future efforts aimed at increasing behaviors that promote healthy weight status among early adolescents.

Quantification of HTLV-1 reverse transcriptase activity in ATL patients treated with zidovudine and interferon-α.

PubMed

Macchi, Beatrice; Balestrieri, Emanuela; Frezza, Caterina; Grelli, Sandro; Valletta, Elena; Marçais, Ambroise; Marino-Merlo, Francesca; Turpin, Jocelyn; Bangham, Charles R; Hermine, Olivier; Mastino, Antonio; Bazarbachi, Ali

2017-05-09

The therapeutic efficacy of the AZT and IFN combination in ATL presumably reflects the inhibition of RT-related functions.HTLV-1-RT activity from short-term cultured PBMCs may represent a predictive correlate of clinical response to AZT/IFN in ATL patients.

Progress and prospects for blood-stage malaria vaccines.

PubMed

Miura, Kazutoyo

2016-06-01

There have been significant decreases in malaria mortality and morbidity in the last 10-15 years, and the most advanced pre-erythrocytic malaria vaccine, RTS,S, received a positive opinion from European regulators in July 2015. However, no blood-stage vaccine has reached a phase III trial. The first part of this review summarizes the pros and cons of various assays and models that have been and will be used to predict the efficacy of blood-stage vaccines. In the second part, blood-stage vaccine candidates that showed some efficacy in human clinical trials or controlled human malaria infection models are discussed. Then, candidates under clinical investigation are described in the third part, and other novel candidates and strategies are reviewed in the last part.

Biomarkers for Allergen Immunotherapy: A "Panoromic" View.

PubMed

Moingeon, Philippe

2016-02-01

Biomarkers (BMKs) are biological parameters that can be measured to predict or monitor disease severity or treatment efficacy. The induction of regulatory dendritic cells (DCs) concomitantly with a downregulation of proallergic DC2s (ie, DCs supporting the differentiation of T-helper lymphocyte type 2 cells) in the blood of patients allergic to grass pollen has been correlated with the early onset of allergen immunotherapy efficacy. The combined use of omics technologies to compare biological samples from clinical responders and nonresponders is being implemented in the context of nonhypothesis-driven approaches. Such comprehensive "panoromic" strategies help identify completely novel candidate BMKs, to be subsequently validated as companion diagnostics in large-scale clinical trials. Copyright © 2016 Elsevier Inc. All rights reserved.

The Health Action Process Approach as a motivational model for physical activity self-management for people with multiple sclerosis: a path analysis.

PubMed

Chiu, Chung-Yi; Lynch, Ruth T; Chan, Fong; Berven, Norman L

2011-08-01

To evaluate the Health Action Process Approach (HAPA) as a motivational model for physical activity self-management for people with multiple sclerosis (MS). Quantitative descriptive research design using path analysis. One hundred ninety-five individuals with MS were recruited from the National Multiple Sclerosis Society and a neurology clinic at a university teaching hospital in the Midwest. Outcome was measured by the Physical Activity Stages of Change Instrument, along with measures for nine predictors (severity, action self-efficacy, outcome expectancy, risk perception, perceived barriers, intention, maintenance self-efficacy, action and coping planning, and recovery self-efficacy). The respecified HAPA physical activity model fit the data relatively well (goodness-of-fit index = .92, normed fit index = .91, and comparative fit index = .93) explaining 38% of the variance in physical activity. Recovery self-efficacy, action and coping planning, and perceived barriers directly contributed to the prediction of physical activity. Outcome expectancy significantly influenced intention and the relationship between intention and physical activity is mediated by action and coping planning. Action self-efficacy, maintenance self-efficacy, and recovery self-efficacy directly or indirectly affected physical activity. Severity of MS and action self-efficacy had an inverse relationship with perceived barriers and perceived barriers influenced physical activity. Empirical support was found for the proposed HAPA model of physical activity for people with MS. The HAPA model appears to provide useful information for clinical rehabilitation and health promotion interventions.

Efficacy of the Clinical Agent VT-1161 against Fluconazole-Sensitive and -Resistant Candida albicans in a Murine Model of Vaginal Candidiasis

PubMed Central

Hoekstra, W. J.; Schotzinger, R. J.; Sobel, J. D.; Lilly, E. A.; Fidel, P. L.

2015-01-01

Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) remain major health problems for women. VT-1161, a novel fungal CYP51 inhibitor which has potent antifungal activity against fluconazole-sensitive Candida albicans, retained its in vitro potency (MIC50 of ≤0.015 and MIC90 of 0.12 μg/ml) against 10 clinical isolates from VVC or RVVC patients resistant to fluconazole (MIC50 of 8 and MIC90 of 64 μg/ml). VT-1161 pharmacokinetics in mice displayed a high volume of distribution (1.4 liters/kg), high oral absorption (73%), and a long half-life (>48 h) and showed rapid penetration into vaginal tissue. In a murine model of vaginal candidiasis using fluconazole-sensitive yeast, oral doses as low as 4 mg/kg VT-1161 significantly reduced the fungal burden 1 and 4 days posttreatment (P < 0.0001). Similar VT-1161 efficacy was measured when an isolate highly resistant to fluconazole (MIC of 64 μg/ml) but fully sensitive in vitro to VT-1161 was used. When an isolate partially sensitive to VT-1161 (MIC of 0.12 μg/ml) and moderately resistant to fluconazole (MIC of 8 μg/ml) was used, VT-1161 remained efficacious, whereas fluconazole was efficacious on day 1 but did not sustain efficacy 4 days posttreatment. Both agents were inactive in treating an infection with an isolate that demonstrated weaker potency (MICs of 2 and 64 μg/ml for VT-1161 and fluconazole, respectively). Finally, the plasma concentrations of free VT-1161 were predictive of efficacy when in excess of the in vitro MIC values. These data support the clinical development of VT-1161 as a potentially more efficacious treatment for VVC and RVVC. PMID:26124165

Combat Wound Initiative program.

PubMed

Stojadinovic, Alexander; Elster, Eric; Potter, Benjamin K; Davis, Thomas A; Tadaki, Doug K; Brown, Trevor S; Ahlers, Stephen; Attinger, Christopher E; Andersen, Romney C; Burris, David; Centeno, Jose; Champion, Hunter; Crumbley, David R; Denobile, John; Duga, Michael; Dunne, James R; Eberhardt, John; Ennis, William J; Forsberg, Jonathan A; Hawksworth, Jason; Helling, Thomas S; Lazarus, Gerald S; Milner, Stephen M; Mullick, Florabel G; Owner, Christopher R; Pasquina, Paul F; Patel, Chirag R; Peoples, George E; Nissan, Aviram; Ring, Michael; Sandberg, Glenn D; Schaden, Wolfgang; Schultz, Gregory S; Scofield, Tom; Shawen, Scott B; Sheppard, Forest R; Stannard, James P; Weina, Peter J; Zenilman, Jonathan M

2010-07-01

The Combat Wound Initiative (CWI) program is a collaborative, multidisciplinary, and interservice public-private partnership that provides personalized, state-of-the-art, and complex wound care via targeted clinical and translational research. The CWI uses a bench-to-bedside approach to translational research, including the rapid development of a human extracorporeal shock wave therapy (ESWT) study in complex wounds after establishing the potential efficacy, biologic mechanisms, and safety of this treatment modality in a murine model. Additional clinical trials include the prospective use of clinical data, serum and wound biomarkers, and wound gene expression profiles to predict wound healing/failure and additional clinical patient outcomes following combat-related trauma. These clinical research data are analyzed using machine-based learning algorithms to develop predictive treatment models to guide clinical decision-making. Future CWI directions include additional clinical trials and study centers and the refinement and deployment of our genetically driven, personalized medicine initiative to provide patient-specific care across multiple medical disciplines, with an emphasis on combat casualty care.

The Influence of Big (Clinical) Data and Genomics on Precision Medicine and Drug Development.

PubMed

Denny, Joshua C; Van Driest, Sara L; Wei, Wei-Qi; Roden, Dan M

2018-03-01

Drug development continues to be costly and slow, with medications failing due to lack of efficacy or presence of toxicity. The promise of pharmacogenomic discovery includes tailoring therapeutics based on an individual's genetic makeup, rational drug development, and repurposing medications. Rapid growth of large research cohorts, linked to electronic health record (EHR) data, fuels discovery of new genetic variants predicting drug action, supports Mendelian randomization experiments to show drug efficacy, and suggests new indications for existing medications. New biomedical informatics and machine-learning approaches advance the ability to interpret clinical information, enabling identification of complex phenotypes and subpopulations of patients. We review the recent history of use of "big data" from EHR-based cohorts and biobanks supporting these activities. Future studies using EHR data, other information sources, and new methods will promote a foundation for discovery to more rapidly advance precision medicine. © 2017 American Society for Clinical Pharmacology and Therapeutics.

The mediating role of spirituality on professional values and self-efficacy: a study of senior nursing students.

PubMed

Jun, Won Hee; Lee, Gyungjoo

2016-12-01

The aim of this study was to identify the significance of spirituality in enhancing self-efficacy related to professional values in senior nursing students. Self-efficacy can predict job satisfaction and performance as professional nurses in clinical settings. Senior nursing students should have the level of self-efficacy that enables them to perform professional roles based on professional values, because they will enter clinical settings immediately after graduation. Spirituality may help senior nursing students during the transition to professional life to reflect on their skills, knowledge and situations to enhance self-efficacy based on professional values. An exploratory, cross-sectional design was used in this study. A total of 194 senior nursing students in South Korea were recruited in 2014. They completed self-reported questionnaires consisting of demographic questions, Spiritual Assessment Scale, Self-Efficacy Scale and Nursing Professional Values inventory. A Sobel test was done to determine the mediating effect of spirituality on the relationship between nursing professional values and self-efficacy. The findings showed a positive correlation between professional values, spirituality and self-efficacy in nursing students. According to the Sobel test, spirituality had a mediating effect on the relationship between professional values and self-efficacy in senior nursing students. Spirituality can be a foundation that provides senior nursing students with higher self-efficacy so that they are able to perform their professional roles based on their professional values. The findings can guide nursing educators to include spiritual development of nursing students to enhance the self-efficacy of senior nursing students, the future of the nursing profession. © 2016 John Wiley & Sons Ltd.

The roles of self-efficacy and motivation in the prediction of short- and long-term adherence to exercise among patients with coronary heart disease.

PubMed

Slovinec D'Angelo, Monika E; Pelletier, Luc G; Reid, Robert D; Huta, Veronika

2014-11-01

Poor adherence to regular exercise is a documented challenge among people with heart disease. Identifying key determinants of exercise adherence and distinguishing between the processes driving short- and long-term adherence to regular exercise is a valuable endeavor. The purpose of the present study was to test a model of exercise behavior change, which incorporates motivational orientations and self-efficacy for exercise behavior, in the prediction of short- and long-term exercise adherence. Male and female patients (N = 801) hospitalized for coronary heart disease were recruited from 3 tertiary care cardiac centers and followed for a period of 1 year after hospital discharge. A prospective, longitudinal design was used to examine the roles of motivation and self-efficacy (measured at recruitment and at 2 and 6 months after discharge) in the prediction of exercise behavior at 6 and 12 months. Baseline measures of exercise and clinical and demographic covariates were included in the analyses. Structural equation modeling showed that both autonomous motivation and self-efficacy were important determinants of short-term (6-month) exercise behavior regulation, but that only autonomous motivation remained a significant predictor of long-term (12-month) exercise behavior. Self-efficacy partially mediated the relationship between motivation for exercise and 6-month exercise behavior. This research confirmed the roles of autonomous motivation and self-efficacy in the health behavior change process and emphasized the key function of autonomous motivation in exercise maintenance. Theoretical and cardiac rehabilitation program applications of this research are discussed. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Role of illness perception and self-efficacy in lifestyle modification among non-alcoholic fatty liver disease patients.

PubMed

Zelber-Sagi, Shira; Bord, Shiran; Dror-Lavi, Gali; Smith, Matthew Lee; Towne, Samuel D; Buch, Assaf; Webb, Muriel; Yeshua, Hanny; Nimer, Assy; Shibolet, Oren

2017-03-14

To describe the relationships between non-alcoholic fatty-liver disease (NAFLD) patient's disease consequences and treatment perceptions, self-efficacy, and healthy lifestyle maintenance. A cross-sectional study among 146 ultrasound diagnosed NAFLD patients who visited the fatty liver clinic at the Tel-Aviv Medical Center. Eighty-seven of these individuals, participated in a clinical trial of physical activity and underwent fasting blood tests, analyzed at the same lab. Exclusion criteria included positivity for serum HBsAg or anti-HCV antibodies; fatty liver suspected to be secondary to hepatotoxic drugs; excessive alcohol consumption (≥ 30 g/d in men or ≥ 20 g/d in women) and positive markers of genetic or immune-mediated liver diseases. Patients were asked to complete a self-report structured questionnaire, assembled by the Israeli Center for Disease Control. Nutrition habits were measured using six yes/no questions (0 = no, 1 = yes) adopted from the national survey questionnaire. Participants in the clinical trial completed a detailed semi-quantitative food frequency questionnaire (FFQ) reporting their habitual nutritional intake during the past year. Self-efficacy was assessed by the Self-Efficacy Scale questionnaire, emotional representation, degree of illness understanding, timeline perception, treatment perception and symptoms were measured by the Brief Illness Perception questionnaire. Illness consequences were measured by the Personal Models of Diabetes Interview questionnaire. A path analysis was performed to describe the interrelationships between the patients' illness perceptions, and assess the extent to which the data fit a prediction of nutritional habits. The study sample included 54.1% men, with a mean age of 47.76 ± 11.68 years (range: 20-60) and mean body mass index of 31.56 ± 4.6. The average perceived nutrition habits score was 4.73 ± 1.45 on a scale between 0-6, where 6 represents the healthiest eating habits. Most of the study participants (57.2%) did not feel they fully understood what NAFLD is. Better nutritional habits were positively predicted by the degree of illness understanding (β = 0.26; P = 0.002) and self-efficacy (β = 0.25; P = 0.003). Perceptions of more severe illness consequences were related with higher emotional representation (β = 0.55; P < 0.001), which was related with lower self-efficacy (β = -0.17; P = 0.034). The perception of treatment effectiveness was positively related with self-efficacy (β = 0.32; P < 0.001). In accordance with the correlation between self-efficacy and the perceived nutrition habits score, self-efficacy was also correlated with nutrient intake evaluated by the FFQ; negatively with saturated fat (percent of saturated fat calories from total calories) (r = -0.28, P = 0.010) and positively with fiber (r = 0.22, P = 0.047) and vitamin C intake (r = 0.34, P = 0.002). In a sub analysis of the clinical trial participants, objectively measured compliance to physical activity regimen was positively correlated with the self-efficacy level (r = 0.34, P = 0.046). Self-efficacy and illness understanding are major determinants of lifestyle-modification among NAFLD patients. This information can assist clinicians in improving compliance with lifestyle changes among these patients.

Neonatal Pulmonary MRI of Bronchopulmonary Dysplasia Predicts Short-term Clinical Outcomes.

PubMed

Higano, Nara S; Spielberg, David R; Fleck, Robert J; Schapiro, Andrew H; Walkup, Laura L; Hahn, Andrew D; Tkach, Jean A; Kingma, Paul S; Merhar, Stephanie L; Fain, Sean B; Woods, Jason C

2018-05-23

Bronchopulmonary dysplasia (BPD) is a serious neonatal pulmonary condition associated with premature birth, but the underlying parenchymal disease and trajectory are poorly characterized. The current NICHD/NHLBI definition of BPD severity is based on degree of prematurity and extent of oxygen requirement. However, no clear link exists between initial diagnosis and clinical outcomes. We hypothesized that magnetic resonance imaging (MRI) of structural parenchymal abnormalities will correlate with NICHD-defined BPD disease severity and predict short-term respiratory outcomes. Forty-two neonates (20 severe BPD, 6 moderate, 7 mild, 9 non-BPD controls; 40±3 weeks post-menstrual age) underwent quiet-breathing structural pulmonary MRI (ultrashort echo-time and gradient echo) in a NICU-sited, neonatal-sized 1.5T scanner, without sedation or respiratory support unless already clinically prescribed. Disease severity was scored independently by two radiologists. Mean scores were compared to clinical severity and short-term respiratory outcomes. Outcomes were predicted using univariate and multivariable models including clinical data and scores. MRI scores significantly correlated with severities and predicted respiratory support at NICU discharge (P<0.0001). In multivariable models, MRI scores were by far the strongest predictor of respiratory support duration over clinical data, including birth weight and gestational age. Notably, NICHD severity level was not predictive of discharge support. Quiet-breathing neonatal pulmonary MRI can independently assess structural abnormalities of BPD, describe disease severity, and predict short-term outcomes more accurately than any individual standard clinical measure. Importantly, this non-ionizing technique can be implemented to phenotype disease and has potential to serially assess efficacy of individualized therapies.

Integrated Social- and Neurocognitive Model of Physical Activity Behavior in Older Adults with Metabolic Disease.

PubMed

Olson, Erin A; Mullen, Sean P; Raine, Lauren B; Kramer, Arthur F; Hillman, Charles H; McAuley, Edward

2017-04-01

Despite the proven benefits of physical activity to treat and prevent metabolic diseases, such as diabetes (T2D) and metabolic syndrome (MetS), most individuals with metabolic disease do not meet physical activity (PA) recommendations. PA is a complex behavior requiring substantial motivational and cognitive resources. The purpose of this study was to examine social cognitive and neuropsychological determinants of PA behavior in older adults with T2D and MetS. The hypothesized model theorized that baseline self-regulatory strategy use and cognitive function would indirectly influence PA through self-efficacy. Older adults with T2D or MetS (M age  = 61.8 ± 6.4) completed either an 8-week physical activity intervention (n = 58) or an online metabolic health education course (n = 58) and a follow-up at 6 months. Measures included cognitive function, self-efficacy, self-regulatory strategy use, and PA. The data partially supported the hypothesized model (χ 2  = 158.535(131), p > .05, comparative fit index = .96, root mean square error of approximation = .04, standardized root mean square residual = .06) with self-regulatory strategy use directly predicting self-efficacy (β = .33, p < .05), which in turn predicted PA (β = .21, p < .05). Performance on various cognitive function tasks predicted PA directly and indirectly via self-efficacy. Baseline physical activity (β = .62, p < .01) and intervention group assignment via self-efficacy (β = -.20, p < .05) predicted follow-up PA. The model accounted for 54.4 % of the variance in PA at month 6. Findings partially support the hypothesized model and indicate that select cognitive functions (i.e., working memory, inhibition, attention, and task-switching) predicted PA behavior 6 months later. Future research warrants the development of interventions targeting cognitive function, self-regulatory skill development, and self-efficacy enhancement. The trial was registered with the clinical trial number NCT01790724.

Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements

PubMed Central

Sprouse, Alyssa A.

2016-01-01

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug–botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John’s wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug–botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug–botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism. PMID:26438626

Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements.

PubMed

Sprouse, Alyssa A; van Breemen, Richard B

2016-02-01

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John's wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug-botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug-botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Predicting and detecting adverse drug reactions in old age: challenges and opportunities.

PubMed

Mangoni, Arduino A

2012-05-01

Increased, often inappropriate, drug exposure, pharmacokinetic and pharmacodynamic changes, reduced homeostatic reserve and frailty increase the risk of adverse drug reactions (ADRs) in the older population, thereby imposing a significant public health burden. Predicting and diagnosing ADRs in old age presents significant challenges for the clinician, even when specific risk scoring systems are available. The picture is further compounded by the potential adverse impact of several drugs on more 'global' health indicators, for example, physical function and independence, and the fragmentation of care (e.g., increased number of treating doctors and care transitions) experienced by older patients during their clinical journey. The current knowledge of drug safety in old age is also curtailed by the lack of efficacy and safety data from pre-marketing studies. Moreover, little consideration is given to individual patients' experiences and reporting of specific ADRs, particularly in the presence of cognitive impairment. Pending additional data on these issues, the close review and monitoring of individual patients' drug prescribing, clinical status and biochemical parameters remain essential to predict and detect ADRs in old age. Recently developed strategies, for example, medication reconciliation and trigger tool methodology, have the potential for ADRs risk mitigation in this population. However, more information is required on their efficacy and applicability in different healthcare settings.

Social anxiety, alcohol expectancies, and self-efficacy as predictors of heavy drinking in college students.

PubMed

Gilles, Donna M; Turk, Cynthia L; Fresco, David M

2006-03-01

Burke and Stephens (1999) [Burke, R.S., Stephens, R.S. Social anxiety and drinking in college students: A social cognitive theory analysis. Clinical Psychology Review, 19, (1999) 513-530.] proposed a social cognitive theory of heavy drinking in college students. According to this theory, alcohol expectancies for social facilitation and self-efficacy for refusing heavy drinking in anxiety-producing social situations moderate the relationship between social anxiety and drinking. In the current study, a significant three-way interaction was observed among social anxiety, expectancies, and self-efficacy when amount and frequency of drinking was the dependent variable. As predicted by the model, socially anxious college students with low self-efficacy for avoiding heavy drinking in social situations and high positive expectancies for social facilitation reported more alcohol consumption than other socially anxious individuals.

Predictive probability methods for interim monitoring in clinical trials with longitudinal outcomes.

PubMed

Zhou, Ming; Tang, Qi; Lang, Lixin; Xing, Jun; Tatsuoka, Kay

2018-04-17

In clinical research and development, interim monitoring is critical for better decision-making and minimizing the risk of exposing patients to possible ineffective therapies. For interim futility or efficacy monitoring, predictive probability methods are widely adopted in practice. Those methods have been well studied for univariate variables. However, for longitudinal studies, predictive probability methods using univariate information from only completers may not be most efficient, and data from on-going subjects can be utilized to improve efficiency. On the other hand, leveraging information from on-going subjects could allow an interim analysis to be potentially conducted once a sufficient number of subjects reach an earlier time point. For longitudinal outcomes, we derive closed-form formulas for predictive probabilities, including Bayesian predictive probability, predictive power, and conditional power and also give closed-form solutions for predictive probability of success in a future trial and the predictive probability of success of the best dose. When predictive probabilities are used for interim monitoring, we study their distributions and discuss their analytical cutoff values or stopping boundaries that have desired operating characteristics. We show that predictive probabilities utilizing all longitudinal information are more efficient for interim monitoring than that using information from completers only. To illustrate their practical application for longitudinal data, we analyze 2 real data examples from clinical trials. Copyright © 2018 John Wiley & Sons, Ltd.

Progress and prospects for blood-stage malaria vaccines

PubMed Central

Miura, Kazutoyo

2016-01-01

ABSTRACT There have been significant decreases in malaria mortality and morbidity in the last 10-15 years, and the most advanced pre-erythrocytic malaria vaccine, RTS,S, received a positive opinion from European regulators in July 2015. However, no blood-stage vaccine has reached a phase III trial. The first part of this review summarizes the pros and cons of various assays and models that have been and will be used to predict the efficacy of blood-stage vaccines. In the second part, blood-stage vaccine candidates that showed some efficacy in human clinical trials or controlled human malaria infection models are discussed. Then, candidates under clinical investigation are described in the third part, and other novel candidates and strategies are reviewed in the last part. PMID:26760062

The role of objective personality inventories in suicide risk assessment: an evaluation and proposal.

PubMed

Johnson, W B; Lall, R; Bongar, B; Nordlund, M D

1999-01-01

Objective personality assessment instruments offer a comparatively underutilized source of clinical data in attempts to evaluate and predict risk for suicide. In contrast to focal suicide risk measures, global personality inventories may be useful in identification of long-standing styles that predispose persons to eventual suicidal behavior. This article reviews the empirical literature regarding the efficacy of established personality inventories in predicting suicidality. The authors offer several recommendations for future research with these measures and conclude that such objective personality instruments offer only marginal utility as sources of clinical information in comprehensive suicide risk evaluations. Personality inventories may offer greatest utility in long-term assessment of suicide risk.

Identifying treatment responders and predictors of improvement after cognitive-behavioral therapy for juvenile fibromyalgia.

PubMed

Sil, Soumitri; Arnold, Lesley M; Lynch-Jordan, Anne; Ting, Tracy V; Peugh, James; Cunningham, Natoshia; Powers, Scott W; Lovell, Daniel J; Hashkes, Philip J; Passo, Murray; Schikler, Kenneth N; Kashikar-Zuck, Susmita

2014-07-01

The primary objective of this study was to estimate a clinically significant and quantifiable change in functional disability to identify treatment responders in a clinical trial of cognitive-behavioral therapy (CBT) for youth with juvenile fibromyalgia (JFM). The second objective was to examine whether baseline functional disability (Functional Disability Inventory), pain intensity, depressive symptoms (Children's Depression Inventory), coping self-efficacy (Pain Coping Questionnaire), and parental pain history predicted treatment response in disability at 6-month follow-up. Participants were 100 adolescents (11-18 years of age) with JFM enrolled in a recently published clinical trial comparing CBT to a fibromyalgia education (FE) intervention. Patients were identified as achieving a clinically significant change in disability (i.e., were considered treatment responders) if they achieved both a reliable magnitude of change (estimated as a > or = 7.8-point reduction on the FDI) using the Reliable Change Index, and a reduction in FDI disability grade based on established clinical reference points. Using this rigorous standard, 40% of patients who received CBT (20 of 50) were identified as treatment responders, compared to 28% who received FE (14 of 50). For CBT, patients with greater initial disability and higher coping efficacy were significantly more likely to achieve a clinically significant improvement in functioning. Pain intensity, depressive symptoms, and parent pain history did not significantly predict treatment response. Estimating clinically significant change for outcome measures in behavioral trials sets a high bar but is a potentially valuable approach to improve the quality of clinical trials, to enhance interpretability of treatment effects, and to challenge researchers to develop more potent and tailored interventions. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Perspectives on treatment options for mesial temporal lobe epilepsy with hippocampal sclerosis.

PubMed

Palleria, Caterina; Coppola, Antonietta; Citraro, Rita; Del Gaudio, Luigi; Striano, Salvatore; De Sarro, Giovambattista; Russo, Emilio

2015-01-01

Mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) is a syndrome that is often refractory to drug treatment. The effects on specific syndromes are not currently available from the pre-marketing clinical development of new AEDs; this does not allow the prediction of whether new drugs will be more effective in the treatment of some patients. We have reviewed all the existing literature relevant to the understanding of a potential effectiveness in MTLE-HS patients for the latest AEDs, namely brivaracetam, eslicarbazepine, lacosamide, perampanel and retigabine also including the most relevant clinical data and a brief description of their pharmacological profile. Records were identified using predefined search criteria using electronic databases (e.g., PubMed, Cochrane Library Database of Systematic Reviews). Primary peer-reviewed articles published up to the 15 June 2015 were included. All the drugs considered have the potential to be effective in the treatment of MTLE-HS; in fact, they possess proven efficacy in animal models; currently considered valuable tools for predicting drug efficacy in TLE. Furthermore, for some of these (e.g., lacosamide and eslicarbazepine) data are already available from post-marketing studies while brivaracetam acting on SV2A like levetiracetam might have the same potential effectiveness with the possibility to be more efficacious considering its ability to inhibit voltage gated sodium channels; finally, perampanel and retigabine are very effective drugs in animal models of TLE.

Recent developments in the behavioural and pharmacological enhancement of extinction of drug seeking.

PubMed

Chesworth, Rose; Corbit, Laura H

2017-01-01

One of the principal barriers to overcoming addiction is the propensity to relapse, even after months or years of abstinence. Relapse can be precipitated by cues and contexts associated with drug use; thus, decreasing the conditioned properties of these cues and contexts may assist in preventing relapse. The predictive power of drug cues and contexts can be reduced by repeatedly presenting them in the absence of the drug reinforcer, a process known as extinction. The potential of extinction to limit relapse has generated considerable interest and research over the past few decades. While pre-clinical animal models suggest extinction learning assists relapse prevention, treatment efficacy is often lacking when extinction learning principles are translated into clinical trials. Conklin and Tiffany (Addiction, 2002) suggest the lack of efficacy in clinical practice may be due to limited translation of procedures demonstrated through animal research and propose several methodological improvements to enhance extinction learning for drug addiction. This review will examine recent advances in the behavioural and pharmacological manipulation of extinction learning, based on research from pre-clinical models. In addition, the translation of pre-clinical findings-both those suggested by Conklin and Tiffany () and novel demonstrations from the past 13 years-into clinical trials and the efficacy of these methods in reducing craving and relapse, where available, will be discussed. Finally, we highlight areas where promising pre-clinical models have not yet been integrated into current clinical practice but, if applied, could improve upon existing behavioural and pharmacological methods. © 2015 Society for the Study of Addiction.

Anthrax vaccine-induced antibodies provide cross-species prediction of survival to aerosol challenge.

PubMed

Fay, Michael P; Follmann, Dean A; Lynn, Freyja; Schiffer, Jarad M; Stark, Gregory V; Kohberger, Robert; Quinn, Conrad P; Nuzum, Edwin O

2012-09-12

Because clinical trials to assess the efficacy of vaccines against anthrax are not ethical or feasible, licensure for new anthrax vaccines will likely involve the Food and Drug Administration's "Animal Rule," a set of regulations that allow approval of products based on efficacy data only in animals combined with immunogenicity and safety data in animals and humans. U.S. government-sponsored animal studies have shown anthrax vaccine efficacy in a variety of settings. We examined data from 21 of those studies to determine whether an immunological bridge based on lethal toxin neutralization activity assay (TNA) can predict survival against an inhalation anthrax challenge within and across species and genera. The 21 studies were classified into 11 different settings, each of which had the same animal species, vaccine type and formulation, vaccination schedule, time of TNA measurement, and challenge time. Logistic regression models determined the contribution of vaccine dilution dose and TNA on prediction of survival. For most settings, logistic models using only TNA explained more than 75% of the survival effect of the models with dose additionally included. Cross-species survival predictions using TNA were compared to the actual survival and shown to have good agreement (Cohen's κ ranged from 0.55 to 0.78). In one study design, cynomolgus macaque data predicted 78.6% survival in rhesus macaques (actual survival, 83.0%) and 72.6% in rabbits (actual survival, 64.6%). These data add support for the use of TNA as an immunological bridge between species to extrapolate data in animals to predict anthrax vaccine effectiveness in humans.

Efficacy of N-Acetylcysteine in Idiopathic Pulmonary Fibrosis

PubMed Central

Sun, Tong; Liu, Jing; Zhao, De Wei

2016-01-01

Abstract There are a number of conflicting reports describing the clinical outcomes of using N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis. We have, therefore, performed a meta-analysis to evaluate the efficacy of N-acetylcysteine, compared with control, for the treatment of idiopathic pulmonary fibrosis. Original controlled clinical trials evaluating the efficacy of N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis were included in the analysis. Searches for relevant articles were carried out in July 2014 by 2 independent researchers using PubMed, Embase, Cochrane Central, and Google Scholar. Change in forced vital capacity, change in percentage of predicted vital capacity, change in percentage of predicted carbon monoxide diffusing capacity, changes in 6 minutes walking test distance, rate of adverse events, and rate of death were expressed as outcomes using RevMan 5.0.1. Five trials, with a total of 564 patients, were included in this meta-analysis. The meta-analysis showed that the control group had significant decreases in percentage of predicted vital capacity (standardized mean difference [SMD] = 0.37; 95% confidence interval [CI]: 0.13 to −0.62; P = 0.003) and 6 minutes walking test distance (SMD = 0.25; 95% CI: 0.02–0.48; P = 0.04). There were no statistically significant differences in forced vital capacity (SMD = 0.07; 95% CI: −0.13–0.27; P = 0.52), percentage of predicted carbon monoxide diffusing capacity (SMD = 0.12; 95% CI: −0.06–0.30; P = 0.18), rates of adverse events (odd ratio = 4.50; 95% CI: 0.19–106.41; P = 0.35), or death rates (odd ratio = 1.79; 95% CI: 0.3–5.12; P = 0.28) between the N-acetylcysteine group and the control group. N-Acetylcysteine was found to have a significant effect only on decreases in percentage of predicted vital capacity and 6 minutes walking test distance. N-acetylcysteine showed no beneficial effect on changes in forced vital capacity, changes in predicted carbon monoxide diffusing capacity, rates of adverse events, or death rates. PMID:27175674

Efficacy of N-Acetylcysteine in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.

PubMed

Sun, Tong; Liu, Jing; Zhao, De Wei

2016-05-01

There are a number of conflicting reports describing the clinical outcomes of using N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis. We have, therefore, performed a meta-analysis to evaluate the efficacy of N-acetylcysteine, compared with control, for the treatment of idiopathic pulmonary fibrosis.Original controlled clinical trials evaluating the efficacy of N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis were included in the analysis. Searches for relevant articles were carried out in July 2014 by 2 independent researchers using PubMed, Embase, Cochrane Central, and Google Scholar. Change in forced vital capacity, change in percentage of predicted vital capacity, change in percentage of predicted carbon monoxide diffusing capacity, changes in 6 minutes walking test distance, rate of adverse events, and rate of death were expressed as outcomes using RevMan 5.0.1.Five trials, with a total of 564 patients, were included in this meta-analysis. The meta-analysis showed that the control group had significant decreases in percentage of predicted vital capacity (standardized mean difference [SMD] = 0.37; 95% confidence interval [CI]: 0.13 to -0.62; P = 0.003) and 6 minutes walking test distance (SMD = 0.25; 95% CI: 0.02-0.48; P = 0.04). There were no statistically significant differences in forced vital capacity (SMD = 0.07; 95% CI: -0.13-0.27; P = 0.52), percentage of predicted carbon monoxide diffusing capacity (SMD = 0.12; 95% CI: -0.06-0.30; P = 0.18), rates of adverse events (odd ratio = 4.50; 95% CI: 0.19-106.41; P = 0.35), or death rates (odd ratio = 1.79; 95% CI: 0.3-5.12; P = 0.28) between the N-acetylcysteine group and the control group.N-Acetylcysteine was found to have a significant effect only on decreases in percentage of predicted vital capacity and 6 minutes walking test distance. N-acetylcysteine showed no beneficial effect on changes in forced vital capacity, changes in predicted carbon monoxide diffusing capacity, rates of adverse events, or death rates.

Clinical evidence vs preliminary speculation in newspaper coverage of diabetes innovations: a quantitative analysis.

PubMed

Vehof, H; Sanders, J; van Dooren, A; Heerdink, E; Das, E

2018-05-04

Researchers have discussed that journalistic reporting of medical developments is often characterised by exaggeration or lack of context, but additional quantitative evidence to support this claim is needed. This study introduces a quantitative approach to assessing coverage of medical innovations, by aiming at provided references to observed clinical effects. Although observed clinical effects reflect increased chances for future medical applications, it is unknown to which extent newspaper articles refer to it when spreading health information. We aimed to assess, over a 6-year period, newspaper publication characteristics of diabetes innovations, arising from all scientific areas of interest, regarding the total count and the proportion of articles that provide references to demonstrated clinical efficacy. Quantitative content analysis of newspaper articles covering innovative treatments for diabetes. We performed a systematic review of newspaper articles between 2011 and 2016 printed in the largest six Dutch newspapers. By assessing in-article references, it was possible to quickly distinguish between (1) articles that referred to actual clinical efficacy demonstrated in a scientific setting and (2) articles that presented either predictions, fundamental research, preclinical research or personal experiences and recommendations. Proportion differences between scientific areas of interest were analysed using the chi-squared test. A total of 613 articles were categorised. Total newspaper publication frequency increased with 9.9 articles per year (P = .031). In total, 17% of the articles contained a reference to any proven clinical efficacy. Articles about human nutrition science (7%; P = .001) and (neuro)psychology (4.3%; P = .014) less frequently provided a reference to actual clinical efficacy. Our findings show that less than one in five newspaper articles about diabetes research contains a reference to relevant clinical effects, while the publication count is increasing. These statistics may contribute to feelings of false hope and confusion in patients. Copyright © 2018 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Efficacy of an evidence-based clinical decision support in primary care practices: a randomized clinical trial.

PubMed

McGinn, Thomas G; McCullagh, Lauren; Kannry, Joseph; Knaus, Megan; Sofianou, Anastasia; Wisnivesky, Juan P; Mann, Devin M

2013-09-23

There is consensus that incorporating clinical decision support into electronic health records will improve quality of care, contain costs, and reduce overtreatment, but this potential has yet to be demonstrated in clinical trials. To assess the influence of a customized evidence-based clinical decision support tool on the management of respiratory tract infections and on the effectiveness of integrating evidence at the point of care. In a randomized clinical trial, we implemented 2 well-validated integrated clinical prediction rules, namely, the Walsh rule for streptococcal pharyngitis and the Heckerling rule for pneumonia. INTERVENTIONS AND MAIN OUTCOMES AND MEASURES: The intervention group had access to the integrated clinical prediction rule tool and chose whether to complete risk score calculators, order medications, and generate progress notes to assist with complex decision making at the point of care. The intervention group completed the integrated clinical prediction rule tool in 57.5% of visits. Providers in the intervention group were significantly less likely to order antibiotics than the control group (age-adjusted relative risk, 0.74; 95% CI, 0.60-0.92). The absolute risk of the intervention was 9.2%, and the number needed to treat was 10.8. The intervention group was significantly less likely to order rapid streptococcal tests compared with the control group (relative risk, 0.75; 95% CI, 0.58-0.97; P= .03). The integrated clinical prediction rule process for integrating complex evidence-based clinical decision report tools is of relevant importance for national initiatives, such as Meaningful Use. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01386047.

ASPsiRNA: A Resource of ASP-siRNAs Having Therapeutic Potential for Human Genetic Disorders and Algorithm for Prediction of Their Inhibitory Efficacy

PubMed Central

Monga, Isha; Qureshi, Abid; Thakur, Nishant; Gupta, Amit Kumar; Kumar, Manoj

2017-01-01

Allele-specific siRNAs (ASP-siRNAs) have emerged as promising therapeutic molecules owing to their selectivity to inhibit the mutant allele or associated single-nucleotide polymorphisms (SNPs) sparing the expression of the wild-type counterpart. Thus, a dedicated bioinformatics platform encompassing updated ASP-siRNAs and an algorithm for the prediction of their inhibitory efficacy will be helpful in tackling currently intractable genetic disorders. In the present study, we have developed the ASPsiRNA resource (http://crdd.osdd.net/servers/aspsirna/) covering three components viz (i) ASPsiDb, (ii) ASPsiPred, and (iii) analysis tools like ASP-siOffTar. ASPsiDb is a manually curated database harboring 4543 (including 422 chemically modified) ASP-siRNAs targeting 78 unique genes involved in 51 different diseases. It furnishes comprehensive information from experimental studies on ASP-siRNAs along with multidimensional genetic and clinical information for numerous mutations. ASPsiPred is a two-layered algorithm to predict efficacy of ASP-siRNAs for fully complementary mutant (Effmut) and wild-type allele (Effwild) with one mismatch by ASPsiPredSVM and ASPsiPredmatrix, respectively. In ASPsiPredSVM, 922 unique ASP-siRNAs with experimentally validated quantitative Effmut were used. During 10-fold cross-validation (10nCV) employing various sequence features on the training/testing dataset (T737), the best predictive model achieved a maximum Pearson’s correlation coefficient (PCC) of 0.71. Further, the accuracy of the classifier to predict Effmut against novel genes was assessed by leave one target out cross-validation approach (LOTOCV). ASPsiPredmatrix was constructed from rule-based studies describing the effect of single siRNA:mRNA mismatches on the efficacy at 19 different locations of siRNA. Thus, ASPsiRNA encompasses the first database, prediction algorithm, and off-target analysis tool that is expected to accelerate research in the field of RNAi-based therapeutics for human genetic diseases. PMID:28696921

Efficacy of /sup 67/Ga-scintigraphy in predicting the diagnostic yield of transbronchial lung biopsy in pulmonary sarcoidosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ackart, R.S.; Munzel, T.L.; Rodriguez, J.J.

1982-07-01

Nineteen consecutive patients with clinically suspected sarcoidosis underwent /sup 67/Ga-scintigraphy prior to transbronchial lung biopsy (TBLB) to determine if /sup 67/Ga uptake in lung parenchyma would increase the diagnostic yield of the biopsy procedure. Biopsies were obtained from the areas showing parenchymal uptake on the /sup 67/Ga scan in 13 of the 19 patients. In the six patients not demonstrating uptake of /sup 67/Ga in the lung parenchyma, biopsies were obtained at random from the right lower lobe. There was no correlation between /sup 67/Ga uptake in hilar nodes or pulmonary parenchyma tissue and the diagnostic yield from TBLB. Researchersmore » conclude that /sup 67/Ga scanning is neither efficacious nor cost-effective in predicting the diagnostic yield of TBLB in sarcoidosis.« less

Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an integrative modelling study.

PubMed

Martin, N K; Robey, I F; Gaffney, E A; Gillies, R J; Gatenby, R A; Maini, P K

2012-03-27

Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts. We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies. The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1-7.2. Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1-7.2 is most promising.

Preclinical pharmacokinetics of the novel PI3K inhibitor GDC-0941 and prediction of its pharmacokinetics and efficacy in human.

PubMed

Salphati, Laurent; Pang, Jodie; Plise, Emile G; Chou, Bilin; Halladay, Jason S; Olivero, Alan G; Rudewicz, Patrick J; Tian, Qingping; Wong, Susan; Zhang, Xiaolin

2011-12-01

The phosphatidylinositol 3-kinase (PI3K) pathway is a major determinant of cell cycling and proliferation. Its deregulation is associated with the development of many cancers. GDC-0941, a potent and selective inhibitor of PI3K, was characterised preclinically in in vitro and in vivo studies. Plasma protein binding was extensive, with free fraction less than 7%, and blood-to-plasma ratio ranged from 0.6 to 1.2 among the species tested. GDC-0941 human hepatic clearance was predicted to be moderate by liver microsomal incubations. GDC-0941 had high permeability in Madin-Darby canine kidney cells. The clearance of GDC-0941 was high in mouse (63.7 mL/min/kg), rat (49.3 mL/min/kg) and cynomolgus monkey (58.6 mL/min/kg), and moderate in dog (11.9 mL/min/kg). The volume of distribution ranged from 2.52 L/kg in rat to 2.94 L/kg in monkey. Oral bioavailability ranged from 18.6% in monkey to 77.9% in mouse. Predicted human clearance and volume of distribution using allometry were 6 mL/min/kg and 2.9 L/kg, respectively. The human efficacious doses were predicted based on results from preclinical pharmacokinetic studies and xenograft models. GDC-0941 preclinical characterisation and predictions of its properties in human supported its progression towards clinical development. GDC-0941 is currently in phase II clinical trials.

Behavioral Activation Therapy for Depressed Cancer Patients: Factors Associated with Treatment Outcome and Attrition

ERIC Educational Resources Information Center

Hopko, D. R.; Robertson, S. M. C.; Colman, L.

2008-01-01

In recent years there has been increased focus on evaluating the efficacy of psychosocial interventions for cancer patients. Among the several limitations inherent to these programs of research, few studies have targeted patients with well-diagnosed clinical depression and little is known about factors that best predict treatment outcome and…

Enhanced performance of macrophage-encapsulated nanoparticle albumin-bound-paclitaxel in hypo-perfused cancer lesions

NASA Astrophysics Data System (ADS)

Leonard, Fransisca; Curtis, Louis T.; Yesantharao, Pooja; Tanei, Tomonori; Alexander, Jenolyn F.; Wu, Min; Lowengrub, John; Liu, Xuewu; Ferrari, Mauro; Yokoi, Kenji; Frieboes, Hermann B.; Godin, Biana

2016-06-01

Hypovascularization in tumors such as liver metastases originating from breast and other organs correlates with poor chemotherapeutic response and higher mortality. Poor prognosis is linked to impaired transport of both low- and high-molecular weight drugs into the lesions and to high washout rate. Nanoparticle albumin-bound-paclitaxel (nAb-PTX) has demonstrated benefits in clinical trials when compared to paclitaxel and docetaxel. However, its therapeutic efficacy for breast cancer liver metastasis is disappointing. As macrophages are the most abundant cells in the liver tumor microenvironment, we design a multistage system employing macrophages to deliver drugs into hypovascularized metastatic lesions, and perform in vitro, in vivo, and in silico evaluation. The system encapsulates nAb-PTX into nanoporous biocompatible and biodegradable multistage vectors (MSV), thus promoting nAb-PTX retention in macrophages. We develop a 3D in vitro model to simulate clinically observed hypo-perfused tumor lesions surrounded by macrophages. This model enables evaluation of nAb-PTX and MSV-nab PTX efficacy as a function of transport barriers. Addition of macrophages to this system significantly increases MSV-nAb-PTX efficacy, revealing the role of macrophages in drug transport. In the in vivo model, a significant increase in macrophage number, as compared to unaffected liver, is observed in mice, confirming the in vitro findings. Further, a mathematical model linking drug release and retention from macrophages is implemented to project MSV-nAb-PTX efficacy in a clinical setting. Based on macrophage presence detected via liver tumor imaging and biopsy, the proposed experimental/computational approach could enable prediction of MSV-nab PTX performance to treat metastatic cancer in the liver.Hypovascularization in tumors such as liver metastases originating from breast and other organs correlates with poor chemotherapeutic response and higher mortality. Poor prognosis is linked to impaired transport of both low- and high-molecular weight drugs into the lesions and to high washout rate. Nanoparticle albumin-bound-paclitaxel (nAb-PTX) has demonstrated benefits in clinical trials when compared to paclitaxel and docetaxel. However, its therapeutic efficacy for breast cancer liver metastasis is disappointing. As macrophages are the most abundant cells in the liver tumor microenvironment, we design a multistage system employing macrophages to deliver drugs into hypovascularized metastatic lesions, and perform in vitro, in vivo, and in silico evaluation. The system encapsulates nAb-PTX into nanoporous biocompatible and biodegradable multistage vectors (MSV), thus promoting nAb-PTX retention in macrophages. We develop a 3D in vitro model to simulate clinically observed hypo-perfused tumor lesions surrounded by macrophages. This model enables evaluation of nAb-PTX and MSV-nab PTX efficacy as a function of transport barriers. Addition of macrophages to this system significantly increases MSV-nAb-PTX efficacy, revealing the role of macrophages in drug transport. In the in vivo model, a significant increase in macrophage number, as compared to unaffected liver, is observed in mice, confirming the in vitro findings. Further, a mathematical model linking drug release and retention from macrophages is implemented to project MSV-nAb-PTX efficacy in a clinical setting. Based on macrophage presence detected via liver tumor imaging and biopsy, the proposed experimental/computational approach could enable prediction of MSV-nab PTX performance to treat metastatic cancer in the liver. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr07796f

Use of sequential endorectal US to predict the tumor response of preoperative chemoradiotherapy in rectal cancer.

PubMed

Li, Ning; Dou, Lizhou; Zhang, Yueming; Jin, Jing; Wang, Guiqi; Xiao, Qin; Li, Yexiong; Wang, Xin; Ren, Hua; Fang, Hui; Wang, Weihu; Wang, Shulian; Liu, Yueping; Song, Yongwen

2017-03-01

Accurate prediction of the response to preoperative chemoradiotherapy (CRT) potentially assists in the individualized selection of treatment. Endorectal US (ERUS) is widely used for the pretreatment staging of rectal cancer, but its use for preoperatively predicting the effects of CRT is not well evaluated because of the inflammation, necrosis, and fibrosis induced by CRT. This study assessed the value of sequential ERUS in predicting the efficacy of preoperative CRT for locally advanced rectal cancer. Forty-one patients with clinical stage II/III rectal adenocarcinoma were enrolled prospectively. Radiotherapy was delivered to the pelvis with concurrent chemotherapy of capecitabine and oxaliplatin. Total mesorectal excision was performed 6 to 8 weeks later. EUS measurements of primary tumor maximum diameter were performed before (ERUS1), during (ERUS2), and 6 to 8 weeks after (ERUS3) CRT, and the ratios of these were calculated. Correlations between ERUS values, tumor regression grade (TRG), T down-staging rate, and pathologic complete response (pCR) rate were assessed, and survival was analyzed. There was no significant correlation between ERUS2/ERUS1 and TRG. The value of ERUS3/ERUS1 correlated with pCR rate and TRG but not T down-staging rate. An ERUS3 value of 6.3 mm and ERUS3/ERUS1 of 52% were used as the cut-off for predicting pCR, and patients were divided into good and poor prognosis groups. Although not statistically significant, 3-year recurrence and survival rates of the good prognosis group were better than those of the poor prognosis group. Sequential ERUS may predict therapeutic efficacy of preoperative CRT for locally advanced rectal cancer. (Clinical trial registration number: NCT01582750.). Copyright © 2017 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Pharmacological validation of a novel nonhuman primate measure of thermal responsivity with utility for predicting analgesic effects.

PubMed

Vardigan, Joshua D; Houghton, Andrea K; Lange, Henry S; Adarayan, Emily D; Pall, Parul S; Ballard, Jeanine E; Henze, Darrell A; Uslaner, Jason M

2018-01-01

The development of novel analgesics to treat acute or chronic pain has been a challenge due to a lack of translatable measurements. Preclinical end points with improved translatability are necessary to more accurately inform clinical testing paradigms, which may help guide selection of viable drug candidates. In this study, a nonhuman primate biomarker which is sensitive to standard analgesics at clinically relevant plasma concentrations, can differentiate analgesia from sedation and utilizes a protocol very similar to that which can be employed in human clinical studies is described. Specifically, acute heat stimuli were delivered to the volar forearm using a contact heat thermode in the same manner as the clinical setting. Clinically efficacious exposures of morphine, fentanyl, and tramadol produced robust analgesic effects, whereas doses of diazepam that produce sedation had no effect. We propose that this assay has predictive utility that can help improve the probability of success for developing novel analgesics.

Pharmacological validation of a novel nonhuman primate measure of thermal responsivity with utility for predicting analgesic effects

PubMed Central

Vardigan, Joshua D; Houghton, Andrea K; Lange, Henry S; Adarayan, Emily D; Pall, Parul S; Ballard, Jeanine E; Henze, Darrell A; Uslaner, Jason M

2018-01-01

Introduction The development of novel analgesics to treat acute or chronic pain has been a challenge due to a lack of translatable measurements. Preclinical end points with improved translatability are necessary to more accurately inform clinical testing paradigms, which may help guide selection of viable drug candidates. Methods In this study, a nonhuman primate biomarker which is sensitive to standard analgesics at clinically relevant plasma concentrations, can differentiate analgesia from sedation and utilizes a protocol very similar to that which can be employed in human clinical studies is described. Specifically, acute heat stimuli were delivered to the volar forearm using a contact heat thermode in the same manner as the clinical setting. Results Clinically efficacious exposures of morphine, fentanyl, and tramadol produced robust analgesic effects, whereas doses of diazepam that produce sedation had no effect. Conclusion We propose that this assay has predictive utility that can help improve the probability of success for developing novel analgesics. PMID:29692626

Sources of science self-efficacy beliefs of middle school students

NASA Astrophysics Data System (ADS)

Britner, Shari L.; Pajares, Frank

2006-05-01

The purpose of this study was to investigate the degree to which A. Bandura's ([1997]) hypothesized sources of self-efficacy predict the science self-efficacy beliefs of middle school students (N = 319), to replicate previous findings that science self-efficacy predicts science achievement, and to explore how science self-efficacy and its antecedents differ by gender. Significant correlations were found between mastery experiences, vicarious experiences, social persuasions, physiological arousal, and self-efficacy. Only mastery experiences significantly predicted science self-efficacy. Girls reported stronger science self-efficacy than did boys. Findings support and extend the theoretical tenets of Bandura's social cognitive theory.

miR-125b-1 and miR-378a are predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer.

PubMed

Tanaka, Hironori; Hazama, Shoichi; Iida, Michihisa; Tsunedomi, Ryouichi; Takenouchi, Hiroko; Nakajima, Masao; Tokumitsu, Yukio; Kanekiyo, Shinsuke; Shindo, Yoshitaro; Tomochika, Shinobu; Tokuhisa, Yoshihiro; Sakamoto, Kazuhiko; Suzuki, Nobuaki; Takeda, Shigeru; Yamamoto, Shigeru; Yoshino, Shigefumi; Ueno, Tomio; Hamamoto, Yoshihiko; Fujita, Yusuke; Tanaka, Hiroaki; Tahara, Ko; Shimizu, Ryoichi; Okuno, Kiyotaka; Fujita, Koji; Kuroda, Masahiko; Nakamura, Yusuke; Nagano, Hiroaki

2017-11-01

Many clinical trials of peptide vaccines have been conducted. However, these vaccines have provided clinical benefits in only a small fraction of patients. The purpose of the present study was to explore microRNAs (miRNAs) as novel predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. First, we carried out microarray analysis of pretreatment cancer tissues in a phase I study, in which peptide vaccines alone were given. Candidate miRNAs were selected by comparison of the better prognosis group with the poorer prognosis group. Next, we conducted microarray analysis of cancer tissues in a phase II study, in which peptide vaccines combined with chemotherapy were given. Candidate miRNAs were further selected by a similar comparison of prognosis. Subsequently, we carried out reverse-transcription PCR analysis of phase II cases, separating cancer tissues into cancer cells and stromal tissue using laser capture microdissection. Treatment effect in relation to overall survival (OS) and miRNA expression was analyzed. Three miRNA predictors were negatively associated with OS: miR-125b-1 in cancer cells (P = 0.040), and miR-378a in both cancer cells (P = 0.009) and stromal cells (P < 0.001). Multivariate analysis showed that expression of miR-378a in stromal cells was the best among the three predictors (HR, 2.730; 95% CI, 1.027-7.585; P = 0.044). In conclusion, miR-125b-1 and miR-378a expression might be considered as novel biomarkers to predict the efficacy of vaccine treatment against colorectal cancer. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Safety and Efficacy of Catheter Direct Thrombolysis in Management of Acute Iliofemoral Deep Vein Thrombosis: A Systematic Review.

PubMed

Elbasty, Ahmed; Metcalf, James

2017-12-01

Catheter direct thrombolysis (CDT) has been shown to be an effective treatment for deep venous thrombosis. The objective of the review is to improve safety and efficacy of the CDT by using ward based protocol, better able to predict complications and treatment outcome through monitoring of haemostatic parameters and clinical observation during thrombolysis procedure. MEDLINE, EMBASE, CENTRAL and Web of Science were searched for all articles on deep venous thrombosis, thrombolysis and correlations of clinical events (bleeding, successful thrombolysis) during thrombolysis with hemostatic parameters to March 2016. The risk of bias in included studies was assessed by Cochrane Collaboration's tool and Cochrane Risk of Bias Assessment Tool: for Non-Randomized Studies of Interventions. Twenty-four studies were included in the review and we found that improving safety and efficacy of CDT by using ward based protocol depending on eight factors; strict patient selection criteria, types of fibrinolytic drugs, mode of fibrinolytic drug injection, biochemical markers monitoring (fibrinogen, D-dimer, activated partial thromboplastin time, plasminogen activator inhibitor-1), timing of intervention, usage of intermittent pneumatic calf, ward monitoring and thrombolysis imaging assessment (intravascular ultrasound). These factors may help to improve safety and efficacy by reducing total thrombolytic drug dosage and at the same time ensure successful lysis. There is a marked lack of randomized controlled trials discussing the safety and efficacy of catheter direct thrombolysis. CDT can be performed safely and efficiently in clinical ward, providing that careful nursing, biochemical monitoring, proper selection and mode of infusion of fibrinolytic drugs, usage of Intermittent pneumatic calf and adequate thrombolysis imaging assessment are ensured.

[Hardy personality, self-efficacy, and general health in nursing professionals of intensive and emergency services].

PubMed

Ríos Rísquez, María Isabel; Sánchez Meca, Julio; Godoy Fernández, Carmen

2010-11-01

In this study, the predictive power of hardy personality and generalized self-efficacy on general health perception was investigated in a sample of nursing personnel working in emergency and intensive care services. A cross-sectional retrospective design was used, and the following measurement instruments were applied: a sociodemographic and work questionnaire, Goldberg's GHQ-28 Health Questionnaire, the Baessler and Schwarzer General Self-efficacy Questionnaire, and the Hardy Personality Subscale of Moreno's Nursing Burnout Questionnaire (CDPE). The results revealed a positive and statistically significant relationship between the individual variables of generalized self-efficacy and hardy personality. A canonical correlation analysis carried out on the psychological distress symptoms with self-efficacy and hardy personality as predictor variables, led us to emphasize the relevance of the construct total hardy personality as a predictor and, consequently, as a protective factor against the onset of psychological distress symptoms in the sample of professionals studied. Lastly, the implications of the results for clinical practice are discussed.

Role of illness perception and self-efficacy in lifestyle modification among non-alcoholic fatty liver disease patients

PubMed Central

Zelber-Sagi, Shira; Bord, Shiran; Dror-Lavi, Gali; Smith, Matthew Lee; Towne Jr, Samuel D; Buch, Assaf; Webb, Muriel; Yeshua, Hanny; Nimer, Assy; Shibolet, Oren

2017-01-01

AIM To describe the relationships between non-alcoholic fatty-liver disease (NAFLD) patient’s disease consequences and treatment perceptions, self-efficacy, and healthy lifestyle maintenance. METHODS A cross-sectional study among 146 ultrasound diagnosed NAFLD patients who visited the fatty liver clinic at the Tel-Aviv Medical Center. Eighty-seven of these individuals, participated in a clinical trial of physical activity and underwent fasting blood tests, analyzed at the same lab. Exclusion criteria included positivity for serum HBsAg or anti-HCV antibodies; fatty liver suspected to be secondary to hepatotoxic drugs; excessive alcohol consumption (≥ 30 g/d in men or ≥ 20 g/d in women) and positive markers of genetic or immune-mediated liver diseases. Patients were asked to complete a self-report structured questionnaire, assembled by the Israeli Center for Disease Control. Nutrition habits were measured using six yes/no questions (0 = no, 1 = yes) adopted from the national survey questionnaire. Participants in the clinical trial completed a detailed semi-quantitative food frequency questionnaire (FFQ) reporting their habitual nutritional intake during the past year. Self-efficacy was assessed by the Self-Efficacy Scale questionnaire, emotional representation, degree of illness understanding, timeline perception, treatment perception and symptoms were measured by the Brief Illness Perception questionnaire. Illness consequences were measured by the Personal Models of Diabetes Interview questionnaire. A path analysis was performed to describe the interrelationships between the patients’ illness perceptions, and assess the extent to which the data fit a prediction of nutritional habits. RESULTS The study sample included 54.1% men, with a mean age of 47.76 ± 11.68 years (range: 20-60) and mean body mass index of 31.56 ± 4.6. The average perceived nutrition habits score was 4.73 ± 1.45 on a scale between 0-6, where 6 represents the healthiest eating habits. Most of the study participants (57.2%) did not feel they fully understood what NAFLD is. Better nutritional habits were positively predicted by the degree of illness understanding (β = 0.26; P = 0.002) and self-efficacy (β = 0.25; P = 0.003). Perceptions of more severe illness consequences were related with higher emotional representation (β = 0.55; P < 0.001), which was related with lower self-efficacy (β = -0.17; P = 0.034). The perception of treatment effectiveness was positively related with self-efficacy (β = 0.32; P < 0.001). In accordance with the correlation between self-efficacy and the perceived nutrition habits score, self-efficacy was also correlated with nutrient intake evaluated by the FFQ; negatively with saturated fat (percent of saturated fat calories from total calories) (r = -0.28, P = 0.010) and positively with fiber (r = 0.22, P = 0.047) and vitamin C intake (r = 0.34, P = 0.002). In a sub analysis of the clinical trial participants, objectively measured compliance to physical activity regimen was positively correlated with the self-efficacy level (r = 0.34, P = 0.046). CONCLUSION Self-efficacy and illness understanding are major determinants of lifestyle-modification among NAFLD patients. This information can assist clinicians in improving compliance with lifestyle changes among these patients. PMID:28348495

Type D Personality, Self-Efficacy, and Medication Adherence in Patients with Heart Failure

PubMed Central

Wu, Jia-Rong; Song, Eun Kyeung; Moser, Debra K.

2015-01-01

Background Type D personality is a known predictor of non-adherence to prescribed medication regimens among patients with heart failure (HF). Both Type D personality and non-adherence are independent predictors of poor health outcomes among HF patients. Self-efficacy, which is modifiable, is also associated with medication adherence. Objectives To determine the relationships among Type D personality, medication self-efficacy, and medication adherence in 84 patients with HF. Methods Medication self-efficacy, Type D personality, medication adherence, demographic and clinical data were collected. Hierarchical linear regression and mediation analyses were used. Results Type D patients were more likely to have lower medication self-efficacy (p = .023) and poorer medication adherence (p = .027) compared with non-Type D patients. Low medication self-efficacy was associated with poor medication adherence (p < .001). Type D did not predict (p = .422) medication adherence after entering medication self-efficacy in the model demonstrating that medication self-efficacy was a mediator of the relationship between Type D and medication adherence. Conclusions Medication self-efficacy mediates the relationship between Type D personality and medication adherence. Developing and applying interventions to enhance medication self-efficacy for Type D patients may help to sever the link between Type D personality and poor outcomes. PMID:25979573

Efficacy of Diffusion Tensor Imaging Indices in Assessing Postoperative Neural Recovery in Cervical Spondylotic Myelopathy.

PubMed

Rajasekaran, S; Kanna, Rishi M; Chittode, Vishnuprasath S; Maheswaran, Anupama; Aiyer, Siddharth N; Shetty, Ajoy P

2017-01-01

Prospective observational cohort study. The aim of this study was to analyze the efficacy of diffusion tensor imaging (DTI) anisotropy indices in predicting the postoperative recovery in cervical spondylotic myelopathy (CSM) patients and to describe postoperative changes in the DTI indices based on neurological recovery after surgery. Surgical results of CSM are unpredictable and cannot be estimated based on preoperative MRI. DTI indices were found to have good sensitivity to detect changes in CSM, but their efficacy in predicting postoperative recovery and postoperative changes in DTI indices has not been studied before. Thirty-five patients who underwent surgical decompression for cervical spondylotic myelopathy underwent DTI evaluation preoperatively and postoperatively at 12 months. DTI indices-fractional anisotropy, apparent diffusion coefficient (ADC), relative anisotropy, volume ratio, and eigen vectors (E1, E2, and E3)-were obtained and clinical evaluations were made preoperatively and 12 months postoperatively. Twenty-six patients were available for final follow-up at 12 months. Twenty patients showed improvement by at least 1 Nurick grade, five maintained the preoperative Nurick grade status and one patient was noted to have deterioration by 1 grade. The preoperative DTI values could not predict neurological recovery patterns postoperatively. Although conventional MRI showed adequate decompression in all patients irrespective of the clinical outcome, DTI indices showed variable results. There were significant improvements in postoperative DTI indices for ADC (P = 0.002), E1 (P < 0.001), and E2 (P = 0.012) values in patients who showed neurological recovery at 12 months. Postoperative DTI indices for coefficients ADC, E1, and E2 in neurologically static/worsened individuals remained unchanged or insignificant (P = 0.05) CONCLUSION.: The DTI indices were sensitive enough to indicate postoperative neurological recovery observed following surgery. Preoperative DTI evaluation could not predict postoperative recovery for patients with cervical spondylotic myelopathy. 4.

Advances in the Treatment of Non-small Cell Lung Cancer: Focus on Nivolumab, Pembrolizumab, and Atezolizumab.

PubMed

Leventakos, Konstantinos; Mansfield, Aaron S

2016-10-01

Immunotherapy is revolutionizing the treatment of non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors, including programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) monoclonal antibodies, are being introduced to routine clinical practice. This review summarizes clinical trials of nivolumab, pembrolizumab, and atezolizumab in patients with NSCLC. These agents have efficacy against NSCLC and a unique toxicity profile. The role of PD-L1 as a predictive biomarker is still unclear, partially because of the nuances of PD-L1 testing. These novel therapies also challenge our existing methodologies of radiologic assessment and efficacy analysis. This new era of immunotherapy has ushered in as much hope for patients as questions from physicians that need to be answered to clarify the optimal use of these agents.

A Bayesian prediction model between a biomarker and the clinical endpoint for dichotomous variables.

PubMed

Jiang, Zhiwei; Song, Yang; Shou, Qiong; Xia, Jielai; Wang, William

2014-12-20

Early biomarkers are helpful for predicting clinical endpoints and for evaluating efficacy in clinical trials even if the biomarker cannot replace clinical outcome as a surrogate. The building and evaluation of an association model between biomarkers and clinical outcomes are two equally important concerns regarding the prediction of clinical outcome. This paper is to address both issues in a Bayesian framework. A Bayesian meta-analytic approach is proposed to build a prediction model between the biomarker and clinical endpoint for dichotomous variables. Compared with other Bayesian methods, the proposed model only requires trial-level summary data of historical trials in model building. By using extensive simulations, we evaluate the link function and the application condition of the proposed Bayesian model under scenario (i) equal positive predictive value (PPV) and negative predictive value (NPV) and (ii) higher NPV and lower PPV. In the simulations, the patient-level data is generated to evaluate the meta-analytic model. PPV and NPV are employed to describe the patient-level relationship between the biomarker and the clinical outcome. The minimum number of historical trials to be included in building the model is also considered. It is seen from the simulations that the logit link function performs better than the odds and cloglog functions under both scenarios. PPV/NPV ≥0.5 for equal PPV and NPV, and PPV + NPV ≥1 for higher NPV and lower PPV are proposed in order to predict clinical outcome accurately and precisely when the proposed model is considered. Twenty historical trials are required to be included in model building when PPV and NPV are equal. For unequal PPV and NPV, the minimum number of historical trials for model building is proposed to be five. A hypothetical example shows an application of the proposed model in global drug development. The proposed Bayesian model is able to predict well the clinical endpoint from the observed biomarker data for dichotomous variables as long as the conditions are satisfied. It could be applied in drug development. But the practical problems in applications have to be studied in further research.

High self-efficacy predicts adherence to surveillance colonoscopy in inflammatory bowel disease.

PubMed

Friedman, Sonia; Cheifetz, Adam S; Farraye, Francis A; Banks, Peter A; Makrauer, Frederick L; Burakoff, Robert; Farmer, Barbara; Torgersen, Leanne N; Wahl, Kelly E

2014-09-01

Patients with extensive ulcerative colitis or Crohn's disease of the colon have an increased risk of colon cancer and require colonoscopic surveillance. In this study, we assessed individual self-efficacy (SE) to estimate the probability of adherence to surveillance colonoscopies. Three hundred seventy-eight patients with ulcerative colitis or Crohn's disease of the colon for at least 7 years and with at least one third of the colon involved participated in this cross-sectional questionnaire study performed at 3 tertiary referral inflammatory bowel disease clinics. Medical charts were abstracted for demographic and clinical variables. The questionnaire contained a group of items assessing SE for undergoing colonoscopy. We validated our 20-question SE scale and used 8 of the items that highlighted scheduling, preparation, and postprocedure recovery, to develop 2 shorter SE scales. All 3 scales were reliable with Cronbach's α ranging from 0.845 to 0.905 and correlated with chart-documented adherence to surveillance colonoscopy (P < 0.001). We then developed logistic regression models to predict adherence to surveillance colonoscopy using each scale separately along with other key variables (i.e., disease location, knowledge of correct adherence intervals, and information sources of patients consulted regarding Crohn's disease and ulcerative colitis) and demonstrated model accuracy up to 74%. SE, as measured by our validated scales, correlates with chart-adherence to surveillance colonoscopy. Our adherence model, which includes SE, predicts adherence with 74% certainty. An 8-item validated clinical questionnaire can be administered to assess whether patients in this population may require further intervention for adherence.

The impact of depression on abstinence self-efficacy and substance use outcomes among emerging adults in residential treatment.

PubMed

Greenfield, Brenna L; Venner, Kamilla L; Kelly, John F; Slaymaker, Valerie; Bryan, Angela D

2012-06-01

A large proportion of emerging adults treated for substance use disorder (SUD) present with symptoms of negative affect and major depressive disorder (MDD). However, little is known regarding how these comorbidities influence important mechanisms of treatment response, such as increases in abstinence self-efficacy (ASE). This study tested the degree to which MDD and/or depressive symptoms interacted with during-treatment changes in ASE and examined these variables' relation to outcome at 3 months' posttreatment. Participants (N = 302; 74% male) completed measures at intake, midtreatment, end-of-treatment, and at 3-month follow-up. ASE was measured with the Alcohol and Drug Use Self-Efficacy (ADUSE) scale; depressive symptoms were assessed with the Brief Symptom Inventory 18 (BSI 18) Depression scale; and current MDD diagnoses were deduced from the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Random coefficient regression analyses focused on during-treatment changes in ASE, with BSI 18 scores and MDD diagnosis included as moderators. At intake, individuals with MDD or high levels of depressive symptoms had significantly lower ASE, particularly in negative affect situations. No evidence for moderation was found: ASE significantly increased during treatment regardless of MDD status. There was a main effect of BSI 18 Depression scores: those with lower BSI 18 scores had lower ASE scores at each time point. MDD and BSI 18 Depression did not predict 3-month outcome, but similar to previous findings ASE did predict abstinence status at 3 months. Treatment-seeking emerging adults with MDD merit particular clinical attention because of their lower reported self-efficacy throughout treatment.

The Impact of Depression on Abstinence Self-Efficacy and Substance Use Outcomes among Emerging Adults in Residential Treatment

PubMed Central

Greenfield, Brenna L.; Venner, Kamilla L.; Kelly, John F.; Slaymaker, Valerie; Bryan, Angela D.

2012-01-01

A large proportion of emerging adults treated for substance use disorder (SUD) present with symptoms of negative affect and major depressive disorder (MDD). However, little is known regarding how these comorbidities influence important mechanisms of treatment response, such as increases in abstinence self-efficacy (ASE). This study tested the degree to which MDD and/or depressive symptoms interacted with during-treatment changes in ASE and examined these variables' relation to outcome at 3-months post-treatment. Participants (N = 302; 74% male) completed measures at intake, mid-treatment, end-of-treatment, and at 3-month follow-up. ASE was measured with the Alcohol and Drug Use Self-Efficacy (ADUSE) scale; depressive symptoms were assessed with the Brief Symptom Inventory 18 (BSI 18) Depression scale; and current MDD diagnoses were deduced from the Structured Clinical Interview for the DSM-IV. Random coefficient regression analyses focused on during-treatment changes in ASE, with BSI 18 scores and MDD diagnosis included as moderators. At intake, individuals with MDD or high levels of depressive symptoms had significantly lower ASE, particularly in negative affect situations. No evidence for moderation was found: ASE significantly increased during treatment regardless of MDD status. There was a main effect of BSI 18 Depression scores: those with lower BSI 18 scores had lower ASE scores at each time point. MDD and BSI 18 Depression did not predict three-month outcome, but similar to previous findings ASE did predict abstinence status at three months. Treatment-seeking emerging adults with MDD merit particular clinical attention because of their lower reported self-efficacy throughout treatment. PMID:22288980

Comparison of the efficacy of icotinib in patients with non-small-cell lung cancer according to the type of epidermal growth factor receptor mutation.

PubMed

Xue, Zhang Xiao; Wen, Wang Xiu; Zhuang, Yu; Hua, Zang Jian; Xia, Yang Ni

2016-09-01

Icotinib hydrochloride is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with preclinical and clinical activity in non-small-cell lung cancer (NSCLC). Exon 19 deletion and L858R point mutation are the most commonly encountered EGFR mutations in NSCLC, and they predict improved clinical outcomes following treatment with icotinib. The objective of this study was to evaluate the differential clinical efficacy of icotinib in patients with exon 19 deletion or L858R point mutation of the EGFR gene. A total of 104 patients with advanced NSCLC, who harbored exon 19 deletion or L858R point mutation of EGFR and were treated with icotinib, were enrolled in this study. The tumor response and progression-free survival were evaluated. There were no significant differences between patients with EGFR exon 19 deletion and those with L858R point mutation who received treatment with icotinib.

Improving external beam radiotherapy by combination with internal irradiation.

PubMed

Dietrich, A; Koi, L; Zöphel, K; Sihver, W; Kotzerke, J; Baumann, M; Krause, M

2015-07-01

The efficacy of external beam radiotherapy (EBRT) is dose dependent, but the dose that can be applied to solid tumour lesions is limited by the sensitivity of the surrounding tissue. The combination of EBRT with systemically applied radioimmunotherapy (RIT) is a promising approach to increase efficacy of radiotherapy. Toxicities of both treatment modalities of this combination of internal and external radiotherapy (CIERT) are not additive, as different organs at risk are in target. However, advantages of both single treatments are combined, for example, precise high dose delivery to the bulk tumour via standard EBRT, which can be increased by addition of RIT, and potential targeting of micrometastases by RIT. Eventually, theragnostic radionuclide pairs can be used to predict uptake of the radiotherapeutic drug prior to and during therapy and find individual patients who may benefit from this treatment. This review aims to highlight the outcome of pre-clinical studies on CIERT and resultant questions for translation into the clinic. Few clinical data are available until now and reasons as well as challenges for clinical implementation are discussed.

Predictors of Consistent Condom Use Among Young African American Women

PubMed Central

DiClemente, Ralph J.; Salazar, Laura F.; Wingood, Gina M.; McDermott-Sales, Jessica; Young, April M.; Rose, Eve

2012-01-01

The purpose of this study was to determine the predictive value of selected factors to the consistent use of condoms among high-risk young African American women. A clinic-based, prospective, study of 242 young, African-American women (ages 15–21) was conducted. In multivariate analysis, consistent condom use was predicted by having greater perceptions of condom negotiation self-efficacy, lower fear of negotiating condom use, and having communicated with sex partners (during the recall period) about condom use. Relational variables were predictive of consistent condom use among young African American women. STD/HIV preventive interventions should target these factors, perhaps in dyad-level interventions. PMID:21796442

Predictors of consistent condom use among young African American women.

PubMed

Crosby, Richard A; DiClemente, Ralph J; Salazar, Laura F; Wingood, Gina M; McDermott-Sales, Jessica; Young, April M; Rose, Eve

2013-03-01

The purpose of this study was to determine the predictive value of selected factors to the consistent use of condoms among high-risk young African American women. A clinic-based, prospective, study of 242 young, African-American women (ages 15-21) was conducted. In multivariate analysis, consistent condom use was predicted by having greater perceptions of condom negotiation self-efficacy, lower fear of negotiating condom use, and having communicated with sex partners (during the recall period) about condom use. Relational variables were predictive of consistent condom use among young African American women. STD/HIV preventive interventions should target these factors, perhaps in dyad-level interventions.

Efficacy of the clinical agent VT-1161 against fluconazole-sensitive and -resistant Candida albicans in a murine model of vaginal candidiasis.

PubMed

Garvey, E P; Hoekstra, W J; Schotzinger, R J; Sobel, J D; Lilly, E A; Fidel, P L

2015-09-01

Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) remain major health problems for women. VT-1161, a novel fungal CYP51 inhibitor which has potent antifungal activity against fluconazole-sensitive Candida albicans, retained its in vitro potency (MIC50 of ≤0.015 and MIC90 of 0.12 μg/ml) against 10 clinical isolates from VVC or RVVC patients resistant to fluconazole (MIC50 of 8 and MIC90 of 64 μg/ml). VT-1161 pharmacokinetics in mice displayed a high volume of distribution (1.4 liters/kg), high oral absorption (73%), and a long half-life (>48 h) and showed rapid penetration into vaginal tissue. In a murine model of vaginal candidiasis using fluconazole-sensitive yeast, oral doses as low as 4 mg/kg VT-1161 significantly reduced the fungal burden 1 and 4 days posttreatment (P < 0.0001). Similar VT-1161 efficacy was measured when an isolate highly resistant to fluconazole (MIC of 64 μg/ml) but fully sensitive in vitro to VT-1161 was used. When an isolate partially sensitive to VT-1161 (MIC of 0.12 μg/ml) and moderately resistant to fluconazole (MIC of 8 μg/ml) was used, VT-1161 remained efficacious, whereas fluconazole was efficacious on day 1 but did not sustain efficacy 4 days posttreatment. Both agents were inactive in treating an infection with an isolate that demonstrated weaker potency (MICs of 2 and 64 μg/ml for VT-1161 and fluconazole, respectively). Finally, the plasma concentrations of free VT-1161 were predictive of efficacy when in excess of the in vitro MIC values. These data support the clinical development of VT-1161 as a potentially more efficacious treatment for VVC and RVVC. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

HIV-specific Th2 and Th17 responses predict HIV vaccine protection efficacy

PubMed Central

Sauce, Delphine; Gorochov, Guy; Larsen, Martin

2016-01-01

Understanding the factors that delineate the efficacy of T-cell responses towards pathogens is crucial for our ability to develop potent therapies and vaccines against infectious diseases, such as HIV. Here we show that a recently developed analytical tool, the polyfunctionality index (PI), not only enables prediction of protection after vaccination against HIV, but also allows identification of the immunological pathways involved. Our data suggest that induction of a synergistic network of CD4+ T-cell subsets is implicated in HIV-protection. Accordingly, we provide evidence that vaccine-induced protection is associated with CD40L expressing Th2 cells and IL-2 secreting Th17 cells. In conclusion, we describe a novel approach that is widely applicable and readily interpretable in a biological and clinical context. This approach could greatly impact our fundamental understanding of T-cell immunity as well as the search for effective vaccines. PMID:27324186

A consultation on the optimization of controlled human malaria infection by mosquito bite for evaluation of candidate malaria vaccines.

PubMed

Laurens, Matthew B; Duncan, Christopher J; Epstein, Judith E; Hill, Adrian V; Komisar, Jack L; Lyke, Kirsten E; Ockenhouse, Christian F; Richie, Thomas L; Roestenberg, Meta; Sauerwein, Robert W; Spring, Michele D; Talley, Angela K; Moorthy, Vasee S

2012-08-03

Early clinical investigations of candidate malaria vaccines and antimalarial medications increasingly employ an established model of controlled human malaria infection (CHMI). Study results are used to guide further clinical development of vaccines and antimalarial medications as CHMI results to date are generally predictive of efficacy in malaria-endemic areas. The urgency to rapidly develop an efficacious malaria vaccine has increased demand for efficacy studies that include CHMI and the need for comparability of study results among the different centres conducting CHMI. An initial meeting with the goal to optimize and standardise CHMI procedures was held in 2009 with follow-up meetings in March and June 2010 to harmonise methods used at different centres. The end result is a standardised document for the design and conduct of CHMI and a second document for the microscopy methods used to determine the patency endpoint. These documents will facilitate high accuracy and comparability of CHMI studies and will be revised commensurate with advances in the field. Copyright © 2012. Published by Elsevier Ltd.. All rights reserved.

Application of ''Earl's Assessment "as", Assessment "for", and Assessment "of" Learning Model'' with Orthopaedic Assessment Clinical Competence

ERIC Educational Resources Information Center

Lafave, Mark R.; Katz, Larry; Vaughn, Norman

2013-01-01

Context: In order to study the efficacy of assessment methods, a theoretical framework of Earl's model of assessment was introduced. Objective: (1) Introduce the predictive learning assessment model (PLAM) as an application of Earl's model of learning; (2) test Earl's model of learning through the use of the Standardized Orthopedic Assessment Tool…

In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

DOE PAGES

Pienaar, Elsje; Dartois, Véronique; Linderman, Jennifer J.; ...

2015-11-14

Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes. We pair a spatio-temporal computational model of host immunity with pharmacokinetic and pharmacodynamic data on isoniazid and rifampin. The model is calibrated to plasma pharmacokinetic and granuloma bacterial load data frommore » non-human primate models of tuberculosis and to tissue and granuloma measurements of isoniazid and rifampin in rabbit granulomas. We predict the efficacy of regimens containing different doses and frequencies of isoniazid and rifampin. We predict impacts of pharmacokinetic/pharmacodynamic modifications on antibiotic efficacy. We demonstrate that suboptimal antibiotic concentrations within granulomas lead to poor performance of intermittent regimens compared to daily regimens. Improvements from dose and frequency changes are limited by inherent antibiotic properties, and we propose that changes in intracellular accumulation ratios and antimicrobial activity would lead to the most significant improvements in treatment outcomes. Results suggest that an increased risk of drug resistance in fully intermittent as compared to daily regimens arises from higher bacterial population levels early during treatment. In conclusion, our systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development.« less

In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pienaar, Elsje; Dartois, Véronique; Linderman, Jennifer J.

Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes. We pair a spatio-temporal computational model of host immunity with pharmacokinetic and pharmacodynamic data on isoniazid and rifampin. The model is calibrated to plasma pharmacokinetic and granuloma bacterial load data frommore » non-human primate models of tuberculosis and to tissue and granuloma measurements of isoniazid and rifampin in rabbit granulomas. We predict the efficacy of regimens containing different doses and frequencies of isoniazid and rifampin. We predict impacts of pharmacokinetic/pharmacodynamic modifications on antibiotic efficacy. We demonstrate that suboptimal antibiotic concentrations within granulomas lead to poor performance of intermittent regimens compared to daily regimens. Improvements from dose and frequency changes are limited by inherent antibiotic properties, and we propose that changes in intracellular accumulation ratios and antimicrobial activity would lead to the most significant improvements in treatment outcomes. Results suggest that an increased risk of drug resistance in fully intermittent as compared to daily regimens arises from higher bacterial population levels early during treatment. In conclusion, our systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development.« less

Predicted effect size of lisdexamfetamine treatment of attention deficit/hyperactivity disorder (ADHD) in European adults: Estimates based on indirect analysis using a systematic review and meta-regression analysis.

PubMed

Fridman, M; Hodgkins, P S; Kahle, J S; Erder, M H

2015-06-01

There are few approved therapies for adults with attention-deficit/hyperactivity disorder (ADHD) in Europe. Lisdexamfetamine (LDX) is an effective treatment for ADHD; however, no clinical trials examining the efficacy of LDX specifically in European adults have been conducted. Therefore, to estimate the efficacy of LDX in European adults we performed a meta-regression of existing clinical data. A systematic review identified US- and Europe-based randomized efficacy trials of LDX, atomoxetine (ATX), or osmotic-release oral system methylphenidate (OROS-MPH) in children/adolescents and adults. A meta-regression model was then fitted to the published/calculated effect sizes (Cohen's d) using medication, geographical location, and age group as predictors. The LDX effect size in European adults was extrapolated from the fitted model. Sensitivity analyses performed included using adult-only studies and adding studies with placebo designs other than a standard pill-placebo design. Twenty-two of 2832 identified articles met inclusion criteria. The model-estimated effect size of LDX for European adults was 1.070 (95% confidence interval: 0.738, 1.401), larger than the 0.8 threshold for large effect sizes. The overall model fit was adequate (80%) and stable in the sensitivity analyses. This model predicts that LDX may have a large treatment effect size in European adults with ADHD. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Simulated annealing model of acupuncture

NASA Astrophysics Data System (ADS)

Shang, Charles; Szu, Harold

2015-05-01

The growth control singularity model suggests that acupuncture points (acupoints) originate from organizers in embryogenesis. Organizers are singular points in growth control. Acupuncture can cause perturbation of a system with effects similar to simulated annealing. In clinical trial, the goal of a treatment is to relieve certain disorder which corresponds to reaching certain local optimum in simulated annealing. The self-organizing effect of the system is limited and related to the person's general health and age. Perturbation at acupoints can lead a stronger local excitation (analogous to higher annealing temperature) compared to perturbation at non-singular points (placebo control points). Such difference diminishes as the number of perturbed points increases due to the wider distribution of the limited self-organizing activity. This model explains the following facts from systematic reviews of acupuncture trials: 1. Properly chosen single acupoint treatment for certain disorder can lead to highly repeatable efficacy above placebo 2. When multiple acupoints are used, the result can be highly repeatable if the patients are relatively healthy and young but are usually mixed if the patients are old, frail and have multiple disorders at the same time as the number of local optima or comorbidities increases. 3. As number of acupoints used increases, the efficacy difference between sham and real acupuncture often diminishes. It predicted that the efficacy of acupuncture is negatively correlated to the disease chronicity, severity and patient's age. This is the first biological - physical model of acupuncture which can predict and guide clinical acupuncture research.

Development and validation of risk models and molecular diagnostics to permit personalized management of cancer.

PubMed

Pu, Xia; Ye, Yuanqing; Wu, Xifeng

2014-01-01

Despite the advances made in cancer management over the past few decades, improvements in cancer diagnosis and prognosis are still poor, highlighting the need for individualized strategies. Toward this goal, risk prediction models and molecular diagnostic tools have been developed, tailoring each step of risk assessment from diagnosis to treatment and clinical outcomes based on the individual's clinical, epidemiological, and molecular profiles. These approaches hold increasing promise for delivering a new paradigm to maximize the efficiency of cancer surveillance and efficacy of treatment. However, they require stringent study design, methodology development, comprehensive assessment of biomarkers and risk factors, and extensive validation to ensure their overall usefulness for clinical translation. In the current study, the authors conducted a systematic review using breast cancer as an example and provide general guidelines for risk prediction models and molecular diagnostic tools, including development, assessment, and validation. © 2013 American Cancer Society.

Biomarker-based risk prediction in the community.

PubMed

AbouEzzeddine, Omar F; McKie, Paul M; Scott, Christopher G; Rodeheffer, Richard J; Chen, Horng H; Michael Felker, G; Jaffe, Allan S; Burnett, John C; Redfield, Margaret M

2016-11-01

Guided by predictive characteristics of cardiovascular biomarkers, we explored the clinical implications of a simulated biomarker-guided heart failure (HF) and major adverse cardiovascular events (MACE) prevention strategy in the community. In a community cohort (n = 1824), the predictive characteristics for HF and MACE of galectin-3 (Gal-3), ST2, high-sensitivity cardiac troponin I (hscTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-brain natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP) were established. We performed number needed to screen (NNS) and treat (NNT) with the intervention analyses according to biomarker screening strategy and intervention efficacy in persons with at least one cardiovascular risk factor. In the entire cohort, for both HF and MACE, the predictive characteristics of NT-proBNP and hscTnI were superior to other biomarkers; alone, in a multimarker model, and adjusting for clinical risk factors. An NT-proBNP-guided preventative intervention with an intervention effect size (4-year hazard ratio for intervention in biomarker positive cohort) of ≤0.7 would reduce the global burden of HF by ≥20% and MACE by ≥15%. From this simulation, the NNS to prevent one HF event or MACE in 4 years would be ≤100 with a NNT to prevent one HF event of ≤20 and one MACE of ≤10. The predictive characteristics of NT-proBNP and hscTnI for HF or MACE in the community are superior to other biomarkers. Biomarker-guided preventative interventions with reasonable efficacy would compare favourably to established preventative interventions. This data provides a framework for biomarker selection which may inform design of biomarker-guided preventative intervention trials. © 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.

The public health impact of malaria vaccine RTS,S in malaria endemic Africa: country-specific predictions using 18 month follow-up Phase III data and simulation models.

PubMed

Penny, Melissa A; Galactionova, Katya; Tarantino, Michael; Tanner, Marcel; Smith, Thomas A

2015-07-29

The RTS,S/AS01 malaria vaccine candidate recently completed Phase III trials in 11 African sites. Recommendations for its deployment will partly depend on predictions of public health impact in endemic countries. Previous predictions of these used only limited information on underlying vaccine properties and have not considered country-specific contextual data. Each Phase III trial cohort was simulated explicitly using an ensemble of individual-based stochastic models, and many hypothetical vaccine profiles. The true profile was estimated by Bayesian fitting of these models to the site- and time-specific incidence of clinical malaria in both trial arms over 18 months of follow-up. Health impacts of implementation via two vaccine schedules in 43 endemic sub-Saharan African countries, using country-specific prevalence, access to care, immunisation coverage and demography data, were predicted via weighted averaging over many simulations. The efficacy against infection of three doses of vaccine was initially approximately 65 % (when immunising 6-12 week old infants) and 80 % (children 5-17 months old), with a 1 year half-life (exponential decay). Either schedule will avert substantial disease, but predicted impact strongly depends on the decay rate of vaccine effects and average transmission intensity. For the first time Phase III site- and time-specific data were available to estimate both the underlying profile of RTS,S/AS01 and likely country-specific health impacts. Initial efficacy will probably be high, but decay rapidly. Adding RTS,S to existing control programs, assuming continuation of current levels of malaria exposure and of health system performance, will potentially avert 100-580 malaria deaths and 45,000 to 80,000 clinical episodes per 100,000 fully vaccinated children over an initial 10-year phase.

The Mechanisms for Within-Host Influenza Virus Control Affect Model-Based Assessment and Prediction of Antiviral Treatment

PubMed Central

Cao, Pengxing

2017-01-01

Models of within-host influenza viral dynamics have contributed to an improved understanding of viral dynamics and antiviral effects over the past decade. Existing models can be classified into two broad types based on the mechanism of viral control: models utilising target cell depletion to limit the progress of infection and models which rely on timely activation of innate and adaptive immune responses to control the infection. In this paper, we compare how two exemplar models based on these different mechanisms behave and investigate how the mechanistic difference affects the assessment and prediction of antiviral treatment. We find that the assumed mechanism for viral control strongly influences the predicted outcomes of treatment. Furthermore, we observe that for the target cell-limited model the assumed drug efficacy strongly influences the predicted treatment outcomes. The area under the viral load curve is identified as the most reliable predictor of drug efficacy, and is robust to model selection. Moreover, with support from previous clinical studies, we suggest that the target cell-limited model is more suitable for modelling in vitro assays or infection in some immunocompromised/immunosuppressed patients while the immune response model is preferred for predicting the infection/antiviral effect in immunocompetent animals/patients. PMID:28933757

A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials

PubMed Central

de Sola, Susana; de la Torre, Rafael; Sánchez-Benavides, Gonzalo; Benejam, Bessy; Cuenca-Royo, Aida; del Hoyo, Laura; Rodríguez, Joan; Catuara-Solarz, Silvina; Sanchez-Gutierrez, Judit; Dueñas-Espin, Ivan; Hernandez, Gimena; Peña-Casanova, Jordi; Langohr, Klaus; Videla, Sebastia; Blehaut, Henry; Farre, Magi; Dierssen, Mara; Cuenca-Royo, Aida

2015-01-01

The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of DS. PMID:26089807

Self-Efficacy Beliefs, Motivation, Race, and Gender in Middle School Science

NASA Astrophysics Data System (ADS)

Britner, Shari L.; Pajares, Frank

The purpose of this study was to discover whether the science motivation beliefs of middle school students (N = 262) vary as a function of their gender or race/ethnicity and to determine whether science self-efficacy beliefs predict science achievement when motivation variables shown to predict achievement in other academic areas are controlled. Girls reported stronger science self-efficacy and self-efficacy for self-regulation, and they received higher grades in science. Boys had stronger performance-approach goals. White students had stronger self-efficacy and achievement, and African American students reported stronger task goals. Self-efficacy was the only motivation variable to predict the science achievement of girls, boys, and White students. Self-efficacy and self-concept predicted the science achievement of African American students. Results are interpreted from the perspective of Bandura's social cognitive theory.

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial

PubMed Central

Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

2016-01-01

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD. PMID:27552585

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial.

PubMed

Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

2016-08-23

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.

Safety and Efficacy of Catheter Direct Thrombolysis in Management of Acute Iliofemoral Deep Vein Thrombosis: A Systematic Review

PubMed Central

Elbasty, Ahmed; Metcalf, James

2017-01-01

Purpose Catheter direct thrombolysis (CDT) has been shown to be an effective treatment for deep venous thrombosis. The objective of the review is to improve safety and efficacy of the CDT by using ward based protocol, better able to predict complications and treatment outcome through monitoring of haemostatic parameters and clinical observation during thrombolysis procedure. Materials and Methods MEDLINE, EMBASE, CENTRAL and Web of Science were searched for all articles on deep venous thrombosis, thrombolysis and correlations of clinical events (bleeding, successful thrombolysis) during thrombolysis with hemostatic parameters to March 2016. The risk of bias in included studies was assessed by Cochrane Collaboration’s tool and Cochrane Risk of Bias Assessment Tool: for Non-Randomized Studies of Interventions. Results Twenty-four studies were included in the review and we found that improving safety and efficacy of CDT by using ward based protocol depending on eight factors; strict patient selection criteria, types of fibrinolytic drugs, mode of fibrinolytic drug injection, biochemical markers monitoring (fibrinogen, D-dimer, activated partial thromboplastin time, plasminogen activator inhibitor-1), timing of intervention, usage of intermittent pneumatic calf, ward monitoring and thrombolysis imaging assessment (intravascular ultrasound). These factors may help to improve safety and efficacy by reducing total thrombolytic drug dosage and at the same time ensure successful lysis. There is a marked lack of randomized controlled trials discussing the safety and efficacy of catheter direct thrombolysis. Conclusion CDT can be performed safely and efficiently in clinical ward, providing that careful nursing, biochemical monitoring, proper selection and mode of infusion of fibrinolytic drugs, usage of Intermittent pneumatic calf and adequate thrombolysis imaging assessment are ensured. PMID:29354622

Prematurity and parental self-efficacy: the Preterm Parenting & Self-Efficacy Checklist.

PubMed

Pennell, Claire; Whittingham, Koa; Boyd, Roslyn; Sanders, Matthew; Colditz, Paul

2012-12-01

There is a lack of research investigating parental self-efficacy in parents of infants born preterm as well as a paucity of parental self-efficacy measures that are domain-specific and theoretically grounded. This study aimed to compare parental self-efficacy in parents of infants born term, preterm and very preterm as well as to test whether parental self-efficacy mediates the relationship between psychological symptoms and parental competence. In order to achieve this, a new measure of parental self-efficacy and parental competence relevant for the preterm population and consistent with Bandura's (1977, 1986, 1989) conceptualisation of self-efficacy was developed. Participants included 155 parents, 83 of whom were parents of very preterm (GA<32 weeks), 40 parents of preterm (GA<37 weeks) and 32 parents of term born infants. Parents completed the Preterm Parenting & Self-Efficacy Checklist (the new measure), Family Demographic Questionnaire, Depression Anxiety Stress Scale and Self-Efficacy Questionnaire. This initial study indicates that the Preterm Parenting & Self-Efficacy Checklist has adequate content validity, construct validity, internal consistency and split half reliability. Contrary to expectations, parents of very preterm infants did not report significantly lower overall levels of parental self-efficacy or significantly higher levels of psychological symptoms compared to parents of preterm and term infants. Parental self-efficacy about parenting tasks mediated the relationship between psychological symptoms and self perceived parental competence as predicted. Clinical implications of the results and suggestions for future research are discussed. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

Evaluating principal surrogate endpoints with time-to-event data accounting for time-varying treatment efficacy.

PubMed

Gabriel, Erin E; Gilbert, Peter B

2014-04-01

Principal surrogate (PS) endpoints are relatively inexpensive and easy to measure study outcomes that can be used to reliably predict treatment effects on clinical endpoints of interest. Few statistical methods for assessing the validity of potential PSs utilize time-to-event clinical endpoint information and to our knowledge none allow for the characterization of time-varying treatment effects. We introduce the time-dependent and surrogate-dependent treatment efficacy curve, ${\\mathrm {TE}}(t|s)$, and a new augmented trial design for assessing the quality of a biomarker as a PS. We propose a novel Weibull model and an estimated maximum likelihood method for estimation of the ${\\mathrm {TE}}(t|s)$ curve. We describe the operating characteristics of our methods via simulations. We analyze data from the Diabetes Control and Complications Trial, in which we find evidence of a biomarker with value as a PS.

The Wisconsin Predicting Patients' Relapse questionnaire

PubMed Central

Bolt, Daniel M.; McCarthy, Danielle E.; Japuntich, Sandra J.; Fiore, Michael C.; Smith, Stevens S.; Baker, Timothy B.

2009-01-01

Introduction: Relapse is the most common smoking cessation outcome. Accurate prediction of relapse likelihood could be an important clinical tool used to influence treatment selection or duration. The aim of this research was to develop a brief clinical relapse proneness questionnaire to be used with smokers interested in quitting in a clinical setting where time is at a premium. Methods: Diverse items assessing constructs shown in previous research to be related to relapse risk, such as nicotine dependence and self-efficacy, were evaluated to determine their independent contributions to relapse prediction. In an exploratory dataset, candidate items were assessed among smokers motivated to quit smoking who enrolled in one of three randomized controlled smoking cessation trials. A cross-validation dataset was used to compare the relative predictive power of the new instrument against the Fagerström Test for Nicotine Dependence (FTND) at 1-week, 8-week, and 6-month postquit assessments. Results: We selected seven items with relatively nonoverlapping content for the Wisconsin Predicting Patient's Relapse (WI-PREPARE) measure, a brief, seven-item questionnaire that taps physical dependence, environmental factors, and individual difference characteristics. Cross-validation analyses suggested that the WI-PREPARE demonstrated a stronger prediction of relapse at 1-week and 8-week postquit assessments than the FTND and comparable prediction to the FTND at a 6-month postquit assessment. Discussion: The WI-PREPARE is easy to score, suggests the nature of a patient's relapse risk, and predicts short- and medium-term relapse better than the FTND. PMID:19372573

Sources of Science Self-Efficacy Beliefs of Middle School Students

ERIC Educational Resources Information Center

Britner, Shari L.; Pajares, Frank

2006-01-01

The purpose of this study was to investigate the degree to which A. Bandura's ([1997]) hypothesized sources of self-efficacy predict the science self-efficacy beliefs of middle school students (N = 319), to replicate previous findings that science self-efficacy predicts science achievement, and to explore how science self-efficacy and its…

Efficacy, end points and eventualities: sumatriptan/naproxen versus butalbital/paracetamol/caffeine in the treatment of migraine.

PubMed

Fox, Anthony W

2012-09-01

Migraine is a widespread, relapsing, remittent syndrome. No animal model predicts whether test medications will be clinically useful. Using a modern, well-controlled, sophisticated study design, Derosier et al. demonstrates not only that a butalbital formulation has modest efficacy as an acute treatment for migraine but also that a sumatriptan-naproxen combination is superior. These conclusions are reached using a variety of internally consistent secondary efficacy end points. The primary end point chosen (highly conservative and fashionable in some academic circles) was a technical failure (and not a negative experimental finding). Migraine is intrinsically pleiomorphic: diverse treatment options help match patient with therapy. This study does not justify blanket bans on (admittedly hazardous) barbiturate therapies, and regulators should not impose end point conservatism to an extent that will stifle further progress.

Efficacy of Various Scoring Systems for Predicting the 28-Day Survival Rate among Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease Requiring Emergency Intensive Care.

PubMed

Feng, Zhihong; Wang, Tao; Liu, Ping; Chen, Sipeng; Xiao, Han; Xia, Ning; Luo, Zhiming; Wei, Bing; Nie, Xiuhong

2017-01-01

We aimed to investigate the efficacy of four severity-of-disease scoring systems in predicting the 28-day survival rate among patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) requiring emergency care. Clinical data of patients with AECOPD who required emergency care were recorded over 2 years. APACHE II, SAPS II, SOFA, and MEDS scores were calculated from severity-of-disease indicators recorded at admission and compared between patients who died within 28 days of admission (death group; 46 patients) and those who did not (survival group; 336 patients). Compared to the survival group, the death group had a significantly higher GCS score, frequency of comorbidities including hypertension and heart failure, and age ( P < 0.05 for all). With all four systems, scores of age, gender, renal inadequacy, hypertension, coronary heart disease, heart failure, arrhythmia, anemia, fracture leading to bedridden status, tumor, and the GCS were significantly higher in the death group than the survival group. The prediction efficacy of the APACHE II and SAPS II scores was 88.4%. The survival rates did not differ significantly between APACHE II and SAPS II ( P = 1.519). Our results may guide triage for early identification of critically ill patients with AECOPD in the emergency department.

Scientific Inquiry Self-Efficacy and Computer Game Self-Efficacy as Predictors and Outcomes of Middle School Boys' and Girls' Performance in a Science Assessment in a Virtual Environment

NASA Astrophysics Data System (ADS)

Bergey, Bradley W.; Ketelhut, Diane Jass; Liang, Senfeng; Natarajan, Uma; Karakus, Melissa

2015-10-01

The primary aim of the study was to examine whether performance on a science assessment in an immersive virtual environment was associated with changes in scientific inquiry self-efficacy. A secondary aim of the study was to examine whether performance on the science assessment was equitable for students with different levels of computer game self-efficacy, including whether gender differences were observed. We examined 407 middle school students' scientific inquiry self-efficacy and computer game self-efficacy before and after completing a computer game-like assessment about a science mystery. Results from path analyses indicated that prior scientific inquiry self-efficacy predicted achievement on end-of-module questions, which in turn predicted change in scientific inquiry self-efficacy. By contrast, computer game self-efficacy was neither predictive of nor predicted by performance on the science assessment. While boys had higher computer game self-efficacy compared to girls, multi-group analyses suggested only minor gender differences in how efficacy beliefs related to performance. Implications for assessments with virtual environments and future design and research are discussed.

Teacher' Interpersonal Self-Efficacy: Evaluation and Predictive Capacity of Teacher Burnout

ERIC Educational Resources Information Center

García-Ros, Rafael; Fuentes, María C.; Fernández, Basilio

2015-01-01

Introduction: This study analyzed the predictive capacity and incremental validity of teachers' interpersonal self-efficacy on their levels of burnout. First, it presents the validation process of a Spanish adaptation of the Teacher Interpersonal Self-Efficacy Scale--TISES--(Browers & Tomic, 1999, 2001). Second, the predictive capacity of…

Falls efficacy, postural balance, and risk for falls in older adults with falls-related emergency department visits: prospective cohort study.

PubMed

Pua, Yong-Hao; Ong, Peck-Hoon; Clark, Ross Allan; Matcher, David B; Lim, Edwin Choon-Wyn

2017-12-21

Risk for falls in older adults has been associated with falls efficacy (self-perceived confidence in performing daily physical activities) and postural balance, but available evidence is limited and mixed. We examined the interaction between falls efficacy and postural balance and its association with future falls. We also investigated the association between falls efficacy and gait decline. Falls efficacy, measured by the Modified Falls Efficacy Scale (MFES), and standing postural balance, measured using computerized posturography on a balance board, were obtained from 247 older adults with a falls-related emergency department visit. Six-month prospective fall rate and habitual gait speed at 6 months post baseline assessment were also measured. In multivariable proportional odds analyses adjusted for potential confounders, falls efficacy modified the association between postural balance and fall risk (interaction P = 0.014): increasing falls efficacy accentuated the increased fall risk related to poor postural balance. Low baseline falls efficacy was strongly predictive of worse gait speed (0.11 m/s [0.06 to 0.16] slower gait speed per IQR decrease in MFES; P < 0.001). Older adults with high falls efficacy but poor postural balance were at greater risk for falls than those with low falls efficacy; however, low baseline falls efficacy was strongly associated with worse gait function at follow-up. Further research into these subgroups of older adults is warranted. ClinicalTrials.gov identifier: NCT01713543 .

Prosociality: the contribution of traits, values, and self-efficacy beliefs.

PubMed

Caprara, Gian Vittorio; Alessandri, Guido; Eisenberg, Nancy

2012-06-01

The present study examined how agreeableness, self-transcendence values, and empathic self-efficacy beliefs predict individuals' tendencies to engage in prosocial behavior (i.e., prosociality) across time. Participants were 340 young adults, 190 women and 150 men, age approximately 21 years at Time 1 and 25 years at Time 2. Measures of agreeableness, self-transcendence, empathic self-efficacy beliefs, and prosociality were collected at 2 time points. The findings corroborated the posited paths of relations, with agreeableness directly predicting self-transcendence and indirectly predicting empathic self-efficacy beliefs and prosociality. Self-transcendence mediated the relation between agreeableness and empathic self-efficacy beliefs. Empathic self-efficacy beliefs mediated the relation of agreeableness and self-transcendence to prosociality. Finally, earlier prosociality predicted agreeableness and empathic self-efficacy beliefs assessed at Time 2. The posited conceptual model accounted for a significant portion of variance in prosociality and provides guidance to interventions aimed at promoting prosociality. 2012 APA, all rights reserved

Connecting Technological Innovation in Artificial Intelligence to Real-world Medical Practice through Rigorous Clinical Validation: What Peer-reviewed Medical Journals Could Do

PubMed Central

2018-01-01

Artificial intelligence (AI) is projected to substantially influence clinical practice in the foreseeable future. However, despite the excitement around the technologies, it is yet rare to see examples of robust clinical validation of the technologies and, as a result, very few are currently in clinical use. A thorough, systematic validation of AI technologies using adequately designed clinical research studies before their integration into clinical practice is critical to ensure patient benefit and safety while avoiding any inadvertent harms. We would like to suggest several specific points regarding the role that peer-reviewed medical journals can play, in terms of study design, registration, and reporting, to help achieve proper and meaningful clinical validation of AI technologies designed to make medical diagnosis and prediction, focusing on the evaluation of diagnostic accuracy efficacy. Peer-reviewed medical journals can encourage investigators who wish to validate the performance of AI systems for medical diagnosis and prediction to pay closer attention to the factors listed in this article by emphasizing their importance. Thereby, peer-reviewed medical journals can ultimately facilitate translating the technological innovations into real-world practice while securing patient safety and benefit. PMID:29805337

Connecting Technological Innovation in Artificial Intelligence to Real-world Medical Practice through Rigorous Clinical Validation: What Peer-reviewed Medical Journals Could Do.

PubMed

Park, Seong Ho; Kressel, Herbert Y

2018-05-28

Artificial intelligence (AI) is projected to substantially influence clinical practice in the foreseeable future. However, despite the excitement around the technologies, it is yet rare to see examples of robust clinical validation of the technologies and, as a result, very few are currently in clinical use. A thorough, systematic validation of AI technologies using adequately designed clinical research studies before their integration into clinical practice is critical to ensure patient benefit and safety while avoiding any inadvertent harms. We would like to suggest several specific points regarding the role that peer-reviewed medical journals can play, in terms of study design, registration, and reporting, to help achieve proper and meaningful clinical validation of AI technologies designed to make medical diagnosis and prediction, focusing on the evaluation of diagnostic accuracy efficacy. Peer-reviewed medical journals can encourage investigators who wish to validate the performance of AI systems for medical diagnosis and prediction to pay closer attention to the factors listed in this article by emphasizing their importance. Thereby, peer-reviewed medical journals can ultimately facilitate translating the technological innovations into real-world practice while securing patient safety and benefit.

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling.

PubMed

Mehrotra, Nitin; Bhattaram, Atul; Earp, Justin C; Florian, Jeffry; Krudys, Kevin; Lee, Jee Eun; Lee, Joo Yeon; Liu, Jiang; Mulugeta, Yeruk; Yu, Jingyu; Zhao, Ping; Sinha, Vikram

2016-07-01

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy. Copyright © 2016 U.S. Government work not protected by U.S. copyright.

ASPsiRNA: A Resource of ASP-siRNAs Having Therapeutic Potential for Human Genetic Disorders and Algorithm for Prediction of Their Inhibitory Efficacy.

PubMed

Monga, Isha; Qureshi, Abid; Thakur, Nishant; Gupta, Amit Kumar; Kumar, Manoj

2017-09-07

Allele-specific siRNAs (ASP-siRNAs) have emerged as promising therapeutic molecules owing to their selectivity to inhibit the mutant allele or associated single-nucleotide polymorphisms (SNPs) sparing the expression of the wild-type counterpart. Thus, a dedicated bioinformatics platform encompassing updated ASP-siRNAs and an algorithm for the prediction of their inhibitory efficacy will be helpful in tackling currently intractable genetic disorders. In the present study, we have developed the ASPsiRNA resource (http://crdd.osdd.net/servers/aspsirna/) covering three components viz (i) ASPsiDb , (ii) ASPsiPred , and (iii) analysis tools like ASP-siOffTar ASPsiDb is a manually curated database harboring 4543 (including 422 chemically modified) ASP-siRNAs targeting 78 unique genes involved in 51 different diseases. It furnishes comprehensive information from experimental studies on ASP-siRNAs along with multidimensional genetic and clinical information for numerous mutations. ASPsiPred is a two-layered algorithm to predict efficacy of ASP-siRNAs for fully complementary mutant (Eff mut ) and wild-type allele (Eff wild ) with one mismatch by ASPsiPred SVM and ASPsiPred matrix , respectively. In ASPsiPred SVM , 922 unique ASP-siRNAs with experimentally validated quantitative Eff mut were used. During 10-fold cross-validation (10nCV) employing various sequence features on the training/testing dataset (T737), the best predictive model achieved a maximum Pearson's correlation coefficient (PCC) of 0.71. Further, the accuracy of the classifier to predict Eff mut against novel genes was assessed by leave one target out cross-validation approach (LOTOCV). ASPsiPred matrix was constructed from rule-based studies describing the effect of single siRNA:mRNA mismatches on the efficacy at 19 different locations of siRNA. Thus, ASPsiRNA encompasses the first database, prediction algorithm, and off-target analysis tool that is expected to accelerate research in the field of RNAi-based therapeutics for human genetic diseases. Copyright © 2017 Monga et al.

High School Students' Cognitive Flexibility Is Predicted by Self-Efficacy and Achievement

ERIC Educational Resources Information Center

Esen, Binnaz Kiran; Özcan, H. Duygu; Sezgin, Mehtap

2017-01-01

In this research, the prediction cognitive flexibility obtained by general self-efficacy, academic self-efficacy, social self-efficacy, emotional self-efficacy and achievement is examined. This study is executed in 2014-2015 academic year on 760 high school students who are between ages 15 and 18. Cognitive flexibility Scale is developed by Bilgin…

Therapist correlates of attitudes toward sexual minority individuals, affirmative counseling self-efficacy, and beliefs about affirmative practice.

PubMed

Alessi, Edward J; Dillon, Frank R; Kim, Hillary Mi-Sung

2016-07-01

The purpose of this study was to examine the influence of training in sexual minority issues, professional identification, and gender on attitudes toward lesbian, gay, and bisexual individuals, affirmative counseling self-efficacy, and beliefs about affirmative practice among mental health practitioners in the USA. We used the Internet to recruit a nationwide sample of 443 heterosexual psychologists (n = 270), clinical social workers (n = 110), and marriage and family therapists (n = 63) residing in the USA. When controlling for years of practice experience and age, results from structural equation modeling analysis showed that training was associated with more affirmative attitudes, higher levels of affirmative counseling self-efficacy, and more positive beliefs. Female therapists reported more affirmative attitudes and higher levels of affirmative counseling self-efficacy than male therapists. Professional identification did not predict any criterion variables, when controlling for years of practice experience and age. Findings suggest that it will be important for educational and training initiatives to consider the effect of gender role socialization on attitudes and affirmative counseling self-efficacy, especially among beginning male therapists.

The observed correlation between in vivo clinical pharmacokinetic parameters and in vitro potency of VEGFR-2 inhibitors. Can this be used as a prospective guide for the development of novel compounds?

PubMed

Benjamin, B; Sahu, M; Bhatnagar, U; Abhyankar, D; Srinivas, N R

2012-04-01

Literature data on the clinical pharmacokinetics of various VEGFR-2 inhibitors along with in vitro potency data were correlated and a linear relationship was established in spite of limited data set. In this work, a model set comprised of axitinib, recentin, sunitinib, pazopanib, and sorafenib were used. The in vitro potencies of the model set compounds were correlated with the published unbound plasma concentrations (Cmax, Cavg, Ctrough). The established linear regression (r2>0.90) equation was used to predict Cmax, Cavg, Ctrough of the 'prediction set' (motesanib, telatinib, CP547632, vatalanib, vandetanib) using in vitro potency and unbound protein free fraction. Cavg and Ctrough of prediction set were closely matched (0.2-1.8 fold of reported), demonstrating the usefulness of such predictions for tracking the target related modulation and/or efficacy signals within the clinically optimized population average. In case of Cmax where correlation was least anticipated, the predicted values were within 0.1-1.1 fold of those reported. Such predictions of appropriate parameters would provide rough estimates of whether or not therapeutically relevant dose(s) have been administered when clinical investigations of novel agents of this class are being performed. Therefore, it may aid in increasing clinical doses to a desired level if safety of the compound does not compromise such dose increases. In conclusion, the proposed model may prospectively guide the dosing strategies and would greatly aid the development of novel compounds in this class. © Georg Thieme Verlag KG Stuttgart · New York.

FAST INdiCATE Trial protocol. Clinical efficacy of functional strength training for upper limb motor recovery early after stroke: neural correlates and prognostic indicators.

PubMed

Pomeroy, Valerie M; Ward, Nick S; Johansen-Berg, Heidi; van Vliet, Paulette; Burridge, Jane; Hunter, Susan M; Lemon, Roger N; Rothwell, John; Weir, Christopher J; Wing, Alan; Walker, Andrew A; Kennedy, Niamh; Barton, Garry; Greenwood, Richard J; McConnachie, Alex

2014-02-01

Functional strength training in addition to conventional physical therapy could enhance upper limb recovery early after stroke more than movement performance therapy plus conventional physical therapy. To determine (a) the relative clinical efficacy of conventional physical therapy combined with functional strength training and conventional physical therapy combined with movement performance therapy for upper limb recovery; (b) the neural correlates of response to conventional physical therapy combined with functional strength training and conventional physical therapy combined with movement performance therapy; (c) whether any one or combination of baseline measures predict motor improvement in response to conventional physical therapy combined with functional strength training or conventional physical therapy combined with movement performance therapy. Randomized, controlled, observer-blind trial. The sample will consist of 288 participants with upper limb paresis resulting from a stroke that occurred within the previous 60 days. All will be allocated to conventional physical therapy combined with functional strength training or conventional physical therapy combined with movement performance therapy. Functional strength training and movement performance therapy will be undertaken for up to 1·5 h/day, five-days/week for six-weeks. Measurements will be undertaken before randomization, six-weeks thereafter, and six-months after stroke. Primary efficacy outcome will be the Action Research Arm Test. Explanatory measurements will include voxel-wise estimates of brain activity during hand movement, brain white matter integrity (fractional anisotropy), and brain-muscle connectivity (e.g. latency of motor evoked potentials). The primary clinical efficacy analysis will compare treatment groups using a multilevel normal linear model adjusting for stratification variables and for which therapist administered the treatment. Effect of conventional physical therapy combined with functional strength training versus conventional physical therapy combined with movement performance therapy will be summarized using the adjusted mean difference and 95% confidence interval. To identify the neural correlates of improvement in both groups, we will investigate associations between change from baseline in clinical outcomes and each explanatory measure. To identify baseline measurements that independently predict motor improvement, we will develop a multiple regression model. © 2013 The Authors. International Journal of Stroke published by John Wiley & Sons Ltd on behalf of World Stroke Organization.

Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors.

PubMed

Bodei, L; Kidd, M; Modlin, I M; Severi, S; Drozdov, I; Nicolini, S; Kwekkeboom, D J; Krenning, E P; Baum, R P; Paganelli, G

2016-05-01

Peptide receptor radionuclide therapy (PRRT) is an effective method for treating neuroendocrine tumors (NETs). It is limited, however, in the prediction of individual tumor response and the precise and early identification of changes in tumor size. Currently, response prediction is based on somatostatin receptor expression and efficacy by morphological imaging and/or chromogranin A (CgA) measurement. The aim of this study was to assess the accuracy of circulating NET transcripts as a measure of PRRT efficacy, and moreover to identify prognostic gene clusters in pretreatment blood that could be interpolated with relevant clinical features in order to define a biological index for the tumor and a predictive quotient for PRRT efficacy. NET patients (n = 54), M: F 37:17, median age 66, bronchial: n = 13, GEP-NET: n = 35, CUP: n = 6 were treated with (177)Lu-based-PRRT (cumulative activity: 6.5-27.8 GBq, median 18.5). At baseline: 47/54 low-grade (G1/G2; bronchial typical/atypical), 31/49 (18)FDG positive and 39/54 progressive. Disease status was assessed by RECIST1.1. Transcripts were measured by real-time quantitative reverse transcription PCR (qRT-PCR) and multianalyte algorithmic analysis (NETest); CgA by enzyme-linked immunosorbent assay (ELISA). Gene cluster (GC) derivations: regulatory network, protein:protein interactome analyses. chi-square, non-parametric measurements, multiple regression, receiver operating characteristic and Kaplan-Meier survival. The disease control rate was 72 %. Median PFS was not achieved (follow-up: 1-33 months, median: 16). Only grading was associated with response (p < 0.01). At baseline, 94 % of patients were NETest-positive, while CgA was elevated in 59 %. NETest accurately (89 %, χ(2) = 27.4; p = 1.2 × 10(-7)) correlated with treatment response, while CgA was 24 % accurate. Gene cluster expression (growth-factor signalome and metabolome) had an AUC of 0.74 ± 0.08 (z-statistic = 2.92, p < 0.004) for predicting response (76 % accuracy). Combination with grading reached an AUC: 0.90 ± 0.07, irrespective of tumor origin. Circulating transcripts correlated accurately (94 %) with PRRT responders (SD+PR+CR; 97 %) vs. non-responders (91 %). Blood NET transcript levels and the predictive quotient (circulating gene clusters+grading) accurately predicted PRRT efficacy. CgA was non-informative.

The clinical course over the first year of whiplash associated disorders (WAD): pain-related disability predicts outcome in a mildly affected sample.

PubMed

Åsenlöf, Pernilla; Bring, Annika; Söderlund, Anne

2013-12-21

Different recovery patterns are reported for those befallen a whip-lash injury, but little is known about the variability within subgroups. The aims were (1) to compare a self-selected mildly affected sample (MILD) with a self-selected moderately to severely affected sample (MOD/SEV) with regard to background characteristics and pain-related disability, pain intensity, functional self-efficacy, fear of movement/(re)injury, pain catastrophising, post-traumatic stress symptoms in the acute stage (at baseline), (2) to study the development over the first year after the accident for the above listed clinical variables in the MILD sample, and (3) to study the validity of a prediction model including baseline levels of clinical variables on pain-related disability one year after baseline assessments. The study had a prospective and correlative design. Ninety-eight participants were consecutively selected. Inclusion criteria; age 18 to 65 years, WAD grade I-II, Swedish language skills, and subjective report of not being in need of treatment due to mild symptoms. A multivariate linear regression model was applied for the prediction analysis. The MILD sample was less affected in all study variables compared to the MOD/SEV sample. Pain-related disability, pain catastrophising, and post-traumatic stress symptoms decreased over the first year after the accident, whereas functional self-efficacy and fear of movement/(re)injury increased. Pain intensity was stable. Pain-related disability at baseline emerged as the only statistically significant predictor of pain-related disability one year after the accident (Adj r² = 0.67). A good prognosis over the first year is expected for the majority of individuals with WAD grade I or II who decline treatment due to mild symptoms. The prediction model was not valid in the MILD sample except for the contribution of pain-related disability. An implication is that early observations of individuals with elevated levels of pain-related disability are warranted, although they may decline treatment.

Early presence of anti-angiogenesis-related adverse events as a potential biomarker of antitumor efficacy in metastatic gastric cancer patients treated with apatinib: a cohort study.

PubMed

Liu, Xinyang; Qin, Shukui; Wang, Zhichao; Xu, Jianming; Xiong, Jianping; Bai, Yuxian; Wang, Zhehai; Yang, Yan; Sun, Guoping; Wang, Liwei; Zheng, Leizhen; Xu, Nong; Cheng, Ying; Guo, Weijian; Yu, Hao; Liu, Tianshu; Lagiou, Pagona; Li, Jin

2017-09-05

Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients. We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan-Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival. Presence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64-0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53-0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p < 0.001). Results remained significant in landmark analyses. The onset of any single AE or any combinations of the AEs were all statistically significantly associated with prolonged OS, except for the presence of proteinuria. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting overall survival. Presence of HTN, proteinuria, or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients.

Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: development and application of a bayesian random-effects model.

PubMed

Coudeville, Laurent; Bailleux, Fabrice; Riche, Benjamin; Megas, Françoise; Andre, Philippe; Ecochard, René

2010-03-08

Antibodies directed against haemagglutinin, measured by the haemagglutination inhibition (HI) assay are essential to protective immunity against influenza infection. An HI titre of 1:40 is generally accepted to correspond to a 50% reduction in the risk of contracting influenza in a susceptible population, but limited attempts have been made to further quantify the association between HI titre and protective efficacy. We present a model, using a meta-analytical approach, that estimates the level of clinical protection against influenza at any HI titre level. Source data were derived from a systematic literature review that identified 15 studies, representing a total of 5899 adult subjects and 1304 influenza cases with interval-censored information on HI titre. The parameters of the relationship between HI titre and clinical protection were estimated using Bayesian inference with a consideration of random effects and censorship in the available information. A significant and positive relationship between HI titre and clinical protection against influenza was observed in all tested models. This relationship was found to be similar irrespective of the type of viral strain (A or B) and the vaccination status of the individuals. Although limitations in the data used should not be overlooked, the relationship derived in this analysis provides a means to predict the efficacy of inactivated influenza vaccines when only immunogenicity data are available. This relationship can also be useful for comparing the efficacy of different influenza vaccines based on their immunological profile.

Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

PubMed Central

Vandenberk, Lien; Van Woensel, Matthias; Schaaf, Marco; De Vleeschouwer, Steven; Agostinis, Patrizia

2017-01-01

ABSTRACT Glioblastoma (GBM) is resistant to most multimodal therapies. Clinical success of immune-checkpoint inhibitors (ICIs) has spurred interest in applying ICIs targeting CTLA4, PD1 or IDO1 against GBM. This amplifies the need to ascertain GBM's intrinsic susceptibility (or resistance) toward these ICIs, through clinical biomarkers that may also “guide and prioritize” preclinical testing. Here, we interrogated the TCGA and/or REMBRANDT human patient-cohorts to predict GBM's predisposition toward ICIs. We exploited various broad clinical biomarkers, including mutational or predicted-neoantigen burden, pre-existing or basal levels of tumor-infiltrating T lymphocytes (TILs), differential expression of immune-checkpoints within the tumor and their correlation with particular TILs/Treg-associated functional signature and prognostic impact of differential immune-checkpoint expression. Based on these analyses, we found that predictive biomarkers of ICI responsiveness exhibited inconsistent patterns in GBM patients, i.e., they either predicted ICI resistance (as compared with typical ICI-responsive cancer-types like melanoma, lung cancer or bladder cancer) or susceptibility to therapeutic targeting of CTLA4 or IDO1. On the other hand, our comprehensive literature meta-analysis and preclinical testing of ICIs using an orthotopic GL261-glioma mice model, indicated significant antitumor properties of anti-PD1 antibody, whereas blockade of IDO1 or CTLA4 either failed or provided very marginal advantage. These trends raise the need to better assess the applicability of ICIs and associated biomarkers for GBM. PMID:28507806

Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an integrative modelling study

PubMed Central

Martin, N K; Robey, I F; Gaffney, E A; Gillies, R J; Gatenby, R A; Maini, P K

2012-01-01

Background: Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts. Methods: We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies. Results: The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1–7.2. Conclusion: Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1–7.2 is most promising. PMID:22382688

Teaching efficacy of nurses in clinical practice education: A cross-sectional study.

PubMed

Kim, Eun-Kyeung; Shin, Sujin

2017-07-01

Clinical nurses play a vital role in clinical practice education; thus, it is necessary to help clinical nurses have teaching efficacy through the development and application of systematic education programs. To identify nurses' teaching efficacy for clinical education and analyze the influencing factors of teaching efficacy. The study used a cross-sectional design. We used a convenience sample of 263 nurses from two hospitals. Teaching efficacy, general characteristics, and perception of clinical practice education were collected via self-reported questionnaires. Teaching efficacy was measured using Hwang's (2006) questionnaire, while perception of clinical practice education was measured using the Clinical Nurse Teacher Survey developed by Nishioka et al. (2014). Participants completed the questionnaire directly. The collected data were then analyzed using descriptive statistics, t-tests, ANOVAs, and multiple regression analysis with PASW Statistics 18.0. The mean total score of teaching efficacy was 72.5 (range 21-105). The leadership for students subscale had the highest score (3.56±0.59). The factors influencing teaching efficacy were length of clinical career (β=0.26, p<0.001) and perceptions of work satisfaction (β=0.20, p=.005), clinical supervisory relationship (β=0.18, p=.010), and nursing at the hospital ward (β=0.13, p=.029). Altogether, these variables explained 28% of the variance in teaching efficacy in nurses. Based on these results, nursing educators might need to develop greater confidence in their knowledge and enhance control of their teaching strategies. Nursing schools and hospitals might need to provide greater support and educational opportunities to nurse clinical practice instructors. Furthermore, constructing a system of cooperation between these colleges and educational hospitals, developing programs to enhance teaching efficacy, and identifying the clinical instructor's role are all necessary to promote clinical practice education. Copyright © 2017. Published by Elsevier Ltd.

A Bayesian elicitation of veterinary beliefs regarding systemic dry cow therapy: variation and importance for clinical trial design.

PubMed

Higgins, H M; Dryden, I L; Green, M J

2012-09-15

The two key aims of this research were: (i) to conduct a probabilistic elicitation to quantify the variation in veterinarians' beliefs regarding the efficacy of systemic antibiotics when used as an adjunct to intra-mammary dry cow therapy and (ii) to investigate (in a Bayesian statistical framework) the strength of future research evidence required (in theory) to change the beliefs of practising veterinary surgeons regarding the efficacy of systemic antibiotics, given their current clinical beliefs. The beliefs of 24 veterinarians in 5 practices in England were quantified as probability density functions. Classic multidimensional scaling revealed major variations in beliefs both within and between veterinary practices which included: confident optimism, confident pessimism and considerable uncertainty. Of the 9 veterinarians interviewed holding further cattle qualifications, 6 shared a confidently pessimistic belief in the efficacy of systemic therapy and whilst 2 were more optimistic, they were also more uncertain. A Bayesian model based on a synthetic dataset from a randomised clinical trial (showing no benefit with systemic therapy) predicted how each of the 24 veterinarians' prior beliefs would alter as the size of the clinical trial increased, assuming that practitioners would update their beliefs rationally in accordance with Bayes' theorem. The study demonstrated the usefulness of probabilistic elicitation for evaluating the diversity and strength of practitioners' beliefs. The major variation in beliefs observed raises interest in the veterinary profession's approach to prescribing essential medicines. Results illustrate the importance of eliciting prior beliefs when designing clinical trials in order to increase the chance that trial data are of sufficient strength to alter the clinical beliefs of practitioners and do not merely serve to satisfy researchers. Copyright © 2012 Elsevier B.V. All rights reserved.

Lacosamide efficacy and tolerability in clinical practice - Post marketing analysis from a single dedicated epilepsy center.

PubMed

Baker, Mark D; Abou-Khalil, Bassel W; Arain, Amir; Tummala, Pavan; Azar, Nabil J; Haas, Kevin F; Sonmezturk, Hasan H

2018-06-13

Post marketing analysis of anti-epileptic drug (AED) efficacy and tolerability is of great value to the clinician since it is more representative of clinical practice than clinical trial data. We analyzed our experience with lacosamide (LCM) in patients treated after marketing. We identified all patients who were treated with LCM during the four year period after marketing, excluding patients who were in clinical trials. We recorded demographic data and analyzed efficacy and tolerability in patients who had at least one follow up visit or telephone call 3 months after the initiation of LCM. A total of 165 patients met our inclusion criteria. The mean age was 41 years. The majority of the cohort had focal epilepsy (146 patients) (88.4%). The mean duration of treatment was 31.2 months. Eighty one patients (49.1%) were continuing LCM at last follow up. Adverse effects (AEs) and discontinuation were significantly more common when LCM was added to one or more Na-channel blocking agents (NCB) (p = 0.0003 and 0.17). The 50% responder rate was 26% at 3 months and increased to 49% at 36 months. Patients were more likely to continue the drug and less likely to have AEs with slower titration over >4 weeks (p = 0.02 for each). Four or more previously failed AEDs predicted poorer response rate compared to three or less AEDs (p = 0.001). LCM use in clinical practice was associated with greater rate of seizure freedom than in clinical trials. Discontinuation and occurrence of AEs were significantly more likely with faster titration and adding LCM to NCB agents. Copyright © 2018 Elsevier B.V. All rights reserved.

The Role of Means Efficacy When Predicting Creative Performance

ERIC Educational Resources Information Center

Simmons, Aneika L.; Payne, Stephanie C.; Pariyothorn, Matthew M.

2014-01-01

According to the "Internal-External Efficacy model", self-efficacy is an insufficient explanation for self-regulated behavior because it ignores the influence of external resources. Applying this theory of motivation to the prediction of creative performance, the extent to which means efficacy or the belief in the utility of external…

A structural model of family empowerment for families of children with special needs.

PubMed

Han, Kuem Sun; Yang, Yunkyung; Hong, Yeong Seon

2018-03-01

To explain and predict family empowerment in families of children with special needs. Family empowerment of families of children with special needs can be explained using the Double ABCX model. Although constant stressors such as parenting stress and family demands can have negative effects on family empowerment, family resources and parenting efficacy can mediate the negative effect through effective coping strategies. A cross-sectional research design was employed. A survey was conducted with 240 parents of children with special needs. Upon exclusion of four responses deemed inadequate to the statistics process, 236 responses were selected for the analysis. Based on the items used in the previous research, we used the scale of family demands 38, the scale of parenting stress 24, the scale of parenting efficacy 37, the scale of pattern of organisation 30, the scale of communication process 16 and the scale of family empowerment 32. In families of children with special needs, parenting stress had a negative effect on parenting efficacy and family resources, namely, pattern of organisation and communication process. Family needs had a positive effect on parenting efficacy. Parenting stress and family demands influenced family empowerment through parenting efficacy and family resources (pattern of organisation and communication process), while parenting efficacy contributed to family empowerment. This study empirically analysed the usefulness of the Double ABCX model in predicting family empowerment. Family resource factors (organisation pattern and communication process) and perception or judgement factors (such as parenting efficacy) were found to mediate the negative impact of various stressors experienced by families of children with special needs. The study findings suggest that clinical practice and management should focus on providing efficient intervention methods to lower stress in families of children with special needs. Reinforcing factors contributing to family empowerment, such as parenting efficacy, organisation pattern and communication process, will alleviate families' stress, resulting in a positive educational and developmental impact on children with special needs. © 2017 John Wiley & Sons Ltd.

A Systems Approach to Designing Effective Clinical Trials Using Simulations

PubMed Central

Fusaro, Vincent A.; Patil, Prasad; Chi, Chih-Lin; Contant, Charles F.; Tonellato, Peter J.

2013-01-01

Background Pharmacogenetics in warfarin clinical trials have failed to show a significant benefit compared to standard clinical therapy. This study demonstrates a computational framework to systematically evaluate pre-clinical trial design of target population, pharmacogenetic algorithms, and dosing protocols to optimize primary outcomes. Methods and Results We programmatically created an end-to-end framework that systematically evaluates warfarin clinical trial designs. The framework includes options to create a patient population, multiple dosing strategies including genetic-based and non-genetic clinical-based, multiple dose adjustment protocols, pharmacokinetic/pharmacodynamics (PK/PD) modeling and international normalization ratio (INR) prediction, as well as various types of outcome measures. We validated the framework by conducting 1,000 simulations of the CoumaGen clinical trial primary endpoints. The simulation predicted a mean time in therapeutic range (TTR) of 70.6% and 72.2% (P = 0.47) in the standard and pharmacogenetic arms, respectively. Then, we evaluated another dosing protocol under the same original conditions and found a significant difference in TTR between the pharmacogenetic and standard arm (78.8% vs. 73.8%; P = 0.0065), respectively. Conclusions We demonstrate that this simulation framework is useful in the pre-clinical assessment phase to study and evaluate design options and provide evidence to optimize the clinical trial for patient efficacy and reduced risk. PMID:23261867

Computational models of Bitemporal, Bifrontal and Right Unilateral ECT predict differential stimulation of brain regions associated with efficacy and cognitive side effects.

PubMed

Bai, S; Gálvez, V; Dokos, S; Martin, D; Bikson, M; Loo, C

2017-03-01

Extensive clinical research has shown that the efficacy and cognitive outcomes of electroconvulsive therapy (ECT) are determined, in part, by the type of electrode placement used. Bitemporal ECT (BT, stimulating electrodes placed bilaterally in the frontotemporal region) is the form of ECT with relatively potent clinical and cognitive side effects. However, the reasons for this are poorly understood. This study used computational modelling to examine regional differences in brain excitation between BT, Bifrontal (BF) and Right Unilateral (RUL) ECT, currently the most clinically-used ECT placements. Specifically, by comparing similarities and differences in current distribution patterns between BT ECT and the other two placements, the study aimed to create an explanatory model of critical brain sites that mediate antidepressant efficacy and sites associated with cognitive, particularly memory, adverse effects. High resolution finite element human head models were generated from MRI scans of three subjects. The models were used to compare differences in activation between the three ECT placements, using subtraction maps. In this exploratory study on three realistic head models, Bitemporal ECT resulted in greater direct stimulation of deep midline structures and also left temporal and inferior frontal regions. Interpreted in light of existing knowledge on depressive pathophysiology and cognitive neuroanatomy, it is suggested that the former sites are related to efficacy and the latter to cognitive deficits. We hereby propose an approach using binarised subtraction models that can be used to optimise, and even individualise, ECT therapies. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Recognizing Maternal Depressive Symptoms: An Opportunity to Improve Outcomes in Early Intervention Programs.

PubMed

Beeber, Linda S; Meltzer-Brody, Samantha; Martinez, Maria; Matsuda, Yui; Wheeler, Anne C; Mandel, Marcia; LaForett, Dore; Waldrop, Julee

2017-04-01

Objective A higher rate of depressive symptoms is found among mothers of children with disabilities compared to other parents. However, there is a lack of study of mothers with children <3 years of age participating in Early Intervention (EI) programs. This study aims to more fully describe the extent of mood disorders in these mothers including estimated prevalence, severity and factors associated with maternal mental health, using gold standard clinical diagnostic and symptom measures, and test models associating depressive symptoms with contextual factors and child behavior. Methods A cross-sectional study was conducted with 106 women who had at least one child enrolled in EI. Mothers were interviewed and completed reliable, valid measures to evaluate mental health, health status, family conflict, parent-child interaction, self-efficacy, social support, child behavioral problems, hardship, endangerment, and child disability. Descriptive statistics and multivariate analyses were performed. Results We found 8 % of participants met all criteria for a Major Depressive Episode (MDE) with 44 % of the sample reporting a past episode and 43 % endorsing recurrent episodes. Using the CES-D to assess depressive symptom severity approximately 34 % of mothers screened in a clinically significant range. Using linear regression to predict severity of current depressive symptoms demonstrated that current depression severity was primarily predicted by poorer maternal health status, lower self-efficacy and past MDE (p < 0.05). Conclusions for practice A brief assessment of maternal mood, health and self-efficacy are important factors to assess when evaluating how to support mothers of children in EI.

Predictive validity of the HCR-20 for inpatient aggression: the effect of intellectual disability on accuracy.

PubMed

O'Shea, L E; Picchioni, M M; McCarthy, J; Mason, F L; Dickens, G L

2015-11-01

People with intellectual disability (ID) account for a large proportion of aggressive incidents in secure and forensic psychiatric services. Although the Historical, Clinical, Risk Management 20 (HCR-20) has good predictive validity in inpatient settings, it does not perform equally in all groups and there is little evidence for its efficacy in those with ID. A pseudo-prospective cohort study of the predictive efficacy of the HCR-20 for those with ID (n = 109) was conducted in a UK secure mental health setting using routinely collected risk data. Performance of the HCR-20 in the ID group was compared with a comparison group of adult inpatients without an ID (n = 504). Analysis controlled for potential covariates including security level, length of stay, gender and diagnosis. The HCR-20 total score was a significant predictor of any aggression and of physical aggression for both groups, although the area under the curve values did not reach the threshold for a large effect size. The clinical subscale performed significantly better in those without an ID compared with those with. The ID group had a greater number of relevant historical and risk management items. The clinicians' summary judgment significantly predicted both types of aggressive outcomes in the ID group, but did not predict either in those without an ID. This study demonstrates that, after controlling for a range of potential covariates, the HCR-20 is a significant predictor of inpatient aggression in people with an ID and performs as well as for a comparison group of mentally disordered individuals without ID. The potency of HCR-20 subscales and items varied between the ID and comparison groups suggesting important target areas for improved prediction and risk management interventions in those with ID. © 2015 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Crizotinib in patients with anaplastic lymphoma kinase-positive advanced non-small cell lung cancer versus chemotherapy as a first-line treatment.

PubMed

Zhou, Jianya; Zheng, Jing; Zhang, Xiaochen; Zhao, Jing; Zhu, Yanping; Shen, Qian; Wang, Yuehong; Sun, Ke; Zhang, Zeying; Pan, Zhijie; Shen, Yihong; Zhou, Jianying

2018-01-03

To compare the efficacy of crizotinib, pemetrexed and other chemotherapy regimens as a first-line treatment in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in real world clinical use and to evaluate the +86-571-87,236,876 predictive clinical factors of the efficacy of crizotinib. The 73 patients with ALK-positive advanced NSCLC were divided into three groups based on the first-line treatment: first-line crizotinib group (1-CRZ group, n = 32); first-line platinum-based pemetrexed treatment group (1-PP group, n = 28), and first-line chemotherapy platinum-based non-pemetrexed group (N1-PP, n = 12). Sixty eight of the 73 patients received crizotinib treatment and followed up in our hospital. Differences in the objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were compared in the different groups. The clinical factors were evaluated to predict the efficacy of crizotinib by the Kaplan-Meier survival analysis and Cox proportional hazards model. The PFS, ORR, DCR were 16.1 months, 78.1% (25/32) and 100% (32/32) in the 1-CRZ group; were 6.0 months, 17.9% (5/28) and 57.2% (16/28) in the 1-PP group; and were 2.9 months, 15.4% (2/13) and 46.2% (6/13) in the N1-PP group. The PFS of the 1-CRZ group was significantly longer than that of the 1-PP group (P < 0.001) and the N1-PP group (P < 0.001). The ORR and DCR of the 1-CRZ group was significantly greater than that of the 1-PP group and the N1-PP group (all the P < 0.001). Higher Eastern Cooperative Oncology Group (ECOG) performance status score (> = 2) (HR 2.345, 95% CI 1.137-4.834, P = 0.021) and patients received crizotinib after N1-PP chemotherapy (HR 2.345, 95% CI 1.137-4.834, P = 0.021) were two factors associated with shorter PFS after crizotinib treatment. In patients with ALK-positive NSCLC who did not receive previous treatment, crizotinib was superior to standard chemotherapy for the longer PFS and greater ORR and DCR. Higher ECOG score (> = 2) and patients received crizotinib after N1-PP chemotherapy predict poor efficacy of crizotinib.

Combined baseline and one-month changes in big endothelin-1 and brain natriuretic peptide plasma concentrations predict clinical outcomes in patients with left ventricular dysfunction after acute myocardial infarction: Insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study.

PubMed

Olivier, A; Girerd, N; Michel, J B; Ketelslegers, J M; Fay, R; Vincent, J; Bramlage, P; Pitt, B; Zannad, F; Rossignol, P

2017-08-15

Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI. In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients. When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint). Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies. In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies. Copyright © 2017 Elsevier B.V. All rights reserved.

Immunotherapy for metastatic urothelial carcinoma: status quo and the future.

PubMed

Necchi, Andrea; Rink, Michael; Giannatempo, Patrizia; Raggi, Daniele; Xylinas, Evanguelos

2018-01-01

The treatment paradigm of urothelial carcinoma has been revolutionized by the advent of multiple anti-programmed-cell death-1/ligand-1 (PD-1/PD-L1) antibodies. Significant improvements have been obtained in the locally advanced or metastatic stage, which was lacking of therapeutic standards. This review reports key findings from completed and ongoing clinical trials that highlight the potential of PD-1/PD-L1 blockade in this disease. Anti-PD-1/PD-L1 monoclonal antibodies have shown efficacy and safety in patients with urothelial carcinoma, regardless of their prognostic features. Efficacy was similar across different compounds, with objective responses that approximate 20%, with some differences favoring PD-L1-expressing patients. Typically, responding patients have good chances of achieving durable response, but biomarkers predictive of therapeutic effect are lacking. To date, evidences from randomized studies are limited to the second-line, postplatinum therapy. Despite the activity of PD-1/PD-L1 inhibitors is well established in metastatic urothelial carcinoma, multiple gray zones still exist regarding their optimal use in clinical practice. These uncertainties are related to patient and treatment-related criteria, to the optimal duration of treatment, including combination or sequence with standard chemotherapy. Special issues are represented by pseudoprogression or hyperprogression. Generally, enhanced predictive tools are needed and a myriad of further investigations are underway.

Feasibility, efficacy, and predictive factors for the technical success of endoscopic nasogallbladder drainage: a prospective study.

PubMed

Yane, Kei; Maguchi, Hiroyuki; Katanuma, Akio; Takahashi, Kuniyuki; Osanai, Manabu; Kin, Toshifumi; Takaki, Ryo; Matsumoto, Kazuyuki; Gon, Katsushige; Matsumori, Tomoaki; Tomonari, Akiko; Nojima, Masanori

2015-03-01

Several studies have shown the useful-ness of endoscopic nasogallbladder drainage (ENGBD) in patients with acute cholecystitis. However, the procedure is difficult, and factors that affect technical success have not yet been clarified. We conducted a prospective study to eval-uate the technical feasibility, efficacy, and predictive factors for the technical success of ENGBD in patients with acute cholecystitis. All patients with moderate or severe acute cholecystitis who were enrolled underwent ENGBD between April 2009 and April 2011. Patients with surgically altered anatomy or pancreatobiliary malignancies were ex-cluded. The primary outcomes included technical success, clinical success, and complications. Factors that could affect the technical success were also examined. Of the 27 patients who underwent ENGBD during the study period, technical success was achieved in 21 (78%) and clinical improvement was achieved in 20 (95%). Early complications were encountered in four patients (15%). Gallbladder wall thickness (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.08 to 2.47) and age (OR, 1.16; 95% CI, 1.00 to 1.35) were effective predictors of technical failure. ENGBD was effective in resolving acute cholecystitis; however, this modality was technically challenging and had a limited suc-cess rate. Because of technical difficulties, ENGBD should be reserved for limited indications. (Gut Liver, 2015;9239-246).

Testing Pneumonia Vaccines in the Elderly: Determining a Case Definition for Pneumococcal Pneumonia in the Absence of a Gold Standard.

PubMed

Jokinen, Jukka; Snellman, Marja; Palmu, Arto A; Saukkoriipi, Annika; Verlant, Vincent; Pascal, Thierry; Devaster, Jeanne-Marie; Hausdorff, William P; Kilpi, Terhi M

2018-06-01

Clinical assessments of vaccines to prevent pneumococcal community-acquired pneumonia (CAP) require sensitive and specific case definitions, but there is no gold standard diagnostic test. To develop a new case definition suitable for vaccine efficacy studies, we applied latent class analysis (LCA) to the results from 7 diagnostic tests for pneumococcal etiology on clinical specimens from 323 elderly persons with radiologically confirmed pneumonia enrolled in the Finnish Community-Acquired Pneumonia Epidemiology study during 2005-2007. Compared with the conventional use of LCA, which is mainly to determine sensitivities and specificities of different tests, we instead used LCA as an appropriate instrument to predict the probability of pneumococcal etiology for each CAP case based on individual test profiles, and we used the predictions to minimize the sample size that would be needed for a vaccine efficacy trial. When compared with the conventional laboratory criteria of encapsulated pneumococci in culture, in blood culture or high-quality sputum culture, or urine antigen positivity, our optimized case definition for pneumococcal CAP resulted in a trial sample size that was almost 20,000 subjects smaller. We believe that the novel application of LCA detailed here to determine a case definition for pneumococcal CAP could also be similarly applied to other diseases without a gold standard.

Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy.

PubMed

Honeyborne, Isobella; McHugh, Timothy D; Kuittinen, Iitu; Cichonska, Anna; Evangelopoulos, Dimitrios; Ronacher, Katharina; van Helden, Paul D; Gillespie, Stephen H; Fernandez-Reyes, Delmiro; Walzl, Gerhard; Rousu, Juho; Butcher, Philip D; Waddell, Simon J

2016-04-07

New treatment options are needed to maintain and improve therapy for tuberculosis, which caused the death of 1.5 million people in 2013 despite potential for an 86 % treatment success rate. A greater understanding of Mycobacterium tuberculosis (M.tb) bacilli that persist through drug therapy will aid drug development programs. Predictive biomarkers for treatment efficacy are also a research priority. Genome-wide transcriptional profiling was used to map the mRNA signatures of M.tb from the sputa of 15 patients before and 3, 7 and 14 days after the start of standard regimen drug treatment. The mRNA profiles of bacilli through the first 2 weeks of therapy reflected drug activity at 3 days with transcriptional signatures at days 7 and 14 consistent with reduced M.tb metabolic activity similar to the profile of pre-chemotherapy bacilli. These results suggest that a pre-existing drug-tolerant M.tb population dominates sputum before and after early drug treatment, and that the mRNA signature at day 3 marks the killing of a drug-sensitive sub-population of bacilli. Modelling patient indices of disease severity with bacterial gene expression patterns demonstrated that both microbiological and clinical parameters were reflected in the divergent M.tb responses and provided evidence that factors such as bacterial load and disease pathology influence the host-pathogen interplay and the phenotypic state of bacilli. Transcriptional signatures were also defined that predicted measures of early treatment success (rate of decline in bacterial load over 3 days, TB test positivity at 2 months, and bacterial load at 2 months). This study defines the transcriptional signature of M.tb bacilli that have been expectorated in sputum after two weeks of drug therapy, characterizing the phenotypic state of bacilli that persist through treatment. We demonstrate that variability in clinical manifestations of disease are detectable in bacterial sputa signatures, and that the changing M.tb mRNA profiles 0-2 weeks into chemotherapy predict the efficacy of treatment 6 weeks later. These observations advocate assaying dynamic bacterial phenotypes through drug therapy as biomarkers for treatment success.

Imaging macrophages with nanoparticles

NASA Astrophysics Data System (ADS)

Weissleder, Ralph; Nahrendorf, Matthias; Pittet, Mikael J.

2014-02-01

Nanomaterials have much to offer, not only in deciphering innate immune cell biology and tracking cells, but also in advancing personalized clinical care by providing diagnostic and prognostic information, quantifying treatment efficacy and designing better therapeutics. This Review presents different types of nanomaterial, their biological properties and their applications for imaging macrophages in human diseases, including cancer, atherosclerosis, myocardial infarction, aortic aneurysm, diabetes and other conditions. We anticipate that future needs will include the development of nanomaterials that are specific for immune cell subsets and can be used as imaging surrogates for nanotherapeutics. New in vivo imaging clinical tools for noninvasive macrophage quantification are thus ultimately expected to become relevant to predicting patients' clinical outcome, defining treatment options and monitoring responses to therapy.

Personalizing oncology treatments by predicting drug efficacy, side-effects, and improved therapy: mathematics, statistics, and their integration.

PubMed

Agur, Zvia; Elishmereni, Moran; Kheifetz, Yuri

2014-01-01

Despite its great promise, personalized oncology still faces many hurdles, and it is increasingly clear that targeted drugs and molecular biomarkers alone yield only modest clinical benefit. One reason is the complex relationships between biomarkers and the patient's response to drugs, obscuring the true weight of the biomarkers in the overall patient's response. This complexity can be disentangled by computational models that integrate the effects of personal biomarkers into a simulator of drug-patient dynamic interactions, for predicting the clinical outcomes. Several computational tools have been developed for personalized oncology, notably evidence-based tools for simulating pharmacokinetics, Bayesian-estimated tools for predicting survival, etc. We describe representative statistical and mathematical tools, and discuss their merits, shortcomings and preliminary clinical validation attesting to their potential. Yet, the individualization power of mathematical models alone, or statistical models alone, is limited. More accurate and versatile personalization tools can be constructed by a new application of the statistical/mathematical nonlinear mixed effects modeling (NLMEM) approach, which until recently has been used only in drug development. Using these advanced tools, clinical data from patient populations can be integrated with mechanistic models of disease and physiology, for generating personal mathematical models. Upon a more substantial validation in the clinic, this approach will hopefully be applied in personalized clinical trials, P-trials, hence aiding the establishment of personalized medicine within the main stream of clinical oncology. © 2014 Wiley Periodicals, Inc.

Possible Selves and Self-Regulatory Beliefs: Exploring the Relationship Between Health Selves, Health Efficacy, and Psychological Well-Being.

PubMed

Dark-Freudeman, Alissa; West, Robin L

2016-03-01

The present study identified middle-aged (ages 40-64) and older individuals (ages 65-90) who reported a highly important possible self related to health. The relationship between age, physical health, health efficacy, and psychological well-being were examined among these individuals. We tested a model in which health efficacy predicted both positive and negative psychological well-being. For both age groups, self-reported health predicted health self-efficacy; however, the direct effects of health efficacy on both positive and negative psychological well-being were also significant. Higher levels of health efficacy were associated with higher levels of positive psychological well-being and lower levels of negative well-being, as predicted. Physical health indirectly predicted well-being through its impact on health self-efficacy for middle-aged and older individuals who valued their health highly. Overall, these results support the notion that health efficacy related to a most important health self is a predictor of psychological well-being in mid and late life. © The Author(s) 2016.

Comparing student clinical self-efficacy and team process outcomes for a DEU, blended, and traditional clinical setting: A quasi-experimental research study.

PubMed

Plemmons, Christina; Clark, Michele; Feng, Du

2018-03-01

Clinical education is vital to both the development of clinical self-efficacy and the integration of future nurses into health care teams. The dedicated education unit clinical teaching model is an innovative clinical partnership, which promotes skill development, professional growth, clinical self-efficacy, and integration as a team member. Blended clinical teaching models are combining features of the dedicated education unit and traditional clinical model. The aims of this study are to explore how each of three clinical teaching models (dedicated education unit, blended, traditional) affects clinical self-efficacy and attitude toward team process, and to compare the dedicated education unit model and blended model to traditional clinical. A nonequivalent control-group quasi-experimental design was utilized. The convenience sample of 272 entry-level baccalaureate nursing students included 84 students participating in a dedicated education unit model treatment group, 66 students participating in a blended model treatment group, and 122 students participating in a traditional model control group. Perceived clinical self-efficacy was evaluated by the pretest/posttest scores obtained on the General Self-Efficacy scale. Attitude toward team process was evaluated by the pretest/posttest scores obtained on the TeamSTEPPS® Teamwork Attitude Questionnaire. All three clinical teaching models resulted in significant increases in both clinical self-efficacy (p=0.04) and attitude toward team process (p=0.003). Students participating in the dedicated education unit model (p=0.016) and students participating in the blended model (p<0.001) had significantly larger increases in clinical self-efficacy compared to students participating in the traditional model. These findings support the use of dedicated education unit and blended clinical partnerships as effective alternatives to the traditional model to promote both clinical self-efficacy and team process among entry-level baccalaureate nursing students. Copyright © 2017 Elsevier Ltd. All rights reserved.

Progress and Challenges Associated with the Development of Ricin Toxin Subunit Vaccines

PubMed Central

Vance, David J.; Mantis, Nicholas J.

2016-01-01

Summary The past several years have seen major advances in the development of a safe and efficacious ricin toxin vaccine, including the completion of two Phase I clinical trials with two different recombinant A subunit (RTA)-based vaccines: RiVax™ and RVEc™ adsorbed to aluminum salt adjuvant, as well as a non-human primate study demonstrating that parenteral immunization with RiVax elicits a serum antibody response that was sufficient to protect against a lethal dose aerosolized ricin exposure. One of the major obstacles moving forward is assessing vaccine efficacy in humans, when neither ricin-specific serum IgG endpoint titers nor toxin-neutralizing antibody levels are accepted as definitive predictors of protective immunity. In this review we summarize ongoing efforts to leverage recent advances in our understanding of RTA-antibody interactions at the structural level to develop novel assays to predict vaccine efficacy in humans. PMID:26998662

Progress and challenges associated with the development of ricin toxin subunit vaccines.

PubMed

Vance, David J; Mantis, Nicholas J

2016-09-01

The past several years have seen major advances in the development of a safe and efficacious ricin toxin vaccine, including the completion of two Phase I clinical trials with two different recombinant A subunit (RTA)-based vaccines: RiVax™ and RVEc™ adsorbed to aluminum salt adjuvant, as well as a non-human primate study demonstrating that parenteral immunization with RiVax elicits a serum antibody response that was sufficient to protect against a lethal dose aerosolized ricin exposure. One of the major obstacles moving forward is assessing vaccine efficacy in humans, when neither ricin-specific serum IgG endpoint titers nor toxin-neutralizing antibody levels are accepted as definitive predictors of protective immunity. In this review we summarize ongoing efforts to leverage recent advances in our understanding of RTA-antibody interactions at the structural level to develop novel assays to predict vaccine efficacy in humans.

Atezolizumab: feasible second-line therapy for patients with non-small cell lung cancer? A review of efficacy, safety and place in therapy.

PubMed

Jean, Fanny; Tomasini, Pascale; Barlesi, Fabrice

2017-12-01

Advanced non-small cell lung cancer (NSCLC) prognosis is still poor and has recently been reformed by the development of immune checkpoint inhibitors and the approval of anti-PD-1 (programmed cell-death 1) treatments such as nivolumab and pembrolizumab in second line. More recently, atezolizumab (MDPL 3280A), a programmed cell-death-ligand 1 (PD-L1) inhibitor, was also studied in this setting. Here, we report a review of the literature assessing the efficacy, safety, and place of atezolizumab in the second-line treatment of advanced NSCLC. We performed a literature search of PubMed, American Society of Clinical Oncology, European Society of Medical Oncology and World Conference on Lung Cancer meetings. Atezolizumab showed a good tolerance profile and efficacy in comparison with docetaxel for second-line treatment of advanced NSCLC. Potential predictive biomarkers also have to be assessed.

Atezolizumab: feasible second-line therapy for patients with non-small cell lung cancer? A review of efficacy, safety and place in therapy

PubMed Central

Jean, Fanny; Tomasini, Pascale; Barlesi, Fabrice

2017-01-01

Advanced non-small cell lung cancer (NSCLC) prognosis is still poor and has recently been reformed by the development of immune checkpoint inhibitors and the approval of anti-PD-1 (programmed cell-death 1) treatments such as nivolumab and pembrolizumab in second line. More recently, atezolizumab (MDPL 3280A), a programmed cell-death-ligand 1 (PD-L1) inhibitor, was also studied in this setting. Here, we report a review of the literature assessing the efficacy, safety, and place of atezolizumab in the second-line treatment of advanced NSCLC. We performed a literature search of PubMed, American Society of Clinical Oncology, European Society of Medical Oncology and World Conference on Lung Cancer meetings. Atezolizumab showed a good tolerance profile and efficacy in comparison with docetaxel for second-line treatment of advanced NSCLC. Potential predictive biomarkers also have to be assessed. PMID:29449897

Drink refusal training as part of a combined behavioral intervention: Effectiveness and mechanisms of change

PubMed Central

Witkiewitz, Katie; Donovan, Dennis M.; Hartzler, Bryan

2012-01-01

Objective Many trials have demonstrated the effectiveness of cognitive behavioral interventions for alcohol dependence, yet few studies have examined why particular treatments are effective. This study was designed to evaluate whether drink refusal training was an effective component of a combined behavioral intervention (CBI) and whether change in self-efficacy was a mechanism of change following drink refusal training for individuals with alcohol dependence. Method The current study is a secondary analysis of data from the COMBINE study, a randomized clinical trial that combined pharmacotherapy with behavioral intervention in the treatment of alcohol dependence. The goal of the current study was to examine whether a drink refusal skills training module, administered as part of a 16-week CBI (n=776; 31% female, 23% non-White, average age=44) predicted changes in drinking frequency and self-efficacy during and following the CBI, and whether changes in self-efficacy following drink refusal training predicted changes in drinking frequency up to one year following treatment. Results Participants (n=302) who received drink refusal skills training had significantly fewer drinking days during treatment (d=0.50) and up to one year following treatment (d=0.23). In addition the effect of the drink refusal skills training module on drinking outcomes following treatment was significantly mediated by changes in self-efficacy, even after controlling for changes in drinking outcomes during treatment (proportion mediated = 0.47). Conclusions Drink refusal training is an effective component of CBI and some of the effectiveness may be attributed to changes in client self-efficacy. PMID:22289131

Exposure–response model for sibutramine and placebo: suggestion for application to long-term weight-control drug development

PubMed Central

Han, Seunghoon; Jeon, Sangil; Hong, Taegon; Lee, Jongtae; Bae, Soo Hyeon; Park, Wan-su; Park, Gab-jin; Youn, Sunil; Jang, Doo Yeon; Kim, Kyung-Soo; Yim, Dong-Seok

2015-01-01

No wholly successful weight-control drugs have been developed to date, despite the tremendous demand. We present an exposure–response model of sibutramine mesylate that can be applied during clinical development of other weight-control drugs. Additionally, we provide a model-based evaluation of sibutramine efficacy. Data from a double-blind, randomized, placebo-controlled, multicenter study were used (N=120). Subjects in the treatment arm were initially given 8.37 mg sibutramine base daily, and those who lost <2 kg after 4 weeks’ treatment were escalated to 12.55 mg. The duration of treatment was 24 weeks. Drug concentration and body weight were measured predose and at 4 weeks, 8 weeks, and 24 weeks after treatment initiation. Exposure and response to sibutramine, including the placebo effect, were modeled using NONMEM 7.2. An asymptotic model approaching the final body weight was chosen to describe the time course of weight loss. Extent of weight loss was described successfully using a sigmoidal exposure–response relationship of the drug with a constant placebo effect in each individual. The placebo effect was influenced by subjects’ sex and baseline body mass index. Maximal weight loss was predicted to occur around 1 year after treatment initiation. The difference in mean weight loss between the sibutramine (daily 12.55 mg) and placebo groups was predicted to be 4.5% in a simulation of 1 year of treatment, with considerable overlap of prediction intervals. Our exposure–response model, which included the placebo effect, is the first example of a quantitative model that can be used to predict the efficacy of weight-control drugs. Similar approaches can help decision-making during clinical development of novel weight-loss drugs. PMID:26392753

Exposure-response model for sibutramine and placebo: suggestion for application to long-term weight-control drug development.

PubMed

Han, Seunghoon; Jeon, Sangil; Hong, Taegon; Lee, Jongtae; Bae, Soo Hyeon; Park, Wan-su; Park, Gab-jin; Youn, Sunil; Jang, Doo Yeon; Kim, Kyung-Soo; Yim, Dong-Seok

2015-01-01

No wholly successful weight-control drugs have been developed to date, despite the tremendous demand. We present an exposure-response model of sibutramine mesylate that can be applied during clinical development of other weight-control drugs. Additionally, we provide a model-based evaluation of sibutramine efficacy. Data from a double-blind, randomized, placebo-controlled, multicenter study were used (N=120). Subjects in the treatment arm were initially given 8.37 mg sibutramine base daily, and those who lost <2 kg after 4 weeks' treatment were escalated to 12.55 mg. The duration of treatment was 24 weeks. Drug concentration and body weight were measured predose and at 4 weeks, 8 weeks, and 24 weeks after treatment initiation. Exposure and response to sibutramine, including the placebo effect, were modeled using NONMEM 7.2. An asymptotic model approaching the final body weight was chosen to describe the time course of weight loss. Extent of weight loss was described successfully using a sigmoidal exposure-response relationship of the drug with a constant placebo effect in each individual. The placebo effect was influenced by subjects' sex and baseline body mass index. Maximal weight loss was predicted to occur around 1 year after treatment initiation. The difference in mean weight loss between the sibutramine (daily 12.55 mg) and placebo groups was predicted to be 4.5% in a simulation of 1 year of treatment, with considerable overlap of prediction intervals. Our exposure-response model, which included the placebo effect, is the first example of a quantitative model that can be used to predict the efficacy of weight-control drugs. Similar approaches can help decision-making during clinical development of novel weight-loss drugs.

An online study combining the constructs from the theory of planned behaviour and protection motivation theory in predicting intention to test for chlamydia in two testing contexts.

PubMed

Powell, Rachael; Pattison, Helen M; Francis, Jill J

2016-01-01

Chlamydia is a common sexually transmitted infection that has potentially serious consequences unless detected and treated early. The health service in the UK offers clinic-based testing for chlamydia but uptake is low. Identifying the predictors of testing behaviours may inform interventions to increase uptake. Self-tests for chlamydia may facilitate testing and treatment in people who avoid clinic-based testing. Self-testing and being tested by a health care professional (HCP) involve two contrasting contexts that may influence testing behaviour. However, little is known about how predictors of behaviour differ as a function of context. In this study, theoretical models of behaviour were used to assess factors that may predict intention to test in two different contexts: self-testing and being tested by a HCP. Individuals searching for or reading about chlamydia testing online were recruited using Google Adwords. Participants completed an online questionnaire that addressed previous testing behaviour and measured constructs of the Theory of Planned Behaviour and Protection Motivation Theory, which propose a total of eight possible predictors of intention. The questionnaire was completed by 310 participants. Sufficient data for multiple regression were provided by 102 and 118 respondents for self-testing and testing by a HCP respectively. Intention to self-test was predicted by vulnerability and self-efficacy, with a trend-level effect for response efficacy. Intention to be tested by a HCP was predicted by vulnerability, attitude and subjective norm. Thus, intentions to carry out two testing behaviours with very similar goals can have different predictors depending on test context. We conclude that interventions to increase self-testing should be based on evidence specifically related to test context.

Circulating tumor DNA evaluated by Next-Generation Sequencing is predictive of tumor response and prolonged clinical benefit with nivolumab in advanced non-small cell lung cancer.

PubMed

Giroux Leprieur, Etienne; Herbretau, Guillaume; Dumenil, Coraline; Julie, Catherine; Giraud, Violaine; Labrune, Sylvie; Dumoulin, Jennifer; Tisserand, Julie; Emile, Jean-François; Blons, Hélène; Chinet, Thierry

2018-01-01

Nivolumab is an anti-PD1 antibody, given in second-line or later treatment in advanced non-small cell lung cancer (NSCLC). The objective of this study was to describe the predictive value of circulating tumor DNA (ctDNA) on the efficacy of nivolumab in advanced NSCLC. We prospectively included all consecutive patients with advanced NSCLC treated with nivolumab in our Department between June 2015 and October 2016. Plasma samples were obtained before the first injection of nivolumab and at the first tumor evaluation with nivolumab. ctDNA was analyzed by Next-Generation Sequencing (NGS), and the predominant somatic mutation was followed for each patient and correlated with tumor response, clinical benefit (administration of nivolumab for more than 6 months), and progression-free survival (PFS). Of 23 patients, 15 had evaluable NGS results at both times of analysis. ctDNA concentration at the first tumor evaluation and ctDNA change correlated with tumor response, clinical benefit and PFS. ROC curve analyses showed good diagnostic performances for tumor response and clinical benefit, both for ctDNA concentration at the first tumor evaluation (tumor response: positive predictive value (PPV) at 100.0% and negative predictive value (NPV) at 71.0%; clinical benefit: PPV at 83.3% and NPV 77.8%) and the ctDNA change (tumor response: PPV 100.0% and NPV 62.5%; clinical benefit: PPV 100.0% and NPV 80.0%). Patients without ctDNA concentration increase >9% at 2 months had a long-term benefit of nivolumab. In conclusion, NGS analysis of ctDNA allows the early detection of tumor response and long-term clinical benefit with nivolumab in NSCLC.

Preclinical models used for immunogenicity prediction of therapeutic proteins.

PubMed

Brinks, Vera; Weinbuch, Daniel; Baker, Matthew; Dean, Yann; Stas, Philippe; Kostense, Stefan; Rup, Bonita; Jiskoot, Wim

2013-07-01

All therapeutic proteins are potentially immunogenic. Antibodies formed against these drugs can decrease efficacy, leading to drastically increased therapeutic costs and in rare cases to serious and sometimes life threatening side-effects. Many efforts are therefore undertaken to develop therapeutic proteins with minimal immunogenicity. For this, immunogenicity prediction of candidate drugs during early drug development is essential. Several in silico, in vitro and in vivo models are used to predict immunogenicity of drug leads, to modify potentially immunogenic properties and to continue development of drug candidates with expected low immunogenicity. Despite the extensive use of these predictive models, their actual predictive value varies. Important reasons for this uncertainty are the limited/insufficient knowledge on the immune mechanisms underlying immunogenicity of therapeutic proteins, the fact that different predictive models explore different components of the immune system and the lack of an integrated clinical validation. In this review, we discuss the predictive models in use, summarize aspects of immunogenicity that these models predict and explore the merits and the limitations of each of the models.

A computational cognitive model of self-efficacy and daily adherence in mHealth.

PubMed

Pirolli, Peter

2016-12-01

Mobile health (mHealth) applications provide an excellent opportunity for collecting rich, fine-grained data necessary for understanding and predicting day-to-day health behavior change dynamics. A computational predictive model (ACT-R-DStress) is presented and fit to individual daily adherence in 28-day mHealth exercise programs. The ACT-R-DStress model refines the psychological construct of self-efficacy. To explain and predict the dynamics of self-efficacy and predict individual performance of targeted behaviors, the self-efficacy construct is implemented as a theory-based neurocognitive simulation of the interaction of behavioral goals, memories of past experiences, and behavioral performance.

Resilience among first responders.

PubMed

Pietrantoni, Luca; Prati, Gabriele

2008-12-01

Emergency rescue personnel can be considered a "high risk" occupational group in that they could experience a broad range of health and mental health consequences as a result of work-related exposures to critical incidents. This study examined the resilience factors that protect mental health among first responders. Nine hundred and sixty-one first responders filled out an on-line questionnaire, containing measure of sense of community, collective efficacy, self-efficacy and work-related mental health outcomes (compassion fatigue, burnout and compassion satisfaction). First responders reported high level of compassion satisfaction and low level of burnout and compassion fatigue. Compassion fatigue was predicted by self-efficacy, burnout was predicted by self-efficacy, collective efficacy and sense of community, compassion satisfaction was predicted by self-efficacy and sense of community. Resilience following critical events is common among first responders. Self-efficacy, collective efficacy and sense of community could be considered resilience factors that preserve first responders' work-related mental health.

Relative contributions of self-efficacy, self-regulation, and self-handicapping in predicting student procrastination.

PubMed

Strunk, Kamden K; Steele, Misty R

2011-12-01

The relative contributions of self-efficacy, self-regulation, and self-handicapping student procrastination were explored. College undergraduate participants (N = 138; 40 men, 97 women, one not reporting sex) filled out the Procrastination Scale, the Self-Handicapping Scale-Short Form, and the Self-regulation and Self-handicapping scales of the Motivated Strategies for Learning Questionnaire. A hierarchical regression of the above measures indicated that self-efficacy, self-regulation, and self-handicapping all predicted scores on the Procrastination Scale, but self-regulation fully accounted for the predictive power of self-efficacy. The results suggested self-regulation and self-handicapping predict procrastination independently. These findings are discussed in relation to the literature on the concept of "self-efficacy for self-regulation" and its use in the field of procrastination research.

Biomarkers for Psychiatry: The Journey from Fantasy to Fact, a Report of the 2013 CINP Think Tank

PubMed Central

Millan, Mark J.; Bahn, Sabine; Bertolino, Alessandro; Turck, Christoph W.; Kapur, Shitij; Möller, Hans-Jürgen; Dean, Brian

2015-01-01

Background: A think tank sponsored by the Collegium Internationale Neuropsychopharmacologium (CINP) debated the status and prospects of biological markers for psychiatric disorders, focusing on schizophrenia and major depressive disorder. Methods: Discussions covered markers defining and predicting specific disorders or domains of dysfunction, as well as predicting and monitoring medication efficacy. Deliberations included clinically useful and viable biomarkers, why suitable markers are not available, and the need for tightly-controlled sample collection. Results: Different types of biomarkers, appropriate sensitivity, specificity, and broad-based exploitability were discussed. Whilst a number of candidates are in the discovery phases, all will require replication in larger, real-life cohorts. Clinical cost-effectiveness also needs to be established. Conclusions: Since a single measure is unlikely to suffice, multi-modal strategies look more promising, although they bring greater technical and implementation complexities. Identifying reproducible, robust biomarkers will probably require pre-competitive consortia to provide the resources needed to identify, validate, and develop the relevant clinical tests. PMID:25899066

The relationship between maternal self-efficacy and parenting practices: implications for parent training.

PubMed

Sanders, M R; Woolley, M L

2005-01-01

The present study examined the relationship between maternal self-efficacy, dysfunctional discipline practices and child conduct problems. Specifically, three levels of self-efficacy, global, domain and task-specific self-efficacy, were assessed in mothers of 2- to 8-year-old children with conduct problems (clinic group, n=45) and non-clinic mothers from the community (non-clinic group, n=79). Measures of global, domain and task-specific self-efficacy were completed by mothers. Clinic mothers reported significantly lower self-efficacy than non-clinic mothers for all but one of the parenting tasks assessed. Both groups of mothers reported lowest self-efficacy for similar parenting tasks. In the sample as a whole self-efficacy measures were significant predictors of maternal discipline style after controlling for other parent, child and risk factors. Of the self-efficacy variables behavioural self-efficacy was the best predictor of mothers discipline style. The findings support the importance of developing parenting strategies that enable parents to generalize their parenting skills to a diverse range of diverse parenting contexts both in the home and in the community.

Emerging biomarkers in breast cancer care.

PubMed

Napieralski, Rudolf; Brünner, Nils; Mengele, Karin; Schmitt, Manfred

2010-08-01

Currently, decision-making for breast cancer treatment in the clinical setting is mainly based on clinical data, histomorphological features of the tumor tissue and a few cancer biomarkers such as steroid hormone receptor status (estrogen and progesterone receptors) and oncoprotein HER2 status. Although various therapeutic options were introduced into the clinic in recent decades, with the objective of improving surgery, radiotherapy, biochemotherapy and chemotherapy, varying response of individual patients to certain types of therapy and therapy resistance is still a challenge in breast cancer care. Therefore, since breast cancer treatment should be based on individual features of the patient and her tumor, tailored therapy should be an option by integrating cancer biomarkers to define patients at risk and to reliably predict their course of the disease and/or response to cancer therapy. Recently, candidate-marker approaches and genome-wide transcriptomic and epigenetic screening of different breast cancer tissues and bodily fluids resulted in new promising biomarker panels, allowing breast cancer prognosis, prediction of therapy response and monitoring of therapy efficacy. These biomarkers are now subject of validation in prospective clinical trials.

Genetic and Antigenic Typing of Seasonal Influenza Virus Breakthrough Cases from a 2008-2009 Vaccine Efficacy Trial

PubMed Central

Durviaux, Serge; Treanor, John; Beran, Jiri; Duval, Xavier; Esen, Meral; Feldman, Gregory; Frey, Sharon E.; Launay, Odile; Leroux-Roels, Geert; McElhaney, Janet E.; Nowakowski, Andrzej; Ruiz-Palacios, Guillermo M.; van Essen, Gerrit A.; Oostvogels, Lidia; Devaster, Jeanne-Marie

2014-01-01

Estimations of the effectiveness of vaccines against seasonal influenza virus are guided by comparisons of the antigenicities between influenza virus isolates from clinical breakthrough cases with strains included in a vaccine. This study examined whether the prediction of antigenicity using a sequence analysis of the hemagglutinin (HA) gene-encoded HA1 domain is a simpler alternative to using the conventional hemagglutination inhibition (HI) assay, which requires influenza virus culturing. Specimens were taken from breakthrough cases that occurred in a trivalent influenza virus vaccine efficacy trial involving >43,000 participants during the 2008-2009 season. A total of 498 influenza viruses were successfully subtyped as A(H3N2) (380 viruses), A(H1N1) (29 viruses), B(Yamagata) (23 viruses), and B(Victoria) (66 viruses) from 603 PCR- or culture-confirmed specimens. Unlike the B strains, most A(H3N2) (377 viruses) and all A(H1N1) viruses were classified as homologous to the respective vaccine strains based on their HA1 domain nucleic acid sequence. HI titers relative to the respective vaccine strains and PCR subtyping were determined for 48% (182/380) of A(H3N2) and 86% (25/29) of A(H1N1) viruses. Eighty-four percent of the A(H3N2) and A(H1N1) viruses classified as homologous by sequence were matched to the respective vaccine strains by HI testing. However, these homologous A(H3N2) and A(H1N1) viruses displayed a wide range of relative HI titers. Therefore, although PCR is a sensitive diagnostic method for confirming influenza virus cases, HA1 sequence analysis appeared to be of limited value in accurately predicting antigenicity; hence, it may be inappropriate to classify clinical specimens as homologous or heterologous to the vaccine strain for estimating vaccine efficacy in a prospective clinical trial. PMID:24371255

Clinical and biological predictors of response to electroconvulsive therapy (ECT): a review.

PubMed

Pinna, Martina; Manchia, Mirko; Oppo, Rossana; Scano, Filomena; Pillai, Gianluca; Loche, Anna Paola; Salis, Piergiorgio; Minnai, Gian Paolo

2018-03-16

Electroconvulsive therapy (ECT), developed in the 30's by Bini and Cerletti, remains a key element of the therapeutic armamentarium in psychiatry, particularly for severe and life-threatening psychiatric symptoms. However, despite its well-established clinical efficacy, the prescription of ECT has declined constantly over the years due to concerns over its safety (cognitive side effects) and an increasingly negative public perception. As for other treatments in the field of psychiatry, ECT is well suited to a personalized approach that would increment its efficacy, as well as reducing the impact of side effects. This should be based on the priori identification of sub-populations of patients sharing common clinical and biological features that predict a good response to ECT. In this review we have selectively reviewed the evidence on clinical and biological predictors of ECT response. Clinical features such as an older age, presence of psychotic and melancholic depression, a high severity of suicide behavior, and speed of response, appear to be shared by ECT good responders with depressive symptoms. In mania, a greater severity of the index episode, and a reduction of whole brain cortical blood flow are associated with ECT good response. Biological determinants of ECT response in depressive patients are the presence of pre-treatment hyperconnectivity between key areas of brain circuitry of depression, as well as of reduced glutamine/glutamate levels, particularly in the anterior cingulated cortex (ACC). Furthermore, pre ECT high plasma homovanillic acid (HVA) levels, as well as of tumor necrosis factor (TNF)-α, and low pre-ECT levels of S-100B protein, appear to predict ECT response. Finally, polymorphisms within the genes encoding for the brain-derived neurotrophic factor (BDNF), the dopamine 2 receptor gene (DRD2), the dopamine receptor 3 gene (DRD3), the cathechol-o-methyltransferase (COMT), the serotonin-transporter (5-HTT), the 5-hydroxytryptamine 2A receptor (5-HT 2A ), and the norepinephrine transporter (NET), appear to predict a good response to ECT. The integration of these data in specific treatment algorithm might facilitate a personalized approach in ECT. Copyright © 2016. Published by Elsevier B.V.

Sources of self-efficacy for physical activity.

PubMed

Warner, Lisa M; Schüz, Benjamin; Wolff, Julia K; Parschau, Linda; Wurm, Susanne; Schwarzer, Ralf

2014-11-01

The effects of self-efficacy beliefs on physical activity are well documented, but much less is known about the origins of self-efficacy beliefs. This article proposes scales to assess the sources of self-efficacy for physical activity aims and to comparatively test their predictive power for physical activity via self-efficacy over time to detect the principal sources of self-efficacy beliefs for physical activity. A study of 1,406 German adults aged 16-90 years was conducted to construct scales to assess the sources of self-efficacy for physical activity (Study 1). In Study 2, the scales' predictive validity for self-efficacy and physical activity was tested in a sample of 310 older German adults. Short, reliable and valid instruments to measure six sources of self-efficacy for physical activity were developed that enable researchers to comparatively test the predictive value of the sources of self-efficacy. The results suggest that mastery experience, self-persuasion, and reduction in negative affective states are the most important predictors of self-efficacy for physical activity in community-dwelling older adults. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Quantitative Sensory Testing Predicts Pregabalin Efficacy in Painful Chronic Pancreatitis

PubMed Central

Olesen, Søren S.; Graversen, Carina; Bouwense, Stefan A. W.; van Goor, Harry; Wilder-Smith, Oliver H. G.; Drewes, Asbjørn M.

2013-01-01

Background A major problem in pain medicine is the lack of knowledge about which treatment suits a specific patient. We tested the ability of quantitative sensory testing to predict the analgesic effect of pregabalin and placebo in patients with chronic pancreatitis. Methods Sixty-four patients with painful chronic pancreatitis received pregabalin (150–300 mg BID) or matching placebo for three consecutive weeks. Analgesic effect was documented in a pain diary based on a visual analogue scale. Responders were defined as patients with a reduction in clinical pain score of 30% or more after three weeks of study treatment compared to baseline recordings. Prior to study medication, pain thresholds to electric skin and pressure stimulation were measured in dermatomes T10 (pancreatic area) and C5 (control area). To eliminate inter-subject differences in absolute pain thresholds an index of sensitivity between stimulation areas was determined (ratio of pain detection thresholds in pancreatic versus control area, ePDT ratio). Pain modulation was recorded by a conditioned pain modulation paradigm. A support vector machine was used to screen sensory parameters for their predictive power of pregabalin efficacy. Results The pregabalin responders group was hypersensitive to electric tetanic stimulation of the pancreatic area (ePDT ratio 1.2 (0.9–1.3)) compared to non-responders group (ePDT ratio: 1.6 (1.5–2.0)) (P = 0.001). The electrical pain detection ratio was predictive for pregabalin effect with a classification accuracy of 83.9% (P = 0.007). The corresponding sensitivity was 87.5% and specificity was 80.0%. No other parameters were predictive of pregabalin or placebo efficacy. Conclusions The present study provides first evidence that quantitative sensory testing predicts the analgesic effect of pregabalin in patients with painful chronic pancreatitis. The method can be used to tailor pain medication based on patient’s individual sensory profile and thus comprises a significant step towards personalized pain medicine. PMID:23469256

Clinical impact of concomitant immunomodulators on biologic therapy: Pharmacokinetics, immunogenicity, efficacy and safety.

PubMed

Xu, Zhenhua; Davis, Hugh M; Zhou, Honghui

2015-03-01

Immune-mediated inflammatory diseases encompass a variety of different clinical syndromes, manifesting as either common diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis, or rare diseases such as cryopyrin-associated periodic syndromes. The therapy for these diseases often involves the use of a wide range of drugs including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, immunomodulators, and biologic therapies. Due to the abundance of relevant clinical data, this article provides a general overview on the clinical impact of the concomitant use of immunomodulators and biologic therapies, with a focus on anti-tumor necrosis factor-α agents (anti-TNFα), for the treatment of RA and Crohn's disease (CD). Compared to biologic monotherapy, concomitant use of immunomodulators (methotrexate, azathioprine, and 6-mercaptopurine) often increases the systemic exposure of the anti-TNFα agent and decreases the formation of antibodies to the anti-TNFα agent, consequently enhancing clinical efficacy. Nevertheless, long-term combination therapy with immunomodulators and anti-TNFα agents may be associated with increased risks of serious infections and malignancies. Therefore, the determination whether combination therapy is suitable for a patient should always be based on an individualized benefit-risk evaluation. More research should be undertaken to identify and validate prognostic markers for predicting patients who would benefit the most and those who are at greater risk from combination therapy with immunomodulators and anti-TNFα agents. © 2015, The American College of Clinical Pharmacology.

Effect of the dedicated education unit on nursing student self-efficacy: A quasi-experimental research study.

PubMed

George, Lynn E; Locasto, Lisa W; Pyo, Katrina A; W Cline, Thomas

2017-03-01

Although the Dedicated Education Unit (DEU) has shown initial promise related to satisfaction with the teaching/learning environment, few studies have examined student outcomes related to the use of the DEU as a clinical education model beyond student satisfaction. The purpose of this quantitative, quasi-experimental study was to compare student outcomes from the traditional clinical education (TCE) model with those from the DEU model. Participants were students enrolled in a four-year baccalaureate program in nursing (n = 193) who had clinical education activities in one of three clinical agencies. Participants were assigned to either the DEU or a TCE model. Pre-clinical and post-clinical self-efficacy scores were measured for each group using an adapted Generalized Self-Efficacy Scale (Schwarzer and Jerusalem, 1995). Both groups experienced a significant increase in self-efficacy scores post clinical education. The increase in self-efficacy for the DEU students was significantly greater than the increase in self-efficacy for the traditional students. Self-efficacy is considered an important outcome of nursing education because high self-efficacy has been linked to making an easier transition from student to nursing professional. This study supports the quality of the DEU as a clinical education model by examining student self-efficacy outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Machine Learning Model Analysis and Data Visualization with Small Molecules Tested in a Mouse Model of Mycobacterium tuberculosis Infection (2014–2015)

PubMed Central

2016-01-01

The renewed urgency to develop new treatments for Mycobacterium tuberculosis (Mtb) infection has resulted in large-scale phenotypic screening and thousands of new active compounds in vitro. The next challenge is to identify candidates to pursue in a mouse in vivo efficacy model as a step to predicting clinical efficacy. We previously analyzed over 70 years of this mouse in vivo efficacy data, which we used to generate and validate machine learning models. Curation of 60 additional small molecules with in vivo data published in 2014 and 2015 was undertaken to further test these models. This represents a much larger test set than for the previous models. Several computational approaches have now been applied to analyze these molecules and compare their molecular properties beyond those attempted previously. Our previous machine learning models have been updated, and a novel aspect has been added in the form of mouse liver microsomal half-life (MLM t1/2) and in vitro-based Mtb models incorporating cytotoxicity data that were used to predict in vivo activity for comparison. Our best Mtbin vivo models possess fivefold ROC values > 0.7, sensitivity > 80%, and concordance > 60%, while the best specificity value is >40%. Use of an MLM t1/2 Bayesian model affords comparable results for scoring the 60 compounds tested. Combining MLM stability and in vitroMtb models in a novel consensus workflow in the best cases has a positive predicted value (hit rate) > 77%. Our results indicate that Bayesian models constructed with literature in vivoMtb data generated by different laboratories in various mouse models can have predictive value and may be used alongside MLM t1/2 and in vitro-based Mtb models to assist in selecting antitubercular compounds with desirable in vivo efficacy. We demonstrate for the first time that consensus models of any kind can be used to predict in vivo activity for Mtb. In addition, we describe a new clustering method for data visualization and apply this to the in vivo training and test data, ultimately making the method accessible in a mobile app. PMID:27335215

Predictive value of work-related self-efficacy change on RTW for employees with common mental disorders.

PubMed

Lagerveld, Suzanne E; Brenninkmeijer, Veerle; Blonk, Roland W B; Twisk, Jos; Schaufeli, Wilmar B

2017-05-01

To improve interventions that aim to promote return to work (RTW) of workers with common mental disorders (CMD), insight into modifiable predictors of RTW is needed. This study tested the predictive value of self-efficacy change for RTW in addition to preintervention levels of self-efficacy. RTW self-efficacy was measured 5 times within 9 months among 168 clients of a mental healthcare organisation who were on sick leave due to CMD. Self-efficacy parameters were modelled with multilevel analyses and added as predictors into a Cox regression analysis. Results showed that both high baseline self-efficacy and self-efficacy increase until full RTW were predictive of a shorter duration until full RTW. Both self-efficacy parameters remained significant predictors of RTW when controlled for several relevant covariates and within subgroups of employees with either high or low preintervention self-efficacy levels. This is the first study that demonstrated the prognostic value of self-efficacy change, over and above the influence of psychological symptoms, for RTW among employees with CMD. By showing that RTW self-efficacy increase predicted a shorter duration until full RTW, this study points to the relevance of enhancing RTW self-efficacy in occupational or mental health interventions for employees with CMD. Efforts to improve self-efficacy appear valuable both for people with relatively low and high baseline self-efficacy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans.

PubMed

Gengenbacher, Martin; Duque-Correa, Maria A; Kaiser, Peggy; Schuerer, Stefanie; Lazar, Doris; Zedler, Ulrike; Reece, Stephen T; Nayyar, Amit; Cole, Stewart T; Makarov, Vadim; Barry Iii, Clifton E; Dartois, Véronique; Kaufmann, Stefan H E

2017-08-18

During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2 -/- mice incapable of NO-production in immune cells as microbial defence uniformly develop hypoxic necrotizing lung lesions, widely observed in human TB. To study the impact of hypoxic necrosis on the efficacy of antimycobacterials and drug candidates, we subjected Nos2 -/- mice with TB to monotherapy before or after establishment of human-like pathology. Isoniazid induced a drug-tolerant persister population only when necrotic lesions were present. Rifapentine was more potent than rifampin prior to development of human-like pathology and equally potent thereafter, in agreement with recent clinical trials. Pretomanid, delamanid and the pre-clinical candidate BTZ043 were bactericidal independent of pulmonary pathology. Linezolid was bacteriostatic in TB-infected Nos2 -/- mice but significantly improved lung pathology. Hypoxic necrotizing lesions rendered moxifloxacin less active. In conclusion, Nos2 -/- mice are a predictive TB drug development tool owing to their consistent development of human-like pathology.

From Metabonomics to Pharmacometabonomics: The Role of Metabolic Profiling in Personalized Medicine

PubMed Central

Everett, Jeremy R.

2016-01-01

Variable patient responses to drugs are a key issue for medicine and for drug discovery and development. Personalized medicine, that is the selection of medicines for subgroups of patients so as to maximize drug efficacy and minimize toxicity, is a key goal of twenty-first century healthcare. Currently, most personalized medicine paradigms rely on clinical judgment based on the patient's history, and on the analysis of the patients' genome to predict drug effects i.e., pharmacogenomics. However, variability in patient responses to drugs is dependent upon many environmental factors to which human genomics is essentially blind. A new paradigm for predicting drug responses based on individual pre-dose metabolite profiles has emerged in the past decade: pharmacometabonomics, which is defined as “the prediction of the outcome (for example, efficacy or toxicity) of a drug or xenobiotic intervention in an individual based on a mathematical model of pre-intervention metabolite signatures.” The new pharmacometabonomics paradigm is complementary to pharmacogenomics but has the advantage of being sensitive to environmental as well as genomic factors. This review will chart the discovery and development of pharmacometabonomics, and provide examples of its current utility and possible future developments. PMID:27660611

Stigma predicts residential treatment length for substance use disorder

PubMed Central

Luoma, Jason B.; Kulesza, Magdalena; Hayes, Steven C.; Kohlenberg, Barbara; Larimer, Mary

2016-01-01

Background Stigma has been suggested as a possible contributor to the high rates of treatment attrition in substance-dependent individuals, but no published empirical studies have examined this association. Objectives The present paper assessed the relationship between baseline stigma variables and length of treatment stay in a sample of patients in a residential addictions treatment unit. Methods The relationship between baseline stigma variables (self-stigma, enacted stigma, and shame) and length of stay for participants (n = 103) in a residential addictions treatment unit was examined. Results Higher self-stigma predicted longer stay in residential addictions treatment, even after controlling for age, marital status, race, overall mental health, social support, enacted stigma, and internalized shame. However, other stigma variables (i.e. internalized shame, stigma-related rejection) did not reliably predict length of treatment stay. Conclusion These results are consistent with other findings suggesting that people with higher self-stigma may have a lowered sense of self-efficacy and heightened fear of being stigmatized and therefore retreat into more protected settings such as residential treatment, potentially resulting in higher treatment costs. Specialized clinical interventions may be necessary to help participants cope with reduced self-efficacy and fear of being stigmatized. PMID:24766087

The future of breast cancer systemic therapy: the next 10 years.

PubMed

Telli, Melinda L; Sledge, George W

2015-02-01

Over the past 50 years, substantial progress has been made in the systemic treatment of early-stage and advanced breast cancer. The use of chemotherapy in the adjuvant and metastatic settings has demonstrated proven efficacy and it has been clearly demonstrated that targeting the estrogen receptor and human growth factor receptor 2 (HER2) is efficacious in early and advanced disease. Despite these advances, vexing clinical challenges remain particularly related to the treatment of triple-negative breast cancer (TNBC; estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, and HER2-negative) where little progress has been made therapeutically in more than a decade. While recurrences of hormone-responsive breast cancer are overall less common, late relapses after cessation of endocrine therapy are a more frequent occurrence in modern times and reflect the problem of underlying tumor dormancy that as yet has not been overcome. Multiple molecular tools are now available to interrogate the biology of breast cancer, though exactly how to make this information meaningful in the clinic has proven challenging, and molecularly driven clinical trials have faced feasibility challenges. In parallel, focus has expanded from tumor to host with the ability to ascertain underlying germline alterations, such as inherited BRCA1 and BRCA2 mutations, which may be responsible for breast cancer carcinogenesis and, importantly, may have implications for treatment. These clinical advances in germline genetics, made possible by both scientific investigation as well as the courts, still face challenges related to increasing encounters with variants of unknown significance and difficulty in predicting risks associated with less well-characterized inherited cancer predisposition syndromes. In this paper, we attempt to predict the next 10 years of breast cancer, in particular focusing on how the past serves as prologue to the future in this disease.

In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia

PubMed Central

Yang, Pei‐Chi; Moreno, Jonathan D.; Miyake, Christina Y.; Vaughn‐Behrens, Steven B.; Jeng, Mao‐Tsuen; Grandi, Eleonora; Wehrens, Xander H. T.; Noskov, Sergei Y.

2016-01-01

Key points The mechanism of therapeutic efficacy of flecainide for catecholaminergic polymorphic ventricular tachycardia (CPVT) is unclear.Model predictions suggest that Na+ channel effects are insufficient to explain flecainide efficacy in CPVT.This study represents a first step toward predicting therapeutic mechanisms of drug efficacy in the setting of CPVT and then using these mechanisms to guide modelling and simulation to predict alternative drug therapies. Abstract Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by fatal ventricular arrhythmias in structurally normal hearts during β‐adrenergic stimulation. Current treatment strategies include β‐blockade, flecainide and ICD implementation – none of which is fully effective and each comes with associated risk. Recently, flecainide has gained considerable interest in CPVT treatment, but its mechanism of action for therapeutic efficacy is unclear. In this study, we performed in silico mutagenesis to construct a CPVT model and then used a computational modelling and simulation approach to make predictions of drug mechanisms and efficacy in the setting of CPVT. Experiments were carried out to validate model results. Our simulations revealed that Na+ channel effects are insufficient to explain flecainide efficacy in CPVT. The pure Na+ channel blocker lidocaine and the antianginal ranolazine were additionally tested and also found to be ineffective. When we tested lower dose combination therapy with flecainide, β‐blockade and CaMKII inhibition, our model predicted superior therapeutic efficacy than with flecainide monotherapy. Simulations indicate a polytherapeutic approach may mitigate side‐effects and proarrhythmic potential plaguing CPVT pharmacological management today. Importantly, our prediction of a novel polytherapy for CPVT was confirmed experimentally. Our simulations suggest that flecainide therapeutic efficacy in CPVT is unlikely to derive from primary interactions with the Na+ channel, and benefit may be gained from an alternative multi‐drug regimen. PMID:26515697

Perceived exercise self-efficacy as a predictor of exercise behavior in individuals aging with spinal cord injury.

PubMed

Kroll, Thilo; Kratz, Anna; Kehn, Matthew; Jensen, Mark P; Groah, Suzanne; Ljungberg, Inger H; Molton, Ivan R; Bombardier, Charles

2012-08-01

The purpose of this study was to test the hypothesized association between exercise self-efficacy and exercise behavior, controlling for demographic variables and clinical characteristics, in a sample of individuals with spinal cord injuries. A cross-sectional national survey of 612 community-dwelling adults with spinal cord injury in the United States ranging from 18 to 89 yrs of age was conducted. Sample consisted of 63.1% men with a mean (SD) duration of 15.8 (12.79) yrs postinjury; 86.3% reported using a wheelchair. Self-efficacy was the only independent variable that consistently predicted all four exercise outcomes. Self-efficacy beliefs were significantly related to frequency and intensity of resistance training (R(2) change = 0.08 and 0.03, respectively; P < 0.01 for all) and aerobic training (R(2) change = 0.07 and 0.05, respectively; P < 0.01 for all), thus explaining between 3% and 8% of the variance. Hierarchical linear regression analysis revealed that controlling for other demographic and physical capability variables, the age-related variables made statistically significant contributions and explained between 1% and 3% of the variance in aerobic exercise frequency and intensity (R(2) change = 0.01 and 0.03, respectively; P < 0.01 for all). Clinical functional characteristics but not demographic variables explained participation in resistance exercise. Self-efficacy beliefs play an important role as predictors of exercise. Variations in exercise intensity along the age continuum have implications for exercise prescription and composition. Future research should replicate findings with objective activity measures.

Innovation Incentives and Biomarkers.

PubMed

Stern, Ariel D; Alexander, Brian M; Chandra, Amitabh

2018-01-01

Previously, we have discussed the importance of economic incentives in shaping markets for precision medicines. Here we consider incentives for biomarker development, including discovery and establishment. Biomarkers can reveal valuable information regarding diagnosis and prognosis, predict treatment efficacy or toxicity, serve as markers of disease progression, and serve as auxiliary endpoints for clinical trials. Some have multiple uses, while others have a specialized role, resulting in diverse incentives across players in the healthcare system. © 2017, ASCPT.

Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: development and application of a bayesian random-effects model

PubMed Central

2010-01-01

Background Antibodies directed against haemagglutinin, measured by the haemagglutination inhibition (HI) assay are essential to protective immunity against influenza infection. An HI titre of 1:40 is generally accepted to correspond to a 50% reduction in the risk of contracting influenza in a susceptible population, but limited attempts have been made to further quantify the association between HI titre and protective efficacy. Methods We present a model, using a meta-analytical approach, that estimates the level of clinical protection against influenza at any HI titre level. Source data were derived from a systematic literature review that identified 15 studies, representing a total of 5899 adult subjects and 1304 influenza cases with interval-censored information on HI titre. The parameters of the relationship between HI titre and clinical protection were estimated using Bayesian inference with a consideration of random effects and censorship in the available information. Results A significant and positive relationship between HI titre and clinical protection against influenza was observed in all tested models. This relationship was found to be similar irrespective of the type of viral strain (A or B) and the vaccination status of the individuals. Conclusion Although limitations in the data used should not be overlooked, the relationship derived in this analysis provides a means to predict the efficacy of inactivated influenza vaccines when only immunogenicity data are available. This relationship can also be useful for comparing the efficacy of different influenza vaccines based on their immunological profile. PMID:20210985

Pharmacodynamics of temazepam in primary insomnia: assessment of the value of quantitative electroencephalography and saccadic eye movements in predicting improvement of sleep.

PubMed

Tuk, B; Oberyé, J J; Pieters, M S; Schoemaker, R C; Kemp, B; van Gerven, J; Danhof, M; Kamphuisen, H A; Cohen, A F; Breimer, D D; Peck, C C

1997-10-01

Quantitative electroencephalographic parameters and saccadic eye movements are frequently used as pharmacodynamic measures of benzodiazepine effect. We investigated the relationship between these measures and the hypnotic effect. The correlation between the pharmacodynamic measures and sleep quality was determined in 21 patients with primary insomnia. The pharmacokinetic-pharmacodynamic relationships were characterized after administration of 20 mg oral temazepam. The hypnotic effect was determined on the basis of polysomnographic sleep recordings and a subjective sleep evaluation questionnaire. Correlations between pharmacodynamic measures and the improvement of sleep were investigated. The pharmacokinetic-pharmacodynamic relationships for the parameters derived from electroencephalography and saccadic eye movements showed considerable interindividual variability. Administration of temazepam led to a significant improvement in the objective parameters sleep period efficiency, wake time after sleep onset, and sleep efficiency and in the subjective assessment of sleep quality. No significant correlations were observed between the pharmacokinetic-pharmacodynamic-derived parameters and the improvement in objective or subjective sleep parameters. In subjects with primary insomnia the administration of 20 mg oral temazepam results in changes in both the pharmacodynamic measures and in quality of sleep. No individual correlations between the pharmacodynamic measures and quality of sleep were observed. We concluded that the investigated pharmacodynamic measures are of value in the first assessment of clinical efficacy and for the selection of the dose(s) to be investigated in subsequent trials that aim at showing clinical efficacy. However, the conclusive quantification of clinical efficacy should be performed only on the basis of the clinical end point itself.

A Cross-Cultural Investigation of the Efficacy Beliefs of South Asian Immigrant and Anglo Canadian Nonimmigrant Early Adolescents

ERIC Educational Resources Information Center

Klassen, Robert M.

2004-01-01

The author explored the mathematics efficacy beliefs of 270 South Asian (Indo Canadian) immigrant and Anglo Canadian nonimmigrant Grade 7 students. Self-efficacy beliefs strongly predicted mathematics performance for both cultural groups, but there were differences between the 2 groups in the sources of self-efficacy, the predictiveness of the…

Correlates of protection for rotavirus vaccines: Possible alternative trial endpoints, opportunities, and challenges.

PubMed

Angel, Juana; Steele, A Duncan; Franco, Manuel A

2014-01-01

Rotavirus (RV) is a major vaccine-preventable killer of young children worldwide. Two RV vaccines are globally commercially available and other vaccines are in different stages of development. Due to the absence of a suitable correlate of protection (CoP), all RV vaccine efficacy trials have had clinical endpoints. These trials represent an important challenge since RV vaccines have to be introduced in many different settings, placebo-controlled studies are unethical due to the availability of licensed vaccines, and comparator assessments for new vaccines with clinical endpoints are very large, complex, and expensive to conduct. A CoP as a surrogate endpoint would allow predictions of vaccine efficacy for new RV vaccines and enable a regulatory pathway, contributing to the more rapid development of new RV vaccines. The goal of this review is to summarize experiences from RV natural infection and vaccine studies to evaluate potential CoP for use as surrogate endpoints for assessment of new RV vaccines, and to explore challenges and opportunities in the field.

Office Visits to Monitor Stimulant Medication Safety and Efficacy: Recommended Care.

PubMed

Zima, Bonnie T; Norquist, Grayson S; Altchuler, Steven I; Behrens, Jacob; Iles-Shih, Matthew D; Ng, Yiu Kee Warren; Schaepper, Mary Ann

2018-06-01

The clinical guidance based on the research article, "Specific Components of Pediatricians' Medication-Related Care Predict Attention-Deficit/Hyperactivity Disorder Improvement," published in the June 2017 issue, 1 might be premature. The authors, Epstein et al., suggest that "Physicians do not need to necessarily rely on office visits to monitor medication response and side effects in the week(s) after initially prescribing medication, but instead could use phone calls or email correspondence to check in with the family" (p. 489). However, this advice has the potential to be misinterpreted that phone or email contact is acceptable clinical practice to monitor stimulant medication safety and efficacy, especially during the maintenance phase. It also could be erroneously interpreted that phone or email contact is sufficient for follow-up care for children receiving medication treatment for attention-deficit/hyperactivity disorder (ADHD) for national quality measures. Copyright © 2018 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Cognitive Vulnerability to Depressive Symptoms in Children: The Protective Role of Self-efficacy Beliefs in a Multi-Wave Longitudinal Study

PubMed Central

Steca, P.; Abela, J. R. Z.; Monzani, D.; Greco, A.; Hazel, N. A.; Hankin, B. L.

2015-01-01

The current multi-wave longitudinal study on childhood examined the role that social and academic self-efficacy beliefs and cognitive vulnerabilities play in predicting depressive symptoms in response to elevations in idiographic stressors. Children (N = 554; males: 51.4%) attending second and third grade completed measures of depressive symptoms, negative cognitive styles, negative life events, and academic and social self-efficacy beliefs at four time-points over 6 months. Results showed that high levels of academic and social self-efficacy beliefs predicted lower levels of depressive symptoms, whereas negative cognitive styles about consequences predicted higher depression. Furthermore, children reporting higher social self-efficacy beliefs showed a smaller elevation in levels of depressive symptoms when reporting an increases in stress than children with lower social self-efficacy beliefs. Findings point to the role of multiple factors in predicting children’s depression in the long term and commend the promotion of self-efficacy beliefs and the modification of cognitive dysfunctional styles as relevant protective factors. PMID:23740171

Elucidation of the molecular mechanisms underlying adverse reactions associated with a kinase inhibitor using systems toxicology

PubMed Central

Amemiya, Takahiro; Honma, Masashi; Kariya, Yoshiaki; Ghosh, Samik; Kitano, Hiroaki; Kurachi, Yoshihisa; Fujita, Ken-ichi; Sasaki, Yasutsuna; Homma, Yukio; Abernethy, Darrel R; Kume, Haruki; Suzuki, Hiroshi

2015-01-01

Background/Objectives: Targeted kinase inhibitors are an important class of agents in anticancer therapeutics, but their limited tolerability hampers their clinical performance. Identification of the molecular mechanisms underlying the development of adverse reactions will be helpful in establishing a rational method for the management of clinically adverse reactions. Here, we selected sunitinib as a model and demonstrated that the molecular mechanisms underlying the adverse reactions associated with kinase inhibitors can efficiently be identified using a systems toxicological approach. Methods: First, toxicological target candidates were short-listed by comparing the human kinase occupancy profiles of sunitinib and sorafenib, and the molecular mechanisms underlying adverse reactions were predicted by sequential simulations using publicly available mathematical models. Next, to evaluate the probability of these predictions, a clinical observation study was conducted in six patients treated with sunitinib. Finally, mouse experiments were performed for detailed confirmation of the hypothesized molecular mechanisms and to evaluate the efficacy of a proposed countermeasure against adverse reactions to sunitinib. Results: In silico simulations indicated the possibility that sunitinib-mediated off-target inhibition of phosphorylase kinase leads to the generation of oxidative stress in various tissues. Clinical observations of patients and mouse experiments confirmed the validity of this prediction. The simulation further suggested that concomitant use of an antioxidant may prevent sunitinib-mediated adverse reactions, which was confirmed in mouse experiments. Conclusions: A systems toxicological approach successfully predicted the molecular mechanisms underlying clinically adverse reactions associated with sunitinib and was used to plan a rational method for the management of these adverse reactions. PMID:28725458

Clinical Evaluation of Efficacy and Performance of All-Poly Tibial Freedom® Total Knee System for Treating Osteoarthritis Patients: Three-Year Follow Up Study.

PubMed

Singh, Avatar; Singh, Kanwar Kulwinder

2017-09-01

Advancement in technology in terms of design and building materials has made Total Knee Replacement (TKR) a highly effective, safe, and predictable orthopedic procedure. To review the clinical outcomes for efficacy and performance of Freedom Total Knee System for the management of Osteoarthritis (OA), at a minimum of three years follow up. For this retrospective, post-marketing study, clinical data of patients treated with Freedom Total Knee System was retrieved from the clinical records after approval from the Institutional Ethics Committee . All the patients above the age of 18 years who completed at least three years after TKR were observed for the study purpose. Patients treated for OA were included while the patients who received the implant for treatment of rheumatoid arthritis and traumatic injury were excluded. Factors such as aseptic loosening, implant failure, and need for revision surgery were observed to evaluate implant performance. Cases were recruited for clinical assessment of primary efficacy endpoint in terms of post-surgery maximun range of motion. Secondary efficacy endpoint was to determine the clinical and social quality of life as per the American Knee Society Score (AKSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and stiffness scores. A total of 158 patients who had 191 TKR were observed for performance. The mean age of the patients was 67.67 years; mean BMI was 28.97±3.33, and the group comprised of 43% men and 57% women. Telephonic follow up at three years of 158 patients identified that none of them required revision surgery or had aseptic loosening suggesting excellent performance. Final clinical follow up at three years was available for only 35 patients (41 knee implants). The range of motion significantly improved from preoperative 104°±5.67° (range, 85°-119°) to 119.8°±11.05° (98°-123°) at follow-up (p<0.05). There was a significant improvement in clinical and functional AKSS score and WOMAC score at follow-up. The evaluation of Freedom Total Knee System for TKR in treating OA, at a minimum of three years follow up showed excellent outcomes in terms of performance, range of motion, reduced postoperative stiffness and pain, and improved functionality.

Clinical Evaluation of Efficacy and Performance of All-Poly Tibial Freedom® Total Knee System for Treating Osteoarthritis Patients: Three-Year Follow Up Study

PubMed Central

Singh, Kanwar Kulwinder

2017-01-01

Introduction Advancement in technology in terms of design and building materials has made Total Knee Replacement (TKR) a highly effective, safe, and predictable orthopedic procedure. Aim To review the clinical outcomes for efficacy and performance of Freedom Total Knee System for the management of Osteoarthritis (OA), at a minimum of three years follow up. Materials and Methods For this retrospective, post-marketing study, clinical data of patients treated with Freedom Total Knee System was retrieved from the clinical records after approval from the Institutional Ethics Committee . All the patients above the age of 18 years who completed at least three years after TKR were observed for the study purpose. Patients treated for OA were included while the patients who received the implant for treatment of rheumatoid arthritis and traumatic injury were excluded. Factors such as aseptic loosening, implant failure, and need for revision surgery were observed to evaluate implant performance. Cases were recruited for clinical assessment of primary efficacy endpoint in terms of post-surgery maximun range of motion. Secondary efficacy endpoint was to determine the clinical and social quality of life as per the American Knee Society Score (AKSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and stiffness scores. Results A total of 158 patients who had 191 TKR were observed for performance. The mean age of the patients was 67.67 years; mean BMI was 28.97±3.33, and the group comprised of 43% men and 57% women. Telephonic follow up at three years of 158 patients identified that none of them required revision surgery or had aseptic loosening suggesting excellent performance. Final clinical follow up at three years was available for only 35 patients (41 knee implants). The range of motion significantly improved from preoperative 104°±5.67° (range, 85°-119°) to 119.8°±11.05° (98°-123°) at follow-up (p<0.05). There was a significant improvement in clinical and functional AKSS score and WOMAC score at follow-up. Conclusion The evaluation of Freedom Total Knee System for TKR in treating OA, at a minimum of three years follow up showed excellent outcomes in terms of performance, range of motion, reduced postoperative stiffness and pain, and improved functionality. PMID:29207792

Motivation for HPV Vaccination Among Young Adult Men: Validation of TTM Decisional Balance and Self-Efficacy Constructs.

PubMed

Fernandez, Anne C; Amoyal, Nicole R; Paiva, Andrea L; Prochaska, James O

2016-01-01

In the United States, 36% of human papillomavirus (HPV)-related cancers occur among men. HPV vaccination can substantially reduce the risk of HPV infection; however, the vast majority of men are unvaccinated. This study developed and validated transtheoretical model-based measures for HPV vaccination in young adult men. Cross-sectional measurement development. Online survey of young adult men. Three hundred twenty-nine mostly college-attending men, ages 18 to 26. Stage of change, decisional balance (pros/cons), and self-efficacy. The sample was randomly split into halves for exploratory principal components analysis (PCA), followed by confirmatory factor analyses (CFA) to test measurement models. Multivariate analyses examined relationships between scales. For decisional balance, PCA revealed two uncorrelated five-item factors (pros α = .78; cons α = .83). For the self-efficacy scale, PCA revealed a single-factor solution (α = .83). CFA confirmed that the two-factor uncorrelated model for decisional balance and a single-factor model for self-efficacy. Follow-up analyses of variance supported the theoretically predicted relationships between stage of change, pros, and self-efficacy. This study resulted in reliable and valid measures of pros and self-efficacy for HPV vaccination that can be used in future clinical research.

Understanding the Link between Professional Learning Communities and Teacher Collective Efficacy

ERIC Educational Resources Information Center

Voelkel, Robert H., Jr.; Chrispeels, Janet H.

2017-01-01

Research suggests effective professional learning communities (PLCs) enhance teacher collaboration and student achievement. Some studies indicate that these communities also predict greater collective efficacy, while others suggest teacher efficacy is predictive of teachers working together. Although studies have identified effective,…

Ideal Teacher Behaviors: Student Motivation and Self-Efficacy Predict Preferences

ERIC Educational Resources Information Center

Komarraju, Meera

2013-01-01

Differences in students' academic self-efficacy and motivation were examined in predicting preferred teacher traits. Undergraduates (261) completed the Teaching Behavior Checklist, Academic Self-Concept scale, and Academic Motivation scale. Hierarchical regression analyses indicated that academic self-efficacy and extrinsic motivation explained…

Complimentary mechanisms of dual checkpoint blockade expand unique T-cell repertoires and activate adaptive anti-tumor immunity in triple-negative breast tumors

PubMed Central

Wei, Junping; Yang, Xiao Yi; Lei, Gangjun; Wang, Tao; Liu, Cong-Xiao; Morse, Michael A.; Gouin, Kenneth; Knott, Simon R. V.; Hartman, Zachary C.

2018-01-01

ABSTRACT Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (∼80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB. While promising, these modest response rates highlight the need for mechanistic studies to understand how different ICBs function, how their combination impacts functionality and efficacy, as well as what immunologic parameters predict efficacy to different ICBs regimens in TNBC. To address these issues, we tested anti-PD1 and anti-CTLA4 in multiple models of TNBC and found that their combination profoundly enhanced the efficacy of either treatment alone. We demonstrate that this efficacy is due to anti-CTLA4-driven expansion of an individually unique T-cell receptor (TCR) repertoire whose functionality is enhanced by both intratumoral Treg suppression and anti-PD1 blockade of tumor expressed PDL1. Notably, the individuality of the TCR repertoire was observed regardless of whether the tumor cells expressed a nonself antigen (ovalbumin) or if tumor-specific transgenic T-cells were transferred prior to sequencing. However, responsiveness was strongly correlated with systemic measures of tumor-specific T-cell and B-cell responses, which along with systemic assessment of TCR expansion, may serve as the most useful predictors for clinical responsiveness in future clinical trials of TNBC utilizing anti-PD1/anti-CTLA4 ICB. PMID:29721371

What Influences Recommendations Issued by the Agency for Health Technology Assessment in Poland? A Glimpse Into Decision Makers' Preferences.

PubMed

Niewada, Maciej; Polkowska, Małgorzata; Jakubczyk, Michał; Golicki, Dominik

This study aimed to evaluate the factors that are associated with positive (supporting public funding) and negative recommendations of the Agency for Health Technology Assessment in Poland. Two independent analysts reviewed all the recommendations publicly available online before October 7, 2011. For each recommendation, predefined decision rationales, that is, clinical efficacy, safety, cost-effectiveness, and formal aspects, were sought, either advocating or discouraging the public financing. In the analysis, we used descriptive statistics and a logistic regression model so as to identify the association between predefined criteria and the recommendation being positive. We identified 344 recommendations-218 positive (62.8%) and 126 negative (37.2%). Negative recommendations were better justified and also the comments were less ambiguous in accordance with the recommendation (except for clinical efficacy). In general, the specified criteria supported the decision (either positive or negative) in 209 (60.8%), 107 (31.1%), 124 (36.0%), 96 (27.9%), and 61 (17.7%) recommendations, respectively, and ran contrary to the actual decision in the remaining ones. Threshold values for either cost-effectiveness or budget impact distinguishing positive from negative recommendations could not be specified. The following parameters reached statistical significance in logistic regression: clinical efficacy (both explicitly positive and explicitly negative evaluations impacted in opposite directions), lack of impact on hard end points, unfavorable safety profile, cost-effectiveness results, and formal shortcomings (all reduced the probability of a positive recommendation). Decision making of the Agency for Health Technology Assessment in Poland is multicriterial, and its results cannot be easily decomposed into simple associations or easily predicted. Still, efficacy and safety seem to contribute most to final recommendations. Copyright © 2013, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.

Control of humoral immunity and auto-immunity by the CXCR4/CXCL12 axis in lupus patients following influenza vaccine.

PubMed

Launay, Odile; Paul, Stéphane; Servettaz, Amélie; Roguet, Gwénaëlle; Rozenberg, Flore; Lucht, Frédéric; Lambert, Claude; Presles, Emilie; Goulvestre, Claire; Méritet, Jean-François; Galtier, Florence; Dubray, Claude; Lebon, Pierre; Weill, Bernard; Batteux, Frédéric

2013-08-02

CXCR4 is a chemokine receptor with multiple effects on the immune system, upregulated in patients with SLE, and correlated with disease severity. This study has investigated whether the levels of CXCR4 expressed on leucocyte subsets in lupus patients are correlated with the efficacy and the safety of the influenza vaccine. Twenty-seven patients were vaccinated and vaccine immunogenicity and tolerance were evaluated. CXCR4 was assayed on leucocyte subsets and correlated with clinical and immunological signs of diseases activity. A significant increase in the titres of antibodies to the three viral strains was observed along with trends towards an increased vaccine efficacy in patients with quiescent disease vs patients with active disease. Recent flu vaccine history and, to a lesser extent, immunosuppressive treatment may influence vaccine immunogenicity. Influenza immunization was not associated with clinical side-effects or clinical lupus flare but with an increase in rheumatoid factor levels. Our study also confirms the correlation of CXCR4 expression with biological autoimmunity as shown by the correlation between the percentage of CXCR4-positive T cells and the ANA titres at D0, and the reverse correlation between CXCR4 expression and vaccine immunogenicity as demonstrated by the higher percentage of CXCR4-positive T cells at D0 and D30 in non-responders vs responders. Altogether, our study confirms the efficacy and the safety of flu vaccine in SLE patients, highlights the role of CXCR4 as a surrogate marker for autoimmunity in lupus and shows that CXCR4 expression on T cells is predictive of vaccine efficacy in SLE patients. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Exposure-efficacy Relationships for Vedolizumab Induction Therapy in Patients with Ulcerative Colitis or Crohn's Disease.

PubMed

Rosario, Maria; French, Jonathan L; Dirks, Nathanael L; Sankoh, Serap; Parikh, Asit; Yang, Huyuan; Danese, Silvio; Colombel, Jean-Frédéric; Smyth, Michael; Sandborn, William J; Feagan, Brian G; Reinisch, Walter; Sands, Bruce E; Sans, Miguel; Fox, Irving

2017-08-01

A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis [UC] or Crohn's disease [CD] has been reported. Here we further explore exposure-efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data. Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated. Exposure-efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 [Caverage] as exposure measure. Higher vedolizumab concentrations were associated with higher clinical remission rates; the exposure-efficacy relationship was steeper for UC than CD. Unadjusted analyses overestimated the relationship, more so for CD. From covariate-adjusted models, average probability of remission at Week 6 increased by approximately 15% for UC and 10% for CD between Caverage values of 35 and 84 µg/ml [5th and 95th percentiles, respectively]. On average, patients with higher albumin, lower faecal calprotectin [UC only], lower C-reactive protein [CD only], and no previous tumour necrosis factor-α [TNFα] antagonist use had a higher remission probability. Previous TNFα antagonist use had the greatest impact; remission probability was approximately 10% higher in treatment-naïve patients. Higher vedolizumab serum concentrations were associated with higher remission rates after induction therapy in patients with moderately to severely active UC or CD. This relationship is affected by several factors, including previous TNFα antagonist use. Prospective studies are needed to assess vedolizumab dose individualisation and optimisation. Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

Mind-body medicine: state of the science, implications for practice.

PubMed

Astin, John A; Shapiro, Shauna L; Eisenberg, David M; Forys, Kelly L

2003-01-01

Although emerging evidence during the past several decades suggests that psychosocial factors can directly influence both physiologic function and health outcomes, medicine had failed to move beyond the biomedical model, in part because of lack of exposure to the evidence base supporting the biopsychosocial model. The literature was reviewed to examine the efficacy of representative psychosocial-mind-body interventions, including relaxation, (cognitive) behavioral therapies, meditation, imagery, biofeedback, and hypnosis for several common clinical conditions. An electronic search was undertaken of the MEDLINE, PsycLIT, and the Cochrane Library databases and a manual search of the reference sections of relevant articles for related clinical trials and reviews of the literature. Studies examining mind-body interventions for psychological disorders were excluded. Owing to space limitations, studies examining more body-based therapies, such as yoga and tai chi chuan, were also not included. Data were extracted from relevant systematic reviews, meta-analyses, and randomized controlled trials. Drawing principally from systematic reviews and meta-analyses, there is considerable evidence of efficacy for several mind-body therapies in the treatment of coronary artery disease (eg, cardiac rehabilitation), headaches, insomnia, incontinence, chronic low back pain, disease and treatment-related symptoms of cancer, and improving postsurgical outcomes. We found moderate evidence of efficacy for mind-body therapies in the areas of hypertension and arthritis. Additional research is required to clarify the relative efficacy of different mind-body therapies, factors (such as specific patient characteristics) that might predict more or less successful outcomes, and mechanisms of action. Research is also necessary to examine the cost offsets associated with mind-body therapies. There is now considerable evidence that an array of mind-body therapies can be used as effective adjuncts to conventional medical treatment for a number of common clinical conditions.

Complimentary mechanisms of dual checkpoint blockade expand unique T-cell repertoires and activate adaptive anti-tumor immunity in triple-negative breast tumors.

PubMed

Crosby, Erika J; Wei, Junping; Yang, Xiao Yi; Lei, Gangjun; Wang, Tao; Liu, Cong-Xiao; Agarwal, Pankaj; Korman, Alan J; Morse, Michael A; Gouin, Kenneth; Knott, Simon R V; Lyerly, H Kim; Hartman, Zachary C

2018-01-01

Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (∼80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB. While promising, these modest response rates highlight the need for mechanistic studies to understand how different ICBs function, how their combination impacts functionality and efficacy, as well as what immunologic parameters predict efficacy to different ICBs regimens in TNBC. To address these issues, we tested anti-PD1 and anti-CTLA4 in multiple models of TNBC and found that their combination profoundly enhanced the efficacy of either treatment alone. We demonstrate that this efficacy is due to anti-CTLA4-driven expansion of an individually unique T-cell receptor (TCR) repertoire whose functionality is enhanced by both intratumoral Treg suppression and anti-PD1 blockade of tumor expressed PDL1. Notably, the individuality of the TCR repertoire was observed regardless of whether the tumor cells expressed a nonself antigen (ovalbumin) or if tumor-specific transgenic T-cells were transferred prior to sequencing. However, responsiveness was strongly correlated with systemic measures of tumor-specific T-cell and B-cell responses, which along with systemic assessment of TCR expansion, may serve as the most useful predictors for clinical responsiveness in future clinical trials of TNBC utilizing anti-PD1/anti-CTLA4 ICB.

The role of the pharmaceutical animal health industry in post-marketing surveillance of resistance.

PubMed

Lens, S

1993-06-01

The pharmaceutical animal health industry must be committed to the total life cycle of products, i.e. during both the pre- and post-marketing period. Support of antibacterial agents during the postmarketing period is not restricted to maintaining a well-established distribution and promotion system. Care has to be taken continuously to maintain and/or improve the quality, safety (for user, target animal and environment) and clinical efficacy. The pharmaceutical industry contributes to this by: 1. Introducing antibacterials in different animal species for the most effective disease condition only and by ensuring the veterinary profession is informed about relevant findings on: a. the mechanism of action; b. pharmacodynamic properties; c. pharmacokinetic properties (plasma, target tissue); d. clinical efficacy data and in vitro sensitivity data; e. valid species-specific MIC breakpoints; f. precise dose and treatment regime. 2. Updating on a regular basis on: a. new findings on the mechanism of action (in vitro and in vivo); b. the optimal use program in the light of changes in animal husbandry, farm management and epidemiology on national and international level; c. adjustment of species-specific MIC breakpoints when necessary. 3. Providing continuous information in collaboration with animal health laboratories about: a. clinical field surveillance for efficacy (national, international); b. in vitro sensitivity/resistance surveillance (national, international); c. use of in vitro data to support prediction of in vivo efficacy. Surveillance of resistance, in vitro, is therefore part of a package of information needed on a routine basis by the pharmaceutical industry to allow the best possible use of antibacterials and to minimize induction of resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Beliefs about emotion: implications for avoidance-based emotion regulation and psychological health.

PubMed

De Castella, Krista; Platow, Michael J; Tamir, Maya; Gross, James J

2018-06-01

People's beliefs about their ability to control their emotions predict a range of important psychological outcomes. It is not clear, however, whether these beliefs are playing a causal role, and if so, why this might be. In the current research, we tested whether avoidance-based emotion regulation explains the link between beliefs and psychological outcomes. In Study 1 (N = 112), a perceived lack of control over emotions predicted poorer psychological health outcomes (increased self-reported avoidance, lower well-being, and higher levels of clinical symptoms), and avoidance strategies indirectly explained these links between emotion beliefs and psychological health. In Study 2 (N = 101), we experimentally manipulated participants' emotion beliefs by leading participants to believe that they struggled (low regulatory self-efficacy) or did not struggle (high regulatory self-efficacy) with controlling their emotions. Participants in the low regulatory self-efficacy condition reported increased intentions to engage in avoidance strategies over the next month and were more likely to avoid seeking psychological help. When asked if they would participate in follow-up studies, these participants were also more likely to display avoidance-based emotion regulation. These findings provide initial evidence for the causal role of emotion beliefs in avoidance-based emotion regulation, and document their impact on psychological health-related outcomes.

How health-related quality of life assessment should be used in advanced colorectal cancer clinical trials.

PubMed

Bonnetain, F; Borg, C; Adams, R R; Ajani, J A; Benson, A; Bleiberg, H; Chibaudel, B; Diaz-Rubio, E; Douillard, J Y; Fuchs, C S; Giantonio, B J; Goldberg, R; Heinemann, V; Koopman, M; Labianca, R; Larsen, A K; Maughan, T; Mitchell, E; Peeters, M; Punt, C J A; Schmoll, H J; Tournigand, C; de Gramont, A

2017-09-01

Traditionally, the efficacy of cancer treatment in patients with advance or metastatic disease in clinical studies has been studied using overall survival and more recently tumor-based end points such as progression-free survival, measurements of response to treatment. However, these seem not to be the relevant clinical end points in current situation if such end points were no validated as surrogate of overall survival to demonstrate the clinical efficacy. Appropriate, meaningful, primary patient-oriented and patient-reported end points that adequately measure the effects of new therapeutic interventions are then crucial for the advancement of clinical research in metastatic colorectal cancer to complement the results of tumor-based end points. Health-related quality of life (HRQoL) is effectively an evaluation of quality of life and its relationship with health over time. HRQoL includes the patient report at least of the way a disease or its treatment affects its physical, emotional and social well-being. Over the past few years, several phase III trials in a variety of solid cancers have assessed the incremental value of HRQoL in addition to the traditional end points of tumor response and survival results. HRQoL could provide not only complementary clinical data to the primary outcomes, but also more precise predictive and prognostic value. This end point is useful for both clinicians and patients in order to achieve the dogma of precision medicine. The present article examines the use of HRQoL in phase III metastatic colorectal cancer clinical trials, outlines the importance of HRQoL assessment methods, analysis, and results presentation. Moreover, it discusses the relevance of including HRQoL as a primary/co-primary end point to support the progression-free survival results and to assess efficacy of treatment in the advanced disease setting. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Visumax femtolasik versus Moria M2 microkeratome in mild to moderate myopia: efficacy, safety, predictability, aberrometric changes and flap thickness predictability.

PubMed

Torky, Magda A; Al Zafiri, Yousif A; Khattab, Abeer M; Farag, Rania K; Awad, Eman A

2017-07-17

This is an interventional prospective clinical study which was conducted to evaluate the efficacy, safety, predictability, ocular aberrations, and flap thickness predictability of Visumax femtosecond laser (FSL) compared to Moria M2 microkeratome (MK) in mild to moderate myopia. This study included 60 eyes who were divided into two groups. Thirty eyes in group (I) in which the flap was created with Visumax FSL, while in group II (30 eyes) the Moria M2 MK was used. Keratometric, refractive, and aberrometric measurements were compared preoperatively and 3 months postoperatively. The intraoperative subtraction pachymetry (the SP 100 Handy pachymeter (Tomey, Nagoya, Japan) was used for preoperative pachymetry and flap thickness measurement. No significant difference was found between the two groups in regards to postoperative manifest sphere, spherical equivalent, astigmatism, safety indices nor ocular aberrations. Twenty six eyes (86.6%) in group I and 23 eyes in group II (76.6%) were within ±0.5D of the intended correction and 23 eyes (76.6%) in group I and 15 eyes in group II (50%) were within ±0.25D of the intended correction. In group I, the mean postoperative actual flap thickness was 100.12 ± 16.1 μm (81 to 122 μm), while in group II, it was 104.6 ± 20.1 μm (62 to 155 μm). The difference was statistically significant (p = 0.001). Both Visumax and Moria M2 MK are safe and effective in treating myopia with no statistically significant difference in induction of ocular aberrations but with potential advantage for Visumax regarding predictability. More accurate flap thickness is achieved with Visumax femtolasik. This study was retrospectively registered on 19/6/2017. Trial registration number NCT03193411 , clinicalTrials.gov .

The Cynomolgus Macaque Natural History Model of Pneumonic Tularemia for Predicting Clinical Efficacy Under the Animal Rule

PubMed Central

Guina, Tina; Lanning, Lynda L.; Omland, Kristian S.; Williams, Mark S.; Wolfraim, Larry A.; Heyse, Stephen P.; Houchens, Christopher R.; Sanz, Patrick; Hewitt, Judith A.

2018-01-01

Francisella tularensis is a highly infectious Gram-negative bacterium that is the etiologic agent of tularemia in animals and humans and a Tier 1 select agent. The natural incidence of pneumonic tularemia worldwide is very low; therefore, it is not feasible to conduct clinical efficacy testing of tularemia medical countermeasures (MCM) in human populations. Development and licensure of tularemia therapeutics and vaccines need to occur under the Food and Drug Administration's (FDA's) Animal Rule under which efficacy studies are conducted in well-characterized animal models that reflect the pathophysiology of human disease. The Tularemia Animal Model Qualification (AMQ) Working Group is seeking qualification of the cynomolgus macaque (Macaca fascicularis) model of pneumonic tularemia under Drug Development Tools Qualification Programs with the FDA based upon the results of studies described in this manuscript. Analysis of data on survival, average time to death, average time to fever onset, average interval between fever and death, and bacteremia; together with summaries of clinical signs, necropsy findings, and histopathology from the animals exposed to aerosolized F. tularensis Schu S4 in five natural history studies and one antibiotic efficacy study form the basis for the proposed cynomolgus macaque model. Results support the conclusion that signs of pneumonic tularemia in cynomolgus macaques exposed to 300–3,000 colony forming units (cfu) aerosolized F. tularensis Schu S4, under the conditions described herein, and human pneumonic tularemia cases are highly similar. Animal age, weight, and sex of animals challenged with 300–3,000 cfu Schu S4 did not impact fever onset in studies described herein. This study summarizes critical parameters and endpoints of a well-characterized cynomolgus macaque model of pneumonic tularemia and demonstrates this model is appropriate for qualification, and for testing efficacy of tularemia therapeutics under Animal Rule. PMID:29670861

An allometric pharmacokinetic/pharmacodynamics model for BI 893923, a novel IGF-1 receptor inhibitor.

PubMed

Titze, Melanie I; Schaaf, Otmar; Hofmann, Marco H; Sanderson, Michael P; Zahn, Stephan K; Quant, Jens; Lehr, Thorsten

2017-03-01

BI 893923 is a novel IGF1R/INSR inhibitor with promising anti-tumor efficacy. Dose-limiting hyperglycemia has been observed for other IGF1R/INSR inhibitors in clinical trials. To counterbalance anti-tumor efficacy with the risk of hyperglycemia and to determine the therapeutic window, we aimed to develop a translational pharmacokinetic/pharmacodynamics model for BI 893923. This aimed to translate pharmacokinetics and pharmacodynamics from animals to humans by an allometrically scaled semi-mechanistic model. Model development was based on a previously published PK/PD model for BI 893923 in mice (Titze et al., Cancer Chemother Pharmacol 77:1303-1314, 13). PK and blood glucose parameters were scaled by allometric principles using body weight as a scaling factor along with an estimation of the parameter exponents. Biomarker and tumor growth parameters were extrapolated from mouse to human using the body weight ratio as scaling factor. The allometric PK/PD model successfully described BI 893923 pharmacokinetics and blood glucose across mouse, rat, dog, minipig, and monkey. BI 893923 human exposure as well as blood glucose and tumor growth were predicted and compared for different dosing scenarios. A comprehensive risk-benefit analysis was conducted by determining the net clinical benefit for each schedule. An oral dose of 2750 mg BI 893923 divided in three evenly distributed doses was identified as the optimal human dosing regimen, predicting a tumor growth inhibition of 90.4% without associated hyperglycemia. Our model supported human therapeutic dose estimation by rationalizing the optimal efficacious dosing regimen with minimal undesired effects. This modeling approach may be useful for PK/PD scaling of other IGF1R/INSR inhibitors.

Personality modulates the efficacy of treatment in patients with major depressive disorder.

PubMed

Wardenaar, Klaas J; Conradi, Henk Jan; Bos, Elisabeth H; de Jonge, Peter

2014-09-01

Effects of depression treatment are obscured by heterogeneity among patients. Personality types could be one source of heterogeneity that explains variability in treatment response. Clinically meaningful variations in personality patterns could be captured with data-driven subgroups. The aim of this study was to identify such personality types and to explore their predictive value for treatment efficacy. Participants (N = 146) in the current exploratory study came from a randomized controlled trial in primary care depressed patients, conducted between January 1998 and June 2003, comparing different treatments. All participants were diagnosed with a major depressive disorder (MDD) according to the DSM-IV. Primary (care as usual [CAU] or CAU plus a psychoeducational prevention program [PEP]) and specialized (CAU + PEP + psychiatric consultation or cognitive-behavioral therapy) treatment were compared. Personality was assessed with the Neuroticism-Extraversion-Openness Five-Factor Inventory (NEO-FFI). Personality classes were identified with latent profile analysis (LPA). During 1 year, weekly depression ratings were obtained by trimonthly assessment with the Composite International Diagnostic Interview. Mixed models were used to analyze the effects of personality on treatment efficacy. A 2-class LPA solution fit best to the NEO-FFI data: Class 1 (vulnerable, n = 94) was characterized by high neuroticism, low extraversion, and low conscientiousness, and Class 2 (resilient, n = 52) by medium neuroticism and extraversion and higher agreeableness and conscientiousness. Recovery was quicker in the resilient class (class × time: P < .001). Importantly, specialized treatment had added value only in the vulnerable class, in which it was associated with quicker recovery than primary treatment (class × time × treatment: P < .001). Personality profile may predict whether specialized clinical efforts have added value, showing potential implications for planning of treatments. © Copyright 2014 Physicians Postgraduate Press, Inc.

Predictors of Iranian women's intention to first papanicolaou test practice: An application of protection motivation theory.

PubMed

Dehdari, T; Hassani, L; Shojaeizadeh, D; Hajizadeh, E; Nedjat, S; Abedini, M

2016-01-01

Given the importance of papanicolaou (Pap) test in the early detection and timely treatment of cervical cancer, present study was designed to determine predictors of a sample of Iranian women's intention to first Pap test practice based on the protection motivation theory (PMT) variables. In this cross-sectional study, a total of 240 women referral to the 30 primary health care clinics were selected. They completed a developed scale based on PMT variables including intention, perceived vulnerability and severity, fear, response costs, response efficacy and self-efficacy. Path analysis was used to determine the association between predictive factors and intention. The results showed that PMT had goodness of fit with a χ2/df = 2.37, df = 28, P= 0.001 and RMSEA = 0.076. PMT explained 42% of the variance in women's intention to get first Pap smear test. Self-efficacy (b = 0.55, P< 0.001) and response efficacy (b = 0.19, P< 0.001) were found to be the predictors of intention. These findings may be used to develop tailored, theory-based educational interventions associated with Pap testing among women.

Pharmacokinetic evaluation of vortioxetine for the treatment of major depressive disorder.

PubMed

Dubovsky, Steven L

2014-05-01

Major depressive disorder (MDD), one of the most common disorders in medical practice and one of the leading causes of disability worldwide, is frequently comorbid with anxiety disorders. Vortioxetine (Lu AA21004) is a new antidepressant that combines a number of neurotransmitter reuptake and receptor effects that have been thought to predict efficacy as a treatment for depressive and anxiety disorders. This review summarizes the pharmacology and neurobiology of vortioxetine. Studies of its efficacy and tolerability in major depression and generalized anxiety disorder are critically reviewed. Despite the fact that industry-sponsored studies are more likely than other clinical trials to support efficacy of the experimental drug, results have been mixed. Some studies supported that vortioxetine is superior to placebo in the treatment of MDD and some do not. Two studies supported the efficacy of vortioxetine in the treatment of generalized anxiety disorder and two do not. The incidence of sexual dysfunction has varied considerably in different studies, but cardiac effects and psychomotor impairment seem to be minimal. Advantages of vortioxetine over existing antidepressants are not yet clear.

Clinical evaluation of the efficacy of a GTR membrane (HEALIGUIDE) and demineralised bone matrix (OSSEOGRAFT) as a space maintainer in the treatment of Miller's Class I gingival recession.

PubMed

Nanditha, S; Priya, M S; Sabitha, S; Arun, K V; Avaneendra, T

2011-04-01

Periodontal plastic surgical procedures aimed at coverage of exposed root surface have evolved into routine treatment modalities. The present study was designed to evaluate the effectiveness and predictability of using a collagen barrier along with a demineralized bone matrix in the treatment of recession defects in a single surgical procedure. Seventeen patients with Miller's class I recession were treated with a combination of a collagen barrier used along with a bone graft and coronally advanced flap technique. Clinical parameters were recorded at baseline, 3 months, 6 months, and 9 months. The study showed a highly significant reduction in the recession depth (70.29 ± 21.96%) at the end of the study. This study showed that the use of this technique for recession coverage is highly predictable and highly esthetic root coverage can be obtained.

A systematic review of anti-rotavirus serum IgA antibody titer as a potential correlate of rotavirus vaccine efficacy.

PubMed

Patel, Manish; Glass, Roger I; Jiang, Baoming; Santosham, Mathuram; Lopman, Ben; Parashar, Umesh

2013-07-15

Identifying an immunological correlate of protection for rotavirus vaccines (Rotarix [RV1] and RotaTeq [RV5]) would substantially facilitate testing of interventions for improving efficacy in developing countries and evaluating additional candidate rotavirus vaccines. We accessed PubMed and ClinicalTrials.gov to identify immunogenicity and efficacy trials for RV1 and RV5 to correlate anti-rotavirus serum immunoglobulin A (IgA) antibody titers vs efficacy in regions stratified by all-cause under-5 mortality rates (u5MR). We established a cutoff point for IgA geometric mean concentration or titer (GMC) that predicted lower efficacy and calculated pooled vaccine efficacy among countries with high vs low IgA titers. We observed an inverse correlation between u5MR and IgA titers for RV1 (r(2) = 0.72; P < .001 and RV5 (r(2) = 0.66; P < .001) and between efficacy and IgA titers for both vaccines (r(2) = 0.56; P = .005). Postimmunization anti-rotavirus IgA GMC <90 were associated with decline in vaccine efficacy. Efficacy during first 2 years of life was significantly lower among countries with IgA GMC < 90 (44%; 95% confidence interval [CI], 30-55) compared to countries with GMC > 90 (85%; 95% CI, 82-88). We observed a significant correlation between IgA titers and rotavirus vaccine efficacy and hypothesize that a critical level of IgA antibody titer is associated with a sufficient level of sustained protection after rotavirus vaccination.

Botulinum toxin type A products are not interchangeable: a review of the evidence

PubMed Central

Brin, Mitchell F; James, Charmaine; Maltman, John

2014-01-01

Botulinum toxin type A (BoNTA) products are injectable biologic medications derived from Clostridium botulinum bacteria. Several different BoNTA products are marketed in various countries, and they are not interchangeable. Differences between products include manufacturing processes, formulations, and the assay methods used to determine units of biological activity. These differences result in a specific set of interactions between each BoNTA product and the tissue injected. Consequently, the products show differences in their in vivo profiles, including preclinical dose response curves and clinical dosing, efficacy, duration, and safety/adverse events. Most, but not all, published studies document these differences, suggesting that individual BoNTA products act differently depending on experimental and clinical conditions, and these differences may not always be predictable. Differentiation through regulatory approvals provides a measure of confidence in safety and efficacy at the specified doses for each approved indication. Moreover, the products differ in the amount of study to which they have been subjected, as evidenced by the number of publications in the peer-reviewed literature and the quantity and quality of clinical studies. Given that BoNTAs are potent biological products that meet important clinical needs, it is critical to recognize that their dosing and product performance are not interchangeable and each product should be used according to manufacturer guidelines. PMID:25336912

Influence of motivation, self-efficacy and situational factors on the teaching quality of clinical educators.

PubMed

Dybowski, Christoph; Sehner, Susanne; Harendza, Sigrid

2017-05-08

Being exposed to good teachers has been shown to enhance students' knowledge and their clinical performance, but little is known about the underlying psychological mechanisms that provide the basis for being an excellent medical teacher. Self-Determination Theory (SDT) postulates that more self-regulated types of motivation are associated with higher performance. Social Cognitive Theory (SCT) focuses on self-efficacy that has been shown to be positively associated with performance. To investigate the influences of different types of teaching motivation, teaching self-efficacy, and teachers' perceptions of students' skills, competencies and motivation on teaching quality. Before the winter semester 2014, physicians involved in bedside teaching in internal medicine at the University Medical Center Hamburg-Eppendorf completed a questionnaire with sociodemographic items and instruments measuring different dimensions of teaching motivation as well as teaching self-efficacy. During the semester, physicians rated their perceptions of the participating students who rated the teaching quality after each lesson. We performed a random intercept mixed-effects linear regression with students' ratings of teaching quality as the dependent variable and students' general interest in a subject as covariate. We explored potential associations between teachers' dispositions and their perceptions of students' competencies in a mixed-effects random intercept logistic regression. 94 lessons given by 55 teachers with 500 student ratings were analyzed. Neither teaching motivation nor teaching self-efficacy were directly associated with students' rating of teaching quality. Teachers' perceptions of students' competencies and students' general interest in the lesson's subject were positively associated with students' rating of teaching quality. Physicians' perceptions of their students' competencies were significantly positively predicted by their teaching self-efficacy. Teaching quality might profit from teachers who are self-efficacious and able to detect their students' competencies. Students' general interest in a lesson's subject needs to be taken into account when they are asked to evaluate teaching quality.

Immunotherapy in new pre-clinical models of HPV-associated oral cancers.

PubMed

Paolini, Francesca; Massa, Silvia; Manni, Isabella; Franconi, Rosella; Venuti, Aldo

2013-03-01

Cervical, anal, penile and a sub-set of head and neck (HN) tumors are critical health problems caused by high risk Human Papilloma Viruses (HPVs), like HPV type 16. No specific/effective pharmacological treatments exist. A valid preventive vaccination as well as the immunotherapy of persistent infections, pre-cancerous lesions or early-stage cancers could drive the HPV disease burden down. These treatments might be featured through low-cost platforms like those based on DNA and plant biotechnologies to produce tailored and enhanced formulations taking profit from the use of plants as bio-factories and as a source of immune-stimulators. Finally, and regardless of the formulation type, pre-clinical tests and models are crucial to foresee efficacy of immunotherapy before clinical trials.   In this study, we created an orthotopic mouse model for HPV-related oral tumors, a subset of HN tumors for which no models have been generated before. The model was obtained by inducing the stable expression of the HPV16 E7 protein into the mouse oral squamous cell carcinoma (OSCC) AT-84 (AT-84 E7). The AT-84 E7 cells were injected into the mouth pavement of C3H mice via an extra-oral route to obtain orthotopic tumors. The model turned out to mimic the natural history of the human HPV oral cancer. From AT-84 E7, through engineering to express luciferase, the bioluminescent AT-84 E7-Luc cells were obtained for a fast and easy monitoring by imaging. The AT-84 E7 and the AT-84 E7-Luc tumors were used to test the efficacy of E7-based therapeutic vaccines that we had previously generated and that had been already proven to be active in mice against non-orthotopic E7-expressing tumors (TC-1 cells). In particular, we used genetic and plant-derived formulations based on attenuated HPV16 E7 variants either fused to plant virus genes with immunological activity or produced by tobacco plants. Mice were monitored by imaging allowing to test the size reduction of the mouth implanted experimental tumors in function of the different regimens used. The proposed tumor model is easy to handle and to reproduce and it is efficacious in monitoring immunotherapy. Furthermore, it is expected to be more predictive of clinical outcome of therapeutic vaccines than non-orthotopic models that are currently used. Finally, imaging offers unique opportunities to predict formulation efficacy through measuring tumor growth in vivo.

The Efficacy of Endoscopic Palliation of Obstructive Jaundice in Hepatocellular Carcinoma

PubMed Central

Park, Semi; Park, Jeong Youp; Chung, Moon Jae; Chung, Jae Bock; Park, Seung Woo; Han, Kwang-Hyub; Song, Si Young

2014-01-01

Purpose Obstructive jaundice in patients with hepatocellular carcinoma (HCC) is uncommon (0.5-13%). Unlike other causes of obstructive jaundice, the role of endoscopic intervention in obstructive jaundice complicated by HCC has not been clearly defined. The aim of this study was to evaluate the clinical characteristics of obstructive jaundice caused by HCC and predictive factors for successful endoscopic intervention. Materials and Methods From 1999 to 2009, 54 patients with HCC who underwent endoscopic intervention to relieve obstructive jaundice were included. We defined endoscopic intervention as a clinical success when the obstructive jaundice was relieved within 4 weeks. Results Clinical success was achieved in 23 patients (42.6%). Patients in the clinical success group showed better Child-Pugh liver function (C-P grade A or B/C; 17/6 vs. 8/20), lower total bilirubin levels (8.1±5.3 mg/dL vs. 23.1±10.4 mg/dL) prior to the treatment, and no history of alcohol consumption. The only factor predictive of clinical success by multivariate analysis was low total bilirubin level at the time of endoscopic intervention, regardless of history of alcohol consumption [odds ratio 1.223 (95% confidence interval, 1.071-1.396), p=0.003]. The cut-off value of pre-endoscopic treatment total bilirubin level was 12.8 mg/dL for predicting the clinical prognosis. Median survival after endoscopic intervention in the clinical success group was notably longer than that in the clinical failure group (5.6 months vs. 1.5 months, p≤0.001). Conclusion Before endoscopic intervention, liver function, especially total bilirubin level, should be checked to achieve the best clinical outcome. Endoscopic intervention can be helpful to relieve jaundice in well selected patients with HCC. PMID:25048484

Highlights from the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, USA, 12–15 May 2001

PubMed Central

Lohrisch, Caroline

2001-01-01

Key issues discussed at the breast cancer sessions of the 37th American Society of Clinical Oncology (ASCO) meeting, 2001, included the following: breast cancer in the elderly; toxicity; updates on HER2 and use of trastuzumab (anti-HER2) in metastatic disease; and several early reports on novel therapeutic strategies. As was stated by numerous speakers both at this and other meetings, and as demonstrated by several abstracts, the use of predictive factors appears to be the most effective way to enhance the efficacy of numerous therapies, both target specific and nonspecific.

A model to predict disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD): the ADPKD Outcomes Model.

PubMed

McEwan, Phil; Bennett Wilton, Hayley; Ong, Albert C M; Ørskov, Bjarne; Sandford, Richard; Scolari, Francesco; Cabrera, Maria-Cristina V; Walz, Gerd; O'Reilly, Karl; Robinson, Paul

2018-02-13

Autosomal dominant polycystic kidney disease (ADPKD) is the leading inheritable cause of end-stage renal disease (ESRD); however, the natural course of disease progression is heterogeneous between patients. This study aimed to develop a natural history model of ADPKD that predicted progression rates and long-term outcomes in patients with differing baseline characteristics. The ADPKD Outcomes Model (ADPKD-OM) was developed using available patient-level data from the placebo arm of the Tolvaptan Efficacy and Safety in Management of ADPKD and its Outcomes Study (TEMPO 3:4; ClinicalTrials.gov identifier NCT00428948). Multivariable regression equations estimating annual rates of ADPKD progression, in terms of total kidney volume (TKV) and estimated glomerular filtration rate, formed the basis of the lifetime patient-level simulation model. Outputs of the ADPKD-OM were compared against external data sources to validate model accuracy and generalisability to other ADPKD patient populations, then used to predict long-term outcomes in a cohort matched to the overall TEMPO 3:4 study population. A cohort with baseline patient characteristics consistent with TEMPO 3:4 was predicted to reach ESRD at a mean age of 52 years. Most patients (85%) were predicted to reach ESRD by the age of 65 years, with many progressing to ESRD earlier in life (18, 36 and 56% by the age of 45, 50 and 55 years, respectively). Consistent with previous research and clinical opinion, analyses supported the selection of baseline TKV as a prognostic factor for ADPKD progression, and demonstrated its value as a strong predictor of future ESRD risk. Validation exercises and illustrative analyses confirmed the ability of the ADPKD-OM to accurately predict disease progression towards ESRD across a range of clinically-relevant patient profiles. The ADPKD-OM represents a robust tool to predict natural disease progression and long-term outcomes in ADPKD patients, based on readily available and/or measurable clinical characteristics. In conjunction with clinical judgement, it has the potential to support decision-making in research and clinical practice.

Parental Mediation Regarding Children's Smartphone Use: Role of Protection Motivation and Parenting Style.

PubMed

Hwang, Yoori; Choi, Inho; Yum, Jung-Yoon; Jeong, Se-Hoon

2017-06-01

Parental mediation is a type of behavior that could protect children against the negative uses and effects of smartphones. Based on protection motivation theory, this research (a) predicted parental mediation based on parents' threat and efficacy perceptions and (b) predicted threat and efficacy perceptions based on parenting styles and parents' addiction to smartphone use. An online survey of 448 parents of fourth to sixth graders was conducted. Results showed that both restrictive and active parental mediation were predicted by perceived severity, response efficacy, and self-efficacy. With regard to parenting styles, (a) authoritative parenting was positively related to perceived severity as well as response- and self-efficacy, whereas (b) permissive parenting was negatively related to self-efficacy. In addition, parents' addiction was a negative predictor of perceived severity, but a positive predictor of perceived susceptibility.

Planning a Stigmatized Nonvisible Illness Disclosure: Applying the Disclosure Decision-Making Model

PubMed Central

Choi, Soe Yoon; Venetis, Maria K.; Greene, Kathryn; Magsamen-Conrad, Kate; Checton, Maria G.; Banerjee, Smita C.

2016-01-01

This study applied the disclosure decision-making model (DD-MM) to explore how individuals plan to disclose nonvisible illness (Study 1), compared to planning to disclose personal information (Study 2). Study 1 showed that perceived stigma from the illness negatively predicted disclosure efficacy; closeness predicted anticipated response (i.e., provision of support) although it did not influence disclosure efficacy; disclosure efficacy led to reduced planning, with planning leading to scheduling. Study 2 demonstrated that when information was considered to be intimate, it negatively influenced disclosure efficacy. Unlike the model with stigma (Study 1), closeness positively predicted both anticipated response and disclosure efficacy. The rest of the hypothesized relationships showed a similar pattern to Study 1: disclosure efficacy reduced planning, which then positively influenced scheduling. Implications of understanding stages of planning for stigmatized information are discussed. PMID:27662447

Planning a Stigmatized Nonvisible Illness Disclosure: Applying the Disclosure Decision-Making Model.

PubMed

Choi, Soe Yoon; Venetis, Maria K; Greene, Kathryn; Magsamen-Conrad, Kate; Checton, Maria G; Banerjee, Smita C

2016-11-16

This study applied the disclosure decision-making model (DD-MM) to explore how individuals plan to disclose nonvisible illness (Study 1), compared to planning to disclose personal information (Study 2). Study 1 showed that perceived stigma from the illness negatively predicted disclosure efficacy; closeness predicted anticipated response (i.e., provision of support) although it did not influence disclosure efficacy; disclosure efficacy led to reduced planning, with planning leading to scheduling. Study 2 demonstrated that when information was considered to be intimate, it negatively influenced disclosure efficacy. Unlike the model with stigma (Study 1), closeness positively predicted both anticipated response and disclosure efficacy. The rest of the hypothesized relationships showed a similar pattern to Study 1: disclosure efficacy reduced planning, which then positively influenced scheduling. Implications of understanding stages of planning for stigmatized information are discussed.

Rationale and design of a randomized double-blind clinical trial in breast cancer: dextromethorphan in chemotherapy-induced peripheral neuropathy.

PubMed

Martin, Elodie; Morel, Véronique; Joly, Dominique; Villatte, Christine; Delage, Noémie; Dubray, Claude; Pereira, Bruno; Pickering, Gisèle

2015-03-01

Anti-cancer chemotherapy often induces peripheral neuropathy and consequent cognitive and quality of life impairment. Guidelines recommend antiepileptics or antidepressants but their efficacy is limited.Dextromethorphan, a N-methyl-D-aspartate receptor antagonist, has shown its efficacy in painful diabetic neuropathy and in post-operative pain but has not been studied in chemotherapy-induced peripheral neuropathy. This clinical trial evaluates the effect of dextromethorphan on pain, cognition and quality of life in patients who suffer from neuropathic pain induced by chemotherapy for breast cancer. It also assesses the impact of dextromethorphan genetic polymorphism on analgesia. This trial is a randomized, placebo-controlled, double-blind clinical study in two parallel groups (NCT02271893). It includes 40 breast cancer patients suffering from chemotherapy-induced peripheral neuropathy. They are randomly allocated to dextromethorphan (maximal dose 90 mg/day) or placebo for 4 weeks. The primary endpoint is pain intensity measured after 4 weeks of treatment on a (0-10) Numeric Pain Rating Scale. Secondary outcomes include assessment of neuropathic pain, cognitive function, anxiety/depression, sleep and quality of life. Data analysis is performed using mixed models and the tests are two-sided, with a type I error set at α=0.05. Considering the poor efficacy of available drugs in chemotherapy-induced neuropathic pain, dextromethorphan may be a valuable therapeutic option. Pharmacogenetics may provide predictive factors of dextromethorphan response in patients suffering from breast cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

Practice of Regulatory Science (Development of Medical Devices).

PubMed

Niimi, Shingo

2017-01-01

Prototypes of medical devices are made in accordance with the needs of clinical practice, and for systems required during the initial process of medical device development for new surgical practices. Verification of whether these prototypes produce the intended performance specifications is conducted using basic tests such as mechanical and animal tests. The prototypes are then improved and modified until satisfactory results are obtained. After a prototype passes through a clinical trial process similar to that for new drugs, application for approval is made. In the approval application process, medical devices are divided into new, improved, and generic types. Reviewers judge the validity of intended use, indications, operation procedures, and precautions, and in addition evaluate the balance between risk and benefit in terms of efficacy and safety. Other characteristics of medical devices are the need for the user to attain proficiency in usage techniques to ensure efficacy and safety, and the existence of a variety of medical devices for which assessment strategies differ, including differences in impact on the body in cases in which a physical burden to the body or failure of a medical device develops. Regulatory science of medical devices involves prediction, judgment, and evaluation of efficacy, safety, and quality, from which data result which can become indices in the development stages from design to application for approval. A reduction in the number of animals used for testing, improvement in efficiency, reduction of the necessity for clinical trials, etc. are expected through rational setting of evaluation items.

Safety issues from a Phase 3 clinical trial of a live-attenuated chimeric yellow fever tetravalent dengue vaccine.

PubMed

Halstead, Scott B

2018-02-26

A tetravalent live-attenuated 3-dose vaccine composed of chimeras of yellow fever 17D and the four dengue viruses (CYD, also called Dengvaxia) completed phase 3 clinical testing in over 35,000 children leading to a recommendation that vaccine be administered to >/ = 9 year-olds residing in highly dengue- endemic countries. When clinical trial results were assessed 2 years after the first dose, vaccine efficacy among seropositives was high, but among seronegatives efficacy was marginal. Breakthrough dengue hospitalizations of vaccinated children occurred continuously over a period of 4-5 years post 3rd dose in an age distribution suggesting these children had been vaccinated when seronegative. This surmise was validated recently when the manufacturer reported that dengue NS1 IgG antibodies were absent in sera from hospitalized vaccinated children, an observation consistent with their having received Dengvaxia when seronegative. Based upon published efficacy data and in compliance with initial published recommendations by the manufacturer and WHO the Philippine government undertook to vaccinate 800,000-plus 9 year-olds starting in April 2016. Eighteen months later, dengue hospitalizations and a deaths were reported among vaccinated children. The benefits of administering Dengvaxia predicted by the manufacturer, WHO and others derive from scoring dengue hospitalizations of vaccinated children as vaccine failures rather than as vaccine enhanced dengue disease. Recommended regimens for administration of Dengvaxia should have been structured to warn of and avoid serious adverse events.

Sentinel node localization in oral cavity and oropharynx squamous cell cancer.

PubMed

Taylor, R J; Wahl, R L; Sharma, P K; Bradford, C R; Terrell, J E; Teknos, T N; Heard, E M; Wolf, G T; Chepeha, D B

2001-08-01

To evaluate the feasibility and predictive ability of the sentinel node localization technique for patients with squamous cell carcinoma of the oral cavity or oropharynx and clinically negative necks. Prospective, efficacy study comparing the histopathologic status of the sentinel node with that of the remaining neck dissection specimen. Tertiary referral center. Patients with T1 or T2 disease and clinically negative necks were eligible for the study. Nine previously untreated patients with oral cavity or oropharyngeal squamous cell carcinoma were enrolled in the study. Unfiltered technetium Tc 99m sulfur colloid injections of the primary tumor and lymphoscintigraphy were performed on the day before surgery. Intraoperatively, the sentinel node(s) was localized with a gamma probe and removed after tumor resection and before neck dissection. The primary outcome was the negative predictive value of the histopathologic status of the sentinel node for predicting cervical metastases. Sentinel nodes were identified in 9 previously untreated patients. In 5 patients, there were no positive nodes. In 4 patients, the sentinel nodes were the only histopathologically positive nodes. In previously untreated patients, the sentinel node technique had a negative predictive value of 100% for cervical metastasis. Our preliminary investigation shows that sentinel node localization is technically feasible in head and neck surgery and is predictive of cervical metastasis. The sentinel node technique has the potential to decrease the number of neck dissections performed in clinically negative necks, thus reducing the associated morbidity for patients in this group.

Evaluating Fidelity: Predictive Validity for a Measure of Competent Adherence to the Oregon Model of Parent Management Training

PubMed Central

Forgatch, Marion S.; Patterson, Gerald R.; DeGarmo, David S.

2006-01-01

When efficacious interventions are implemented in real-world conditions, it is important to evaluate whether or not the programs are practiced as intended. This article presents the Fidelity of Implementation Rating System (FIMP), an observation-based measure assessing competent adherence to the Oregon model of Parent Management Training (PMTO). FIMP evaluates 5 dimensions of competent adherence to PMTO (i.e., knowledge, structure, teaching skill, clinical skill, and overall effectiveness) specified in the intervention model. Predictive validity for FIMP was evaluated with a subsample of stepfamilies participating in a preventive PMTO intervention. As hypothesized, high FIMP ratings predicted change in observed parenting practices from baseline to 12 months. The rigor and scope of adherence measures are discussed. PMID:16718302

Fighting Cancer with Mathematics and Viruses.

PubMed

Santiago, Daniel N; Heidbuechel, Johannes P W; Kandell, Wendy M; Walker, Rachel; Djeu, Julie; Engeland, Christine E; Abate-Daga, Daniel; Enderling, Heiko

2017-08-23

After decades of research, oncolytic virotherapy has recently advanced to clinical application, and currently a multitude of novel agents and combination treatments are being evaluated for cancer therapy. Oncolytic agents preferentially replicate in tumor cells, inducing tumor cell lysis and complex antitumor effects, such as innate and adaptive immune responses and the destruction of tumor vasculature. With the availability of different vector platforms and the potential of both genetic engineering and combination regimens to enhance particular aspects of safety and efficacy, the identification of optimal treatments for patient subpopulations or even individual patients becomes a top priority. Mathematical modeling can provide support in this arena by making use of experimental and clinical data to generate hypotheses about the mechanisms underlying complex biology and, ultimately, predict optimal treatment protocols. Increasingly complex models can be applied to account for therapeutically relevant parameters such as components of the immune system. In this review, we describe current developments in oncolytic virotherapy and mathematical modeling to discuss the benefit of integrating different modeling approaches into biological and clinical experimentation. Conclusively, we propose a mutual combination of these research fields to increase the value of the preclinical development and the therapeutic efficacy of the resulting treatments.

Using Data Augmentation to Facilitate Conduct of Phase I–II Clinical Trials with Delayed Outcomes

PubMed Central

Jin, Ick Hoon; Liu, Suyu; Thall, Peter F.; Yuan, Ying

2014-01-01

A practical impediment in adaptive clinical trials is that outcomes must be observed soon enough to apply decision rules to choose treatments for new patients. For example, if outcomes take up to six weeks to evaluate and the accrual rate is one patient per week, on average three new patients will be accrued while waiting to evaluate the outcomes of the previous three patients. The question is how to treat the new patients. This logistical problem persists throughout the trial. Various ad hoc practical solutions are used, none entirely satisfactory. We focus on this problem in phase I–II clinical trials that use binary toxicity and efficacy, defined in terms of event times, to choose doses adaptively for successive cohorts. We propose a general approach to this problem that treats late-onset outcomes as missing data, uses data augmentation to impute missing outcomes from posterior predictive distributions computed from partial follow-up times and complete outcome data, and applies the design’s decision rules using the completed data. We illustrate the method with two cancer trials conducted using a phase I–II design based on efficacy-toxicity trade-offs, including a computer stimulation study. PMID:25382884

Fighting Cancer with Mathematics and Viruses

PubMed Central

Santiago, Daniel N.; Heidbuechel, Johannes P. W.; Kandell, Wendy M.; Walker, Rachel; Djeu, Julie; Abate-Daga, Daniel; Enderling, Heiko

2017-01-01

After decades of research, oncolytic virotherapy has recently advanced to clinical application, and currently a multitude of novel agents and combination treatments are being evaluated for cancer therapy. Oncolytic agents preferentially replicate in tumor cells, inducing tumor cell lysis and complex antitumor effects, such as innate and adaptive immune responses and the destruction of tumor vasculature. With the availability of different vector platforms and the potential of both genetic engineering and combination regimens to enhance particular aspects of safety and efficacy, the identification of optimal treatments for patient subpopulations or even individual patients becomes a top priority. Mathematical modeling can provide support in this arena by making use of experimental and clinical data to generate hypotheses about the mechanisms underlying complex biology and, ultimately, predict optimal treatment protocols. Increasingly complex models can be applied to account for therapeutically relevant parameters such as components of the immune system. In this review, we describe current developments in oncolytic virotherapy and mathematical modeling to discuss the benefit of integrating different modeling approaches into biological and clinical experimentation. Conclusively, we propose a mutual combination of these research fields to increase the value of the preclinical development and the therapeutic efficacy of the resulting treatments. PMID:28832539

Can Nursing Students Practice What Is Preached? Factors Impacting Graduating Nurses' Abilities and Achievement to Apply Evidence-Based Practices.

PubMed

Blackman, Ian R; Giles, Tracey M

2017-04-01

In order to meet national Australian nursing registration requisites, nurses need to meet competency requirements for evidence-based practices (EBPs). A hypothetical model was formulated to explore factors that influenced Australian nursing students' ability and achievement to understand and employ EBPs related to health care provision. A nonexperimental, descriptive survey method was used to identify self-reported EBP efficacy estimates of 375 completing undergraduate nursing students. Factors influencing participants' self-rated EBP abilities were validated by Rasch analysis and then modeled using the partial least squares analysis (PLS Path) program. Graduating nursing students' ability to understand and apply EBPs for clinical improvement can be directly and indirectly predicted by eight variables including their understanding in the analysis, critique and synthesis of clinically based nursing research, their ability to communicate research to others and whether they had actually witnessed other staff delivering EBP. Forty-one percent of the variance in the nursing students' self-rated EBP efficacy scores is able to be accounted for by this model. Previous exposure to EBP studies facilitates participants' confidence with EBP, particularly with concurrent clinical EBP experiences. © 2017 Sigma Theta Tau International.

Dissonance-based eating disorder program reduces cardiac risk: A preliminary trial.

PubMed

Green, Melinda A; Willis, Mary; Fernandez-Kong, Kristen; Reyes, Shuhan; Linkhart, Ruby; Johnson, Molly; Thorne, Tyler; Kroska, Emily; Woodward, Halley; Lindberg, Jessica

2017-04-01

We conducted a randomized, controlled preliminary trial to examine the effect of a dissonance-based eating disorder program on eating disorder symptoms and cardiac risk indices in a community sample of women with subclinical and clinical symptoms (N = 47), examining the efficacy of the program in both the indicated prevention and treatment realms. Eating disorder symptoms, body mass index, and biomarkers of cardiac risk were examined in dissonance and assessment-only control conditions at baseline, postintervention, and 2-month follow-up. Specifically, we assessed mean R wave amplitude, QT interval length, vagal tone (high frequency spectral power of heart rate variability), and sympathetic tone (low/high frequency spectral power ratio) via electocardiography (ECG) at each assessment period. We predicted a statistically significant 2 (condition: control, dissonance) × 3 (time: baseline, postintervention, 2-month follow-up) interaction in the mixed factorial MANOVA results. Results confirmed this hypothesis. Eating disorder symptoms and cardiac risk indices decreased significantly among participants in the dissonance condition at postintervention and 2-month follow-up compared with baseline. Results provide support for the efficacy of a dissonance-based program in the reduction of eating disorder symptoms and cardiac risk indices among women with subclinical and clinical eating disorder symptoms. Findings establish the efficaciousness of this dissonance-based approach in the indicated prevention and treatment realms and establish its efficacy in reducing cardiac risk indicators. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Determinants of User Adoption of Policy and Procedure Software: An Examination of Relationships between Task-Specific Computer Self-Efficacy, Perceived Relevance, Perceived Complexity and Predictions of Intent to Use Information Technology

ERIC Educational Resources Information Center

Brown, Lori Jill

2012-01-01

For nurses or physicians practicing in any healthcare setting today, nothing seems to be as unsettling then change associated with the introduction of new information technology. The need for information technology has created a new host of challenges that do not easily align to clinical practice. In this study, perceptions of usefulness, ease of…

Biomarkers and surrogate endpoints in glaucoma clinical trials

PubMed Central

Medeiros, Felipe A

2015-01-01

Surrogate endpoints are often used as replacements for true clinically relevant endpoints in several areas of medicine, as they enable faster and less expensive clinical trials. However, without proper validation, the use of surrogates may lead to incorrect conclusions about the efficacy and safety of treatments. This article reviews the general requirements for validating surrogate endpoints and provides a critical assessment of the use of intraocular pressure (IOP), visual fields, and structural measurements of the optic nerve as surrogate endpoints in glaucoma clinical trials. A valid surrogate endpoint must be able to predict the clinically relevant endpoint and fully capture the effect of an intervention on that endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has ever been conducted for any class of IOP-lowering treatments. Evidence has accumulated with regard to the role of imaging measurements of optic nerve damage as surrogate endpoints in glaucoma. These measurements are predictive of functional losses in the disease and may explain, at least in part, treatment effects on clinically relevant endpoints. The use of composite endpoints in glaucoma trials may overcome weaknesses of the use of structural or functional endpoints in isolation. Unless research is dedicated to fully develop and validate suitable endpoints that can be used in glaucoma clinical trials, we run the risk of inappropriate judgments about the value of new therapies. PMID:25034049

Precision Oncology beyond Targeted Therapy: Combining Omics Data with Machine Learning Matches the Majority of Cancer Cells to Effective Therapeutics.

PubMed

Ding, Michael Q; Chen, Lujia; Cooper, Gregory F; Young, Jonathan D; Lu, Xinghua

2018-02-01

Precision oncology involves identifying drugs that will effectively treat a tumor and then prescribing an optimal clinical treatment regimen. However, most first-line chemotherapy drugs do not have biomarkers to guide their application. For molecularly targeted drugs, using the genomic status of a drug target as a therapeutic indicator has limitations. In this study, machine learning methods (e.g., deep learning) were used to identify informative features from genome-scale omics data and to train classifiers for predicting the effectiveness of drugs in cancer cell lines. The methodology introduced here can accurately predict the efficacy of drugs, regardless of whether they are molecularly targeted or nonspecific chemotherapy drugs. This approach, on a per-drug basis, can identify sensitive cancer cells with an average sensitivity of 0.82 and specificity of 0.82; on a per-cell line basis, it can identify effective drugs with an average sensitivity of 0.80 and specificity of 0.82. This report describes a data-driven precision medicine approach that is not only generalizable but also optimizes therapeutic efficacy. The framework detailed herein, when successfully translated to clinical environments, could significantly broaden the scope of precision oncology beyond targeted therapies, benefiting an expanded proportion of cancer patients. Mol Cancer Res; 16(2); 269-78. ©2017 AACR . ©2017 American Association for Cancer Research.

Prospectively Predicting Dietary Restraint: The Role of Interpersonal Self-Efficacy, Weight/Shape Self-Efficacy, and Interpersonal Stress

PubMed Central

Cain, A.S.; Bardone-Cone, A.M.; Abramson, L.Y.; Vohs, K.D.; Joiner, T.E.

2009-01-01

Objective This study investigated how the precursors of interpersonal self-efficacy and weight/shape self-efficacy would interact in the face of interpersonal stress to prospectively predict dietary restraint. Three models were explored, each with a different type of interpersonal stress: stress from same sex friendships, opposite sex friendships, or romantic relationships. Method At Time 1 (T1), participants (N = 406) reported on their typical levels of interpersonal self-efficacy and weight/shape self-efficacy, and recent (past 28 days) dietary restraint. At Time 2 (T2), 11 weeks after T1, participants reported on their recent (past 28 days) levels of dietary restraint at that time. Between T1 and T2, participants completed inventories weekly on the previous week’s interpersonal stressors. Results Consistent with prediction, low interpersonal self-efficacy and high weight/shape self-efficacy combined with high interpersonal stress (whether from same sex friendships, opposite sex friendships, or romantic relationships) to predict the highest levels of T2 dietary restraint after controlling for T1 levels. Conclusion These results further link the interpersonal domain with dietary restraint and elucidate characteristics of women particularly apt to increase dietary restraint in response to interpersonal stress. PMID:19718670

Supervised Risk Predictor of Breast Cancer Based on Intrinsic Subtypes

PubMed Central

Parker, Joel S.; Mullins, Michael; Cheang, Maggie C.U.; Leung, Samuel; Voduc, David; Vickery, Tammi; Davies, Sherri; Fauron, Christiane; He, Xiaping; Hu, Zhiyuan; Quackenbush, John F.; Stijleman, Inge J.; Palazzo, Juan; Marron, J.S.; Nobel, Andrew B.; Mardis, Elaine; Nielsen, Torsten O.; Ellis, Matthew J.; Perou, Charles M.; Bernard, Philip S.

2009-01-01

Purpose To improve on current standards for breast cancer prognosis and prediction of chemotherapy benefit by developing a risk model that incorporates the gene expression–based “intrinsic” subtypes luminal A, luminal B, HER2-enriched, and basal-like. Methods A 50-gene subtype predictor was developed using microarray and quantitative reverse transcriptase polymerase chain reaction data from 189 prototype samples. Test sets from 761 patients (no systemic therapy) were evaluated for prognosis, and 133 patients were evaluated for prediction of pathologic complete response (pCR) to a taxane and anthracycline regimen. Results The intrinsic subtypes as discrete entities showed prognostic significance (P = 2.26E-12) and remained significant in multivariable analyses that incorporated standard parameters (estrogen receptor status, histologic grade, tumor size, and node status). A prognostic model for node-negative breast cancer was built using intrinsic subtype and clinical information. The C-index estimate for the combined model (subtype and tumor size) was a significant improvement on either the clinicopathologic model or subtype model alone. The intrinsic subtype model predicted neoadjuvant chemotherapy efficacy with a negative predictive value for pCR of 97%. Conclusion Diagnosis by intrinsic subtype adds significant prognostic and predictive information to standard parameters for patients with breast cancer. The prognostic properties of the continuous risk score will be of value for the management of node-negative breast cancers. The subtypes and risk score can also be used to assess the likelihood of efficacy from neoadjuvant chemotherapy. PMID:19204204

Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers.

PubMed

Schievink, Bauke; de Zeeuw, Dick; Smink, Paul A; Andress, Dennis; Brennan, John J; Coll, Blai; Correa-Rotter, Ricardo; Hou, Fan Fan; Kohan, Donald; Kitzman, Dalane W; Makino, Hirofumi; Parving, Hans-Henrik; Perkovic, Vlado; Remuzzi, Giuseppe; Tobe, Sheldon; Toto, Robert; Hoekman, Jarno; Lambers Heerspink, Hiddo J

2016-05-01

A recent phase II clinical trial (Reducing Residual Albuminuria in Subjects with Diabetes and Nephropathy with AtRasentan trial and an identical trial in Japan (RADAR/JAPAN)) showed that the endothelin A receptor antagonist atrasentan lowers albuminuria, blood pressure, cholesterol, hemoglobin, and increases body weight in patients with type 2 diabetes and nephropathy. We previously developed an algorithm, the Parameter Response Efficacy (PRE) score, which translates short-term drug effects into predictions of long-term effects on clinical outcomes. We used the PRE score on data from the RADAR/JAPAN study to predict the effect of atrasentan on renal and heart failure outcomes. We performed a post-hoc analysis of the RADAR/JAPAN randomized clinical trials in which 211 patients with type-2 diabetes and nephropathy were randomly assigned to atrasentan 0.75 mg/day, 1.25 mg/day, or placebo. A PRE score was developed in a background set of completed clinical trials using multivariate Cox models. The score was applied to baseline and week-12 risk marker levels of RADAR/JAPAN participants, to predict atrasentan effects on clinical outcomes. Outcomes were defined as doubling serum creatinine or end-stage renal disease and hospitalization for heart failure. The PRE score predicted renal risk changes of -23% and -30% for atrasentan 0.75 and 1.25 mg/day, respectively. PRE scores also predicted a small non-significant increase in heart failure risk for atrasentan 0.75 and 1.25 mg/day (+2% vs. +7%). Selecting patients with >30% albuminuria reduction from baseline (responders) improved renal outcome to almost 50% risk reduction, whereas non-responders showed no renal benefit. Based on the RADAR/JAPAN study, with short-term changes in risk markers, atrasentan is expected to decrease renal risk without increased risk of heart failure. Within this population albuminuria responders appear to contribute to the predicted improvements, whereas non-responders showed no benefit. The ongoing hard outcome trial (SONAR) in type 2 diabetic patients with >30% albuminuria reduction to atrasentan will allow us to assess the validity of these predictions. © The European Society of Cardiology 2015.

The clinical course over the first year of Whiplash Associated Disorders (WAD): pain-related disability predicts outcome in a mildly affected sample

PubMed Central

2013-01-01

Background Different recovery patterns are reported for those befallen a whip-lash injury, but little is known about the variability within subgroups. The aims were (1) to compare a self-selected mildly affected sample (MILD) with a self-selected moderately to severely affected sample (MOD/SEV) with regard to background characteristics and pain-related disability, pain intensity, functional self-efficacy, fear of movement/(re)injury, pain catastrophising, post-traumatic stress symptoms in the acute stage (at baseline), (2) to study the development over the first year after the accident for the above listed clinical variables in the MILD sample, and (3) to study the validity of a prediction model including baseline levels of clinical variables on pain-related disability one year after baseline assessments. Methods The study had a prospective and correlative design. Ninety-eight participants were consecutively selected. Inclusion criteria; age 18 to 65 years, WAD grade I-II, Swedish language skills, and subjective report of not being in need of treatment due to mild symptoms. A multivariate linear regression model was applied for the prediction analysis. Results The MILD sample was less affected in all study variables compared to the MOD/SEV sample. Pain-related disability, pain catastrophising, and post-traumatic stress symptoms decreased over the first year after the accident, whereas functional self-efficacy and fear of movement/(re)injury increased. Pain intensity was stable. Pain-related disability at baseline emerged as the only statistically significant predictor of pain-related disability one year after the accident (Adj r2 = 0.67). Conclusion A good prognosis over the first year is expected for the majority of individuals with WAD grade I or II who decline treatment due to mild symptoms. The prediction model was not valid in the MILD sample except for the contribution of pain-related disability. An implication is that early observations of individuals with elevated levels of pain-related disability are warranted, although they may decline treatment. PMID:24359208

Predictive factors of adherence to frequency and duration components in home exercise programs for neck and low back pain: an observational study

PubMed Central

2009-01-01

Background Evidence suggests that to facilitate physical activity sedentary people may adhere to one component of exercise prescriptions (intensity, duration or frequency) without adhering to other components. Some experts have provided evidence for determinants of adherence to different components among healthy people. However, our understanding remains scarce in this area for patients with neck or low back pain. The aims of this study are to determine whether patients with neck or low back pain have different rates of adherence to exercise components of frequency per week and duration per session when prescribed with a home exercise program, and to identify if adherence to both exercise components have distinct predictive factors. Methods A cohort of one hundred eighty-four patients with chronic neck or low back pain who attended physiotherapy in eight primary care centers were studied prospectively one month after intervention. The study had three measurement periods: at baseline (measuring characteristics of patients and pain), at the end of physiotherapy intervention (measuring characteristics of the home exercise program) and a month later (measuring professional behaviors during clinical encounters, environmental factors and self-efficacy, and adherence behavior). Results Adherence to duration per session (70.9% ± 7.1) was more probable than adherence to frequency per week (60.7% ± 7.0). Self-efficacy was a relevant factor for both exercise components (p < 0.05). The total number of exercises prescribed was predictive of frequency adherence (p < 0.05). Professional behaviors have a distinct influence on exercise components. Frequency adherence is more probable if patients received clarification of their doubts (adjusted OR: 4.1; p < 0.05), and duration adherence is more probable if they are supervised during the learning of exercises (adjusted OR: 3.3; p < 0.05). Conclusion We have shown in a clinic-based study that adherence to exercise prescription frequency and duration components have distinct levels and predictive factors. We recommend additional study, and advise that differential attention be given in clinical practice to each exercise component for improving adherence. PMID:19995464

Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper.

PubMed

Shamji, M H; Kappen, J H; Akdis, M; Jensen-Jarolim, E; Knol, E F; Kleine-Tebbe, J; Bohle, B; Chaker, A M; Till, S J; Valenta, R; Poulsen, L K; Calderon, M A; Demoly, P; Pfaar, O; Jacobsen, L; Durham, S R; Schmidt-Weber, C B

2017-08-01

Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers. The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG-subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE-FAB and IgE-BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?). All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed. It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE-FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Prediction of the efficacy of immunotherapy by measuring the integrity of cell-free DNA in plasma in colorectal cancer.

PubMed

Kitahara, Masahiro; Hazama, Shoichi; Tsunedomi, Ryouichi; Takenouchi, Hiroko; Kanekiyo, Shinsuke; Inoue, Yuka; Nakajima, Masao; Tomochika, Shinobu; Tokuhisa, Yoshihiro; Iida, Michihisa; Sakamoto, Kazuhiko; Suzuki, Nobuaki; Takeda, Shigeru; Ueno, Tomio; Yamamoto, Shigeru; Yoshino, Shigefumi; Nagano, Hiroaki

2016-12-01

We previously reported a phase II study of a cancer vaccine using five novel peptides recognized by HLA-A*2402-restricted CTL in combination with oxaliplatin-containing chemotherapy (FXV study) as first-line therapy for patients with metastatic colorectal cancer and demonstrated the safety and promising potential of our five-peptide cocktail. The objective of this analysis was to identify predictive biomarkers for identifying patients who are likely to receive a clinical benefit from immunochemotherapy. Circulating cell-free DNA (cfDNA) in plasma has been reported to be a candidate molecular biomarker for the efficacy of anticancer therapy. Unlike uniformly truncated small-sized DNA released from apoptotic normal cells, DNA released from necrotic cancer cells varies in size. The integrity of plasma cfDNA (i.e. the ratio of longer fragments [400 bp] to shorter fragments [100 bp] of cfDNA), may be clinically useful for detecting colorectal cancer progression. We assessed plasma samples collected from 93 patients prior to receiving immunochemotherapy. The cfDNA levels and integrity were analyzed by semi-quantitative real-time PCR. Progression-free survival was significantly better in patients with a low plasma cfDNA integrity value than in those with a high value (P = 0.0027). Surprisingly, in the HLA-A*2402-matched group, patients with a low plasma cfDNA integrity value had significantly better progression-free survival than those with a high value (P = 0.0015). This difference was not observed in the HLA-A*2402-unmatched group. In conclusion, the integrity of plasma cfDNA may provide important clinical information and may be a useful predictive biomarker of the outcome of immunotherapy in metastatic colorectal cancer. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Incorporating prognostic imaging biomarkers into clinical practice

PubMed Central

Miles, Kenneth A.

2013-01-01

Abstract A prognostic imaging biomarker can be defined as an imaging characteristic that is objectively measurable and provides information on the likely outcome of the cancer disease in an untreated individual and should be distinguished from predictive imaging biomarkers and imaging markers of response. A range of tumour characteristics of potential prognostic value can be measured using a variety imaging modalities. However, none has currently been adopted into routine clinical practice. This article considers key examples of emerging prognostic imaging biomarkers and proposes an evaluation framework that aims to demonstrate clinical efficacy and so support their introduction into the clinical arena. With appropriate validation within an established evaluation framework, prognostic imaging biomarkers have the potential to contribute to individualized cancer care, in some cases reducing the financial burden of expensive cancer treatments by facilitating their more rational use. PMID:24060808

An extended version of the theory of planned behaviour: the role of self-efficacy and past behaviour in predicting the physical activity of Chinese adolescents.

PubMed

Wang, Lijuan; Zhang, Ying

2016-01-01

This study aimed to use an extended theory of planned behaviour (TPB), which incorporated additional self-efficacy and past behaviour, to predict the intention to engage in moderate-to-vigorous physical activity (MVPA) and the MVPA level of Chinese adolescents. Questionnaires that focused on MVPA, attitude, subjective norm, perceived behavioural control (PBC), self-efficacy and past behaviour related to the MVPA engagement were administered to a sample of 488 young people. Multiple regression analyses provided moderate support for TPB. Three TPB constructs predicted 28.7% of the variance in intentions to engage in MVPA, and that PBC, but not intention, explained 3.4% of the variance in MVPA. Self-efficacy significantly affected intention and behaviour over and above the influence of TPB. Past behaviour had a small but significant improvement in the prediction of intention, but no improvement in the prediction of MVPA. Based on the results, interventions should target adolescent self-efficacy and PBC in physical activity participation.

Genetic risk variants as therapeutic targets for Crohn's disease.

PubMed

Gabbani, Tommaso; Deiana, Simona; Marocchi, Margherita; Annese, Vito

2017-04-01

The pathogenesis of Inflammatory bowel diseases (IBD) is multifactorial, with interactions between genetic and environmental factors. Despite the existence of genetic factors being largely demonstrated by epidemiological data and several genetic studies, only a few findings have been useful in term of disease prediction, disease progression and targeting therapy. Areas covered: This review summarizes the results of genome-wide association studies in Crohn's disease, the role of epigenetics and the recent discovery by genetic studies of new pathogenetic pathways. Furthermore, it focuses on the importance of applying genetic data to clinical practice, and more specifically how to better target therapy and predict potential drug-related toxicity. Expert opinion: Some genetic markers identified in Crohn`s disease have allowed investigators to hypothesize about, and in some cases, prove the usefulness of new specific therapeutic agents. However, the heterogeneity and complexity of this disease has so far limited the daily clinical use of genetic information. Finally, the study of the implications of genetics on therapy, either to predict efficacy or avoid toxicity, is considered still to be in its infancy.

Behavioral indices in medical care outcome: the working alliance, adherence, and related factors.

PubMed

Fuertes, Jairo N; Boylan, Laura S; Fontanella, Jessie A

2009-01-01

The working alliance has been shown to be a consistent predictor of patient outcome and satisfaction in psychotherapy. This study examines the role of the working alliance and related behavioral indices in predicting medical outcome. Cognitive and emotional dimensions of the physician-patient relationship were examined in relation to patients' ratings of physician empathy, physician multicultural competence, perceived utility of treatment, and patients' adherence self-efficacy. These factors were then examined as part of a theoretical framework using path analyses to explain patient self-reported adherence to and satisfaction with treatment. The study was based on an ex-post facto field correlation design. One hundred fifty-two adult outpatients from a neurology clinic at Bellevue Hospital, a large municipal hospital in New York City, participated in the study. Surveys given to participants. We used the following measurements: Physician-Patient Working Alliance Scale, Perceived Utility Scale, Treatment Adherence Self-Efficacy Scale, Medical Outcome Study Adherence Scale, Physician Empathy Questionnaire, Physician Multicultural Competence Questionnaire, Medical Patient Satisfaction Questionnaire. The effect sizes for adherence are between 0.07 and 0.21 and for satisfaction between 0.10 to >0.50. Regression and path analyses showed that ratings of physician multicultural competence and patient adherence self-efficacy beliefs predicted patient adherence (SB = 0.34) and (SB = 0.30) and satisfaction (SB = 0.18) and (SB = 0.12), respectively. Working alliance ratings also predicted patient satisfaction (SB = 0.49). Psychological and interpersonal dimensions of medical care are related to patient adherence and satisfaction. Medical care providers may be able to use these dimensions to target and improve health care outcomes.

Predictive Power of the Sources of Primary School Students' Self-Efficacy Beliefs on Their Self-Efficacy Beliefs for Learning and Performance

ERIC Educational Resources Information Center

Arslan, Ali

2012-01-01

The purpose of this study is to reveal the extent to which the sources of 6th- 8th grade students' self-efficacy beliefs predict their self-efficacy beliefs for learning and performance. The study is correlational and was conducted on a total of 1049 students during the fall term of the educational year 2010-2011. The data of the study were…

Outcomes of Occupational Self-Efficacy in Older Workers

PubMed Central

Paggi, Michelle E.; Jopp, Daniela S.

2016-01-01

Because of the increasing number of older workers, it is important to develop models of work-related constructs for this population. The present article developed a model surrounding occupational self-efficacy, testing its relation to other factors (e.g., intrinsic job motivation), predictors (e.g., self-perceptions of aging), and outcomes (e.g., job satisfaction). Employed adults of ages 50 and older (n= 313) were recruited via organizations and social media sites. Study participants (M= 59.7, SD= 6.1, range = 50–78) volunteered to fill out an Internet survey. Occupational self-efficacy predicted job satisfaction, and intrinsic job motivation fully mediated this relationship. More negative self-perceptions of aging predicted poorer occupational self-efficacy. Occupational self-efficacy also predicted life satisfaction. Expected retirement age and job performance were unrelated to occupational self-efficacy. These findings may inform workplace interventions that seek to maintain or increase older worker job and life satisfaction. PMID:26394821

Evaluation of a new in-clinic test system to detect feline immunodeficiency virus and feline leukemia virus infection.

PubMed

Sand, Christina; Englert, Theresa; Egberink, Herman; Lutz, Hans; Hartmann, Katrin

2010-06-01

Many in-house tests for the diagnosis of feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) infection are licensed for use in veterinary practice. A new test with unknown performance has recently appeared on the market. The aims of this study were to define the efficacy of a new in-clinic test system, the Anigen Rapid FIV Ab/FeLV Ag Test, and to compare it with the current leading in-clinic test, the SNAP Kombi Plus FeLV Antigen/FIB Antibody Test. Three-hundred serum samples from randomly selected healthy and diseased cats presented to the Clinic of Small Animal Medicine at Ludwig Maximilian University were tested using both the Anigen Rapid Test and the SNAP Kombi Plus Test. Diagnostic sensitivity, specificity, and positive and negative predictive values were calculated for both tests using Western blot as the gold standard for verification of FIV infection and PCR as the gold standard for FeLV infection. The presence of antibodies against FIV was confirmed by Western blot in 9/300 samples (prevalence 3%). FeLV DNA was detected by PCR in 15/300 samples (prevalence 5%). For FIV infection the Anigen Rapid Test had a sensitivity of 88.9%, specificity of 99.7%, positive predictive value of 88.9%, and negative predictive value of 99.7%. For FeLV infection, the Anigen Rapid Test had a sensitivity of 40.0%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 96.9%. Diagnostic accuracy was similar to that of the SNAP Kombi Plus Test. The new Anigen Rapid FIV Ab/FeLV Ag Test performed very well and can be recommended for use in veterinary practice.

Clinical prediction model to identify vulnerable patients in ambulatory surgery: towards optimal medical decision-making.

PubMed

Mijderwijk, Herjan; Stolker, Robert Jan; Duivenvoorden, Hugo J; Klimek, Markus; Steyerberg, Ewout W

2016-09-01

Ambulatory surgery patients are at risk of adverse psychological outcomes such as anxiety, aggression, fatigue, and depression. We developed and validated a clinical prediction model to identify patients who were vulnerable to these psychological outcome parameters. We prospectively assessed 383 mixed ambulatory surgery patients for psychological vulnerability, defined as the presence of anxiety (state/trait), aggression (state/trait), fatigue, and depression seven days after surgery. Three psychological vulnerability categories were considered-i.e., none, one, or multiple poor scores, defined as a score exceeding one standard deviation above the mean for each single outcome according to normative data. The following determinants were assessed preoperatively: sociodemographic (age, sex, level of education, employment status, marital status, having children, religion, nationality), medical (heart rate and body mass index), and psychological variables (self-esteem and self-efficacy), in addition to anxiety, aggression, fatigue, and depression. A prediction model was constructed using ordinal polytomous logistic regression analysis, and bootstrapping was applied for internal validation. The ordinal c-index (ORC) quantified the discriminative ability of the model, in addition to measures for overall model performance (Nagelkerke's R (2) ). In this population, 137 (36%) patients were identified as being psychologically vulnerable after surgery for at least one of the psychological outcomes. The most parsimonious and optimal prediction model combined sociodemographic variables (level of education, having children, and nationality) with psychological variables (trait anxiety, state/trait aggression, fatigue, and depression). Model performance was promising: R (2)  = 30% and ORC = 0.76 after correction for optimism. This study identified a substantial group of vulnerable patients in ambulatory surgery. The proposed clinical prediction model could allow healthcare professionals the opportunity to identify vulnerable patients in ambulatory surgery, although additional modification and validation are needed. (ClinicalTrials.gov number, NCT01441843).

Efficacy of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinone derivatives against different Trypanosoma cruzi discrete type units: Identification of a promising hit compound.

PubMed

Lara, L S; Moreira, C S; Calvet, C M; Lechuga, G C; Souza, R S; Bourguignon, S C; Ferreira, V F; Rocha, D; Pereira, M C S

2018-01-20

The limited efficacy of benznidazole (Bz) indicated by failures of current Phase II clinical trials emphasizes the urgent need to identify new drugs with improved safety and efficacy for treatment of Chagas disease (CD). Herein, we analyzed the efficacy of a series of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against different Trypanosoma cruzi discrete type units (DTUs) of relevant clinical forms of CD. Cytotoxic and trypanocidal effect of naphthoquinone derivatives were assessed in mammalian cells, trypomastigotes and intracellular amastigotes using, luminescent assays (CellTiter-Glo and T. cruzi Dm28c-luciferase) and/or counting with a light microscope. Reactive oxygen species (ROS) production and intracellular targets of promising compounds were assessed with 2',7'-dichlorodihydrofluorescein diacetate (H 2 DCFDA) probe and ultrastructural analysis, respectively. ADMET properties were analyzed by in silico modeling. Most of the compounds showed low cytotoxic effect. Only two compounds (Compounds 2 and 11) had IC 50 values lower than Bz, showing higher susceptibility of bloodstream trypomastigotes. Compound 2 exhibited greater efficacy against trypomastigotes from different T. cruzi DTUs, even better than Bz against Brazil and CL strains. Ultrastructural analysis revealed changes in intracellular compartments, suggesting autophagy as one possible mechanism of action. Oxidative stress, induced by Compound 2, resulted in elevated level of ROS, leading to parasite death. Compound 2 was also effective against intracellular amastigotes, showing high selectivity index. ADMET analysis predicted good oral bioavailability, reduced drug metabolism and no carcinogenic potential for Compound 2. The data highlight Compound 2 as a hit compound and stimulate further structural and pharmacological optimization to potentiate its trypanocidal activity and selectivity. Copyright © 2017. Published by Elsevier Masson SAS.

Clinical staging of Fibrodysplasia Ossificans Progressiva (FOP).

PubMed

Pignolo, Robert J; Kaplan, Frederick S

2018-04-01

Fibrodyplasia ossificans progressiva (FOP) is an ultra-rare genetic condition of heterotopic ossification (HO) that results in progressive loss of joint function, ultimately rendering movement impossible. Death is most commonly the result of thoracic insufficiency syndrome, or complications related to recurrent respiratory infections. There are no current treatments for FOP, but early and emerging clinical trials offer hope for this devastating disease. With the recent reporting of a comprehensive global natural history study, scales to assess joint dysfunction, and a more accurate prediction of joint survival, it is now possible to construct a conceptual framework for the clinical staging of FOP. Based on assessment of FOP features in seven areas, it is possible to assign five clinical stages. FOP features include flare-up activity, body regions affected, thoracic insufficiency, other complications, activities of daily living (ADLs), ambulatory status, and the cumulative joint involvement scale (CAJIS) score. Assessments of these features assign an individual with FOP to early/mild, moderate, severe, profound, or late-stage disease. These criteria seek to be flexible enough to be used by clinicians without reliance on advanced imaging or specialized testing, as well as by investigators involved in research or clinical trial studies who would have these tools available. These staging measures for FOP assess the influence of HO and accelerated joint dysfunction (due to congenital abnormalities) on the ability to perform common functional activities, and thus a delay or lack of progression from one stage to the next represents the ultimate test of efficacy for drug trials. This framework will serve both as a prediction tool for FOP progression as well as a critical opportunity to substantiate therapeutic interventions. The staging system proposed here will permit an accurate assessment of severity to appropriately develop or revise clinical plans of care, define operational research criteria, and identify the effectiveness of interventions. Ultimately, this clinical staging will aid the field in moving toward earlier intervention at a stage where disease-modifying therapies may be most efficacious. Copyright © 2017 Elsevier Inc. All rights reserved.

"Yes, we can!": Perceptions of collective efficacy sources in volleyball.

PubMed

Fransen, Katrien; Vanbeselaere, Norbert; Exadaktylos, Vasileios; Vande Broek, Gert; De Cuyper, Bert; Berckmans, Daniel; Ceux, Tanja; De Backer, Maarten; Boen, Filip

2012-01-01

Collective efficacy can be defined as a group's shared confidence that they will successfully achieve their goal. We examined which behaviours and events are perceived as sources of collective efficacy beliefs in a volleyball context. In study 1, volleyball coaches from the highest volleyball leagues (n = 33) in Belgium indicated the most important sources of collective efficacy. This list was then adapted based on the literature and on feedback given by an expert focus group, resulting in a 40-item questionnaire. In Study 2, coaches and players from all levels of volleyball in Belgium (n = 2365) rated each of these sources on their predictive value for collective efficacy. A principal component analysis revealed that the 40 sources could be divided into eight internally consistent factors. Positive supportive communication (e.g., enthusiasm after making a point) was identified as the factor most predictive for positive collective efficacy beliefs. The factor referring to the negative emotional reactions of players (e.g., discouraging body language) was the most predictive for negative collective efficacy beliefs. These findings offer a starting point for the design of continuous measurements of collective efficacy through observation.

Safety and efficacy of pirfenidone in idiopathic pulmonary fibrosis in clinical practice.

PubMed

Okuda, Ryo; Hagiwara, Eri; Baba, Tomohisa; Kitamura, Hideya; Kato, Terufumi; Ogura, Takashi

2013-09-01

Previous pirfenidone trials have only involved patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the safety and efficacy of pirfenidone in patients with mild-to-severe IPF in clinical practice. The clinical records of 76 patients who were diagnosed with IPF and received pirfenidone were reviewed. The most frequent adverse event was anorexia, although the grade of anorexia in most patients was mild. Dose reduction of pirfenidone improved anorexia in 84% affected patients, which resulted in a high medication compliance rate. The mean forced vital capacity (FVC) at the initiation of pirfenidone therapy in this study was approximately 10% lower than that in previous clinical trials. The mean change in FVC during the 6-month period prior to the therapy initiation was -188 mL, which improved to -19 mL during the 6-month period after therapy. Significant attenuation in percentage predicted diffusion capacity of the lung for carbon monoxide decline was also achieved after pirfenidone therapy initiation. The efficacy of pirfenidone in attenuating the degree of FVC decline was higher in the group with FVC decline of ≥150 mL during the 6-month period prior to therapy initiation. The levels of serum markers, such as KL-6 and SP-D, were also lowered by the therapy. These results showed that pirfenidone was well-tolerated and had beneficial effects in patients with mild-to-severe and/or progressive IPF. The degree of disease progression prior to the initiation of pirfenidone therapy had an impact on the response to the therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Gender identity, research self-efficacy and research intention in trainee clinical psychologists in the UK.

PubMed

Wright, Anne B; Holttum, Sue

2012-01-01

This study tested, with a sample of United Kingdom (UK) trainee clinical psychologists, part of an existing model of factors that influence clinical psychologists' levels of research activity, in which gender identity is hypothesized to influence research self-efficacy and this in turn strength of intention to do research. A sample of 121 trainee clinical psychologists (56 men and 65 women) completed a measure of gender identity, research intention, and a research self-efficacy scale. Results indicated no differences in levels of research intention or research self-efficacy between the biological sexes or according to category-based gender identities (masculine and feminine). However, masculinity as a scale quantity was statistically significantly related to stronger research intention, preference for conducting quantitative research and research self-efficacy. Multiple regression analysis provided evidence that research self-efficacy may mediate between masculinity and strength of research intention. Research self-efficacy was the strongest predictor of intention to do research in the future. Findings have relevance for clinical psychology training as research activity directly impacts upon advances in the discipline of clinical psychology, implementation of research into practice, and evaluation of psychological therapies. Copyright © 2010 John Wiley & Sons, Ltd.

HTR2A A-1438G/T102C polymorphisms predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients.

PubMed

Chen, Shih-Fen; Shen, Yu-Chih; Chen, Chia-Hsiang

2009-08-01

Aripiprazole acts as a partial agonist at dopamine D2 and D3 and serotonin 1A receptors and as an antagonist at serotonin 2A receptors (HTR2A). Since aripiprazole acts as an antagonist at HTR2A, genetic variants of HTR2A may be important in explaining variability in response to aripiprazole. This study investigated whether the efficacy of aripiprazole can be predicted by functional HTR2A A-1438G/T102C polymorphisms (rs63311/rs6313) as modified by clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. After hospitalization, the patients (n = 128) were given a 4-week course of aripiprazole. Patients were genotyped for HTR2A A-1438G/T102C polymorphisms via the restriction fragment length polymorphism method. Clinical factors such as gender, age, duration of illness, education level, diagnostic subtype, and medication dosage were noted as well. The researchers measured psychopathology biweekly, using the Positive and Negative Syndrome Scale (PANSS). A mixed model regression approach (SAS Proc MIXED) was used to analyze the effects of genetic and clinical factors on PANSS performance after aripiprazole treatment. We found that the GG/CC genotype group of HTR2A A-1438G/T102C polymorphisms predicts poor aripiprazole response specifically for negative symptoms. In addition, the clinical factors, including dosage of aripiprazole, age, duration of illness, and diagnostic subtype, were found to influence PANSS performance after aripiprazole treatment. The data suggest HTR2A A-1438G/T102C polymorphisms may predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients as modified by clinical factors.

Impact of critical thinking disposition, general self-efficacy, and leadership on clinical competence in nursing students.

PubMed

Park, Jee Won; Kim, Chun Ja; Kim, Yong Soon; Yoo, Moon Sook; Yoo, Hyera; Chae, Sun Mi; Ahn, Jeong Ah

2012-09-01

The purpose of this study was to evaluate the relationships among critical thinking disposition, general self-efficacy, leadership and clinical competence, and identify the factors influencing clinical competence in nursing students. In this descriptive study, 153 nursing students (from 2nd to 4th school year) of a university in South Korea were enrolled in December 2010. The instruments for this study were the Korean versions of the Critical Thinking Disposition Scale, General Self-Efficacy Scale, Leadership Inventory, and Clinical Competence Scale. Data were analyzed by descriptive statistics, t-test, MANOVA, Pearson correlation, and multiple linear regression with PASW 18.0 software. The mean scores (ranging from 1 to 5) in nursing students for critical thinking disposition, general self-efficacy, leadership, and clinical competence were 3.44, 3.51, 3.55, and 3.42, respectively. Positive correlations were found for clinical competence with critical thinking disposition, general self-efficacy, and leadership. The strongest predictor of clinical competence was leadership. In addition, leadership, nursing school year, and subjective academic achievement accounted for 34.5% of variance in clinical competence. This study revealed that developing leadership, critical thinking disposition, and self-efficacy in undergraduate nursing education is important to improve clinical competence of nursing students.

Nurse burnout: personal and environmental factors as predictors.

PubMed

Wang, Shanshan; Liu, Yanhui; Wang, Linlin

2015-02-01

The aim of this study is to investigate the level of burnout of clinical nurses and to examine the influence of personal and environmental factors on nurse burnout. A total of 717 full-time nurses from six hospitals in Tianjin, China, completed five questionnaires: a demographic questionnaire, the Maslach Burnout Inventory, the General Self-Efficacy Scale, the Practice Environment Scale of the Nursing Work Index and the Nurse Job Stressor Scale. The participants had moderate levels of emotional exhaustion (mean score 23.95 ± 11.11) and depersonalization (mean score 7.90 ± 6.58) and a high level of reduced personal accomplishment (mean score 27.51 ± 10.96). Both personal and environmental factors were correlated with nurse burnout; however, personal factors played bigger roles in predicting personal accomplishment, whereas environmental factors played bigger roles in predicting emotional exhaustion and depersonalization. In order to reduce nurse job burnout effectively, administrators should pay more attention to the improvement of nurses' self-efficacy and professional nursing practice environment and the reduction of stressors. © 2013 Wiley Publishing Asia Pty Ltd.

Clinic Appointment Attendance in Adults with Serious Mental Illness and Diabetes.

PubMed

Gunzler, Douglas D; Morris, Nathan; Dalton, Jarrod E; McCormick, Richard; Dawson, Neal V; Thomas, Charles; Kanuch, Stephanie; Cassidy, Kristin A; Athey, Melanie; Fuentes-Casiano, Edna; Lawless, Mary Ellen; Martin, Siobhan; Einstadter, Douglas; Sajatovic, Martha

2017-11-01

We assessed characteristics that may predict outpatient appointment attendance in outpatient medical clinics among patients comorbid for serious mental illness (SMI) and type 2 diabetes (DM). Baseline covariate data from 200 individuals with SMI-DM enrolled in a randomized controlled trial (RCT) were used to examine characteristics associated with electronic health record-identified clinic appointment attendance using a generalized estimating equations approach. The analyses evaluated the relationship between clinic attendance and potentially modifiable factors including disease knowledge, self-efficacy, social support, physical health, and mental health, as well as demographic information. Demographic and mental health characteristics were most associated with clinic attendance in adults with SMI-DM. Physical health was not associated with clinic attendance. Information on clinical and demographic characteristics and factors potentially modifiable by psychological interventions may be useful in improving adherence to treatment among SMI-DM patients. It is our hope that clinicians and researchers will use these results to help tailor adherence-facilitating interventions among people at particular risk for poor engagement in care.

Motivation for change as a predictor of treatment response for dysthymia.

PubMed

Frías Ibáñez, Álvaro; González Vallespí, Laura; Palma Sevillano, Carol; Farriols Hernando, Núria

2016-05-01

Dysthymia constitutes a chronic, mild affective disorder characterized by heterogeneous treatment effects. Several predictors of clinical response and attendance have been postulated, although research on the role of the psychological variables involved in this mental disorder is still scarce. Fifty-four adult patients, who met criteria for dysthymia completed an ongoing naturalistic treatment based on the brief interpersonal psychotherapy (IPT-B), which was delivered bimonthly over 16 months. As potential predictor variables, the therapeutic alliance, coping strategies, perceived self-efficacy, and motivation for change were measured at baseline. Outcome variables were response to treatment (Clinical Global Impression and Beck’s Depression Inventory) and treatment attendance. Stepwise multiple linear regression analyses revealed that higher motivation for change predicted better response to treatment. Moreover, higher motivation for change also predicted treatment attendance. Therapeutic alliance was not a predictor variable of neither clinical response nor treatment attendance. These preliminary findings support the adjunctive use of motivational interviewing (MI) techniques in the treatment of dysthymia. Further research with larger sample size and follow-up assessment is warranted.

[Research and development on efficacy of Chinese herbal compound].

PubMed

Liu, Jian-Xun; Ren, Jian-Xun; Lin, Cheng-Ren

2016-03-01

The efficacy not only is summarized by clinical effect of Chinese herbal compound on theory of traditional Chinese medicine, but also is manifested to clinical effect by interaction of many intricate chemical substances. The efficacy of Chinese herbal compound is current research focus in field of traditional Chinese medicine. By currently knowing in different aspects which included the progression in efficacy of Chinese herbal compound, symptomatic efficacy of Chinese herbal compound, the relationship between the efficacy and pharmacologic effect of Chinese herbal compound, the efficacy related pharmacodynamic substance and the evaluation of efficacy, it had been summarized mainly problems and methods in research and development process of the efficacy of Chinese herbal compound in this paper. Paper also elucidated problems that need to pay attention in research of efficacy in order to provide references for clinical and experimental studies of efficacy in Chinese herbal compound, boost research and development level of new traditional Chinese drug and facilitate modernization of traditional Chinese medicines. Copyright© by the Chinese Pharmaceutical Association.

Safety and efficacy of pirfenidone in severe Idiopathic Pulmonary Fibrosis: A real-world observational study.

PubMed

Tzouvelekis, Argyrios; Ntolios, Paschalis; Karampitsakos, Theodoros; Tzilas, Vasilios; Anevlavis, Stavros; Bouros, Evangelos; Steiropoulos, Paschalis; Koulouris, Nikolaos; Stratakos, Grigoris; Froudarakis, Marios; Bouros, Demosthenes

2017-10-01

Pirfenidone is a novel anti-fibrotic drug that has shown efficacy in five randomized multicenter clinical trials enrolling patients with Idiopathic Pulmonary Fibrosis of mild-to-moderate disease severity. Scarce data supports the use of pirfenidone in IPF patients with more advanced disease. To investigate the safety and efficacy profile of pirfenidone in IPF patients with severe lung function impairment. This was a retrospective study enrolling patients with advanced IPF (FVC%predicted < 50% and/or (DLco%predicted <35%) receiving pirfenidone for at least 6 months. Between September 2011 and March 2013, we identified 43 patients with severe IPF (baseline meanFVC%predicted±SD: 63.8 ± 20.3, meanDL CO %predicted: 27.3 ± 8.2), of mean age±SD: 66.3 + 9.7, 34 males (81%) that received pirfenidone (2.403 mg/daily) for one year. Pirfenidone treatment was associated with a trend towards decrease in functional decline compared to 6-months before treatment initiation but failed to show any benefit after one year of treatment (ΔFVC: -3.3 ± 4.6 vs 0.49 ± 11.4 and vs. -5.8 ± 11.8, p = 0.06 and p = 0.04, respectively and ΔDL CO : -13.3 ± 15.2 vs. -10.1 ± 16.6 and vs. 28.3 ± 19.2, p = 0.39 and p = 0.002, respectively). Gastrointestinal disorders (34.9%), fatigue (23.2%) and photosensitivity (18.6%) were the most common adverse events. Adverse events led to treatment discontinuation in 9 patients (20.9%) and dose reduction in 14 (32.5%). Pirfenidone appears to be safe when administered in patients with advanced IPF. Pirfenidone efficacy in IPF patients with severe lung function impairment may diminish after 6 months of treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Adolescents' protection motivation and smoking behaviour.

PubMed

Thrul, Johannes; Stemmler, Mark; Bühler, Anneke; Kuntsche, Emmanuel

2013-08-01

The protection motivation theory (PMT) is a well-known theory of behaviour change. This study tested the applicability of the sub-constructs of threat and coping appraisal in predicting adolescents' smoking-related behavioural intentions and smoking behaviour longitudinally. Adolescents (N = 494) aged 11-16 years and not currently smoking at baseline participated in the study. Predictive validity of PMT constructs was tested in a path analysis model. Self-efficacy significantly predicted behavioural intention at baseline, which significantly predicted behavioural intention at follow-up, which in turn predicted smoking behaviour at follow-up. The effect of self-efficacy on behavioural intention at follow-up was mediated by behavioural intention at baseline and the effect of self-efficacy on smoking behaviour was mediated by behavioural intention at baseline and follow-up. In conclusion, we found support for one part of the PMT, namely for the predictive validity of the coping appraisal construct self-efficacy in predicting adolescents' smoking-related behavioural intention and smoking behaviour. These results fail to support the appropriateness of the PMT's construct threat appraisal in longitudinally predicting adolescents' smoking as well as the applicability of communicating fear and negative information as preventive interventions for this target group.

The Role of Parents' Critical Thinking About Media in Shaping Expectancies, Efficacy and Nutrition Behaviors for Families.

PubMed

Austin, Erica Weintraub; Pinkleton, Bruce E; Radanielina-Hita, Marie Louise; Ran, Weina

2015-01-01

A convenience survey completed online by 137 4-H parents in Washington state explored their orientation toward critical thinking regarding media sources and content and its implications for family dietary behaviors. Parents' critical thinking toward media sources predicted their information efficacy about content. Critical thinking toward media content predicted information efficacy about sources, expectancies for parental mediation, and expectancies for family receptiveness to lower-fat dietary changes. Expectancies for receptiveness to dietary changes and expectancies for parental mediation predicted efficacy for implementing healthy dietary practices; this strongly predicted healthy dietary practices. Media-related critical thinking, therefore, indirectly but consistently affected self-reported family dietary behaviors through its effects on efficacy for managing media and expectancies for the family's receptiveness to healthy dietary changes. The results suggest parents' media literacy skills affect their family's dietary behavior. Health campaigns that help parents interpret and manage the media environment may benefit all family members.

Research Design and the Predictive Power of Measures of Self-Efficacy

ERIC Educational Resources Information Center

Moriarty, Beverley

2014-01-01

The purpose of this enquiry was to examine how research design impacts on the predictive power of measures of self-efficacy. Three cautions for designing research into self-efficacy drawn from the seminal work of Albert Bandura (1986) and a further caution proposed by the current author together form the analytical framework for this enquiry. For…

DPYD*2A and MTHFR C677T predict toxicity and efficacy, respectively, in patients on chemotherapy with 5-fluorouracil for colorectal cancer.

PubMed

Nahid, Noor Ahmed; Apu, Mohd Nazmul Hasan; Islam, Md Reazul; Shabnaz, Samia; Chowdhury, Surid Mohammad; Ahmed, Maizbha Uddin; Nahar, Zabun; Islam, Md Siddiqul; Islam, Mohammad Safiqul; Hasnat, Abul

2018-01-01

Significant inter-individual variation in the sensitivity to 5-fluorouracil (5-FU) represents a major therapeutic hindrance either by impairing drug response or inducing adverse drug reactions (ADRs). This study aimed at exploring the cause behind this inter-individual alterations in consequences of 5-fluorouracil-based chemotherapy by investigating the effects of DPYD*2A and MTHFR C677T polymorphisms on toxicity and response of 5-FU in Bangladeshi colorectal cancer patients. Colorectal cancer patients (n = 161) receiving 5-FU-based chemotherapy were prospectively enrolled. DPYD and MTHFR polymorphisms were assessed in peripheral leukocytes. Multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity and efficacy. Multivariate analyses showed that DPYD*2A polymorphism was a predictive factor (P = 0.023) for grade 3 and grade 4 5-fluorouracil-related toxicities. Although MTHFR C677T polymorphism might act as forecasters for grade 3 or grade 4 neutropenia, diarrhea, and mucositis, this polymorphism was found to increase significantly (P = 0.006) the response of 5-FU. DPYD*2A and MTHFR C677T polymorphisms could explain 5-FU toxicity or clinical outcome in Bangladeshi colorectal patients.

Psychosocial predictors of four health-promoting behaviors for cancer prevention using the stage of change of Transtheoretical Model.

PubMed

Choi, Jean H; Chung, Kyong-Mee; Park, Keeho

2013-10-01

The present study aimed to examine whether demographic as well as psychosocial variables related to the five stages of change of the Transtheoretical Model can predict non-clinical adults' cancer preventive and health-promoting behaviors. This study specifically focused on cancer, one of the major chronic diseases, which is a serious threat of national health. A total of 1530 adults participated in the study and completed questionnaires. Collected data were analyzed by using multinominal logistic regression. The significant predictors of later stages varied among the types of health-promoting behaviors. Certain cancer preventive health-promoting behaviors such as well-balanced diet and exercise were significantly associated with psychosocial variables including cancer prevention-related self-efficacy, personality traits, psychosocial stress, and social support. On the other hand, smoking cessation and moderate or abstinence from drinking were more likely to be predicted by demographic variables including sex and age. The present study found that in addition to self-efficacy-a relatively well-studied psychological variable-other personality traits and psychological factors including introversion, neuroticism, psychosocial stress, and social support also significantly predicted later stages of change with respect to cancer preventive health-promoting behaviors. The implications of this study are also discussed. Copyright © 2013 John Wiley & Sons, Ltd.

Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B.

PubMed

Dietrich, Barbara; Schiviz, Alexandra; Hoellriegl, Werner; Horling, Frank; Benamara, Karima; Rottensteiner, Hanspeter; Turecek, Peter L; Schwarz, Hans Peter; Scheiflinger, Friedrich; Muchitsch, Eva-Maria

2013-11-01

Baxter has developed a new recombinant factor IX (rFIX) drug product (BAX326) for treating patients with hemophilia B, or congenital FIX deficiency. An extensive preclinical program evaluated the pharmacokinetics, efficacy, and safety of BAX326 in different species. The efficacy of BAX326 was tested in three mouse models of primary pharmacodynamics: tail-tip bleeding, carotid occlusion, and thrombelastography. The pharmacokinetics was evaluated after a single intravenous bolus injection in mice, rats, and macaques. Toxicity was assessed in rats and macaques, safety pharmacology in rabbits and macaques, and immunogenicity in mice. BAX326 was shown to be efficacious in all three primary pharmacodynamic studies (P ≤ 0.0076). Hemostatic efficacy was dose related and similar for the three lots tested. Pharmacokinetic results showed that rFIX activity and rFIX antigen concentrations declined in a bi-phasic manner, similar to a previously licensed rFIX product. BAX326 was well tolerated in rabbits and macaques at all dose levels; no thrombogenic events and no adverse clinical, respiratory, or cardiovascular effects occurred. BAX326 was also shown to have a similar immunogenicity profile to the comparator rFIX product in mice. These results demonstrate that BAX326 has a favorable preclinical safety and efficacy profile, predictive of a comparable effect to that of the previously licensed rFIX in humans.

Role of Alexithymia, Anxiety, and Depression in Predicting Self-Efficacy in Academic Students

PubMed Central

2017-01-01

Objective. Little research is available on the predictive factors of self-efficacy in college students. The aim of the present study is to examine the role of alexithymia, anxiety, and depression in predicting self-efficacy in academic students. Design. In a cross-sectional study, a total of 133 students at Babol University of Medical Sciences (Medicine, Dentistry, and Paramedicine) participated in the study between 2014 and 2015. All participants completed the Toronto Alexithymia Scale (TAS-20), College Academic Self-Efficacy Scale (CASES), and 14 items on anxiety and depression derived from the 28 items of the General Health Questionnaire (28-GHQ). Results. Pearson correlation coefficients revealed negative significant relationships between alexithymia and the three subscales with student self-efficacy. There was no significant correlation between anxiety/depression symptoms and student self-efficacy. A backward multiple regression analysis revealed that alexithymia was a negative significant predictor of self-efficacy in academic students (B = −0.512, P < 0.001). The prevalence of alexithymia was 21.8% in students. Multiple backward logistic analysis regression revealed that number of passed semesters, gender, mother's education, father's education, and doctoral level did not accurately predict alexithymia in college students. Conclusion. As alexithymia is prevalent in college students and affects self-efficacy and academic functioning, we suggest it should be routinely evaluated by mental physicians at universities. PMID:28154839

Role of Alexithymia, Anxiety, and Depression in Predicting Self-Efficacy in Academic Students.

PubMed

Faramarzi, Mahbobeh; Khafri, Soraya

2017-01-01

Objective . Little research is available on the predictive factors of self-efficacy in college students. The aim of the present study is to examine the role of alexithymia, anxiety, and depression in predicting self-efficacy in academic students. Design . In a cross-sectional study, a total of 133 students at Babol University of Medical Sciences (Medicine, Dentistry, and Paramedicine) participated in the study between 2014 and 2015. All participants completed the Toronto Alexithymia Scale (TAS-20), College Academic Self-Efficacy Scale (CASES), and 14 items on anxiety and depression derived from the 28 items of the General Health Questionnaire (28-GHQ). Results . Pearson correlation coefficients revealed negative significant relationships between alexithymia and the three subscales with student self-efficacy. There was no significant correlation between anxiety/depression symptoms and student self-efficacy. A backward multiple regression analysis revealed that alexithymia was a negative significant predictor of self-efficacy in academic students ( B = -0.512, P < 0.001). The prevalence of alexithymia was 21.8% in students. Multiple backward logistic analysis regression revealed that number of passed semesters, gender, mother's education, father's education, and doctoral level did not accurately predict alexithymia in college students. Conclusion . As alexithymia is prevalent in college students and affects self-efficacy and academic functioning, we suggest it should be routinely evaluated by mental physicians at universities.

Comparison of efficacy and safety of laser in situ keratomileusis using 2 femtosecond laser platforms in contralateral eyes.

PubMed

Rosman, Mohamad; Hall, Reece C; Chan, Cordelia; Ang, Andy; Koh, Jane; Htoon, Hla Myint; Tan, Donald T H; Mehta, Jodhbir S

2013-07-01

To compare the efficacy, predictability, and refractive outcomes of laser in situ keratomileusis (LASIK) using 2 femtosecond platforms for flap creation. Multisurgeon single center. Clinical trial. Bilateral femtosecond LASIK was performed using the Wavelight Allegretto Eye-Q 400 Hz excimer laser system. The Visumax femtosecond platform (Group 1) was used to create the LASIK flap in 1 eye, while the Intralase femtosecond platform (Group 2) was used to create the LASIK flap in the contralateral eye. The preoperative, 1-month, and 3-month postoperative visual acuities, refraction, and contrast sensitivity in the 2 groups were compared. The study enrolled 45 patients. Three months after femtosecond LASIK, 79.5% of eyes in Group 1 and 82.1% in Group 2 achieved an uncorrected distance visual acuity of 20/20 (P=.808). The mean efficacy index was 0.97 in Group 1 and 0.98 in Group 2 at 3 months (P=.735); 89.7% of eyes in Group 1 and 84.6% of eyes in Group 2 were within ± 0.50 diopter of emmetropia at 3 months (P=.498). No eye in either group lost more than 2 lines of corrected distance visual acuity. The mean safety index at 3 months was 1.11 in Group 1 and 1.10 in Group 2 (P=.570). The results of LASIK with both femtosecond lasers were similar, and both platforms produced efficacious and predictable LASIK outcomes. No author has a financial or proprietary interest in any material or method mentioned. Copyright © 2013 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

Efficacy of pirfenidone and disease severity of idiopathic pulmonary fibrosis: Extended analysis of phase III trial in Japan.

PubMed

Taguchi, Yoshio; Ebina, Masahito; Hashimoto, Seishu; Ogura, Takashi; Azuma, Arata; Taniguchi, Hiroyuki; Kondoh, Yasuhiro; Suga, Moritaka; Takahashi, Hiroki; Nakata, Koichiro; Sugiyama, Yukihiko; Kudoh, Shoji; Nukiwa, Toshihiro

2015-11-01

A phase III clinical trial of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) in Japan has revealed that pirfenidone attenuated the decline in vital capacity (VC) and improved progression-free survival (PFS). We conducted an extended analysis of the pirfenidone trial to investigate its efficacy with respect to IPF severity in the trial population. Patients in the phase III trial were stratified by baseline pulmonary functions including %VC predicted, %diffusion capacity for carbon monoxide predicted, and oxygen saturation by pulse oximetry on exertion and were categorized into mild, moderate, and severe groups of functional impairment. The efficacy of pirfenidone for VC and PFS over 52 weeks was compared among the three sub-populations. Of 264 patients, 102 (39%), 90 (34%), and 72 patients (27%) were classified as having mild, moderate, and severe grades of functional impairment, respectively. This classification was associated with arterial oxygen partial pressure at rest and degree of dyspnea at baseline. While pirfenidone attenuated VC decline at all grades of severity, covariance analysis revealed pirfenidone to have better efficacy in the sub-population with mild-grade IPF. Mixed model repeated measures analysis confirmed that pirfenidone markedly attenuated VC decline in patients with mild-grade IPF compared to its effects in patients with moderate or severe IPF. Pirfenidone also improved PFS markedly in patients with mild-grade IPF. This extended analysis suggested that pirfenidone exerted better therapeutic effects in patients with milder IPF. Further analysis with a larger population is needed to confirm these results. Copyright © 2015. Published by Elsevier B.V.

Effects of Point Mutations in Plasmodium falciparum Dihydrofolate Reductase and Dihydropterate Synthase Genes on Clinical Outcomes and In Vitro Susceptibility to Sulfadoxine and Pyrimethamine

DTIC Science & Technology

2009-08-01

therapeutic efficacy of SP in two locations in the Amazon rainforest region of Peru, and to correlate the presence of molecular markers associated with...pyrimethamine at two locations in the Peruvian Amazon enrolling 99 patients of which, 86 patients completed the protocol specified 28 day follow up. Our...the Amazon basin, it may be possible to predict treatment failure with sulfadoxine- pyrimethamine equally well by determination of either of the

Basic mechanisms of gabitril (tiagabine) and future potential developments.

PubMed

Meldrum, B S; Chapman, A G

1999-01-01

Gabitril (tiagabine) is a potent selective inhibitor of the principal neuronal gamma-aminobutyric acid (GABA) transporter (GAT-1) in the cortex and hippocampus. By slowing the reuptake of synaptically-released GABA, it prolongs inhibitory postsynaptic potentials. In animal models of epilepsy, tiagabine is particularly effective against kindled (limbic) seizures and against reflexly-induced generalized convulsive seizures. These data are predictive of its efficacy in complex partial seizures in humans. Possible clinical applications outside the field of epilepsy include bipolar disorder and pain.

Self-System Therapy for Distress Associated with Persistent Low Back Pain: A Randomized Clinical Trial

PubMed Central

Waters, Sandra J.; McKee, Daphne C.; Campbell, Lisa C.; Shelby, Rebecca A.; Dixon, Kim E.; Fras, Anne Marie; Keefe, Francis J.

2015-01-01

Objective Persistent low back pain (PLBP) is associated with vulnerability to depression. PLBP frequently requires major changes in occupation and lifestyle, which can lead to a sense of failing to attain one’s personal goals (self-discrepancy). Method We conducted a clinical trial to examine the efficacy of self-system therapy (SST), a brief structured therapy for depression based on self-discrepancy theory. A total of 101 patients with PLBP and clinically significant depressive symptoms were randomized either to SST, pain education, or standard care. Results Patients receiving SST showed significantly greater improvement in depressive symptoms. Reduction in self-discrepancy predicted reduction in depressive symptoms only within the SST condition. Conclusions Findings support the utility of SST for individuals facing persistent pain and associated depression. PMID:26079438

The role of depression pharmacogenetic decision support tools in shared decision making.

PubMed

Arandjelovic, Katarina; Eyre, Harris A; Lenze, Eric; Singh, Ajeet B; Berk, Michael; Bousman, Chad

2017-10-29

Patients discontinue antidepressant medications due to lack of knowledge, unrealistic expectations, and/or unacceptable side effects. Shared decision making (SDM) invites patients to play an active role in their treatment and may indirectly improve outcomes through enhanced engagement in care, adherence to treatment, and positive expectancy of medication outcomes. We believe decisional aids, such as pharmacogenetic decision support tools (PDSTs), facilitate SDM in the clinical setting. PDSTs may likewise predict drug tolerance and efficacy, and therefore adherence and effectiveness on an individual-patient level. There are several important ethical considerations to be navigated when integrating PDSTs into clinical practice. The field requires greater empirical research to demonstrate clinical utility, and the mechanisms thereof, as well as exploration of the ethical use of these technologies.

Pharmacogenetics in cardiovascular diseases: State of the art and implementation-recommendations of the French National Network of Pharmacogenetics (RNPGx).

PubMed

Lamoureux, Fabien; Duflot, Thomas

2017-04-01

The use of genomic markers to predict drug response and effectiveness has the potential to improve healthcare by increasing drug efficacy and minimizing adverse effects. Polymorphisms associated with inter-individual variability in drug metabolism, transport, or pharmacodynamics of major cardiovascular drugs have been identified. These include single nucleotide polymorphisms (SNP) affecting clinical outcomes in patients receiving antiplatelet agents, oral anticoagulants and statins. Based on clinical evidence supporting genetic testing in the management of cardiovascular diseases using these drug classes, this short review presents clinical guidance regarding current pharmacogenetics implementation in routine medical practice. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Advances in pediatric dehydration therapy.

PubMed

Niescierenko, Michelle; Bachur, Richard

2013-06-01

To review the advances in the assessment, treatment, and evaluation of care for pediatric dehydration. Recent studies have added new information across the spectrum of care for dehydration. Advances in the assessment of dehydration allow more accurate clinical evaluation, but do not help predict the treatment outcomes. Antiemetics as an adjunct to oral rehydration therapy have been proven well tolerated, efficacious, and cost-effective. Rapid, large-volume intravenous rehydration for outpatients with dehydration did not show any benefit over more standard regimens. Clinical guidelines incorporate all these aspects of care; however, physicians show poor adherence to the guidelines despite the evidence that guidelines improve outcomes and reduce cost. Dehydration burdens the healthcare system worldwide. Through advances in its assessment, treatment with antiemetics and intravenous fluids, and standardization of practice with clinical guidelines, this burden could be reduced.

Positive Exercise Experience Facilitates Behavior Change via Self-Efficacy.

PubMed

Parschau, Linda; Fleig, Lena; Warner, Lisa Marie; Pomp, Sarah; Barz, Milena; Knoll, Nina; Schwarzer, Ralf; Lippke, Sonia

2014-08-01

Motivational processes can be set in motion when positive consequences of physical exercise are experienced. However, relationships between positive exercise experience and determinants of the motivational and the volitional phases of exercise change have attracted only sparse attention in research. This research examines direct and indirect associations between positive experience and motivational as well as volitional self-efficacy, intention, action planning, and exercise in two distinct longitudinal samples. The first one originates from an online observational study in the general population with three measurement points in time (N = 350) and the second one from a clinical intervention study in a rehabilitation context with four measurement points (N = 275). Structural equation modeling revealed the following: Positive experience is directly related with motivational self-efficacy as well as intentions in both samples. In the online sample only, positive experience is associated with volitional self-efficacy. In each sample, experience is indirectly associated with action planning via motivational self-efficacy and intentions. Moreover, action planning, in turn, predicts changes in physical exercise levels. Findings suggest a more prominent role of positive experience in the motivational than in the volitional phase of physical exercise change. Thus, this research contributes to the understanding of how positive experience is involved in the behavior change process. © 2014 Society for Public Health Education.

Predicting performance and performance satisfaction: mindfulness and beliefs about the ability to deal with social barriers in sport.

PubMed

Blecharz, Jan; Luszczynska, Aleksandra; Scholz, Urte; Schwarzer, Ralf; Siekanska, Malgorzata; Cieslak, Roman

2014-05-01

This research investigates the role of beliefs about the ability to deal with specific social barriers and its relationships to mindfulness, football performance, and satisfaction with one's own and team performance. Study 1 aimed at eliciting these social barriers. Study 2 tested (i) whether self-efficacy referring to social barriers would predict performance over and above task-related self-efficacy and collective efficacy and (ii) the mediating role of self-efficacy to overcome social barriers in the relationship between mindfulness and performance. Participants were football (soccer) players aged 16-21 years (Study 1: N=30; Study 2: N=101, longitudinal sample: n=88). Study 1 resulted in eliciting 82 social barriers referring to team, peer leadership, and coaches. Study 2 showed that task-related self-efficacy and collective efficacy explained performance satisfaction at seven-month follow-up, whereas self-efficacy referring to social barriers explained shooting performance at seven-month follow-up. Indirect associations between mindfulness and performance were found with three types of self-efficacy referring to social barriers, operating as parallel mediators. Results provide evidence for the role of beliefs about the ability to cope with social barriers and show a complex interplay between different types of self-efficacy and collective efficacy in predicting team sport performance.

Pilot Study of Implementation of an Internet-Based Depression Prevention Intervention (CATCH-IT) for Adolescents in 12 US Primary Care Practices: Clinical and Management/Organizational Behavioral Perspectives

PubMed Central

Eisen, Jeffrey C.; Marko-Holguin, Monika; Fogel, Joshua; Cardenas, Alonso; Bahn, My; Bradford, Nathan; Fagan, Blake; Wiedmann, Peggy

2013-01-01

Objective: To explore the implementation of CATCH-IT (Competent Adulthood Transition with Cognitive-behavioral Humanistic and Interpersonal Training), an Internet-based depression intervention program in 12 primary care sites, occurring as part of a randomized clinical trial comparing 2 versions of the intervention (motivational interview + Internet program versus brief advice + Internet program) in 83 adolescents aged 14 to 21 years recruited from February 1, 2007, to November 31, 2007. Method: The CATCH-IT intervention model consists of primary care screening to assess risk, a primary care physician interview to encourage participation, and 14 online modules of Internet training to teach adolescents how to reduce behaviors that increase vulnerability to depressive disorders. Specifically, we evaluated this program from both a management/organizational behavioral perspective (provider attitudes and demonstrated competence) and a clinical outcomes perspective (depressed mood scores) using the RE-AIM model (Reach, Efficacy, Adoption, Implementation, and Maintenance of the intervention). Results: While results varied by clinic, overall, clinics demonstrated satisfactory reach, efficacy, adoption, implementation, and maintenance of the CATCH-IT depression prevention program. Measures of program implementation and management predicted clinical outcomes at practices in exploratory analyses. Conclusion: Multidisciplinary approaches may be essential to evaluating the impact of complex interventions to prevent depression in community settings. Primary care physicians and nurses can use Internet-based programs to create a feasible and cost-effective model for the prevention of mental disorders in adolescents in primary care settings. Trial Registration: ClinicalTrials.gov identifiers: NCT00152529 and NCT00145912 PMID:24800110

Pilot Study of Implementation of an Internet-Based Depression Prevention Intervention (CATCH-IT) for Adolescents in 12 US Primary Care Practices: Clinical and Management/Organizational Behavioral Perspectives.

PubMed

Eisen, Jeffrey C; Marko-Holguin, Monika; Fogel, Joshua; Cardenas, Alonso; Bahn, My; Bradford, Nathan; Fagan, Blake; Wiedmann, Peggy; Van Voorhees, Benjamin W

2013-01-01

To explore the implementation of CATCH-IT (Competent Adulthood Transition with Cognitive-behavioral Humanistic and Interpersonal Training), an Internet-based depression intervention program in 12 primary care sites, occurring as part of a randomized clinical trial comparing 2 versions of the intervention (motivational interview + Internet program versus brief advice + Internet program) in 83 adolescents aged 14 to 21 years recruited from February 1, 2007, to November 31, 2007. The CATCH-IT intervention model consists of primary care screening to assess risk, a primary care physician interview to encourage participation, and 14 online modules of Internet training to teach adolescents how to reduce behaviors that increase vulnerability to depressive disorders. Specifically, we evaluated this program from both a management/organizational behavioral perspective (provider attitudes and demonstrated competence) and a clinical outcomes perspective (depressed mood scores) using the RE-AIM model (Reach, Efficacy, Adoption, Implementation, and Maintenance of the intervention). While results varied by clinic, overall, clinics demonstrated satisfactory reach, efficacy, adoption, implementation, and maintenance of the CATCH-IT depression prevention program. Measures of program implementation and management predicted clinical outcomes at practices in exploratory analyses. Multidisciplinary approaches may be essential to evaluating the impact of complex interventions to prevent depression in community settings. Primary care physicians and nurses can use Internet-based programs to create a feasible and cost-effective model for the prevention of mental disorders in adolescents in primary care settings. ClinicalTrials.gov identifiers: NCT00152529 and NCT00145912.

Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis.

PubMed

Sieberts, Solveig K; Zhu, Fan; García-García, Javier; Stahl, Eli; Pratap, Abhishek; Pandey, Gaurav; Pappas, Dimitrios; Aguilar, Daniel; Anton, Bernat; Bonet, Jaume; Eksi, Ridvan; Fornés, Oriol; Guney, Emre; Li, Hongdong; Marín, Manuel Alejandro; Panwar, Bharat; Planas-Iglesias, Joan; Poglayen, Daniel; Cui, Jing; Falcao, Andre O; Suver, Christine; Hoff, Bruce; Balagurusamy, Venkat S K; Dillenberger, Donna; Neto, Elias Chaibub; Norman, Thea; Aittokallio, Tero; Ammad-Ud-Din, Muhammad; Azencott, Chloe-Agathe; Bellón, Víctor; Boeva, Valentina; Bunte, Kerstin; Chheda, Himanshu; Cheng, Lu; Corander, Jukka; Dumontier, Michel; Goldenberg, Anna; Gopalacharyulu, Peddinti; Hajiloo, Mohsen; Hidru, Daniel; Jaiswal, Alok; Kaski, Samuel; Khalfaoui, Beyrem; Khan, Suleiman Ali; Kramer, Eric R; Marttinen, Pekka; Mezlini, Aziz M; Molparia, Bhuvan; Pirinen, Matti; Saarela, Janna; Samwald, Matthias; Stoven, Véronique; Tang, Hao; Tang, Jing; Torkamani, Ali; Vert, Jean-Phillipe; Wang, Bo; Wang, Tao; Wennerberg, Krister; Wineinger, Nathan E; Xiao, Guanghua; Xie, Yang; Yeung, Rae; Zhan, Xiaowei; Zhao, Cheng; Greenberg, Jeff; Kremer, Joel; Michaud, Kaleb; Barton, Anne; Coenen, Marieke; Mariette, Xavier; Miceli, Corinne; Shadick, Nancy; Weinblatt, Michael; de Vries, Niek; Tak, Paul P; Gerlag, Danielle; Huizinga, Tom W J; Kurreeman, Fina; Allaart, Cornelia F; Louis Bridges, S; Criswell, Lindsey; Moreland, Larry; Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid; Gregersen, Peter K; Friend, Stephen; Plenge, Robert; Stolovitzky, Gustavo; Oliva, Baldo; Guan, Yuanfang; Mangravite, Lara M; Bridges, S Louis; Criswell, Lindsey; Moreland, Larry; Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid; Gregersen, Peter K; Friend, Stephen; Plenge, Robert; Stolovitzky, Gustavo; Oliva, Baldo; Guan, Yuanfang; Mangravite, Lara M

2016-08-23

Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h(2)=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.

Clinical results of excimer laser photorefractive keratectomy: a multicenter study of 265 eyes.

PubMed

Aron-Rosa, D S; Colin, J; Aron, B; Burin, N; Cochener, B; Febraro, J L; Gallinaro, C; Ganem, S; Valdes, R

1995-11-01

Efficacy, predictability, and safety of excimer laser photorefractive keratectomy were evaluated at centers in Paris and Brest, France. Photoablation was performed with the VISX laser on 265 eyes (151 at the Paris center and 114 at the Brest center). The eyes were clinically and statistically evaluated over a six month follow-up. Initial myopia ranged from -0.7 to -19.4 diopters (D) (mean spherical equivalent [SE] -5.9 D) in the Paris center and from -0.9 to -14.5 D (SE -4.5 D) in the Brest center. At both centers, the mean uncorrected visual acuity was worse than 20/200; over 90% of cases in each center had a best uncorrected visual acuity of 20/100 or worse. Results are reported globally and for subgroups of myopia: Group A, SE better than or equal to -3.0 D; Group B, SE worse than -3.0 D and better than or equal to -7.0 D; Group C, SE worse than -7.0 D. Uncorrected visual acuity was significantly improved in the patients followed for six months; 64% of Paris cases and 62% of Brest cases obtained an uncorrected visual acuity of 20/40 or better. Predictability of the treatment was good; 67% of Paris eyes and 74% of Brest eyes were less than 1.0 D from the intended correction after six months. The data suggest that the initial myopia affected the efficacy and predictability of the treatment; results in the mild to moderate myopia eyes were significantly better than results in the severe myopia eyes. One case of visual acuity regression (less than one line) was observed in the two groups. This was associated with corneal haze of moderate intensity.

Observational study on the efficacy of adalimumab for the treatment of ulcerative colitis and predictors of outcome.

PubMed

García-Bosch, Orlando; Gisbert, Javier P; Cañas-Ventura, Alex; Merino, Olga; Cabriada, José L; García-Sánchez, Valle; Gutiérrez, Ana; Nos, Pilar; Peñalva, Mireia; Hinojosa, Joaquin; García-Planella, Esther; Muñoz, Fernando; Calvet, Xavier; Panés, Julián

2013-10-01

Information on efficacy and predictors of response to adalimumab in ulcerative colitis (UC) clinical practice is limited. Assessment of response to adalimumab and its predictors in an observational cohort study. Retrospective cohort study based on data obtained from ENEIDA registry. All patients diagnosed with UC treated with adalimumab were included. Response to adalimumab was evaluated at weeks 12, 28, and 54 according to the partial Mayo score, and requirement of colectomy until end of follow-up. 48 patients with UC treated with adalimumab were included; 39 (81.3%) had previously received infliximab. Response rates at weeks 12, 28 and 54 were 70.8%, 43.2% and 35% respectively. Response to prior treatment with infliximab was the only predictive factor of response to adalimumab at week 12, which was obtained in 90% of infliximab remitters, 53.8% of responders and 33.3% of primary non-responders (p=0.01). Colectomy was required in 11 patients (22.9%), after a mean time of 205 days. The only clinical independent predictor of colectomy was non-response to adalimumab at week 12: colectomy rates were 5/34 (14.7%) in responders and 6/14 (42.9%) in non-responders (p=0.035), time free of colectomy was significantly reduced in non-responders (p=0.01). Adalimumab withdrawal due to adverse events occurred in 4.2% of patients. This study shows that adalimumab is an effective treatment in patients with UC. If used as a second anti-TNF, previous achievement of remission with the first anti-TNF predicts response, and failure to achieve response at week 12 predicts colectomy. Copyright © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Principals' transformational leadership and teachers' collective efficacy.

PubMed

Dussault, Marc; Payette, Daniel; Leroux, Mathieu

2008-04-01

The study was designed to test the relationship of principals' transformational, transactional, and laissez-faire leadership with teachers' collective efficacy. Bandura's theory of efficacy applied to the group and Bass's transformational leadership theory were used as the theoretical framework. Participants included 487 French Canadian teachers from 40 public high schools. As expected, there were positive and significant correlations between principals' transformational and transactional leadership and teachers' collective efficacy. Also, there was a negative and significant correlation between laissez-faire leadership and teachers' collective efficacy. Moreover, regression analysis showed transformational leadership significantly enhanced the predictive capabilities of transactional leadership on teachers' collective efficacy. These results confirm the importance of leadership to predict collective efficacy and, by doing so, strengthen Bass's theory of leadership.

Twelve-Year Follow-Up of Laser In Situ Keratomileusis for Moderate to High Myopia

PubMed Central

Ikeda, Tetsuya; Igarashi, Akihito; Kasahara, Sumie

2017-01-01

Purpose To assess the long-term clinical outcomes of conventional laser in situ keratomileusis (LASIK) for moderate to high myopia. Methods We retrospectively examined sixty-eight eyes of 37 consecutive patients who underwent conventional LASIK for the correction of myopia (−3.00 to −12.75 diopters (D)). At 3 months and 1, 4, 8, and 12 years postoperatively, we assessed the safety, efficacy, predictability, stability, mean keratometry, central corneal thickness, and adverse events. Results The safety and efficacy indices were 0.82 ± 0.29 and 0.67 ± 0.37, respectively, 12 years postoperatively. At 12 years, 53% and 75% of the eyes were within 0.5 and 1.0 D, respectively, of the targeted correction. Manifest refraction changes of −0.74 ± 0.99 D occurred from 3 months to 12 years after LASIK (p < 0.001). We found a significant correlation of refractive regression with the changes in keratometric readings from 3 months to 12 years postoperatively (Pearson correlation coefficient, r = −0.28, p = 0.02), but not with the changes in central corneal thickness (r = −0.08, p = 0.63). No vision-threatening complications occurred in any case. Conclusions Conventional LASIK offered good safety outcomes during the 12-year observation period. However, the efficacy and the predictability gradually decreased with time owing to myopic regression in relation to corneal steepening. PMID:28596969

Twelve-Year Follow-Up of Laser In Situ Keratomileusis for Moderate to High Myopia.

PubMed

Ikeda, Tetsuya; Shimizu, Kimiya; Igarashi, Akihito; Kasahara, Sumie; Kamiya, Kazutaka

2017-01-01

To assess the long-term clinical outcomes of conventional laser in situ keratomileusis (LASIK) for moderate to high myopia. We retrospectively examined sixty-eight eyes of 37 consecutive patients who underwent conventional LASIK for the correction of myopia (-3.00 to -12.75 diopters (D)). At 3 months and 1, 4, 8, and 12 years postoperatively, we assessed the safety, efficacy, predictability, stability, mean keratometry, central corneal thickness, and adverse events. The safety and efficacy indices were 0.82 ± 0.29 and 0.67 ± 0.37, respectively, 12 years postoperatively. At 12 years, 53% and 75% of the eyes were within 0.5 and 1.0 D, respectively, of the targeted correction. Manifest refraction changes of -0.74 ± 0.99 D occurred from 3 months to 12 years after LASIK ( p < 0.001). We found a significant correlation of refractive regression with the changes in keratometric readings from 3 months to 12 years postoperatively (Pearson correlation coefficient, r = -0.28, p = 0.02), but not with the changes in central corneal thickness ( r = -0.08, p = 0.63). No vision-threatening complications occurred in any case. Conventional LASIK offered good safety outcomes during the 12-year observation period. However, the efficacy and the predictability gradually decreased with time owing to myopic regression in relation to corneal steepening.

Toxicity Testing in the 21st Century Beyond Environmental Chemicals

PubMed Central

Rovida, Costanza; Asakura, Shoji; Daneshian, Mardas; Hofman-Huether, Hana; Leist, Marcel; Meunier, Leo; Reif, David; Rossi, Anna; Schmutz, Markus; Valentin, Jean-Pierre; Zurlo, Joanne; Hartung, Thomas

2018-01-01

Summary After the publication of the report titled Toxicity Testing in the 21st Century – A Vision and a Strategy, many initiatives started to foster a major paradigm shift for toxicity testing – from apical endpoints in animal-based tests to mechanistic endpoints through delineation of pathways of toxicity (PoT) in human cell based systems. The US EPA has funded an important project to develop new high throughput technologies based on human cell based in vitro technologies. These methods are currently being incorporated into the chemical risk assessment process. In the pharmaceutical industry, the efficacy and toxicity of new drugs are evaluated during preclinical investigations that include drug metabolism, pharmacokinetics, pharmacodynamics and safety toxicology studies. The results of these studies are analyzed and extrapolated to predict efficacy and potential adverse effects in humans. However, due to the high failure rate of drugs during the clinical phases, a new approach for a more predictive assessment of drugs both in terms of efficacy and adverse effects is getting urgent. The food industry faces the challenge of assessing novel foods and food ingredients for the general population, while using animal safety testing for extrapolation purposes is often of limited relevance. The question is whether the latest paradigm shift proposed by the Tox21c report for chemicals may provide a useful tool to improve the risk assessment approach also for drugs and food ingredients. PMID:26168280

Comparison of Laser Doppler and Laser-Assisted Indocyanine Green Angiography Prediction of Flap Survival in a Novel Modification of the McFarlane Flap.

PubMed

Fourman, Mitchell Stephen; Gersch, Robert P; Phillips, Brett T; Nasser, Ahmed; Rivara, Andrew; Verma, Richa; Dagum, Alexander B; Rosengart, Todd K; Bui, Duc T

2015-07-01

The McFarlane rat ischemic dorsal skin flap model has been commonly used for clinical vector studies, as well as the testing of noninvasive diagnostics. However, variability of this model secondary to flap contact with the wound bed has led many to question its validity. Here we present a novel modification to the McFarlane skin flap using sterile silicone. We also use this model to test the prognostic efficacy of laser-assisted indocyanine green (ICG) angiography and laser Doppler imaging (LDI). A 3 × 9-cm dorsal skin flap with a cranially based pedicle was created, centered 1 cm distal to the scapulae. The flap was undermined, and in one of the 2 groups, a sterile silicone sheet was placed onto the wound bed. All flaps were then reapproximated with sutures 1-cm intervals. Clinical assessment and perfusion imaging was performed immediately postoperative, and at 24, 48, and 72 hours postsurgery. Postoperative day 7 clinical assessment was obtained before euthanasia. A comparative study using silicone blocked versus unblocked models (n = 6 per group) showed that, clinically, both models had equivalent flap survival [8.5 (0.913) vs 9.5 (1.01) cm]. However, a statistically significant increase in perfusion in the mid-third of unblocked models was observed on POD3 [20.28% (2.7%) vs blocked 13.45% (2.5%), P < 0.05], with a similar increase in the distal third on POD7 [18.73% (2.064%) vs 10.91% (4.19%), P < 0.05]. A prognostic study comparing LDI and ICG angiography prediction of POD7 survival at early time points (n = 10) found that LDI underpredicted flap survival at early time points [84.2% (12.03%) on POD0, 87.35% (16.11%) on POD1]. In contrast, ICG was more proficient [100.1% (10.1%) on POD0]. We present a modification of the McFarlane skin flap model that results in similar clinical results, but with a noted reduction in perfusion inconsistencies noted in unblocked models. The ICG angiography is superior to LDI in predicting POD7 flap necrosis within the first 48 hours postinjury. Future work will focus on histologic validation of our model, and vector efficacy testing.

The effect of alternative clinical teaching experience on preservice science teachers' self-efficacy

NASA Astrophysics Data System (ADS)

Klett, Mitchell Dean

The purpose of this study was to compare different methods of alternative clinical experience; family science nights and Saturday science (authentic teaching) against micro-teaching (peer teaching) in terms of self-efficacy in science teaching and teaching self-efficacy. The independent variable, or cause, is teaching experiences (clinical vs. peer teaching); the dependent variable, or effect, is two levels of self-efficacy. This study was conducted at the University of Idaho's main campus in Moscow and extension campus in Coeur d'Alene. Four sections of science methods were exposed to the same science methods curriculum and will have opportunities to teach. However, each of the four sections were exposed to different levels or types of clinical experience. One section of preservice teachers worked with students in a Saturday science program. Another section worked with students during family science nights. The third worked with children at both the Saturday science program and family science nights. The last section did not have a clinical experience with children, instead they taught in their peer groups and acted as a control group. A pre-test was given at the beginning of the semester to measure their content knowledge, teaching self-efficacy and self-efficacy in science teaching. A post-test was given at the end of the semester to see if there was any change in self-efficacy or science teaching self-efficacy. Throughout the semester participants kept journals about their experiences and were interviewed after their alternative clinical teaching experiences. These responses were categorized into three groups; gains in efficacy, no change in efficacy, and drop in efficacy. There was a rise in teaching efficacy for all groups. The mean scores for personal teaching efficacy dropped for the Monday-Wednesday and Tuesday-Thursday group while the both Coeur D'Alene groups remained nearly unchanged. There was no significant change in the overall means for science teaching efficacy for any of the groups. Finally, the mean scores for all groups dropped for personal science teaching efficacy.

Association of the clinical efficacy of vancomycin with the novel pharmacokinetic parameter area under the trough level (AUTL) in elderly patients with hospital-acquired pneumonia.

PubMed

Fukumori, S; Tsuji, Y; Mizoguchi, A; Kasai, H; Ishibashi, T; Iwamura, N; To, H

2016-08-01

The pharmacokinetic-pharmacodynamic parameter that best predicts the efficacy of vancomycin is the ratio of the area under the concentration versus time curve (AUC) to the minimum inhibitory concentration (MIC). A 24-h AUC (AUC24 )/MIC ratio ≥ 400 was recommended in an American consensus review, but vancomycin treatment occasionally fails despite maintenance of AUC24 /MIC ≥ 400. We evaluated the association between clinical efficacy of vancomycin and two novel pharmacokinetic parameters, the 'area under the trough level' (AUTL) and the 'area above the trough level' (AATL), in hospitalized elderly patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. The subjects were hospitalized elderly patients who were administered vancomycin for treatment of MRSA pneumonia between 2006 and 2012 at Sasebo Chuo Hospital (Nagasaki, Japan). Pharmacokinetic parameters of vancomycin were estimated for each patient by Bayesian analysis using population pharmacokinetic parameters for Japanese patients. Based on the patient-specific parameters thus obtained, AUC24 values were calculated as the vancomycin dosage divided by vancomycin clearance. AUTL was calculated as the trough serum concentration multiplied by 24 h, whereas AATL was calculated by subtracting AUTL from AUC24 . Logistic regression analysis demonstrated that efficacy of vancomycin was more strongly associated with AUTL than AUC24 . The optimal cut-off value of AUTL was 331 μg∙h/mL, which means that the optimal cut-off value of the trough serum concentration was 13·8 μg/mL. Efficacy of vancomycin was associated with AUTL, a novel pharmacokinetic parameter. Determining the target AUTL or trough concentration may enhance the efficacy of vancomycin therapy in elderly patients with MRSA pneumonia. Given that nephrotoxicity may increase with a Ctrough in excess of 15 μg/mL, this level should ideally not be exceeded. © 2016 John Wiley & Sons Ltd.

One size fits one: pharmacogenetics in gastroenterology.

PubMed

Porayette, Prashanth; Flockhart, David; Gupta, Sandeep K

2014-04-01

Individual variability in response and development of adverse effects to drugs is a major challenge in clinical practice. Pharmacogenomics refers to the aspect of personalized medicine where the patient's genetic information instructs the selection and dosage of therapy while also predicting its adverse effects profile. Sequencing of the entire human genome has given us the opportunity to study commonly used drugs as well as newer therapeutic agents in a new light, opening up opportunities for better drug efficacy and decreased adverse effects. This article highlights developments in pharmacogenomics, relates these to practice of gastroenterology, and outlines roadblocks in translation of this knowledge into clinical practice. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Leg pain and psychological variables predict outcome 2-3 years after lumbar fusion surgery.

PubMed

Abbott, Allan D; Tyni-Lenné, Raija; Hedlund, Rune

2011-10-01

Prediction studies testing a thorough range of psychological variables in addition to demographic, work-related and clinical variables are lacking in lumbar fusion surgery research. This prospective cohort study aimed at examining predictions of functional disability, back pain and health-related quality of life (HRQOL) 2-3 years after lumbar fusion by regressing nonlinear relations in a multivariate predictive model of pre-surgical variables. Before and 2-3 years after lumbar fusion surgery, patients completed measures investigating demographics, work-related variables, clinical variables, functional self-efficacy, outcome expectancy, fear of movement/(re)injury, mental health and pain coping. Categorical regression with optimal scaling transformation, elastic net regularization and bootstrapping were used to investigate predictor variables and address predictive model validity. The most parsimonious and stable subset of pre-surgical predictor variables explained 41.6, 36.0 and 25.6% of the variance in functional disability, back pain intensity and HRQOL 2-3 years after lumbar fusion. Pre-surgical control over pain significantly predicted functional disability and HRQOL. Pre-surgical catastrophizing and leg pain intensity significantly predicted functional disability and back pain while the pre-surgical straight leg raise significantly predicted back pain. Post-operative psychomotor therapy also significantly predicted functional disability while pre-surgical outcome expectations significantly predicted HRQOL. For the median dichotomised classification of functional disability, back pain intensity and HRQOL levels 2-3 years post-surgery, the discriminative ability of the prediction models was of good quality. The results demonstrate the importance of pre-surgical psychological factors, leg pain intensity, straight leg raise and post-operative psychomotor therapy in the predictions of functional disability, back pain and HRQOL-related outcomes.

Incorporating Communication into the Theory of Planned Behavior to Predict Condom Use Among African American Women

PubMed Central

Guan, Mengfei; Coles, Valerie B.; Samp, Jennifer A.; Sales, Jessica McDermott; DiClemente, Ralph J.; Monahan, Jennifer L.

2016-01-01

The present research extends the Theory of Planned Behavior (TPB) to investigate how communication-related variables influence condom use intention and behavior among African American women. According to the TPB, attitudes, subjective norms, and self-efficacy are associated with behavioral intent, which predicts behavior. For women, it was argued that condom negotiation self-efficacy was more important than condom use self-efficacy in predicting consistent condom use. Moreover, an important environmental factor that affects condom use for African American women is fear or worry when negotiating condom use because the sex partners might leave, threaten, or abuse them. Fears associated with negotiating condom use were predicted to be negatively associated with attitudes, subjective norms, and self-efficacy. African American women (N = 560; M age = 20.58) completed assessments of TPB variables at baseline and condom use three months later. Condom negotiation self-efficacy was a significant indicator of behavioral intent while condom use self-efficacy was not. Fear of condom negotiation was negatively associated with all TPB components, which was in turn significantly associated with behavioral intent and condom use. Implications for the TPB, safer sex literature, and STI prevention intervention design are discussed. PMID:27565192

[A test of screening to predict lung cancer among dust-exposed tin miners with sputum imaging cytometry].

PubMed

Liu, Yue-wei; Chen, Jing-qiong; Sun, Xiao-rong; Yang, Jian; Liu, Yong; Chen, Wei-hong

2008-04-01

To evaluate efficacy of sputum imaging cytometry in early diagnosis on lung cancer among tin miners exposed to dust and analyze possible risk factors related to lung cancer among tin miners. From a cohort of tin miners in Guangxi Province, a total of 345 male tin miners higher than 45 years old and with high exposure to crystalline silica dust were randomly selected as the objects. Imaging cytometry was used to implement the sputum analysis for the screening on lung cancer according to the experience diagnostic standard. All objects were then followed up to the end of 2006. Clinical diagnosis of lung cancer was used as the golden standard to evaluate the efficacy of screening. From 1998 to 2006, 11 new cases were diagnosed as clinical lung cancer. Except of age and exposure to occupational hazards, smoking status (P = 0.0384) and mean smoking dose (P = 0.0078) were significantly associated with lung cancer, and the adjusted odds ratio of high level to the low was 18.21 (2.15 approximately 154.39). The sensitivity, specificity and Youden's index of the sputum imaging cytometry for the experience diagnosis were 27.3%, 83.9% and 11.2% respectively. According to the ROC curve analysis, area under ROC Curve (AUC) of C2.5 (the percentage when the DNA index ranged from 1.25 to 2.50) was 0.647 (0.525 approximately 0.768), with the optimal operating point (OOP) of 1.70%. Sensitivity, specificity, agreement rate, positive predictive value, negative predictive value and Youden's index for predicting lung cancers in high-exposure tin miners were found to be 72.7%, 62.3%, 62.6%, 6.0%, 98.6% and 35.0% respectively. Smoking is confirmed as an important risk factor of lung cancer in tin miners. The diagnostic efficiency can be improved if the diagnostic point of C2.5 is adjusted to 1.70%.

Relationship between Internet Self-Efficacy and Internet Anxiety: A Nuanced Approach to Understanding the Connection

ERIC Educational Resources Information Center

Paul, Narmada; Glassman, Michael

2017-01-01

The present study makes the case that the individual constituents of internet self-efficacy--search self-efficacy, communication self-efficacy, organisation self-efficacy, differentiation self-efficacy, and reactive/generative self-efficacy--may be of differential importance in predicting internet anxiety within web-assisted learning environments.…

Revisiting photodynamic therapy dosimetry: reductionist & surrogate approaches to facilitate clinical success

NASA Astrophysics Data System (ADS)

Pogue, Brian W.; Elliott, Jonathan T.; Kanick, Stephen C.; Davis, Scott C.; Samkoe, Kimberley S.; Maytin, Edward V.; Pereira, Stephen P.; Hasan, Tayyaba

2016-04-01

Photodynamic therapy (PDT) can be a highly complex treatment, with many parameters influencing treatment efficacy. The extent to which dosimetry is used to monitor and standardize treatment delivery varies widely, ranging from measurement of a single surrogate marker to comprehensive approaches that aim to measure or estimate as many relevant parameters as possible. Today, most clinical PDT treatments are still administered with little more than application of a prescribed drug dose and timed light delivery, and thus the role of patient-specific dosimetry has not reached widespread clinical adoption. This disconnect is at least partly due to the inherent conflict between the need to measure and understand multiple parameters in vivo in order to optimize treatment, and the need for expedience in the clinic and in the regulatory and commercialization process. Thus, a methodical approach to selecting primary dosimetry metrics is required at each stage of translation of a treatment procedure, moving from complex measurements to understand PDT mechanisms in pre-clinical and early phase I trials, towards the identification and application of essential dose-limiting and/or surrogate measurements in phase II/III trials. If successful, identifying the essential and/or reliable surrogate dosimetry measurements should help facilitate increased adoption of clinical PDT. In this paper, examples of essential dosimetry points and surrogate dosimetry tools that may be implemented in phase II/III trials are discussed. For example, the treatment efficacy as limited by light penetration in interstitial PDT may be predicted by the amount of contrast uptake in CT, and so this could be utilized as a surrogate dosimetry measurement to prescribe light doses based upon pre-treatment contrast. Success of clinical ALA-based skin lesion treatment is predicted almost uniquely by the explicit or implicit measurements of photosensitizer and photobleaching, yet the individualization of treatment based upon each patients measured bleaching needs to be attempted. In the case of ALA, lack of PpIX is more likely an indicator that alternative PpIX production methods must be implemented. Parsimonious dosimetry, using surrogate measurements that are clinically acceptable, might strategically help to advance PDT in a medical world that is increasingly cost and time sensitive. Careful attention to methodologies that can identify and advance the most critical dosimetric measurements, either direct or surrogate, are needed to ensure successful incorporation of PDT into niche clinical procedures.

Does the Social Working Environment Predict Beginning Teachers' Self-Efficacy and Feelings of Depression?

ERIC Educational Resources Information Center

Devos, Christelle; Dupriez, Vincent; Paquay, Leopold

2012-01-01

We investigate how the social working environment predicts beginning teachers' self-efficacy and feelings of depression. Two quantitative studies are presented. The results show that the goal structure of the school culture (mastery or performance orientation) predicts both outcomes. Frequent collaborative interactions with colleagues are related…

Neurobehavioral testing in subarachnoid hemorrhage: A review of methods and current findings in rodents.

PubMed

Turan, Nefize; Miller, Brandon A; Heider, Robert A; Nadeem, Maheen; Sayeed, Iqbal; Stein, Donald G; Pradilla, Gustavo

2017-11-01

The most important aspect of a preclinical study seeking to develop a novel therapy for neurological diseases is whether the therapy produces any clinically relevant functional recovery. For this purpose, neurobehavioral tests are commonly used to evaluate the neuroprotective efficacy of treatments in a wide array of cerebrovascular diseases and neurotrauma. Their use, however, has been limited in experimental subarachnoid hemorrhage studies. After several randomized, double-blinded, controlled clinical trials repeatedly failed to produce a benefit in functional outcome despite some improvement in angiographic vasospasm, more rigorous methods of neurobehavioral testing became critical to provide a more comprehensive evaluation of the functional efficacy of proposed treatments. While several subarachnoid hemorrhage studies have incorporated an array of neurobehavioral assays, a standardized methodology has not been agreed upon. Here, we review neurobehavioral tests for rodents and their potential application to subarachnoid hemorrhage studies. Developing a standardized neurobehavioral testing regimen in rodent studies of subarachnoid hemorrhage would allow for better comparison of results between laboratories and a better prediction of what interventions would produce functional benefits in humans.

Efficient ablation of genes in human hematopoietic stem and effector cells using CRISPR/Cas9

PubMed Central

Mandal, Pankaj K.; Ferreira, Leonardo M. R.; Collins, Ryan; Meissner, Torsten B.; Boutwell, Christian L.; Friesen, Max; Vrbanac, Vladimir; Garrison, Brian S.; Stortchevoi, Alexei; Bryder, David; Musunuru, Kiran; Brand, Harrison; Tager, Andrew M.; Allen, Todd M.; Talkowski, Michael E.; Rossi, Derrick J.; Cowan, Chad A.

2014-01-01

SUMMARY Genome editing via CRISPR/Cas9 has rapidly become the tool of choice by virtue of its efficacy and ease of use. However, CRISPR/Cas9 mediated genome editing in clinically relevant human somatic cells remains untested. Here, we report CRISPR/Cas9 targeting of two clinically relevant genes, B2M and CCR5, in primary human CD4+ T cells and CD34+ hematopoietic stem and progenitor cells (HSPCs). Use of single RNA guides led to highly efficient mutagenesis in HSPCs but not in T cells. A dual guide approach improved gene deletion efficacy in both cell types. HSPCs that had undergone genome editing with CRISPR/Cas9 retained multi-lineage potential. We examined predicted on- and off-target mutations via target capture sequencing in HSPCs and observed low levels of off-target mutagenesis at only one site. These results demonstrate that CRISPR/Cas9 can efficiently ablate genes in HSPCs with minimal off-target mutagenesis, which could have broad applicability for hematopoietic cell-based therapy. PMID:25517468

Impact of Prior Treatment on Remission of Late-Life Depression with Venlafaxine and Subsequent Aripiprazole or Placebo Augmentation.

PubMed

Hsu, Jonathan H; Mulsant, Benoit H; Lenze, Eric J; Karp, Jordan F; Lavretsky, Helen; Roose, Steven P; Reynolds, Charles F; Blumberger, Daniel M

2016-10-01

Treatment history can inform clinical decisions about subsequent treatment choices. The authors examined the impact of prior antidepressant treatment on treatment outcomes with venlafaxine only and then with augmentation with aripiprazole or placebo in depressed older adults. The authors analyzed outcome data from a randomized, placebo-controlled clinical trial of aripiprazole augmentation in depressed older adults. The study consisted of an open-label lead-in phase with venlafaxine XR, followed by a placebo-controlled phase of aripiprazole augmentation. Treatment history was assessed with the Antidepressant Treatment History Form. Documented prior treatment failure predicted a reduced remission rate with venlafaxine. However, aripiprazole augmentation was efficacious in those with prior treatment failure (42.6% remission with aripiprazole versus 25.8% with placebo; χ(2) = 3.87 df = 1, p = 0.049). Aripiprazole augmentation is an efficacious strategy in older depressed adults who fail to remit with two or more adequate antidepressant trials, including a course of venlafaxine. Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Care delivery and compensation system changes: a case study of organizational readiness within a large dental care practice organization in the United States.

PubMed

Cunha-Cruz, Joana; Milgrom, Peter; Huebner, Colleen E; Scott, JoAnna; Ludwig, Sharity; Dysert, Jeanne; Mitchell, Melissa; Allen, Gary; Shirtcliff, R Mike

2017-12-20

Dental care delivery systems in the United States are consolidating and large practice organizations are becoming more common. At the same time, greater accountability for addressing disparities in access to care is being demanded when public funds are used to pay for care. As change occurs within these new practice structures, attempts to implement change in the delivery system may be hampered by failure to understand the organizational climate or fail to prepare employees to accommodate new goals or processes. Studies of organizational behavior within oral health care are sparse and have not addressed consolidation of current delivery systems. The objective of this case study was to assess organizational readiness for implementing change in a large dental care organization consisting of staff model clinics and affiliated dental practices and test associations of readiness with workforce characteristics and work environment. A dental care organization implemented a multifaceted quality improvement program, called PREDICT, in which community-based mobile and clinic-based dental services were integrated and the team compensated based in part on meeting performance targets. Dental care providers and supporting staff members (N = 181) were surveyed before program implementation and organizational readiness for implementing change (ORIC) was assessed by two 5-point scales: change commitment and efficacy. Providers and staff demonstrated high organizational readiness for change. Median change commitment was 3.8 (Interquartile range [IQR]: 3.3-4.3) and change efficacy was 3.8 (IQR: 3.0-4.2). In the adjusted regression model, change commitment was associated with organizational climate, support for methods to arrest tooth decay and was inversely related to office chaos. Change efficacy was associated with organizational climate, support for the company's mission and was inversely related to burnout. Each unit increase in the organizational climate scale predicted 0.45 and 0.8-unit increases in change commitment and change efficacy. The survey identified positive readiness for change and highlighted weaknesses that are important cautions for this organization and others initiating change. Future studies will examine how organizational readiness to change, workforce characteristics and work environment influenced successful implementation within this organization.

Cross-trial prediction of treatment outcome in depression: a machine learning approach.

PubMed

Chekroud, Adam Mourad; Zotti, Ryan Joseph; Shehzad, Zarrar; Gueorguieva, Ralitza; Johnson, Marcia K; Trivedi, Madhukar H; Cannon, Tyrone D; Krystal, John Harrison; Corlett, Philip Robert

2016-03-01

Antidepressant treatment efficacy is low, but might be improved by matching patients to interventions. At present, clinicians have no empirically validated mechanisms to assess whether a patient with depression will respond to a specific antidepressant. We aimed to develop an algorithm to assess whether patients will achieve symptomatic remission from a 12-week course of citalopram. We used patient-reported data from patients with depression (n=4041, with 1949 completers) from level 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D; ClinicalTrials.gov, number NCT00021528) to identify variables that were most predictive of treatment outcome, and used these variables to train a machine-learning model to predict clinical remission. We externally validated the model in the escitalopram treatment group (n=151) of an independent clinical trial (Combining Medications to Enhance Depression Outcomes [COMED]; ClinicalTrials.gov, number NCT00590863). We identified 25 variables that were most predictive of treatment outcome from 164 patient-reportable variables, and used these to train the model. The model was internally cross-validated, and predicted outcomes in the STAR*D cohort with accuracy significantly above chance (64·6% [SD 3·2]; p<0·0001). The model was externally validated in the escitalopram treatment group (N=151) of COMED (accuracy 59·6%, p=0.043). The model also performed significantly above chance in a combined escitalopram-buproprion treatment group in COMED (n=134; accuracy 59·7%, p=0·023), but not in a combined venlafaxine-mirtazapine group (n=140; accuracy 51·4%, p=0·53), suggesting specificity of the model to underlying mechanisms. Building statistical models by mining existing clinical trial data can enable prospective identification of patients who are likely to respond to a specific antidepressant. Yale University. Copyright © 2016 Elsevier Ltd. All rights reserved.

The clinical significance of 5% change in vital capacity in patients with idiopathic pulmonary fibrosis: extended analysis of the pirfenidone trial

PubMed Central

2011-01-01

Background Our phase III clinical trial of pirfenidone for patients with idiopathic pulmonary fibrosis (IPF) revealed the efficacy in reducing the decline of vital capacity (VC) and increasing the progression-free survival (PFS) time by pirfenidone. Recently, marginal decline in forced VC (FVC) has been reported to be associated with poor outcome in IPF. We sought to evaluate the efficacy of pirfenidone from the aspects of 5% change in VC. Methods Improvement ratings based on 5% change in absolute VC, i.e., "improved (VC ≥ 5% increase)", "stable (VC < 5% change)", and "worsened (VC ≥ 5% decrease)" at month 3, 6, 9 and 12 were compared between high-dose pirfenidone (1800 mg/day; n = 108) and placebo (n = 104) groups, and (high-dose and low-dose (1200 mg/day; n = 55)) pirfenidone (n = 163) and placebo groups. PFS times with defining the disease progression as death or a ≥ 5% decline in VC were also compared between high-dose pirfenidone and placebo groups, and low-dose pirfenidone and placebo groups. Furthermore, considering "worsened" and "non-worsened (improved and stable)" of the ratings at months 3 and 12 as "positive" and "negative", respectively, and the positive and negative predictive values of the ratings were calculated in each group. Results In the comparison of the improvement ratings, the statistically significant differences were clearly revealed at months 3, 6, 9, and 12 between pirfenidone and placebo groups. Risk reductions by pirfenidone to placebo were approximately 35% over the study period. In the comparison of the PFS times, statistically significant difference was also observed between pirfenidone and placebo groups. The positive/negative predictive values in placebo and pirfenidone groups were 86.1%/50.8% and 87.1%/71.7%, respectively. Further, the baseline characteristics of patients worsened at month 3 had generally severe impairment, and their clinical outcomes including mortality were also significantly worsened after 1 year. Conclusions The efficacy of pirfenidone in Japanese phase III trial was supported by the rating of 5% decline in VC, and the VC changes at month 3 may be used as a prognostic factor of IPF. Trial Registration This clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13th, 2005 (Registration Number: JAPICCTI-050121). PMID:21756364

Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy.

PubMed

Hector, Suzanne; Rehm, Markus; Schmid, Jasmin; Kehoe, Joan; McCawley, Niamh; Dicker, Patrick; Murray, Frank; McNamara, Deborah; Kay, Elaine W; Concannon, Caoimhin G; Huber, Heinrich J; Prehn, Jochen H M

2012-05-01

Key to the clinical management of colorectal cancer is identifying tools which aid in assessing patient prognosis and determining more effective and personalised treatment strategies. We evaluated whether an experimental systems biology strategy which analyses the susceptibility of cancer cells to undergo caspase activation can be exploited to predict patient responses to 5-fluorouracil-based chemotherapy and to case-specifically identify potential alternative targeted treatments to reactivate apoptosis. We quantified five essential apoptosis-regulating proteins (Pro-Caspases 3 and 9, APAF-1, SMAC and XIAP) in samples of Stage II (n = 13) and III (n=17) tumour and normal colonic (n = 8) tissue using absolute quantitative immunoblotting and employed systems simulations of apoptosis signalling to predict the susceptibility of tumour cells to execute apoptosis. Additional systems analyses assessed the efficacy of novel apoptosis-inducing therapeutics such as XIAP antagonists, proteasome inhibitors and Pro-Caspase-3-activating compounds in restoring apoptosis execution in apoptosis-incompetent tumours. Comparisons of caspase activity profiles demonstrated that the likelihood of colorectal tumours to undergo apoptosis decreases with advancing disease stage. Systems-level analysis correctly predicted positive or negative outcome in 85% (p=0.004) of colorectal cancer patients receiving 5-fluorouracil based chemotherapy and significantly outperformed common uni- and multi-variate statistical approaches. Modelling of individual patient responses to novel apoptosis-inducing therapeutics revealed markedly different inter-individual responses. Our study represents the first proof-of-concept example demonstrating the significant clinical potential of systems biology-based approaches for predicting patient outcome and responsiveness to novel targeted treatment paradigms.

Idiopathic Pulmonary Fibrosis: Clinically Meaningful Primary Endpoints in Phase 3 Clinical Trials

PubMed Central

Collard, Harold R.; Anstrom, Kevin J.; Flaherty, Kevin R.; Fleming, Thomas R.; King, Talmadge E.; Martinez, Fernando J.; Brown, Kevin K.

2012-01-01

Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint—that is, an endpoint that directly measures how a patient feels (symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or funtional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints. PMID:22505745

Design of the INPULSIS™ trials: two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis.

PubMed

Richeldi, Luca; Cottin, Vincent; Flaherty, Kevin R; Kolb, Martin; Inoue, Yoshikazu; Raghu, Ganesh; Taniguchi, Hiroyuki; Hansell, David M; Nicholson, Andrew G; Le Maulf, Florence; Stowasser, Susanne; Collard, Harold R

2014-07-01

Nintedanib is in clinical development as a treatment for idiopathic pulmonary fibrosis (IPF). Data from the Phase II TOMORROW study suggested that nintedanib 150 mg twice daily had clinical benefits with an acceptable safety profile. The INPULSIS™ trials are replicate Phase III, randomized, double-blind, studies comparing the efficacy and safety of nintedanib 150 mg twice daily with placebo in patients with IPF. Eligible patients were aged ≥40 years with a diagnosis of IPF within 5 years before randomization who had undergone a chest high-resolution computed tomography (HRCT) scan within 1-year before screening, and who had a forced vital capacity (FVC) of ≥50% predicted and a diffusing capacity for carbon monoxide of 30-79% predicted. Participants were randomized 3:2 to receive nintedanib or placebo for 52 weeks. The primary endpoint is the annual rate of decline in FVC. The key secondary endpoints are change from baseline in the total score on the St. George's Respiratory Questionnaire (a measure of health-related quality of life) over 52 weeks and time to first acute exacerbation. Enrolment of 1066 patients in 24 countries was completed in September 2012. Results will be reported in the first half of 2014. The INPULSIS™ trials will determine the efficacy of nintedanib in patients with IPF, including its impact on disease progression as defined by decline in FVC, acute exacerbations and health-related quality of life. In addition, they will characterise the adverse event profile of nintedanib in this patient population. Registered at ClinicalTrials.gov (identifiers: NCT01335464 and NCT01335477). Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Efficacy of a tool to predict short-term mortality in older people presenting at emergency departments: Protocol for a multi-centre cohort study.

PubMed

Cardona, Magnolia; Lewis, Ebony T; Turner, Robin M; Alkhouri, Hatem; Asha, Stephen; Mackenzie, John; Perkins, Margaret; Suri, Sam; Holdgate, Anna; Winoto, Luis; Chang, Chan-Wei; Gallego-Luxan, Blanca; McCarthy, Sally; Kristensen, Mette R; O'Sullivan, Michael; Skjøt-Arkil, Helene; Ekmann, Anette A; Nygaard, Hanne H; Jensen, Jonas J; Jensen, Rune O; Pedersen, Jonas L; Breen, Dorothy; Petersen, John A; Jensen, Birgitte N; Mogensen, Christian Backer; Hillman, Ken; Brabrand, Mikkel

Prognostic uncertainty inhibits clinicians from initiating timely end-of-life discussions and advance care planning. This study evaluates the efficacy of the CriSTAL (Criteria for Screening and Triaging to Appropriate aLternative care) checklist in emergency departments. Prospective cohort study of patients aged ≥65 years with any diagnosis admitted via emergency departments in ten hospitals in Australia, Denmark and Ireland. Electronic and paper clinical records will be used to extract risk factors such as nursing home residency, physiological deterioration warranting a rapid response call, personal history of active chronic disease, history of hospitalisations or intensive care unit admission in the past year, evidence of proteinuria or ECG abnormalities, and evidence of frailty to be concurrently measured with Fried Score and Clinical Frailty Scale. Patients or their informal caregivers will be contacted by telephone around three months after initial assessment to ascertain survival, self-reported health, post-discharge frailty and health service utilisation since discharge. Logistic regression and bootstrapping techniques and AUROC curves will be used to test the predictive accuracy of CriSTAL for death within 90 days of admission and in-hospital death. The CriSTAL checklist is an objective and practical tool for use in emergency departments among older patients to determine individual probability of death in the short-term. Its validation in this cohort is expected to reduce clinicians' prognostic uncertainty on the time to patients' death and encourage timely end-of-life conversations to support clinical decisions with older frail patients and their families about their imminent or future care choices. Copyright © 2018 Elsevier B.V. All rights reserved.

Determinants of physical activity promotion by smoking cessation advisors as an aid for quitting: support for the Transtheoretical Model.

PubMed

Everson, Emma S; Taylor, Adrian H; Ussher, Michael

2010-01-01

Physical activity (PA) can reduce cigarette cravings and aid quitting but little is known about its promotion by smoking cessation advisors. This study aimed to: (1) determine the extent to which smoking cessation advisors promote PA; and (2) examine the relationship between PA promotion as a cessation aid and advisor characteristics and cognitions, within the Transtheoretical Model (TM) framework. Self-report surveys assessing PA promotion, TM variables, advisors' own PA levels and demographics were completed by 170 advisors in England and Scotland. Advisors reported spending 29min promoting PA over a 6/7-week clinic. Those in later stages of readiness for promoting PA as a cessation aid and those spending more time promoting PA held more positive beliefs regarding pros and cons, self-efficacy, outcome efficacy and importance of PA within smoking cessation. Time spent promoting PA and stage of readiness were strongly associated. There was a trend for the more physically active advisors to promote PA more often. About half the advisors promoted PA and TM variables predicted this variability. PA promotion among smoking cessation advisors may be facilitated by enhancing self-efficacy, outcome efficacy and pro- and con-beliefs related to PA promotion.

Radiation treatment in older patients: a framework for clinical decision making.

PubMed

Smith, Grace L; Smith, Benjamin D

2014-08-20

In older patients, radiation treatment plays a vital role in curative and palliative cancer therapy. Radiation treatment recommendations should be informed by a comprehensive, personalized risk-benefit assessment that evaluates treatment efficacy and toxicity. We review several clinical factors that distinctly affect efficacy and toxicity of radiation treatment in older patients. First, locoregional tumor behavior may be more indolent in older patients for some disease sites but more aggressive for other sites. Assessment of expected locoregional relapse risk informs the magnitude and timeframe of expected radiation treatment benefits. Second, assessment of the competing cancer versus noncancer mortality and morbidity risks contextualizes cancer treatment priorities holistically within patients' entire spectrum and time course of health needs. Third, assessment of functional reserve helps predict patients' acute treatment tolerance, differentiating those patients who are unlikely to benefit from treatment or who are at high risk for treatment complications. Potential radiation treatment options include immediate curative treatment, delayed curative treatment, and no treatment, with additional consideration given to altered radiation target, dose, or sequencing with chemotherapy and/or surgery. Finally, when cure is not feasible, palliative radiation therapy remains valuable for managing symptoms and achieving meaningful quality-of-life improvements. Our proposed decision-making framework integrates these factors to help radiation oncologists formulate strategic treatment recommendations within a multidisciplinary context. Future research is still needed to identify how advanced technologies can be judiciously applied in curative and palliative settings to enhance risk-benefit profiles of radiation treatment in older patients and more accurately quantify treatment efficacy in this group. © 2014 by American Society of Clinical Oncology.

Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials.

PubMed

Carlezon, William A; Krystal, Andrew D

2016-10-01

Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin that in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs-the endogenous receptors for dynorphin-produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans. © 2016 Wiley Periodicals, Inc.

Are the Performance Based Logistics Prophets Using Science or Alchemy to Create Life-Cycle Affordability? Using Theory to Predict the Efficacy of Performance Based Logistics

DTIC Science & Technology

2013-10-01

Based Logistics Prophets Using Science or Alchemy to Create Life-Cycle Affordability? Using Theory to Predict the Efficacy of Performance Based...Using Science or Alchemy to Create Life-Cycle Affordability? Using Theory to Predict the Efficacy of Performance Based Logistics 5a. CONTRACT NUMBER 5b...Are the PBL Prophets Using Science or Alchemy to Create Life Cycle Affordability? 328Defense ARJ, October 2013, Vol. 20 No. 3 : 325–348 Defense

Differential efficacy of human mesenchymal stem cells based on source of origin

PubMed Central

Collins, Erin; Gu, Fei; Qi, Maosong; Molano, Ivan; Ruiz, Phillip; Sun, Linyun; Gilkeson, Gary S.

2014-01-01

Mesenchymal stem cells (MSCs) are useful in tissue repair, but also possess immunomodulatory properties. Murine and uncontrolled human trials suggest efficacy of MSCs in treating lupus. Autologous cells are preferable, however, recent studies suggest that lupus derived MSCs lack efficacy in treating disease. Thus, the optimum derivation of MSCs for use in lupus is unknown. It is also unknown which in vitro assays of MSC function predict in vivo efficacy. The objectives for this study were to provide insight into the optimum source of MSCs and to identify in vitro assays that predict in vivo efficacy. We derived MSCs from four umbilical cords (UC), four healthy bone marrows (HBM) and four lupus bone marrows (LBM). In diseased MRL/lpr mice, MSCs from HBM and UC significantly decreased renal disease, while LBM-MSCs only delayed disease. Current in vitro assays did not differentiate efficacy of the different MSCs. Inhibition of B cell proliferation did differentiate based on efficacy. Our results suggest that autologous MSCs from lupus patients are not effective in treating disease. Furthermore, standard in vitro assays for MSC licensing are not predictive of in vivo efficacy, while inhibiting B cell proliferation appears to differentiate effective from ineffective MSCs. PMID:25274529

Computer-aided global breast MR image feature analysis for prediction of tumor response to chemotherapy: performance assessment

NASA Astrophysics Data System (ADS)

Aghaei, Faranak; Tan, Maxine; Hollingsworth, Alan B.; Zheng, Bin; Cheng, Samuel

2016-03-01

Dynamic contrast-enhanced breast magnetic resonance imaging (DCE-MRI) has been used increasingly in breast cancer diagnosis and assessment of cancer treatment efficacy. In this study, we applied a computer-aided detection (CAD) scheme to automatically segment breast regions depicting on MR images and used the kinetic image features computed from the global breast MR images acquired before neoadjuvant chemotherapy to build a new quantitative model to predict response of the breast cancer patients to the chemotherapy. To assess performance and robustness of this new prediction model, an image dataset involving breast MR images acquired from 151 cancer patients before undergoing neoadjuvant chemotherapy was retrospectively assembled and used. Among them, 63 patients had "complete response" (CR) to chemotherapy in which the enhanced contrast levels inside the tumor volume (pre-treatment) was reduced to the level as the normal enhanced background parenchymal tissues (post-treatment), while 88 patients had "partially response" (PR) in which the high contrast enhancement remain in the tumor regions after treatment. We performed the studies to analyze the correlation among the 22 global kinetic image features and then select a set of 4 optimal features. Applying an artificial neural network trained with the fusion of these 4 kinetic image features, the prediction model yielded an area under ROC curve (AUC) of 0.83+/-0.04. This study demonstrated that by avoiding tumor segmentation, which is often difficult and unreliable, fusion of kinetic image features computed from global breast MR images without tumor segmentation can also generate a useful clinical marker in predicting efficacy of chemotherapy.

Safety and efficacy of long-term use of sodium oxybate for narcolepsy with cataplexy in routine clinical practice.

PubMed

Drakatos, Panagis; Lykouras, Dimosthenis; D'Ancona, Grainne; Higgins, Sean; Gildeh, Nadia; Macavei, Raluca; Rosenzweig, Ivana; Steier, Joerg; Williams, Adrian J; Muza, Rexford; Kent, Brian D; Leschziner, Guy

2017-07-01

Sodium oxybate is licensed in Europe for the treatment of narcolepsy with cataplexy in adults. The aim of this study was to assess the efficacy and safety of sodium oxybate in clinical practice in patients with narcolepsy and cataplexy refractory to other treatments. This was a retrospective single centre study including patients with severe narcolepsy with cataplexy refractory to other treatments, who were initiated on sodium oxybate between 2009 and 2015. Patients were allowed to be on other stimulants or/and anti-cataplectic agents. Epworth sleepiness scale (ESS) and weekly cataplexy events were recorded. Side effects (SEs) were recorded at every follow-up visit. 90 patients were prescribed sodium oxybate, with a total of 3116 patient-months of drug exposure. ESS and weekly cataplexy events were significantly reduced by sodium oxybate for all patients (ΔESS = 4.3 ± 4.4 and Δcataplexy = 21.8 ± 18.5 events/week; p < 0.0001, respectively). The required maintenance dose could not be predicted based upon gender, body mass index, or clinical factors. 60% of patients were able to reduce or come off other medications. Half of the patients experienced at least one SE, and 26.6% had to stop treatment due to limiting SEs. Nausea, mood swings and enuresis were the most commonly reported SEs. SEs that led to drug discontinuation, particularly psychosis, were associated with increasing age and were observed early after the initiation of the drug. Sodium oxybate provides a good clinical efficacy and acceptable safety profile in routine clinical practice for the treatment of patients suffering from narcolepsy with cataplexy. A quarter of patients experience SEs requiring withdrawal of the drug with older patients being more vulnerable to the more serious SEs. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Treatment of scalp psoriasis with clobetasol-17 propionate 0.05% shampoo: a study on daily clinical practice.

PubMed

Bovenschen, H J; Van de Kerkhof, P C M

2010-04-01

Safety and clinical effectiveness of clobetasol-17 propionate 0.05% shampoo have been shown in patients with scalp psoriasis. First, to evaluate treatment satisfaction, user convenience safety and effectiveness of clobetasol-17 propionate 0.05% shampoo treatment in daily clinical practice. Second, to identify subgroup variables that may predict treatment success or failure. A total of 56 patients with scalp psoriasis were treated with short-contact clobetasol-17 propionate 0.05% shampoo once daily for 4 weeks. Data on treatment satisfaction, user convenience, safety and effectiveness were assessed on a 7-point Likert scale using postal questionnaires. Subgroup analyses were performed to identify variables that may predict treatment outcome. A total of 41 patients returned both questionnaires (73%). Positive treatment satisfaction and user convenience were reported by 66% and 79% of patients respectively. Patient-rated indicators for disease severity improved by 39-46% (P < 0.05%). No major side-effects were reported. Subgroup analyses did not reveal any statistically significant patient variable that may predict treatment outcome. However, a tendency towards improved treatment satisfaction was observed in patients who had received fewer topical antipsoriatic treatments previously (P > 0.05). Short-contact treatment with clobetasol-17 propionate 0.05% shampoo has high user convenience and patient satisfaction rates. Moreover, the treatment is well-tolerated and efficacious from patients' perspective. Subgroup analyses did not reveal factors predicting treatment outcome, although treatment success tended to be more evident in patients who had received fewer treatments previously.

The closer 'We' are, the stronger 'I' am: the impact of couple identity on cancer coping self-efficacy.

PubMed

Ahmad, Saunia; Fergus, Karen; Shatokhina, Kristina; Gardner, Sandra

2017-06-01

The present study tested the supposition that greater levels of couple identity (or we-ness) increase a woman's coping self-efficacy in relation to breast cancer, which, in turn, predicts better psychosocial adjustment. Women (N = 112) in committed relationships completed surveys assessing their levels of couple identity, cancer coping self-efficacy, and aspects of their psychosocial adjustment (specifically, depression, anxiety and functional well-being) during one of their outpatient visits to the cancer centre. As predicted, the more women identified with their relationships, the lower their levels of depression and anxiety were and the greater their functional well-being was. This relationship was mediated by coping self-efficacy: greater identification with one's relationship predicted greater confidence in one's ability to cope, which, in turn, predicted better adjustment. The role intimate relationships play in women's adjustment to breast cancer, as well as directions for further research, are discussed.

DeSigN: connecting gene expression with therapeutics for drug repurposing and development.

PubMed

Lee, Bernard Kok Bang; Tiong, Kai Hung; Chang, Jit Kang; Liew, Chee Sun; Abdul Rahman, Zainal Ariff; Tan, Aik Choon; Khang, Tsung Fei; Cheong, Sok Ching

2017-01-25

The drug discovery and development pipeline is a long and arduous process that inevitably hampers rapid drug development. Therefore, strategies to improve the efficiency of drug development are urgently needed to enable effective drugs to enter the clinic. Precision medicine has demonstrated that genetic features of cancer cells can be used for predicting drug response, and emerging evidence suggest that gene-drug connections could be predicted more accurately by exploring the cumulative effects of many genes simultaneously. We developed DeSigN, a web-based tool for predicting drug efficacy against cancer cell lines using gene expression patterns. The algorithm correlates phenotype-specific gene signatures derived from differentially expressed genes with pre-defined gene expression profiles associated with drug response data (IC 50 ) from 140 drugs. DeSigN successfully predicted the right drug sensitivity outcome in four published GEO studies. Additionally, it predicted bosutinib, a Src/Abl kinase inhibitor, as a sensitive inhibitor for oral squamous cell carcinoma (OSCC) cell lines. In vitro validation of bosutinib in OSCC cell lines demonstrated that indeed, these cell lines were sensitive to bosutinib with IC 50 of 0.8-1.2 μM. As further confirmation, we demonstrated experimentally that bosutinib has anti-proliferative activity in OSCC cell lines, demonstrating that DeSigN was able to robustly predict drug that could be beneficial for tumour control. DeSigN is a robust method that is useful for the identification of candidate drugs using an input gene signature obtained from gene expression analysis. This user-friendly platform could be used to identify drugs with unanticipated efficacy against cancer cell lines of interest, and therefore could be used for the repurposing of drugs, thus improving the efficiency of drug development.

Combining clinical and magnetic resonance imaging markers enhances prediction of 12-year disability in multiple sclerosis.

PubMed

Uher, Tomas; Vaneckova, Manuela; Sobisek, Lukas; Tyblova, Michaela; Seidl, Zdenek; Krasensky, Jan; Ramasamy, Deepa; Zivadinov, Robert; Havrdova, Eva; Kalincik, Tomas; Horakova, Dana

2017-01-01

Disease progression and treatment efficacy vary among individuals with multiple sclerosis. Reliable predictors of individual disease outcomes are lacking. To examine the accuracy of the early prediction of 12-year disability outcomes using clinical and magnetic resonance imaging (MRI) parameters. A total of 177 patients from the original Avonex-Steroids-Azathioprine study were included. Participants underwent 3-month clinical follow-ups. Cox models were used to model the associations between clinical and MRI markers at baseline or after 12 months with sustained disability progression (SDP) over the 12-year observation period. At baseline, T2 lesion number, T1 and T2 lesion volumes, corpus callosum (CC), and thalamic fraction were the best predictors of SDP (hazard ratio (HR) = 1.7-4.6; p ⩽ 0.001-0.012). At 12 months, Expanded Disability Status Scale (EDSS) and its change, number of new or enlarging T2 lesions, and CC volume % change were the best predictors of SDP over the follow-up (HR = 1.7-3.5; p ⩽  0.001-0.017). A composite score was generated from a subset of the best predictors of SDP. Scores of ⩾4 had greater specificity (90%-100%) and were associated with greater cumulative risk of SDP (HR = 3.2-21.6; p < 0.001) compared to the individual predictors. The combination of established MRI and clinical indices with MRI volumetric predictors improves the prediction of SDP over long-term follow-up and may provide valuable information for therapeutic decisions.

Predicting Self-Management Behaviors in Familial Hypercholesterolemia Using an Integrated Theoretical Model: the Impact of Beliefs About Illnesses and Beliefs About Behaviors.

PubMed

Hagger, Martin S; Hardcastle, Sarah J; Hingley, Catherine; Strickland, Ella; Pang, Jing; Watts, Gerald F

2016-06-01

Patients with familial hypercholesterolemia (FH) are at markedly increased risk of coronary artery disease. Regular participation in three self-management behaviors, physical activity, healthy eating, and adherence to medication, can significantly reduce this risk in FH patients. We aimed to predict intentions to engage in these self-management behaviors in FH patients using a multi-theory, integrated model that makes the distinction between beliefs about illness and beliefs about self-management behaviors. Using a cross-sectional, correlational design, patients (N = 110) diagnosed with FH from a clinic in Perth, Western Australia, self-completed a questionnaire that measured constructs from three health behavior theories: the common sense model of illness representations (serious consequences, timeline, personal control, treatment control, illness coherence, emotional representations); theory of planned behavior (attitudes, subjective norms, perceived behavioral control); and social cognitive theory (self-efficacy). Structural equation models for each self-management behavior revealed consistent and statistically significant effects of attitudes on intentions across the three behaviors. Subjective norms predicted intentions for health eating only and self-efficacy predicted intentions for physical activity only. There were no effects for the perceived behavioral control and common sense model constructs in any model. Attitudes feature prominently in determining intentions to engage in self-management behaviors in FH patients. The prominence of these attitudinal beliefs about self-management behaviors, as opposed to illness beliefs, suggest that addressing these beliefs may be a priority in the management of FH.

Feasibility of extended use of an electromagnetic lithotripter beyond the manufacturer's recommended maintenance schedule.

PubMed

Chen, Tony Y H; Ponsot, Yves; Brouillette, Martin; Tétrault, Jean-Píerre; Tu, Le Mai

2007-06-01

The study evaluates the effect of chronic usage, beyond the recommended maintenance schedule, on the efficacy of electromagnetic lithotripter. To our knowledge, there is no publication investigating the effect of chronic usage on the electromagnetic lithotripter, despite the maintenance schedule established by the manufacturers. Our goal is to verify if the acoustic parameters of the shock wave changed with usage, and if this change could be associated with change in clinical efficacy. This study lasted 18 months. Every 6 months the lithotripter's efficacy was evaluated in two ways: objectively and clinically. Objective efficacy was measured using a piezoelectric hydrophone and artificial stones to capture the acoustic parameters and the crater of fragmentation, respectively. Clinical efficacy data was collected by studying the rate of successful extracorporeal shock wave lithotripsy treatment in patients with urolithiasis. The changes in clinical efficacy, acoustic parameters, and craters of fragmentation were compared and analyzed with appropriate statistical methods. Five hundred twenty five patients participated in the study. The clinical efficacy remained stable throughout the three observation periods (55.7%, 66.2% and 55.5%; p = 0.11). The focal head of the lithotripter was used three times the recommended schedule. There was no obvious change in the acoustic parameters of the shock waves, and the focal zone remained stable. The clinical efficacy of the electromagnetic lithotripter appears to be stable despite usage beyond the recommended maintenance schedule. More studies are needed to validate the safety of this practice.

Relative contributions of protection motivation theory components in predicting exercise intentions and behavior.

PubMed

Wurtele, S K; Maddux, J E

1987-01-01

A factorial design was employed to test the relative effectiveness of the four cognitive appraisal processes (severity, vulnerability, response efficacy, and self-efficacy) contained in the revised protection motivation theory (PMT). One hundred sixty undergraduate women read persuasive appeals for increasing exercise, which varied on these four dimensions. As predicted, both the vulnerability and self-efficacy variables enhanced intentions to exercise along with similar effects on self-reported exercising. Intentions were predictive of self-reported changes in behavior. The obtained interaction between vulnerability, self-efficacy, and response efficacy suggests that individuals employed a "precaution strategy": They intended to adopt the recommended behavior even though they held weak beliefs about its effectiveness and were not convinced of their at-risk status. These findings are compared to others obtained using the PMT, and the issue of main and interactive effects produced by the model is also addressed.

Influence of pharmacogenomic profiling prior to pharmaceutical treatment in metastatic colorectal cancer on cost effectiveness : a systematic review.

PubMed

Frank, Martin; Mittendorf, Thomas

2013-03-01

Metastatic colorectal cancer (mCRC) imposes a substantial health burden on individual patients and society. Furthermore, rising costs in oncology cause a growing concern about reimbursement for innovations in this sector. The promise of pharmacogenomic profiling and related stratified therapies in mCRC is to improve treatment efficacy and potentially save costs. Among other examples, the commonly used epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab are only effective in patients with kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type cancers. Hence, the adaptation of predictive biomarker testing might be a valid strategy for healthcare systems worldwide. This study aims to review the clinical and economic evidence supporting pharmacogenomic profiling prior to the administration of pharmaceutical treatment in mCRC. Moreover, key drivers and areas of uncertainty in cost-effectiveness evaluations are analysed. A systematic literature review was conducted to identify studies evaluating the cost effectiveness of predictive biomarkers and the result dependent usage of pharmaceutical agents in mCRC. The application of predictive biomarkers to detect KRAS mutations prior to the administration of EGFR antibodies saved treatment costs and was cost effective in all identified evaluations. However, because of the lack of data regarding cost-effectiveness analyses for predictive biomarker testing, e.g. for first-line treatment, definitive conclusions cannot be stated. Key drivers and areas of uncertainty in current cost-effectiveness analyses are, among others, the consideration of predictive biomarker costs, the characteristics of single predictive biomarkers and the availability of clinical data for the respective pharmaceutical intervention. Especially the cost effectiveness of uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1) mutation analysis prior to irinotecan-based chemotherapy remains unclear. Pharmacogenomic profiling has the potential to improve the cost effectiveness of pharmaceutical treatment in mCRC. Hence, quantification of the economic impact of stratified medicine as well as cost-effectiveness analyses of pharmacogenomic profiling are becoming more important. Nevertheless, the methods applied in cost-effectiveness evaluations for the usage of predictive biomarkers for patient selection as well as the level of evidence required to determine clinical effectiveness are areas for further research. However, mCRC is one of the first indications in which stratified therapies are used in clinical practice. Thus, clinical and economic experiences could be helpful when adopting pharmacogenomic profiling into clinical practice for other indications.

Physicochemical properties of dietary phytochemicals can predict their passive absorption in the human small intestine.

PubMed

Selby-Pham, Sophie N B; Miller, Rosalind B; Howell, Kate; Dunshea, Frank; Bennett, Louise E

2017-05-16

A diet high in phytochemical-rich plant foods is associated with reducing the risk of chronic diseases such as cardiovascular and neurodegenerative diseases, obesity, diabetes and cancer. Oxidative stress and inflammation (OSI) is the common component underlying these chronic diseases. Whilst the positive health effects of phytochemicals and their metabolites have been demonstrated to regulate OSI, the timing and absorption for best effect is not well understood. We developed a model to predict the time to achieve maximal plasma concentration (T max ) of phytochemicals in fruits and vegetables. We used a training dataset containing 67 dietary phytochemicals from 31 clinical studies to develop the model and validated the model using three independent datasets comprising a total of 108 dietary phytochemicals and 98 pharmaceutical compounds. The developed model based on dietary intake forms and the physicochemical properties lipophilicity and molecular mass accurately predicts T max of dietary phytochemicals and pharmaceutical compounds over a broad range of chemical classes. This is the first direct model to predict T max of dietary phytochemicals in the human body. The model informs the clinical dosing frequency for optimising uptake and sustained presence of dietary phytochemicals in circulation, to maximise their bio-efficacy for positively affect human health and managing OSI in chronic diseases.

Strategies to design clinical studies to identify predictive biomarkers in cancer research.

PubMed

Perez-Gracia, Jose Luis; Sanmamed, Miguel F; Bosch, Ana; Patiño-Garcia, Ana; Schalper, Kurt A; Segura, Victor; Bellmunt, Joaquim; Tabernero, Josep; Sweeney, Christopher J; Choueiri, Toni K; Martín, Miguel; Fusco, Juan Pablo; Rodriguez-Ruiz, Maria Esperanza; Calvo, Alfonso; Prior, Celia; Paz-Ares, Luis; Pio, Ruben; Gonzalez-Billalabeitia, Enrique; Gonzalez Hernandez, Alvaro; Páez, David; Piulats, Jose María; Gurpide, Alfonso; Andueza, Mapi; de Velasco, Guillermo; Pazo, Roberto; Grande, Enrique; Nicolas, Pilar; Abad-Santos, Francisco; Garcia-Donas, Jesus; Castellano, Daniel; Pajares, María J; Suarez, Cristina; Colomer, Ramon; Montuenga, Luis M; Melero, Ignacio

2017-02-01

The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework-the DESIGN guidelines-to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

An increase in serum tumour necrosis factor-α during anti-tumour necrosis factor-α therapy for Crohn's disease - A paradox or a predictive index?

PubMed

Eder, Piotr; Korybalska, Katarzyna; Łykowska-Szuber, Liliana; Stawczyk-Eder, Kamila; Krela-Kaźmierczak, Iwona; Łuczak, Joanna; Czepulis, Natasza; Linke, Krzysztof; Witowski, Janusz

2016-10-01

Soluble tumour necrosis factor-α (sTNF-α) has been reported to increase in the course of anti-TNF-α therapy for rheumatoid and skin diseases. To assess changes in sTNF-α and clinical efficacy of anti-TNF-α agents in Crohn's disease (CD). Sixty-four patients on infliximab or adalimumab were analyzed. Clinical outcomes were assessed by using CD Activity Index after the induction therapy and at week 52. sTNF-α was measured before and after the induction therapy with high-sensitivity immunoassay. In the majority of patients, sTNF-α increased significantly. Those with the greatest increase were more likely to experience long-term response, were more often treated with infliximab, had less frequently isolated small bowel CD, and tended to have sTNF-α levels at baseline that correlated with C-reactive protein. Neutralization of sTNF-α does not seem to be critical for the efficacy of anti-TNF-α therapy in CD. Paradoxically - an increase in sTNF-α may reflect an ongoing process that is beneficial for the clinical outcome. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Disease models for the development of therapies for lysosomal storage diseases.

PubMed

Xu, Miao; Motabar, Omid; Ferrer, Marc; Marugan, Juan J; Zheng, Wei; Ottinger, Elizabeth A

2016-05-01

Lysosomal storage diseases (LSDs) are a group of rare diseases in which the function of the lysosome is disrupted by the accumulation of macromolecules. The complexity underlying the pathogenesis of LSDs and the small, often pediatric, population of patients make the development of therapies for these diseases challenging. Current treatments are only available for a small subset of LSDs and have not been effective at treating neurological symptoms. Disease-relevant cellular and animal models with high clinical predictability are critical for the discovery and development of new treatments for LSDs. In this paper, we review how LSD patient primary cells and induced pluripotent stem cell-derived cellular models are providing novel assay systems in which phenotypes are more similar to those of the human LSD physiology. Furthermore, larger animal disease models are providing additional tools for evaluation of the efficacy of drug candidates. Early predictors of efficacy and better understanding of disease biology can significantly affect the translational process by focusing efforts on those therapies with the higher probability of success, thus decreasing overall time and cost spent in clinical development and increasing the overall positive outcomes in clinical trials. © 2016 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.

The role of pirfenidone in the treatment of idiopathic pulmonary fibrosis

PubMed Central

2013-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease, with a median survival time of 2–5 years. The search for effective treatment has involved numerous clinical trials of investigational agents without significant success. However, in 2011, pirfenidone was the first drug to be approved for the treatment of IPF in Europe. Four key clinical trials supported the efficacy and tolerability of pirfenidone. In the two recently published Phase III CAPACITY trials evaluating pirfenidone (studies 004 and 006), patients with mild-to-moderate IPF were treated with pirfenidone or placebo. Study 004 and pooled analysis of primary endpoint data from both studies showed that pirfenidone significantly reduced decline in percent-predicted forced vital capacity (FVC) compared with placebo (p<0.005). Evidence of beneficial effects of pirfenidone treatment was also observed with regard to several secondary endpoints. Pirfenidone was generally well tolerated, with the most common side effects being gastrointestinal and photosensitivity. Data from the RECAP extension phase of the CAPACITY studies, where patients were treated with pirfenidone for up to three years, further support the manageable tolerability profile of pirfenidone. The efficacy data, coupled with long-term safety data, provide further evidence of a clinically-meaningful treatment effect with pirfenidone in patients with IPF. PMID:23734908

Self-controlled learning benefits: exploring contributions of self-efficacy and intrinsic motivation via path analysis.

PubMed

Ste-Marie, Diane M; Carter, Michael J; Law, Barbi; Vertes, Kelly; Smith, Victoria

2016-09-01

Research has shown learning advantages for self-controlled practice contexts relative to yoked (i.e., experimenter-imposed) contexts; yet, explanations for this phenomenon remain relatively untested. We examined, via path analysis, whether self-efficacy and intrinsic motivation are important constructs for explaining self-controlled learning benefits. The path model was created using theory-based and empirically supported relationships to examine causal links between these psychological constructs and physical performance. We hypothesised that self-efficacy and intrinsic motivation would have greater predictive power for learning under self-controlled compared to yoked conditions. Participants learned double-mini trampoline progressions, and measures of physical performance, self-efficacy and intrinsic motivation were collected over two practice days and a delayed retention day. The self-controlled group (M = 2.04, SD = .98) completed significantly more skill progressions in retention than their yoked counterparts (M = 1.3, SD = .65). The path model displayed adequate fit, and similar significant path coefficients were found for both groups wherein each variable was predominantly predicted by its preceding time point (e.g., self-efficacy time 1 predicts self-efficacy time 2). Interestingly, the model was not moderated by group; thus, failing to support the hypothesis that self-efficacy and intrinsic motivation have greater predictive power for learning under self-controlled relative to yoked conditions.

Translating New Science Into the Drug Review Process

PubMed Central

Rouse, Rodney; Kruhlak, Naomi; Weaver, James; Burkhart, Keith; Patel, Vikram; Strauss, David G.

2017-01-01

In 2011, the US Food and drug Administration (FDA) developed a strategic plan for regulatory science that focuses on developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products. In line with this, the Division of Applied Regulatory Science was created to move new science into the Center for Drug Evaluation and Research (CDER) review process and close the gap between scientific innovation and drug review. The Division, located in the Office of Clinical Pharmacology, is unique in that it performs mission-critical applied research and review across the translational research spectrum including in vitro and in vivo laboratory research, in silico computational modeling and informatics, and integrated clinical research covering clinical pharmacology, experimental medicine, and postmarket analyses. The Division collaborates with Offices throughout CDER, across the FDA, other government agencies, academia, and industry. The Division is able to rapidly form interdisciplinary teams of pharmacologists, biologists, chemists, computational scientists, and clinicians to respond to challenging regulatory questions for specific review issues and for longer-range projects requiring the development of predictive models, tools, and biomarkers to speed the development and regulatory evaluation of safe and effective drugs. This article reviews the Division’s recent work and future directions, highlighting development and validation of biomarkers; novel humanized animal models; translational predictive safety combining in vitro, in silico, and in vivo clinical biomarkers; chemical and biomedical informatics tools for safety predictions; novel approaches to speed the development of complex generic drugs, biosimilars, and antibiotics; and precision medicine. PMID:29568713

Clinical evaluation of the efficacy of a GTR membrane (HEALIGUIDE®) and demineralised bone matrix (OSSEOGRAFT®) as a space maintainer in the treatment of Miller's Class I gingival recession

PubMed Central

Nanditha, S.; Priya, M. S.; Sabitha, S.; Arun, K. V.; Avaneendra, T.

2011-01-01

Background: Periodontal plastic surgical procedures aimed at coverage of exposed root surface have evolved into routine treatment modalities. The present study was designed to evaluate the effectiveness and predictability of using a collagen barrier along with a demineralized bone matrix in the treatment of recession defects in a single surgical procedure. Materials and Methods: Seventeen patients with Miller's class I recession were treated with a combination of a collagen barrier used along with a bone graft and coronally advanced flap technique. Clinical parameters were recorded at baseline, 3 months, 6 months, and 9 months. Results: The study showed a highly significant reduction in the recession depth (70.29 ± 21.96%) at the end of the study. This study showed that the use of this technique for recession coverage is highly predictable and highly esthetic root coverage can be obtained. PMID:21976841

GetReal in mathematical modelling: a review of studies predicting drug effectiveness in the real world.

PubMed

Panayidou, Klea; Gsteiger, Sandro; Egger, Matthias; Kilcher, Gablu; Carreras, Máximo; Efthimiou, Orestis; Debray, Thomas P A; Trelle, Sven; Hummel, Noemi

2016-09-01

The performance of a drug in a clinical trial setting often does not reflect its effect in daily clinical practice. In this third of three reviews, we examine the applications that have been used in the literature to predict real-world effectiveness from randomized controlled trial efficacy data. We searched MEDLINE, EMBASE from inception to March 2014, the Cochrane Methodology Register, and websites of key journals and organisations and reference lists. We extracted data on the type of model and predictions, data sources, validation and sensitivity analyses, disease area and software. We identified 12 articles in which four approaches were used: multi-state models, discrete event simulation models, physiology-based models and survival and generalized linear models. Studies predicted outcomes over longer time periods in different patient populations, including patients with lower levels of adherence or persistence to treatment or examined doses not tested in trials. Eight studies included individual patient data. Seven examined cardiovascular and metabolic diseases and three neurological conditions. Most studies included sensitivity analyses, but external validation was performed in only three studies. We conclude that mathematical modelling to predict real-world effectiveness of drug interventions is not widely used at present and not well validated. © 2016 The Authors Research Synthesis Methods Published by John Wiley & Sons Ltd. © 2016 The Authors Research Synthesis Methods Published by John Wiley & Sons Ltd.

A novel artificial neural network method for biomedical prediction based on matrix pseudo-inversion.

PubMed

Cai, Binghuang; Jiang, Xia

2014-04-01

Biomedical prediction based on clinical and genome-wide data has become increasingly important in disease diagnosis and classification. To solve the prediction problem in an effective manner for the improvement of clinical care, we develop a novel Artificial Neural Network (ANN) method based on Matrix Pseudo-Inversion (MPI) for use in biomedical applications. The MPI-ANN is constructed as a three-layer (i.e., input, hidden, and output layers) feed-forward neural network, and the weights connecting the hidden and output layers are directly determined based on MPI without a lengthy learning iteration. The LASSO (Least Absolute Shrinkage and Selection Operator) method is also presented for comparative purposes. Single Nucleotide Polymorphism (SNP) simulated data and real breast cancer data are employed to validate the performance of the MPI-ANN method via 5-fold cross validation. Experimental results demonstrate the efficacy of the developed MPI-ANN for disease classification and prediction, in view of the significantly superior accuracy (i.e., the rate of correct predictions), as compared with LASSO. The results based on the real breast cancer data also show that the MPI-ANN has better performance than other machine learning methods (including support vector machine (SVM), logistic regression (LR), and an iterative ANN). In addition, experiments demonstrate that our MPI-ANN could be used for bio-marker selection as well. Copyright © 2013 Elsevier Inc. All rights reserved.

Behavioral Indices in Medical Care Outcome: The Working Alliance, Adherence, and Related Factors

PubMed Central

Boylan, Laura S.; Fontanella, Jessie A.

2008-01-01

Background The working alliance has been shown to be a consistent predictor of patient outcome and satisfaction in psychotherapy. This study examines the role of the working alliance and related behavioral indices in predicting medical outcome. Objective Cognitive and emotional dimensions of the physician–patient relationship were examined in relation to patients’ ratings of physician empathy, physician multicultural competence, perceived utility of treatment, and patients’ adherence self-efficacy. These factors were then examined as part of a theoretical framework using path analyses to explain patient self-reported adherence to and satisfaction with treatment. Design The study was based on an ex-post facto field correlation design. Participants One hundred fifty-two adult outpatients from a neurology clinic at Bellevue Hospital, a large municipal hospital in New York City, participated in the study. Interventions Surveys given to participants. Measurements We used the following measurements: Physician–Patient Working Alliance Scale, Perceived Utility Scale, Treatment Adherence Self-Efficacy Scale, Medical Outcome Study Adherence Scale, Physician Empathy Questionnaire, Physician Multicultural Competence Questionnaire, Medical Patient Satisfaction Questionnaire. Main Results The effect sizes for adherence are between 0.07 and 0.21 and for satisfaction between 0.10 to >0.50. Regression and path analyses showed that ratings of physician multicultural competence and patient adherence self-efficacy beliefs predicted patient adherence (SB = 0.34) and (SB = 0.30) and satisfaction (SB = 0.18) and (SB = 0.12), respectively. Working alliance ratings also predicted patient satisfaction (SB = 0.49). Conclusions Psychological and interpersonal dimensions of medical care are related to patient adherence and satisfaction. Medical care providers may be able to use these dimensions to target and improve health care outcomes. PMID:18972089

Pneumatic balloon dilation in pediatric achalasia: efficacy and factors predicting outcome at a single tertiary pediatric gastroenterology center.

PubMed

Di Nardo, Giovanni; Rossi, Paolo; Oliva, Salvatore; Aloi, Marina; Cozzi, Denis A; Frediani, Simone; Redler, Adriano; Mallardo, Saverio; Ferrari, Federica; Cucchiara, Salvatore

2012-11-01

The use of pneumatic dilation (PD) is well established in adults with achalasia; however, it is less commonly used in children. To evaluate the efficacy of PD in pediatric achalasia and to define predictive factors for its treatment failure. Single-center, prospective cohort study. Academic tertiary referral center. Twenty-four patients with achalasia were enrolled from January 2004 to November 2009 and were followed for a median of 6 years. PD was performed with the patients under general anesthesia. Efficacy and safety of PD. Follow-up was performed by using the Eckardt score, barium swallow contrast studies, and esophageal manometry at baseline; 1, 3, and 6 months after dilation; and every year thereafter. A Cox regression model was used to identify independent predictors of failure after the first PD. The PD success rate was 67%. In 8 patients, the first PD failed, but the parents of one patient refused a second PD and requested surgery. Of the 7 patients who underwent repeated treatment, the second PD failed in 3 (43%). Overall, only 3 of the 24 patients underwent surgery (overall success rate after a maximum of 3 PDs was 87%). Multivariate analysis showed that only older age was independently associated with a higher probability of the procedure success (hazard ratio [HR] 0.66; 95% CI, 0.45-0.97). Small sample size, single-center study. PD is a safe and effective technique in the management of pediatric achalasia. Young age is an independent negative predictive factor for successful clinical outcome. Copyright © 2012 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

In search of a new paradigm for protective immunity to TB.

PubMed

Nunes-Alves, Cláudio; Booty, Matthew G; Carpenter, Stephen M; Jayaraman, Pushpa; Rothchild, Alissa C; Behar, Samuel M

2014-04-01

Clinical trials of vaccines against Mycobacterium tuberculosis are well under way and results are starting to come in. Some of these results are not so encouraging, as exemplified by the latest Aeras-422 and MVA85A trials. Other than empirically determining whether a vaccine reduces the number of cases of active tuberculosis, which is a daunting prospect given the chronic nature of the disease, we have no way of assessing vaccine efficacy. Therefore, investigators seek to identify biomarkers that predict vaccine efficacy. Historically, focus has been on the production of interferon-γ by CD4(+) T cells, but this has not been a useful correlate of vaccine-induced protection. In this Opinion article, we discuss recent advances in our understanding of the immune control of M. tuberculosis and how this knowledge could be used for vaccine design and evaluation.

ADDME – Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective

PubMed Central

Tsaioun, Katya; Bottlaender, Michel; Mabondzo, Aloise

2009-01-01

The advent of early absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening has increased the attrition rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and its place in pharmaceutical development, and central nervous system drug discovery in particular. Assays that have been developed in response to specific needs and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of absorption and toxicity are discussed. The paper concludes with the authors' forecast of new models that will better predict human efficacy and toxicity. PMID:19534730

Ultrasonographic Changes at 12 Weeks of Anti-TNF Drugs Predict 1-year Sonographic Response and Clinical Outcome in Crohn's Disease: A Multicenter Study.

PubMed

Ripollés, Tomás; Paredes, José M; Martínez-Pérez, María J; Rimola, Jordi; Jauregui-Amezaga, Arantza; Bouzas, Rosa; Martin, Gregorio; Moreno-Osset, Eduardo

2016-10-01

The objective was to assess the long-term effect of biological treatment on transmural lesions of Crohn's disease evaluated with ultrasound, including contrast-enhanced ultrasound. Fifty-one patients with active Crohn's disease were included in a prospective multicenter longitudinal study. All patients underwent a clinical assessment and sonographic examination at baseline, 12 weeks after treatment initiation, and after 1-year of treatment. Patients were clinically followed at least 2 years from inclusion until the end of the study. Ultrasonographic evaluation included bowel wall thickness, color Doppler grade, parietal enhancement, and presence of transmural complications or stenosis. Sonographic changes after treatment were classified as normalization, improvement, or lack of response. Improvement at 52 weeks was more frequent in patients with improvement at final of induction (12 weeks) compared with patients who did not improve (85% versus 28%; P < 0.0001). One-year sonographic evolution correlated with clinical response; 28 of the 29 (96.5%) patients with sonographic improvement at 52 weeks showed clinical remission or response. Patients without sonographic improvement at 52 weeks of treatment were more likely to have a change or intensification in medication or surgery (13/20, 65%) during the next year of follow-up than patients with improvement on the sonography (3/28, 11%). Stricturing behavior was the only sonographic feature associated to a negative predictive value of response (P = 0.0001). Sonographic response after 12 weeks of therapy is more pronounced and predicts 1-year sonographic response. Sonographic response at 1-year examination correlates with 1-year clinical response and is a predictor of further treatment's efficacy, 1-year or longer period of follow-up.

Cultural differences in the understanding of modelling and feedback as sources of self-efficacy information.

PubMed

Ahn, Hyun Seon; Usher, Ellen L; Butz, Amanda; Bong, Mimi

2016-03-01

The potential role of culture in the development and operation of self-efficacy has been acknowledged by researchers. Clearer understanding of this cultural impact will benefit from research that shows how the same efficacy information is evaluated across cultures. We tested whether two sources of self-efficacy information delivered by multiple social agents (i.e., vicarious experience and social persuasion) were weighed differently by adolescents in different cultures. Of 2,893 middle school students in Korea (n = 416), the Philippines (n = 522), and the United States (n = 1,955) who completed the survey, 400 students were randomly pooled from each country. Invariance of the measurement and of the latent means for self-efficacy and self-efficacy sources across the groups was tested by multigroup confirmatory factor analysis. Predictive utility of the self-efficacy sources was compared by multigroup structural equation modelling. Compared to the students in the two collectivistic countries, the US students reported significantly higher mathematics self-efficacy. Whereas the efficacy beliefs of the Korean and the US students were predicted equally well by the vicarious experience from their teachers and the social persuasion by their family and peers, those of the Filipino adolescents were best predicted by the social persuasion from their peers. This study provided empirical evidence that socially conveyed sources of self-efficacy information are construed and evaluated differently across cultures, depending on who delivered the efficacy-relevant information. © 2015 The British Psychological Society.

Longitudinal Relationship between Self-efficacy and Posttraumatic Stress Symptoms 8 Years after a Violent Assault: An Autoregressive Cross-Lagged Model

PubMed Central

Nygaard, Egil; Johansen, Venke A.; Siqveland, Johan; Hussain, Ajmal; Heir, Trond

2017-01-01

Self-efficacy is assumed to promote posttraumatic adaption, and several cross-sectional studies support this notion. However, there is a lack of prospective longitudinal studies to further illuminate the temporal relationship between self-efficacy and posttraumatic stress symptoms. Thus, an important unresolved research question is whether posttraumatic stress disorder (PTSD) symptoms affect the level of self-efficacy or vice versa or whether they mutually influence each other. The present prospective longitudinal study investigated the reciprocal relationship between general self-efficacy (GSE) and posttraumatic stress symptoms in 143 physical assault victims. We used an autoregressive cross-lagged model across four assessment waves: within 4 months after the assault (T1) and then 3 months (T2), 12 months (T3) and 8 years (T4) after the first assessment. Stress symptoms at T1 and T2 predicted subsequent self-efficacy, while self-efficacy at T1 and T2 was not related to subsequent stress symptoms. These relationships were reversed after T3; higher levels of self-efficacy at T3 predicted lower levels of posttraumatic stress symptoms at T4, while posttraumatic tress symptoms at T3 did not predict self-efficacy at T4. In conclusion, posttraumatic stress symptoms may have a deteriorating effect on self-efficacy in the early phase after physical assault, whereas self-efficacy may promote recovery from posttraumatic stress symptoms over the long term. PMID:28620334

Longitudinal Relationship between Self-efficacy and Posttraumatic Stress Symptoms 8 Years after a Violent Assault: An Autoregressive Cross-Lagged Model.

PubMed

Nygaard, Egil; Johansen, Venke A; Siqveland, Johan; Hussain, Ajmal; Heir, Trond

2017-01-01

Self-efficacy is assumed to promote posttraumatic adaption, and several cross-sectional studies support this notion. However, there is a lack of prospective longitudinal studies to further illuminate the temporal relationship between self-efficacy and posttraumatic stress symptoms. Thus, an important unresolved research question is whether posttraumatic stress disorder (PTSD) symptoms affect the level of self-efficacy or vice versa or whether they mutually influence each other. The present prospective longitudinal study investigated the reciprocal relationship between general self-efficacy (GSE) and posttraumatic stress symptoms in 143 physical assault victims. We used an autoregressive cross-lagged model across four assessment waves: within 4 months after the assault (T1) and then 3 months (T2), 12 months (T3) and 8 years (T4) after the first assessment. Stress symptoms at T1 and T2 predicted subsequent self-efficacy, while self-efficacy at T1 and T2 was not related to subsequent stress symptoms. These relationships were reversed after T3; higher levels of self-efficacy at T3 predicted lower levels of posttraumatic stress symptoms at T4, while posttraumatic tress symptoms at T3 did not predict self-efficacy at T4. In conclusion, posttraumatic stress symptoms may have a deteriorating effect on self-efficacy in the early phase after physical assault, whereas self-efficacy may promote recovery from posttraumatic stress symptoms over the long term.

Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours

PubMed Central

2012-01-01

Background Ewing sarcoma/PNET is managed with treatment paradigms involving combinations of chemotherapy, surgery, and sometimes radiation. Although the 5-year survival rate of non-metastatic disease approaches 70%, those cases that are metastatic and those that recur have 5-year survival rates of less than 20%. Molecularly targeted treatments offer the potential to further improve treatment outcomes. Methods A PUBMED search was performed from 1997 to 2011. Published literature that included the topic of the Ewing sarcoma/PNET was also referenced. Results Insulin-like growth factor-1 receptor (IGF-1R) antagonists have demonstrated modest single agent efficacy in phase I/II clinical trials in Ewing sarcoma/PNET, but have a strong preclinical rationale. Based on in vitro and animal data, treatment using antisense RNA and cDNA oligonucleotides directed at silencing the EWS-FLI chimera that occurs in most Ewing sarcoma/PNET may have potential therapeutic importance. However drug delivery and degradation problems may limit this therapeutic approach. Protein-protein interactions can be targeted by inhibition of RNA helicase A, which binds to EWS/FLI as part of the transcriptional complex. Tumour necrosis factor related apoptosis inducing ligand induction using interferon has been used in preclinical models. Interferons may be incorporated into future chemotherapeutic treatment paradigms. Histone deacetylase inhibitors can restore TGF-β receptor II allowing TFF-β signalling, which appears to inhibit growth of Ewing sarcoma/PNET cell lines in vitro. Immunotherapy using allogeneic natural killer cells has activity in Ewing sarcoma/PNET cell lines and xenograft models. Finally, cyclin dependent kinase inhibitors such as flavopiridol may be clinically efficacious in relapsed Ewing sarcoma/PNET. Conclusion Preclinical evidence exists that targeted therapeutics may be efficacious in the ESFT. IGF-1R antagonists have demonstrated efficacy in phase I/II clinical trials, although predicting responses remains a challenge. The future treatment of Ewing sarcoma/PNET is likely to be improved by these scientific advances. PMID:22587874

Efficacy and Safety of Baclofen for Alcohol Dependence: A Randomized, Double-Blind, Placebo-Controlled Trial

PubMed Central

Garbutt, James C; Kampov-Polevoy, Alexei B; Gallop, Robert; Kalka-Juhl, Linda; Flannery, Barbara A.

2010-01-01

Background Recent clinical trials and case-reports indicate that baclofen, a GABAB agonist, may have efficacy for alcohol dependence. Baclofen has been shown to enhance abstinence, to reduce drinking quantity, to reduce craving, and to reduce anxiety in alcohol dependent individuals in two placebo-controlled trials in Italy. However, the clinical trial data with baclofen is limited. The purpose of the present study was to test the efficacy and tolerability of baclofen in alcohol dependence in the United States. Methods The study was a double-blind, placebo-controlled, randomized study comparing 30 mg per day of baclofen to placebo over 12 weeks of treatment and utilizing eight sessions of BRENDA, a low-intensity psychosocial intervention. 121 subjects were screened to yield 80 randomized subjects (44 male) with randomization balanced for gender. Percent heavy drinking days was the primary outcome measure with other drinking outcomes, anxiety levels, and craving as secondary outcomes. Tolerability was examined. Results 76% of subjects completed the study. No difference by drug condition was seen in % heavy drinking days where on-average rates were 25.5% (± 23.6%) for placebo and 25.9% (± 23.2%) for baclofen during treatment (t(73)=0.59, p=0.56). Similarly, no differences were seen by drug condition in % days abstinent, time to first drink, or time to relapse to heavy drinking. Baclofen was associated with a significant reduction in state anxiety (F(1,73)=5.39, p=0.02). Baclofen was well tolerated with only two individuals stopping baclofen because of adverse events. There were no serious adverse events. Conclusions Baclofen, a GABAB agonist, represents a possible new pharmacotherapeutic approach to alcohol dependence. Despite encouraging preclinical data and prior positive clinical trials with baclofen in Italy, the current trial did not find evidence that baclofen is superior to placebo in the treatment of alcohol dependence. Additional clinical trial work is necessary to establish whether baclofen does or does not have therapeutic efficacy in alcohol dependence and, if it does, what factors are predictive of response. PMID:20662805

[Molecular Biology for Surgical Treatment of Lung Cancer].

PubMed

Suda, Kenichi; Mitsudomi, Tetsuya

2017-01-01

Progress in lung cancer research achieved during the last 10 years was summarized. These include identification of novel driver mutations and application of targeted therapies, resistance mechanisms to targeted therapies, and immunotherapy with immune checkpoint inhibitors. Molecular biology also affects the field of surgical treatment. Several molecular markers have been reported to predict benign/ malignant or stable/growing tumors, although far from clinical application. In perioperative period, there is a possibility of atrial natriuretic peptide to prevent cancer metastasis. As adjuvant settings, although biomarker-based cytotoxic therapies failed to show clinical efficacy, several trials are ongoing employing molecular targeted agents (EGFR-TKI or ALK-TKI) or immune checkpoint inhibitors. In clinical practice, mutational information is sometimes used to distinguish 2nd primary tumors from pulmonary metastases of previous cancers. Surgery also has important role for oligo-progressive disease during molecular targeted therapies.

Physical Activity Enjoyment and Self-Efficacy As Predictors of Cancer Patients' Physical Activity Level

PubMed Central

Ungar, Nadine; Wiskemann, Joachim; Sieverding, Monika

2016-01-01

Background: Physical activity (PA) can support cancer patients during medical treatment by reducing side-effects and increasing quality of life. However, PA levels mostly decline after diagnosis. Which factors can explain if patients are able to remain or even increase their PA level? Self-efficacy is an important cognitive factor that has been linked to cancer patients' PA across many studies. In contrast, affective factors such as PA enjoyment have rarely been examined. We compare the influence of self-efficacy and PA enjoyment on cancer patients' PA levels after completion of an exercise or stress-management intervention. Methods: Outpatient cancer patients [N = 72; 54% female; M = 56 years, SD = 12.34; most with breast or colon cancer (34%, 15%)] were enrolled in the MOTIVACTION study, a 4-week intervention (1 h counseling followed by weekly phone calls), with pre-test (T1), post-test (T2), and a 10-week follow-up (T3). Participants were randomized to either an exercise intervention (emphasizing self-regulatory strategies for behavior change) or to a stress management intervention (coping and relaxation techniques). Sixty-seven patients remained in the study and completed the SQUASH assessment of PA, a measure of maintenance self-efficacy (7 items, Cronbach's α = 0.88) and PA enjoyment (2 items, Cronbach's α = 0.89). Regression analyses were calculated with PA level (at T2 and T3) as dependent variable and relative weight analyses were conducted. The study was registered at clinicalTrials.gov (unique identifier:NCT01576107; URL: https://clinicaltrials.gov/ct2/show/NCT01576107?term=motivaction&rank=1). Results: Baseline self-efficacy and change in PA enjoyment significantly predicted cancer patients' PA level at T2 adjusting for baseline PA and type of intervention. Relative weight (RW) analysis revealed that PA enjoyment (baseline and change together) explained 34.3% of the dependent variable, self-efficacy (baseline and change) explained 38.4%. At follow-up, self-efficacy was still a significant predictor of PA (RW = 74.6%), whereas PA enjoyment was no longer a relevant factor (RW = 5.2%). Conclusion: The affective factor PA enjoyment was equally important as self-efficacy for predicting cancer patient' PA level directly after completion of the intervention. Reasons for the reduced relevance at follow-up and a broader range of affective factors should be analyzed in future studies on cancer patients' PA level. PMID:27445882

A bioinformatics approach to identify patients with symptomatic peanut allergy using peptide microarray immunoassay

PubMed Central

Lin, Jing; Bruni, Francesca M.; Fu, Zhiyan; Maloney, Jennifer; Bardina, Ludmilla; Boner, Attilio L.; Gimenez, Gustavo; Sampson, Hugh A.

2013-01-01

Background Peanut allergy is relatively common, typically permanent, and often severe. Double-blind, placebo-controlled food challenge is considered the gold standard for the diagnosis of food allergy–related disorders. However, the complexity and potential of double-blind, placebo-controlled food challenge to cause life-threatening allergic reactions affects its clinical application. A laboratory test that could accurately diagnose symptomatic peanut allergy would greatly facilitate clinical practice. Objective We sought to develop an allergy diagnostic method that could correctly predict symptomatic peanut allergy by using peptide microarray immunoassays and bioinformatic methods. Methods Microarray immunoassays were performed by using the sera from 62 patients (31 with symptomatic peanut allergy and 31 who had outgrown their peanut allergy or were sensitized but were clinically tolerant to peanut). Specific IgE and IgG4 binding to 419 overlapping peptides (15 mers, 3 offset) covering the amino acid sequences of Ara h 1, Ara h 2, and Ara h 3 were measured by using a peptide microarray immunoassay. Bioinformatic methods were applied for data analysis. Results Individuals with peanut allergy showed significantly greater IgE binding and broader epitope diversity than did peanut-tolerant individuals. No significant difference in IgG4 binding was found between groups. By using machine learning methods, 4 peptide biomarkers were identified and prediction models that can predict the outcome of double-blind, placebo-controlled food challenges with high accuracy were developed by using a combination of the biomarkers. Conclusions In this study, we developed a novel diagnostic approach that can predict peanut allergy with high accuracy by combining the results of a peptide microarray immunoassay and bioinformatic methods. Further studies are needed to validate the efficacy of this assay in clinical practice. PMID:22444503

Neither Basic Life Support knowledge nor self-efficacy are predictive of skills among dental students.

PubMed

Mac Giolla Phadraig, C; Ho, J D; Guerin, S; Yeoh, Y L; Mohamed Medhat, M; Doody, K; Hwang, S; Hania, M; Boggs, S; Nolan, A; Nunn, J

2017-08-01

Basic life support (BLS) is considered a core competence for the graduating dentist. This study aimed to measure BLS knowledge, self-efficacy and skills of undergraduate dental students in Dublin. This study consisted of a cross-sectional survey measuring BLS knowledge and self-efficacy, accompanied by a directly observed BLS skills assessment in a subsample of respondents. Data were collected in January 2014. Bivariate correlations between descriptive and outcome variables (knowledge, self-efficacy and skills) were tested using Pearson's chi-square. We included knowledge and self-efficacy as predictor variables, along with other variables showing association, into a binary logistic regression model with BLS skills as the outcome measure. One hundred and thirty-five students participated. Almost all (n = 133, 98.5%) participants had BLS training within the last 2 years. One hundred and four (77%) felt that they were capable of providing effective BLS (self-efficacy), whilst only 46 (34.1%) scored >80% of knowledge items correct. Amongst the skills (n = 85) subsample, 38.8% (n = 33) were found to pass the BLS skills assessment. Controlling for gender, age and skills assessor, the regression model did not identify a predictive relationship between knowledge or self-efficacy and BLS skills. Neither knowledge nor self-efficacy was predictive of BLS skills. Dental students had low levels of knowledge and skills in BLS. Despite this, their confidence in their ability to perform BLS was high and did not predict actual competence. There is a need for additional hands-on training, focusing on self-efficacy and BLS skills, particularly the use of AED. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pharmacogenetics of warfarin: challenges and opportunities

PubMed Central

Ta Michael Lee, Ming; Klein, Teri E

2014-01-01

Since the introduction in the 1950s, warfarin has become the commonly used oral anticoagulant for the prevention of thromboembolism in patients with deep vein thrombosis, atrial fibrillation or prosthetic heart valve replacement. Warfarin is highly efficacious; however, achieving the desired anticoagulation is difficult because of its narrow therapeutic window and highly variable dose response among individuals. Bleeding is often associated with overdose of warfarin. There is overwhelming evidence that an individual's warfarin maintenance is associated with clinical factors and genetic variations, most notably polymorphisms in cytochrome P450 2C9 and vitamin K epoxide reductase subunit 1. Numerous dose-prediction algorithms incorporating both genetic and clinical factors have been developed and tested clinically. However, results from major clinical trials are not available yet. This review aims to provide an overview of the field of warfarin which includes information about the drug, genetics of warfarin dose requirements, dosing algorithms developed and the challenges for the clinical implementation of warfarin pharmacogenetics. PMID:23657428

Predictors of medication adherence in high risk youth of color living with HIV.

PubMed

Macdonell, Karen E; Naar-King, Sylvie; Murphy, Debra A; Parsons, Jeffrey T; Harper, Gary W

2010-07-01

To test predictors of medication adherence in high-risk racial or ethnic minority youth living with HIV (YLH) using a conceptual model of social cognitive predictors including a continuous measure of motivational readiness. Youth were participants in a multi-site clinical trial examining the efficacy of a motivational intervention. Racial-minority YLH (primarily African American) who were prescribed antiretroviral medication were included (N = 104). Data were collected using computer-assisted personal interviewing method via an Internet-based application and questionnaires. Using path analysis with bootstrapping, most youth reported suboptimal adherence, which predicted higher viral load. Higher motivational readiness predicted optimal adherence, and higher social support predicted readiness. Decisional balance was indirectly related to adherence. The model provided a plausible framework for understanding adherence in this population. Culturally competent interventions focused on readiness and social support may be helpful for improving adherence in YLH.

A novel 3D human glioblastoma cell culture system for modeling drug and radiation responses

PubMed Central

Stevenson, Katrina; Gilmour, Lesley; Hamilton, Graham; Chalmers, Anthony J

2017-01-01

Abstract Background. Glioblastoma (GBM) is the most common primary brain tumor, with dismal prognosis. The failure of drug–radiation combinations with promising preclinical data to translate into effective clinical treatments may relate to the use of simplified 2-dimensional in vitro GBM cultures. Methods. We developed a customized 3D GBM culture system based on a polystyrene scaffold (Alvetex) that recapitulates key histological features of GBM and compared it with conventional 2D cultures with respect to their response to radiation and to molecular targeted agents for which clinical data are available. Results. In 3 patient-derived GBM lines, no difference in radiation sensitivity was observed between 2D and 3D cultures, as measured by clonogenic survival. Three different molecular targeted agents, for which robust clinical data are available were evaluated in 2D and 3D conditions: (i) temozolomide, which improves overall survival and is standard of care for GBM, exhibited statistically significant effects on clonogenic survival in both patient-derived cell lines when evaluated in the 3D model compared with only one cell line in 2D cells; (ii) bevacizumab, which has been shown to increase progression-free survival when added to standard chemoradiation in phase III clinical trials, exhibited marked radiosensitizing activity in our 3D model but had no effect on 2D cells; and (iii) erlotinib, which had no efficacy in clinical trials, displayed no activity in our 3D GBM model, but radiosensitized 2D cells. Conclusions. Our 3D model reliably predicted clinical efficacy, strongly supporting its clinical relevance and potential value in preclinical evaluation of drug–radiation combinations for GBM. PMID:27576873

Attributions and self-efficacy for physical activity in multiple sclerosis.

PubMed

Nickel, D; Spink, K; Andersen, M; Knox, K

2014-01-01

Self-efficacy is an important predictor of health-related physical activity in multiple sclerosis (MS). While past experiences are believed to influence efficacy beliefs, the explanations individuals provide for these experiences also may be critical. Our objective was to test the hypothesis that perceived success or failure to accumulate 150 min of physical activity in the previous week would moderate the relationship between the attributional dimension of stability and self-efficacy to exercise in the future. Forty-two adults with MS participated in this cross-sectional descriptive study. Participants completed questions assessing physical activity, perceived outcome for meeting the recommended level of endurance activity, attributions for the outcome, and exercise self-efficacy. Results from hierarchical multiple regression revealed a significant main effect for perceived outcome predicting self-efficacy that was qualified by a significant interaction. The final model, which included perceived outcome, stability, and the interaction term, predicted 37% of the variance in exercise self-efficacy, F (3, 38) = 7.27, p = .001. Our findings suggest that the best prediction of self-efficacy in the MS population may include the interaction of specific attributional dimensions with success/failure at meeting the recommended physical activity dose. Attributions may be another target for interventions aimed at increasing the physical activity in MS.

Z-LASIK and Trans-PRK for correction of high-grade myopia: safety, efficacy, predictability and clinical outcomes.

PubMed

Gershoni, Assaf; Mimouni, Michael; Livny, Eitan; Bahar, Irit

2018-03-12

The aim of the study was to examine the outcomes of transepithelial photorefractive keratectomy (Trans-PRK) and Femtosecond Laser-assisted in situ keratomileusis (Z-LASIK) for the correction of high myopia. A retrospective cohort study design was used. The study group included 792 eyes with high-grade myopia (- 6.0 diopters or higher) or high-grade myopia with astigmatism that were treated with Z-LASIK or Trans-PRK in 2013 through 2014 in an optical outpatient clinic of a large private medical service. The Trans-PRK group comprised of 674 eyes with a spherical equivalent (SE) of - 7.87 ± 1.46 and the Z-LASIK group comprised of 118 eyes with a SE of - 7.19 ± 0.81 (P < 0.001). The mean postoperative SE in the Trans-PRK group was - 0.06 and - 0.02 in the Z-LASIK group (P = 0.545). Efficacy index values were 0.92 in the Trans-PRK group and 0.95 in the Z-LASIK group (P = 0.083), and corresponding safety index values were 0.95 and 0.97 (P = 0.056). An UCVA of 20/40 or better was achieved in 94.20% of eyes in the Trans-PRK group, and 98.31% in the Z-LASIK group (P = 0.063). The majority of eyes in both the Trans-PRK and Z-LASIK groups were within ± 0.5D of attempted correction: 59.35 and 64.71%, respectively (P = 0.271). Both Trans-PRK and Z-LASIK demonstrated excellent efficacy, safety and predictability profiles, with results comparable and in some cases superior to the current literature. Results of Z-LASIK were slightly better than those of Trans-PRK, though the preoperative SE of the latter was higher.

Next Generation Vaccine Biomarkers workshop October 30–31, 2014 – Ottawa, Canada

PubMed Central

Twine, Susan M; Fulton, Kelly M; Spika, John; Ouellette, Marc; Raven, Jennifer F; Conlan, J Wayne; Krishnan, Lakshmi; Barreto, Luis; Richards, James C

2015-01-01

Vaccine biomarkers are critical to many aspects of vaccine development and licensure, including bridging findings in pre-clinical studies to clinical studies, predicting potential adverse events, and predicting vaccine efficacy. Despite advances in our understanding of various biological pathways, and advances in systems analyses of the immune response, there remains much to learn about qualitative and quantitative aspects of the human host response to vaccination. To stimulate discussion and identify opportunities for collaborative ways to advance the field of vaccine biomarkers, A Next Generation Vaccine Biomarker workshop was held in Ottawa. The two day workshop, sponsored by the National Research Council Canada, Canadian Institutes of Health Research, Public Health Agency of Canada, Pfizer, and Medicago, brought together stakeholders from Canadian and international industry, government and academia. The workshop was grouped in themes, covering vaccine biomarker challenges in the pre-clinical and clinical spaces, veterinary vaccines, regulatory challenges, and development of biomarkers for adjuvants and cancer vaccines. The use of case studies allowed participants to identify the needs and gaps requiring innovation. The workshop concluded with a discussion on opportunities for vaccine biomarker discovery, the Canadian context, and approaches for moving forward. This article provides a synopsis of these discussions and identifies steps forward for advancing vaccine biomarker research in Canada. PMID:26383909

Helicobacter pylori and Gastric Mucosa-associated Lymphoid Tissue (MALT) Lymphoma: Updated Review of Clinical Outcomes and the Molecular Pathogenesis.

PubMed

Suzuki, Hidekazu; Saito, Yoshimasa; Hibi, Toshifumi

2009-06-01

In most H. pylori-positive patients, gastric low-grade mucosa-associated lymphoid tissue (MALT) lymphomas regress both endoscopically and histopathologically after H. pylori eradication, but no factors that can be predictive of the response to the eradication have been definitively identified, and there is little information on how to determine the optimal observation period before additional treatment can be started. Here, clinical studies dealing with the diagnosis and treatment of gastric MALT lymphomas and H. pylori published during the last 5 years were systematically reviewed, and studies identifying the molecular approaches involved in the pathogenesis were summarized. Most of the clinical studies indicate a favorable effect of H. pylori eradication on the clinical outcome of gastric MALT lymphomas. Some studies suggest the necessity of additional treatment in nonresponders to H. pylori eradication, while others suggest the adoption of a watch-and-wait strategy. The molecular characteristics of MALT lymphomas could play an important role in prognostic prediction and the selection of further therapeutic intervention after the eradication. This updated review of gastric MALT lymphomas illustrates the potential efficacy of H. pylori eradication in tumor remission, but further molecular characterization is necessary to establish the most suitable therapeutic strategy for patients who do not respond to eradication.

Clinical importance of pharmacogenetics in the treatment of hepatitis C virus infection.

PubMed

Kamal, Adina Maria; MitruŢ, Paul; Kamal, Kamal Constantin; Tica, Oana Sorina; Niculescu, Mihaela; Alexandru, Dragoş Ovidiu; Tica, Andrei Adrian

2016-01-01

Globally, over 4% of the world population is affected by hepatitis C virus (HCV) infection. The current standard of care for hepatitis C infection is combination therapy with pegylated interferon and ribavirin for 48 weeks, which yield a sustained virological response in only a little over half of the patients with genotype 1 HCV. We investigated the clinical importance of pharmacogenetics in treatment efficacy and prediction of hematotoxicity. A total of 148 patients infected with HCV were enrolled. All patients were treated for a period of 48 weeks or less with pegylated interferon and ribavirin. Four genotypes were investigated: inosine triphosphatase (ITPA) rs1127354, C20orf194 rs6051702, interferon lambda (IFNL)3 rs8099917, IFNL3÷4 rs12979860 in the population from southwestern Romania. Genetic variants for rs129798660 and rs6051702 proved once more to represent an indisputable clinical tool for predicting sustained virological response (SVR) (69.23%, chi-square p=0.007846, p<0.05 and 63.29%, chi-square p=0.007846, p<0.05, respectively). ITPA genetic variants protect against ribavirin-induced hemolytic anemia and C20orf194 also proved to be protective against thrombocytopenia. These clinical findings strengthen the belief that pharmacogenetics should play a constant role in treatment decisions for patients infected with hepatitis C virus.

Identifying a predictive model for response to atypical antipsychotic monotherapy treatment in south Indian schizophrenia patients.

PubMed

Gupta, Meenal; Moily, Nagaraj S; Kaur, Harpreet; Jajodia, Ajay; Jain, Sanjeev; Kukreti, Ritushree

2013-08-01

Atypical antipsychotic (AAP) drugs are the preferred choice of treatment for schizophrenia patients. Patients who do not show favorable response to AAP monotherapy are subjected to random prolonged therapeutic treatment with AAP multitherapy, typical antipsychotics or a combination of both. Therefore, prior identification of patients' response to drugs can be an important step in providing efficacious and safe therapeutic treatment. We thus attempted to elucidate a genetic signature which could predict patients' response to AAP monotherapy. Our logistic regression analyses indicated the probability that 76% patients carrying combination of four SNPs will not show favorable response to AAP therapy. The robustness of this prediction model was assessed using repeated 10-fold cross validation method, and the results across n-fold cross-validations (mean accuracy=71.91%; 95%CI=71.47-72.35) suggest high accuracy and reliability of the prediction model. Further validations of these results in large sample sets are likely to establish their clinical applicability. Copyright © 2013 Elsevier Inc. All rights reserved.

Robust tumor morphometry in multispectral fluorescence microscopy

NASA Astrophysics Data System (ADS)

Tabesh, Ali; Vengrenyuk, Yevgen; Teverovskiy, Mikhail; Khan, Faisal M.; Sapir, Marina; Powell, Douglas; Mesa-Tejada, Ricardo; Donovan, Michael J.; Fernandez, Gerardo

2009-02-01

Morphological and architectural characteristics of primary tissue compartments, such as epithelial nuclei (EN) and cytoplasm, provide important cues for cancer diagnosis, prognosis, and therapeutic response prediction. We propose two feature sets for the robust quantification of these characteristics in multiplex immunofluorescence (IF) microscopy images of prostate biopsy specimens. To enable feature extraction, EN and cytoplasm regions were first segmented from the IF images. Then, feature sets consisting of the characteristics of the minimum spanning tree (MST) connecting the EN and the fractal dimension (FD) of gland boundaries were obtained from the segmented compartments. We demonstrated the utility of the proposed features in prostate cancer recurrence prediction on a multi-institution cohort of 1027 patients. Univariate analysis revealed that both FD and one of the MST features were highly effective for predicting cancer recurrence (p <= 0.0001). In multivariate analysis, an MST feature was selected for a model incorporating clinical and image features. The model achieved a concordance index (CI) of 0.73 on the validation set, which was significantly higher than the CI of 0.69 for the standard multivariate model based solely on clinical features currently used in clinical practice (p < 0.0001). The contributions of this work are twofold. First, it is the first demonstration of the utility of the proposed features in morphometric analysis of IF images. Second, this is the largest scale study of the efficacy and robustness of the proposed features in prostate cancer prognosis.

Health literacy predicts change in physical activity self-efficacy among sedentary Latinas.

PubMed

Dominick, Gregory M; Dunsiger, Shira I; Pekmezi, Dorothy W; Marcus, Bess H

2013-06-01

Health literacy (HL) is associated with preventive health behaviors. Self-efficacy is a predictor of health behavior, including physical activity (PA); however, causal pathways between HL and self-efficacy for PA are unknown, especially among Latinas who are at risk for chronic disease. To explore this potential relationship, secondary analyses were conducted on data [Shortened Test of Functional Health Literacy in Adults (STOFHLA), PA self-efficacy, and socio-demographics] from a 6-month, randomized controlled trial of a print-based PA intervention (n = 89 Spanish-speaking Latinas). Linear regression models revealed associations between HL and baseline self-efficacy in addition to changes in self-efficacy at 6-months. After controlling for significant covariates, higher HL scores were associated with lower baseline PA self-efficacy. Regardless of treatment assignment, higher HL scores at baseline predicted greater changes in PA self-efficacy at 6-months. HL may contribute to Latinas' improved PA self-efficacy, though further research is warranted.

Comparison of performances of femtosecond laser and microkeratome for thin-flap laser in situ keratomileusis.

PubMed

Kasetsuwan, Ngamjit; Satitpitakul, Vannarut; Puangsricharern, Vilavun; Reinprayoon, Usanee; Pariyakanok, Lalida

2016-08-01

To compare the clinical outcomes of femtosecond laser (FS) and microkeratome (MK) for thin-flap in situ keratomileusis (LASIK). Data from patients with moderate to high myopia (spherical equivalent, >-4 diopters [D]) who underwent thin-flap LASIK using FS (199 eyes/110 patients) and MK (157 eyes/86 patients) were analyzed in this retrospective study. Preoperative and postoperative data were recorded from day 1 and months 1 and 3, postoperatively. Visual and refractive outcomes were compared for efficacy, safety, predictability, stability, and the efficacy and safety indices. Three months postoperatively, more eyes in the FS group had an uncorrected distance visual acuity (UCVA) of 20/40 or better compared to MK group (relative risk [RR] 1.01, 95% confidence interval [CI], 0.97-1.05, P = 0.58); significantly more eyes in FS group had an UCVA of 20/20 or better (RR, 1.26, 95%CI, 1.08-1.48, P = 0.003). Intraoperative bleeding occurred in 5% and 36.7%, respectively, of FS and MK groups. There were no significant differences in the refractive predictability within spherical equivalents of 0.5 D (FS, 72%; MK, 63%) and 1.0 D (FS, 90%; MK, 86%). Both groups showed good stability 3 months, postoperatively. The efficacy index in FS group was 113.4%; that in MK group was 102.5% at 3 months postoperatively (P < 0.05). The safety indices for FS and MK groups at 3 months postoperatively were 116.4% and 108.2%, respectively (P < 0.05). Both methods of thin-flap created LASIK were effective, safe, predicable, and stable. FS group had significant improvements in efficacy and safety, confirmed by the efficacy and safety indices, compared to MK group. Lasers Surg. Med. 48:596-601, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Diagnostic Efficacy of Cell Block Immunohistochemistry, Smear Cytology, and Liquid-Based Cytology in Endoscopic Ultrasound-Guided Fine-Needle Aspiration of Pancreatic Lesions: A Single-Institution Experience

PubMed Central

Qin, Shan-yu; Zhou, You; Li, Ping; Jiang, Hai-xing

2014-01-01

Background The diagnostic efficiency of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) cytology varies widely depending on the treatment method of the specimens. The present study aimed to evaluate the diagnostic efficacy of cell block (CB) immunohistochemistry, smear cytology (SC), and liquid-based cytology (LBC) in patients with pancreatic lesions without consulting an on-site cytopathologist. Methods This study prospectively enrolled 72 patients with pancreatic lesions. The EUS-FNA specimens were examined by SC, LBC, and CB immunohistochemistry. The diagnostic efficacy of the 3 methods was then compared. Patients’ final diagnosis was confirmed by surgical resection specimens, diagnostic imaging, and clinical follow-up. Results Our results included 60 malignant and 12 benign pancreatic lesions. The diagnostic sensitivity (90%), negative predictive value (66.7%), and accuracy (91.7%) of CB immunohistochemistry were significantly higher than those of SC (70.0%, 30.0%, and 75.0%, respectively) and LBC (73.3%, 31.6%, and 77.8%, respectively) (all P<0.05). The combination of CB and SC, or CB and LBC, did not significantly increase the efficacy compared to CB immunohistochemistry alone. Conclusion Our findings suggest that in the absence of an on-site cytopathologist, CB immunohistochemistry on EUS-FNA specimens offers a higher diagnostic efficacy in patients with pancreatic lesions than does SC and LBC. PMID:25259861

Social Cognitive Theory Predictors of Exercise Behavior in Endometrial Cancer Survivors

PubMed Central

Basen-Engquist, Karen; Carmack, Cindy L.; Li, Yisheng; Brown, Jubilee; Jhingran, Anuja; Hughes, Daniel C.; Perkins, Heidi Y.; Scruggs, Stacie; Harrison, Carol; Baum, George; Bodurka, Diane C.; Waters, Andrew

2014-01-01

Objective This study evaluated whether social cognitive theory (SCT) variables, as measured by questionnaire and ecological momentary assessment (EMA), predicted exercise in endometrial cancer survivors. Methods One hundred post-treatment endometrial cancer survivors received a 6-month home-based exercise intervention. EMAs were conducted using hand-held computers for 10- to 12-day periods every 2 months. Participants rated morning self-efficacy and positive and negative outcome expectations using the computer, recorded exercise information in real time and at night, and wore accelerometers. At the midpoint of each assessment period participants completed SCT questionnaires. Using linear mixed-effects models, we tested whether morning SCT variables predicted minutes of exercise that day (Question 1) and whether exercise minutes at time point Tj could be predicted by questionnaire measures of SCT variables from time point Tj-1 (Question 2). Results Morning self-efficacy significantly predicted that day’s exercise minutes (p<.0001). Morning positive outcome expectations was also associated with exercise minutes (p=0.0003), but the relationship was attenuated when self-efficacy was included in the model (p=0.4032). Morning negative outcome expectations was not associated with exercise minutes. Of the questionnaire measures of SCT variables, only exercise self-efficacy predicted exercise at the next time point (p=0.003). Conclusions The consistency of the relationship between self-efficacy and exercise minutes over short (same day) and longer (Tj to Tj-1) time periods provides support for a causal relationship. The strength of the relationship between morning self-efficacy and exercise minutes suggest that real-time interventions that target daily variation in self-efficacy may benefit endometrial cancer survivors’ exercise adherence. PMID:23437853

Menstrual Migraine: Therapeutic Approaches

PubMed Central

2009-01-01

The development of diagnostic criteria has enabled greater recognition of menstrual migraine as a highly prevalent and disabling condition meriting specific treatment. Although few therapeutic trials have yet been undertaken in accordance with the criteria, the results of those published to date confirm the efficacy of acute migraine drugs for symptomatic treatment. If this approach is insufficient, the predictability of attacks provides the opportunity for perimenstrual prophylaxis. Continuous contraceptive strategies provide an additional option for management, although clinical trial data are limited. Future approaches to treatment could explore the genomic and nongenomic actions of sex steroids. PMID:21180623

Effects of a simulated emergency airway management education program on the self-efficacy and clinical performance of intensive care unit nurses.

PubMed

Han, Myong-Ja; Lee, Ju-Ry; Shin, Yu-Jung; Son, Jeong-Suk; Choi, Eun-Joo; Oh, Yun-Hee; Lee, Soon-Haeng; Choi, Hye-Ran

2017-12-21

To examine the effects of a simulated emergency airway management education program on the self-efficacy and clinical performance among nurses in intensive care units. A one-group, pre- and post-test design was used. Thirty-five nurses who were working in adult intensive care units participated in this study. The simulation education program included lectures, skill demonstration, skill training, team-based practice, and debriefing. Self-efficacy and clinical performance questionnaires were completed before the program and 1 week after its completion. The data were analyzed by using descriptive statistics and the paired t-test to compare the mean differences between the pre-test and post-test. The scores before and after education were compared. After education, there was a significant improvement in the nurses' self-efficacy and clinical performance in emergency airway management situations. Simulation education effectively improved the self-efficacy and clinical performance of the nurses who were working in intensive care units. Based on the program for clinical nurses within a hospital, it will provide information that might advance clinical nursing education. © 2017 Japan Academy of Nursing Science.

Targeted adenoviral vectors

NASA Astrophysics Data System (ADS)

Douglas, Joanne T.

The practical implementation of gene therapy in the clinical setting mandates gene delivery vehicles, or vectors, capable of efficient gene delivery selectively to the target disease cells. The utility of adenoviral vectors for gene therapy is restricted by their dependence on the native adenoviral primary cellular receptor for cell entry. Therefore, a number of strategies have been developed to allow CAR-independent infection of specific cell types, including the use of bispecific conjugates and genetic modifications to the adenoviral capsid proteins, in particular the fibre protein. These targeted adenoviral vectors have demonstrated efficient gene transfer in vitro , correlating with a therapeutic benefit in preclinical animal models. Such vectors are predicted to possess enhanced efficacy in human clinical studies, although anatomical barriers to their use must be circumvented.

A low-cost, high-quality new drug discovery process using patient-derived induced pluripotent stem cells.

PubMed

Giri, Shibashish; Bader, Augustinus

2015-01-01

Knockout, knock-in and conditional mutant gene-targeted mice are routinely used for disease modeling in the drug discovery process, but the human response is often difficult to predict from these models. It is believed that patient-derived induced pluripotent stem cells (iPSCs) could replace millions of animals currently sacrificed in preclinical testing and provide a route to new safer pharmaceutical products. In this review, we discuss the use of IPSCs in the drug discovery process. We highlight how they can be used to assess the toxicity and clinical efficacy of drug candidates before the latter are moved into costly and lengthy preclinical and clinical trials. Copyright © 2014 Elsevier Ltd. All rights reserved.

The predictive value of quantitative DCE metrics for immediate therapeutic response of high-intensity focused ultrasound ablation (HIFU) of symptomatic uterine fibroids.

PubMed

Wei, Chao; Fang, Xin; Wang, Chuan-Bin; Chen, Yu; Xu, Xiao; Dong, Jiang-Ning

2017-12-04

The aim of this study was to investigate the value of quantitative DCE-MRI parameters for predicting the immediate non-perfused volume ratio (NPVR) of HIFU therapy in the treatment of symptomatic uterine fibroids. A total of 78 symptomatic uterine fibroids in 65 female patients were treated with US-HIFU therapy. All patients underwent conventional MRI and DCE-MRI scans 1 day before and 3 days after HIFU treatment. Permeability parameters K trans , K ep , V e , and V p and T1 perfusion parameters BF and BV of pretreatment were measured as a baseline, while NPVR was used to assess immediate ablation efficiency. Data were assigned to NPVR ≧ 70% and NPVR < 70% groups. Then, the predictive performances of different parameters for ablation efficacy were studied to seek the optimal cut-off value, and the length of time to calculate the variable parameters in each case was recorded. (1) It was observed that the pretreatment K trans , K ep , V e , and BF values of the NPVR ≧ 70% group were significantly lower compared to the NPVR < 70% group (p < 0.05). (2) The immediate NPVR was negatively correlated with the K trans , BF, and BV values before HIFU treatment (r = - 0.561, - 0.712, and - 0.528, respectively, p < 0.05 for all). (3) The AUCs of pretreatment K trans , BF, BV values, and K trans combined with BF used to predict the immediate NPVR were 0.810, 0.909, 0.795, and 0.922, respectively (p < 0.05 for all). (4) The mean time to calculate the variable parameters in each case was 7.5 min. Higher K trans , BF, and BV values at baseline DCE-MRI suggested a poor ablation efficacy of HIFU therapy for symptomatic uterine fibroids, while the pretreatment DCE-MRI parameters could be useful biomarkers for predicting the ablation efficacy in select cases. The software used to calculate DCE-MRI parameters was simpler, quicker, and easier to incorporate into clinical practice.

Efficacy of duplex ultrasound surveillance after infrainguinal vein bypass may be enhanced by identification of characteristics predictive of graft stenosis development.

PubMed

Tinder, Chelsey N; Chavanpun, Joe P; Bandyk, Dennis F; Armstrong, Paul A; Back, Martin R; Johnson, Brad L; Shames, Murray L

2008-09-01

Controversy regarding the efficacy of duplex ultrasound surveillance after infrainguinal vein bypass led to an analysis of patient and bypass graft characteristics predictive for development of graft stenosis and a decision of secondary intervention. Retrospective analysis of a contemporary, consecutive series of 353 clinically successful infrainguinal vein bypasses performed in 329 patients for critical (n = 284; 80%) or noncritical (n = 69; 20%) limb ischemia enrolled in a surveillance program to identify and repair duplex-detected graft stenosis. Variables correlated with graft stenosis and bypass repair included: procedure indication, conduit type (saphenous vs nonsaphenous vein; reversed vs nonreversed orientation), prior bypass graft failure, postoperative ankle-brachial index (ABI) < 0.85, and interpretation of the first duplex surveillance study as "normal" or "abnormal" based on peak systolic velocity (PSV) and velocity ratio (Vr) criteria. Overall, 126 (36%) of the 353 infrainguinal bypasses had 174 secondary interventions (endovascular, 100; surgery, 74) based on duplex surveillance; resulting in 3-year Kaplan-Meier primary (46%), assisted-primary (80%), and secondary (81%) patency rates. Characteristics predictive of duplex-detected stenosis leading to intervention (PSV: 443 +/- 94 cm/s; Vr: 8.6 +/- 9) were: "abnormal" initial duplex testing indicating moderate (PSV: 180-300 cm/s, Vr: 2-3.5) stenosis (P < .0001), non-single segment saphenous vein conduit (P < .01), warfarin drug therapy (P < .01), and redo bypass grafting (P < .001). Procedure indication, postoperative ABI level, statin drug therapy, and vein conduit orientation were not predictive of graft revision. The natural history of 141 (40%) bypasses with an abnormal first duplex scan differed from "normal" grafts by more frequent (51% vs 24%, P < .001) and earlier (7 months vs 11 months) graft revision for severe stenosis and a lower 3-year assisted primary patency (68% vs 87%; P < .001). In 52 (15%) limbs, the bypass graft failed and 20 (6%) limbs required amputation. The efficacy of duplex surveillance after infrainguinal vein bypass may be enhanced by modifying testing protocols, eg, rigorous surveillance for "higher risk" bypasses, based on the initial duplex scan results and other characteristics (warfarin therapy, non- single segment saphenous vein conduit, redo bypass) predictive for stenosis development.

Clinical magnification and residual refraction after implantation of a double intraocular lens system in patients with macular degeneration.

PubMed

Amselem, Luis; Diaz-Llopis, Manuel; Felipe, Adelina; Artigas, Jose M; Navea, Amparo; García-Delpech, Salvador

2008-09-01

To evaluate the efficacy of a standard double intraocular lens (IOL) system (IOL-Vip) in patients with low vision and central scotoma due to macular degeneration and assess the predictability of the residual refraction and magnification. Ophthalmology Department, Hospital General Universitario, Valencia, Spain. This interventional prospective noncomparative case series comprised 13 consecutive surgical procedures in 10 patients with central scotoma. Follow-up was 12 months. Evaluation included the difference between preoperative and postoperative best corrected visual acuity (BCVA), refraction, position of the IOLs, endothelial cell density, and occurrence of postoperative complications. Residual refraction and eye magnification were calculated using a theory developed in a previous study, and the values were compared with the clinical results. The mean BCVA was 1.37 logMAR preoperatively and 0.68 logMAR 1 year postoperatively. The mean best corrected clinical gain was 44%. There was no statistically significant difference between the clinically evaluated and theoretically calculated residual refractions (P = .17). No intraoperative or postoperative complications occurred. Implantation of the double IOL system improved BCVA in patients with low vision due to advanced maculopathy. The results were best in myopic patients (long eyes); patients with hyperopia (short eyes) had high residual refraction. The postoperative clinical gain and residual refraction were predictable, showing the feasibility of implanting a customized double IOL.

Audit method suited for DSS in clinical environment.

PubMed

Vicente, Javier

2015-01-01

This chapter presents a novel online method to audit predictive models using a Bayesian perspective. The auditing model has been specifically designed for Decision Support Systems (DSSs) suited for clinical or research environments. Taking as starting point the working diagnosis supplied by the clinician, this method compares and evaluates the predictive skills of those models able to answer to that diagnosis. The approach consists in calculating the posterior odds of a model through the composition of a prior odds, a static odds, and a dynamic odds. To do so, this method estimates the posterior odds from the cases that the comparing models had in common during the design stage and from the cases already viewed by the DSS after deployment in the clinical site. In addition, if an ontology of the classes is available, this method can audit models answering related questions, which offers a reinforcement to the decisions the user already took and gives orientation on further diagnostic steps.The main technical novelty of this approach lies in the design of an audit model adapted to suit the decision workflow of a clinical environment. The audit model allows deciding what is the classifier that best suits each particular case under evaluation and allows the detection of possible misbehaviours due to population differences or data shifts in the clinical site. We show the efficacy of our method for the problem of brain tumor diagnosis with Magnetic Resonance Spectroscopy (MRS).

Treating anemia in heart failure patients: a review of erythropoiesis-stimulating agents.

PubMed

Geisler, Benjamin P

2010-08-01

Prevalence of chronic heart failure (CHF) is increasing, and despite improvements in the past decade the prognosis in terms of mortality and health-related quality of life remains poor. Anemia is often found concomitantly in CHF patients. Erythropoiesis-stimulating agents (ESAs) are a new treatment option for these anemic CHF patients, promising to decrease mortality and hospitalizations, and increase health-related quality of life. CHF epidemiology is briefly discussed. Currently available clinical efficacy and safety data are critically appraised. Health care utilization by CHF patients, particularly hospitalizations, are reviewed in order predict cost-effectiveness of ESAs. The efficacy for the most pertinent endpoints has not been proven by a pivotal trial or a meta-analysis free of bias, and there might be increased cardiovascular events and cancer incidence rates above a currently unknown target value or with multiple doses. However, subgroups should be identified in which ESAs might prove to be more efficacious and as safe as usual care and either cost-saving or cost-effective. Nevertheless, depending on the subgroup, the budget effect for payors might be dramatic due to the large number of CHF patients.

Auditory rhythmic cueing in movement rehabilitation: findings and possible mechanisms

PubMed Central

Schaefer, Rebecca S.

2014-01-01

Moving to music is intuitive and spontaneous, and music is widely used to support movement, most commonly during exercise. Auditory cues are increasingly also used in the rehabilitation of disordered movement, by aligning actions to sounds such as a metronome or music. Here, the effect of rhythmic auditory cueing on movement is discussed and representative findings of cued movement rehabilitation are considered for several movement disorders, specifically post-stroke motor impairment, Parkinson's disease and Huntington's disease. There are multiple explanations for the efficacy of cued movement practice. Potentially relevant, non-mutually exclusive mechanisms include the acceleration of learning; qualitatively different motor learning owing to an auditory context; effects of increased temporal skills through rhythmic practices and motivational aspects of musical rhythm. Further considerations of rehabilitation paradigm efficacy focus on specific movement disorders, intervention methods and complexity of the auditory cues. Although clinical interventions using rhythmic auditory cueing do not show consistently positive results, it is argued that internal mechanisms of temporal prediction and tracking are crucial, and further research may inform rehabilitation practice to increase intervention efficacy. PMID:25385780

Can we "predict" long-term outcome for ambulatory transcutaneous electrical nerve stimulation in patients with chronic pain?

PubMed

Köke, Albère J; Smeets, Rob J E M; Perez, Roberto S; Kessels, Alphons; Winkens, Bjorn; van Kleef, Maarten; Patijn, Jacob

2015-03-01

Evidence for effectiveness of transcutaneous electrical nerve stimulation (TENS) is still inconclusive. As heterogeneity of chronic pain patients might be an important factor for this lack of efficacy, identifying factors for a successful long-term outcome is of great importance. A prospective study was performed to identify variables with potential predictive value for 2 outcome measures on long term (6 months); (1) continuation of TENS, and (2) a minimally clinical important pain reduction of ≥ 33%. At baseline, a set of risk factors including pain-related variables, psychological factors, and disability was measured. In a multiple logistic regression analysis, higher patient's expectations, neuropathic pain, no severe pain (< 80 mm visual analogue scale [VAS]) were independently related to long-term continuation of TENS. For the outcome "minimally clinical important pain reduction," the multiple logistic regression analysis indicated that no multisited pain (> 2 pain locations) and intermittent pain were positively and independently associated with a minimally clinical important pain reduction of ≥ 33%. The results showed that factors associated with a successful outcome in the long term are dependent on definition of successful outcome. © 2014 World Institute of Pain.

Diffusion MRI in early cancer therapeutic response assessment

PubMed Central

Galbán, C. J.; Hoff, B. A.; Chenevert, T. L.; Ross, B. D.

2016-01-01

Imaging biomarkers for the predictive assessment of treatment response in patients with cancer earlier than standard tumor volumetric metrics would provide new opportunities to individualize therapy. Diffusion-weighted MRI (DW-MRI), highly sensitive to microenvironmental alterations at the cellular level, has been evaluated extensively as a technique for the generation of quantitative and early imaging biomarkers of therapeutic response and clinical outcome. First demonstrated in a rodent tumor model, subsequent studies have shown that DW-MRI can be applied to many different solid tumors for the detection of changes in cellularity as measured indirectly by an increase in the apparent diffusion coefficient (ADC) of water molecules within the lesion. The introduction of quantitative DW-MRI into the treatment management of patients with cancer may aid physicians to individualize therapy, thereby minimizing unnecessary systemic toxicity associated with ineffective therapies, saving valuable time, reducing patient care costs and ultimately improving clinical outcome. This review covers the theoretical basis behind the application of DW-MRI to monitor therapeutic response in cancer, the analytical techniques used and the results obtained from various clinical studies that have demonstrated the efficacy of DW-MRI for the prediction of cancer treatment response. PMID:26773848

Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms.

PubMed

Warren, R B; Smith, R L; Campalani, E; Eyre, S; Smith, C H; Barker, J N W N; Worthington, J; Griffiths, C E M

2009-02-01

The use of methotrexate is limited by interindividual variability in response. Previous studies in patients with either rheumatoid arthritis or psoriasis suggest that genetic variation across the methotrexate metabolic pathway might enable prediction of both efficacy and toxicity of the drug. To assess if single nucleotide polymorphisms (SNPs) across four genes that are relevant to methotrexate metabolism [folypolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC)] are related to treatment outcomes in patients with psoriasis. DNA was collected from 374 patients with psoriasis who had been treated with methotrexate. Data were available on individual outcomes to therapy, namely efficacy and toxicity. Haplotype-tagging SNPs (r(2) > 0.8) for the four genes with a minor allele frequency of > 5% were selected from the HAPMAP phase II data. Genotyping was undertaken using the MassARRAY spectrometric method (Sequenom). There were no significant associations detected between clinical outcomes in patients with psoriasis treated with methotrexate and SNPs in the four genes investigated. Genetic variation in four key genes relevant to the intracellular metabolism of methotrexate does not appear to predict response to methotrexate therapy in patients with psoriasis.

Identification of alsterpaullone as a novel small molecule inhibitor to target group 3 medulloblastoma.

PubMed

Faria, Claudia C; Agnihotri, Sameer; Mack, Stephen C; Golbourn, Brian J; Diaz, Roberto J; Olsen, Samantha; Bryant, Melissa; Bebenek, Matthew; Wang, Xin; Bertrand, Kelsey C; Kushida, Michelle; Head, Renee; Clark, Ian; Dirks, Peter; Smith, Christian A; Taylor, Michael D; Rutka, James T

2015-08-28

Advances in the molecular biology of medulloblastoma revealed four genetically and clinically distinct subgroups. Group 3 medulloblastomas are characterized by frequent amplifications of the oncogene MYC, a high incidence of metastasis, and poor prognosis despite aggressive therapy. We investigated several potential small molecule inhibitors to target Group 3 medulloblastomas based on gene expression data using an in silico drug screen. The Connectivity Map (C-MAP) analysis identified piperlongumine as the top candidate drug for non-WNT medulloblastomas and the cyclin-dependent kinase (CDK) inhibitor alsterpaullone as the compound predicted to have specific antitumor activity against Group 3 medulloblastomas. To validate our findings we used these inhibitors against established Group 3 medulloblastoma cell lines. The C-MAP predicted drugs reduced cell proliferation in vitro and increased survival in Group 3 medulloblastoma xenografts. Alsterpaullone had the highest efficacy in Group 3 medulloblastoma cells. Genomic profiling of Group 3 medulloblastoma cells treated with alsterpaullone confirmed inhibition of cell cycle-related genes, and down-regulation of MYC. Our results demonstrate the preclinical efficacy of using a targeted therapy approach for Group 3 medulloblastomas. Specifically, we provide rationale for advancing alsterpaullone as a targeted therapy in Group 3 medulloblastoma.

Efficacy and safety of selective glucocorticoid receptor modulators in comparison to glucocorticoids in arthritis, a systematic review.

PubMed

Safy, M; de Hair, M J H; Jacobs, J W G; Buttgereit, F; Kraan, M C; van Laar, J M

2017-01-01

Long-term treatment with glucocorticoids (GCs) plays an important role in the management of arthritis patients, although the efficacy/safety balance is unfavorable. Alternatives with less (severe) adverse effects but with good efficacy are needed. Selective GC receptor modulators (SGRMs) are designed to engage the GC receptor with dissociative characteristics: transactivation of genes, which is mainly responsible for unwanted effects, is less strong while trans-repression of genes, reducing inflammation, is maintained. It is expected that SGRMs thus have a better efficacy/safety balance than GCs. A systematic review providing an overview of the evidence in arthritis is lacking. To systematically review the current literature on efficacy and safety of oral SGRMs in comparison to GCs in arthritis. A search was performed in Medline, Embase and the Cochrane Library, from inception dates of databases until May 2017. Experimental studies involving animal arthritis models or human material of arthritis patients, as well as clinical studies in arthritis patients were included, provided they reported original data. All types of arthritis were included. Data was extracted on the SGRM studied and on the GC used as reference standard; the design or setting of the study was extracted as well as the efficacy and safety results. A total of 207 articles was retrieved of which 17 articles were eligible for our analysis. Two studies concerned randomized controlled trials (RCT), five studies were pre-clinical studies using human material, and 10 studies involved pre-clinical animal models (acute and/or chronic arthritis induced in mice or rats). PF-04171327, the only compound investigated in a clinical trial setting, had a better efficacy/safety balance compared to GCs: better clinical anti-inflammatory efficacy and similar safety. Studies assessing both efficacy and safety of SGRMs are scarce. There is limited evidence for dissociation of anti-inflammatory and metabolic effects of the SGRMs studied. Development of many SGRMs is haltered in a preclinical phase. One SGRM showed a better clinical efficacy/safety balance.

Improving glycaemic control self-efficacy and glycaemic control behaviour in Chinese patients with type 2 diabetes mellitus: randomised controlled trial.

PubMed

Shi, Qifang; Ostwald, Sharon K; Wang, Shaopeng

2010-02-01

To examine the effect of a hospital-based clinic intervention on glycaemic control self-efficacy and glycaemic control behaviour of Chinese patients with type 2 diabetes mellitus (DM). Self-efficacy expectations are related to self-management of diabetes and, in conjunction with environmental support, are better predictors of behaviour than are knowledge and skills. Enhancing self-efficacy in patients with DM has been shown to have a positive effect on behavioural change and positively influence long-term glycaemic control. A randomised controlled trial study consisting of two-group pretest-post-test. One hundred and fifty-seven patients with type 2 DM were randomly divided into two groups: (1) the experimental group (77 patients) receiving one-month hospital-based clinic intervention and (2) the control group (80 patients) receiving usual care. Data collection instruments used in this study were Diabetes Management Self-Efficacy Scale and Summary of Diabetes Self-Care Activities Measure. Outcomes were determined by changes in glycaemic control self-efficacy and glycaemic control behaviour of patients with type 2 DM. The findings revealed that the experimental group showed statistically significant improvement in glycaemic control self-efficacy and glycaemic control behaviour immediately and four months after the intervention (F = 26.888, df = 1, 155, p < 0.05 and F = 18.619, df = 1, 155, p < 0.05, respectively). One-month hospital-based clinic intervention could be useful in improving glycaemic control self-efficacy and glycaemic control behaviour. Nurses can learn and use the sources of self-efficacy to enhance patients' self-efficacy on their glycaemic control in clinical care. The health education is most important in nursing care and should be considered while organising the hospital-based clinic intervention.

Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study.

PubMed

Bogenschutz, Michael P; Forcehimes, Alyssa A; Pommy, Jessica A; Wilcox, Claire E; Barbosa, P C R; Strassman, Rick J

2015-03-01

Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms. NCT02061293. © The Author(s) 2015.

Manage Your Life Online (MYLO): a pilot trial of a conversational computer-based intervention for problem solving in a student sample.

PubMed

Gaffney, Hannah; Mansell, Warren; Edwards, Rachel; Wright, Jason

2014-11-01

Computerized self-help that has an interactive, conversational format holds several advantages, such as flexibility across presenting problems and ease of use. We designed a new program called MYLO that utilizes the principles of METHOD of Levels (MOL) therapy--based upon Perceptual Control Theory (PCT). We tested the efficacy of MYLO, tested whether the psychological change mechanisms described by PCT mediated its efficacy, and evaluated effects of client expectancy. Forty-eight student participants were randomly assigned to MYLO or a comparison program ELIZA. Participants discussed a problem they were currently experiencing with their assigned program and completed measures of distress, resolution and expectancy preintervention, postintervention and at 2-week follow-up. MYLO and ELIZA were associated with reductions in distress, depression, anxiety and stress. MYLO was considered more helpful and led to greater problem resolution. The psychological change processes predicted higher ratings of MYLO's helpfulness and reductions in distress. Positive expectancies towards computer-based problem solving correlated with MYLO's perceived helpfulness and greater problem resolution, and this was partly mediated by the psychological change processes identified. The findings provide provisional support for the acceptability of the MYLO program in a non-clinical sample although its efficacy as an innovative computer-based aid to problem solving remains unclear. Nevertheless, the findings provide tentative early support for the mechanisms of psychological change identified within PCT and highlight the importance of client expectations on predicting engagement in computer-based self-help.

Gender differences in cannabis use disorder treatment: Change readiness and taking steps predict worse cannabis outcomes for women.

PubMed

Sherman, Brian J; Baker, Nathaniel L; McRae-Clark, Aimee L

2016-09-01

Gender differences in cannabis use and cannabis use disorder have been established. Regarding treatment, some evidence suggests that women are less responsive, though the mechanisms are not well understood. Motivation to change and self-efficacy are associated with better outcomes overall, and may help explain gender differences in cannabis use outcomes. A secondary data analysis of a double-blind placebo controlled trial of buspirone treatment for cannabis dependence (N=175) was conducted. Self-report assessments of motivation to change, self-efficacy, and other clinical correlates were completed at baseline, and cannabis use was measured throughout the study. There was a significant interaction between gender and taking steps on abstinence. Counter to hypothesis, higher taking steps reduced likelihood of achieving abstinence among women; there was no association among men. Subsequently, taking steps was associated with self-efficacy and quantity of use among men, and cannabis related problems among women. There was a significant interaction between gender and readiness to change on creatinine adjusted cannabinoid levels. Change readiness was positively associated with cannabinoid levels among women, but not men. Motivation to change and initiation of change behavior predict worse cannabis outcomes in women. Men and women differ in what motivates change behavior. Social desirability, neurobiology, and treatment type may impact these effects. Gender differences in cannabis use and treatment responsiveness must be considered in future studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

PubMed Central

Ye, Zheng; Rae, Charlotte L.; Nombela, Cristina; Ham, Timothy; Rittman, Timothy; Jones, Peter Simon; Rodríguez, Patricia Vázquez; Coyle‐Gilchrist, Ian; Regenthal, Ralf; Altena, Ellemarije; Housden, Charlotte R.; Maxwell, Helen; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

2016-01-01

Abstract Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinson's disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double‐blind randomized three‐way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinson's disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion‐weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinson's disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave‐one‐out cross‐validation (LOOCV) to predict patients’ responses in terms of improved stopping efficiency. We identified two optimal models: (1) a “clinical” model that predicted the response of an individual patient with 77–79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion‐weighted imaging scan; and (2) a “mechanistic” model that explained the behavioral response with 85% accuracy for each drug, using drug‐induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinson's disease, the individual patient's response to each drug can be predicted using a pattern of clinical and neuroimaging features. Hum Brain Mapp 37:1026–1037, 2016. © 2016 Wiley Periodicals, Inc. PMID:26757216

Clinical evidence supporting pharmacogenomic biomarker testing provided in US Food and Drug Administration drug labels.

PubMed

Wang, Bo; Canestaro, William J; Choudhry, Niteesh K

2014-12-01

Genetic biomarkers that predict a drug's efficacy or likelihood of toxicity are assuming increasingly important roles in the personalization of pharmacotherapy, but concern exists that evidence that links use of some biomarkers to clinical benefit is insufficient. Nevertheless, information about the use of biomarkers appears in the labels of many prescription drugs, which may add confusion to the clinical decision-making process. To evaluate the evidence that supports pharmacogenomic biomarker testing in drug labels and how frequently testing is recommended. Publicly available US Food and Drug Administration databases. We identified drug labels that described the use of a biomarker and evaluated whether the label contained or referenced convincing evidence of its clinical validity (ie, the ability to predict phenotype) and clinical utility (ie, the ability to improve clinical outcomes) using guidelines published by the Evaluation of Genomic Applications in Practice and Prevention Working Group. We graded the completeness of the citation of supporting studies and determined whether the label recommended incorporation of biomarker test results in therapeutic decision making. Of the 119 drug-biomarker combinations, only 43 (36.1%) had labels that provided convincing clinical validity evidence, whereas 18 (15.1%) provided convincing evidence of clinical utility. Sixty-one labels (51.3%) made recommendations about how clinical decisions should be based on the results of a biomarker test; 36 (30.3%) of these contained convincing clinical utility data. A full description of supporting studies was included in 13 labels (10.9%). Fewer than one-sixth of drug labels contained or referenced convincing evidence of clinical utility of biomarker testing, whereas more than half made recommendations based on biomarker test results. It may be premature to include biomarker testing recommendations in drug labels when convincing data that link testing to patient outcomes do not exist.

The relationships of information efficacy and media literacy skills to knowledge and self-efficacy for health-related decision making.

PubMed

Austin, Erica Weintraub; Pinkleton, Bruce E; Austin, Bruce W; Van de Vord, Rebecca

2012-01-01

To compare the extent to which information efficacy (confidence for acquiring useful information) and media literacy skills predict knowledge and self-efficacy for preventing or treating the health threat of influenza. A random-sample survey of 1,379 residential students enrolled at a northwestern public university was conducted in fall 2009. Students accessed an Internet survey through a link provided in an e-mail. Students who self-diagnosed correctly demonstrated higher levels of media literacy skills than those who self-diagnosed incorrectly. Among those who self-diagnosed incorrectly, the only predictor of knowledge was accessibility of information sources; low accessibility was associated with reduced knowledge. Information efficacy predicted self-efficacy for both groups. The results illustrate the limitations of information efficacy in the absence of media literacy skills. To decrease health risks, college health practitioners should promote media literacy while also ensuring easy access to high-quality information.

[Hypnosis for anxiety and phobic disorders: A review of clinical studies].

PubMed

Pelissolo, Antoine

2016-03-01

Hypnosis is classically presented as a useful psychotherapy for various psychiatric conditions, especially in the field of stress and anxiety. However, its place in therapeutic of chronic anxiety disorders remains unclear and questioned. Thus, the goal of this systematic review was to analyse the papers reporting clinical data on the efficacy of hypnosis in anxiety disorders. A literature search was conducted on Pubmed to retrieve all original papers, published between 1980 and 2015, reporting clinical information on the efficacy of hypnosis in six categories of anxiety disorders. Each paper has been assessed from a methodological point of view, and the results have been analysed. Only three controlled studies have been identified, one in panic disorder and two in post-traumatic stress disorder (PTSD). The other papers related open-design studies (4 articles), or single case reports (20 articles). The controlled study conducted in panic disorder suggested that the combination of hypnosis with cognitive-behavior therapy was not an effective strategy, and this negative result was also obtained in one of the studies conducted in PTSD. The third study, including 48 Indonesian children with PTSD, showed a significant improvement with a specific hypnosis technique adapted to the local culture. Other papers related also positive results but in non-controlled studies or in case reports, their conclusions cannot be generalized. To date, evidence is negative or insufficient to support the efficacy of hypnosis in chronic anxiety disorders, in any categories whatsoever - including phobia or PTSD. Specific further studies are needed to identify some potential profiles predictive of response to hypnosis in these conditions. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Contemporary clinical trials in ventricular tachycardia and fibrillation: implications of ESVEM, CASCADE, and CASH for clinical management.

PubMed

Anderson, J L

1995-10-01

Recent clinical trials in patients with ventricular tachycardia (VT) or fibrillation (VF) have occurred in the setting of the disappointing results of postinfarction secondary prevention studies using Class I antiarrhythmics (e.g., CAST). ESVEM addressed in a randomized trial whether electrophysiologic study (EPS) or Holter monitoring (HM) is a more accurate predictor of long-term antiarrhythmic drug efficacy in VT/VF patients (N=486) and what the relative efficacy of various antiarrhythmic agents is for VT/VF. Surprisingly, arrhythmia recurrence rates were not significantly different by the method of determining an efficacy prediction. However, arrhythmia recurrence and mortality were lower (by about 50% at 1 year) in patients treated with sotalol (a mixed Class II/III agent) than with other drugs (Class I). CASCADE evaluated empiric amiodarone versus guided (EPS or HM) standard (Class I) therapy in survivors of out-of-hospital cardiac arrest due to VF. The primary endpoint of cardiac death, resuscitated VF, or syncopal shock (in ICD patients) was reduced by amiodarone compared with conventional therapy (9% vs 23% at 1 year). An interim report of the ongoing CASH study suggested in 230 survivors of cardiac arrest that propafenone (Class IC) provided less effective prophylaxis (approximately 20% 1-year mortality) compared with randomly assigned therapies with amiodarone, metoprolol, or an ICD (approximately 14% mortality rates) and was excluded from further study. These studies have led to a paradigm shift in the approach to antiarrhythmic therapy of VT/VF: drugs with antisympathetic plus Class III (refractoriness prolonging) action (i.e., sotalol, amiodarone) are superior to traditional drugs with Class I( conduction slowing) effects, even when guided by EPS or HM.

Efficacy of terbinafine compared to lanoconazole and luliconazole in the topical treatment of dermatophytosis in a guinea pig model.

PubMed

Ghannoum, M A; Long, L; Kim, H G; Cirino, A J; Miller, A R; Mallefet, P

2010-05-01

The in vivo efficacy of terbinafine was compared to lanoconazole and luliconazole in the topical treatment of dermatophytosis caused by Trichophyton mentagrophytes using a guinea pig model. Topical antifungal treatment commenced three days post-infection, and each agent was applied once daily for seven consecutive days. Upon completion of the treatment period, evaluations of clinical and mycological efficacies were performed, as was scanning electron microscopy (SEM) analyses. Data showed that while all tested antifungals demonstrated significant mycological efficacy in terms of eradicating the fungi over untreated control, terbinafine and luliconazole showed superior clinical efficacy compared to lanoconazole (P-values < 0.001 & 0.003, respectively). Terbinafine demonstrated the highest clinical percent efficacy. SEM analysis revealed hairs from terbinafine and lanoconazole-treated animals had near complete clearance of fungi, while samples from luliconazole-treated animals were covered with debris and few conidia. This study demonstrates that, in general, terbinafine possessed similar efficacy to lanoconazole and luliconazole in the treatment of dermatophytosis. Terbinafine tended to have superior clinical efficacy compared to the azoles tested, although this difference was not statistically significant against luliconazole. This apparent superiority may be due to the fungicidal activity of terbinafine compared to the fungistatic effect of the other two drugs.

Universal antifungal therapy is not needed in persistent febrile neutropenia: a tailored diagnostic and therapeutic approach

PubMed Central

Aguilar-Guisado, Manuela; Martín-Peña, Almudena; Espigado, Ildefonso; Ruiz Pérez de Pipaon, Maite; Falantes, José; de la Cruz, Fátima; Cisneros, José M.

2012-01-01

Background Giving antifungal therapy exclusively to selected patients with persistent febrile neutropenia may avoid over-treatment without increasing mortality. The aim of this study was to validate an innovative diagnostic and therapeutic approach based on assessing patients’ risk profile and clinical criteria in order to select those patients requiring antifungal therapy. The efficacy of this approach was compared to that of universal empirical antifungal therapy. Design and Methods This was a prospective study which included all consecutive adult hematology patients with neutropenia and fever refractory to 5 days of empirical antibacterial therapy admitted to a teaching hospital in Spain over a 2-year period. A diagnostic and therapeutic approach based on clinical criteria and risk profile was applied in order to select patients for antifungal therapy. The sensitivity, specificity and negative predictive value of this approach and also the overall success rate, according to the same criteria of efficacy described in classical clinical trials, were analyzed. Results Eighty-five episodes were included, 35 of them (41.2%) in patients at high risk of invasive fungal infections. Antifungal therapy was not indicated in 33 episodes (38.8%). The overall incidence of proven and probable invasive fungal infections was 14.1%, all of which occurred in patients who had received empirical antifungal therapy. The 30-day crude mortality rate was 15.3% and the invasive fungal infection-related mortality rate was 2.8% (2/72). The overall success rate following the diagnostic and therapeutic approach was 36.5% compared with 33.9% and 33.7% obtained in the trial by Walsh et al. The sensitivity, specificity and negative predictive value of the study approach were 100%, 52.4% and 100%, respectively. Conclusions Based on the high negative predictive value of this diagnostic and therapeutic approach in persistent febrile neutropenia patients with hematologic malignancies or patients who have received a hematopoietic stem cell transplant, the approach is useful for identifying patients who are not likely to develop invasive fungal infection and do not, therefore, require antifungal therapy. The effectiveness of the strategy is similar to that of universal empirical antifungal therapy reported in controlled trials. PMID:22058202

Efficacy of annexin A3 blockade in sensitizing hepatocellular carcinoma to sorafenib and regorafenib.

PubMed

Tong, Man; Che, Noélia; Zhou, Lei; Luk, Steve T; Kau, Phillis W; Chai, Stella; Ngan, Elly S; Lo, Chung-Mau; Man, Kwan; Ding, Jin; Lee, Terence K; Ma, Stephanie

2018-06-06

Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Sorafenib is the only FDA approved first-line targeted drug for advanced HCC, but its effect on patients' survival gain is limited. Further, patients ultimately present disease progression. A better understanding of causes of sorafenib resistance, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCC. Functional effects of ANXA3 in conferring sorafenib resistance in HCC cells were analyzed in apoptotic and tumorigenicity assays. Role of ANXA3/PKCδ-mediated p38 signaling thus subsequently altering autophagic and apoptotic events was assessed by immunoprecipitation, immunoblotting, immunofluorescence and transmission electron microscopy assays. Prognostic value of ANXA3 in predicting response to sorafenib was evaluated by immunohistochemistry. Therapeutic value of targeting ANXA3 to combat HCC with anti-ANXA3 monoclonal antibody (mAb) alone or in combination with sorafenib/regorafenib, were investigated ex vivo and in vivo. ANXA3 conferred ability of HCC cells to resist sorafenib. ANXA3 was found enriched in sorafenib-resistant HCC cells and patient-derived xenografts. Mechanistically, overexpression of ANXA3 in sorafenib-resistant HCC cells suppressed PKCδ/p38 associated apoptosis and activated autophagy for cell survival. Clinically, ANXA3 expression correlated positively with the autophagic marker LC3B in HCC and was associated with a worst overall survival in patients who went on to receive sorafenib treatment. Anti-ANXA3 mAb therapy combined with sorafenib/regorafenib impaired tumor growth in vivo and significantly increased survival. Anti-ANXA3 therapy in combination with sorafenib/regorafenib represents a novel therapeutic strategy for HCC treatment. ANXA3 represents a useful predictive biomarker to stratify HCC patients for sorafenib treatment. LAY SUMMARY This study represents the most extensive pre-clinical characterization of anti-ANXA3 mAb for HCC treatment to date and supports its clinical trial development in combination with sorafenib/regorafenib. Further studies will optimize patient target selection as well as the best treatment combinations. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Anxiety sensitivity, catastrophic misinterpretations and panic self-efficacy in the prediction of panic disorder severity: towards a tripartite cognitive model of panic disorder.

PubMed

Sandin, Bonifacio; Sánchez-Arribas, Carmen; Chorot, Paloma; Valiente, Rosa M

2015-04-01

The present study examined the contribution of three main cognitive factors (i.e., anxiety sensitivity, catastrophic misinterpretations of bodily symptoms, and panic self-efficacy) in predicting panic disorder (PD) severity in a sample of patients with a principal diagnosis of panic disorder. It was hypothesized that anxiety sensitivity (AS), catastrophic misinterpretation of bodily sensations, and panic self-efficacy are uniquely related to panic disorder severity. One hundred and sixty-eight participants completed measures of AS, catastrophic misinterpretations of panic-like sensations, and panic self-efficacy prior to receiving treatment. Results of multiple linear regression analyses indicated that AS, catastrophic misinterpretations and panic self-efficacy independently predicted panic disorder severity. Results of path analyses indicated that AS was direct and indirectly (mediated by catastrophic misinterpretations) related with panic severity. Results provide evidence for a tripartite cognitive account of panic disorder. Copyright © 2015 Elsevier Ltd. All rights reserved.

Self-Efficacy, Health Literacy, and Nutrition and Exercise Behaviors in a Low-Income, Hispanic Population.

PubMed

Guntzviller, Lisa M; King, Andy J; Jensen, Jakob D; Davis, LaShara A

2017-04-01

Public health goals have emphasized healthy nutrition and exercise behaviors, especially in underserved populations. According to social cognitive theory (SCT), self-efficacy and capability (e.g., health literacy) may interact to predict preventative behaviors. We surveyed 100 low-income, native Spanish-speakers living in the United States who were low in English proficiency and predominantly of Mexican heritage. Participants reported their nutritional and exercise self-efficacy, Spanish health literacy, and nutrition and physical activity behaviors. Consistent with SCT, the interaction of self-efficacy and health literacy significantly predicted fruit and vegetable consumption and weekly exercise, and marginally predicted avoidance of high fat foods. For all three interactions, higher health literacy levels strengthened the positive relationship between self-efficacy and health behaviors. The results offer support for the tenets of SCT and suggest-for low-income, Spanish-speaking adults-that a combination of behavioral confidence and literacy capability are necessary to enact appropriate health behaviors.

Biomarkers and surrogate endpoints in glaucoma clinical trials.

PubMed

Medeiros, Felipe A

2015-05-01

Surrogate endpoints are often used as replacements for true clinically relevant endpoints in several areas of medicine, as they enable faster and less expensive clinical trials. However, without proper validation, the use of surrogates may lead to incorrect conclusions about the efficacy and safety of treatments. This article reviews the general requirements for validating surrogate endpoints and provides a critical assessment of the use of intraocular pressure (IOP), visual fields, and structural measurements of the optic nerve as surrogate endpoints in glaucoma clinical trials. A valid surrogate endpoint must be able to predict the clinically relevant endpoint and fully capture the effect of an intervention on that endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has ever been conducted for any class of IOP-lowering treatments. Evidence has accumulated with regard to the role of imaging measurements of optic nerve damage as surrogate endpoints in glaucoma. These measurements are predictive of functional losses in the disease and may explain, at least in part, treatment effects on clinically relevant endpoints. The use of composite endpoints in glaucoma trials may overcome weaknesses of the use of structural or functional endpoints in isolation. Unless research is dedicated to fully develop and validate suitable endpoints that can be used in glaucoma clinical trials, we run the risk of inappropriate judgments about the value of new therapies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

The enhanced in vivo activity of the combination of a MEK and a PI3K inhibitor correlates with [18F]-FLT PET in human colorectal cancer xenograft tumour-bearing mice.

PubMed

Haagensen, Emma J; Thomas, Huw D; Wilson, Ian; Harnor, Suzannah J; Payne, Sara L; Rennison, Tommy; Smith, Kate M; Maxwell, Ross J; Newell, David R

2013-01-01

Combined targeting of the MAPK and PI3K signalling pathways in cancer may be necessary for optimal therapeutic activity. To support clinical studies of combination therapy, 3'-deoxy-3'-[(18)F]-fluorothymidine ([(18)F]-FLT) uptake measured by Positron Emission Tomography (PET) was evaluated as a non-invasive surrogate response biomarker in pre-clinical models. The in vivo anti-tumour efficacy and PK-PD properties of the MEK inhibitor PD 0325901 and the PI3K inhibitor GDC-0941, alone and in combination, were evaluated in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice, and [(18)F]-FLT PET investigated in mice bearing HCT116 xenografts. Dual targeting of PI3K and MEK induced marked tumour growth inhibition in vivo, and enhanced anti-tumour activity was predicted by [(18)F]-FLT PET scanning after 2 days of treatment. Pharmacodynamic analyses using the combination of the PI3K inhibitor GDC-0941 and the MEK inhibitor PD 0325901 revealed that increased efficacy is associated with an enhanced inhibition of the phosphorylation of ERK1/2, S6 and 4EBP1, compared to that observed with either single agent, and maintained inhibition of AKT phosphorylation. Pharmacokinetic studies indicated that there was no marked PK interaction between the two drugs. Together these results indicate that the combination of PI3K and MEK inhibitors can result in significant efficacy, and demonstrate for the first time that [(18)F]-FLT PET can be correlated to the improved efficacy of combined PI3K and MEK inhibitor treatment.

The Enhanced In Vivo Activity of the Combination of a MEK and a PI3K Inhibitor Correlates with [18F]-FLT PET in Human Colorectal Cancer Xenograft Tumour-Bearing Mice

PubMed Central

Haagensen, Emma J.; Thomas, Huw D.; Wilson, Ian; Harnor, Suzannah J.; Payne, Sara L.; Rennison, Tommy; Smith, Kate M.; Maxwell, Ross J.; Newell, David R.

2013-01-01

Combined targeting of the MAPK and PI3K signalling pathways in cancer may be necessary for optimal therapeutic activity. To support clinical studies of combination therapy, 3′-deoxy-3′-[18F]-fluorothymidine ([18F]-FLT) uptake measured by Positron Emission Tomography (PET) was evaluated as a non-invasive surrogate response biomarker in pre-clinical models. The in vivo anti-tumour efficacy and PK-PD properties of the MEK inhibitor PD 0325901 and the PI3K inhibitor GDC-0941, alone and in combination, were evaluated in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice, and [18F]-FLT PET investigated in mice bearing HCT116 xenografts. Dual targeting of PI3K and MEK induced marked tumour growth inhibition in vivo, and enhanced anti-tumour activity was predicted by [18F]-FLT PET scanning after 2 days of treatment. Pharmacodynamic analyses using the combination of the PI3K inhibitor GDC-0941 and the MEK inhibitor PD 0325901 revealed that increased efficacy is associated with an enhanced inhibition of the phosphorylation of ERK1/2, S6 and 4EBP1, compared to that observed with either single agent, and maintained inhibition of AKT phosphorylation. Pharmacokinetic studies indicated that there was no marked PK interaction between the two drugs. Together these results indicate that the combination of PI3K and MEK inhibitors can result in significant efficacy, and demonstrate for the first time that [18F]-FLT PET can be correlated to the improved efficacy of combined PI3K and MEK inhibitor treatment. PMID:24339963

Prediction of loss to follow-up in long-term supportive periodontal therapy in patients with chronic periodontitis

PubMed Central

Yang, Hai Jing

2018-01-01

Aim This study examined the predictors of loss to follow-up in long-term supportive periodontal therapy in patients with chronic periodontitis. Methods A total of 280 patients with moderate to severe chronic periodontitis in a tertiary care hospital in China were investigated and followed over the course of study. Questionnaires on clinical and demographic characteristics, self-efficacy for oral self-care and dental fear at baseline were completed. Participants were followed to determine whether they could adhere to long-term supportive periodontal therapy. Binary logistic regression analysis was used to examine the association between clinical and demographic characteristics, self-efficacy for oral self-care, dental fear and loss to follow-up in long-term supportive periodontal therapy. Results The loss to follow-up in long-term supportive periodontal therapy was significantly associated with age [adjusted OR = 1.042, 95% confidence interval (CI): 1.012–1.074, p = 0.006], severe periodontitis [adjusted OR = 4.892, 95%CI: 2.280–10.499, p<0.001], periodontal surgery [adjusted OR = 11.334, 95% CI: 2.235–57.472, p = 0.003], and middle and low-scoring of self-efficacy scale for self-care groups. The adjusted ORs of loss to follow-up for the middle- (54–59) and low-scoring groups (15–53) were 71.899 (95%CI: 23.926–216.062, p<0.001) and 4.800 (95% CI: 2.263–10.182, p<0.001), respectively, compared with the high-scoring SESS group (60–75). Conclusion Age, severity of periodontitis, periodontal surgery and the level of self-efficacy for self-care may be effective predictors of loss to follow-up in long-term supportive periodontal therapy in patients with chronic periodontitis. PMID:29420586

Impact of electronic-alerting of acute kidney injury: workgroup statements from the 15(th) ADQI Consensus Conference.

PubMed

Hoste, Eric A J; Kashani, Kianoush; Gibney, Noel; Wilson, F Perry; Ronco, Claudio; Goldstein, Stuart L; Kellum, John A; Bagshaw, Sean M

2016-01-01

Among hospitalized patients, acute kidney injury is common and associated with significant morbidity and risk for mortality. The use of electronic health records (EHR) for prediction and detection of this important clinical syndrome has grown in the past decade. The steering committee of the 15(th) Acute Dialysis Quality Initiative (ADQI) conference dedicated a workgroup with the task of identifying elements that may impact the course of events following Acute Kidney Injury (AKI) e-alert. Following an extensive, non-systematic literature search, we used a modified Delphi process to reach consensus regarding several aspects of the utilization of AKI e-alerts. Topics discussed in this workgroup included progress in evidence base practices, the characteristics of an optimal e-alert, the measures of efficacy and effectiveness, and finally what responses would be considered best practices following AKI e-alerts. Authors concluded that the current evidence for e-alert system efficacy, although growing, remains insufficient. Technology and human-related factors were found to be crucial elements of any future investigation or implementation of such tools. The group also concluded that implementation of such systems should not be done without a vigorous plan to evaluate the efficacy and effectiveness of e-alerts. Efficacy and effectiveness of e-alerts should be measured by context-specific process and patient outcomes. Finally, the group made several suggestions regarding the clinical decision support that should be considered following successful e-alert implementation. This paper reflects the findings of a non-systematic review and expert opinion. We recommend implementation of the findings of this workgroup report for use of AKI e-alerts.

Ursodiol in patients with parenteral nutrition-associated cholestasis.

PubMed

San Luis, Valerie A; Btaiche, Imad F

2007-11-01

To review the role of ursodeoxycholic acid (ursodiol) in treating parenteral nutrition-associated cholestasis (PNAC). A MEDLINE (1950-May 2007) search was performed using the key terms parenteral nutrition, cholestasis, ursodeoxycholic acid, and ursodiol. All English-language articles that evaluated the safety and efficacy of ursodiol for PNAC were included in this review. The benefits of exogenous ursodiol administration in the treatment of cholestasis can be explained by its alteration of effects on bile composition and flow and provision of cytoprotective, membrane stabilizing, and immunomodulatory effects. Two animal studies, 2 case reports, and 6 human studies (2 prospective and 3 retrospective pediatric studies, 1 adult prospective study) evaluated the efficacy of ursodiol in patients with PNAC. Ursodiol 10-30 mg/kg/day in children and 10-15 mg/kg/day in adults administered in 2-3 doses improved the biochemical and clinical signs and symptoms of PNAC. However, short-term improvement in biochemical parameters may not necessarily predict the outcome of PNAC patients. At recommended doses, ursodiol may not be effective in patients with short bowel syndrome or in those with resected terminal ileum because of reduced ursodiol absorption. Studies supporting the efficacy of ursodiol in treatment of PNAC are limited by small sample size, absence of randomization and controls, short duration, and lack of accountancy to confounding variables. Large, prospective, randomized, placebo-controlled, long-term follow-up studies evaluating the efficacy and optimal dosing and duration of ursodiol therapy for PNAC are not yet available. Ursodiol may improve the biochemical signs and clinical symptoms of PNAC. However, optimal dosing, timing, duration of therapy, and long-term effects on PNAC outcome and prognosis require further studies.

Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis

PubMed Central

Sieberts, Solveig K.; Zhu, Fan; García-García, Javier; Stahl, Eli; Pratap, Abhishek; Pandey, Gaurav; Pappas, Dimitrios; Aguilar, Daniel; Anton, Bernat; Bonet, Jaume; Eksi, Ridvan; Fornés, Oriol; Guney, Emre; Li, Hongdong; Marín, Manuel Alejandro; Panwar, Bharat; Planas-Iglesias, Joan; Poglayen, Daniel; Cui, Jing; Falcao, Andre O.; Suver, Christine; Hoff, Bruce; Balagurusamy, Venkat S. K.; Dillenberger, Donna; Neto, Elias Chaibub; Norman, Thea; Aittokallio, Tero; Ammad-ud-din, Muhammad; Azencott, Chloe-Agathe; Bellón, Víctor; Boeva, Valentina; Bunte, Kerstin; Chheda, Himanshu; Cheng, Lu; Corander, Jukka; Dumontier, Michel; Goldenberg, Anna; Gopalacharyulu, Peddinti; Hajiloo, Mohsen; Hidru, Daniel; Jaiswal, Alok; Kaski, Samuel; Khalfaoui, Beyrem; Khan, Suleiman Ali; Kramer, Eric R.; Marttinen, Pekka; Mezlini, Aziz M.; Molparia, Bhuvan; Pirinen, Matti; Saarela, Janna; Samwald, Matthias; Stoven, Véronique; Tang, Hao; Tang, Jing; Torkamani, Ali; Vert, Jean-Phillipe; Wang, Bo; Wang, Tao; Wennerberg, Krister; Wineinger, Nathan E.; Xiao, Guanghua; Xie, Yang; Yeung, Rae; Zhan, Xiaowei; Zhao, Cheng; Calaza, Manuel; Elmarakeby, Haitham; Heath, Lenwood S.; Long, Quan; Moore, Jonathan D.; Opiyo, Stephen Obol; Savage, Richard S.; Zhu, Jun; Greenberg, Jeff; Kremer, Joel; Michaud, Kaleb; Barton, Anne; Coenen, Marieke; Mariette, Xavier; Miceli, Corinne; Shadick, Nancy; Weinblatt, Michael; de Vries, Niek; Tak, Paul P.; Gerlag, Danielle; Huizinga, Tom W. J.; Kurreeman, Fina; Allaart, Cornelia F.; Louis Bridges Jr., S.; Criswell, Lindsey; Moreland, Larry; Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid; Gregersen, Peter K.; Friend, Stephen; Plenge, Robert; Stolovitzky, Gustavo; Oliva, Baldo; Guan, Yuanfang; Mangravite, Lara M.

2016-01-01

Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h2=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data. PMID:27549343

Personalized medicine: is it a pharmacogenetic mirage?

PubMed Central

Shah, Rashmi R; Shah, Devron R

2012-01-01

The notion of personalized medicine has developed from the application of the discipline of pharmacogenetics to clinical medicine. Although the clinical relevance of genetically-determined inter-individual differences in pharmacokinetics is poorly understood, and the genotype-phenotype association data on clinical outcomes often inconsistent, officially approved drug labels frequently include pharmacogenetic information concerning the safety and/or efficacy of a number of drugs and refer to the availability of the pharmacogenetic test concerned. Regulatory authorities differ in their approach to these issues. Evidence emerging subsequently has generally revealed the pharmacogenetic information included in the label to be premature. Revised drugs labels, together with a flurry of other collateral activities, have raised public expectations of personalized medicine, promoted as ‘the right drug at the right dose the first time.’ These expectations place the prescribing physician in a dilemma and at risk of litigation, especially when evidence-based information on genotype-related dosing schedules is to all intent and purposes non-existent and guidelines, intended to improve the clinical utility of available pharmacogenetic information or tests, distance themselves from any responsibility. Lack of efficacy or an adverse drug reaction is frequently related to non-genetic factors. Phenoconversion, arising from drug interactions, poses another often neglected challenge to any potential success of personalized medicine by mimicking genetically-determined enzyme deficiency. A more realistic promotion of personalized medicine should acknowledge current limitations and emphasize that pharmacogenetic testing can only improve the likelihood of diminishing a specific toxic effect or increasing the likelihood of a beneficial effect and that application of pharmacogenetics to clinical medicine cannot adequately predict drug response in individual patients. PMID:22591598

Usefulness of hounsfield unit and density in the assessment and treatment of urinary stones

PubMed Central

Gücük, Adnan; Üyetürk, Uğur

2014-01-01

Computed tomography (CT) is widely used to examine stones in the urinary system. In addition to the size and location of the stone and the overall health of the kidney, CT can also assess the density of the stone in Hounsfield units (HU). The HU, or Hounsfield density, measured by CT, is related to the density of the tissue or stone. A number of studies have assessed the use of HU in urology. HUs have been used to predict the type and opacity of stones during diagnosis, and the efficacy has been assessed using methods including extracorporeal shock wave lithotripsy (ESWL), percutaneous nephrolithotomy (PCNL), ureterorenoscopic ureterolithotripsy (URSL), and medical expulsive treatment (MET). Previous studies have focused on the success rate of HU for predicting the type of stone and of ESWL treatment. Understanding the composition of the stone plays a key role in determining the most appropriate treatment modality. The most recent reports have suggested that the HU value and its variants facilitate prediction of stone composition. However, the inclusion of data regarding urine, such as pH and presence of crystals, increases the predictive accuracy. HUs, which now form part of the clinical guidelines, allow us to predict the success of ESWL; therefore, they should be taken into account when ESWL is considered as a treatment option. However, there are currently insufficient data available regarding the value of HU for assessing the efficacy of PCNL, URSL, and MET. Studies performed to date suggest that these values would make a significant contribution to the diagnosis and treatment of urinary system stones. However, more data are required to assess this further. PMID:25374823

PRRT genomic signature in blood for prediction of 177Lu-octreotate efficacy.

PubMed

Bodei, Lisa; Kidd, Mark S; Singh, Aviral; van der Zwan, Wouter A; Severi, Stefano; Drozdov, Ignat A; Cwikla, Jaroslaw; Baum, Richard P; Kwekkeboom, Dik J; Paganelli, Giovanni; Krenning, Eric P; Modlin, Irvin M

2018-07-01

Peptide receptor radionuclide therapy (PRRT) utilizes somatostatin receptor (SSR) overexpression on neuroendocrine tumors (NET) to deliver targeted radiotherapy. Intensity of uptake at imaging is considered related to efficacy but has low sensitivity. A pretreatment strategy to determine individual PRRT response remains a key unmet need. NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ) which stratifies PRRT "responders" from "non-responders". This study clinically validates the utility of the PPQ in NETs. The development and validation of the PPQ was undertaken in three independent 177 Lu-PRRT treated cohorts. Specificity was tested in two separate somatostatin analog-treated cohorts. Prognostic value of the marker was defined in a cohort of untreated patients. The developmental cohort included lung and gastroenteropancreatic [GEP] NETs (n = 72) from IRST Meldola, Italy. The majority were GEP (71%) and low grade (86% G1-G2). Prospective validation cohorts were from Zentralklinik Bad Berka, Germany (n = 44), and Erasmus Medical Center, Rotterdam, Netherlands (n = 42). Each cohort included predominantly well differentiated, low grade (86-95%) lung and GEP-NETs. The non-PRRT comparator cohorts included SSA cohort I, n = 28 (100% low grade, 100% GEP-NET); SSA cohort II, n = 51 (98% low grade; 76% GEP-NET); and an untreated cohort, n = 44 (64% low grade; 91% GEP-NET). Baseline evaluations included clinical information (disease status, grade, SSR) and biomarker (CgA). NET blood gene transcripts (n = 8: growth factor signaling and metabolism) were measured pre-therapy and integrated with tumor Ki67 using a logistic regression model. This provided a binary output: "predicted responder" (PPQ+); "predicted non-responder" (PPQ-). Treatment response was evaluated using RECIST criteria [Responder (stable, partial and complete response) vs Non-Responder)]. Sample measurement and analyses were blinded to study outcome. Statistical evaluation included Kaplan-Meier survival and standard test evaluation analyses. In the developmental cohort, 56% responded to PRRT. The PPQ predicted 100% of responders and 84% of non-responders (accuracy: 93%). In the two validation cohorts (response: 64-79%), the PPQ was 95% accurate (Bad Berka: PPQ + =97%, PPQ- = 93%; Rotterdam: PPQ + =94%, PPQ- = 100%). Overall, the median PFS was not reached in PPQ+ vs PPQ- (10-14 months; HR: 18-77, p < 0.0001). In the comparator cohorts, the predictor (PPQ) was 47-50% accurate for SSA-treatment and 50% as a prognostic. No differences in PFS were respectively noted (PPQ+: 10-12 months vs. PPQ-: 9-15 months). The PPQ derived from circulating NET specific genes and tumor grade prior to the initiation of therapy is a highly specific predictor of the efficacy of PRRT with an accuracy of 95%.

Explaining infant feeding: The role of previous personal and vicarious experience on attitudes, subjective norms, self-efficacy, and breastfeeding outcomes.

PubMed

Bartle, Naomi C; Harvey, Kate

2017-11-01

Breastfeeding confers important health benefits to both infants and their mothers, but rates are low in the United Kingdom and other developed countries despite widespread promotion. This study examined the relationships between personal and vicarious experience of infant feeding, self-efficacy, the theory of planned behaviour variables of attitudes and subjective norm, and the likelihood of breastfeeding at 6-8 weeks post-natally. A prospective questionnaire study of both first-time mothers (n = 77) and experienced breastfeeders (n = 72) recruited at an antenatal clinic in South East England. Participants completed a questionnaire at 32 weeks pregnant assessing personal and vicarious experience of infant feeding (breastfeeding, formula-feeding, and maternal grandmother's experience of breastfeeding), perceived control, self-efficacy, intentions, attitudes (to breastfeeding and formula-feeding), and subjective norm. Infant feeding behaviour was recorded at 6-8 weeks post-natally. Multiple linear regression modelled the influence of vicarious experience on attitudes, subjective norm, and self-efficacy (but not perceived control) and modelled the influence of attitude, subjective norm, self-efficacy, and past experience on intentions to breastfeed. Logistic regression modelled the likelihood of breastfeeding at 6-8 weeks. Previous experience (particularly personal experience of breastfeeding) explained a significant amount of variance in attitudes, subjective norm, and self-efficacy. Intentions to breastfeed were predicted by subjective norm and attitude to formula-feeding and, in experienced mothers, self-efficacy. Breastfeeding at 6 weeks was predicted by intentions and vicarious experience of formula-feeding. Vicarious experience, particularly of formula-feeding, has been shown to influence the behaviour of first-time and experienced mothers both directly and indirectly via attitudes and subjective norm. Interventions that reduce exposure to formula-feeding (perhaps by limiting advertising) or cushion mothers from its effects may enable more mothers to meet their breastfeeding goals. Statement of contribution What is already known on this subject? Rates of breastfeeding in the United Kingdom are low and resistant to change. Self-efficacy may be an important and modifiable factor for breastfeeding initiation and maintenance. What does this study add? Self-efficacy may only be a relevant factor among mothers who already have personal experience of breastfeeding. Vicarious experience of formula-feeding has been shown to be related to a lower rate of breastfeeding at 6 weeks. © 2017 The Authors. British Journal of Health Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.

Exploring learners' self-efficacy, autonomy and motivation toward e-learning.

PubMed

Huang, Hsiu-Mei; Liaw, Shu-Sheng

2007-10-01

A questionnaire survey was conducted with 116 college students (47 men, 69 women) in Central Taiwan to investigate predictive relationships among four attitudinal variables, perceived self-efficacy, learners' autonomy, intrinsic motivation, and extrinsic motivation toward e-learning. Analysis showed learners' autonomy was predictive of both intrinsic (57% independent variance explained) and extrinsic motivation (61% independent variance explained). Although perceived self-efficacy was not a predictor of intrinsic motivation and extrinsic motivation, it correlated significantly with extrinsic motivation.

Assessing the validity of sales self-efficacy: a cautionary tale.

PubMed

Gupta, Nina; Ganster, Daniel C; Kepes, Sven

2013-07-01

We developed a focused, context-specific measure of sales self-efficacy and assessed its incremental validity against the broad Big 5 personality traits with department store salespersons, using (a) both a concurrent and a predictive design and (b) both objective sales measures and supervisory ratings of performance. We found that in the concurrent study, sales self-efficacy predicted objective and subjective measures of job performance more than did the Big 5 measures. Significant differences between the predictability of subjective and objective measures of performance were not observed. Predictive validity coefficients were generally lower than concurrent validity coefficients. The results suggest that there are different dynamics operating in concurrent and predictive designs and between broad and contextualized measures; they highlight the importance of distinguishing between these designs and measures in meta-analyses. The results also point to the value of focused, context-specific personality predictors in selection research. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Dissociable Effects of the Cannabinoid Receptor Agonists Δ9-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

PubMed Central

Kwilasz, Andrew J.

2012-01-01

Cannabinoid receptor agonists produce reliable antinociception in most preclinical pain assays but have inconsistent analgesic efficacy in humans. This disparity suggests that conventional preclinical assays of nociception are not sufficient for the prediction of cannabinoid effects related to clinical analgesia. To extend the range of preclinical cannabinoid assessment, this study compared the effects of the marijuana constituent and low-efficacy cannabinoid agonist Δ9-tetrahydrocannabinol (THC) and the high-efficacy synthetic cannabinoid agonist 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol (CP55940) in assays of pain-stimulated and pain-depressed behavior. Intraperitoneal injection of dilute lactic acid (1.8% in 1 ml/kg) stimulated a stretching response or depressed intracranial self-stimulation (ICSS) in separate groups of male Sprague-Dawley rats. THC (0.1–10 mg/kg) and CP55940 (0.0032–0.32 mg/kg) dose-dependently blocked acid- stimulated stretching but only exacerbated acid-induced depression of ICSS at doses that also decreased control ICSS in the absence of a noxious stimulus. Repeated THC produced tolerance to sedative rate-decreasing effects of THC on control ICSS in the absence of the noxious stimulus but failed to unmask antinociception in the presence of the noxious stimulus. THC and CP55940 also failed to block pain-related depression of feeding in rats, although THC did attenuate satiation-related depression of feeding. In contrast to the effects of the cannabinoid agonists, the clinically effective analgesic and nonsteroidal anti-inflammatory drug ketoprofen (1 mg/kg) blocked acid-stimulated stretching and acid-induced depression of both ICSS and feeding. The poor efficacy of THC and CP55940 to block acute pain-related depression of behavior in rats agrees with the poor efficacy of cannabinoids to treat acute pain in humans. PMID:22892341

Child Adjustment and Parent Efficacy Scale-Developmental Disability (CAPES-DD): First psychometric evaluation of a new child and parenting assessment tool for children with a developmental disability.

PubMed

Emser, Theresa S; Mazzucchelli, Trevor G; Christiansen, Hanna; Sanders, Matthew R

2016-01-01

This study examined the psychometric properties of the Child Adjustment and Parent Efficacy Scale-Developmental Disability (CAPES-DD), a brief inventory for assessing emotional and behavioral problems of children with developmental disabilities aged 2- to 16-years, as well as caregivers' self-efficacy in managing these problems. A sample of 636 parents participated in the study. Children's ages ranged from 2 to 15. Exploratory and confirmatory factor analyses supported a 21-item, three-factor model of CAPES-DD child adjustment with 13 items describing behavioral (10 items) and emotional (3 items) problems and 8 items describing prosocial behavior. Three additional items were included due to their clinical usefulness and contributed to a Total Problem Score. Factor analyses also supported a 16-item, one factor model of CAPES-DD self-efficacy. Psychometric evaluation of the CAPES-DD revealed scales had satisfactory to very good internal consistency, as well as very good convergent and predictive validity. The instrument is to be in the public domain and free for practitioners and researchers to use. Potential uses of the measure and implications for future validation studies are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Psychological determinants of job retention in multiple sclerosis.

PubMed

Ford, Helen L; Wicks, Charlotte R; Stroud, Amanda; Tennant, Alan

2018-01-01

Maintaining paid work is a key issue for people with multiple sclerosis (PwMS). Different factors, including psychological attributes, can influence job retention. Understanding their role should inform potential interventions to help PwMS retain employment. The aim of this study was to identify the key factors which improve job retention in an employed cohort of PwMS. This three-year longitudinal study used validated self-completed measures of physical and psychological factors at four time points over 28 months. Of 208 employed PwMS, just over 1 in 10 was no longer working at the end of the study. Three variables were predictive of continuing employment; low 'work instability' at baseline increased the odds of job retention by a factor of 12.76; high levels of self-efficacy by a factor of 4.66 and being less than 50 years of age increased the odds of job retention by a factor of 3.90. Path analysis demonstrated the mediating role of self-efficacy between the physical impact of MS and the level of work instability at exit. Screening for work instability and self-efficacy in a clinical setting followed by appropriate interventions to increase self-efficacy and reduce work instability could aid job retention in MS.

A Syrian golden hamster model recapitulating ebola hemorrhagic fever.

PubMed

Ebihara, Hideki; Zivcec, Marko; Gardner, Donald; Falzarano, Darryl; LaCasse, Rachel; Rosenke, Rebecca; Long, Dan; Haddock, Elaine; Fischer, Elizabeth; Kawaoka, Yoshihiro; Feldmann, Heinz

2013-01-15

Ebola hemorrhagic fever (EHF) is a severe viral infection for which no effective treatment or vaccine is currently available. While the nonhuman primate (NHP) model is used for final evaluation of experimental vaccines and therapeutic efficacy, rodent models have been widely used in ebolavirus research because of their convenience. However, the validity of rodent models has been questioned given their low predictive value for efficacy testing of vaccines and therapeutics, a result of the inconsistent manifestation of coagulopathy seen in EHF. Here, we describe a lethal Syrian hamster model of EHF using mouse-adapted Ebola virus. Infected hamsters displayed most clinical hallmarks of EHF, including severe coagulopathy and uncontrolled host immune responses. Thus, the hamster seems to be superior to the existing rodent models, offering a better tool for understanding the critical processes in pathogenesis and providing a new model for evaluating prophylactic and postexposure interventions prior to testing in NHPs.

A Syrian Golden Hamster Model Recapitulating Ebola Hemorrhagic Fever

PubMed Central

Ebihara, Hideki; Zivcec, Marko; Gardner, Donald; Falzarano, Darryl; LaCasse, Rachel; Rosenke, Rebecca; Long, Dan; Haddock, Elaine; Fischer, Elizabeth; Kawaoka, Yoshihiro; Feldmann, Heinz

2013-01-01

Ebola hemorrhagic fever (EHF) is a severe viral infection for which no effective treatment or vaccine is currently available. While the nonhuman primate (NHP) model is used for final evaluation of experimental vaccines and therapeutic efficacy, rodent models have been widely used in ebolavirus research because of their convenience. However, the validity of rodent models has been questioned given their low predictive value for efficacy testing of vaccines and therapeutics, a result of the inconsistent manifestation of coagulopathy seen in EHF. Here, we describe a lethal Syrian hamster model of EHF using mouse-adapted Ebola virus. Infected hamsters displayed most clinical hallmarks of EHF, including severe coagulopathy and uncontrolled host immune responses. Thus, the hamster seems to be superior to the existing rodent models, offering a better tool for understanding the critical processes in pathogenesis and providing a new model for evaluating prophylactic and postexposure interventions prior to testing in NHPs. PMID:23045629

Combating resistance: application of the emerging science of pharmacokinetics and pharmacodynamics.

PubMed

Jacobs, Michael R

2007-12-01

During the last 10-15 years understanding of relationships between pharmacokinetic (PK) and pharmacodynamic (PD) parameters and bacteriological and clinical outcomes has expanded allowing correlation between in vitro potency and in vivo efficacy. PK and PD principles can be applied to development of new antibacterials and formulation of existing agents to help address the increasing prevalence of antibacterial resistance. For beta-lactams, such as penicillins, the unbound serum concentration of the drug exceeding the minimum inhibitory concentration of the causative pathogen for 40-50% of the dosing interval is predictive of bacteriologic efficacy (bacterial eradication) and can be used to determine a PK/PD breakpoint for that specific dosing regimen. Amoxicillin/clavulanate was one of the earliest antibacterials to use the unique approach of PK/PD principles to develop new and enhanced formulations, allowing it to remain a significant antibacterial agent in the management of respiratory tract infections.

Modeling Combinations of Pre-erythrocytic Plasmodium falciparum Malaria Vaccines.

PubMed

Walker, Andrew S; Lourenço, José; Hill, Adrian V S; Gupta, Sunetra

2015-12-01

Despite substantial progress in the control of Plasmodium falciparum infection due to the widespread deployment of insecticide-treated bed nets and artemisinin combination therapies, malaria remains a prolific killer, with over half a million deaths estimated to have occurred in 2013 alone. Recent evidence of the development of resistance to treatments in both parasites and their mosquito vectors has underscored the need for a vaccine. Here, we use a mathematical model of the within-host dynamics of P. falciparum infection, fit to data from controlled human malaria infection clinical trials, to predict the efficacy of co-administering the two most promising subunit vaccines, RTS,S/AS01 and ChAd63-MVA ME-TRAP. We conclude that currently available technologies could be combined to induce very high levels of sterile efficacy, even in immune-naive individuals. © The American Society of Tropical Medicine and Hygiene.

How best to capture the respiratory consequences of prematurity?

PubMed

Ciuffini, Francesca; Robertson, Colin F; Tingay, David G

2018-03-31

Chronic respiratory morbidity is a common complication of premature birth, generally defined by the presence of bronchopulmonary dysplasia, both clinically and in trials of respiratory therapies. However, recent data have highlighted that bronchopulmonary dysplasia does not correlate with chronic respiratory morbidity in older children born preterm. Longitudinally evaluating pulmonary morbidity from early life through to childhood provides a more rational method of defining the continuum of chronic respiratory morbidity of prematurity, and offers new insights into the efficacy of neonatal respiratory interventions. The changing nature of preterm lung disease suggests that a multimodal approach using dynamic lung function assessment will be needed to assess the efficacy of a neonatal respiratory therapy and predict the long-term respiratory consequences of premature birth. Our aim is to review the literature regarding the long-term respiratory outcomes of neonatal respiratory strategies, the difficulties of assessing dynamic lung function in infants, and potential new solutions. Copyright ©ERS 2018.

The Influence of Self-Efficacy, Fear-Avoidance Belief, and Coping Styles on Quality of Life for Chinese Patients with Chronic Nonspecific Low Back Pain: A Multisite Cross-Sectional Study.

PubMed

Du, Shizheng; Hu, Lingli; Bai, Yamei; Dong, Jianshu; Jin, Shengji; Zhang, Heng; Zhu, Ying

2017-11-23

As a bio-psycho-social issue, chronic low back pain (CLBP) has been a significant topic in health management, and patients' quality of life (QOL) is gaining extensive attention. Self-efficacy, pain fear-avoidance belief (FAB), and coping styles play important roles in the QOL of CLBP patients. However, it remains unclear how self-efficacy and FAB influence QOL through specific coping styles. This study aimed to explore the influencing paths of self-efficacy, FAB, and coping styles on the QOL of patients with CLBP. This study relies on a multisite, cross-sectional design involving 221 CLBP patients. Stepwise multiple regression and structural equation modeling were employed. CLBP patients lived with a poor global QOL. Self-efficacy played a direct, positive role in predicting QOL for patients with CLBP (β = 0.35), and it also played an indirect, positive role in predicting QOL (β = 0.19) through active coping styles (β = 0.31). FAB played a direct, negative role in predicting QOL (β = -0.33), and it also played an indirect, negative role in predicting QOL (β = -0.32) through passive coping styles (β = 0.32). Self-efficacy and FAB are both directly and indirectly related to global QOL, and coping styles are important mediating variables. Self-efficacy and active coping are protective factors for the QOL of CLBP patients, while FAB and passive coping are risk factors. Health education strategies are recommended by medical personnel to enhance CLBP patients' pain self-efficacy, decrease pain FAB, and modify pain coping styles, so that their global QOL can be improved. © 2017 World Institute of Pain.

How modeling and simulation have enhanced decision making in new drug development.

PubMed

Miller, Raymond; Ewy, Wayne; Corrigan, Brian W; Ouellet, Daniele; Hermann, David; Kowalski, Kenneth G; Lockwood, Peter; Koup, Jeffrey R; Donevan, Sean; El-Kattan, Ayman; Li, Cheryl S W; Werth, John L; Feltner, Douglas E; Lalonde, Richard L

2005-04-01

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled "Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products" made this scientific approach to the drug approval process possible.

Effects of therapeutic horseback riding on post-traumatic stress disorder in military veterans.

PubMed

Johnson, Rebecca A; Albright, David L; Marzolf, James R; Bibbo, Jessica L; Yaglom, Hayley D; Crowder, Sandra M; Carlisle, Gretchen K; Willard, Amy; Russell, Cynthia L; Grindler, Karen; Osterlind, Steven; Wassman, Marita; Harms, Nathan

2018-01-19

Large numbers of post-deployment U.S. veterans are diagnosed with post-traumatic stress disorder (PTSD) and/or traumatic brain injury (TBI), leading to an urgent need for effective interventions to reduce symptoms and increase veterans' coping. PTSD includes anxiety, flashbacks, and emotional numbing. The symptoms increase health care costs for stress-related illnesses and can make veterans' civilian life difficult. We used a randomized wait-list controlled design with repeated measures of U.S. military veterans to address our specific aim to test the efficacy of a 6-week therapeutic horseback riding (THR) program for decreasing PTSD symptoms and increasing coping self-efficacy, emotion regulation, social and emotional loneliness. Fifty-seven participants were recruited and 29 enrolled in the randomized trial. They were randomly assigned to either the horse riding group (n = 15) or a wait-list control group (n = 14). The wait-list control group experienced a 6-week waiting period, while the horse riding group began THR. The wait-list control group began riding after 6 weeks of participating in the control group. Demographic and health history information was obtained from all the participants. PTSD symptoms were measured using the standardized PTSD Checklist-Military Version (PCL-M). The PCL-M as well as other instruments including, The Coping Self Efficacy Scale (CSES), The Difficulties in Emotion Regulation Scale (DERS) and The Social and Emotional Loneliness Scale for Adults-short version (SELSA) were used to access different aspects of individual well-being and the PTSD symptoms. Participants had a statistically significant decrease in PTSD scores after 3 weeks of THR (P ≤ 0.01) as well as a statistically and clinically significant decrease after 6 weeks of THR (P ≤ 0.01). Logistic regression showed that participants had a 66.7% likelihood of having lower PTSD scores at 3 weeks and 87.5% likelihood at 6 weeks. Under the generalized linear model(GLM), our ANOVA findings for the coping self-efficacy, emotion regulation, and social and emotional loneliness did not reach statistical significance. The results for coping self-efficacy and emotion regulation trended in the predicted direction. Results for emotional loneliness were opposite the predicted direction. Logistic regression provided validation that outcome effects were caused by riding longer. The findings suggest that THR may be a clinically effective intervention for alleviating PTSD symptoms in military veterans.

Self-Regulation and Recall: Growth Curve Modeling of Intervention Outcomes for Older Adults

PubMed Central

West, Robin L.; Hastings, Erin C.

2013-01-01

Memory training has often been supported as a potential means to improve performance for older adults. Less often studied are the characteristics of trainees that benefit most from training. Using a self-regulatory perspective, the current project examined a latent growth curve model to predict training-related gains for middle-aged and older adult trainees from individual differences (e.g., education), information processing skills (strategy use) and self-regulatory factors such as self-efficacy, control, and active engagement in training. For name recall, a model including strategy usage and strategy change as predictors of memory gain, along with self-efficacy and self-efficacy change, showed comparable fit to a more parsimonious model including only self-efficacy variables as predictors. The best fit to the text recall data was a model focusing on self-efficacy change as the main predictor of memory change, and that model showed significantly better fit than a model also including strategy usage variables as predictors. In these models, overall performance was significantly predicted by age and memory self-efficacy, and subsequent training-related gains in performance were best predicted directly by change in self-efficacy (text recall), or indirectly through the impact of active engagement and self-efficacy on gains (name recall). These results underscore the benefits of targeting self-regulatory factors in intervention programs designed to improve memory skills. PMID:21604891

Self-regulation and recall: growth curve modeling of intervention outcomes for older adults.

PubMed

West, Robin L; Hastings, Erin C

2011-12-01

Memory training has often been supported as a potential means to improve performance for older adults. Less often studied are the characteristics of trainees that benefit most from training. Using a self-regulatory perspective, the current project examined a latent growth curve model to predict training-related gains for middle-aged and older adult trainees from individual differences (e.g., education), information processing skills (strategy use) and self-regulatory factors such as self-efficacy, control, and active engagement in training. For name recall, a model including strategy usage and strategy change as predictors of memory gain, along with self-efficacy and self-efficacy change, showed comparable fit to a more parsimonious model including only self-efficacy variables as predictors. The best fit to the text recall data was a model focusing on self-efficacy change as the main predictor of memory change, and that model showed significantly better fit than a model also including strategy usage variables as predictors. In these models, overall performance was significantly predicted by age and memory self-efficacy, and subsequent training-related gains in performance were best predicted directly by change in self-efficacy (text recall), or indirectly through the impact of active engagement and self-efficacy on gains (name recall). These results underscore the benefits of targeting self-regulatory factors in intervention programs designed to improve memory skills.