Strategic characterization of anti-drug antibody responses for the assessment of clinical relevance and impact.

PubMed

Tatarewicz, Suzanna M; Mytych, Daniel T; Manning, Marta Starcevic; Swanson, Steven J; Moxness, Michael S; Chirmule, Narendra

2014-06-01

All therapeutic proteins have the potential to induce anti-drug antibodies (ADA). Clinically relevant ADA can impact efficacy and/or safety of a biological therapeutic. Immunogenicity assessment strategy evaluates binding and neutralizing ADA, and the need for additional characterization (e.g., epitope, titer and so on) is determined using a risk-based approach. The choice of characterization assays depends on the type, application and immunogenicity of the therapeutic. ADA characterization can impact the interpretation of the risk profile of a given therapeutic, and offers insight into opportunities for risk mitigation and management. This article describes common ADA characterization methods. Strategic assessment and characterization of clinically relevant ADA are discussed, in order to support clinical options for safe and effective patient care and disease management.

Dental Blogs, Podcasts, and Associated Social Media: Descriptive Mapping and Analysis.

PubMed

Melkers, Julia; Hicks, Diana; Rosenblum, Simone; Isett, Kimberley R; Elliott, Jacqueline

2017-07-26

Studies of social media in both medicine and dentistry have largely focused on the value of social media for marketing to and communicating with patients and for clinical education. There is limited evidence of how dental clinicians contribute to and use social media to disseminate and access information relevant to clinical care. The purpose of this study was to inventory and assess the entry, growth, sources, and content of clinically relevant social media in dentistry. We developed an inventory of blogs, podcasts, videos, and associated social media disseminating clinical information to dentists. We assessed hosts' media activity in terms of their combinations of modalities, entry and exit dates, frequency of posting, types of content posted, and size of audience. Our study showed that clinically relevant information is posted by dentists and hygienists on social media. Clinically relevant information was provided in 89 blogs and podcasts, and topic analysis showed motives for blogging by host type: 55% (49 hosts) were practicing dentists or hygienists, followed by consultants (27 hosts, 30%), media including publishers and discussion board hosts (8 hosts, 9%), and professional organizations and corporations. We demonstrated the participation of and potential for practicing dentists and hygienists to use social media to share clinical and other information with practicing colleagues. There is a clear audience for these social media sites, suggesting a changing mode of information diffusion in dentistry. This study was a first effort to fill the gap in understanding the nature and potential role of social media in clinical dentistry. ©Julia Melkers, Diana Hicks, Simone Rosenblum, Kimberley R Isett, Jacqueline Elliott. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 26.07.2017.

Clinical practice guidelines for delirium management: potential application in palliative care.

PubMed

Bush, Shirley H; Bruera, Eduardo; Lawlor, Peter G; Kanji, Salmaan; Davis, Daniel H J; Agar, Meera; Wright, David Kenneth; Hartwick, Michael; Currow, David C; Gagnon, Bruno; Simon, Jessica; Pereira, José L

2014-08-01

Delirium occurs in patients across a wide array of health care settings. The extent to which formal management guidelines exist or are adaptable to palliative care is unclear. This review aims to 1) source published delirium management guidelines with potential relevance to palliative care settings, 2) discuss the process of guideline development, 3) appraise their clinical utility, and 4) outline the processes of their implementation and evaluation and make recommendations for future guideline development. We searched PubMed (1990-2013), Scopus, U.S. National Guideline Clearinghouse, Google, and relevant reference lists to identify published guidelines for the management of delirium. This was supplemented with multidisciplinary input from delirium researchers and other relevant stakeholders at an international delirium study planning meeting. There is a paucity of high-level evidence for pharmacological and non-pharmacological interventions in the management of delirium in palliative care. However, multiple delirium guidelines for clinical practice have been developed, with recommendations derived from "expert opinion" for areas where research evidence is lacking. In addition to their potential benefits, limitations of clinical guidelines warrant consideration. Guidelines should be appraised and then adapted for use in a particular setting before implementation. Further research is needed on the evaluation of guidelines, as disseminated and implemented in a clinical setting, focusing on measurable outcomes in addition to their impact on quality of care. Delirium clinical guidelines are available but the level of evidence is limited. More robust evidence is required for future guideline development. Copyright © 2014 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Clinically Relevant Physical Benefits of Exercise Interventions in Breast Cancer Survivors.

PubMed

Kirkham, Amy A; Bland, Kelcey A; Sayyari, Sarah; Campbell, Kristin L; Davis, Margot K

2016-02-01

Evidence is currently limited for the effect of exercise on breast cancer clinical outcomes. However, several of the reported physical benefits of exercise, including peak oxygen consumption, functional capacity, muscle strength and lean mass, cardiovascular risk factors, and bone health, have established associations with disability, cardiovascular disease risk, morbidity, and mortality. This review will summarize the clinically relevant physical benefits of exercise interventions in breast cancer survivors and discuss recommendations for achieving these benefits. It will also describe potential differences in intervention delivery that may impact outcomes and, lastly, describe current physical activity guidelines for cancer survivors.

Repairing quite swimmingly: advances in regenerative medicine using zebrafish.

PubMed

Goessling, Wolfram; North, Trista E

2014-07-01

Regenerative medicine has the promise to alleviate morbidity and mortality caused by organ dysfunction, longstanding injury and trauma. Although regenerative approaches for a few diseases have been highly successful, some organs either do not regenerate well or have no current treatment approach to harness their intrinsic regenerative potential. In this Review, we describe the modeling of human disease and tissue repair in zebrafish, through the discovery of disease-causing genes using classical forward-genetic screens and by modulating clinically relevant phenotypes through chemical genetic screening approaches. Furthermore, we present an overview of those organ systems that regenerate well in zebrafish in contrast to mammalian tissue, as well as those organs in which the regenerative potential is conserved from fish to mammals, enabling drug discovery in preclinical disease-relevant models. We provide two examples from our own work in which the clinical translation of zebrafish findings is either imminent or has already proven successful. The promising results in multiple organs suggest that further insight into regenerative mechanisms and novel clinically relevant therapeutic approaches will emerge from zebrafish research in the future. © 2014. Published by The Company of Biologists Ltd.

Using an Ishikawa diagram as a tool to assist memory and retrieval of relevant medical cases from the medical literature.

PubMed

Wong, Kam Cheong

2011-03-29

Studying medical cases is an effective way to enhance clinical reasoning skills and reinforce clinical knowledge. An Ishikawa diagram, also known as a cause-and-effect diagram or fishbone diagram, is often used in quality management in manufacturing industries.In this report, an Ishikawa diagram is used to demonstrate how to relate potential causes of a major presenting problem in a clinical setting. This tool can be used by teams in problem-based learning or in self-directed learning settings.An Ishikawa diagram annotated with references to relevant medical cases and literature can be continually updated and can assist memory and retrieval of relevant medical cases and literature. It could also be used to cultivate a lifelong learning habit in medical professionals.

Cryopreserved or Fresh Mesenchymal Stromal Cells: Only a Matter of Taste or Key to Unleash the Full Clinical Potential of MSC Therapy?

PubMed

Moll, Guido; Geißler, Sven; Catar, Rusan; Ignatowicz, Lech; Hoogduijn, Martin J; Strunk, Dirk; Bieback, Karen; Ringdén, Olle

2016-01-01

Mesenchymal stromal cells (MSCs) harbor great therapeutic potential for numerous diseases. From early clinical trials, success and failure analysis, bench-to-bedside and back-to-bench approaches, there has been a great gain in knowledge, still leaving a number of questions to be answered regarding optimal manufacturing and quality of MSCs for clinical application. For treatment of many acute indications, cryobanking may remain a prerequisite, but great uncertainty exists considering the therapeutic value of freshly thawed (thawed) and continuously cultured (fresh) MSCs. The field has seen an explosion of new literature lately, outlining the relevance of the topic. MSCs appear to have compromised immunomodulatory activity directly after thawing for clinical application. This may provide a possible explanation for failure of early clinical trials. It is not clear if and how quickly MSCs recover their full therapeutic activity, and if the "cryo stun effect" is relevant for clinical success. Here, we will share our latest insights into the relevance of these observations for clinical practice that will be discussed in the context of the published literature. We argue that the differences of fresh and thawed MSCs are limited but significant. A key issue in evaluating potency differences is the time point of analysis after thawing. To date, prospective double-blinded randomized clinical studies to evaluate potency of both products are lacking, although recent progress was made with preclinical assessment. We suggest refocusing therapeutic MSC development on potency and safety assays with close resemblance of the clinical reality.

How to apply clinical cases and medical literature in the framework of a modified "failure mode and effects analysis" as a clinical reasoning tool--an illustration using the human biliary system.

PubMed

Wong, Kam Cheong

2016-04-06

Clinicians use various clinical reasoning tools such as Ishikawa diagram to enhance their clinical experience and reasoning skills. Failure mode and effects analysis, which is an engineering methodology in origin, can be modified and applied to provide inputs into an Ishikawa diagram. The human biliary system is used to illustrate a modified failure mode and effects analysis. The anatomical and physiological processes of the biliary system are reviewed. Failure is defined as an abnormality caused by infective, inflammatory, obstructive, malignancy, autoimmune and other pathological processes. The potential failures, their effect(s), main clinical features, and investigation that can help a clinician to diagnose at each anatomical part and physiological process are reviewed and documented in a modified failure mode and effects analysis table. Relevant medical and surgical cases are retrieved from the medical literature and weaved into the table. A total of 80 clinical cases which are relevant to the modified failure mode and effects analysis for the human biliary system have been reviewed and weaved into a designated table. The table is the backbone and framework for further expansion. Reviewing and updating the table is an iterative and continual process. The relevant clinical features in the modified failure mode and effects analysis are then extracted and included in the relevant Ishikawa diagram. This article illustrates an application of engineering methodology in medicine, and it sows the seeds of potential cross-pollination between engineering and medicine. Establishing a modified failure mode and effects analysis can be a teamwork project or self-directed learning process, or a mix of both. Modified failure mode and effects analysis can be deployed to obtain inputs for an Ishikawa diagram which in turn can be used to enhance clinical experiences and clinical reasoning skills for clinicians, medical educators, and students.

Efficient generation of mouse models of human diseases via ABE- and BE-mediated base editing.

PubMed

Liu, Zhen; Lu, Zongyang; Yang, Guang; Huang, Shisheng; Li, Guanglei; Feng, Songjie; Liu, Yajing; Li, Jianan; Yu, Wenxia; Zhang, Yu; Chen, Jia; Sun, Qiang; Huang, Xingxu

2018-06-14

A recently developed adenine base editor (ABE) efficiently converts A to G and is potentially useful for clinical applications. However, its precision and efficiency in vivo remains to be addressed. Here we achieve A-to-G conversion in vivo at frequencies up to 100% by microinjection of ABE mRNA together with sgRNAs. We then generate mouse models harboring clinically relevant mutations at Ar and Hoxd13, which recapitulates respective clinical defects. Furthermore, we achieve both C-to-T and A-to-G base editing by using a combination of ABE and SaBE3, thus creating mouse model harboring multiple mutations. We also demonstrate the specificity of ABE by deep sequencing and whole-genome sequencing (WGS). Taken together, ABE is highly efficient and precise in vivo, making it feasible to model and potentially cure relevant genetic diseases.

Raising financing through strategic timing

NASA Astrophysics Data System (ADS)

Maine, Elicia; Thomas, V. J.

2017-02-01

Strategic timing can be key for nano-drug-delivery ventures to get financing. Timely publications engage potential partners; early broad, blocking, relevant patents demonstrate the potential to appropriate value; and venture formation closer to clinical viability better aligns its timeline with that of venture capitalists.

Theragnostics for tumor and plaque angiogenesis with perfluorocarbon nanoemulsions

PubMed Central

Winter, P. M.; Caruthers, S. D.; Hughes, M. S.; Hu, Grace; Schmieder, A. H.; Wickline, S. A.

2011-01-01

Molecular imaging agents are extending the potential of noninvasive medical diagnosis from basic gross anatomical descriptions to complicated phenotypic characterizations based upon the recognition of unique cell-surface biochemical signatures. Although originally the purview of nuclear medicine, “molecular imaging” is now studied in conjunction with all clinically relevant imaging modalities. Of the myriad of particles that have emerged as prospective candidates for clinical translation, perfluorocarbon nanoparticles offer great potential for combining targeted imaging with drug delivery, much like the “magic bullet” envisioned by Paul Ehrlich 100 years ago. Perfluorocarbon nanoparticles, once studied in Phase III clinical trials as blood substitutes, have found new life for molecular imaging and drug delivery. The particles have been adapted for use with all clinically relevant modalities and for targeted drug delivery. In particular, their intravascular constraint due to particle size provides a distinct advantage for angiogenesis imaging and antiangiogenesis therapy. As perfluorocarbon nanoparticles have recently entered Phase I clinical study, this review provides a timely focus on the development of this platform technology and its application for angiogenesis-related pathologies. PMID:20411320

Updates in venous thromboembolism management: evidence published in 2017.

PubMed

Bartlett, Matthew A; Bierle, Dennis M; Saadiq, Rayya A; Mauck, Karen F; Daniels, Paul R

2018-06-20

Venous thromboembolism (VTE) management is rapidly evolving and staying up-to-date is challenging. We identified the most practice-informing articles published in 2017 relevant to the nonspecialist provider managing VTE. We performed a systematic search of the literature (Appendix A), limiting the search to a publication date of 2017. Two reviewers screened the 2735 resulting abstracts to identify high-quality, clinically relevant publications related to VTE management. One-hundred and six full-text articles were considered for inclusion. The five authors used a modified Delphi method to reach consensus on inclusion of seven articles for in-depth appraisal, following predetermined criteria of clinical relevance to nonspecialist providers, potential for practice change, and strength of the evidence.

DNA Repair in Prostate Cancer: Biology and Clinical Implications.

PubMed

Mateo, Joaquin; Boysen, Gunther; Barbieri, Christopher E; Bryant, Helen E; Castro, Elena; Nelson, Pete S; Olmos, David; Pritchard, Colin C; Rubin, Mark A; de Bono, Johann S

2017-03-01

For more precise, personalized care in prostate cancer (PC), a new classification based on molecular features relevant for prognostication and treatment stratification is needed. Genomic aberrations in the DNA damage repair pathway are common in PC, particularly in late-stage disease, and may be relevant for treatment stratification. To review current knowledge on the prevalence and clinical significance of aberrations in DNA repair genes in PC, particularly in metastatic disease. A literature search up to July 2016 was conducted, including clinical trials and preclinical basic research studies. Keywords included DNA repair, BRCA, ATM, CRPC, prostate cancer, PARP, platinum, predictive biomarkers, and hereditary cancer. We review how the DNA repair pathway is relevant to prostate carcinogenesis and progression. Data on how this may be relevant to hereditary cancer and genetic counseling are included, as well as data from clinical trials of PARP inhibitors and platinum therapeutics in PC. Relevant studies have identified genomic defects in DNA repair in PCs in 20-30% of advanced castration-resistant PC cases, a proportion of which are germline aberrations and heritable. Phase 1/2 clinical trial data, and other supporting clinical data, support the development of PARP inhibitors and DNA-damaging agents in this molecularly defined subgroup of PC following success in other cancer types. These studies may be an opportunity to improve patient care with personalized therapeutic strategies. Key literature on how genomic defects in the DNA damage repair pathway are relevant for prostate cancer biology and clinical management is reviewed. Potential implications for future changes in patient care are discussed. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Prevalence and psychosocial correlates of depressive symptoms in urban Chinese women during midlife.

PubMed

Wong, Carmen K M; Liang, Jun; Chan, Man L; Chan, Yin H; Chan, Laam; Wan, Kwong Y; Ng, Ming S; Chan, Dicken C C; Wong, Samuel Y S; Wong, Martin C S

2014-01-01

Depression is common in women with much research focusing on hormonal changes and menopausal symptoms but with little exploration of psychosocial problems in midlife. This study investigates the prevalence of clinically relevant depressive symptoms in midlife Chinese women and its association with psychosocial factors. A cross-sectional, community-based household survey of women aged 45 to 64 years of age was conducted in Hong Kong from September 2010 to March 2011. The structured questionnaire included demographic data, educational status, marital status and household income, as well as perceived current stressful events and significant life events in the past 12 months. Information on clinically relevant depressive symptoms was measured by the validated chinese Patient Health Questionnaire (PHQ-9). A total of 402 participants were recruited in the study period. Of the 393 women who completed the questionnaire, the prevalence of clinically relevant depressive symptoms (PHQ-9 score≧10) was 11.0%. In multiple regression analysis, being single/divorced/separated/widowed, having an educational level of primary school level or below, having multiple chronic diseases, loss of hobby or loss of close social support in the past 12 months in midlife were associated with clinically relevant depressive symptoms. Correlates of clinically relevant depressive symptoms in midlife Chinese women can be used to identify those at increased risk and potentiate further studies to explore early psychosocial and community interventions.

Best clinical trials reported in 2010.

PubMed

Garner, John B; Grayburn, Paul A; Yancy, Clyde W

2011-07-01

Each year, a number of clinical trials emerge with data sufficient to change clinical practice. Determining which findings will result in practice change and which will provide only incremental benefit can be a dilemma for clinicians. The authors review selected clinical trials reported in 2010 in journals, at society meetings, and at conferences, focusing on those studies that have the potential to change clinical practice. This review offers 3 separate means of analysis: an abbreviated text summary, organized by subject area; a comprehensive table of relevant clinical trials that provides a schematic review of the hypotheses, interventions, methods, primary end points, results, and implications; and a complete bibliography for further reading as warranted. It is hoped that this compilation of relevant clinical trials and their important findings released in 2010 will be of benefit in the everyday practice of cardiovascular medicine. Copyright © 2011 Elsevier Inc. All rights reserved.

4D co-registration of X-ray and MR-mammograms: initial clinical results and potential incremental diagnostic value.

PubMed

Dietzel, Matthias; Hopp, Torsten; Ruiter, Nicole V; Kaiser, Clemens G; Kaiser, Werner A; Baltzer, Pascal A

2015-01-01

4D co-registration of X-ray- and MR-mammograms (XM and MM) is a new method of image fusion. The present study aims to evaluate its clinical feasibility, radiological accuracy, and potential clinical value. XM and MM of 25 patients were co-registered. Results were evaluated by a blinded reader. Precision of the 4D co-registration was "very good" (mean-score [ms]=7), and lesions were "easier to delineate" (ms=5). In 88.8%, "relevant additional diagnostic information" was present, accounting for a more "confident diagnosis" in 76% (ms=5). 4D co-registration is feasible, accurate, and of potential clinical value. Copyright © 2015 Elsevier Inc. All rights reserved.

There's an App for That? Highlighting the Difficulty in Finding Clinically Relevant Smartphone Applications.

PubMed

Wiechmann, Warren; Kwan, Daniel; Bokarius, Andrew; Toohey, Shannon L

2016-03-01

The use of personal mobile devices in the medical field has grown quickly, and a large proportion of physicians use their mobile devices as an immediate resource for clinical decision-making, prescription information and other medical information. The iTunes App Store (Apple, Inc.) contains approximately 20,000 apps in its "Medical" category, providing a robust repository of resources for clinicians; however, this represents only 2% of the entire App Store. The App Store does not have strict criteria for identifying content specific to practicing physicians, making the identification of clinically relevant content difficult. The objective of this study is to quantify the characteristics of existing medical applications in the iTunes App Store that could be used by emergency physicians, residents, or medical students. We found applications related to emergency medicine (EM) by searching the iTunes App Store for 21 terms representing core content areas of EM, such as "emergency medicine," "critical care," "orthopedics," and "procedures." Two physicians independently reviewed descriptions of these applications in the App Store and categorized each as the following: Clinically Relevant, Book/Published Source, Non-English, Study Tools, or Not Relevant. A third physician reviewer resolved disagreements about categorization. Descriptive statistics were calculated. We found a total of 7,699 apps from the 21 search terms, of which 17.8% were clinical, 9.6% were based on a book or published source, 1.6% were non-English, 0.7% were clinically relevant patient education resources, and 4.8% were study tools. Most significantly, 64.9% were considered not relevant to medical professionals. Clinically relevant apps make up approximately 6.9% of the App Store's "Medical" Category and 0.1% of the overall App Store. Clinically relevant apps represent only a small percentage (6.9%) of the total App volume within the Medical section of the App Store. Without a structured search-and-evaluation strategy, it may be difficult for the casual user to identify this potentially useful content. Given the increasing adoption of devices in healthcare, national EM associations should consider curating these resources for their members.

Perspectives on Creating Clinically Relevant Blast Models for Mild Traumatic Brain Injury and Post Traumatic Stress Disorder Symptoms

PubMed Central

Brenner, Lisa A.; Bahraini, Nazanin; Hernández, Theresa D.

2012-01-01

Military personnel are returning from Iraq and Afghanistan and reporting non-specific physical (somatic), behavioral, psychological, and cognitive symptoms. Many of these symptoms are frequently associated with mild traumatic brain injury (mTBI) and/or post traumatic stress disorder (PTSD). Despite significant attention and advances in assessment and intervention for these two conditions, challenges persist. To address this, clinically relevant blast models are essential in the full characterization of this type of injury, as well as in the testing and identification of potential treatment strategies. In this publication, existing diagnostic challenges and current treatment practices for mTBI and/or PTSD will be summarized, along with suggestions regarding how what has been learned from existing models of PTSD and traditional mechanism (e.g., non-blast) traumatic brain injury can be used to facilitate the development of clinically relevant blast models. PMID:22408635

Molecular Heterogeneity in Glioblastoma: Potential Clinical Implications

PubMed Central

Parker, Nicole Renee; Khong, Peter; Parkinson, Jonathon Fergus; Howell, Viive Maarika; Wheeler, Helen Ruth

2015-01-01

Glioblastomas, (grade 4 astrocytomas), are aggressive primary brain tumors characterized by histopathological heterogeneity. High-resolution sequencing technologies have shown that these tumors also feature significant inter-tumoral molecular heterogeneity. Molecular subtyping of these tumors has revealed several predictive and prognostic biomarkers. However, intra-tumoral heterogeneity may undermine the use of single biopsy analysis for determining tumor genotype and has implications for potential targeted therapies. The clinical relevance and theories of tumoral molecular heterogeneity in glioblastoma are discussed. PMID:25785247

A Semantic Web-based System for Mining Genetic Mutations in Cancer Clinical Trials.

PubMed

Priya, Sambhawa; Jiang, Guoqian; Dasari, Surendra; Zimmermann, Michael T; Wang, Chen; Heflin, Jeff; Chute, Christopher G

2015-01-01

Textual eligibility criteria in clinical trial protocols contain important information about potential clinically relevant pharmacogenomic events. Manual curation for harvesting this evidence is intractable as it is error prone and time consuming. In this paper, we develop and evaluate a Semantic Web-based system that captures and manages mutation evidences and related contextual information from cancer clinical trials. The system has 2 main components: an NLP-based annotator and a Semantic Web ontology-based annotation manager. We evaluated the performance of the annotator in terms of precision and recall. We demonstrated the usefulness of the system by conducting case studies in retrieving relevant clinical trials using a collection of mutations identified from TCGA Leukemia patients and Atlas of Genetics and Cytogenetics in Oncology and Haematology. In conclusion, our system using Semantic Web technologies provides an effective framework for extraction, annotation, standardization and management of genetic mutations in cancer clinical trials.

Identifying and applying psychological theory to setting and achieving rehabilitation goals.

PubMed

Scobbie, Lesley; Wyke, Sally; Dixon, Diane

2009-04-01

Goal setting is considered to be a fundamental part of rehabilitation; however, theories of behaviour change relevant to goal-setting practice have not been comprehensively reviewed. (i) To identify and discuss specific theories of behaviour change relevant to goal-setting practice in the rehabilitation setting. (ii) To identify 'candidate' theories that that offer most potential to inform clinical practice. The rehabilitation and self-management literature was systematically searched to identify review papers or empirical studies that proposed a specific theory of behaviour change relevant to setting and/or achieving goals in a clinical context. Data from included papers were extracted under the headings of: key constructs, clinical application and empirical support. Twenty-four papers were included in the review which proposed a total of five theories: (i) social cognitive theory, (ii) goal setting theory, (iii) health action process approach, (iv) proactive coping theory, and (v) the self-regulatory model of illness behaviour. The first three of these theories demonstrated most potential to inform clinical practice, on the basis of their capacity to inform interventions that resulted in improved patient outcomes. Social cognitive theory, goal setting theory and the health action process approach are theories of behaviour change that can inform clinicians in the process of setting and achieving goals in the rehabilitation setting. Overlapping constructs within these theories have been identified, and can be applied in clinical practice through the development and evaluation of a goal-setting practice framework.

Assessment of statistical significance and clinical relevance.

PubMed

Kieser, Meinhard; Friede, Tim; Gondan, Matthias

2013-05-10

In drug development, it is well accepted that a successful study will demonstrate not only a statistically significant result but also a clinically relevant effect size. Whereas standard hypothesis tests are used to demonstrate the former, it is less clear how the latter should be established. In the first part of this paper, we consider the responder analysis approach and study the performance of locally optimal rank tests when the outcome distribution is a mixture of responder and non-responder distributions. We find that these tests are quite sensitive to their planning assumptions and have therefore not really any advantage over standard tests such as the t-test and the Wilcoxon-Mann-Whitney test, which perform overall well and can be recommended for applications. In the second part, we present a new approach to the assessment of clinical relevance based on the so-called relative effect (or probabilistic index) and derive appropriate sample size formulae for the design of studies aiming at demonstrating both a statistically significant and clinically relevant effect. Referring to recent studies in multiple sclerosis, we discuss potential issues in the application of this approach. Copyright © 2012 John Wiley & Sons, Ltd.

Women with epilepsy: clinically relevant issues

PubMed Central

Bangar, Santosh; Shastri, Abhishek; El-Sayeh, Hany; Cavanna, Andrea E.

2016-01-01

Summary Women with epilepsy (WWE) face specific challenges throughout their lifespan due to the effects of seizures and antiepileptic drugs on hormonal function, potentially affecting both sexual and reproductive health. This review article addresses the most common issues of practical relevance to clinicians treating WWE: epidemiology and clinical presentations (including catamenial epilepsy), contraception, reproductive and sexual dysfunction, pregnancy, lactation, menopause-related issues (including bone health), and mental health aspects. Awareness of these gender-specific issues and implementation/adaptation of effective interventions for WWE results in significantly improved health-related quality of life in this patient population. PMID:27678205

Using the MMPI 168 with Medical Inpatients

ERIC Educational Resources Information Center

Erickson, Richard C.; Freeman, Charles

1976-01-01

Explores the potential utility of the MMPI 168 with two inpatient medical populations. Correlations and clinically relevant comparisons suggest that the MMPI 168 predicted the standard MMPI with a high degree accuracy. (Editor/RK)

Classification of drugs with different risk profiles.

PubMed

Saedder, Eva Aggerholm; Brock, Birgitte; Nielsen, Lars Peter; Bonnerup, Dorthe Krogsgaard; Lisby, Marianne

2015-08-01

A risk stratification approach is needed to identify patients at high risk of medication errors and a resulting high need of medication review. The aim of this study was to perform risk stratification (distinguishing between low-risk, medium-risk and high-risk drugs) for drugs found to cause serious adverse reactions due to medication errors. The study employed a modified Delphi technique. Drugs from a systematic literature search were included into two rounds of a Delphi process. A panel of experts was asked to evaluate each identified drug's potential for harm and for clinically relevant drug-drug interactions on a scale from 1 (low risk) to 9 (high risk). A total of 36 experts were appointed to serve on the panel. Consensus was reached for 29/57 (51%) drugs or drug classes that cause harm, and for 32/57 (56%) of the drugs or drug classes that cause interactions. For the remaining drugs, a decision was made based on the median score. Two lists, one stating the drugs' potential for causing harm and the other stating clinically relevant drug-drug interactions, were stratified into low-risk, medium-risk and high-risk drugs. Based on a modified Delphi technique, we created two lists of drugs stratified into a low-risk, a medium-risk and a high-risk group of clinically relevant interactions or risk of harm to patients. The lists could be incorporated into a risk-scoring tool that stratifies the performance of medication reviews according to patients' risk of experiencing adverse reactions. none. not relevant.

Is ginger beneficial for nausea and vomiting? An update of the literature.

PubMed

Marx, Wolfgang; Kiss, Nicole; Isenring, Liz

2015-06-01

Nausea and vomiting can pose a significant burden to patients in a variety of clinical settings. Previous evidence suggests that ginger may be an effective treatment for these symptoms; however, current evidence has been mixed. This article discusses recent clinical trials that have investigated ginger as a treatment for multiple types of nausea and vomiting. In addition, the potential mechanisms of action of ginger will be discussed. This article identified nine studies and seven reviews that investigated ginger for morning sickness, postoperative nausea and vomiting, chemotherapy-induced, and antiretroviral-induced nausea and vomiting. All studies reported that ginger provided a significant reduction in nausea and vomiting; however, the clinical relevance of some studies is less certain. Common limitations within the literature include the lack of standardized extracts, poorly controlled or blinded studies, and limited sample size. In addition, recent evidence has provided further support for 5-HT3 receptor antagonism as a mechanism by which ginger may exert its potentially beneficial effect on nausea and vomiting. The results of studies in this article suggest that ginger is a promising treatment for nausea and vomiting in a variety of clinical settings and possesses a clinically relevant mechanism. However, further studies are required to address the limitations in the current clinical literature before firm recommendations for its use can be made.

Assessing mental imagery in clinical psychology: A review of imagery measures and a guiding framework

PubMed Central

Pearson, David G.; Deeprose, Catherine; Wallace-Hadrill, Sophie M.A.; Heyes, Stephanie Burnett; Holmes, Emily A.

2013-01-01

Mental imagery is an under-explored field in clinical psychology research but presents a topic of potential interest and relevance across many clinical disorders, including social phobia, schizophrenia, depression, and post-traumatic stress disorder. There is currently a lack of a guiding framework from which clinicians may select the domains or associated measures most likely to be of appropriate use in mental imagery research. We adopt an interdisciplinary approach and present a review of studies across experimental psychology and clinical psychology in order to highlight the key domains and measures most likely to be of relevance. This includes a consideration of methods for experimentally assessing the generation, maintenance, inspection and transformation of mental images; as well as subjective measures of characteristics such as image vividness and clarity. We present a guiding framework in which we propose that cognitive, subjective and clinical aspects of imagery should be explored in future research. The guiding framework aims to assist researchers in the selection of measures for assessing those aspects of mental imagery that are of most relevance to clinical psychology. We propose that a greater understanding of the role of mental imagery in clinical disorders will help drive forward advances in both theory and treatment. PMID:23123567

The clinical trial landscape in oncology and connectivity of somatic mutational profiles to targeted therapies.

PubMed

Patterson, Sara E; Liu, Rangjiao; Statz, Cara M; Durkin, Daniel; Lakshminarayana, Anuradha; Mockus, Susan M

2016-01-16

Precision medicine in oncology relies on rapid associations between patient-specific variations and targeted therapeutic efficacy. Due to the advancement of genomic analysis, a vast literature characterizing cancer-associated molecular aberrations and relative therapeutic relevance has been published. However, data are not uniformly reported or readily available, and accessing relevant information in a clinically acceptable time-frame is a daunting proposition, hampering connections between patients and appropriate therapeutic options. One important therapeutic avenue for oncology patients is through clinical trials. Accordingly, a global view into the availability of targeted clinical trials would provide insight into strengths and weaknesses and potentially enable research focus. However, data regarding the landscape of clinical trials in oncology is not readily available, and as a result, a comprehensive understanding of clinical trial availability is difficult. To support clinical decision-making, we have developed a data loader and mapper that connects sequence information from oncology patients to data stored in an in-house database, the JAX Clinical Knowledgebase (JAX-CKB), which can be queried readily to access comprehensive data for clinical reporting via customized reporting queries. JAX-CKB functions as a repository to house expertly curated clinically relevant data surrounding our 358-gene panel, the JAX Cancer Treatment Profile (JAX CTP), and supports annotation of functional significance of molecular variants. Through queries of data housed in JAX-CKB, we have analyzed the landscape of clinical trials relevant to our 358-gene targeted sequencing panel to evaluate strengths and weaknesses in current molecular targeting in oncology. Through this analysis, we have identified patient indications, molecular aberrations, and targeted therapy classes that have strong or weak representation in clinical trials. Here, we describe the development and disseminate system methods for associating patient genomic sequence data with clinically relevant information, facilitating interpretation and providing a mechanism for informing therapeutic decision-making. Additionally, through customized queries, we have the capability to rapidly analyze the landscape of targeted therapies in clinical trials, enabling a unique view into current therapeutic availability in oncology.

The impact of gender on asthma in the daily clinical practice.

PubMed

Ciprandi, Giorgio; Gallo, Fabio

2018-03-01

It is up-to-date to consider the potential gender impact on a disease. There are few data about gender difference in asthma. Therefore, the present cross-sectional study tested this hypothesis in a real-life setting to investigate possible difference between genders. This study was cross-sectional, considering 554 consecutive outpatients suspected of asthma, who were referred for a first specialist visit. Clinical and functional parameters were evaluated. Females with asthma could have a worse perception of asthma control, assessed by asthma control test (ACT), and more anxiety than asthmatic males. However, there was no difference regarding asthma control grading, asthma severity, and asthma medication use between genders; the differences in lung function were without clinical relevance. In the daily clinical practice, it is relevant to consider gender in the management of asthma.

Are evoked potentials in patients with adult-onset pompe disease indicative of clinically relevant central nervous system involvement?

PubMed

Wirsching, Andreas; Müller-Felber, Wolfgang; Schoser, Benedikt

2014-08-01

Pompe disease is a multisystem autosomal recessive glycogen storage disease. Autoptic findings in patients with classic infantile and late-onset Pompe disease have proven that accumulation of glycogen can also be found in the peripheral and central nervous system. To assess the functional role of these pathologic findings, multimodal sensory evoked potentials were analyzed. Serial recordings for brainstem auditory, visual, and somatosensory evoked potentials of 11 late-onset Pompe patients were reviewed. Data at the onset of the enzyme replacement therapy with alglucosidase alfa were compared with follow-up recordings at 12 and 24 months. Brainstem auditory evoked potentials showed a delayed peak I in 1/10 patients and an increased I-III and I-V interpeak latency in 1/10 patients, respectively. The III-V interpeak latencies were in the normal range. Visual evoked potentials were completely normal. Median somatosensory evoked potentials showed an extended interpeak latency in 3/9 patients. Wilcoxon tests comparing age-matched subgroups found significant differences in brainstem auditory evoked potentials and visual evoked potentials. We found that the majority of recordings for evoked potentials were within the ranges for standard values, therefore reflecting the lack of clinically relevant central nervous system involvement. Regular surveillance by means of evoked potentials does not seem to be appropriate in late-onset Pompe patients.

Development and application of two independent real-time PCR assays to detect clinically relevant Mucorales species.

PubMed

Springer, Jan; Goldenberger, Daniel; Schmidt, Friderike; Weisser, Maja; Wehrle-Wieland, Elisabeth; Einsele, Hermann; Frei, Reno; Löffler, Jürgen

2016-03-01

PCR-based detection of Mucorales species could improve diagnosis of suspected invasive fungal infection, leading to a better patient outcome. This study describes two independent probe-based real-time PCR tests for detection of clinically relevant Mucorales, targeting specific fragments of the 18S and the 28S rRNA genes. Both assays have a short turnaround time, allow fast, specific and very sensitive detection of clinically relevant Mucorales and have the potential to be used as quantitative tests. They were validated on various clinical samples (fresh and formalin-fixed paraffin-embedded specimens, mainly biopsies, n = 17). The assays should be used as add-on tools to complement standard techniques; a combined approach of both real-time PCR assays has 100 % sensitivity. Genus identification by subsequent sequencing is possible for amplicons of the 18S PCR assay. In conclusion, combination of the two independent Mucorales assays described in this study, 18S and 28S, detected all clinical samples associated with proven Mucorales infection (n = 10). Reliable and specific identification of Mucorales is a prerequisite for successful antifungal therapy as these fungi show intrinsic resistance to voriconazole and caspofungin.

Meiotic Nondisjunction: Insights into the Origin and Significance of Aneuploidy in Human Spermatozoa.

PubMed

Ioannou, Dimitrios; Tempest, Helen G

2015-01-01

Chromosome aneuploidy refers to changes in the chromosome complement of a genome and can include gain or loss of genetic material. The human genome is delicately balanced, and for the most part perturbations in the chromosome complement are often incompatible with embryonic development. The importance and clinical relevance of paternally derived aneuploidy is often overshadowed by the large maternal contribution; as a result, the paternal contribution to pregnancy loss due to chromosome aneuploidy is rarely considered within the clinic. However, there is increasing evidence to suggest that certain men have significantly higher levels of sperm aneuploidy, which is mirrored by an increase in aneuploidy within their embryos and offspring. Therefore, the paternal contribution to aneuploidy at least for some individuals may have greater clinical significance than is currently perceived. Thus, the main focus of this chapter is to provide insights into the origin and clinical relevance of paternally derived aneuploidy. Furthermore, this section will review the general mechanisms through which aneuploidy arises during spermatogenesis and how numerical (whole chromosome) and structural chromosome aberrations (cytogenetically visible or submicroscopic) may lead to clinically relevant aneuploidy potentially resulting in pregnancy loss, congenital malformations, and cognitive impairment.

The relevance of dietary sodium in hemodialysis

PubMed Central

Mc Causland, Finnian R.; Waikar, Sushrut S.; Brunelli, Steven M.

2013-01-01

Since the earliest days of hemodialysis, dietary sodium restriction has been recommended as a therapeutic means to mitigate problems of extracellular volume overload, hypertension and inter-dialytic weight gain. Recently, there has been a proliferation of human subjects' research examining the potential effects of dietary sodium curtailment. Herein we examine the available evidence with respect to the effects of dietary sodium restriction on clinically relevant endpoints among hemodialysis patients. PMID:23129821

Anxiety at the first radiotherapy session for non-metastatic breast cancer: key communication and communication-related predictors.

PubMed

Lewis, Florence; Merckaert, Isabelle; Liénard, Aurore; Libert, Yves; Etienne, Anne-Marie; Reynaert, Christine; Slachmuylder, Jean-Louis; Scalliet, Pierre; Van Houtte, Paul; Coucke, Philippe; Salamon, Emile; Razavi, Darius

2015-01-01

Patients may experience clinically relevant anxiety at their first radiotherapy (RT) sessions. To date, studies have not investigated during/around the RT simulation the key communication and communication-related predictors of this clinically relevant anxiety. Breast cancer patients (n=227) completed visual analog scale (VAS) assessments of anxiety before and after their first RT sessions. Clinically relevant anxiety was defined as having pre- and post-first RT session VAS scores ⩾4 cm. Communication during RT simulation was assessed with content analysis software (LaComm), and communication-related variables around the RT simulation were assessed with questionnaires. Clinically relevant anxiety at the first RT session was predicted by lower self-efficacy to communicate with the RT team (OR=0.65; p=0.020), the perception of lower support received from the RT team (OR=0.70; p=0.020), lower knowledge of RT-associated side effects (OR=0.95; p=0.057), and higher use of emotion-focused coping (OR=1.09; p=0.013). This study provides RT team members with information about potential communication strategies, which may be used to reduce patient anxiety at the first RT session. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Update on Medical Practices that should be questioned in 2015

PubMed Central

Morgan, Daniel J.; Dhruva, Sanket S.; Wright, Scott M.; Korenstein, Deborah

2016-01-01

Importance Overuse of medical care, consisting primarily of overdiagnosis and overtreatment, is a common clinical problem. Objective To identify and highlight articles published in 2014 that are most likely to impact overuse, organized into the categories of overdiagnosis, overtreatment, and methods to avoid overuse. These manuscripts were reviewed and interpreted for their importance to clinical medicine. Evidence Review A structured review of English-language articles on PubMed published in 2014 and review of tables of contents of relevant journals to identify potential articles that related to medical overuse in adults. Findings We reviewed 910 articles, of which 440 addressed overuse. Of these, 104 were deemed most relevant based on the presentation of original data, quality of methodology, magnitude of clinical impact, and the number of patients potentially affected. The 10 most influential articles were selected by author consensus using the same criteria. Findings included lack of benefit for screening pelvic examinations (positive predictive value <5%), carotid artery and thyroid ultrasounds. Harms of cancer screening included unnecessary surgery and complications. Head CT scans were an overused diagnostic test (4% with clinically significant findings) and overtreatment included acetaminophen for low back pain, prolonged opioid use after surgery (3% of patients on >90 days), perioperative aspirin, medications to increase HDL, and stenting for renal artery stenosis. Conclusions and Relevance Many common medical practices should be reconsidered. It is hoped that our review promotes reflection on these 10 articles and lead to questioning other non-evidence based practices. PMID:26551354

[work motivation -- assessment instruments and their relevance for medical care].

PubMed

Fiedler, Rolf G; Ranft, Andreas; Greitemann, Bernhard; Heuft, Gereon

2005-11-01

The relevance of work motivation for medical research and healthcare, in particular rehabilitation, is described. Four diagnostic instruments in the German language are introduced which can assess work motivation using a scale system: AVEM, JDS, LMI and FBTM. Their possible application and potential usage for the clinical area are discussed. Apart from the FBTM, none of these instruments can be directly used as a general instrument in a normal medical clinical setting. Finally, a current model for work motivation (compensatory model of work motivation and volition) is presented that contains basis concepts, which are judged as important for future research questions concerning the development of motivation diagnostic instruments.

Exploring policy makers' perspectives on a clinical controversy: airway surgery for adult obstructive sleep apnoea.

PubMed

Elshaug, A G; Hiller, J E; Moss, J R

2009-10-01

Worldwide, there is increasing focus on measures to reduce ineffective healthcare practices. Upper airway surgeries for the treatment of adult obstructive sleep apnoea (OSA) represent a case-study in this area, given recent publications that draw into question their efficacy. Policy stakeholders were canvassed to assess their perspectives on this. Senior health policy stakeholders from Australia were criterion and snowball sampled (to identify opinion leaders). Participants were presented with preparatory material and took part in individual semistructured interviews. These focused on eliciting responses to recently published evidence and a relevant Cochrane review. Questions were posed relating to clinical effectiveness and associated policy implications. Interviews were taped and transcribed for thematic analysis. Participant comments were de-identified. Ten stakeholders were interviewed before saturation was reached. Thematic analysis highlighted participant concern with the diversity of procedures on offer, coupled with limited effectiveness (suggesting potential clinical uncertainty) and considerations therefore of resource allocation (potential opportunity cost). Stakeholders seem aware of the methodological complexities, the ethical issues raised and the role of patients in considerations regarding appropriateness. Finally, policy stakeholders acknowledge that these procedures appear appropriate only for a minority, with consensus that policy level restrictions to government funding for these procedures may be warranted. This report highlights that this clinical controversy is of interest and relevance from a policy perspective with lessons and potential implications for clinical practice. It further highlights the need for clinical consensus on definitions of surgical "success" in treating this condition, as this forms an important pretext to policy considerations.

Water displacement leg volumetry in clinical studies - A discussion of error sources

PubMed Central

2010-01-01

Background Water displacement leg volumetry is a highly reproducible method, allowing the confirmation of efficacy of vasoactive substances. Nevertheless errors of its execution and the selection of unsuitable patients are likely to negatively affect the outcome of clinical studies in chronic venous insufficiency (CVI). Discussion Placebo controlled double-blind drug studies in CVI were searched (Cochrane Review 2005, MedLine Search until December 2007) and assessed with regard to efficacy (volume reduction of the leg), patient characteristics, and potential methodological error sources. Almost every second study reported only small drug effects (≤ 30 mL volume reduction). As the most relevant error source the conduct of volumetry was identified. Because the practical use of available equipment varies, volume differences of more than 300 mL - which is a multifold of a potential treatment effect - have been reported between consecutive measurements. Other potential error sources were insufficient patient guidance or difficulties with the transition from the Widmer CVI classification to the CEAP (Clinical Etiological Anatomical Pathophysiological) grading. Summary Patients should be properly diagnosed with CVI and selected for stable oedema and further clinical symptoms relevant for the specific study. Centres require a thorough training on the use of the volumeter and on patient guidance. Volumetry should be performed under constant conditions. The reproducibility of short term repeat measurements has to be ensured. PMID:20070899

Can clinical governance deliver quality improvement in Australian general practice and primary care? A systematic review of the evidence.

PubMed

Phillips, Christine B; Pearce, Christopher M; Hall, Sally; Travaglia, Joanne; de Lusignan, Simon; Love, Tom; Kljakovic, Marjan

2010-11-15

To review the literature on different models of clinical governance and to explore their relevance to Australian primary health care, and their potential contributions on quality and safety. 25 electronic databases, scanning reference lists of articles and consultation with experts in the field. We searched publications in English after 1999, but a search of the German language literature for a specific model type was also undertaken. The grey literature was explored through a hand search of the medical trade press and websites of relevant national and international clearing houses and professional or industry bodies. 11 software packages commonly used in Australian general practice were reviewed for any potential contribution to clinical governance. 19 high-quality studies that assessed outcomes were included. All abstracts were screened by one researcher, and 10% were screened by a second researcher to crosscheck screening quality. Studies were reviewed and coded by four reviewers, with all studies being rated using standard critical appraisal tools such as the Strengthening the Reporting of Observational Studies in Epidemiology checklist. Two researchers reviewed the Australian general practice software. Interviews were conducted with 16 informants representing service, regional primary health care, national and international perspectives. Most evidence supports governance models which use targeted, peer-led feedback on the clinician's own practice. Strategies most used in clinical governance models were audit, performance against indicators, and peer-led reflection on evidence or performance. The evidence base for clinical governance is fragmented, and focuses mainly on process rather than outcomes. Few publications address models that enhance safety, efficiency, sustainability and the economics of primary health care. Locally relevant clinical indicators, the use of computerised medical record systems, regional primary health care organisations that have the capacity to support the uptake of clinical governance at the practice level, and learning from the Aboriginal community-controlled sector will help integrate clinical governance into primary care.

Recognition of Potentially Novel Human Disease-Associated Pathogens by Implementation of Systematic 16S rRNA Gene Sequencing in the Diagnostic Laboratory▿ †

PubMed Central

Keller, Peter M.; Rampini, Silvana K.; Büchler, Andrea C.; Eich, Gerhard; Wanner, Roger M.; Speck, Roberto F.; Böttger, Erik C.; Bloemberg, Guido V.

2010-01-01

Clinical isolates that are difficult to identify by conventional means form a valuable source of novel human pathogens. We report on a 5-year study based on systematic 16S rRNA gene sequence analysis. We found 60 previously unknown 16S rRNA sequences corresponding to potentially novel bacterial taxa. For 30 of 60 isolates, clinical relevance was evaluated; 18 of the 30 isolates analyzed were considered to be associated with human disease. PMID:20631113

Mesenchymal stem cell therapy in cats: Current knowledge and future potential.

PubMed

Quimby, Jessica M; Borjesson, Dori L

2018-03-01

Practical relevance: Stem cell therapy is an innovative field of scientific investigation with tremendous potential for clinical application in veterinary medicine. Based on the known desirable immunomodulatory properties of mesenchymal stem cells, this therapy holds promise for the treatment of a variety of inflammatory diseases in cats. This review details our current understanding of feline stem cell biology and proposed mechanism of action. Studies performed in feline clinical trials for diseases including gingivostomatitis, chronic enteropathy, asthma and kidney disease are summarized, with the goal of providing an overview of the current status of this treatment modality and its potential for the future.

Prediction of tamoxifen outcome by genetic variation of CYP2D6 in post-menopausal women with early breast cancer

PubMed Central

Brauch, Hiltrud; Schwab, Matthias

2014-01-01

The question of whether genetic polymorphisms of CYP2D6 can affect treatment outcome in patients with early post-menopausal oestrogen receptor (ER)-positive breast cancer has been a matter of debate over the past few years. In this article we revisit the hypothesis of CYP2D6 being a potential tamoxifen outcome predictor and provide detailed insight into the ongoing controversy that prevented the CYP2D6 marker from being accepted by the scientific and clinical community. We summarize the available pharmacokinetic, pharmacodynamic and pharmacogenetic evidence and resolve the controversy based on the recognized methodological and statistical issues. The cumulative evidence suggests that genotyping for CYP2D6 is clinically relevant in post-menopausal women. This is important, because the clarification of this issue has the potential to resolve a clinical management question that is relevant to hundreds of thousands of women diagnosed with ER-positive breast cancer each year, who should not be denied effective endocrine therapy. PMID:24033728

Breast-Dedicated Radionuclide Imaging Systems.

PubMed

Hsu, David F C; Freese, David L; Levin, Craig S

2016-02-01

Breast-dedicated radionuclide imaging systems show promise for increasing clinical sensitivity for breast cancer while minimizing patient dose and cost. We present several breast-dedicated coincidence-photon and single-photon camera designs that have been described in the literature and examine their intrinsic performance, clinical relevance, and impact. Recent tracer development is mentioned, results from recent clinical tests are summarized, and potential areas for improvement are highlighted. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Classic hallucinogens in the treatment of addictions.

PubMed

Bogenschutz, Michael P; Johnson, Matthew W

2016-01-04

Addictive disorders are very common and have devastating individual and social consequences. Currently available treatment is moderately effective at best. After many years of neglect, there is renewed interest in potential clinical uses for classic hallucinogens in the treatment of addictions and other behavioral health conditions. In this paper we provide a comprehensive review of both historical and recent clinical research on the use of classic hallucinogens in the treatment of addiction, selectively review other relevant research concerning hallucinogens, and suggest directions for future research. Clinical trial data are very limited except for the use of LSD in the treatment of alcoholism, where a meta-analysis of controlled trials has demonstrated a consistent and clinically significant beneficial effect of high-dose LSD. Recent pilot studies of psilocybin-assisted treatment of nicotine and alcohol dependence had strikingly positive outcomes, but controlled trials will be necessary to evaluate the efficacy of these treatments. Although plausible biological mechanisms have been proposed, currently the strongest evidence is for the role of mystical or other meaningful experiences as mediators of therapeutic effects. Classic hallucinogens have an excellent record of safety in the context of clinical research. Given our limited understanding of the clinically relevant effects of classic hallucinogens, there is a wealth of opportunities for research that could contribute important new knowledge and potentially lead to valuable new treatments for addiction. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of Therapeutic Touch in Patients with Cancer: a Literature Review.

PubMed

Tabatabaee, Amir; Tafreshi, Mansoureh Zagheri; Rassouli, Maryam; Aledavood, Seyed Amir; AlaviMajd, Hamid; Farahmand, Seyed Kazem

2016-04-01

The use of complementary and alternative medicine (CAM) techniques has been growing. The National Center for Complementary and Alternative Medicine places therapeutic touch (TT) into the category of bio field energy. This literature review is aimed at critically evaluating the data from clinical trials examining the clinical efficacy of therapeutic touch as a supportive care modality in adult patients with cancer. Electronic databases (PubMed, Scopus, Scholar Google, and Science Direct) were searched from the year 1990 to 2015 to locate potentially relevant peer-reviewed articles using the key words therapeutic touch, touch therapy, neoplasm, cancer, and CAM. Additionally, relevant journals and references of all the located articles were manually searched for other potentially relevant studies. The number of 334 articles was found on the basis of the key words, of which 17 articles related to the clinical trial were examined in accordance with the objectives of the study. A total of 6 articles were in the final dataset in which several examples of the positive effects of healing touch on pain, nausea, anxiety and fatigue, and life quality and also on biochemical parameters were observed. Based on the results of this study, an affirmation can be made regarding the use of TT, as a non-invasive intervention for improving the health status in patients with cancer. Moreover, therapeutic touch was proved to be a useful strategy for adult patients with cancer.

The impact of the glial spatial buffering on the K(+) Nernst potential.

PubMed

Noori, H R

2011-09-01

Astrocytes play a critical role in CNS metabolism, regulation of volume and ion homeostasis of the interstitial space. Of special relevance is their clearance of K(+) that is released by active neurons into the extracellular space. Mathematical analysis of a modified Nernst equation for the electrochemical equilibrium of neuronal plasma membranes, suggests that K(+) uptake by glial cells is not only relevant during neuronal activity but also has a non-neglectable impact on the basic electrical membrane properties, specifically the resting membrane potential, of neurons and might be clinically valuable as a factor in the genetics and epigenetics of the epilepsy and tuberous sclerosis complex.

The Cancer Genome Atlas Clinical Explorer: a web and mobile interface for identifying clinical-genomic driver associations.

PubMed

Lee, HoJoon; Palm, Jennifer; Grimes, Susan M; Ji, Hanlee P

2015-10-27

The Cancer Genome Atlas (TCGA) project has generated genomic data sets covering over 20 malignancies. These data provide valuable insights into the underlying genetic and genomic basis of cancer. However, exploring the relationship among TCGA genomic results and clinical phenotype remains a challenge, particularly for individuals lacking formal bioinformatics training. Overcoming this hurdle is an important step toward the wider clinical translation of cancer genomic/proteomic data and implementation of precision cancer medicine. Several websites such as the cBio portal or University of California Santa Cruz genome browser make TCGA data accessible but lack interactive features for querying clinically relevant phenotypic associations with cancer drivers. To enable exploration of the clinical-genomic driver associations from TCGA data, we developed the Cancer Genome Atlas Clinical Explorer. The Cancer Genome Atlas Clinical Explorer interface provides a straightforward platform to query TCGA data using one of the following methods: (1) searching for clinically relevant genes, micro RNAs, and proteins by name, cancer types, or clinical parameters; (2) searching for genomic/proteomic profile changes by clinical parameters in a cancer type; or (3) testing two-hit hypotheses. SQL queries run in the background and results are displayed on our portal in an easy-to-navigate interface according to user's input. To derive these associations, we relied on elastic-net estimates of optimal multiple linear regularized regression and clinical parameters in the space of multiple genomic/proteomic features provided by TCGA data. Moreover, we identified and ranked gene/micro RNA/protein predictors of each clinical parameter for each cancer. The robustness of the results was estimated by bootstrapping. Overall, we identify associations of potential clinical relevance among genes/micro RNAs/proteins using our statistical analysis from 25 cancer types and 18 clinical parameters that include clinical stage or smoking history. The Cancer Genome Atlas Clinical Explorer enables the cancer research community and others to explore clinically relevant associations inferred from TCGA data. With its accessible web and mobile interface, users can examine queries and test hypothesis regarding genomic/proteomic alterations across a broad spectrum of malignancies.

Systematic review on the use of matrix-bound sealants in pancreatic resection.

PubMed

Smits, F Jasmijn; van Santvoort, Hjalmar C; Besselink, Marc G H; Borel Rinkes, Inne H M; Molenaar, I Quintus

2015-11-01

Pancreatic fistula is a potentially life-threatening complication after a pancreatic resection. The aim of this systematic review was to evaluate the role of matrix-bound sealants after a pancreatic resection in terms of preventing or ameliorating the course of a post-operative pancreatic fistula. A systematic search was performed in the literature from May 2005 to April 2015. Included were clinical studies using matrix-bound sealants after a pancreatic resection, reporting a post-operative pancreatic fistula (POPF) according to the International Study Group on Pancreatic Fistula classification, in which grade B and C fistulae were considered clinically relevant. Two were studies on patients undergoing pancreatoduodenectomy (sealants n = 67, controls n = 27) and four studies on a distal pancreatectomy (sealants n = 258, controls n = 178). After a pancreatoduodenectomy, 13% of patients treated with sealants versus 11% of patients without sealants developed a POPF (P = 0.76), of which 4% versus 4% were clinically relevant (P = 0.87). After a distal pancreatectomy, 42% of patients treated with sealants versus 52% of patients without sealants developed a POPF (P = 0.03). Of these, 9% versus 12% were clinically relevant (P = 0.19). The present data do not support the routine use of matrix-bound sealants after a pancreatic resection, as there was no effect on clinically relevant POPF. Larger, well-designed studies are needed to determine the efficacy of sealants in preventing POPF after a pancreatoduodenectomy. © 2015 International Hepato-Pancreato-Biliary Association.

Comparative study between ultrasonography and optical coherence tomography in interventional cardiology

NASA Astrophysics Data System (ADS)

Fanjul-Vélez, Félix; de la Torre-Hernández, José María; Ortega-Quijano, Noé; Zueco-Gil, José Javier; Arce-Diego, José Luis

2009-07-01

In this work, we present clinical images of IVUS and OCT in the evaluation of pharmacological stent endothelization. These preliminary imaging results are analyzed and compared in order to determine the ability of these technologies to visualize relevant intravascular features of interest in interventional cardiology. The results enable to compare the performance of both techniques and to evaluate their potential for clinical purposes.

Health Literacy and Atrial Fibrillation: Relevance and Future Directions for Patient-centred Care.

PubMed

Aronis, Konstantinos N; Edgar, Brittany; Lin, Wendy; Martins, Maria Auxiliadora Parreiras; Paasche-Orlow, Michael K; Magnani, Jared W

2017-01-01

Atrial fibrillation (AF) is a common cardiac arrhythmia with significant clinical outcomes, and is associated with high medical and social costs. AF is complicated for patients because of its specialised terminology, long-term adherence, symptom monitoring, referral to specialty care, array of potential interventions and potential for adversity. Health literacy is a frequently under-recognised, yet fundamental, component towards successful care in AF. Health literacy is defined as the capacity to obtain, process and understand health information, and has had markedly limited study in AF. However, health literacy could contribute to how patients interpret symptoms, navigate care, and participate in treatment evaluation and decision-making. This review aims to summarise the clinical importance and essential relevance of health literacy in AF. We focus here on central aspects of AF care that are most related to self-care, including understanding the symptoms of AF, shared decision-making, adherence and anticoagulation for stroke prevention. We discuss opportunities to enhance AF care based on findings from the literature on health literacy, and identify important gaps. Our overall objective is to articulate the importance and relevance of integrating health literacy in the care of individuals with AF.

Modeling BAS Dysregulation in Bipolar Disorder.

PubMed

Hamaker, Ellen L; Grasman, Raoul P P P; Kamphuis, Jan Henk

2016-08-01

Time series analysis is a technique that can be used to analyze the data from a single subject and has great potential to investigate clinically relevant processes like affect regulation. This article uses time series models to investigate the assumed dysregulation of affect that is associated with bipolar disorder. By formulating a number of alternative models that capture different kinds of theoretically predicted dysregulation, and by comparing these in both bipolar patients and controls, we aim to illustrate the heuristic potential this method of analysis has for clinical psychology. We argue that, not only can time series analysis elucidate specific maladaptive dynamics associated with psychopathology, it may also be clinically applied in symptom monitoring and the evaluation of therapeutic interventions.

Automation and apps for clinical dental biomechanics.

PubMed

Adams, Bruce W

2016-09-01

The aim of this research summary is to introduce the current and ongoing work using smartphone video, tracking markers to measure musculoskeletal disorders of cranial and mandibular origin, and the potential significance of the technology to doctors and therapists. The MPA™ biomechanical measuring apps are in beta trials with various doctors and therapists. The technique requires substantial image processing and statistical analysis, best suited to server-side processing. A smartphone environment has enabled a virtual laboratory, which provides automated generation of graphics and in some cases automated interpretation. The system enables highly accurate real-time biomechanics studies using only a smartphone and tracking markers. Despite the technical challenges in setting up and testing of the virtual environment and with interpretation of clinical relevance, the trials have enabled a demonstration of real-time biomechanics studies. The technology has prompted a lot of discussion about the relevance of rapid assessment tools in clinical practice. It seems that a prior bias against motion tracking and its relevance is very strong with occlusion related use cases, yet there has been a general agreement about the use case for cranial movement tracking in managing complex issues related to the head, neck, and TMJ. Measurement of cranial and mandibular functions using a smartphone video as the input have been investigated. Ongoing research will depend upon doctors and therapists to provide feedback as to which uses are considered clinically relevant.

Clinical relevance vs. statistical significance: Using neck outcomes in patients with temporomandibular disorders as an example.

PubMed

Armijo-Olivo, Susan; Warren, Sharon; Fuentes, Jorge; Magee, David J

2011-12-01

Statistical significance has been used extensively to evaluate the results of research studies. Nevertheless, it offers only limited information to clinicians. The assessment of clinical relevance can facilitate the interpretation of the research results into clinical practice. The objective of this study was to explore different methods to evaluate the clinical relevance of the results using a cross-sectional study as an example comparing different neck outcomes between subjects with temporomandibular disorders and healthy controls. Subjects were compared for head and cervical posture, maximal cervical muscle strength, endurance of the cervical flexor and extensor muscles, and electromyographic activity of the cervical flexor muscles during the CranioCervical Flexion Test (CCFT). The evaluation of clinical relevance of the results was performed based on the effect size (ES), minimal important difference (MID), and clinical judgement. The results of this study show that it is possible to have statistical significance without having clinical relevance, to have both statistical significance and clinical relevance, to have clinical relevance without having statistical significance, or to have neither statistical significance nor clinical relevance. The evaluation of clinical relevance in clinical research is crucial to simplify the transfer of knowledge from research into practice. Clinical researchers should present the clinical relevance of their results. Copyright © 2011 Elsevier Ltd. All rights reserved.

Engineering toxin-resistant therapeutic stem cells to treat brain tumors

PubMed Central

Stuckey, Daniel W.; Hingtgen, Shawn D.; Karakas, Nihal; Rich, Benjamin E.; Shah, Khalid

2014-01-01

Pseudomonas exotoxin (PE) potently blocks protein synthesis by catalyzing the inactivation of elongation factor-2 (EF-2), and PE-cytotoxins have been used as anti-tumor agents. However, their effective clinical translation in solid tumors has been confounded by off-target delivery, systemic toxicity and short chemotherapeutic half-life. To overcome these limitations we have created toxin-resistant stem cells by modifying endogenous EF-2, and engineered them to secrete PE-cytotoxins targeting IL13Rα2 and EGFR expressed by many glioblastomas (GBM). Molecular analysis correlated efficacy of PE-targeted cytotoxins with levels of cognate receptor expression, and optical imaging was applied to simultaneously track the kinetics of protein synthesis inhibition and GBM cell viability in vivo. Stem cell-based delivery of IL13-PE in a clinically-relevant GBM resection model led to increased long-term survival of mice compared to IL13-PE protein infusion. Moreover, multiple patient-derived GBM lines responded to treatment, underscoring its clinical relevance. In sum, integrating stem cell-based engineering, multimodal imaging and delivery of PE-cytotoxins in a clinically-relevant GBM model represents a novel strategy and a potential advancement in GBM therapy. PMID:25346520

Case-based reasoning using electronic health records efficiently identifies eligible patients for clinical trials

PubMed Central

Miotto, Riccardo

2015-01-01

Objective To develop a cost-effective, case-based reasoning framework for clinical research eligibility screening by only reusing the electronic health records (EHRs) of minimal enrolled participants to represent the target patient for each trial under consideration. Materials and Methods The EHR data—specifically diagnosis, medications, laboratory results, and clinical notes—of known clinical trial participants were aggregated to profile the “target patient” for a trial, which was used to discover new eligible patients for that trial. The EHR data of unseen patients were matched to this “target patient” to determine their relevance to the trial; the higher the relevance, the more likely the patient was eligible. Relevance scores were a weighted linear combination of cosine similarities computed over individual EHR data types. For evaluation, we identified 262 participants of 13 diversified clinical trials conducted at Columbia University as our gold standard. We ran a 2-fold cross validation with half of the participants used for training and the other half used for testing along with other 30 000 patients selected at random from our clinical database. We performed binary classification and ranking experiments. Results The overall area under the ROC curve for classification was 0.95, enabling the highlight of eligible patients with good precision. Ranking showed satisfactory results especially at the top of the recommended list, with each trial having at least one eligible patient in the top five positions. Conclusions This relevance-based method can potentially be used to identify eligible patients for clinical trials by processing patient EHR data alone without parsing free-text eligibility criteria, and shows promise of efficient “case-based reasoning” modeled only on minimal trial participants. PMID:25769682

Prevalence of statin-drug interactions in older people: a systematic review.

PubMed

Thai, Michele; Reeve, Emily; Hilmer, Sarah N; Qi, Katie; Pearson, Sallie-Anne; Gnjidic, Danijela

2016-05-01

Statins are among the most frequently prescribed medications internationally. Older people are commonly prescribed multiple medications and are at an increased risk of drug-drug interactions, including statin-drug interactions. The aim of this study was to conduct a systematic review of current evidence on the prevalence of statin-drug interactions in older people. A systematic search of observational studies in Embase, Medline, and PubMed was conducted. Articles were included if they were published in English during the period July 2000-July 2014 and reported on the prevalence of statin-drug interactions in people over 65 years of age. Two reviewers independently assessed the articles for eligibility and extracted the data. The search returned 1556 eligible articles. A total of 19 articles met the inclusion criteria. In studies (n = 7) that focused on statin users only, the prevalence of potential statin-drug interactions assessed using different measures ranged from 0.19 to 33.0 %. In studies that examined drug interactions across a population of both statin users and non-users (n = 12), the prevalence of potential statin-drug interactions ranged from 0.1 to 7.1 % (n = 8), and the prevalence of clinically relevant statin-drug interactions ranged from 1.5 to 4 % (n = 4). Current published evidence suggests substantial variations in the prevalence of statin-drug interactions and their clinical relevance. Further studies are necessary to provide a better understanding of the prevalence of clinically significant statin-drug interactions, the medications most frequently contributing to statin-drug interactions, and impact on relevant clinical outcomes in older people.

Approaches for Establishing Clinically Relevant Dissolution Specifications for Immediate Release Solid Oral Dosage Forms.

PubMed

Hermans, Andre; Abend, Andreas M; Kesisoglou, Filippos; Flanagan, Talia; Cohen, Michael J; Diaz, Dorys A; Mao, Y; Zhang, Limin; Webster, Gregory K; Lin, Yiqing; Hahn, David A; Coutant, Carrie A; Grady, Haiyan

2017-11-01

This manuscript represents the perspective of the Dissolution Analytical Working Group of the IQ Consortium. The intent of this manuscript is to highlight the challenges of, and to provide a recommendation on, the development of clinically relevant dissolution specifications (CRS) for immediate release (IR) solid oral dosage forms. A roadmap toward the development of CRS for IR products containing active ingredients with a non-narrow therapeutic window is discussed, within the context of mechanistic dissolution understanding, supported by in-human pharmacokinetic (PK) data. Two case studies present potential outcomes of following the CRS roadmap and setting dissolution specifications. These cases reveal some benefits and challenges of pursuing CRS with additional PK data, in light of current regulatory positions, including that of the US Food and Drug Administration (FDA), who generally favor this approach, but with the understanding that both industry and regulatory agency perspectives are still evolving in this relatively new field. The CRS roadmap discussed in this manuscript also describes a way to develop clinically relevant dissolution specifications based primarily on dissolution data for batches used in pivotal clinical studies, acknowledging that not all IR product development efforts need to be supported by additional PK studies, albeit with the associated risk of potentially unnecessarily tight manufacturing controls. Recommendations are provided on what stages during the life cycle investment into in vivo studies may be valuable. Finally, the opportunities for CRS within the context of post-approval changes, Modeling and Simulation (M&S), and the application of biowaivers, are briefly discussed.

Clinical empathy and narrative competence: the relevance of reading talmudic legends as literary fiction.

PubMed

Davidson, John H

2015-04-01

The "curative potential" in almost any clinical setting depends on a caregiver establishing and maintaining an empathic connection with patients so as to achieve "narrative competence" in discerning and acting in accord with their preferences and best interests. The "narrative medicine" model of shared "close reading of literature and reflective writing" among clinicians as a means of fostering a capacity for clinical empathy has gained validation with recent empirical studies demonstrating the enhancement of theory of mind (ToM), broadly conceived as empathy, in readers of literary fiction. Talmudic legends, like that of Rabbi Judah's death, are under-appreciated, relevant sources of literary fiction for these efforts. The limitations of narrative medicine are readily counterbalanced by simultaneously practiced attention to traditional bioethical principles, including-especially-beneficence, non-maleficence, and autonomy.

An integrative model for in-silico clinical-genomics discovery science.

PubMed

Lussier, Yves A; Sarkar, Indra Nell; Cantor, Michael

2002-01-01

Human Genome discovery research has set the pace for Post-Genomic Discovery Research. While post-genomic fields focused at the molecular level are intensively pursued, little effort is being deployed in the later stages of molecular medicine discovery research, such as clinical-genomics. The objective of this study is to demonstrate the relevance and significance of integrating mainstream clinical informatics decision support systems to current bioinformatics genomic discovery science. This paper is a feasibility study of an original model enabling novel "in-silico" clinical-genomic discovery science and that demonstrates its feasibility. This model is designed to mediate queries among clinical and genomic knowledge bases with relevant bioinformatic analytic tools (e.g. gene clustering). Briefly, trait-disease-gene relationships were successfully illustrated using QMR, OMIM, SNOMED-RT, GeneCluster and TreeView. The analyses were visualized as two-dimensional dendrograms of clinical observations clustered around genes. To our knowledge, this is the first study using knowledge bases of clinical decision support systems for genomic discovery. Although this study is a proof of principle, it provides a framework for the development of clinical decision-support-system driven, high-throughput clinical-genomic technologies which could potentially unveil significant high-level functions of genes.

Clinical Confirmation that the Selective JAK1 Inhibitor Filgotinib (GLPG0634) has a Low Liability for Drug-drug Interactions.

PubMed

Namour, Florence; Desrivot, Julie; Van der Aa, Annegret; Harrison, Pille; Tasset, Chantal; van't Klooster, Gerben

2016-01-01

The selective Janus kinase 1 inhibitor filgotinib (GLPG0634), which is currently in clinical development for the treatment of rheumatoid arthritis (RA) and Crohn's disease, demonstrated encouraging safety and efficacy profiles in RA patients after 4 weeks of daily dosing. As RA patients might be treated with multiple medications simultaneously, possible drug-drug interactions of filgotinib with cytochrome P450 enzymes and with key drug transporters were evaluated in vitro and in clinical studies. The enzymes involved in filgotinib's metabolism and the potential interactions of the parent and its active major metabolite with drug-metabolizing enzymes and drug transporters, were identified using recombinant enzymes, human microsomes, and cell systems. Furthermore, filgotinib's interaction potential with CYP3A4 was examined in an open-label study in healthy volunteers, which evaluated the impact of filgotinib co-administration on the CYP3A4-sensitive substrate midazolam. The potential interaction with the common RA drug methotrexate was investigated in a clinical study in RA patients. In vitro, filgotinib and its active metabolite at clinically relevant concentrations did not interact with cytochrome P450 enzymes and uridine 5'-diphospho-glucuronosyltransferases, and did not inhibit key drug transporters. In the clinic, a lack of relevant pharmacokinetic drug interactions by filgotinib and its active metabolite with substrates of CYP3A4, as well as with organic anion transporters involved in methotrexate elimination were found. the collective in vivo and in vitro data on drug-metabolizing enzymes and on key drug transporters, support co-administration of filgotinib with commonly used RA drugs to patients without the need for dose adjustments.

Repeated ischaemic preconditioning: a novel therapeutic intervention and potential underlying mechanisms.

PubMed

Thijssen, Dick H J; Maxwell, Joseph; Green, Daniel J; Cable, N Timothy; Jones, Helen

2016-06-01

What is the topic of this review? This review discusses the effects of repeated exposure of tissue to ischaemic preconditioning on cardiovascular function, the attendant adaptations and their potential clinical relevance. What advances does it highlight? We discuss the effects of episodic exposure to ischaemic preconditioning to prevent and/or attenuate ischaemic injury and summarize evidence pertaining to improvements in cardiovascular function and structure. Discussion is provided regarding the potential mechanisms that contribute to both local and systemic adaptation. Findings suggest that clinical benefits result from both the prevention of ischaemic events and the attenuation of their consequences. Ischaemic preconditioning (IPC) refers to the phenomenon whereby short periods of cyclical tissue ischaemia confer subsequent protection against ischaemia-induced injury. As a consequence, IPC can ameliorate the myocardial damage following infarction and can reduce infarct size. The ability of IPC to confer remote protection makes IPC a potentially feasible cardioprotective strategy. In this review, we discuss the concept that repeated exposure of tissue to IPC may increase the 'dose' of protection and subsequently lead to enhanced protection against ischaemia-induced myocardial injury. This may be relevant for clinical populations, who demonstrate attenuated efficacy of IPC to prevent or attenuate ischaemic injury (and therefore myocardial infarct size). Furthermore, episodic IPC facilitates repeated exposure to local (e.g. shear stress) and systemic stimuli (e.g. hormones, cytokines, blood-borne substances), which may induce improvement in vascular function and health. Such adaptation may contribute to prevention of cardio- and cerebrovascular events. The clinical benefits of repeated IPC may, therefore, result from both the prevention of ischaemic events and the attenuation of their consequences. We provide an overview of the literature pertaining to the impact of repeated IPC on cardiovascular function, related to both local and remote adaptation, as well as potential clinical implications. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

New and emerging technologies for the treatment of inherited retinal diseases: a horizon scanning review.

PubMed

Smith, J; Ward, D; Michaelides, M; Moore, A T; Simpson, S

2015-09-01

The horizon scanning review aimed to identify new and emerging technologies in development that have the potential to slow or stop disease progression and/or reverse sight loss in people with inherited retinal diseases (IRDs). Potential treatments were identified using recognized horizon scanning methods. These included a combination of online searches using predetermined search terms, suggestions from clinical experts and patient and carer focus groups, and contact with commercial developers. Twenty-nine relevant technologies were identified. These included 9 gene therapeutic approaches, 10 medical devices, 5 pharmacological agents, and 5 regenerative and cell therapies. A further 11 technologies were identified in very early phases of development (typically phase I or pre-clinical) and were included in the final report to give a complete picture of developments 'on the horizon'. Clinical experts and patient and carer focus groups provided helpful information and insights, such as the availability of specialised services for patients, the potential impacts of individual technologies on people with IRDs and their families, and helped to identify additional relevant technologies. This engagement ensured that important areas of innovation were not missed. Most of the health technologies identified are still at an early stage of development and it is difficult to estimate when treatments might be available. Further, well designed trials that generate data on efficacy, applicability, acceptability, and costs of the technologies, as well as the long-term impacts for various conditions are required before these can be considered for adoption into routine clinical practice.

Walk-in clinics versus physician offices and emergency rooms for urgent care and chronic disease management.

PubMed

Chen, Connie E; Chen, Christopher T; Hu, Jia; Mehrotra, Ateev

2017-02-17

Walk-in clinics are growing in popularity around the world as a substitute for traditional medical care delivered in physician offices and emergency rooms, but their clinical efficacy is unclear. To assess the quality of care and patient satisfaction of walk-in clinics compared to that of traditional physician offices and emergency rooms for people who present with basic medical complaints for either acute or chronic issues. We searched CENTRAL, MEDLINE, Embase, six other databases, and two trials registers on 22 March 2016 together with reference checking, citation searching, and contact with study authors to identify additional studies. We applied no restrictions on language, publication type, or publication year. Study design: randomized trials, non-randomized trials, and controlled before-after studies. standalone physical clinics not requiring advance appointments or registration, that provided basic medical care without expectation of follow-up. Comparisons: traditional primary care practices or emergency rooms. We used standard methodological procedures expected by Cochrane and the Cochrane Effective Practice and Organisation of Care (EPOC) Group. The literature search identified 6587 citations, of which we considered 65 to be potentially relevant. We reviewed the abstracts of all 65 potentially relevant studies and retrieved the full texts of 12 articles thought to fit our study criteria. However, following independent author assessment of the full texts, we excluded all 12 articles. Controlled trial evidence about the mortality, morbidity, quality of care, and patient satisfaction of walk-in clinics is currently not available.

Emerging point of care tests for influenza: innovation or status quo.

PubMed

Tayo, Adeoluwa; Ellis, Joanna; Linden Phillips, Luan; Simpson, Sue; Ward, Derek J

2012-07-01

Point of care tests (POCTs) for influenza potentially offer earlier diagnosis, enabling specific treatment, infection control measures and greater patient convenience and satisfaction. Current POCTs have limited sensitivity, some cannot distinguish influenza types, none differentiate subtypes and are relatively expensive.  To identify and characterise influenza POCTs expected to be available for clinical use in the U.K. by mid-2013, highlighting those with potential benefits over existing tests. Potential developers of influenza POCTs were identified through known manufacturers' websites, Medical Technology trade associations, the EuroScan International Network, an expert advisory group and by searching relevant online sources. Identified companies were asked to provide standard information on relevant technologies. Fifty-six companies were identified, and 29 (52%) responded, identifying 57 potentially relevant technologies. Of these, 40 (70%) were already available or had undetermined status and 5 (9%) were excluded as time to results took over 60 minutes. Of the remaining 12 emerging POCTs, 10 (83%) reportedly enabled differentiation of influenza types and eight differentiation of A subtypes. Nasopharyngeal swabs were the most commonly acceptable sample type; the sample volume ranging from 80 μl to 1.4 ml. Most identified emerging influenza POCTs offered differentiation of influenza type and subtype. Tests claiming this capability include several incorporating reverse transcription polymerase chain reaction assays; though, these also had the longest time to result. However, whilst some identified POCTs exhibit high sensitivity and specificity, most lack published clinical data for assessment, and the overall costs of these technologies remains largely unknown. © 2011 Blackwell Publishing Ltd.

Systematic review on the use of matrix-bound sealants in pancreatic resection

PubMed Central

Smits, F Jasmijn; van Santvoort, Hjalmar C; Besselink, Marc G H; Borel Rinkes, Inne H M; Molenaar, I Quintus

2015-01-01

Background Pancreatic fistula is a potentially life-threatening complication after a pancreatic resection. The aim of this systematic review was to evaluate the role of matrix-bound sealants after a pancreatic resection in terms of preventing or ameliorating the course of a post-operative pancreatic fistula. Methods A systematic search was performed in the literature from May 2005 to April 2015. Included were clinical studies using matrix-bound sealants after a pancreatic resection, reporting a post-operative pancreatic fistula (POPF) according to the International Study Group on Pancreatic Fistula classification, in which grade B and C fistulae were considered clinically relevant. Results Two were studies on patients undergoing pancreatoduodenectomy (sealants n = 67, controls n = 27) and four studies on a distal pancreatectomy (sealants n = 258, controls n = 178). After a pancreatoduodenectomy, 13% of patients treated with sealants versus 11% of patients without sealants developed a POPF (P = 0.76), of which 4% versus 4% were clinically relevant (P = 0.87). After a distal pancreatectomy, 42% of patients treated with sealants versus 52% of patients without sealants developed a POPF (P = 0.03). Of these, 9% versus 12% were clinically relevant (P = 0.19). Conclusions The present data do not support the routine use of matrix-bound sealants after a pancreatic resection, as there was no effect on clinically relevant POPF. Larger, well-designed studies are needed to determine the efficacy of sealants in preventing POPF after a pancreatoduodenectomy. PMID:26292846

[Potential improvements in medical education as retrospectively evaluated by candidates for specialist examinations].

PubMed

Hofer, M; Jansen, M; Soboll, S

2006-02-24

As part of the new regulations for licensing doctors there have been numerous attempts at reform by many medical faculties to consider interdisciplinary linkage of the curriculum with emphasis on teaching of small groups of students. This study was undertaken to help answer the question of how much weight should be given to the various subjects and what resources are needed for any reformed curriculum and what key areas of competence need to be given greater importance. 1029 candidates of specialist examinations of the Medical Council of North-Rhine in 2002 and 2003 filled in questionnaires to evaluate retrospectively the actual relevance of individual preclinical and clinical subjects, courses and areas of practical competence to their further medical education and related potentials for improvement in their studies. The participants were from 5 medical faculties in the North-Rhine area of Germany. They were also asked about methods of examination that were effective in aiding their learning behaviour. Those answering the questionnaire considered especially chemistry and physics as well as environmental, occupational and forensic medicine, bio-mathematics, radiotherapy and nuclear medicine among the less relevant subjects. On the other hand, anatomy, physiology, internal medicine, pharmacology and surgery were considered especially relevant. The greatest deficiencies in most of the medical curricula as taught in the North-Rhine medical courses are in the areas of competence in communication and practical clinical skills. Members of this group also pleaded for an increased use of standardized objective structured clinical examinations (OSCE).

Effect of Therapeutic Touch in Patients with Cancer: a Literature Review

PubMed Central

Tabatabaee, Amir; Tafreshi, Mansoureh Zagheri; Rassouli, Maryam; Aledavood, Seyed Amir; AlaviMajd, Hamid; Farahmand, Seyed Kazem

2016-01-01

Background: The use of complementary and alternative medicine (CAM) techniques has been growing. The National Center for Complementary and Alternative Medicine places therapeutic touch (TT) into the category of bio field energy. This literature review is aimed at critically evaluating the data from clinical trials examining the clinical efficacy of therapeutic touch as a supportive care modality in adult patients with cancer. Methods: Electronic databases (PubMed, Scopus, Scholar Google, and Science Direct) were searched from the year 1990 to 2015 to locate potentially relevant peer-reviewed articles using the key words therapeutic touch, touch therapy, neoplasm, cancer, and CAM. Additionally, relevant journals and references of all the located articles were manually searched for other potentially relevant studies. Results: The number of 334 articles was found on the basis of the key words, of which 17 articles related to the clinical trial were examined in accordance with the objectives of the study. A total of 6 articles were in the final dataset in which several examples of the positive effects of healing touch on pain, nausea, anxiety and fatigue, and life quality and also on biochemical parameters were observed. Conclusion: Based on the results of this study, an affirmation can be made regarding the use of TT, as a non-invasive intervention for improving the health status in patients with cancer. Moreover, therapeutic touch was proved to be a useful strategy for adult patients with cancer. PMID:27194823

Understanding the Potential Interethnic Difference in Rosuvastatin Pharmacokinetics.

PubMed

Benet, Leslie Z; Wu, Hsin-Fang

2017-09-01

Here we address the potential difference in rosuvastatin pharmacokinetics in Asians vs. whites. Our prospective study, reported in this issue, shows no ethnic difference when all subjects are wild-type for OATP1B1 and BCRP. We argue that although our study may be under powered to prove no ethnic difference, and that further confirmatory study is required, the virtual clinical study analysis, also reported in this issue, does not contradict the results of our prospective clinical study and that previous retrospective analysis of clinical studies does not include enough relevant subjects to conclude that wild-type OATP1B1 and BCRP do still demonstrate ethnic differences. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Mobile Mental Health: Navigating New Rules and Regulations for Digital Tools.

PubMed

Armontrout, James; Torous, John; Fisher, Matthew; Drogin, Eric; Gutheil, Thomas

2016-10-01

Mobile health (mHealth) apps are becoming much more widely available. As more patients learn about and download apps, clinicians are sure to face more questions about the role these apps can play in treatment. Clinicians thus need to familiarize themselves with the clinical and legal risks that apps may introduce. Regulatory rules and organizations that oversee the safety and efficacy of mHealth apps are currently fragmentary in nature and clinicians should pay special attention to categories of apps which are currently exempt from significant regulation. Uniform HIPAA protection does not apply to personal health data that are shared with apps in many contexts which creates a number of clinically relevant privacy and security concerns. Clinicians should also consider several relatively novel potential adverse clinical outcomes and liability concerns that may be relevant to specific categories of apps, including apps that target (i) medication adherence, (ii) collection of self-reported data, (iii) collection of passive data, and (iv) generation of treatment recommendations for psychotherapeutic and behavioral interventions. Considering these potential pitfalls (and disclosing them to patients as a part of obtaining informed consent) is necessary as clinicians consider incorporating apps into treatment.

Systemic Sclerosis Disease Modification Clinical Trials Design: Quo Vadis?

PubMed Central

Mendoza, Fabian A.; Keyes-Elstein, Lynette L.; Jimenez, Sergio A.

2012-01-01

The purpose of this manuscript is to discuss relevant aspects of clinical trials for Systemic Sclerosis (SSc) and to identify important considerations for the design of SSc disease modification clinical trials. Placebo randomized controlled trials with appropriate identification of SSc patients with diffuse progressive SSc skin involvement of recent onset, along with a rescue strategy for patients with worsening lung and skin involvement are suggested. If change in skin thickening is a major outcome of the study, the selection of patients with recent onset of disease and a predetermined degree of skin involvement are crucial requirements. The trial duration should be of at least 12 months. Sample size calculations should consider differences that exceed the Minimal Important Difference. Other relevant trial designs and potential threats to study validity are also discussed. Previous SSc-disease modifying trials have been beset by high dropout rates. Analyses on the subset of subjects completing the trial or applying the last-observation-carried-forward approach can potentially lead to biased estimates and false conclusions. Strategies for retention of subjects should be included at the design stage and analyses to account for missing data should be performed. PMID:22422541

The Rise of Allogeneic Natural Killer Cells As a Platform for Cancer Immunotherapy: Recent Innovations and Future Developments

PubMed Central

Veluchamy, John P.; Kok, Nina; van der Vliet, Hans J.; Verheul, Henk M. W.; de Gruijl, Tanja D.; Spanholtz, Jan

2017-01-01

Natural killer (NK) cells are critical immune effector cells in the fight against cancer. As NK cells in cancer patients are highly dysfunctional and reduced in number, adoptive transfer of large numbers of cytolytic NK cells and their potential to induce relevant antitumor responses are widely explored in cancer immunotherapy. Early studies from autologous NK cells have failed to demonstrate significant clinical benefit. In this review, the clinical benefits of adoptively transferred allogeneic NK cells in a transplant and non-transplant setting are compared and discussed in the context of relevant NK cell platforms that are being developed and optimized by various biotech industries with a special focus on augmenting NK cell functions. PMID:28620386

SFINX-a drug-drug interaction database designed for clinical decision support systems.

PubMed

Böttiger, Ylva; Laine, Kari; Andersson, Marine L; Korhonen, Tuomas; Molin, Björn; Ovesjö, Marie-Louise; Tirkkonen, Tuire; Rane, Anders; Gustafsson, Lars L; Eiermann, Birgit

2009-06-01

The aim was to develop a drug-drug interaction database (SFINX) to be integrated into decision support systems or to be used in website solutions for clinical evaluation of interactions. Key elements such as substance properties and names, drug formulations, text structures and references were defined before development of the database. Standard operating procedures for literature searches, text writing rules and a classification system for clinical relevance and documentation level were determined. ATC codes, CAS numbers and country-specific codes for substances were identified and quality assured to ensure safe integration of SFINX into other data systems. Much effort was put into giving short and practical advice regarding clinically relevant drug-drug interactions. SFINX includes over 8,000 interaction pairs and is integrated into Swedish and Finnish computerised decision support systems. Over 31,000 physicians and pharmacists are receiving interaction alerts through SFINX. User feedback is collected for continuous improvement of the content. SFINX is a potentially valuable tool delivering instant information on drug interactions during prescribing and dispensing.

Inhaled phage therapy: a promising and challenging approach to treat bacterial respiratory infections.

PubMed

Bodier-Montagutelli, Elsa; Morello, Eric; L'Hostis, Guillaume; Guillon, Antoine; Dalloneau, Emilie; Respaud, Renaud; Pallaoro, Nikita; Blois, Hélène; Vecellio, Laurent; Gabard, Jérôme; Heuzé-Vourc'h, Nathalie

2017-08-01

Bacterial respiratory tract infections (RTIs) are increasingly difficult to treat due to evolving antibiotic resistance. In this context, bacteriophages (or phages) are part of the foreseen alternatives or combination therapies. Delivering phages through the airways seems more relevant to accumulate these natural antibacterial viruses in proximity to their bacterial host, within the infectious site. Areas covered: This review addresses the potential of phage therapy to treat RTIs and discusses preclinical and clinical results of phages administration in this context. Recent phage formulation and aerosolization attempts are also reviewed, raising technical challenges to achieve efficient pulmonary deposition via inhalation. Expert opinion: Overall, the inhalation of phages as antibacterial treatment seems both clinically relevant and technically feasible. Several crucial points still need to be investigated, such as phage product pharmacokinetics and immunogenicity. Furthermore, given phage-specific features, appropriate regulatory and manufacturing guidelines will need to be defined. Finally, randomized controlled clinical trials should be carried out to establish phage therapy's clinical positioning in the antimicrobial arsenal against RTIs.

Brain-computer interfaces for EEG neurofeedback: peculiarities and solutions.

PubMed

Huster, René J; Mokom, Zacharais N; Enriquez-Geppert, Stefanie; Herrmann, Christoph S

2014-01-01

Neurofeedback training procedures designed to alter a person's brain activity have been in use for nearly four decades now and represent one of the earliest applications of brain-computer interfaces (BCI). The majority of studies using neurofeedback technology relies on recordings of the electroencephalogram (EEG) and applies neurofeedback in clinical contexts, exploring its potential as treatment for psychopathological syndromes. This clinical focus significantly affects the technology behind neurofeedback BCIs. For example, in contrast to other BCI applications, neurofeedback BCIs usually rely on EEG-derived features with only a minimum of additional processing steps being employed. Here, we highlight the peculiarities of EEG-based neurofeedback BCIs and consider their relevance for software implementations. Having reviewed already existing packages for the implementation of BCIs, we introduce our own solution which specifically considers the relevance of multi-subject handling for experimental and clinical trials, for example by implementing ready-to-use solutions for pseudo-/sham-neurofeedback. © 2013.

ERP C250 shows the elderly (cognitively normal, Alzheimer's disease) store more stimuli in short-term memory than Young Adults do.

PubMed

Chapman, Robert M; Gardner, Margaret N; Mapstone, Mark; Klorman, Rafael; Porsteinsson, Anton P; Dupree, Haley M; Antonsdottir, Inga M; Kamalyan, Lily

2016-06-01

To determine how aging and dementia affect the brain's initial storing of task-relevant and irrelevant information in short-term memory. We used brain Event-Related Potentials (ERPs) to measure short-term memory storage (ERP component C250) in 36 Young Adults, 36 Normal Elderly, and 36 early-stage AD subjects. Participants performed the Number-Letter task, a cognitive paradigm requiring memory storage of a first relevant stimulus to compare it with a second stimulus. In Young Adults, C250 was more positive for the first task-relevant stimulus compared to all other stimuli. C250 in Normal Elderly and AD subjects was roughly the same to relevant and irrelevant stimuli in Intratrial Parts 1-3 but not 4. The AD group had lower C250 to relevant stimuli in part 1. Both normal aging and dementia cause less differentiation of relevant from irrelevant information in initial storage. There was a large aging effect involving differences in the pattern of C250 responses of the Young Adult versus the Normal Elderly/AD groups. Also, a potential dementia effect was obtained. C250 is a candidate tool for measuring short-term memory performance on a biological level, as well as a potential marker for memory changes due to normal aging and dementia. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

PubMed

Rizzo, Alicia N; Sammani, Saad; Esquinca, Adilene E; Jacobson, Jeffrey R; Garcia, Joe G N; Letsiou, Eleftheria; Dudek, Steven M

2015-12-01

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak. Copyright © 2015 the American Physiological Society.

Use of FEV1 in Cystic Fibrosis Epidemiologic Studies and Clinical Trials: A Statistical Perspective for the Clinical Researcher

PubMed Central

Szczesniak, Rhonda; Heltshe, Sonya L.; Stanojevic, Sanja; Mayer-Hamblett, Nicole

2017-01-01

Background Forced expiratory volume in 1 second (FEV1) is an established marker of cystic fibrosis (CF) disease progression that is used to capture clinical course and evaluate therapeutic efficacy. The research community has established FEV1 surveillance data through a variety of observational data sources such as patient registries, and there is a growing pipeline of new CF therapies demonstrated to be efficacious in clinical trials by establishing improvements in FEV1. Results In this review, we summarize from a statistical perspective the clinical relevance of FEV1 based on its association with morbidity and mortality in CF, its role in epidemiologic studies of disease progression and comparative effectiveness, and its utility in clinical trials. In addition, we identify opportunities to advance epidemiologic research and the clinical development pipeline through further statistical considerations. Conclusions Our understanding of CF disease course, therapeutics, and clinical care has evolved immensely in the past decades, in large part due to the thoughtful application of rigorous research methods and meaningful clinical endpoints such as FEV1. A continued commitment to conduct research that minimizes the potential for bias, maximizes the limited patient population, and harmonizes approaches to FEV1 analysis while maintaining clinical relevance, will facilitate further opportunities to advance CF care. PMID:28117136

Medical sieve: a cognitive assistant for radiologists and cardiologists

NASA Astrophysics Data System (ADS)

Syeda-Mahmood, T.; Walach, E.; Beymer, D.; Gilboa-Solomon, F.; Moradi, M.; Kisilev, P.; Kakrania, D.; Compas, C.; Wang, H.; Negahdar, R.; Cao, Y.; Baldwin, T.; Guo, Y.; Gur, Y.; Rajan, D.; Zlotnick, A.; Rabinovici-Cohen, S.; Ben-Ari, R.; Guy, Amit; Prasanna, P.; Morey, J.; Boyko, O.; Hashoul, S.

2016-03-01

Radiologists and cardiologists today have to view large amounts of imaging data relatively quickly leading to eye fatigue. Further, they have only limited access to clinical information relying mostly on their visual interpretation of imaging studies for their diagnostic decisions. In this paper, we present Medical Sieve, an automated cognitive assistant for radiologists and cardiologists designed to help in their clinical decision-making. The sieve is a clinical informatics system that collects clinical, textual and imaging data of patients from electronic health records systems. It then analyzes multimodal content to detect anomalies if any, and summarizes the patient record collecting all relevant information pertinent to a chief complaint. The results of anomaly detection are then fed into a reasoning engine which uses evidence from both patient-independent clinical knowledge and large-scale patient-driven similar patient statistics to arrive at potential differential diagnosis to help in clinical decision making. In compactly summarizing all relevant information to the clinician per chief complaint, the system still retains links to the raw data for detailed review providing holistic summaries of patient conditions. Results of clinical studies in the domains of cardiology and breast radiology have already shown the promise of the system in differential diagnosis and imaging studies summarization.

Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

PubMed

Pollak, Julia; Rai, Karan G; Funk, Cory C; Arora, Sonali; Lee, Eunjee; Zhu, Jun; Price, Nathan D; Paddison, Patrick J; Ramirez, Jan-Marino; Rostomily, Robert C

2017-01-01

Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.

Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy

PubMed Central

Pollak, Julia; Rai, Karan G.; Funk, Cory C.; Arora, Sonali; Lee, Eunjee; Zhu, Jun; Price, Nathan D.; Paddison, Patrick J.; Ramirez, Jan-Marino; Rostomily, Robert C.

2017-01-01

Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance. PMID:28264064

Current status of matrix-assisted laser desorption ionisation-time of flight mass spectrometry in the clinical microbiology laboratory.

PubMed

Kok, Jen; Chen, Sharon C A; Dwyer, Dominic E; Iredell, Jonathan R

2013-01-01

The integration of matrix-assisted laser desorption ionisation-time of flight mass spectrometry (MALDI-TOF MS) into many clinical microbiology laboratories has revolutionised routine pathogen identification. MALDI-TOF MS complements and has good potential to replace existing phenotypic identification methods. Results are available in a more clinically relevant timeframe, particularly in bacteraemic septic shock. Novel applications include strain typing and the detection of antimicrobial resistance, but these are not widely used. This review discusses the technical aspects, current applications, and limitations of MALDI-TOF MS.

Nitric oxide-releasing polyacrylonitrile disperses biofilms formed by wound-relevant pathogenic bacteria.

PubMed

Craven, M; Kasper, S H; Canfield, M J; Diaz-Morales, R R; Hrabie, J A; Cady, N C; Strickland, A D

2016-04-01

To test the antimicrobial and antibiofilm properties of a nitric oxide (NO)-releasing polymer against wound-relevant bacterial pathogens. Using a variety of 96-well plate assay systems that include standard well plates and the minimum biofilm eradication concentration biofilm assay well plate, a NO-releasing polymer based on (poly)acrylonitrile (PAN/NO) was studied for antimicrobial and antibiofilm activity against the common wound pathogens Pseudomonas aeruginosa (PAO1), Staphylococcus aureus (Mu50) and Enterococcus faecalis (V583). The polymer was capable of dispersing single-species biofilms of Ps. aeruginosa as well as a more clinically relevant multispecies biofilm that incorporates Ps. aeruginosa along with Staph. aureus and Ent. faecalis. PAN/NO also synergistically enhanced the susceptibility of the multispecies biofilms to the common broad-spectrum antibiotic, ciprofloxacin. Multiple in vitro biocompatibility assays show that PAN/NO has limited potential for mammalian cytotoxicity. This study demonstrates the feasibility of utilizing the NO-releasing polymer, PAN/NO, to manage biofilms formed by wound-relevant pathogens, and provides proof-of-concept for use of this NO-releasing polymer platform across multiple disciplines where bacterial biofilms pose significant problems. In the clinical sector, bacterial biofilms represent a substantial treatment challenge for health care professionals and are widely recognized as a key factor in prolonging patient morbidity. This study highlights the potential role for the ubiquitous signalling molecule nitric oxide (NO) as an antibiofilm therapy. © 2016 The Society for Applied Microbiology.

Perspective on Clinical Application of Biomarkers in AKI

PubMed Central

Mansour, Sherry G.

2017-01-01

Several biomarkers of renal injury have been identified but the utility of these biomarkers is largely confined to research studies, whereas widespread clinical applicability is limited. This is partly because the use of serum creatinine as the comparator has several limitations and restricts the full interpretation of biomarker performance. To highlight the potential for clinical application of biomarkers, the most pertinent biomarker data are summarized here, using clinically relevant scenarios in which biomarkers could assist with diagnostic and management dilemmas. The paradigms proposed in this review aim to enhance the clinical diagnosis, management, and prognosis of AKI through the combined use of available clinical markers and novel inflammatory, injury, and repair biomarkers. PMID:28220028

Best strategies to implement clinical pathways in an emergency department setting: study protocol for a cluster randomized controlled trial.

PubMed

Jabbour, Mona; Curran, Janet; Scott, Shannon D; Guttman, Astrid; Rotter, Thomas; Ducharme, Francine M; Lougheed, M Diane; McNaughton-Filion, M Louise; Newton, Amanda; Shafir, Mark; Paprica, Alison; Klassen, Terry; Taljaard, Monica; Grimshaw, Jeremy; Johnson, David W

2013-05-22

The clinical pathway is a tool that operationalizes best evidence recommendations and clinical practice guidelines in an accessible format for 'point of care' management by multidisciplinary health teams in hospital settings. While high-quality, expert-developed clinical pathways have many potential benefits, their impact has been limited by variable implementation strategies and suboptimal research designs. Best strategies for implementing pathways into hospital settings remain unknown. This study will seek to develop and comprehensively evaluate best strategies for effective local implementation of externally developed expert clinical pathways. We will develop a theory-based and knowledge user-informed intervention strategy to implement two pediatric clinical pathways: asthma and gastroenteritis. Using a balanced incomplete block design, we will randomize 16 community emergency departments to receive the intervention for one clinical pathway and serve as control for the alternate clinical pathway, thus conducting two cluster randomized controlled trials to evaluate this implementation intervention. A minimization procedure will be used to randomize sites. Intervention sites will receive a tailored strategy to support full clinical pathway implementation. We will evaluate implementation strategy effectiveness through measurement of relevant process and clinical outcomes. The primary process outcome will be the presence of an appropriately completed clinical pathway on the chart for relevant patients. Primary clinical outcomes for each clinical pathway include the following: Asthma--the proportion of asthmatic patients treated appropriately with corticosteroids in the emergency department and at discharge; and Gastroenteritis--the proportion of relevant patients appropriately treated with oral rehydration therapy. Data sources include chart audits, administrative databases, environmental scans, and qualitative interviews. We will also conduct an overall process evaluation to assess the implementation strategy and an economic analysis to evaluate implementation costs and benefits. This study will contribute to the body of evidence supporting effective strategies for clinical pathway implementation, and ultimately reducing the research to practice gaps by operationalizing best evidence care recommendations through effective use of clinical pathways. ClinicalTrials.gov: NCT01815710.

Implementation science theories to inform efforts for de-implementation of urologic oncology care practices resulting in overuse and misuse.

PubMed

Nielsen, Matthew E; Birken, Sarah A

2018-05-01

The field of implementation science has been conventionally applied in the context of increasing the application of evidence-based practices into clinical care, given evidence of underusage of appropriate interventions in many settings. Increasingly, however, there is recognition of the potential for similar frameworks to inform efforts to reduce the application of ineffective or potentially harmful practices. In this article, we provide some examples of clinical scenarios in which the quality problem may be overuse and misuse, and review relevant theories and frameworks that may inform improvement activities. Copyright © 2018 Elsevier Inc. All rights reserved.

MRI-powered biomedical devices.

PubMed

Hovet, Sierra; Ren, Hongliang; Xu, Sheng; Wood, Bradford; Tokuda, Junichi; Tse, Zion Tsz Ho

2017-11-16

Magnetic resonance imaging (MRI) is beneficial for imaging-guided procedures because it provides higher resolution images and better soft tissue contrast than computed tomography (CT), ultrasound, and X-ray. MRI can be used to streamline diagnostics and treatment because it does not require patients to be repositioned between scans of different areas of the body. It is even possible to use MRI to visualize, power, and control medical devices inside the human body to access remote locations and perform minimally invasive procedures. Therefore, MR conditional medical devices have the potential to improve a wide variety of medical procedures; this potential is explored in terms of practical considerations pertaining to clinical applications and the MRI environment. Recent advancements in this field are introduced with a review of clinically relevant research in the areas of interventional tools, endovascular microbots, and closed-loop controlled MRI robots. Challenges related to technology and clinical feasibility are discussed, including MRI based propulsion and control, navigation of medical devices through the human body, clinical adoptability, and regulatory issues. The development of MRI-powered medical devices is an emerging field, but the potential clinical impact of these devices is promising.

Clinical relevance in anesthesia journals.

PubMed

Lauritsen, Jakob; Møller, Ann M

2006-04-01

The purpose of this review is to present the latest knowledge and research on the definition and distribution of clinically relevant articles in anesthesia journals. It will also discuss the importance of the chosen methodology and outcome of articles. In the last few years, more attention has been paid to evidence-based medicine in anesthesia. Several articles on the subject have focused on the need to base clinical decisions on sound research employing both methodological rigor and clinically relevant outcomes. The number of systematic reviews in anesthesia literature is increasing as well as the focus on diminishing the number of surrogate outcomes. It has been shown that the impact factor is not a valid measure of establishing the level of clinical relevance to a journal. This review presents definitions of clinically relevant anesthesia articles. A clinically relevant article employs both methodological rigor and a clinically relevant outcome. The terms methodological rigor and clinical outcomes are fully discussed in the review as well as problems with journal impact factors.

Assessing commercial feasibility: a practical and ethical prerequisite for human clinical testing.

PubMed

Kirk, Dwayne D; Robert, Jason Scott

2005-01-01

This article proposes that an assessment of commercial feasibility should be integrated as a prerequisite for human clinical testing to improve the quality and relevance of materials being investigated, as an ethical aspect for human subject protection, and as a means of improving accountability where clinical development is funded on promises of successful translational research. A commercial feasibility analysis is not currently required to justify human clinical testing, but is assumed to have been conducted by industry participants, and use of public funds for clinical trials should be defensible in the same manner. Plant-made vaccines (PMVs) are offered in this discussion as a model for evaluating the relevance of commercial feasibility before human clinical testing. PMVs have been proposed as a potential solution for global health, based on a vision of immunizing the world against many infectious diseases. Such a vision depends on translating current knowledge in plant science and immunology into a potent vaccine that can be readily manufactured and distributed to those in need. But new biologics such as PMVs may fail to be manufactured due to financial or logistical reasons--particularly for orphan diseases without sufficient revenue incentive for industry investment--regardless of the effectiveness which might be demonstrated in human clinical testing. Moreover, all potential instruments of global health depend on translational agents well beyond the lab in order to reach those in need. A model compromising five criteria for commercial feasibility is suggested for inclusion by regulators and ethics review boards as part of the review process prior to approval of human clinical testing. Use of this model may help to facilitate safe and appropriate translational research and bring more immediate benefits to those in need.

Depression in Down Syndrome: A Review of the Literature

ERIC Educational Resources Information Center

Walker, J. C.; Dosen, A.; Buitelaar, J. K.; Janzing, J. G. E.

2011-01-01

Background: Depression has been frequently reported in individuals with Down Syndrome (DS). The aim of this article is to provide a comprehensive, critical review of the clinically relevant literature concerning depression in DS, with a focus on epidemiology, potential risk factors, diagnosis, course characteristics and treatment. Methods: We…

Potential drug-drug interactions with antiepileptic drugs in Medicaid recipients.

PubMed

Dickson, Michael; Bramley, Thomas J; Kozma, Chris; Doshi, Dilesh; Rupnow, Marcia F T

2008-09-15

The frequency of potential drug-drug interactions (DDIs) between antiepileptic drugs (AEDs) and other (non-AED) medications in Medicaid patients taking newer AED monotherapy, older AED monotherapy, and combinations of AED treatment was studied. A retrospective, observational study was conducted using administrative claims obtained from South Carolina Medicaid. Patients were included in the analysis if they (1) had at least one prescription for an AED between January 1, 2004, and December 31, 2004, (2) were taking a specific AED for at least 60 days, (3) had at least one epilepsy diagnosis during the 6 months before or during the enrollment period, and (4) were enrolled in Medicaid for at least 11 of the 12 months of the follow-up period. Possible DDI exposure was defined as 10 days of overlap between an AED and a non-AED known to have the potential to cause a clinically relevant interaction. A total of 4955 patients met the inclusion criteria. Approximately 45% of patients receiving monotherapy with an older AED had a potential DDI, compared with 3.9% receiving a newer AED. An average of 0.08 potential DDI per year of exposure occurred in the newer AED monotherapy cohort compared with 1.18 in the older AED monotherapy cohort. The most common potential interaction category was a decreased concentration of the non-AED. Older AEDs were associated with a greater likelihood of a potential DDI than were newer AEDs. Further research is needed to elucidate the relationship between the occurrence of potential DDIs and actual clinically relevant consequences.

Lateral epicondylitis and beyond: imaging of lateral elbow pain with clinical-radiologic correlation.

PubMed

Kotnis, Nikhil A; Chiavaras, Mary M; Harish, Srinivasan

2012-04-01

The diagnosis of lateral epicondylitis is often straightforward and can be made on the basis of clinical findings. However, radiological assessment is valuable where the clinical picture is less clear or where symptoms are refractory to treatment. Demographics, aspects of clinical history, or certain physical signs may suggest an alternate diagnosis. Knowledge of the typical clinical presentation and imaging findings of lateral epicondylitis, in addition to other potential causes of lateral elbow pain, is necessary. These include entrapment of the posterior interosseous and lateral antebrachial cutaneous nerves, posterolateral rotatory instability, posterolateral plica syndrome, Panner's disease, osteochondritis dissecans of the capitellum, radiocapitellar overload syndrome, occult fractures and chondral-osseous impaction injuries, and radiocapitellar arthritis. Knowledge of these potential masquerades of lateral epicondylitis and their characteristic clinical and imaging features is essential for accurate diagnosis. The goal of this review is to provide an approach to the imaging of lateral elbow pain, discussing the relevant anatomy, various causes, and discriminating factors, which will allow for an accurate diagnosis.

Robot-supported assessment of balance in standing and walking.

PubMed

Shirota, Camila; van Asseldonk, Edwin; Matjačić, Zlatko; Vallery, Heike; Barralon, Pierre; Maggioni, Serena; Buurke, Jaap H; Veneman, Jan F

2017-08-14

Clinically useful and efficient assessment of balance during standing and walking is especially challenging in patients with neurological disorders. However, rehabilitation robots could facilitate assessment procedures and improve their clinical value. We present a short overview of balance assessment in clinical practice and in posturography. Based on this overview, we evaluate the potential use of robotic tools for such assessment. The novelty and assumed main benefits of using robots for assessment are their ability to assess 'severely affected' patients by providing assistance-as-needed, as well as to provide consistent perturbations during standing and walking while measuring the patient's reactions. We provide a classification of robotic devices on three aspects relevant to their potential application for balance assessment: 1) how the device interacts with the body, 2) in what sense the device is mobile, and 3) on what surface the person stands or walks when using the device. As examples, nine types of robotic devices are described, classified and evaluated for their suitability for balance assessment. Two example cases of robotic assessments based on perturbations during walking are presented. We conclude that robotic devices are promising and can become useful and relevant tools for assessment of balance in patients with neurological disorders, both in research and in clinical use. Robotic assessment holds the promise to provide increasingly detailed assessment that allows to individually tailor rehabilitation training, which may eventually improve training effectiveness.

The Intestinal Microbiome in Infectious Diseases: The Clinical Relevance of a Rapidly Emerging Field.

PubMed

Harris, Vanessa C; Haak, Bastiaan W; Boele van Hensbroek, Michaël; Wiersinga, Willem J

2017-01-01

The field of infectious disease is undergoing a paradigm shift as the intestinal microbiome is becoming understood. The aim of this review is to inform infectious disease physicians of the potential relevance of the intestinal microbiome to their practice. We searched Medline using both index and text words relating to infectious diseases, microbiome, and probiotics. Relevant articles published up through 2017 were reviewed within Rayyan. The review illustrates pathophysiologic concepts linking the microbiome and infectious diseases; specifically, the intestinal microbiome's relevance to early immune development, the microbiome and enteric infections, the microbiome's relevance in compromised hosts, and antimicrobial resistance. Within each subject, there are specific examples of diseases and at-risk patient populations where a role for the microbiome has been strongly established. This provides an overview of the significance of the intestinal microbiome to microbiology, pediatric and adult infectious diseases with an underpinning of concepts useful for the practicing clinician.

Interaction Between Low-Dose Methotrexate and Nonsteroidal Anti-inflammatory Drugs, Penicillins, and Proton Pump Inhibitors.

PubMed

Hall, Jill J; Bolina, Monika; Chatterley, Trish; Jamali, Fakhreddin

2017-02-01

To review the potential drug interactions between low-dose methotrexate (LD-MTX) and nonsteroidal anti-inflammatory drugs (NSAIDs), penicillins, and proton-pump inhibitors (PPIs) given the disparity between interactions reported for high-dose and low-dose MTX to help guide clinicians. A literature search was performed in MEDLINE (1946 to September 2016), EMBASE (1974 to September 2016), and International Pharmaceutical Abstracts (1970 to January 2015) to identify reports describing potential drug interactions between LD-MTX and NSAIDS, penicillins, or PPIs. Reference lists of included articles were reviewed to find additional eligible articles. All English-language observational, randomized, and pharmacokinetic (PK) studies assessing LD-MTX interactions in humans were analyzed to determine clinical relevance in making recommendations to clinicians. Clinical case reports were assigned a Drug Interaction Probability Scale score. A total of 32 articles were included (28 with NSAIDs, 3 with penicillins, and 2 with PPIs [1 including both PPI and NSAID]). Although there are some PK data to describe increased LD-MTX concentrations when NSAIDs are used concomitantly, the clinical relevance remains unclear. Based on the limited data on LD-MTX with penicillins and PPIs, no clinically meaningful interaction was identified. Given the available evidence, the clinical importance of the interaction between LD-MTX and NSAIDs, penicillins, and PPIs cannot be substantiated. Health care providers should assess the benefit and risk of LD-MTX regardless of concomitant drug use, including factors known to predispose patients to MTX toxicity, and continue to monitor clinical and laboratory parameters per guideline recommendations.

Reliability, Validity and Treatment Sensitivity of the Schizophrenia Cognition Rating Scale

PubMed Central

Keefe, Richard S.E.; Davis, Vicki G.; Spagnola, Nathan B.; Hilt, Dana; Dgetluck, Nancy; Ruse, Stacy; Patterson, Thomas L.; Narasimhan, Meera; Harvey, Philip D.

2014-01-01

Cognitive functioning can be assessed with performance-based assessments such as neuropsychological tests and with interview-based assessments. Both assessment methods have the potential to assess whether treatments for schizophrenia improve clinically relevant aspects of cognitive impairment. However, little is known about the reliability, validity and treatment responsiveness of interview-based measures, especially in the context of clinical trials. Data from two studies were utilized to assess these features of the Schizophrenia Cognition Rating Scale (SCoRS). One of the studies was a validation study involving 79 patients with schizophrenia assessed at 3 academic research centers in the US. The other study was a 32-site clinical trial conducted in the US and Europe comparing the effects of encenicline, an alpha-7 nicotine agonist, to placebo in 319 patients with schizophrenia. The SCoRS interviewer ratings demonstrated excellent test-retest reliability in several different circumstances, including those that did not involve treatment (ICC> 0.90), and during treatment (ICC>0.80). SCoRS interviewer ratings were related to cognitive performance as measured by the MCCB (r= −0.35), and demonstrated significant sensitivity to treatment with encenicline compared to placebo (P<.001). These data suggest that the SCoRS has potential as a clinically relevant measure in clinical trials aiming to improve cognition in schizophrenia, and may be useful for clinical practice. The weaknesses of the SCoRS include its reliance on informant information, which is not available for some patients, and reduced validity when patient self-report is the sole information source. PMID:25028065

Reliability, validity and treatment sensitivity of the Schizophrenia Cognition Rating Scale.

PubMed

Keefe, Richard S E; Davis, Vicki G; Spagnola, Nathan B; Hilt, Dana; Dgetluck, Nancy; Ruse, Stacy; Patterson, Thomas D; Narasimhan, Meera; Harvey, Philip D

2015-02-01

Cognitive functioning can be assessed with performance-based assessments such as neuropsychological tests and with interview-based assessments. Both assessment methods have the potential to assess whether treatments for schizophrenia improve clinically relevant aspects of cognitive impairment. However, little is known about the reliability, validity and treatment responsiveness of interview-based measures, especially in the context of clinical trials. Data from two studies were utilized to assess these features of the Schizophrenia Cognition Rating Scale (SCoRS). One of the studies was a validation study involving 79 patients with schizophrenia assessed at 3 academic research centers in the US. The other study was a 32-site clinical trial conducted in the US and Europe comparing the effects of encenicline, an alpha-7 nicotine agonist, to placebo in 319 patients with schizophrenia. The SCoRS interviewer ratings demonstrated excellent test-retest reliability in several different circumstances, including those that did not involve treatment (ICC> 0.90), and during treatment (ICC>0.80). SCoRS interviewer ratings were related to cognitive performance as measured by the MCCB (r=-0.35), and demonstrated significant sensitivity to treatment with encenicline compared to placebo (P<.001). These data suggest that the SCoRS has potential as a clinically relevant measure in clinical trials aiming to improve cognition in schizophrenia, and may be useful for clinical practice. The weaknesses of the SCoRS include its reliance on informant information, which is not available for some patients, and reduced validity when patient's self-report is the sole information source. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Folded concave penalized learning in identifying multimodal MRI marker for Parkinson’s disease

PubMed Central

Liu, Hongcheng; Du, Guangwei; Zhang, Lijun; Lewis, Mechelle M.; Wang, Xue; Yao, Tao; Li, Runze; Huang, Xuemei

2016-01-01

Background Brain MRI holds promise to gauge different aspects of Parkinson’s disease (PD)-related pathological changes. Its analysis, however, is hindered by the high-dimensional nature of the data. New method This study introduces folded concave penalized (FCP) sparse logistic regression to identify biomarkers for PD from a large number of potential factors. The proposed statistical procedures target the challenges of high-dimensionality with limited data samples acquired. The maximization problem associated with the sparse logistic regression model is solved by local linear approximation. The proposed procedures then are applied to the empirical analysis of multimodal MRI data. Results From 45 features, the proposed approach identified 15 MRI markers and the UPSIT, which are known to be clinically relevant to PD. By combining the MRI and clinical markers, we can enhance substantially the specificity and sensitivity of the model, as indicated by the ROC curves. Comparison to existing methods We compare the folded concave penalized learning scheme with both the Lasso penalized scheme and the principle component analysis-based feature selection (PCA) in the Parkinson’s biomarker identification problem that takes into account both the clinical features and MRI markers. The folded concave penalty method demonstrates a substantially better clinical potential than both the Lasso and PCA in terms of specificity and sensitivity. Conclusions For the first time, we applied the FCP learning method to MRI biomarker discovery in PD. The proposed approach successfully identified MRI markers that are clinically relevant. Combining these biomarkers with clinical features can substantially enhance performance. PMID:27102045

Prefoveal floaters as a differential diagnosis to optic neuritis: "mouches dormantes".

PubMed

Burggraaff, Marloes C; de Vries-Knoppert, Willemine A E J; Petzold, Axel

2017-09-01

This case series describes a new optical coherence tomography (OCT) specific observation relevant to the differential diagnosis of patients with suspected optic neuritis. A tiny prefoveal floater, only detectable by OCT, was found responsible for the symptoms in three patients, one of whom had been referred with unilateral delayed visual evoked potentials. This case series suggests that with increased use of OCT in routine clinical care, entoptic phenomena can be demonstrated as a relevant differential diagnosis to optic neuritis. Patients should be explained the benign nature of their symptoms.

Spiders in dermatology.

PubMed

Kang, Jun K; Bhate, Chinmoy; Schwartz, Robert A

2014-09-01

Spider bites represent an unusual and potentially over-represented clinical diagnosis. Despite a common fear of spiders, known as arachnophobia, current knowledge suggests that only a small number of families within the order Araneae are medically relevant. Moreover, most cutaneous spider reactions, including both evenomations and physical trauma, produce mild, local symptoms which may be managed with supportive care alone. The differential diagnosis for spider bites may be broad, especially if the offending arachnid is not seen or found. We describe a series of spiders relevant to the dermatologist in the United States.

Publications in anesthesia journals: quality and clinical relevance.

PubMed

Lauritsen, Jakob; Moller, Ann M

2004-11-01

Clinicians performing evidence-based anesthesia rely on anesthesia journals for clinically relevant information. The objective of this study was to analyze the proportion of clinically relevant articles in five high impact anesthesia journals. We evaluated all articles published in Anesthesiology, Anesthesia & Analgesia, British Journal of Anesthesia, Anesthesia, and Acta Anaesthesiologica Scandinavica from January to June, 2000. Articles were assessed and classified according to type, outcome, and design; 1379 articles consisting of 5468 pages were evaluated and categorized. The most common types of article were animal and laboratory research (31.2%) and randomized clinical trial (20.4%). A clinically relevant article was defined as an article that used a statistically valid method and had a clinically relevant end-point. Altogether 18.6% of the pages had as their subject matter clinically relevant trials. We compared the Journal Impact Factor (a measure of the number of citations per article in a journal) and the proportion of clinically relevant pages and found that they were inversely proportional to each other.

Profiling Lung Cancer Patients Using Electronic Health Records.

PubMed

Menasalvas Ruiz, Ernestina; Tuñas, Juan Manuel; Bermejo, Guzmán; Gonzalo Martín, Consuelo; Rodríguez-González, Alejandro; Zanin, Massimiliano; González de Pedro, Cristina; Méndez, Marta; Zaretskaia, Olga; Rey, Jesús; Parejo, Consuelo; Cruz Bermudez, Juan Luis; Provencio, Mariano

2018-05-31

If Electronic Health Records contain a large amount of information about the patient's condition and response to treatment, which can potentially revolutionize the clinical practice, such information is seldom considered due to the complexity of its extraction and analysis. We here report on a first integration of an NLP framework for the analysis of clinical records of lung cancer patients making use of a telephone assistance service of a major Spanish hospital. We specifically show how some relevant data, about patient demographics and health condition, can be extracted; and how some relevant analyses can be performed, aimed at improving the usefulness of the service. We thus demonstrate that the use of EHR texts, and their integration inside a data analysis framework, is technically feasible and worth of further study.

Retailing research: increasing the role of evidence in clinical services for childbirth.

PubMed

Lomas, J

1993-01-01

A current review of the structures and assumptions of research transfer for clinical care reveals some progress from "passive diffusion" to "active dissemination" models, but little or no progress has been made toward targeting local influences on practitioner behavior for "coordinated implementation" of clinically relevant research into childbirth (or other) medical practices. The implementation of scientifically valid research syntheses, such as Effective Care in Pregnancy and Childbirth (ECPC), is therefore constrained by a poorly developed marketplace for retailing research information to practitioners. A survey in Canada of the four most significant potential retailing groups demonstrated that whereas clinical and community groups were adopting the necessary knowledge and attitudes, public policy makers and administrators trailed well behind them. To increase the probability of thorough retailing of ECPC, a three-phase plan could be instituted that would identify product champions within potential retailing groups, develop implementation activities for each retailing group, and convene annual conferences.

T-cell receptor gene therapy: critical parameters for clinical success.

PubMed

Linnemann, Carsten; Schumacher, Ton N M; Bendle, Gavin M

2011-09-01

T-cell receptor (TCR) gene therapy aims to induce immune reactivity against tumors by introducing genes encoding a tumor-reactive TCR into patient T cells. This approach has been extensively tested in preclinical mouse models, and initial clinical trials have demonstrated the feasibility and potential of TCR gene therapy as a cancer treatment. However, data obtained from preclinical and clinical studies suggest that both the therapeutic efficacy and the safety of TCR gene therapy can be and needs to be further enhanced. This review highlights those strategies that can be followed to develop TCR gene therapy into a clinically relevant treatment option for cancer patients.

Evidence-based selection of theories for designing behaviour change interventions: using methods based on theoretical construct domains to understand clinicians' blood transfusion behaviour.

PubMed

Francis, Jill J; Stockton, Charlotte; Eccles, Martin P; Johnston, Marie; Cuthbertson, Brian H; Grimshaw, Jeremy M; Hyde, Chris; Tinmouth, Alan; Stanworth, Simon J

2009-11-01

Many theories of behaviour are potentially relevant to predictive and intervention studies but most studies investigate a narrow range of theories. Michie et al. (2005) agreed 12 'theoretical domains' from 33 theories that explain behaviour change. They developed a 'Theoretical Domains Interview' (TDI) for identifying relevant domains for specific clinical behaviours, but the framework has not been used for selecting theories for predictive studies. It was used here to investigate clinicians' transfusion behaviour in intensive care units (ICU). Evidence suggests that red blood cells transfusion could be reduced for some patients without reducing quality of care. (1) To identify the domains relevant to transfusion practice in ICUs and neonatal intensive care units (NICUs), using the TDI. (2) To use the identified domains to select appropriate theories for a study predicting transfusion behaviour. An adapted TDI about managing a patient with borderline haemoglobin by watching and waiting instead of transfusing red blood cells was used to conduct semi-structured, one-to-one interviews with 18 intensive care consultants and neonatologists across the UK. Relevant theoretical domains were: knowledge, beliefs about capabilities, beliefs about consequences, social influences, behavioural regulation. Further analysis at the construct level resulted in selection of seven theoretical approaches relevant to this context: Knowledge-Attitude-Behaviour Model, Theory of Planned Behaviour, Social Cognitive Theory, Operant Learning Theory, Control Theory, Normative Model of Work Team Effectiveness and Action Planning Approaches. This study illustrated, the use of the TDI to identify relevant domains in a complex area of inpatient care. This approach is potentially valuable for selecting theories relevant to predictive studies and resulted in greater breadth of potential explanations than would be achieved if a single theoretical model had been adopted.

Dental Cements for Luting and Bonding Restorations: Self-Adhesive Resin Cements.

PubMed

Manso, Adriana P; Carvalho, Ricardo M

2017-10-01

Self-adhesive resin cements combine easy application of conventional luting materials with improved mechanical properties and bonding capability of resin cements. The presence of functional acidic monomers, dual cure setting mechanism, and fillers capable of neutralizing the initial low pH of the cement are essential elements of the material and should be understood when selecting the ideal luting material for each clinical situation. This article addresses the most relevant aspects of self-adhesive resin cements and their potential impact on clinical performance. Although few clinical studies are available to establish solid clinical evidence, the information presented provides clinical guidance in the dynamic environment of material development. Copyright © 2017 Elsevier Inc. All rights reserved.

Considerations for automated machine learning in clinical metabolic profiling: Altered homocysteine plasma concentration associated with metformin exposure.

PubMed

Orlenko, Alena; Moore, Jason H; Orzechowski, Patryk; Olson, Randal S; Cairns, Junmei; Caraballo, Pedro J; Weinshilboum, Richard M; Wang, Liewei; Breitenstein, Matthew K

2018-01-01

With the maturation of metabolomics science and proliferation of biobanks, clinical metabolic profiling is an increasingly opportunistic frontier for advancing translational clinical research. Automated Machine Learning (AutoML) approaches provide exciting opportunity to guide feature selection in agnostic metabolic profiling endeavors, where potentially thousands of independent data points must be evaluated. In previous research, AutoML using high-dimensional data of varying types has been demonstrably robust, outperforming traditional approaches. However, considerations for application in clinical metabolic profiling remain to be evaluated. Particularly, regarding the robustness of AutoML to identify and adjust for common clinical confounders. In this study, we present a focused case study regarding AutoML considerations for using the Tree-Based Optimization Tool (TPOT) in metabolic profiling of exposure to metformin in a biobank cohort. First, we propose a tandem rank-accuracy measure to guide agnostic feature selection and corresponding threshold determination in clinical metabolic profiling endeavors. Second, while AutoML, using default parameters, demonstrated potential to lack sensitivity to low-effect confounding clinical covariates, we demonstrated residual training and adjustment of metabolite features as an easily applicable approach to ensure AutoML adjustment for potential confounding characteristics. Finally, we present increased homocysteine with long-term exposure to metformin as a potentially novel, non-replicated metabolite association suggested by TPOT; an association not identified in parallel clinical metabolic profiling endeavors. While warranting independent replication, our tandem rank-accuracy measure suggests homocysteine to be the metabolite feature with largest effect, and corresponding priority for further translational clinical research. Residual training and adjustment for a potential confounding effect by BMI only slightly modified the suggested association. Increased homocysteine is thought to be associated with vitamin B12 deficiency - evaluation for potential clinical relevance is suggested. While considerations for clinical metabolic profiling are recommended, including adjustment approaches for clinical confounders, AutoML presents an exciting tool to enhance clinical metabolic profiling and advance translational research endeavors.

Body posture changes in women with migraine with or without temporomandibular disorders

PubMed Central

Ferreira, Mariana C.; Bevilaqua-Grossi, Débora; Dach, Fabíola É.; Speciali, José G.; Gonçalves, Maria C.; Chaves, Thais C.

2014-01-01

Background Migraine and temporomandibular disorders (TMDs) are reported to be associated. However, there are no reports on the association among migraines, TMDs and changes in body posture. Objectives To assess changes in body posture in women suffering migraines with or without TMD compared with a control group. Method Sixty-six women with a mean age of 18 to 45 years participated in this study. The groups were composed of 22 volunteers with migraine and TMD (MTMD), 22 volunteers with migraines without TMD (MG) and 22 women in the control group (CG). Static posture was assessed by photogrammetry, and 19 angles were measured. Results Postural asymmetry was observed in the face for 4 angles measured on the frontal plane in the MG group and for 4 angles of the trunk in the MG and MTMD groups with respect to CG. However, for comparisons between MTMD and CG, clinical relevance was identified for two angles of the sagittal plane (Cervical and Lumbar Lordosis, Effect Size - ES - moderate: 0.53 and 0.60). For comparisons between the MG and CG, the clinical relevance/potential was verified for three angles with moderate ES (ES>0.42). The clinical relevance when comparing MTMD and CG was identified for four angles of facial symmetry head inclination (ES>0.54) and for two angles between MG and CG (ES>0.48). Conclusion The results demonstrated the presence of postural changes compared with a control group in women with migraines with or without TMD, and there were similar clinically relevant postural changes among the patients with migraines with and without TMD. PMID:24675909

Body posture changes in women with migraine with or without temporomandibular disorders.

PubMed

Ferreira, Mariana C; Bevilaqua-Grossi, Débora; Dach, Fabíola E; Speciali, José G; Gonçalves, Maria C; Chaves, Thais C

2014-01-01

Migraine and temporomandibular disorders (TMDs) are reported to be associated. However, there are no reports on the association among migraines, TMDs and changes in body posture. To assess changes in body posture in women suffering migraines with or without TMD compared with a control group. Sixty-six women with a mean age of 18 to 45 years participated in this study. The groups were composed of 22 volunteers with migraine and TMD (MTMD), 22 volunteers with migraines without TMD (MG) and 22 women in the control group (CG). Static posture was assessed by photogrammetry, and 19 angles were measured. Postural asymmetry was observed in the face for 4 angles measured on the frontal plane in the MG group and for 4 angles of the trunk in the MG and MTMD groups with respect to CG. However, for comparisons between MTMD and CG, clinical relevance was identified for two angles of the sagittal plane (Cervical and Lumbar Lordosis, Effect Size - ES - moderate: 0.53 and 0.60). For comparisons between the MG and CG, the clinical relevance/potential was verified for three angles with moderate ES (ES>0.42). The clinical relevance when comparing MTMD and CG was identified for four angles of facial symmetry head inclination (ES>0.54) and for two angles between MG and CG (ES>0.48). The results demonstrated the presence of postural changes compared with a control group in women with migraines with or without TMD, and there were similar clinically relevant postural changes among the patients with migraines with and without TMD.

Obesity and onset of depression among U.S. middle-aged and older adults.

PubMed

Xiang, Xiaoling; An, Ruopeng

2015-03-01

This paper aims to examine the relationship between obesity and onset of depression among U.S. middle-aged and older adults. Data came from 1994 to 2010 waves of the Health and Retirement Study. Study sample consisted of 6514 community-dwelling adults born between 1931 and 1941 who were free of clinically relevant depressive symptoms in 1994. Body mass index (BMI) was calculated from self-reported height/weight. Body weight status was classified into normal weight (18.5kg/m(2)≤BMI<25kg/m(2)), overweight (25kg/m(2)≤BMI<30kg/m(2)), and obesity (BMI≥30kg/m(2)). A score of ≥3 on the 8-item Center for Epidemiologic Studies Depression Scale was used to define clinically relevant depressive symptoms. Kaplan-Meier estimator and time-dependent Cox proportional hazards model were performed to examine the association between body weight status and onset of clinically relevant depressive symptoms. Unhealthy body weight was associated future onset of depression. Compared with their normal weight counterparts, overweight and obese participants were 13% (hazard ratio [HR]=1.13, 95% confidence interval [CI]=1.04-1.23) and 9% (HR=1.09, 95% CI=1.01-1.18) more likely to have onset of clinically relevant depressive symptoms during the 16years of follow-up, respectively. The relationship between obesity and depression onset appeared stronger among females and non-Hispanic whites than their male and racial/ethnic minority counterparts. Health care providers should be aware of the potential risk for depression among obese older adults. Copyright © 2014 Elsevier Inc. All rights reserved.

Oligonucleotide-based pharmaceuticals: Non-clinical and clinical safety signals and non-clinical testing strategies.

PubMed

Mustonen, Enni-Kaisa; Palomäki, Tiina; Pasanen, Markku

2017-11-01

Antisense oligonucleotides, short interfering RNAs (siRNAs) and aptamers are oligonucleotide-based pharmaceuticals with a promising role in targeted therapies. Currently, five oligonucleotide-based pharmaceuticals have achieved marketing authorization in Europe or USA and many more are undergoing clinical testing. However, several safety concerns have been raised in non-clinical and clinical studies. Oligonucleotides share properties with both chemical and biological pharmaceuticals and therefore they pose challenges also from the regulatory point of view. We have analyzed the safety data of oligonucleotides and evaluated the applicability of current non-clinical toxicological guidelines for assessing the safety of oligonucleotide-based pharmaceuticals. Oligonucleotide-based pharmaceuticals display a similar toxicological profile, exerting adverse effects on liver and kidney, evoking hematological alterations, as well as causing immunostimulation and prolonging the coagulation time. It is possible to extrapolate some of these effects from non-clinical studies to humans. However, evaluation strategies for genotoxicity testing of "non-natural" oligonucleotides should be revised. Additionally, the selective use of surrogates and prediction of clinical endpoints for non-clinically observed immunostimulation is complicated by its multiple potential manifestations, demanding improvements in the testing strategies. Utilizing more relevant and mechanistic-based approaches and taking better account of species differences, could possibly improve the prediction of relevant immunological/proinflammatory effects in humans. Copyright © 2017 Elsevier Inc. All rights reserved.

Prevalence and typology of potential drug interactions occurring in primary care patients.

PubMed

Lopez-Picazo, Julio J; Ruiz, Juan C; Sanchez, Jose F; Ariza, Angeles; Aguilera, Belen; Lazaro, Dolores; Sanz, Gonzalo R

2010-06-01

To investigate the prevalence and types of potential drug interactions in primary care patients to detect risky prescriptions as an essential condition to design intervention policies leading to an improvement in patient safety. Cross-sectional descriptive study. Two areas in Spain comprising 715,661 inhabitants. 430,525 subjects with electronic medical records and assigned to a family doctor regularly updating them. On a random day, 29.4% of the population was taking medication. Of these, 73.9% were at risk of suffering interactions, and these were found in 20.6% of them. The amount of interactions was higher among people with chronic conditions, the elderly, females and polymedicated patients. From the total of interactions, 55.1% belonged to the highest clinical relevance 'A' level, and 28.3% should have been avoided. The active ingredients primarily involved were hydrochlorothiazide and ibuprofen and, when focusing on those that should be avoided, omeprazole and acenocoumarol. The most frequent 'A' interaction that should be avoided was between non-conjugated excreted benzodiazepines and proton-pump inhibitors, followed by some NSAIDs and diuretics. 1 in 20 Spanish citizens is currently undergoing a potential drug interaction, including a high rate of clinically relevant ones that should be avoided. These results confirm the existence of a serious safety issue that should be approached and where all parties involved (physicians, health services, medical societies and patients) must do our bit to improve. Health services should foster the implementation of prescription alert systems linked with electronic medical records including clinical data.

Integrating chemical, toxicological and clinical research to assess the potential of reducing health risks associated with cigarette smoking through reducing toxicant emissions.

PubMed

McAdam, Kevin; Murphy, James; Eldridge, Alison; Meredith, Clive; Proctor, Christopher

2018-06-01

The concept of a risk continuum for tobacco and nicotine products has been proposed, which differentiates products according to their propensity to reduce toxicant exposure and risk. Cigarettes are deemed the most risky and medicinal nicotine the least. We assessed whether a Reduced-Toxicant Prototype (RTP) cigarette could sufficiently reduce exposure to toxicants versus conventional cigarettes to be considered a distinct category in the risk continuum. We present findings from both pre-clinical and clinical studies in order to examine the potential for reduced smoke toxicant emissions to lower health risks associated with cigarette smoking. We conclude that current toxicant reducing technologies are unable to reduce toxicant emissions sufficiently to manifest beneficial disease-relevant changes in smokers. These findings point to a minimum toxicant exposure standard that future potentially reduced risk products would need to meet to be considered for full biological assessment. The RTP met WHO TobReg proposed limits on cigarette toxicant emissions, however the absence of beneficial disease relevant changes in smokers after six months reduced toxicant cigarette use, does not provide evidence that these regulatory proposals will positively impact risks of smoking related diseases. Greater toxicant reductions, such as those that can be achieved in next generation products e.g. tobacco heating products and electronic cigarettes are likely to be necessary to clearly reduce risks compared with conventional cigarettes. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes

USDA-ARS?s Scientific Manuscript database

A potentially useful approach for drug discovery is to connect gene expression profiles of disease-affected tissues ("disease signatures") to drug signatures, but it remains to be shown whether it can be used to identify clinically relevant treatment options. We analyzed coexpression networks and ge...

Biologic and plastic effects of experimental traumatic brain injury treatment paradigms and their relevance to clinical rehabilitation

PubMed Central

Garcia, Alexandra N.; Shah, Mansi A.; Dixon, C. Edward; Wagner, Amy K.; Kline, Anthony E.

2011-01-01

Neuroplastic changes, whether induced by traumatic brain injury (TBI) or therapeutic interventions, alter neurobehavioral outcome. Here we present several treatment strategies that have been evaluated using experimental TBI models and discuss potential mechanisms of action (i.e., plasticity) and how such changes affect function. PMID:21703575

Impact of Knowledge Resources Linked to an Electronic Health Record on Frequency of Unnecessary Tests and Treatments

ERIC Educational Resources Information Center

Goodman, Kenneth; Grad, Roland; Pluye, Pierre; Nowacki, Amy; Hickner, John

2012-01-01

Introduction: Electronic knowledge resources have the potential to rapidly provide answers to clinicians' questions. We sought to determine clinicians' reasons for searching these resources, the rate of finding relevant information, and the perceived clinical impact of the information they retrieved. Methods: We asked general internists, family…

Occurrence of carbapenemase-producing bacteria in coastal recreational waters.

PubMed

Montezzi, Lara Feital; Campana, Eloiza Helena; Corrêa, Laís Lisboa; Justo, Livia Helena; Paschoal, Raphael Paiva; da Silva, Isabel Lemos Vieira Dias; Souza, Maria do Carmo Maciel; Drolshagen, Marcia; Picão, Renata Cristina

2015-02-01

The spread of carbapenemase-producing Gram-negative rods is an emerging global problem. Although most infections due to carbapenemase producers are limited to healthcare institutions, reports of the occurrence of clinically relevant carbapenemase producers in sewage and polluted rivers are increasingly frequent. Polluted rivers flowing to oceans may contaminate coastal waters with multidrug-resistant bacteria, potentially threatening the safety of recreational activities in these locations. Here we assessed the occurrence of carbapenemase producers in water from touristic beaches located in Rio de Janeiro, Brazil, showing distinct pollution patterns. The presence of enterobacteria was noted, including the predominantly environmental genus Kluyvera spp., producing either Klebsiella pneumoniae carbapenemase (KPC) or Guyana extended-spectrum (GES)-type carbapenemases and often associated with quinolone resistance determinants. An Aeromonas sp. harbouring blaKPC and qnrS was also observed. These findings strengthen the role of aquatic matrices as reservoirs and vectors of clinically relevant antimicrobial-resistant bacteria, with potential to favour the spread of these resistance threats throughout the community. Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Soluble HLA-G: Are They Clinically Relevant?

PubMed Central

Pistoia, Vito; Morandi, Fabio; Wang, Xinhui; Ferrone, Soldano

2007-01-01

HLA-G is a non-classical HLA-class Ib molecule with multiple immunoregulatory properties. Its main function in physiological conditions is to abrogate maternal NK cell activity against foetal tissue and to establish immune tolerance at maternal-foetal interface. HLA-G is expressed not only as a membrane bound molecule on the surface of cells, but also as a soluble moiety in body fluids. The major isoforms of HLA-G present in serum are soluble HLA-G1 and HLA-G5 which are generated by shedding or proteolytic cleavage of the membrane bound isoform and by secretion of a soluble isoform, respectively. Here we review the data about soluble HLA-G (sHLA-G) serum levels in different pathological conditions, including immune-mediated disorders, transplantation, and malignancies. In particular, we focus on sHLA-G expression and function in human neuroblastoma, a pediatric tumor, with special emphasis on a novel potential immuno escape mechanism utilized by NB to instruct monocytes to produce and release sHLA-G. Finally, the potential clinical relevance of sHLA-G serum levels is discussed. PMID:17825579

Animal to human translational paradigms relevant for approach avoidance conflict decision making.

PubMed

Kirlic, Namik; Young, Jared; Aupperle, Robin L

2017-09-01

Avoidance behavior in clinical anxiety disorders is often a decision made in response to approach-avoidance conflict, resulting in a sacrifice of potential rewards to avoid potential negative affective consequences. Animal research has a long history of relying on paradigms related to approach-avoidance conflict to model anxiety-relevant behavior. This approach includes punishment-based conflict, exploratory, and social interaction tasks. There has been a recent surge of interest in the translation of paradigms from animal to human, in efforts to increase generalization of findings and support the development of more effective mental health treatments. This article briefly reviews animal tests related to approach-avoidance conflict and results from lesion and pharmacologic studies utilizing these tests. We then provide a description of translational human paradigms that have been developed to tap into related constructs, summarizing behavioral and neuroimaging findings. Similarities and differences in findings from analogous animal and human paradigms are discussed. Lastly, we highlight opportunities for future research and paradigm development that will support the clinical utility of this translational work. Copyright © 2017 Elsevier Ltd. All rights reserved.

Exercise with latex sport bands represents a risk for latex allergic patients.

PubMed

Untersmayr, Eva; Lukschal, Anna; Hemmer, Wolfgang; Harwanegg, Christian; Breiteneder, Heimo; Jarisch, Reinhard; Scheiner, Otto; Jensen-Jarolim, Erika

2008-01-29

Based on two clinical observations of adverse reactions during exercise with latex sport bands, we aimed to assess the possible risk for allergic patients posed by this equipment by investigating allergen content and IgE binding potential. Protein extracts of three different latex sport bands were characterized with sera of latex allergic patients. The IgE recognition profile of the allergic patients was identified by component resolved diagnosis and the allergen composition of the extracts was characterized by inhibition assays with the recombinant latex allergens Hev b 1, 3, 5, 6.02, and 8. The sera showed pronounced IgE binding to all three blotted extracts, however with diverse patterns. Inhibition assays revealed the presence of Hev b 1, 3, 5, and 8 in latex sport band extracts. The clinical relevance of contained allergens was demonstrated by strong skin reactions when testing with latex sport bands. From our results we conclude that latex sport bands contain clinically relevant allergens and may cause latex allergic individuals to experience allergic symptoms, potentially amplified by exercise-induced mechanisms. Even though latex is labeled on products, it is important that patients as well as athletic trainers and physical therapists recognize the risk of adverse reactions with these bands.

Phenotypic and genotypic characterization of clinically relevant bacteria isolated from dental waste and waste workers' hands, mucosas and coats.

PubMed

Tagliaferri, T L; Vieira, C D; de Carvalho, M A R; Ladeira, L C D; Magalhães, P P; de Macêdo Farias, L; Dos Santos, S G

2017-10-01

Infectious wastes are potential sources of pathogenic micro-organisms, which may represent a risk to the professionals who manage them. In this study, we aimed to characterize the infectious bacteria present in dental waste and waste workers. The dental waste produced over 24 h was collected and waste workers were sampled by swabbing. Isolate resistance profiles were characterized by Vitek ® and PCR and biofilm formation by Congo Red agar, string test and microtitre assay. To assess similarity between the waste and the workers' samples, a random amplified polymorphic DNA test was used. Twenty-eight bacteria were identified as clinically relevant. The most frequent gene was bla TEM present in five Gram-negative micro-organisms, and one bla SHV in Klebsiella pneumoniae. All Pseudomonas aeruginosa were positive to extracellular polymeric substances formation, except one isolated from a worker. Klebsiella pneumoniae had negative results for the string test. Pseudomonas aeruginosa showed better adherence at 25°C after 48 h of incubation and K. pneumonia had the best biofilm formation at the same temperature, after 24 h. The similarity between P. aeruginosa recovered from dental waste and from workers was low, however, it is important to note that a pathogen was found on a worker's hands and that improvements in biosafety are required. Infectious dental waste can contain clinically relevant bacteria with important resistance and biofilm profiles. These micro-organisms could be transmitted to waste workers, other professionals and patients if the principles of biosafety measures are neglected. To our knowledge, no study has ever evaluated the microbial characterization and the potential contamination risk of dental infectious waste and waste handlers. The presence of clinically relevant bacteria in the hands and nasal mucosa of waste workers highlights the need for studies in this field to clarify the risk of these pathogens in dental healthcare services, and to stress the need for an efficient waste management. © 2017 The Society for Applied Microbiology.

A review of clinical practice guidelines for lung cancer

PubMed Central

Ball, David; Silvestri, Gerard A.

2013-01-01

Clinical practice guidelines are important evidence-based resources to guide complex clinical decision making. However, it is challenging for health professionals to keep abreast available guidelines and to know how and where to access relevant guidelines. This review examines currently available guidelines for lung cancer published in the English language. Important key features are listed for each identified guideline. The methodology, approaches to dissemination and implementation, and associated resources are summarised. General challenges in the area of guideline development are highlighted. The potential to collaborate more widely across lung cancer guideline developers by sharing literature searches and assessments is discussed. PMID:24163752

Naloxegol, an opioid antagonist with reduced CNS penetration: Mode-of-action and human relevance for rat testicular tumours.

PubMed

Andersson, Håkan; Mitchard, Terri; Johnson, Nakpangi; Floettmann, Eike

2017-08-15

Naloxegol is an opioid antagonist which has been developed for the treatment of patients with opioid induced constipation. In the nonclinical safety program naloxegol was shown to have a very benign toxicity profile. In the rat, but not the mouse, 2-year carcinogenicity study a change in tumour pattern with an increase in testicular Leydig cell tumours (LCT) was observed after dosing at high (supra-pharmacological) concentrations. To establish the basis of the increase in LCT and to assess its potential relevance to humans, studies to exclude and potentially identify mode-of-action (MoA) were performed. A genotoxic mechanism was ruled out following negative results in the Ames, mouse lymphoma, and micronucleus assays. An effect on androgen metabolism was excluded since the treatment of rats with naloxegol for 14days did not result in any induction of CYP protein levels. It was demonstrated that administration of centrally restricted opioid antagonists naloxegol or methylnaltrexone at high doses induced an increase in LH release with no clear increase in testosterone, in contrast to the centrally acting opioid antagonist naloxone, which showed marked increases in both LH and testosterone. LCT due to increased LH stimulation is common in rats but not documented in humans. Collectively, the lack of genotoxicity signal, the lack of androgen effect, the increase in LH secretion in rats, which is no considered to be relevant for LCT formation in humans, and high margins to clinical exposures, the observed increase in LCT in the rat is not expected to be clinically relevant. Copyright © 2017 Elsevier Inc. All rights reserved.

Research methods to change clinical practice for patients with rare cancers.

PubMed

Billingham, Lucinda; Malottki, Kinga; Steven, Neil

2016-02-01

Rare cancers are a growing group as a result of reclassification of common cancers by molecular markers. There is therefore an increasing need to identify methods to assess interventions that are sufficiently robust to potentially affect clinical practice in this setting. Methods advocated for clinical trials in rare diseases are not necessarily applicable in rare cancers. This Series paper describes research methods that are relevant for rare cancers in relation to the range of incidence levels. Strategies that maximise recruitment, minimise sample size, or maximise the usefulness of the evidence could enable the application of conventional clinical trial design to rare cancer populations. Alternative designs that address specific challenges for rare cancers with the aim of potentially changing clinical practice include Bayesian designs, uncontrolled n-of-1 trials, and umbrella and basket trials. Pragmatic solutions must be sought to enable some level of evidence-based health care for patients with rare cancers. Copyright © 2016 Elsevier Ltd. All rights reserved.

The role of alprazolam for the treatment of panic disorder in Australia.

PubMed

Moylan, Steven; Giorlando, Francesco; Nordfjærn, Trond; Berk, Michael

2012-03-01

To investigate the potential impact of increasing prescription rates of alprazolam for the treatment of panic disorder (PD) in Australia through a review of efficacy, tolerability and adverse outcome literature. Data were sourced by a literature search using MEDLINE, Embase, PsycINFO and a manual search of scientific journals to identify relevant articles. Clinical practice guidelines from the American Psychiatric Association, National Institute of Clinical Excellence, Royal Australian and New Zealand College of Psychiatrists and World Federation of Societies of Biological Psychiatry were sourced. Prescription data were sourced from Australian governmental sources. Alprazolam has shown efficacy for control of PD symptoms, particularly in short-term controlled clinical trials, but is no longer recommended as a first-line pharmacological treatment due to concerns about the risks of developing tolerance, dependence and abuse potential. Almost no evidence is available comparing alprazolam to current first-line pharmacological treatment. Despite this, prescription rates are increasing. A number of potential issues including use in overdose and impact on car accidents are noted. conclusion: Although effective for PD symptoms in clinical trials, a number of potential issues may exist with use. Consideration of its future place in PD treatment in Australia may be warranted.

Research Gaps in Wilderness Medicine.

PubMed

Tritz, Daniel; Dormire, Kody; Brachtenbach, Travis; Gordon, Joshua; Sanders, Donald; Gearheart, David; Crawford, Julia; Vassar, Matt

2018-05-18

Wilderness medicine involves the treatment of individuals in remote, austere environments. Given the high potential for injuries as well as the unique treatment modalities required in wilderness medicine, evidence-based clinical practice guidelines are necessary to provide optimal care. In this study, we identify evidence gaps from low-quality recommendations in wilderness medicine clinical practice guidelines and identify new/ongoing research addressing them. We included relevant clinical practice guidelines from the Wilderness Medical Society and obtained all 1C or 2C level recommendations. Patient/Problem/Population, intervention, comparison, outcome (PICO) questions were created to address each recommendation. Using 24 search strings, we extracted titles, clinical trial registry number, and recruitment status for 8899 articles. We categorized the articles by trial design to infer the effect they may have on future recommendations. Twelve clinical practice guidelines met inclusion criteria. From these we located 275 low-quality recommendations and used them to create 275 PICO questions. Thirty-three articles were relevant to the PICO questions. Heat-related illness had the highest number of relevant articles (n=9), but acute pain and altitude sickness had the most randomized clinical trials (n=6). Overall, few studies were being conducted to address research gaps in wilderness medicine. Heat-related illness had the most new or ongoing research, whereas no studies were being conducted to address gaps in eye injuries, basic wound management, or spine immobilization. Animals, cadavers, and mannequin research are useful in cases in which human evidence is difficult to obtain. Establishing research priorities is recommended for addressing research gaps identified by guideline panels. Copyright © 2018 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

Synthesis of DTPA analogues derived from piperidine and azepane: potential contrast enhancement agents for magnetic resonance imaging.

PubMed

Chong, H S; Garmestani, K; Bryant, L H; Brechbiel, M W

2001-11-16

Two DTPA derivatives (PIP-DTPA and AZEP-DTPA) as potential contrast enhancement agents in MRI are synthesized. The T1 and T2 relaxivities of their corresponding Gd(III) complexes are reported. At clinically relevant field strengths, the relaxivities of the complexes are comparable to that of the contrast agent, Gd(DTPA) which is in clinical use. The serum stability of the (153)Gd-labeled complexes is assessed by measuring the release of (153)Gd from the ligands. The radiolabeled Gd chelates are found to be kinetically stable in human serum for up to at least 14 days without any measurable loss of radioactivity.

Melaleuca alternifolia and its application against dental plaque and periodontal diseases: A systematic review.

PubMed

Casarin, Maísa; Pazinatto, Josiele; Santos, Roberto Christ Vianna; Zanatta, Fabricio Batistin

2018-02-01

This is a systematic review of clinical and laboratory studies evaluating the effect of Melaleuca alternifolia on periodontopathogens, dental plaque, gingivitis, periodontitis, and inflammatory responses. The PubMed, Cochrane, Web of science, Bireme, Lilacs, Prospero, Open Grey, and Clinical Trials databases were searched to identify potentially eligible studies through October 2016. Of 1,654 potentially eligible studies, 25 were included in the systematic review. Their methodology was evaluated through the Cochrane Handbook for clinical studies and the GRADE system for in vivo/in vitro studies. Although clinical studies must be interpreted with caution due to methodological limitations, laboratory studies have found promising results. In vitro evidences showed that M. alternifolia has bactericidal and bacteriostatic effects against the most prevalent periodontopathogens. Clinical studies found comparable effects to chlorhexidine 0.12% in reducing gingival inflammation, although the antiplaque effect was lower. M. alternifolia also showed antioxidant properties, which are beneficial to the host, allied to the reduction on immune-inflammatory responses to pathogens. This systematic review suggests that the M. alternifolia has potential anti-inflammatory and antimicrobial properties, which can be easily applied to the periodontal tissues. However, further clinical trials are needed to elucidate the clinical relevance of its application. Copyright © 2017 John Wiley & Sons, Ltd.

Healthcare professionals' agreement on clinical relevance of drug-related problems among elderly patients.

PubMed

Bech, Christine Flagstad; Frederiksen, Tine; Villesen, Christine Tilsted; Højsted, Jette; Nielsen, Per Rotbøll; Kjeldsen, Lene Juel; Nørgaard, Lotte Stig; Christrup, Lona Louring

2018-02-01

Background Disagreement among healthcare professionals on the clinical relevance of drug-related problems can lead to suboptimal treatment and increased healthcare costs. Elderly patients with chronic non-cancer pain and comorbidity are at increased risk of drug related problems compared to other patient groups due to complex medication regimes and transition of care. Objective To investigate the agreement among healthcare professionals on their classification of clinical relevance of drug-related problems in elderly patients with chronic non-cancer pain and comorbidity. Setting Multidisciplinary Pain Centre, Rigshospitalet, Copenhagen, Denmark. Method A pharmacist performed medication review on elderly patients with chronic non-cancer pain and comorbidity, identified their drug-related problems and classified these problems in accordance with an existing categorization system. A five-member clinical panel rated the drug-related problems' clinical relevance in accordance with a five-level rating scale, and their agreement was compared using Fleiss' κ. Main outcome measure Healthcare professionals' agreement on clinical relevance of drug related problems, using Fleiss' κ. Results Thirty patients were included in the study. A total of 162 drug related problems were identified, out of which 54% were of lower clinical relevance (level 0-2) and 46% of higher clinical relevance (level 3-4). Only slight agreement (κ = 0.12) was found between the panellists' classifications of clinical relevance using a five-level rating scale. Conclusion The clinical pharmacist identified drug related problems of lower and higher clinical relevance. Poor overall agreement on the severity of the drug related problems was found among the panelists.

Biomarkers for AAA: Encouraging steps but clinical relevance still to be delivered.

PubMed

Htun, Nay Min; Peter, Karlheinz

2014-10-01

Potential biomarkers have been investigated using proteomic studies in a variety of diseases. Some biomarkers have central roles in both diagnosis and monitoring of various disorders in clinical medicine, such as troponins, brain natriuretic peptide, and C-reactive protein. Although several biomarkers have been suggested in human abdominal aortic aneurysm (AAA), reliable markers have been lacking. In this issue, Moxon et al. [Proteomics Clin Appl. 2014, 8, 762-772] undertook a broad and systematic proteomic approach toward identification of biomarkers in a commonly used AAA mouse model (AAA created by angiotensin-II infusion). In this mouse model, apolipoprotein C1 and matrix metalloproteinase-9 were identified as novel biomarkers of stable AAA. This finding represents an important step forward, toward a clinically relevant role of biomarkers in AAA. This also encourages for further studies toward the identification of biomarkers (or their combinations) that can predict AAA progression and rupture, which would represent a major progress in AAA management and would establish an AAA biomarker as a much anticipated clinical tool. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Real time and label free profiling of clinically relevant exosomes

PubMed Central

Sina, Abu Ali Ibn; Vaidyanathan, Ramanathan; Dey, Shuvashis; Carrascosa, Laura G.; Shiddiky, Muhammad J. A.; Trau, Matt

2016-01-01

Tumor-derived exosomes possess significant clinical relevance due to their unique composition of genetic and protein material that is representative of the parent tumor. Specific isolation as well as identification of proportions of these clinically relevant exosomes (CREs) from biological samples could help to better understand their clinical significance as cancer biomarkers. Herein, we present a simple approach for quantification of the proportion of CREs within the bulk exosome population isolated from patient serum. This proportion of CREs can potentially inform on the disease stage and enable non-invasive monitoring of inter-individual variations in tumor-receptor expression levels. Our approach utilises a Surface Plasmon Resonance (SPR) platform to quantify the proportion of CREs in a two-step strategy that involves (i) initial isolation of bulk exosome population using tetraspanin biomarkers (i.e., CD9, CD63), and (ii) subsequent detection of CREs within the captured bulk exosomes using tumor-specific markers (e.g., human epidermal growth factor receptor 2 (HER2)). We demonstrate the isolation of bulk exosome population and detection of as low as 10% HER2(+) exosomes from samples containing designated proportions of HER2(+) BT474 and HER2(−) MDA-MB-231 cell derived exosomes. We also demonstrate the successful isolation of exosomes from a small cohort of breast cancer patient samples and identified that approximately 14–35% of their bulk population express HER2. PMID:27464736

Real time and label free profiling of clinically relevant exosomes.

PubMed

Sina, Abu Ali Ibn; Vaidyanathan, Ramanathan; Dey, Shuvashis; Carrascosa, Laura G; Shiddiky, Muhammad J A; Trau, Matt

2016-07-28

Tumor-derived exosomes possess significant clinical relevance due to their unique composition of genetic and protein material that is representative of the parent tumor. Specific isolation as well as identification of proportions of these clinically relevant exosomes (CREs) from biological samples could help to better understand their clinical significance as cancer biomarkers. Herein, we present a simple approach for quantification of the proportion of CREs within the bulk exosome population isolated from patient serum. This proportion of CREs can potentially inform on the disease stage and enable non-invasive monitoring of inter-individual variations in tumor-receptor expression levels. Our approach utilises a Surface Plasmon Resonance (SPR) platform to quantify the proportion of CREs in a two-step strategy that involves (i) initial isolation of bulk exosome population using tetraspanin biomarkers (i.e., CD9, CD63), and (ii) subsequent detection of CREs within the captured bulk exosomes using tumor-specific markers (e.g., human epidermal growth factor receptor 2 (HER2)). We demonstrate the isolation of bulk exosome population and detection of as low as 10% HER2(+) exosomes from samples containing designated proportions of HER2(+) BT474 and HER2(-) MDA-MB-231 cell derived exosomes. We also demonstrate the successful isolation of exosomes from a small cohort of breast cancer patient samples and identified that approximately 14-35% of their bulk population express HER2.

A Review of the Medical Education Literature for Graduate Medical Education Teachers

PubMed Central

Locke, Kenneth A.; Bates, Carol K.; Karani, Reena; Chheda, Shobhina G.

2013-01-01

Background A rapidly evolving body of literature in medical education can impact the practice of clinical educators in graduate medical education. Objective To aggregate studies published in the medical education literature in 2011 to provide teachers in general internal medicine with an overview of the current, relevant medical education literature. Review We systematically searched major medical education journals and the general clinical literature for medical education studies with sound design and relevance to the educational practice of graduate medical education teachers. We chose 12 studies, grouped into themes, using a consensus method, and critiqued these studies. Results Four themes emerged. They encompass (1) learner assessment, (2) duty hour limits and teaching in the inpatient setting, (3) innovations in teaching, and (4) learner distress. With each article we also present recommendations for how readers may use them as resources to update their clinical teaching. While we sought to identify the studies with the highest quality and greatest relevance to educators, limitation of the studies selected include their single-site and small sample nature, and the frequent lack of objective measures of outcomes. These limitations are shared with the larger body of medical education literature. Conclusions The themes and the recommendations for how to incorporate this information into clinical teaching have the potential to inform the educational practice of general internist educators as well as that of teachers in other specialties. PMID:24404262

Fear of cancer recurrence: a theoretical review and its relevance for clinical presentation and management.

PubMed

Simonelli, Laura E; Siegel, Scott D; Duffy, Nicole M

2017-10-01

There is increasing recognition of the unique physical and psychosocial concerns of the growing population of cancer survivors. An emerging literature demonstrates that fear of cancer recurrence (FCR) is a problematic long-term and late effect for cancer survivors. In fact, FCR is a top concern, and this article provides a necessary synthesis of the extant research evidence and theory. Literature searches were conducted using databases including MEDLINE and PsychINFO using specified search terms including 'fear of recurrence' and 'worry about recurrence'. A comprehensive narrative review summarizes early empirical findings on FCR including current definitions, assessment tools, clinical presentations, quality of life impact, prevalence, trajectory and risk factors. This paper also critically reviews the relevant theoretical frameworks to best understand these findings and considers multiple psychosocial treatment models that may have relevance for addressing FCR in the clinical setting. There is evidence of substantial prevalence and quality of life impact of FCR. Several theories (e.g. self-regulation model of illness, a family-based model, uncertainty in illness theory, social-cognitive processing theory, terror management theory) directly or indirectly help conceptualize FCR and inform potential treatment options for those with clinically significant distress or impairment resulting from FCR. Further investigation into FCR is warranted to promote evidence-based care for this significant cancer survivorship concern. Copyright © 2016 John Wiley & Sons, Ltd.

Bicarbonate in diabetic ketoacidosis - a systematic review

PubMed Central

2011-01-01

Objective This study was designed to examine the efficacy and risk of bicarbonate administration in the emergent treatment of severe acidemia in diabetic ketoacidosis (DKA). Methods PUBMED database was used to identify potentially relevant articles in the pediatric and adult DKA populations. DKA intervention studies on bicarbonate administration versus no bicarbonate in the emergent therapy, acid-base studies, studies on risk association with cerebral edema, and related case reports, were selected for review. Two reviewers independently conducted data extraction and assessed the citation relevance for inclusion. Results From 508 potentially relevant articles, 44 were included in the systematic review, including three adult randomized controlled trials (RCT) on bicarbonate administration versus no bicarbonate in DKA. We observed a marked heterogeneity in pH threshold, concentration, amount, and timing for bicarbonate administration in various studies. Two RCTs demonstrated transient improvement in metabolic acidosis with bicarbonate treatment within the initial 2 hours. There was no evidence of improved glycemic control or clinical efficacy. There was retrospective evidence of increased risk for cerebral edema and prolonged hospitalization in children who received bicarbonate, and weak evidence of transient paradoxical worsening of ketosis, and increased need for potassium supplementation. No studies involved patients with an initial pH < 6.85. Conclusions The evidence to date does not justify the administration of bicarbonate for the emergent treatment of DKA, especially in the pediatric population, in view of possible clinical harm and lack of sustained benefits. PMID:21906367

Prediction of clinical response based on pharmacokinetic/pharmacodynamic models of 5-hydroxytryptamine reuptake inhibitors in mice

PubMed Central

Kreilgaard, M; Smith, D G; Brennum, L T; Sánchez, C

2008-01-01

Background and purpose: Bridging the gap between preclinical research and clinical trials is vital for drug development. Predicting clinically relevant steady-state drug concentrations (Css) in serum from preclinical animal models may facilitate this transition. Here we used a pharmacokinetic/pharmacodynamic (PK/PD) modelling approach to evaluate the predictive validity of 5-hydroxytryptamine (5-HT; serotonin) transporter (SERT) occupancy and 5-hydroxytryptophan (5-HTP)-potentiated behavioral syndrome induced by 5-HT reuptake inhibitor (SRI) antidepressants in mice. Experimental approach: Serum and whole brain drug concentrations, cortical SERT occupancy and 5-HTP-potentiated behavioral syndrome were measured over 6 h after a single subcutaneous injection of escitalopram, paroxetine or sertraline. [3H]2-(2-dimethylaminomethylphenylsulphanyl)-5-methyl-phenylamine ([3H]MADAM) was used to assess SERT occupancy. For PK/PD modelling, an effect-compartment model was applied to collapse the hysteresis and predict the steady-state relationship between drug exposure and PD response. Key results: The predicted Css for escitalopram, paroxetine and sertraline at 80% SERT occupancy in mice are 18 ng mL−1, 18 ng mL−1 and 24 ng mL−1, respectively, with corresponding responses in the 5-HTP behavioral model being between 20–40% of the maximum. Conclusions and implications: Therapeutically effective SERT occupancy for SRIs in depressed patients is approximately 80%, and the corresponding plasma Css are 6–21 ng mL−1, 21-95 ng mL−1 and 20–48 ng mL−1 for escitalopram, paroxetine and sertraline, respectively. Thus, PK/PD modelling using SERT occupancy and 5-HTP-potentiated behavioral syndrome as response markers in mice may be a useful tool to predict clinically relevant plasma Css values. PMID:18552871

Using language models to identify relevant new information in inpatient clinical notes.

PubMed

Zhang, Rui; Pakhomov, Serguei V; Lee, Janet T; Melton, Genevieve B

2014-01-01

Redundant information in clinical notes within electronic health record (EHR) systems is ubiquitous and may negatively impact the use of these notes by clinicians, and, potentially, the efficiency of patient care delivery. Automated methods to identify redundant versus relevant new information may provide a valuable tool for clinicians to better synthesize patient information and navigate to clinically important details. In this study, we investigated the use of language models for identification of new information in inpatient notes, and evaluated our methods using expert-derived reference standards. The best method achieved precision of 0.743, recall of 0.832 and F1-measure of 0.784. The average proportion of redundant information was similar between inpatient and outpatient progress notes (76.6% (SD=17.3%) and 76.7% (SD=14.0%), respectively). Advanced practice providers tended to have higher rates of redundancy in their notes compared to physicians. Future investigation includes the addition of semantic components and visualization of new information.

Using Language Models to Identify Relevant New Information in Inpatient Clinical Notes

PubMed Central

Zhang, Rui; Pakhomov, Serguei V.; Lee, Janet T.; Melton, Genevieve B.

2014-01-01

Redundant information in clinical notes within electronic health record (EHR) systems is ubiquitous and may negatively impact the use of these notes by clinicians, and, potentially, the efficiency of patient care delivery. Automated methods to identify redundant versus relevant new information may provide a valuable tool for clinicians to better synthesize patient information and navigate to clinically important details. In this study, we investigated the use of language models for identification of new information in inpatient notes, and evaluated our methods using expert-derived reference standards. The best method achieved precision of 0.743, recall of 0.832 and F1-measure of 0.784. The average proportion of redundant information was similar between inpatient and outpatient progress notes (76.6% (SD=17.3%) and 76.7% (SD=14.0%), respectively). Advanced practice providers tended to have higher rates of redundancy in their notes compared to physicians. Future investigation includes the addition of semantic components and visualization of new information. PMID:25954438

I PREPARE: development and clinical utility of an environmental exposure history mnemonic.

PubMed

Paranzino, Grace K; Butterfield, Patricia; Nastoff, Teresa; Ranger, Cherryll

2005-01-01

The I PREPARE environmental exposure history mnemonic is a quick reference tool created for primary care providers. Health care providers (N = 159) were asked to evaluate a prototype mnemonic, to suggest new health history questions, and to propose the deletion of less relevant questions. The goal of this evaluation was to create a practical and clinically relevant mnemonic, rather than to obtain quantitative estimates of validity. The final I PREPARE mnemonic cues the provider to "Investigate potential exposures;" ask questions related to "Present work," "Residence," "Environmental concerns," "Past work," and "Activities;" provide "Referrals and resources;" and "Educate" the patient by reviewing a checklist of strategies to prevent or minimize exposures. The sequence of I PREPARE makes intuitive sense by cueing the provider to ask specific questions and provide educational materials to the patient. National improvements in the quality of environmental exposure history data are predicated in part on the creation of simple and convenient tools for use in clinical practice.

Analytical challenges translating mass spectrometry-based phosphoproteomics from discovery to clinical applications

PubMed Central

Iliuk, Anton B.; Arrington, Justine V.; Tao, Weiguo Andy

2014-01-01

Phosphoproteomics is the systematic study of one of the most common protein modifications in high throughput with the aim of providing detailed information of the control, response, and communication of biological systems in health and disease. Advances in analytical technologies and strategies, in particular the contributions of high-resolution mass spectrometers, efficient enrichments of phosphopeptides, and fast data acquisition and annotation, have catalyzed dramatic expansion of signaling landscapes in multiple systems during the past decade. While phosphoproteomics is an essential inquiry to map high-resolution signaling networks and to find relevant events among the apparently ubiquitous and widespread modifications of proteome, it presents tremendous challenges in separation sciences to translate it from discovery to clinical practice. In this mini-review, we summarize the analytical tools currently utilized for phosphoproteomic analysis (with focus on MS), progresses made on deciphering clinically relevant kinase-substrate networks, MS uses for biomarker discovery and validation, and the potential of phosphoproteomics for disease diagnostics and personalized medicine. PMID:24890697

Molecular allergy diagnostics using IgE singleplex determinations: methodological and practical considerations for use in clinical routine: Part 18 of the Series Molecular Allergology.

PubMed

Kleine-Tebbe, Jörg; Jakob, Thilo

Allergen molecules (synonyms: single allergens, allergen components) open up new horizons for the targeted allergen-specific diagnostics of immunoglobulin E (IgE) in singleplex determination. The following rationales support the targeted use of allergen molecules and, more importantly, improve test properties: (1) increased test sensitivity ("analytical sensitivity"), particularly when important allergens are under-represented or lacking in the extract; (2) improved test selectivity (analytical specificity), particularly when the selected IgE repertoire against an allergen yields additional information on: (a) potential risk, (b) possible cross-reactivity, or (c) primary (species-specific) sensitization. However, the appropriate indication for the use of single allergens can only be established on a case-by-case basis (depending on the clinical context and previous history) and in an allergen-specific manner (depending on the allergen source and the single allergens available), rather than in a standardized way. Numerous investigations on suspected food allergy, insect venom allergy, or sensitization to respiratory allergens have meanwhile demonstrated the successful use of defined molecules for allergen-specific singleplex IgE diagnosis. Specific IgE to single allergens is limited in its suitability to predict the clinical relevance of sensitivity on an individual basis. In food allergies, one can at best identify the relative risk of a clinical reaction on the basis of an IgE profile, but no absolutely reliable prediction on (future) tolerance can be made. Ultimately, the clinical relevance of all IgE findings depends on the presence of corresponding symptoms and can only be assessed on an individual basis (previous history, symptom log, and provocation testing with the relevant allergen source where appropriate). Thus, also in molecular allergology, the treating physician and not the test result should determine the clinical relevance of diagnostic findings. Supplementary material is available for this article at 10.1007/s40629-015-0067-z and is accessible for authorized users.

Development and initial evaluation of an instrument to assess physiotherapists' clinical reasoning focused on clients' behavior change.

PubMed

Elvén, Maria; Hochwälder, Jacek; Dean, Elizabeth; Söderlund, Anne

2018-05-01

A systematically developed and evaluated instrument is needed to support investigations of physiotherapists' clinical reasoning integrated with the process of clients' behavior change. This study's aim was to develop an instrument to assess physiotherapy students' and physiotherapists' clinical reasoning focused on clients' activity-related behavior and behavior change, and initiate its evaluation, including feasibility and content validity. The study was conducted in three phases: 1) determination of instrument structure and item generation, based on a model, guidelines for assessing clinical reasoning, and existing measures; 2) cognitive interviews with five physiotherapy students to evaluate item understanding and feasibility; and 3) a Delphi process with 18 experts to evaluate content relevance. Phase 1 resulted in an instrument with four domains: Physiotherapist; Input from client; Functional behavioral analysis; and Strategies for behavior change. The instrument consists of case scenarios followed by items in which key features are identified, prioritized, or interpreted. Phase 2 resulted in revisions of problems and approval of feasibility. Phase 3 demonstrated high level of consensus regarding the instrument's content relevance. This feasible and content-validated instrument shows potential for use in investigations of physiotherapy students' and physiotherapists' clinical reasoning, however continued development and testing are needed.

Cell and Gene Therapies: European View on Challenges in Translation and How to Address Them

PubMed Central

Rousseau, Cécile F.; Mačiulaitis, Romaldas; Śladowski, Dariusz; Narayanan, Gopalan

2018-01-01

Advanced therapy medicinal products (ATMPs), i.e., cell and gene therapy products, is a rapidly evolving field of therapeutic development. A significant proportion of the products are being developed by academia or small/medium-sized enterprises (SMEs). The many challenges in translation posed by this class of products include aspects covering: manufacturing, non-clinical development plan as relevant to clinical trial, marketing authorization, and reimbursement. In this context, the term translation refers to the relevance of non-clinical data in relation to how it impacts on appropriate and efficient clinical development. In order to successfully overcome these challenges, a clear understanding of the requirements and expectations of all the stakeholders is critical. This article aims to cover the potential challenges related to such translation and suggested approaches to find solutions based on experience and learnings from the perspective of European Union. While commercial challenges have a significant impact on the ATMPs in general, it is considered outside the scope of this article. However, by adopting a strong scientific basis for translation as suggested in this article, it is likely such an approach would help rather than harm successful real world clinical use of ATMPs.

Incidental findings in multislice computed tomography prior to transcatheter aortic valve implantation: frequency, clinical relevance and outcome.

PubMed

Trenkwalder, Teresa; Lahmann, Anna Lena; Nowicka, Magdalena; Pellegrini, Costanza; Rheude, Tobias; Mayr, N Patrick; Voss, Stephanie; Bleiziffer, Sabine; Lange, Rüdiger; Joner, Michael; Kasel, Albert M; Kastrati, Adnan; Schunkert, Heribert; Husser, Oliver; Hadamitzky, Martin; Hengstenberg, Christian

2018-02-21

Multislice computed tomography (MSCT) has emerged as the mainstay in patients planned for transcatheter aortic valve implantation (TAVI). Incidental findings (IF) in MSCT are common. However, the exact incidence, clinical relevance and further consequences of IF are unclear and it is controversial whether IF adversely affect patients' outcome. We analyzed MSCT data of 1050 patients screened for TAVI between January 2011 and December 2014. Median follow-up of patients was 20 months. In total, 3194 IF were identified, which were classified into clinically non-relevant IF (2872, 90%) and clinically relevant IF (322, 10%). In 25% of patients (258/1050) at least one clinically relevant IF was present. Age (80 ± 7 vs. 80 ± 7 years; p = 0.198) and EuroSCORE II (3.6% [2.1-5.7] vs. 3.6% [2.1-5.9]; p = 0.874) was similar between patients with and without a clinically relevant IF. TAVI was performed less frequently in patients with a clinically relevant IF (76% vs. 85%; p < 0.001), with more patients receiving surgical aortic valve replacement in that group (14% vs. 11%; p = 0.042), possibly due to the high rate of incidental aneurysms of the ascending aorta (n = 48). If TAVI was performed mortality did not differ (30-days: 4% vs. 3%; p = 0.339, 1-year: 11% vs. 14%; p = 0.226) between patients with and without a clinically relevant IF. Our study is the largest study to analyze prevalence, clinical relevance and therapeutic consequences of IF during screening for TAVI. IF in pre-procedural MSCT are common and clinically relevant in one-quarter of patients. However, these findings had no impact on overall mortality.

First-line first? Trends in thiazide prescribing for hypertensive seniors.

PubMed

Morgan, Steve; Bassett, Kenneth L; Wright, James M; Yan, Lixiang

2005-04-01

Evidence of reduced cardiovascular morbidity and mortality as well as cost support thiazide diuretics as the first-line choice for treatment of hypertension. The purpose of this study was to determine the proportion of senior hypertensives that received thiazide diuretics as first-line treatment, and to determine if cardiovascular and other potentially relevant comorbidities predict the choice of first-line therapy. British Columbia PharmaCare data were used to determine the cohort of seniors (residents aged 65 or older) who received their first reimbursed hypertension drug during the period 1993 to 2000. These individual records were linked to medical and hospital claims data using the British Columbia Linked Health Database to find the subset that had diagnoses indicating the presence of hypertension as well as cardiovascular and other relevant comorbidities. Rates of first-line thiazide prescribing as proportion of all first-line treatment were analysed, accounting for patient age, sex, overall clinical complexity, and potentially relevant comorbidities. For the period 1993 to 2000, 82,824 seniors who had diagnoses of hypertension were identified as new users of hypertension drugs. The overall rate at which thiazides were used as first-line treatment varied from 38% among senior hypertensives without any potentially relevant comorbidity to 9% among hypertensives with previous acute myocardial infarction. The rate of first-line thiazide diuretic prescribing for patients with and without potentially relevant comorbidities increased over the study period. Women were more likely than men, and older patients were more likely than younger, to receive first-line thiazide therapy. Findings indicate that first-line prescribing practices for hypertension are not consistent with the evidence from randomized control trials measuring morbidity and mortality. The health and financial cost of not selecting the most effective and least costly therapeutic options are significant.

Trial Watch—Immunostimulation with cytokines in cancer therapy

PubMed Central

Vacchelli, Erika; Aranda, Fernando; Bloy, Norma; Buqué, Aitziber; Cremer, Isabelle; Eggermont, Alexander; Fridman, Wolf Hervé; Fucikova, Jitka; Galon, Jérôme; Spisek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2016-01-01

ABSTRACT During the past decade, great efforts have been dedicated to the development of clinically relevant interventions that would trigger potent (and hence potentially curative) anticancer immune responses. Indeed, developing neoplasms normally establish local and systemic immunosuppressive networks that inhibit tumor-targeting immune effector cells, be them natural or elicited by (immuno)therapy. One possible approach to boost anticancer immunity consists in the (generally systemic) administration of recombinant immunostimulatory cytokines. In a limited number of oncological indications, immunostimulatory cytokines mediate clinical activity as standalone immunotherapeutic interventions. Most often, however, immunostimulatory cytokines are employed as immunological adjuvants, i.e., to unleash the immunogenic potential of other immunotherapeutic agents, like tumor-targeting vaccines and checkpoint blockers. Here, we discuss recent preclinical and clinical advances in the use of some cytokines as immunostimulatory agents in oncological indications. PMID:27057468

Transfer of knowledge and skills: some implications for nursing and nurse education.

PubMed

Lauder, W; Reynolds, W; Angus, N

1999-08-01

The construct of transfer has enormous importance to nursing as it begins to highlight potential problems in the transfer of knowledge and skills from the campus to the clinical area, from one part of the clinical area to another (e.g. surgical to medical), and from community to the clinical area. Thus, any adequate conceptualization of transfer must account for problems of practice-practice transfer as well as theory-practice transfer. These potential problems are the concern of educators, students and managers who have a responsibility for agency nurses and bank nurses who may find themselves in different specialities on a regular basis. Transfer has relevance to a whole raft of other issues ranging from the application of theories to nursing practice, through to the validity of claims that courses which develop intellectual skills prepare nurses for lifelong learning.

Inhibition of angiogenic attributes by decursin in endothelial cells and ex vivo rat aortic ring angiogenesis model.

PubMed

Bhat, Tariq A; Moon, Jung S; Lee, Sookyeon; Yim, Dongsool; Singh, Rana P

2011-11-01

The present study was undertaken to observe the inhibition of angiogenesis by decursin. It was the first time to show that decursin offered strong anti-angiogenic activities under the biologically relevant growth (with serum) conditions. Decursin significantly inhibited human umbilical vein endothelial cell (HUVEC) proliferation concomitant with G1 phase cell cycle arrest. Decursin also inhibited HUVEC-capillary tube formation and invasion/migration in a dose-dependant manner which was associated with the suppression of matrix metalloproteinase (MMP) -2 and -9 activities. Decursin suppressed angiogenesis in ex vivo rat aortic ring angiogenesis model where it significantly inhibited blood capillary-network sprouting from rat aortic sections. Taken together, these findings suggested anti-angiogenic activity of decursin in biologically relevant condition, and warrants further pre-clinical studies for its potential clinical usefulness.

Event-related potentials in impulsively aggressive juveniles: a retrospective chart-review study.

PubMed

Fisher, William; Ceballos, Natalie; Matthews, Dan; Fisher, Larry

2011-05-30

The assessment, treatment and management of aggressive youth represent a major clinical challenge facing pediatric mental health professionals today. Although a number of studies have examined physiological differences among aggressive patients vs. controls, the current literature lacks a comprehensive examination of the electroencephalographic activity of impulsively aggressive juveniles. The current study was designed to fill this void in the literature via a retrospective chart review of 80 male and female juveniles undergoing inpatient treatment for pathologically impulsive aggression. Clinical reports for mid- and late-latency event-related potentials (ERPs) were examined to determine their correlations with aggression characteristics, as well as any differential predictive utility of hemispheric differences and auditory vs. visual potentials. Results indicated that decrements of mid-latency potentials and ERPs evoked by auditory stimuli (vs. late-latency components and visual ERPs) were more highly predictive of aggressive behavior. No significant hemispheric differences were noted. Taken together, these results have theoretical significance for the etiology of impulsive aggression, and perhaps also clinical relevance for the treatment of this condition. Copyright © 2011 Elsevier Ltd. All rights reserved.

Hidden treasures in "ancient" microarrays: gene-expression portrays biology and potential resistance pathways of major lung cancer subtypes and normal tissue.

PubMed

Kerkentzes, Konstantinos; Lagani, Vincenzo; Tsamardinos, Ioannis; Vyberg, Mogens; Røe, Oluf Dimitri

2014-01-01

Novel statistical methods and increasingly more accurate gene annotations can transform "old" biological data into a renewed source of knowledge with potential clinical relevance. Here, we provide an in silico proof-of-concept by extracting novel information from a high-quality mRNA expression dataset, originally published in 2001, using state-of-the-art bioinformatics approaches. The dataset consists of histologically defined cases of lung adenocarcinoma (AD), squamous (SQ) cell carcinoma, small-cell lung cancer, carcinoid, metastasis (breast and colon AD), and normal lung specimens (203 samples in total). A battery of statistical tests was used for identifying differential gene expressions, diagnostic and prognostic genes, enriched gene ontologies, and signaling pathways. Our results showed that gene expressions faithfully recapitulate immunohistochemical subtype markers, as chromogranin A in carcinoids, cytokeratin 5, p63 in SQ, and TTF1 in non-squamous types. Moreover, biological information with putative clinical relevance was revealed as potentially novel diagnostic genes for each subtype with specificity 93-100% (AUC = 0.93-1.00). Cancer subtypes were characterized by (a) differential expression of treatment target genes as TYMS, HER2, and HER3 and (b) overrepresentation of treatment-related pathways like cell cycle, DNA repair, and ERBB pathways. The vascular smooth muscle contraction, leukocyte trans-endothelial migration, and actin cytoskeleton pathways were overexpressed in normal tissue. Reanalysis of this public dataset displayed the known biological features of lung cancer subtypes and revealed novel pathways of potentially clinical importance. The findings also support our hypothesis that even old omics data of high quality can be a source of significant biological information when appropriate bioinformatics methods are used.

An Overview of the Evidence and Mechanisms of Herb–Drug Interactions

PubMed Central

Fasinu, Pius S.; Bouic, Patrick J.; Rosenkranz, Bernd

2012-01-01

Despite the lack of sufficient information on the safety of herbal products, their use as alternative and/or complementary medicine is globally popular. There is also an increasing interest in medicinal herbs as precursor for pharmacological actives. Of serious concern is the concurrent consumption of herbal products and conventional drugs. Herb–drug interaction (HDI) is the single most important clinical consequence of this practice. Using a structured assessment procedure, the evidence of HDI presents with varying degree of clinical significance. While the potential for HDI for a number of herbal products is inferred from non-human studies, certain HDIs are well established through human studies and documented case reports. Various mechanisms of pharmacokinetic HDI have been identified and include the alteration in the gastrointestinal functions with consequent effects on drug absorption; induction and inhibition of metabolic enzymes and transport proteins; and alteration of renal excretion of drugs and their metabolites. Due to the intrinsic pharmacologic properties of phytochemicals, pharmacodynamic HDIs are also known to occur. The effects could be synergistic, additive, and/or antagonistic. Poor reporting on the part of patients and the inability to promptly identify HDI by health providers are identified as major factors limiting the extensive compilation of clinically relevant HDIs. A general overview and the significance of pharmacokinetic and pharmacodynamic HDI are provided, detailing basic mechanism, and nature of evidence available. An increased level of awareness of HDI is necessary among health professionals and drug discovery scientists. With the increasing number of plant-sourced pharmacological actives, the potential for HDI should always be assessed in the non-clinical safety assessment phase of drug development process. More clinically relevant research is also required in this area as current information on HDI is insufficient for clinical applications. PMID:22557968

What is the benefit of using amniotic membrane in oral surgery? A comprehensive review of clinical studies.

PubMed

Fénelon, M; Catros, S; Fricain, J C

2018-06-01

Since its first use for the reconstruction of tissue defects in the oral cavity in 1985, human amniotic membrane (hAM) has been widely studied in the field of oral surgery. Despite the growing number of publications in this field, there is no systematic review or meta-analysis concerning its clinical applications, outcome assessments, and relevance in oral surgery. The aim of this review is to provide a thorough understanding of the potential use of hAM for soft and hard tissue reconstruction in the oral cavity. A systematic electronic and a manual literature search of the MEDLINE-PubMed database and Scopus database was completed. Patient, Intervention, Comparison and Outcomes (PICO) technique was used to select the relevant articles to meet the objective. Studies using hAM for oral reconstruction, and conducted on human subjects, were included in this survey. A total of 17 articles were analyzed. Five areas of interest were identified as potential clinical application: periodontal surgery, cleft palate and tumor reconstruction, prosthodontics and peri-implant surgery. Overall, periodontal surgery was the only discipline to assess the efficacy of hAM with randomized clinical trials. The wide variability of preservation methods of hAM and the lack of objective measurements were observed in this study. hAM is already used in the field of oral surgery. Despite this, there is weak clinical evidence demonstrating convincingly the benefit of hAM in this area compared to standard surgery. Several studies now suggest the interest of hAM for periodontal tissue repair. Due to its biological and mechanical properties, hAM seems to be a promising treatment for wound healing in various areas of oral reconstruction. However, further randomized clinical trials are needed to confirm these preliminary results.

A methodological approach to identify external factors for indicator-based risk adjustment illustrated by a cataract surgery register

PubMed Central

2014-01-01

Background Risk adjustment is crucial for comparison of outcome in medical care. Knowledge of the external factors that impact measured outcome but that cannot be influenced by the physician is a prerequisite for this adjustment. To date, a universal and reproducible method for identification of the relevant external factors has not been published. The selection of external factors in current quality assurance programmes is mainly based on expert opinion. We propose and demonstrate a methodology for identification of external factors requiring risk adjustment of outcome indicators and we apply it to a cataract surgery register. Methods Defined test criteria to determine the relevance for risk adjustment are “clinical relevance” and “statistical significance”. Clinical relevance of the association is presumed when observed success rates of the indicator in the presence and absence of the external factor exceed a pre-specified range of 10%. Statistical significance of the association between the external factor and outcome indicators is assessed by univariate stratification and multivariate logistic regression adjustment. The cataract surgery register was set up as part of a German multi-centre register trial for out-patient cataract surgery in three high-volume surgical sites. A total of 14,924 patient follow-ups have been documented since 2005. Eight external factors potentially relevant for risk adjustment were related to the outcome indicators “refractive accuracy” and “visual rehabilitation” 2–5 weeks after surgery. Results The clinical relevance criterion confirmed 2 (“refractive accuracy”) and 5 (“visual rehabilitation”) external factors. The significance criterion was verified in two ways. Univariate and multivariate analyses revealed almost identical external factors: 4 were related to “refractive accuracy” and 7 (6) to “visual rehabilitation”. Two (“refractive accuracy”) and 5 (“visual rehabilitation”) factors conformed to both criteria and were therefore relevant for risk adjustment. Conclusion In a practical application, the proposed method to identify relevant external factors for risk adjustment for comparison of outcome in healthcare proved to be feasible and comprehensive. The method can also be adapted to other quality assurance programmes. However, the cut-off score for clinical relevance needs to be individually assessed when applying the proposed method to other indications or indicators. PMID:24965949

Best strategies to implement clinical pathways in an emergency department setting: study protocol for a cluster randomized controlled trial

PubMed Central

2013-01-01

Background The clinical pathway is a tool that operationalizes best evidence recommendations and clinical practice guidelines in an accessible format for ‘point of care’ management by multidisciplinary health teams in hospital settings. While high-quality, expert-developed clinical pathways have many potential benefits, their impact has been limited by variable implementation strategies and suboptimal research designs. Best strategies for implementing pathways into hospital settings remain unknown. This study will seek to develop and comprehensively evaluate best strategies for effective local implementation of externally developed expert clinical pathways. Design/methods We will develop a theory-based and knowledge user-informed intervention strategy to implement two pediatric clinical pathways: asthma and gastroenteritis. Using a balanced incomplete block design, we will randomize 16 community emergency departments to receive the intervention for one clinical pathway and serve as control for the alternate clinical pathway, thus conducting two cluster randomized controlled trials to evaluate this implementation intervention. A minimization procedure will be used to randomize sites. Intervention sites will receive a tailored strategy to support full clinical pathway implementation. We will evaluate implementation strategy effectiveness through measurement of relevant process and clinical outcomes. The primary process outcome will be the presence of an appropriately completed clinical pathway on the chart for relevant patients. Primary clinical outcomes for each clinical pathway include the following: Asthma—the proportion of asthmatic patients treated appropriately with corticosteroids in the emergency department and at discharge; and Gastroenteritis—the proportion of relevant patients appropriately treated with oral rehydration therapy. Data sources include chart audits, administrative databases, environmental scans, and qualitative interviews. We will also conduct an overall process evaluation to assess the implementation strategy and an economic analysis to evaluate implementation costs and benefits. Discussion This study will contribute to the body of evidence supporting effective strategies for clinical pathway implementation, and ultimately reducing the research to practice gaps by operationalizing best evidence care recommendations through effective use of clinical pathways. Trial registration ClinicalTrials.gov: NCT01815710 PMID:23692634

The potential impact of bone tissue engineering in the clinic

PubMed Central

Mishra, Ruchi; Bishop, Tyler; Valerio, Ian L; Fisher, John P; Dean, David

2016-01-01

Bone tissue engineering (BTE) intends to restore structural support for movement and mineral homeostasis, and assist in hematopoiesis and the protective functions of bone in traumatic, degenerative, cancer, or congenital malformation. While much effort has been put into BTE, very little of this research has been translated to the clinic. In this review, we discuss current regenerative medicine and restorative strategies that utilize tissue engineering approaches to address bone defects within a clinical setting. These approaches involve the primary components of tissue engineering: cells, growth factors and biomaterials discussed briefly in light of their clinical relevance. This review also presents upcoming advanced approaches for BTE applications and suggests a probable workpath for translation from the laboratory to the clinic. PMID:27549369

Clinical metabolomics paves the way towards future healthcare strategies

PubMed Central

Collino, Sebastiano; Martin, François‐Pierre J.; Rezzi, Serge

2013-01-01

Metabolomics is recognized as a powerful top‐down system biological approach to understand genetic‐environment‐health paradigms paving new avenues to identify clinically relevant biomarkers. It is nowadays commonly used in clinical applications shedding new light on physiological regulatory processes of complex mammalian systems with regard to disease aetiology, diagnostic stratification and, potentially, mechanism of action of therapeutic solutions. A key feature of metabolomics lies in its ability to underpin the complex metabolic interactions of the host with its commensal microbial partners providing a new way to define individual and population phenotypes. This review aims at describing recent applications of metabolomics in clinical fields with insight into diseases, diagnostics/monitoring and improvement of homeostatic metabolic regulation. PMID:22348240

The Norwegian General Practice--Nursing Home criteria (NORGEP-NH) for potentially inappropriate medication use: A web-based Delphi study.

PubMed

Nyborg, Gunhild; Straand, Jørund; Klovning, Atle; Brekke, Mette

2015-06-01

To develop a set of explicit criteria for pharmacologically inappropriate medication use in nursing homes. In an expert panel, a three-round Delphi consensus process was conducted via survey software. Norway. Altogether 80 participants - specialists in geriatrics or clinical pharmacology, physicians in nursing homes and experienced pharmacists - agreed to participate in the survey. Of these, 62 completed the first round, and 49 panellists completed all three rounds (75.4% of those ultimately entering the survey). The authors developed a list of 27 criteria based on the Norwegian General Practice (NORGEP) criteria, literature, and clinical experience. The main outcome measure was the panellists' evaluation of the clinical relevance of each suggested criterion on a digital Likert scale from 1 (no clinical relevance) to 10. In the first round panellists could also suggest new criteria to be included in the process. For each criterion, degree of consensus was based on the average Likert score and corresponding standard deviation (SD). A list of 34 explicit criteria for potentially inappropriate medication use in nursing homes was developed through a three-round web-based Delphi consensus process. Degree of consensus increased with each round. No criterion was voted out. Suggestions from the panel led to the inclusion of seven additional criteria in round two. The NORGEP-NH list may serve as a tool in the prescribing process and in medication list reviews and may also be used in quality assessment and for research purposes.

Consensus Conference Follow-up: Inter-rater Reliability Assessment of the Best Evidence in Emergency Medicine (BEEM) Rater Scale, a Medical Literature Rating Tool for Emergency Physicians

PubMed Central

Worster, Andrew; Kulasegaram, Kulamakan; Carpenter, Christopher R.; Vallera, Teresa; Upadhye, Suneel; Sherbino, Jonathan; Haynes, R. Brian

2011-01-01

Background Studies published in general and specialty medical journals have the potential to improve emergency medicine (EM) practice, but there can be delayed awareness of this evidence because emergency physicians (EPs) are unlikely to read most of these journals. Also, not all published studies are intended for or ready for clinical practice application. The authors developed “Best Evidence in Emergency Medicine” (BEEM) to ameliorate these problems by searching for, identifying, appraising, and translating potentially practice-changing studies for EPs. An initial step in the BEEM process is the BEEM rater scale, a novel tool for EPs to collectively evaluate the relative clinical relevance of EM-related studies found in more than 120 journals. The BEEM rater process was designed to serve as a clinical relevance filter to identify those studies with the greatest potential to affect EM practice. Therefore, only those studies identified by BEEM raters as having the highest clinical relevance are selected for the subsequent critical appraisal process and, if found methodologically sound, are promoted as the best evidence in EM. Objectives The primary objective was to measure inter-rater reliability (IRR) of the BEEM rater scale. Secondary objectives were to determine the minimum number of EP raters needed for the BEEM rater scale to achieve acceptable reliability and to compare performance of the scale against a previously published evidence rating system, the McMaster Online Rating of Evidence (MORE), in an EP population. Methods The authors electronically distributed the title, conclusion, and a PubMed link for 23 recently published studies related to EM to a volunteer group of 134 EPs. The volunteers answered two demographic questions and rated the articles using one of two randomly assigned seven-point Likert scales, the BEEM rater scale (n = 68) or the MORE scale (n = 66), over two separate administrations. The IRR of each scale was measured using generalizability theory. Results The IRR of the BEEM rater scale ranged between 0.90 (95% confidence interval [CI] = 0.86 to 0.93) to 0.92 (95% CI = 0.89 to 0.94) across administrations. Decision studies showed a minimum of 12 raters is required for acceptable reliability of the BEEM rater scale. The IRR of the MORE scale was 0.82 to 0.84. Conclusions The BEEM rater scale is a highly reliable, single-question tool for a small number of EPs to collectively rate the relative clinical relevance within the specialty of EM of recently published studies from a variety of medical journals. It compares favorably with the MORE system because it achieves a high IRR despite simply requiring raters to read each article’s title and conclusion. PMID:22092904

Triple Reuptake Inhibitors: A Premise and Promise

PubMed Central

Marks, David M.; Patkar, Ashwin A.

2008-01-01

On the horizon there is a new class of psychoactive medications which work by inhibiting the neuronal reuptake of serotonin, norepinephrine, and dopamine. There are multiple potential indications for these drugs. Research suggests that they may have a role in treating depressive disorders, and it is plausible they may have potential efficacy in obesity, addiction, and pain syndromes. The current review describes some of the molecules in development presently and explores the research relevant to possible clinical uses for this class of medications. PMID:20046357

Thermophilic and alkaliphilic Actinobacteria: biology and potential applications

PubMed Central

Shivlata, L.; Satyanarayana, Tulasi

2015-01-01

Microbes belonging to the phylum Actinobacteria are prolific sources of antibiotics, clinically useful bioactive compounds and industrially important enzymes. The focus of the current review is on the diversity and potential applications of thermophilic and alkaliphilic actinobacteria, which are highly diverse in their taxonomy and morphology with a variety of adaptations for surviving and thriving in hostile environments. The specific metabolic pathways in these actinobacteria are activated for elaborating pharmaceutically, agriculturally, and biotechnologically relevant biomolecules/bioactive compounds, which find multifarious applications. PMID:26441937

Hidden Hearing Injury: The Emerging Science and Military Relevance of Cochlear Synaptopathy.

PubMed

Tepe, Victoria; Smalt, Christopher; Nelson, Jeremy; Quatieri, Thomas; Pitts, Kenneth

2017-09-01

The phenomenon recently described as "hidden hearing loss" was the subject of a meeting co-hosted by the Department of Defense Hearing Center of Excellence and MIT Lincoln Laboratory to consider the potential relevance of noise-related synaptopathic injury to military settings and performance, service-related injury scenarios, and military medical priorities. Participants included approximately 50 researchers and subject matter experts from academic, federal, and military laboratories. Here we present a synthesis of discussion topics and concerns, as well as specific research objectives identified to develop militarily relevant knowledge. We consider findings from studies to date that have demonstrated cochlear synaptopathy and neurodegenerative processes apparently linked to noise exposure in animal models. We explore the potential relevance of these findings to the prediction and prevention of military hearing injuries, and to comorbid injuries in the neurological domain. Noise-induced cochlear synaptopathic injury is not detected by conventional audiometric assessment of threshold sensitivity. Animal studies suggest there may be a generous window of opportunity for intervention to mitigate or prevent cochlear neurodegenerative processes, e.g., by administration of neurotrophins or antioxidants. However, it is not yet known if the mechanisms that underlie "hidden hearing loss" also occur in human beings or, if so, how to identify them early, and how and when to intervene. Neurological injuries resulting from noise exposures via the auditory system have potentially significant implications for military Service Member performance, long-term Veteran health, and noise exposure standards. Mediated via auditory pathways, such injuries have possible relationship to clinical impairments including speech perception, and may be a largely overlooked contributor to cognitive symptoms associated with other military service-related injuries such as blast exposure and brain trauma. The potential health and performance consequences of noise-induced cochlear synaptopathic injury are easily overlooked, especially if it is assumed that hearing threshold sensitivity loss is the major concern. There should be a renewed impetus to further characterize and model synaptopathic mechanisms of auditory injury; study its potential impact on human auditory function, cognition, and performance metrics of military relevance; and develop solutions for auditory protection (including noise dosimetry) and treatment if appropriate following noise or blast exposure in military scenarios. We identify specific problems, solution objectives, and research objectives. Recommended research calls for a multidisciplinary approach to address cochlear nerve synaptopathy, central (brain) dysfunction, noise exposure measurement and metrics, and clinical assessment. Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.

Testing the Long-Term Efficacy of a Prevention Program for Improving Marital Conflict in Community Families

ERIC Educational Resources Information Center

Faircloth, W. Brad; Schermerhorn, Alice C.; Mitchell, Patricia M.; Cummings, Jennifer S.; Cummings, E. Mark

2011-01-01

Family-focused prevention programs for community samples have potentially broad, clinically relevant implications but few studies have examined whether any program benefits continue to be observed over the long term. Although benefits of a marital conflict focused parent education program, the Happy Couples and Happy Kids (i.e., HCHK) program,…

Evaluation of indigenous grains from the Peruvian Andean region for antidiabetes and antihypertension potential using in vitro methods.

PubMed

Ranilla, Lena Galvez; Apostolidis, Emmanouil; Genovese, Maria Ines; Lajolo, Franco Maria; Shetty, Kalidas

2009-08-01

The health-relevant functionality of 10 thermally processed Peruvian Andean grains (five cereals, three pseudocereals, and two legumes) was evaluated for potential type 2 diabetes-relevant antihyperglycemia and antihypertension activity using in vitro enzyme assays. Inhibition of enzymes relevant for managing early stages of type 2 diabetes such as hyperglycemia-relevant alpha-glucosidase and alpha-amylase and hypertension-relevant angiotensin I-converting enzyme (ACE) were assayed along with the total phenolic content, phenolic profiles, and antioxidant activity based on the 1,1-diphenyl-2-picrylhydrazyl radical assay. Purple corn (Zea mays L.) (cereal) exhibited high free radical scavenging-linked antioxidant activity (77%) and had the highest total phenolic content (8 +/- 1 mg of gallic acid equivalents/g of sample weight) and alpha-glucosidase inhibitory activity (51% at 5 mg of sample weight). The major phenolic compound in this cereal was protocatechuic acid (287 +/- 15 microg/g of sample weight). Pseudocereals such as Quinoa (Chenopodium quinoa Willd) and Kañiwa (Chenopodium pallidicaule Aellen) were rich in quercetin derivatives (1,131 +/- 56 and 943 +/- 35 microg [expressed as quercetin aglycone]/g of sample weight, respectively) and had the highest antioxidant activity (86% and 75%, respectively). Andean legumes (Lupinus mutabilis cultivars SLP-1 and H-6) inhibited significantly the hypertension-relevant ACE (52% at 5 mg of sample weight). No alpha-amylase inhibitory activity was found in any of the evaluated Andean grains. This in vitro study indicates the potential of combination of Andean whole grain cereals, pseudocereals, and legumes to develop effective dietary strategies for managing type 2 diabetes and associated hypertension and provides the rationale for animal and clinical studies.

Investigation of Central Pain Processing in Post-Operative Shoulder Pain and Disability

PubMed Central

Valencia, Carolina; Fillingim, Roger B.; Bishop, Mark; Wu, Samuel S.; Wright, Thomas W.; Moser, Michael; Farmer, Kevin; George, Steven Z.

2014-01-01

Measures of central pain processing like conditioned pain modulation (CPM), and suprathreshold heat pain response (SHPR) have been described to assess different components of central pain modulatory mechanisms. Central pain processing potentially play a role in the development of postsurgical pain, however, the role of CPM and SHPR in explaining postoperative clinical pain and disability is still unclear. Seventy eight patients with clinical shoulder pain were included in this study. Patients were examined before shoulder surgery, at 3 months, and 6 months after surgery. The primary outcome measures were pain intensity and upper extremity disability. Analyses revealed that the change score (baseline – 3 months) of 5th pain rating of SHPR accounted for a significant amount of variance in 6 month postsurgical clinical pain intensity and disability after age, sex, preoperative pain intensity, and relevant psychological factors were considered. The present study suggests that baseline measures of central pain processing were not predictive of 6 month postoperative pain outcome. Instead, the 3 month change in SHPR might be a relevant factor in the transition to elevated 6-month postoperative pain and disability outcomes. In patients with shoulder pain, the 3 month change in a measure of central pain processing might be a relevant factor in the transition to elevated 6-month postoperative pain and disability scores. PMID:24042347

Conducting feasibilities in clinical trials: an investment to ensure a good study.

PubMed

Rajadhyaksha, Viraj

2010-07-01

Conducting clinical trial feasibility is one of the first steps in clinical trial conduct. This process includes assessing internal and environmental capacity, alignment of the clinical trial in terms of study design, dose of investigational product, comparator, patient type, with the local environment and assessing potential of conducting clinical trial in a specific country. A robust feasibility also ensures a realistic assessment and capability to conduct the clinical trial. For local affiliates of pharmaceutical organizations, and contract research organizations, this is a precursor to study placement and influences the decision of study placement. This article provides details on different types of feasibilities, information which is to be included and relevance of each. The article also aims to provide practical hands-on suggestions to make feasibilities more realistic and informative.

Prevalence of clinically relevant muscle weakness and its association with vitamin D status among older adults in Ecuador.

PubMed

Orces, Carlos H

2017-10-01

Muscle weakness and 25-hydroxyvitamin D (25(OH)D) deficiency have been associated with adverse outcomes among older adults. However, little is known about the relationship between clinically relevant muscle weakness and 25(OH)D levels in Ecuador. To examine the prevalence of muscle weakness and its association with 25(OH)D status among subjects aged 60 years and older in Ecuador. The present study was based on data from 2205 participants in the first National Survey of Health, Wellbeing, and Aging. The Foundation for the National Institute of Health Sarcopenia Project criteria was used to examine muscle weakness prevalence rates. Gender-specific general linear and logistic regression models adjusted for potential confounders were created to compare mean 25(OH)D concentrations and 25(OH)D deficiency across muscle strength categories, respectively. An estimated 32.2% of women and 33.4% of men had evidence of clinically relevant muscle weakness in Ecuador. In general, increased muscle weakness prevalence rates were present among Indigenous, residents in the rural Andes Mountains, underweight subjects, and those with a sedentary lifestyle. Muscle strength was significantly and directly correlated with mean 25(OH)D levels. After controlling for potential confounders, 25(OH)D deficiency prevalence rates were 31 and 43% higher among men and women with muscle weakness than those with normal strength, respectively. One-third of older adults nationwide had evidence of muscle weakness. While the present study found a significant correlation between muscle strength and 25(OH)D concentrations, further research is needed to examine whether optimizing 25(OH)D levels may improve muscle weakness among older adults.

Applications of mid-infrared spectroscopy in the clinical laboratory setting.

PubMed

De Bruyne, Sander; Speeckaert, Marijn M; Delanghe, Joris R

2018-01-01

Fourier transform mid-infrared (MIR-FTIR) spectroscopy is a nondestructive, label-free, highly sensitive and specific technique that provides complete information on the chemical composition of biological samples. The technique both can offer fundamental structural information and serve as a quantitative analysis tool. Therefore, it has many potential applications in different fields of clinical laboratory science. Although considerable technological progress has been made to promote biomedical applications of this powerful analytical technique, most clinical laboratory analyses are based on spectroscopic measurements in the visible or ultraviolet (UV) spectrum and the potential role of FTIR spectroscopy still remains unexplored. In this review, we present some general principles of FTIR spectroscopy as a useful method to study molecules in specimens by MIR radiation together with a short overview of methods to interpret spectral data. We aim at illustrating the wide range of potential applications of the proposed technique in the clinical laboratory setting with a focus on its advantages and limitations and discussing the future directions. The reviewed applications of MIR spectroscopy include (1) quantification of clinical parameters in body fluids, (2) diagnosis and monitoring of cancer and other diseases by analysis of body fluids, cells, and tissues, (3) classification of clinically relevant microorganisms, and (4) analysis of kidney stones, nails, and faecal fat.

[Potential antimicrobial drug interactions in clinical practice: consequences of polypharmacy and multidrug resistance].

PubMed

Martínez-Múgica, Cristina

2015-12-01

Polypharmacy is a growing problem nowadays, which can increase the risk of potential drug interactions, and result in a loss of effectiveness. This is particularly relevant to the anti-infective therapy, especially when infection is produced by resistant bacteria, because therapeutic options are limited and interactions can cause treatment failure. All antimicrobial prescriptions were retrospectively reviewed during a week in the Pharmacy Department, in order to detect potential drug-interactions and analysing their clinical significance. A total of 314 antimicrobial prescriptions from 151 patients were checked. There was at least one potential interaction detected in 40% of patients, being more frequent and severe in those infected with multidrug-resistant microorganisms. Drugs most commonly involved were quinolones, azoles, linezolid and vancomycin. Potential drug interactions with antimicrobial agents are a frequent problem that can result in a loss of effectiveness. This is why they should be detected and avoided when possible, in order to optimize antimicrobial therapy, especially in case of multidrug resistant infections.

Effects of stress and mental toughness on burnout and depressive symptoms: A prospective study with young elite athletes.

PubMed

Gerber, Markus; Best, Simon; Meerstetter, Fabienne; Walter, Marco; Ludyga, Sebastian; Brand, Serge; Bianchi, Renzo; Madigan, Daniel J; Isoard-Gautheur, Sandrine; Gustafsson, Henrik

2018-05-18

To examine in a sample of young elite athletes (a) the presence of clinically relevant symptoms of burnout and depression, and (b) a possible interaction of perceived stress and mental toughness in the prediction of burnout and depressive symptoms. 6-month prospective study. A representative sample of 257 young elite athletes (M=16.82years, SD=1.44, 36% females) was recruited in North-Western Switzerland. 197 athletes were followed-up across a 6-month period. Burnout was assessed with the Shirom-Melamed Burnout Measure (SMBM), and depression with the 9-item depression module of the Patient Health Questionnaire (PHQ). Values of ≥4.40 (SMBM) and >14 (PHQ-9) were considered indicative of clinically relevant burnout or depression. Stress perceptions were assessed with the Perceived Stress Scale (PSS), and mental toughness with the Mental Toughness Questionnaire (MTQ). Hierarchical regression analyses were used to test stress-buffering effects. The percentage of athletes with clinically relevant levels of burnout and depressive symptoms was 12% and 9%, respectively. Both cross-sectional and prospective analyses showed that compared to participants with low mental toughness, those with higher mental toughness scores reported significantly fewer mental health issues, when exposed to high stress. By contrast, when stress levels were low, mental toughness was unrelated to psychological health complaints. About every tenth young elite athlete reported burnout or depressive symptoms of potential clinical relevance. While high perceived stress was associated with increased psychological health complaints, mental toughness was able to off-set some of the negative consequences resulting from high stress exposure. Copyright © 2018 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Treatment Considerations for the Cardiometabolic Signs of Polycystic Ovary Syndrome: A Review of the Literature Since the 2013 Endocrine Society Clinical Practice Guidelines.

PubMed

Fields, Errol L; Trent, Maria E

2016-05-01

Polycystic ovary syndrome is characterized by an excess in androgen levels, ovarian dysfunction, and polycystic ovarian morphology but is also associated with metabolic dysfunction and risk factors for cardiovascular disease. To our knowledge, there are few therapeutic recommendations for these cardiometabolic risk factors and little evidence of their long-term clinical relevance to cardiovascular health. To determine metabolic and/or cardiovascular outcomes in polycystic ovary syndrome treatment literature since the publication of the most recent Endocrine Society clinical practice guidelines in 2013. We searched PubMed using a string of variations of polycystic ovary syndrome, therapy/treatment, and adolescence, and we included English-language original research articles published while the 2013 clinical practice guidelines were disseminated (ie, articles published from January 1, 2011, to June 1, 2015). Articles that appeared relevant based on a review of titles and abstracts were read in full to determine relevancy. References from relevant articles were reviewed for additional studies. Four topic areas emerged: (1) lifestyle modification, (2) metformin vs placebo or estrogen-progestin oral contraceptives, (3) insulin-sensitizing agents, and (4) estrogen-progestin formulations. Most studies assessed the role of metformin as a monotherapy or dual therapy supplement and found significant benefit when including metformin in polycystic ovary syndrome treatment regimens. Studies showed improvements in cardiometabolic risk factors and, in several, androgen excess and cutaneous and menstrual symptoms. Studies were limited by sample size (range, 22-171), few adolescent participants, and short-term outcomes. Findings show potential for metformin and estrogen-progestin dual therapy but warrant longitudinal studies examining outcomes from adolescence through middle age to determine the effect on long-term cardiovascular health.

Use of the NASA Space Radiation Laboratory at Brookhaven National Laboratory to Conduct Charged Particle Radiobiology Studies Relevant to Ion Therapy

PubMed Central

Held, Kathryn D.; Blakely, Eleanor A.; Story, Michael D.; Lowenstein, Derek I.

2016-01-01

Although clinical studies with carbon ions have been conducted successfully in Japan and Europe, the limited radiobiological information about charged particles that are heavier than protons remains a significant impediment to exploiting the full potential of particle therapy. There is growing interest in the U.S. to build a cancer treatment facility that utilizes charged particles heavier than protons. Therefore, it is essential that additional radiobiological knowledge be obtained using state-of-the-art technologies and biological models and end points relevant to clinical outcome. Currently, most such ion radiotherapy-related research is being conducted outside the U.S. This article addresses the substantial contributions to that research that are possible at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), which is the only facility in the U.S. at this time where heavy-ion radiobiology research with the ion species and energies of interest for therapy can be done. Here, we briefly discuss the relevant facilities at NSRL and how selected charged particle biology research gaps could be addressed using those facilities. PMID:27195609

Use of the NASA Space Radiation Laboratory at Brookhaven National Laboratory to Conduct Charged Particle Radiobiology Studies Relevant to Ion Therapy.

PubMed

Held, Kathryn D; Blakely, Eleanor A; Story, Michael D; Lowenstein, Derek I

2016-06-01

Although clinical studies with carbon ions have been conducted successfully in Japan and Europe, the limited radiobiological information about charged particles that are heavier than protons remains a significant impediment to exploiting the full potential of particle therapy. There is growing interest in the U.S. to build a cancer treatment facility that utilizes charged particles heavier than protons. Therefore, it is essential that additional radiobiological knowledge be obtained using state-of-the-art technologies and biological models and end points relevant to clinical outcome. Currently, most such ion radiotherapy-related research is being conducted outside the U.S. This article addresses the substantial contributions to that research that are possible at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), which is the only facility in the U.S. at this time where heavy-ion radiobiology research with the ion species and energies of interest for therapy can be done. Here, we briefly discuss the relevant facilities at NSRL and how selected charged particle biology research gaps could be addressed using those facilities.

Comparison of the cytotoxicity of clinically relevant cobalt-chromium and alumina ceramic wear particles in vitro.

PubMed

Germain, M A; Hatton, A; Williams, S; Matthews, J B; Stone, M H; Fisher, J; Ingham, E

2003-02-01

Concern over polyethylene wear particle induced aseptic loosening of metal-on-polyethylene hip prostheses has led to renewed interest in alternative materials such as metal-on-metal and alumina ceramic-on-alumina ceramic for total hip replacement. This study compared the effects of clinically relevant cobalt-chromium and alumina ceramic wear particles on the viability of U937 histiocytes and L929 fibroblasts in vitro. Clinically relevant cobalt-chromium wear particles were generated using a flat pin-on-plate tribometer. The mean size of the clinically relevant metal particles was 29.5+/-6.3 nm (range 5-200 nm). Clinically relevant alumina ceramic particles were generated in the Leeds MkII anatomical hip simulator from a Mittelmieier prosthesis using micro-separation motion. This produced particles with a bimodal size distribution. The majority (98%) of the clinically relevant alumina ceramic wear debris was 5-20 nm in size. The cytotoxicity of the clinically relevant wear particles was compared to commercially available cobalt-chromium (9.87 microm+/-5.67) and alumina ceramic (0.503+/-0.19 microm) particles. The effects of the particles on the cells over a 5 day period at different particle volume (microm(3)) to cell number ratios were tested and viability determined using ATP-Lite(TM). Clinically relevant cobalt-chromium particles 50 and 5 microm(3) per cell reduced the viability of U937 cells by 97% and 42% and reduced the viability of L929 cells by 95% and 73%, respectively. At 50 microm(3) per cell, the clinically relevant ceramic particles reduced U937 cell viability by 18%. None of the other concentrations of the clinically relevant particles were toxic. The commercial cobalt-chromium and alumina particles did not affect the viability of either the U937 histiocytes or the L929 fibroblasts.Thus at equivalent particle volumes the clinically relevant cobalt-chromium particles were more toxic then the alumina ceramic particles. This study has emphasised the fact that the nature, size and volume of particles are important in assessing biological effects of wear debris on cells in vitro.

Learning Clinical Assessment and Interdisciplinary Team Collaboration in Primary Care. MOOC for Healthcare Practitioners and Students.

PubMed

Lunde, Lene; Moen, Anne; Rosvold, Elin O

2018-01-01

Novel ways to build sufficient capacity to meet the need for competent healthcare providers in primary care are in strong demand. We developed a massive, open, online course (MOOC) to introduce and promote clinical skills development for healthcare workers (physicians, nurse practitioners, nurses, and nurse aids) and students in healthcare education (medical students and master and bachelor students in nursing) focusing on systematic health assessment and strengthening clinical decision making in primary care. Results from the pilot supports that the MOOC was relevant and highly useful for the participants, and has potential to contribute to interdisciplinary collaboration and discussions.

Evidence-based integrative medicine in clinical veterinary oncology.

PubMed

Raditic, Donna M; Bartges, Joseph W

2014-09-01

Integrative medicine is the combined use of complementary and alternative medicine with conventional or traditional Western medicine systems. The demand for integrative veterinary medicine is growing, but evidence-based research on its efficacy is limited. In veterinary clinical oncology, such research could be translated to human medicine, because veterinary patients with spontaneous tumors are valuable translational models for human cancers. An overview of specific herbs, botanics, dietary supplements, and acupuncture evaluated in dogs, in vitro canine cells, and other relevant species both in vivo and in vitro is presented for their potential use as integrative therapies in veterinary clinical oncology. Published by Elsevier Inc.

[Interdisciplinary clinical pathway for colorectal cancer].

PubMed

Fischbach, W; Engemann, R

2006-07-01

Limited financial resources in public health care have led to the introduction of clinical pathways as a means to a better effectivity and efficacy. Colorectal cancer met the requirements for establishing such a pathway in a distinguished way: high patient volume, high costs, interdisciplinary multi-modal treatment concepts in a relevant frequency, and existing evidence based guidelines. This article gives an example of a clinical pathway for colorectal cancer as established in our hospital. The potential of such pathways to save costs as well as their implications on treatment results and patients' satisfaction will have to be critically analyzed in the future before their value can be definitely estimated.

Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data.

PubMed

Wright, Caroline F; Fitzgerald, Tomas W; Jones, Wendy D; Clayton, Stephen; McRae, Jeremy F; van Kogelenberg, Margriet; King, Daniel A; Ambridge, Kirsty; Barrett, Daniel M; Bayzetinova, Tanya; Bevan, A Paul; Bragin, Eugene; Chatzimichali, Eleni A; Gribble, Susan; Jones, Philip; Krishnappa, Netravathi; Mason, Laura E; Miller, Ray; Morley, Katherine I; Parthiban, Vijaya; Prigmore, Elena; Rajan, Diana; Sifrim, Alejandro; Swaminathan, G Jawahar; Tivey, Adrian R; Middleton, Anna; Parker, Michael; Carter, Nigel P; Barrett, Jeffrey C; Hurles, Matthew E; FitzPatrick, David R; Firth, Helen V

2015-04-04

Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount. The Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team. Around 80,000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation. Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene-phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial. Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health. Copyright © 2015 Wright et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.

Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data

PubMed Central

Wright, Caroline F; Fitzgerald, Tomas W; Jones, Wendy D; Clayton, Stephen; McRae, Jeremy F; van Kogelenberg, Margriet; King, Daniel A; Ambridge, Kirsty; Barrett, Daniel M; Bayzetinova, Tanya; Bevan, A Paul; Bragin, Eugene; Chatzimichali, Eleni A; Gribble, Susan; Jones, Philip; Krishnappa, Netravathi; Mason, Laura E; Miller, Ray; Morley, Katherine I; Parthiban, Vijaya; Prigmore, Elena; Rajan, Diana; Sifrim, Alejandro; Swaminathan, G Jawahar; Tivey, Adrian R; Middleton, Anna; Parker, Michael; Carter, Nigel P; Barrett, Jeffrey C; Hurles, Matthew E; FitzPatrick, David R; Firth, Helen V

2015-01-01

Summary Background Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount. Methods The Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team. Findings Around 80 000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation. Interpretation Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene–phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial. Funding Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health. PMID:25529582

Financial toxicity in cancer care.

PubMed

O'Connor, Jeremy M; Kircher, Sheetal M; de Souza, Jonas A

2016-03-01

The cost of cancer care is increasing, with important implications for the delivery of high-quality, patent-centered care. In the clinical setting, patents and physicians express a desire to discuss out-of-pocket costs. Nevertheless, both groups feel inadequately prepared to participate in these discussions, and perhaps not surprisingly, the integration of these discussions into clinical practice seems to be the exception rather than the rule. The resulting neglect of financial issues has the potential to cause unnecessary suffering for oncology patents. In this paper, we review the most relevant literature on financial toxicity in cancer care. In addition, we discuss potential predictors of financial toxicity, and the recent development of instruments to help clinicians and researchers quantify financial burden. ©2016 Frontline Medical Communications.

Diagnosis of response and non-response to dry eye treatment using infrared thermography images

NASA Astrophysics Data System (ADS)

Acharya, U. Rajendra; Tan, Jen Hong; Vidya, S.; Yeo, Sharon; Too, Cheah Loon; Lim, Wei Jie Eugene; Chua, Kuang Chua; Tong, Louis

2014-11-01

The dry eye treatment outcome depends on the assessment of clinical relevance of the treatment effect. The potential approach to assess the clinical relevance of the treatment is to identify the symptoms responders and non-responders to the given treatments using the responder analysis. In our work, we have performed the responder analysis to assess the clinical relevance effect of the dry eye treatments namely, hot towel, EyeGiene®, and Blephasteam® twice daily and 12 min session of Lipiflow®. Thermography is performed at week 0 (baseline), at weeks 4 and 12 after treatment. The clinical parameters such as, change in the clinical irritations scores, tear break up time (TBUT), corneal staining and Schirmer's symptoms tests values are used to obtain the responders and non-responders groups. We have obtained the infrared thermography images of dry eye symptoms responders and non-responders to the three types of warming treatments. The energy, kurtosis, skewness, mean, standard deviation, and various entropies namely Shannon, Renyi and Kapoor are extracted from responders and non-responders thermograms. The extracted features are ranked based on t-values. These ranked features are fed to the various classifiers to get the highest performance using minimum features. We have used decision tree (DT), K nearest neighbour (KNN), Naves Bayesian (NB) and support vector machine (SVM) to classify the features into responder and non-responder classes. We have obtained an average accuracy of 99.88%, sensitivity of 99.7% and specificity of 100% using KNN classifier using ten-fold cross validation.

Percussion use and training: a survey of music therapy clinicians.

PubMed

Scheffel, Stephanie; Matney, Bill

2014-01-01

Percussion instruments are commonly used in music therapy practice; however, the body of published literature regarding music therapy-related percussion training and practice is limited. The purpose of our survey study was to describe: (a) clinician perspectives of their academic percussion training; (b) use of percussion testing during academic training; (c) clinician perspectives on relevance, adequacy, and importance of academic percussion training; (d) clinician perspectives of their nonacademic percussion training; and (e) current use of percussion in clinical practice. Through comparisons of these parameters, we sought to provide information that may inform future percussion use and training. Participants were selected using an email list from the Certification Board for Music Therapists. Board-certified music therapists (MT-BC) were provided with a researcher-created survey about academic percussion training, nonacademic percussion training, and use of percussion in clinical practice. Survey response rate was 14.4% (611/4234). We used demographic data to address potential nonresponse error and ensure population representation for region of residence and region of academic training. Results revealed concerns about perceived adequacy of percussion training received during music therapy education (14.6% reported receiving no academic percussion training; 40.6% reported training was not adequate), and absence of percussion-specific proficiency exams. Of the training received, 62.8% indicated that training was relevant; however, a majority (76.5%) recommended current music therapy students receive more percussion training on instruments and skills most relevant to clinical practice. Comparisons between academic training, perceived needs in academic training, and clinical usage may inform future training and clinical competency. We provide suggestions for developing future training, as well as for furthering clinical implementation and research. © the American Music Therapy Association 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

PubMed Central

Krystal, John H.; Abdallah, Chadi G.; Averill, Lynette A.; Kelmendi, Benjamin; Harpaz-Rotem, Ilan; Sanacora, Gerard; Southwick, Steven M.; Duman, Ronald S.

2018-01-01

Purpose of Review Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity. Recent Findings Here, we will briefly review evidence that PTSD might be a “synaptic disconnection syndrome” and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity. Summary Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics. PMID:28844076

Clinically Relevant Cognitive Impairment in Middle-Aged Adults With Childhood-Onset Type 1 Diabetes

PubMed Central

Nunley, Karen A.; Ryan, Christopher M.; Jennings, J. Richard; Aizenstein, Howard J.; Zgibor, Janice C.; Costacou, Tina; Boudreau, Robert M.; Miller, Rachel; Orchard, Trevor J.; Saxton, Judith A.

2015-01-01

OBJECTIVE The aim of this study was to investigate the presence and correlates of clinically relevant cognitive impairment in middle-aged adults with childhood-onset type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS During 2010–2013, 97 adults diagnosed with T1D and aged <18 years (age and duration 49 ± 7 and 41 ± 6 years, respectively; 51% female) and 138 similarly aged adults without T1D (age 49 ± 7 years; 55% female) completed extensive neuropsychological testing. Biomedical data on participants with T1D were collected periodically since 1986–1988. Cognitive impairment status was based on the number of test scores ≥1.5 SD worse than demographically appropriate published norms: none, mild (only one test), or clinically relevant (two or more tests). RESULTS The prevalence of clinically relevant cognitive impairment was five times higher among participants with than without T1D (28% vs. 5%; P < 0.0001), independent of education, age, or blood pressure. Effect sizes were large (Cohen d 0.6–0.9; P < 0.0001) for psychomotor speed and visuoconstruction tasks and were modest (d 0.3–0.6; P < 0.05) for measures of executive function. Among participants with T1D, prevalent cognitive impairment was related to 14-year average A1c >7.5% (58 mmol/mol) (odds ratio [OR] 3.0; P = 0.009), proliferative retinopathy (OR 2.8; P = 0.01), and distal symmetric polyneuropathy (OR 2.6; P = 0.03) measured 5 years earlier; higher BMI (OR 1.1; P = 0.03); and ankle-brachial index ≥1.3 (OR 4.2; P = 0.01) measured 20 years earlier, independent of education. CONCLUSIONS Clinically relevant cognitive impairment is highly prevalent among these middle-aged adults with childhood-onset T1D. In this aging cohort, chronic hyperglycemia and prevalent microvascular disease were associated with cognitive impairment, relationships shown previously in younger populations with T1D. Two additional potentially modifiable risk factors for T1D-related cognitive impairment, vascular health and BMI, deserve further study. PMID:26153270

A preclinical Talbot-Lau prototype for x-ray dark-field imaging of human-sized objects.

PubMed

Hauke, C; Bartl, P; Leghissa, M; Ritschl, L; Sutter, S M; Weber, T; Zeidler, J; Freudenberger, J; Mertelmeier, T; Radicke, M; Michel, T; Anton, G; Meinel, F G; Baehr, A; Auweter, S; Bondesson, D; Gaass, T; Dinkel, J; Reiser, M; Hellbach, K

2018-06-01

Talbot-Lau x-ray interferometry provides information about the scattering and refractive properties of an object - in addition to the object's attenuation features. Until recently, this method was ineligible for imaging human-sized objects as it is challenging to adapt Talbot-Lau interferometers (TLIs) to the relevant x-ray energy ranges. In this work, we present a preclinical Talbot-Lau prototype capable of imaging human-sized objects with proper image quality at clinically acceptable dose levels. The TLI is designed to match a setup of clinical relevance as closely as possible. The system provides a scan range of 120 × 30 cm 2 by using a scanning beam geometry. Its ultimate load is 100 kg. High aspect ratios and fine grid periods of the gratings ensure a reasonable setup length and clinically relevant image quality. The system is installed in a university hospital and is, therefore, exposed to the external influences of a clinical environment. To demonstrate the system's capabilities, a full-body scan of a euthanized pig was performed. In addition, freshly excised porcine lungs with an extrinsically provoked pneumothorax were mounted into a human thorax phantom and examined with the prototype. Both examination sequences resulted in clinically relevant image quality - even in the case of a skin entrance air kerma of only 0.3 mGy which is in the range of human thoracic imaging. The presented case of a pneumothorax and a reader study showed that the prototype's dark-field images provide added value for pulmonary diagnosis. We demonstrated that a dedicated design of a Talbot-Lau interferometer can be applied to medical imaging by constructing a preclinical Talbot-Lau prototype. We experienced that the system is feasible for imaging human-sized objects and the phase-stepping approach is suitable for clinical practice. Hence, we conclude that Talbot-Lau x-ray imaging has potential for clinical use and enhances the diagnostic power of medical x-ray imaging. © 2018 American Association of Physicists in Medicine.

Potential value of health information exchange for people with epilepsy: crossover patterns and missing clinical data.

PubMed

Grinspan, Zachary M; Abramson, Erika L; Banerjee, Samprit; Kern, Lisa M; Kaushal, Rainu; Shapiro, Jason S

2013-01-01

For people with epilepsy, the potential value of health information exchange (HIE) is unknown. We reviewed two years of clinical encounters for 8055 people with epilepsy from seven Manhattan hospitals. We created network graphs illustrating crossover among these hospitals for multiple encounter types, and calculated a novel metric of care fragmentation: "encounters at risk for missing clinical data." Given two hospitals, a median of 109 [range 46 - 588] patients with epilepsy had visited both. Due to this crossover, recent, relevant clinical data may be missing at the time of care frequently (44.8% of ED encounters, 34.5% inpatient, 24.9% outpatient, and 23.2% radiology). Though a smaller percentage of outpatient encounters were at risk for missing data than ED encounters, the absolute number of outpatient encounters at risk was three times higher (14,579 vs. 5041). People with epilepsy may benefit from HIE. Future HIE initiatives should prioritize outpatient access.

Delivering safer immunotherapies for cancer

PubMed Central

Milling, Lauren; Zhang, Yuan; Irvine, Darrell J.

2017-01-01

Cancer immunotherapy is now a powerful clinical reality, with a steady progression of new drug approvals and a massive pipeline of additional treatments in clinical and preclinical development. However, modulation of the immune system can be a double-edged sword: Drugs that activate immune effectors are prone to serious non-specific systemic inflammation and autoimmune side effects. Drug delivery technologies have an important role to play in harnessing the power of immune therapeutics while avoiding on-target/off-tumor toxicities. Here we review mechanisms of toxicity for clinically-relevant immunotherapeutics, and discuss approaches based in drug delivery technology to enhance the safety and potency of these treatments. These include strategies to merge drug delivery with adoptive cellular therapies, targeting immunotherapies to tumors or select immune cells, and localizing therapeutics intratumorally. Rational design employing lessons learned from the drug delivery and nanomedicine fields has the potential to facilitate immunotherapy reaching its full potential. PMID:28545888

Enteral feeding: drug/nutrient interaction.

PubMed

Lourenço, R

2001-04-01

Enteral nutrition support via a feeding tube is the first choice for artificial nutrition. Most patients also require simultaneous drug therapy, with the potential risk for drug-nutrient interactions which may become relevant in clinical practice. During enteral nutrition, drug-nutrient interactions are more likely to occur than in patients fed orally. However, there is a lack of awareness about its clinical significance, which should be recognised and prevented in order to optimise nutritional and pharmacological therapeutic goals of safety and efficacy. To raise the awareness of potential drug-nutrient interactions and influence on clinical outcomes. To identify factors that can promote drug-nutrient interactions and contribute to nutrition and/or therapeutic failure. To be aware of different types of drug-nutrient interactions. To understand complex underlying mechanisms responsible for drug-nutrient interactions. To learn basic rules for the administration of medications during tube-feeding. Copyright 2001 Harcourt Publishers Ltd.

Clinical trials with rasagiline: evidence for short-term and long-term effects.

PubMed

Siderowf, Andrew; Stern, Matthew

2006-05-23

Rasagiline (N-propargyl-1 (R)-aminoindan) is a selective, potent irreversible inhibitor of MAO-B that possesses neuroprotective and anti-apoptotic properties in a variety of in vitro and in vivo animal models relevant to Parkinson's disease (PD). Several randomized controlled clinical trials have demonstrated the safety and efficacy of rasagiline as monotherapy in PD and as adjunctive therapy for patients receiving levodopa. In addition, the 1-year randomized, delayed-start analysis of the TEMPO study suggests that rasagiline may slow the rate of progression of PD. The randomized delayed-start paradigm has potential to differentiate short-term symptomatic effects from long-term effects of anti-parkinsonian agents. In the future, long-term trials to examine the potential disease-modifying effects of rasagiline, which incorporate biological markers as well as clinical endpoints, may further elucidate the role of rasagiline in the treatment of both early and advanced PD.

MitoQ--a mitochondria-targeted antioxidant.

PubMed

Tauskela, Joseph S

2007-06-01

MitoQ is an orally active antioxidant that has the ability to target mitochondrial dysfunction. The agent is currently under development by Antipodean Pharmaceuticals Inc in phase II clinical trials for Parkinson's disease and liver damage associated with HCV infection. MitoQ has demonstrated encouraging preclinical results in numerous studies in isolated mitochondria, cells and tissues undergoing oxidative stress and apoptotic death. MitoQ aims to not only mimic the role of the endogenous mitochondrial antioxidant coenzyme Q10 (CoQ10), but also to augment substantially the antioxidant capacity of CoQ to supraphysiological levels in a mitochondrial membrane potential-dependent manner. MitoQ represents the first foray into the clinic in an attempt to deliver an antioxidant to an intracellular region that is responsible for the formation of increased levels of potentially deleterious reactive oxygen species. Results from the clinical trials with MitoQ will have important repercussions on the relevance of a mitochondrial-targeted approach.

Toward rational design of electrical stimulation strategies for epilepsy control

PubMed Central

Sunderam, Sridhar; Gluckman, Bruce; Reato, Davide; Bikson, Marom

2009-01-01

Electrical stimulation is emerging as a viable alternative for epilepsy patients whose seizures are not alleviated by drugs or surgery. Its attractions are temporal and spatial specificity of action, flexibility of waveform parameters and timing, and the perception that its effects are reversible unlike resective surgery. However, despite significant advances in our understanding of mechanisms of neural electrical stimulation, clinical electrotherapy for seizures relies heavily on empirical tuning of parameters and protocols. We highlight concurrent treatment goals with potentially conflicting design constraints that must be resolved when formulating rational strategies for epilepsy electrotherapy: namely seizure reduction versus cognitive impairment, stimulation efficacy versus tissue safety, and mechanistic insight versus clinical pragmatism. First, treatment markers, objectives, and metrics relevant to electrical stimulation for epilepsy are discussed from a clinical perspective. Then the experimental perspective is presented, with the biophysical mechanisms and modalities of open-loop electrical stimulation, and the potential benefits of closed-loop control for epilepsy. PMID:19926525

Precision Oncology Medicine: The Clinical Relevance of Patient-Specific Biomarkers Used to Optimize Cancer Treatment.

PubMed

Schmidt, Keith T; Chau, Cindy H; Price, Douglas K; Figg, William D

2016-12-01

Precision medicine in oncology is the result of an increasing awareness of patient-specific clinical features coupled with the development of genomic-based diagnostics and targeted therapeutics. Companion diagnostics designed for specific drug-target pairs were the first to widely utilize clinically applicable tumor biomarkers (eg, HER2, EGFR), directing treatment for patients whose tumors exhibit a mutation susceptible to an FDA-approved targeted therapy (eg, trastuzumab, erlotinib). Clinically relevant germline mutations in drug-metabolizing enzymes and transporters (eg, TPMT, DPYD) have been shown to impact drug response, providing a rationale for individualized dosing to optimize treatment. The use of multigene expression-based assays to analyze an array of prognostic biomarkers has been shown to help direct treatment decisions, especially in breast cancer (eg, Oncotype DX). More recently, the use of next-generation sequencing to detect many potential "actionable" cancer molecular alterations is further shifting the 1 gene-1 drug paradigm toward a more comprehensive, multigene approach. Currently, many clinical trials (eg, NCI-MATCH, NCI-MPACT) are assessing novel diagnostic tools with a combination of different targeted therapeutics while also examining tumor biomarkers that were previously unexplored in a variety of cancer histologies. Results from ongoing trials such as the NCI-MATCH will help determine the clinical utility and future development of the precision-medicine approach. © 2016, The American College of Clinical Pharmacology.

[Clinical relevant procedures for early pregnancy diagnosis in the mare].

PubMed

Bostedt, H; Sieme, H; Bartmann, C-P; Handler, J; Sobiraj, A; Wehrend, A

2014-01-01

This review describes stepwise the recto-manual and transrectal ultrasonographic evidence of early pregnancy detection in the horse. The morphological and physiological conditions in the individual phases of early pregnancy are presented in correlation to the potential clinical findings. The importance of embryonic and early foetal losses is presented. Communication and documentation of findings are also addressed. The final section is devoted to the evaluation of the examination effort. In this regard, it is emphasized that the gynaecological examination for the evaluation of the pregnancy status represents a service contract.

'Bioengineered Bugs' - a patho-biotechnology approach to probiotic research and applications.

PubMed

Sleator, Roy D; Hill, Colin

2008-01-01

Given the increasing commercial and clinical relevance of probiotic cultures, improving their stress tolerance profile and ability to overcome the physiochemical defences of the host is an important biological goal. Pathogenic bacteria have evolved sophisticated strategies to overcome host defences, interact with the immune system and modulate essential host systems. The 'Patho-biotechnology' concept promotes the exploitation of these valuable traits for the design of more technologically robust and effective probiotic cultures with potentially improved biotechnological and clinical applications, as well as the development of novel vaccine and drug delivery platforms.

Engineered pharmabiotics with improved therapeutic potential.

PubMed

Sleator, Roy D; Hill, Colin

2008-01-01

Although described for over a century, scientists and clinicians alike are only now beginning to realize the significant medical applications of probiotic cultures. Given the increasing commercial and clinical relevance of probiotics, improving their stress tolerance profile and ability to overcome the physiochemical defences of the host is an important biological goal. Patho-biotechnology describes the application of pathogen derived (ex vivo and in vivo) stress survival strategies for the design of more technologically robust and effective probiotic cultures with improved biotechnological and clinical applications as well as the development of novel vaccine and drug delivery platforms.

A cross-country comparison of intensive care physicians' beliefs about their transfusion behaviour: a qualitative study using the Theoretical Domains Framework.

PubMed

Islam, Rafat; Tinmouth, Alan T; Francis, Jill J; Brehaut, Jamie C; Born, Jennifer; Stockton, Charlotte; Stanworth, Simon J; Eccles, Martin P; Cuthbertson, Brian H; Hyde, Chris; Grimshaw, Jeremy M

2012-09-21

Evidence of variations in red blood cell transfusion practices have been reported in a wide range of clinical settings. Parallel studies in Canada and the United Kingdom were designed to explore transfusion behaviour in intensive care physicians. The aim of this paper is three-fold: first, to explore beliefs that influence Canadian intensive care physicians' transfusion behaviour; second, to systematically select relevant theories and models using the Theoretical Domains Framework (TDF) to inform a future predictive study; and third, to compare its results with the UK study. Ten intensive care unit (ICU) physicians throughout Canada were interviewed. Physicians' responses were coded into theoretical domains, and specific beliefs were generated for each response. Theoretical domains relevant to behaviour change were identified, and specific constructs from the relevant domains were used to select psychological theories. The results from Canada and the United Kingdom were compared. Seven theoretical domains populated by 31 specific beliefs were identified as relevant to the target behaviour. The domains Beliefs about capabilities (confident to not transfuse if patients' clinical condition is stable), Beliefs about consequences (positive beliefs of reducing infection and saving resources and negative beliefs about risking patients' clinical outcome and potentially more work), Social influences (transfusion decision is influenced by team members and patients' relatives), and Behavioural regulation (wide range of approaches to encourage restrictive transfusion) that were identified in the UK study were also relevant in the Canadian context. Three additional domains, Knowledge (it requires more evidence to support restrictive transfusion), Social/professional role and identity (conflicting beliefs about not adhering to guidelines, referring to evidence, believing restrictive transfusion as professional standard, and believing that guideline is important for other professionals), and Motivation and goals (opposing beliefs about the importance of restrictive transfusion and compatibility with other goals), were also identified in this study. Similar to the UK study, the Theory of Planned Behaviour, Social Cognitive Theory, Operant Learning Theory, Action Planning, and Knowledge-Attitude-Behaviour model were identified as potentially relevant theories and models for further study. Personal project analysis was added to the Canadian study to explore the Motivation and goals domain in further detail. A wide range of beliefs was identified by the Canadian ICU physicians as likely to influence their transfusion behaviour. We were able to demonstrate similar though not identical results in a cross-country comparison. Designing targeted behaviour-change interventions based on unique beliefs identified by physicians from two countries are more likely to encourage restrictive transfusion in ICU physicians in respective countries. This needs to be tested in future prospective clinical trials.

A cross-country comparison of intensive care physicians’ beliefs about their transfusion behaviour: A qualitative study using the theoretical domains framework

PubMed Central

2012-01-01

Background Evidence of variations in red blood cell transfusion practices have been reported in a wide range of clinical settings. Parallel studies in Canada and the United Kingdom were designed to explore transfusion behaviour in intensive care physicians. The aim of this paper is three-fold: first, to explore beliefs that influence Canadian intensive care physicians’ transfusion behaviour; second, to systematically select relevant theories and models using the Theoretical Domains Framework (TDF) to inform a future predictive study; and third, to compare its results with the UK study. Methods Ten intensive care unit (ICU) physicians throughout Canada were interviewed. Physicians’ responses were coded into theoretical domains, and specific beliefs were generated for each response. Theoretical domains relevant to behaviour change were identified, and specific constructs from the relevant domains were used to select psychological theories. The results from Canada and the United Kingdom were compared. Results Seven theoretical domains populated by 31 specific beliefs were identified as relevant to the target behaviour. The domains Beliefs about capabilities (confident to not transfuse if patients’ clinical condition is stable), Beliefs about consequences (positive beliefs of reducing infection and saving resources and negative beliefs about risking patients’ clinical outcome and potentially more work), Social influences (transfusion decision is influenced by team members and patients’ relatives), and Behavioural regulation (wide range of approaches to encourage restrictive transfusion) that were identified in the UK study were also relevant in the Canadian context. Three additional domains, Knowledge (it requires more evidence to support restrictive transfusion), Social/professional role and identity (conflicting beliefs about not adhering to guidelines, referring to evidence, believing restrictive transfusion as professional standard, and believing that guideline is important for other professionals), and Motivation and goals (opposing beliefs about the importance of restrictive transfusion and compatibility with other goals), were also identified in this study. Similar to the UK study, the Theory of Planned Behaviour, Social Cognitive Theory, Operant Learning Theory, Action Planning, and Knowledge-Attitude-Behaviour model were identified as potentially relevant theories and models for further study. Personal project analysis was added to the Canadian study to explore the Motivation and goals domain in further detail. Conclusions A wide range of beliefs was identified by the Canadian ICU physicians as likely to influence their transfusion behaviour. We were able to demonstrate similar though not identical results in a cross-country comparison. Designing targeted behaviour-change interventions based on unique beliefs identified by physicians from two countries are more likely to encourage restrictive transfusion in ICU physicians in respective countries. This needs to be tested in future prospective clinical trials. PMID:22999460

The Netherlands XTC Toxicity (NeXT) study: objectives and methods of a study investigating causality, course, and clinical relevance.

PubMed

De Win, Maartje M L; Jager, Gerry; Vervaeke, Hylke K E; Schilt, Thelma; Reneman, Liesbeth; Booij, Jan; Verhulst, Frank C; Den Heeten, Gerard J; Ramsey, Nick F; Korf, Dirk J; Van den Brink, Wim

2005-01-01

This paper describes the objectives and methods of The Netherlands XTC Toxicity (NeXT) study focussing on the causality, course, and clinical relevance of ecstasy neurotoxicity. Previous studies suggest that ecstasy (3,4 methylene-dioxymethamphetamine, MDMA, XTC) is toxic toward brain serotonin axons, but most of these studies have serious methodological limitations. The current study is a combination of different approaches with three substudies: (1) a crosssectional substudy among heavy ecstasy users and controls with variation in drug use, which will provide information about potential neurotoxic consequences of ecstasy in relation to other drugs; (2) a prospective cohort substudy in ecstasy-naive subjects with high risk for future ecstasy use, which will provide information on the causality and short-term course of ecstasy use and potential neurotoxicity, and (3) a retrospective cohort substudy in lifetime ecstasy users and matched controls of an existing epidemiological sample that will provide information on long-term course and outcome of ecstasy use in the general population. Neurotoxicity is studied using (a) different imaging techniques (beta-CIT SPECT, 1H-MR spectroscopy, diffusion tensor imaging, perfusion weighted imaging and functional magnetic resonance imaging), and (b) neuropsychological and psychiatric assessments of memory, depression, and personality. The combined results will lead to conclusions that can be used in prevention messages, clinical decision making, and the development of an (inter)national ecstasy policy.

Elevated venous thromboembolism risk in preeclampsia: molecular mechanisms and clinical impact.

PubMed

Egan, Karl; Kevane, Barry; Ní Áinle, Fionnuala

2015-08-01

Venous thromboembolism (VTE) remains a leading cause of maternal death and morbidity in the developed world. Strategies for prevention of VTE in pregnancy have been the subject of recent guidelines and consensus statements. These guidelines recommend thrombosis prevention in women who have risk factors associated with an elevated VTE risk. Preeclampsia is characterized by maternal hypertension and proteinuria developing after 20 weeks gestation, complicating up to 7% of pregnancies and is associated with a massive annual morbidity and mortality burden. Women with preeclampsia have been shown to be at increased risk of VTE with studies to date suggesting that this risk may be up to 5-fold greater than the risk of pregnancy-associated VTE in the general population. Despite the fact that preeclampsia is so common and potentially devastating, our understanding of its pathogenesis and potential therapeutic strategies remain poor. In addition, the mechanisms underlying the prothrombotic phenotype in preeclampsia are also poorly characterized although a number of potential mechanisms have been postulated. Derangements of platelet and endothelial activation and impairment of endogenous anti-coagulant pathways have been reported and may contribute to the observed VTE risk. Recently, evidence for the role of neutrophil extracellular traps (NETs) and cell-free DNA in the pathogenesis of VTE has emerged and some evidence exists to suggest that this may be of relevance in preeclampsia. Future studies aimed at understanding the diagnostic and potential therapeutic relevance of this procoagulant state are likely to be of enormous clinical benefit for pregnant women affected with this potentially devastating condition. © 2015 Authors; published by Portland Press Limited.

Attachment and Chronic Pain in Children and Adolescents

PubMed Central

Donnelly, Theresa J.; Jaaniste, Tiina

2016-01-01

Although attachment theory is not new, its theoretical implications for the pediatric chronic pain context have not been thoroughly considered, and the empirical implications and potential clinical applications are worth exploring. The attachment framework broadly focuses on interactions between a child’s developing self-regulatory systems and their caregiver’s responses. These interactions are believed to create a template for how individuals will relate to others in the future, and may help account for normative and pathological patterns of emotions and behavior throughout life. This review outlines relevant aspects of the attachment framework to the pediatric chronic pain context. The theoretical and empirical literature is reviewed regarding the potential role of attachment-based constructs such as vulnerability and maintaining factors of pediatric chronic pain. The nature and targets of attachment-based pediatric interventions are considered, with particular focus on relevance for the pediatric chronic pain context. The potential role of attachment style in the transition from acute to chronic pain is considered, with further research directions outlined. PMID:27792141

Infant formula supplementation with long-chain polyunsaturated fatty acids has no effect on Bayley developmental scores at 18 months of age--IPD meta-analysis of 4 large clinical trials.

PubMed

Beyerlein, Andreas; Hadders-Algra, Mijna; Kennedy, Katherine; Fewtrell, Mary; Singhal, Atul; Rosenfeld, Eva; Lucas, Alan; Bouwstra, Hylco; Koletzko, Berthold; von Kries, Rüdiger

2010-01-01

To find out whether supplementation of formula milk by long-chain polyunsaturated fatty acids (LCPUFA) affects neurodevelopment at 18 months of age in term or preterm infants by an individual patient data (IPD) meta-analysis. Data of 870 children from 4 large randomised clinical trials for formula milk with and without LCPUFAs allowed for assessing the effect of LCPUFA with adjustment for potential confounders and extensive subgroup analysis on prematurity, LCPUFA source, and dosage. Any additional clinical trials examining the effect of LCPUFA supplementation on Bayley Scales of Infant Development at 18 months were regarded as relevant. Two relevant studies were identified by MEDLINE, but were not available to us. An IPD meta-analysis was performed with subgroup analyses by preterm delivery, very low birth weight (<1500 g), trials with higher amounts of docosahexaenoic acid (DHA) and arachidonic acid (AA), and specific sources of LCPUFA. The sample size of 870 children was sufficient to detect clinically relevant differences in Bayley Scales even in subgroups. There were no significant differences in mental or psychomotor developmental indexes between LCPUFA-supplemented and control groups for all children or in subgroups. This was confirmed with adjustment for the possible confounders: sex, gestational age, birth weight, maternal age, and maternal smoking. The adjusted mean differences in mental developmental index and psychomotor developmental index for all of the children were -0.8 (95% confidence interval -2.8 to 1.2) and -1.0 (-2.7 to 0.7), respectively. These data based on considerable sample size provide substantial evidence that LCPUFA supplementation of infant formula does not have a clinically meaningful effect on the neurodevelopment as assessed by Bayley scores at 18 months. Inclusion of all relevant data should not have led to differing conclusions except, possibly, for very-low-birth-weight infants.

Development of a simple 12-item theory-based instrument to assess the impact of continuing professional development on clinical behavioral intentions.

PubMed

Légaré, France; Borduas, Francine; Freitas, Adriana; Jacques, André; Godin, Gaston; Luconi, Francesca; Grimshaw, Jeremy

2014-01-01

Decision-makers in organizations providing continuing professional development (CPD) have identified the need for routine assessment of its impact on practice. We sought to develop a theory-based instrument for evaluating the impact of CPD activities on health professionals' clinical behavioral intentions. Our multipronged study had four phases. 1) We systematically reviewed the literature for instruments that used socio-cognitive theories to assess healthcare professionals' clinically-oriented behavioral intentions and/or behaviors; we extracted items relating to the theoretical constructs of an integrated model of healthcare professionals' behaviors and removed duplicates. 2) A committee of researchers and CPD decision-makers selected a pool of items relevant to CPD. 3) An international group of experts (n = 70) reached consensus on the most relevant items using electronic Delphi surveys. 4) We created a preliminary instrument with the items found most relevant and assessed its factorial validity, internal consistency and reliability (weighted kappa) over a two-week period among 138 physicians attending a CPD activity. Out of 72 potentially relevant instruments, 47 were analyzed. Of the 1218 items extracted from these, 16% were discarded as improperly phrased and 70% discarded as duplicates. Mapping the remaining items onto the constructs of the integrated model of healthcare professionals' behaviors yielded a minimum of 18 and a maximum of 275 items per construct. The partnership committee retained 61 items covering all seven constructs. Two iterations of the Delphi process produced consensus on a provisional 40-item questionnaire. Exploratory factorial analysis following test-retest resulted in a 12-item questionnaire. Cronbach's coefficients for the constructs varied from 0.77 to 0.85. A 12-item theory-based instrument for assessing the impact of CPD activities on health professionals' clinical behavioral intentions showed adequate validity and reliability. Further studies could assess its responsiveness to behavior change following CPD activities and its capacity to predict health professionals' clinical performance.

Development of a Simple 12-Item Theory-Based Instrument to Assess the Impact of Continuing Professional Development on Clinical Behavioral Intentions

PubMed Central

Légaré, France; Borduas, Francine; Freitas, Adriana; Jacques, André; Godin, Gaston; Luconi, Francesca; Grimshaw, Jeremy

2014-01-01

Background Decision-makers in organizations providing continuing professional development (CPD) have identified the need for routine assessment of its impact on practice. We sought to develop a theory-based instrument for evaluating the impact of CPD activities on health professionals' clinical behavioral intentions. Methods and Findings Our multipronged study had four phases. 1) We systematically reviewed the literature for instruments that used socio-cognitive theories to assess healthcare professionals' clinically-oriented behavioral intentions and/or behaviors; we extracted items relating to the theoretical constructs of an integrated model of healthcare professionals' behaviors and removed duplicates. 2) A committee of researchers and CPD decision-makers selected a pool of items relevant to CPD. 3) An international group of experts (n = 70) reached consensus on the most relevant items using electronic Delphi surveys. 4) We created a preliminary instrument with the items found most relevant and assessed its factorial validity, internal consistency and reliability (weighted kappa) over a two-week period among 138 physicians attending a CPD activity. Out of 72 potentially relevant instruments, 47 were analyzed. Of the 1218 items extracted from these, 16% were discarded as improperly phrased and 70% discarded as duplicates. Mapping the remaining items onto the constructs of the integrated model of healthcare professionals' behaviors yielded a minimum of 18 and a maximum of 275 items per construct. The partnership committee retained 61 items covering all seven constructs. Two iterations of the Delphi process produced consensus on a provisional 40-item questionnaire. Exploratory factorial analysis following test-retest resulted in a 12-item questionnaire. Cronbach's coefficients for the constructs varied from 0.77 to 0.85. Conclusion A 12-item theory-based instrument for assessing the impact of CPD activities on health professionals' clinical behavioral intentions showed adequate validity and reliability. Further studies could assess its responsiveness to behavior change following CPD activities and its capacity to predict health professionals' clinical performance. PMID:24643173

Informed consent in surgical trials.

PubMed

Etchells, E

1999-12-01

All participants must provide a valid consent to surgical clinical trials. A valid consent requires patient capacity, adequate disclosure of information, and voluntariness. Capacity is the ability to understand information relevant to making a decision and to appreciate the reasonably foreseeable consequences of a decision or lack of decision. To protect vulnerable persons, an incapable person should not be enrolled in most clinical trials. The only exception is if the study can only be conducted on incapable persons. If the willing research participant is incapable, consent must be obtained from others through a process called substitute (or proxy) consent. Disclosure refers to the provision of relevant information to the patient and its comprehension by the patient. Most surgical trials carry more than minimal risks, so the requirement for careful disclosure of these risks to potential participants is generally stringent. Voluntariness refers to the freedom of a person to make a treatment decision. In specific circumstances related to emergency research, the requirement for consent may be waived. Waiver can be justified only if the delay required to obtain consent would prevent the research from occurring and only after prior consultation with from the "community" of potential research participants.

Detection of candidate biomarkers of prostate cancer progression in serum: a depletion-free 3D LC/MS quantitative proteomics pilot study.

PubMed

Larkin, S E T; Johnston, H E; Jackson, T R; Jamieson, D G; Roumeliotis, T I; Mockridge, C I; Michael, A; Manousopoulou, A; Papachristou, E K; Brown, M D; Clarke, N W; Pandha, H; Aukim-Hastie, C L; Cragg, M S; Garbis, S D; Townsend, P A

2016-10-25

Prostate cancer (PCa) is the most common male cancer in the United Kingdom and we aimed to identify clinically relevant biomarkers corresponding to stage progression of the disease. We used enhanced proteomic profiling of PCa progression using iTRAQ 3D LC mass spectrometry on high-quality serum samples to identify biomarkers of PCa. We identified >1000 proteins. Following specific inclusion/exclusion criteria we targeted seven proteins of which two were validated by ELISA and six potentially interacted forming an 'interactome' with only a single protein linking each marker. This network also includes accepted cancer markers, such as TNF, STAT3, NF-κB and IL6. Our linked and interrelated biomarker network highlights the potential utility of six of our seven markers as a panel for diagnosing PCa and, critically, in determining the stage of the disease. Our validation analysis of the MS-identified proteins found that SAA alongside KLK3 may improve categorisation of PCa than by KLK3 alone, and that TSR1, although not significant in this model, might also be a clinically relevant biomarker.

Towards Prevention of Breast Cancer: What Are the Clinical Challenges?

PubMed

Borgquist, Signe; Hall, Per; Lipkus, Isaac; Garber, Judy E

2018-05-01

The dramatic increase in breast cancer incidence compels a paradigm shift in our preventive efforts. There are several barriers to overcome before prevention becomes an established part of breast cancer management. The objective of this review is to identify the clinical challenges for improved breast cancer prevention and discuss current knowledge on breast cancer risk assessment methods, risk communication, ethics, and interventional efforts with the aim of covering the aspects relevant for a breast cancer prevention trial. Herein, the following five areas are discussed: (i) Adequate tools for identification of women at high risk of breast cancer suggestively entitled Prevent! Online. (ii) Consensus on the definition of high risk, which is regarded as mandatory for all risk communication and potential prophylactic interventions. (iii) Risk perception and communication regarding risk information. (iv) Potential ethical concerns relevant for future breast cancer prevention programs. (v) Risk-reducing programs involving multileveled prevention depending on identified risk. Taken together, devoted efforts from both policy makers and health care providers are warranted to improve risk assessment and risk counseling in women at risk for breast cancer to optimize the prevention of breast cancer. Cancer Prev Res; 11(5); 255-64. ©2018 AACR . ©2018 American Association for Cancer Research.

[Terbinafine : Relevant drug interactions and their management].

PubMed

Dürrbeck, A; Nenoff, P

2016-09-01

The allylamine terbinafine is the probably most frequently prescribed systemic antifungal agent in Germany for the treatment of dermatomycoses and onychomycoses. According to the German drug law, terbinafine is approved for patients who are 18 years and older; however, this antifungal agent is increasingly used off-label for treatment of onychomycoses and tinea capitis in children. Terbinafine is associated with only a few interactions with other drugs, which is why terbinafine can generally be used without problems in older and multimorbid patients. Nevertheless, some potential interactions of terbinafine with certain drug substances are known, including substances of the group of antidepressants/antipsychotics and some cardiovascular drugs. Decisive for the relevance of interactions is-along with the therapeutic index of the substrate and the possible alternative degradation pathways-the genetically determined type of metabolism. When combining terbinafine with tricyclic antidepressants or selective serotonin reuptake inhibitors and serotonin/noradrenalin reuptake inhibitors, the clinical response and potential side effects must be monitored. Problematic is the use of terbinafine with simultaneous treatment with tamoxifen. The administration of potent CYP2D6 inhibitors leads to a diminished efficacy of tamoxifen because one of its most important active metabolites-endoxifen-is not sufficiently available. Therefore, combination of tamoxifen and terbinafine should be avoided. In conclusion, the number of substances which are able to cause clinically relevant interactions in case of simultaneously administration with terbinafine is clear and should be manageable in the dermatological office with adequate monitoring.

Bioinformatics tools for the analysis of NMR metabolomics studies focused on the identification of clinically relevant biomarkers.

PubMed

Puchades-Carrasco, Leonor; Palomino-Schätzlein, Martina; Pérez-Rambla, Clara; Pineda-Lucena, Antonio

2016-05-01

Metabolomics, a systems biology approach focused on the global study of the metabolome, offers a tremendous potential in the analysis of clinical samples. Among other applications, metabolomics enables mapping of biochemical alterations involved in the pathogenesis of diseases, and offers the opportunity to noninvasively identify diagnostic, prognostic and predictive biomarkers that could translate into early therapeutic interventions. Particularly, metabolomics by Nuclear Magnetic Resonance (NMR) has the ability to simultaneously detect and structurally characterize an abundance of metabolic components, even when their identities are unknown. Analysis of the data generated using this experimental approach requires the application of statistical and bioinformatics tools for the correct interpretation of the results. This review focuses on the different steps involved in the metabolomics characterization of biofluids for clinical applications, ranging from the design of the study to the biological interpretation of the results. Particular emphasis is devoted to the specific procedures required for the processing and interpretation of NMR data with a focus on the identification of clinically relevant biomarkers. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

How should doctors disclose conflicts of interest to patients? A focus group investigation.

PubMed

Oakes, J Michael; Whitham, Hilary K; Spaulding, Alicen Burns; Zentner, Lynn A; Beccard, Seth R

2015-01-01

Disclosure is often proposed as a strategy for handling financial conflicts of interest in medicine. Yet there has been no guidance on how clinicians should disclose potential conflicts of interest to patients. To discern patients' attitudes toward conflicts of interest in medicine and their opinions about how physicians should disclose possible conflicts in the clinical setting, we conducted six focus groups with patients recruited from three clinics in the Twin Cities area. Investigators reviewed audio recordings of the focus group discussions independently and identified themes. Maintaining patient-doctor trust was critical to all study participants. Most wanted to know only about conflicts of interest that were directly relevant to their care. In addition, most participants said physicians and other health care providers should offer patients an easy-to-read document about any conflict of interest during clinic check-ins and bring up the subject when discussing specific treatment plans for which the conflict of interest is relevant. Our study offers the first insights into patient attitudes toward and opinions about disclosure practices in clinical settings. More research into the practical aspects of managing conflicts of interest is needed as ineffective disclosure may undermine patients' trust in their doctors.

NIRS in clinical neurology - a 'promising' tool?

PubMed

Obrig, Hellmuth

2014-01-15

Near-infrared spectroscopy (NIRS) has become a relevant research tool in neuroscience. In special populations such as infants and for special tasks such as walking, NIRS has asserted itself as a low resolution functional imaging technique which profits from its ease of application, portability and the option to co-register other neurophysiological and behavioral data in a 'near natural' environment. For clinical use in neurology this translates into the option to provide a bed-side oximeter for the brain, broadly available at comparatively low costs. However, while some potential for routine brain monitoring during cardiac and vascular surgery and in neonatology has been established, NIRS is largely unknown to clinical neurologists. The article discusses some of the reasons for this lack of use in clinical neurology. Research using NIRS in three major neurologic diseases (cerebrovascular disease, epilepsy and headache) is reviewed. Additionally the potential to exploit the established position of NIRS as a functional imaging tool with regard to clinical questions such as preoperative functional assessment and neurorehabilitation is discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

21 CFR 1271.75 - How do I screen a donor?

Code of Federal Regulations, 2011 CFR

2011-04-01

...) Risk factors for, and clinical evidence of, relevant communicable disease agents and diseases... risk factors for and clinical evidence of relevant cell-associated communicable disease agents and... having either of the following: (1) A risk factor for or clinical evidence of any of the relevant...

Evaluating the Process of Generating a Clinical Trial Protocol

PubMed Central

Franciosi, Lui G.; Butterfield, Noam N.; MacLeod, Bernard A.

2002-01-01

The research protocol is the principal document in the conduct of a clinical trial. Its generation requires knowledge about the research problem, the potential experimental confounders, and the relevant Good Clinical Practices for conducting the trial. However, such information is not always available to authors during the writing process. A checklist of over 80 items has been developed to better understand the considerations made by authors in generating a protocol. It is based on the most cited requirements for designing and implementing the randomised controlled trial. Items are categorised according to the trial's research question, experimental design, statistics, ethics, and standard operating procedures. This quality assessment tool evaluates the extent that a generated protocol deviates from the best-planned clinical trial.

Interim analysis: A rational approach of decision making in clinical trial.

PubMed

Kumar, Amal; Chakraborty, Bhaswat S

2016-01-01

Interim analysis of especially sizeable trials keeps the decision process free of conflict of interest while considering cost, resources, and meaningfulness of the project. Whenever necessary, such interim analysis can also call for potential termination or appropriate modification in sample size, study design, and even an early declaration of success. Given the extraordinary size and complexity today, this rational approach helps to analyze and predict the outcomes of a clinical trial that incorporate what is learned during the course of a study or a clinical development program. Such approach can also fill the gap by directing the resources toward relevant and optimized clinical trials between unmet medical needs and interventions being tested currently rather than fulfilling only business and profit goals.

Integrative topological analysis of mass spectrometry data reveals molecular features with clinical relevance in esophageal squamous cell carcinoma

PubMed Central

Gao, She-Gan; Liu, Rui-Min; Zhao, Yun-Gang; Wang, Pei; Ward, Douglas G.; Wang, Guang-Chao; Guo, Xiang-Qian; Gu, Juan; Niu, Wan-Bin; Zhang, Tian; Martin, Ashley; Guo, Zhi-Peng; Feng, Xiao-Shan; Qi, Yi-Jun; Ma, Yuan-Fang

2016-01-01

Combining MS-based proteomic data with network and topological features of such network would identify more clinically relevant molecules and meaningfully expand the repertoire of proteins derived from MS analysis. The integrative topological indexes representing 95.96% information of seven individual topological measures of node proteins were calculated within a protein-protein interaction (PPI) network, built using 244 differentially expressed proteins (DEPs) identified by iTRAQ 2D-LC-MS/MS. Compared with DEPs, differentially expressed genes (DEGs) and comprehensive features (CFs), structurally dominant nodes (SDNs) based on integrative topological index distribution produced comparable classification performance in three different clinical settings using five independent gene expression data sets. The signature molecules of SDN-based classifier for distinction of early from late clinical TNM stages were enriched in biological traits of protein synthesis, intracellular localization and ribosome biogenesis, which suggests that ribosome biogenesis represents a promising therapeutic target for treating ESCC. In addition, ITGB1 expression selected exclusively by integrative topological measures correlated with clinical stages and prognosis, which was further validated with two independent cohorts of ESCC samples. Thus the integrative topological analysis of PPI networks proposed in this study provides an alternative approach to identify potential biomarkers and therapeutic targets from MS/MS data with functional insights in ESCC. PMID:26898710

Multi-modal Patient Cohort Identification from EEG Report and Signal Data

PubMed Central

Goodwin, Travis R.; Harabagiu, Sanda M.

2016-01-01

Clinical electroencephalography (EEG) is the most important investigation in the diagnosis and management of epilepsies. An EEG records the electrical activity along the scalp and measures spontaneous electrical activity of the brain. Because the EEG signal is complex, its interpretation is known to produce moderate inter-observer agreement among neurologists. This problem can be addressed by providing clinical experts with the ability to automatically retrieve similar EEG signals and EEG reports through a patient cohort retrieval system operating on a vast archive of EEG data. In this paper, we present a multi-modal EEG patient cohort retrieval system called MERCuRY which leverages the heterogeneous nature of EEG data by processing both the clinical narratives from EEG reports as well as the raw electrode potentials derived from the recorded EEG signal data. At the core of MERCuRY is a novel multimodal clinical indexing scheme which relies on EEG data representations obtained through deep learning. The index is used by two clinical relevance models that we have generated for identifying patient cohorts satisfying the inclusion and exclusion criteria expressed in natural language queries. Evaluations of the MERCuRY system measured the relevance of the patient cohorts, obtaining MAP scores of 69.87% and a NDCG of 83.21%. PMID:28269938

DEFINING THE RELEVANT OUTCOME MEASURES IN MEDICAL DEVICE ASSESSMENTS: AN ANALYSIS OF THE DEFINITION PROCESS IN HEALTH TECHNOLOGY ASSESSMENT.

PubMed

Jacobs, Esther; Antoine, Sunya-Lee; Prediger, Barbara; Neugebauer, Edmund; Eikermann, Michaela

2017-01-01

Defining relevant outcome measures for clinical trials on medical devices (MD) is complex, as there is a large variety of potentially relevant outcomes. The chosen outcomes vary widely across clinical trials making the assessment in evidence syntheses very challenging. The objective is to provide an overview on the current common procedures of health technology assessment (HTA) institutions in defining outcome measures in MD trials. In 2012-14, the Web pages of 126 institutions involved in HTA were searched for methodological manuals written in English or German that describe methods for the predefinition process of outcome measures. Additionally, the institutions were contacted by email. Relevant information was extracted. All process steps were performed independently by two reviewers. Twenty-four manuals and ten responses from the email request were included in the analysis. Overall, 88.5 percent of the institutions describe the type of outcomes that should be considered in detail and 84.6 percent agree that the main focus should be on patient relevant outcomes. Specifically related to MD, information could be obtained in 26 percent of the included manuals and email responses. Eleven percent of the institutions report a particular consideration of MD related outcomes. This detailed analysis on common procedures of HTA institutions in the context of defining relevant outcome measures for the assessment of MD shows that standardized procedures for MD from the perspective of HTA institutions are not widespread. This leads to the question if a homogenous approach should be implemented in the field of HTA on MD.

Allogeneic Umbilical Cord-Derived Mesenchymal Stem Cells as a Potential Source for Cartilage and Bone Regeneration: An In Vitro Study

PubMed Central

Mattia, S.; Castoldi, F.; Barbero, A.; Bonasia, D. E.; Bruzzone, M.; Dettoni, F.; Scurati, R.

2017-01-01

Umbilical cord (UC) may represent an attractive cell source for allogeneic mesenchymal stem cell (MSC) therapy. The aim of this in vitro study is to investigate the chondrogenic and osteogenic potential of UC-MSCs grown onto tridimensional scaffolds, to identify a possible clinical relevance for an allogeneic use in cartilage and bone reconstructive surgery. Chondrogenic differentiation on scaffolds was confirmed at 4 weeks by the expression of sox-9 and type II collagen; low oxygen tension improved the expression of these chondrogenic markers. A similar trend was observed in pellet culture in terms of matrix (proteoglycan) production. Osteogenic differentiation on bone-graft-substitute was also confirmed after 30 days of culture by the expression of osteocalcin and RunX-2. Cells grown in the hypertrophic medium showed at 5 weeks safranin o-positive stain and an increased CbFa1 expression, confirming the ability of these cells to undergo hypertrophy. These results suggest that the UC-MSCs isolated from minced umbilical cords may represent a valuable allogeneic cell population, which might have a potential for orthopaedic tissue engineering such as the on-demand cell delivery using chondrogenic, osteogenic, and endochondral scaffold. This study may have a clinical relevance as a future hypothetical option for allogeneic single-stage cartilage repair and bone regeneration. PMID:29358953

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.

Inflammation and Immune Regulation as Potential Drug Targets in Antidepressant Treatment

PubMed Central

Schmidt, Frank M.; Kirkby, Kenneth C.; Lichtblau, Nicole

2016-01-01

Growing evidence supports a mutual relationship between inflammation and major depression. A variety of mechanisms are outlined, indicating how inflammation may be involved in the pathogenesis, course and treatment of major depression. In particular, this review addresses 1) inflammatory cytokines as markers of depression and potential predictors of treatment response, 2) findings that cytokines interact with antidepressants and non-pharmacological antidepressive therapies, such as electroconvulsive therapy, deep brain stimulation and physical activity, 3) the influence of cytokines on the cytochrome (CYP) p450-system and drug efflux transporters, and 4) how cascades of inflammation might serve as antidepressant drug targets. A number of clinical trials have focused on agents with immunmodulatory properties in the treatment of depression, of which this review covers nonsteroidal anti-inflammatory drugs (NSAIDs), cytokine inhibitors, ketamine, polyunsaturated fatty acids, statins and curcumin. A perspective is also provided on possible future immune targets for antidepressant therapy, such as toll-like receptor-inhibitors, glycogen synthase kinase-3 inhibitors, oleanolic acid analogs and minocycline. Concluding from the available data, markers of inflammation may become relevant factors for more personalised planning and prediction of response of antidepressant treatment strategies. Agents with anti-inflammatory properties have the potential to serve as clinically relevant antidepressants. Further studies are required to better define and identify subgroups of patients responsive to inflammatory agents as well as to define optimal time points for treatment onset and duration. PMID:26769225

Allogeneic Umbilical Cord-Derived Mesenchymal Stem Cells as a Potential Source for Cartilage and Bone Regeneration: An In Vitro Study.

PubMed

Marmotti, A; Mattia, S; Castoldi, F; Barbero, A; Mangiavini, L; Bonasia, D E; Bruzzone, M; Dettoni, F; Scurati, R; Peretti, G M

2017-01-01

Umbilical cord (UC) may represent an attractive cell source for allogeneic mesenchymal stem cell (MSC) therapy. The aim of this in vitro study is to investigate the chondrogenic and osteogenic potential of UC-MSCs grown onto tridimensional scaffolds, to identify a possible clinical relevance for an allogeneic use in cartilage and bone reconstructive surgery. Chondrogenic differentiation on scaffolds was confirmed at 4 weeks by the expression of sox-9 and type II collagen; low oxygen tension improved the expression of these chondrogenic markers. A similar trend was observed in pellet culture in terms of matrix (proteoglycan) production. Osteogenic differentiation on bone-graft-substitute was also confirmed after 30 days of culture by the expression of osteocalcin and RunX-2. Cells grown in the hypertrophic medium showed at 5 weeks safranin o-positive stain and an increased CbFa1 expression, confirming the ability of these cells to undergo hypertrophy. These results suggest that the UC-MSCs isolated from minced umbilical cords may represent a valuable allogeneic cell population, which might have a potential for orthopaedic tissue engineering such as the on-demand cell delivery using chondrogenic, osteogenic, and endochondral scaffold. This study may have a clinical relevance as a future hypothetical option for allogeneic single-stage cartilage repair and bone regeneration.

Next generation metronomic chemotherapy-report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6-8 May 2016, Mumbai.

PubMed

Pantziarka, Pan; Hutchinson, Lisa; André, Nicolas; Benzekry, Sébastien; Bertolini, Francesco; Bhattacharjee, Atanu; Chiplunkar, Shubhada; Duda, Dan G; Gota, Vikram; Gupta, Sudeep; Joshi, Amit; Kannan, Sadhana; Kerbel, Robert; Kieran, Mark; Palazzo, Antonella; Parikh, Aparna; Pasquier, Eddy; Patil, Vijay; Prabhash, Kumar; Shaked, Yuval; Sholler, Giselle Saulnier; Sterba, Jaroslav; Waxman, David J; Banavali, Shripad

2016-01-01

The 5 th Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6 th - 8 th May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti-angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high-risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and predictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies.

Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing

PubMed Central

Mizani, Tuba; Hamblin, Angela; Parton, Marina; Orosz, Zsolt; Athanasou, Nick; Hassan, Bass; Flanagan, Adrienne M.; Ahmed, Ahmed; Winter, Stuart; Harris, Adrian; Popitsch, Niko; Church, David; Taylor, Jenny C.

2018-01-01

Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer. PMID:29610388

Depression in female adolescents: an IPA analysis.

PubMed

Shaw, Samantha K; Dallos, Rudi; Shoebridge, Philip

2009-04-01

Six female adolescents participated in open-ended interviews regarding their experiences of depression. The transcripts of their interviews were explored using Interpretative Phenomenological Analysis (Smith, 1991). The analysis revealed three inter-connected super-ordinate themes which were: communication, hurt self, and difference. These themes centred on communication processes in participants' families and with peers, issues relating to shifts in identity through adolescence, and feelings of being damaged, distressed, and hurt. Amongst a range of potentially relevant perspectives, an attachment theory (Bowlby, 1969) orientation was found to be particularly relevant and helpful in interpreting the themes that captured these young women's experiences. Some implications for clinical practice are discussed.

Tools in the assessment of sarcopenia

PubMed Central

Cooper, C; Fielding, R; Visser, M; van Loon, LJ; Rolland, Y; Orwoll, E; Reid, K; Boonen, S; Dere, W; Epstein, S; Mitlak, B; Tsouderos, Y; Sayer, AA; Rizzoli, R; Reginster, JY; Kanis, JA

2013-01-01

Summary This review provides a framework for development of an operational definition of sarcopenia and of the potential endpoints that might be adopted in clinical trials among older adults. Introduction While the clinical relevance of sarcopenia is widely recognized, there is currently no universally accepted definition of the disorder. The development of interventions to alter the natural history of sarcopenia also requires consensus on the most appropriate endpoints for determining outcomes of clinical importance which might be utilised in intervention studies. Methods and results We review current approaches to the definition of sarcopenia, and the methods used for the assessment of various aspects of physical function in older people. The potential endpoints of muscle mass, muscle strength, muscle power and muscle fatigue, as well as the relationships between them, are explored with reference to the availability and practicality of the available methods for measuring these endpoints in clinical trials. Conclusions Based on current evidence, none of the four potential outcomes in question is sufficiently comprehensive to recommend as a uniform single outcome in randomised clinical trials. We propose that sarcopenia may be optimally defined (for the purposes of clinical trial inclusion criteria, as well as epidemiological studies) using a combination of measures of muscle mass and physical performance. The choice of outcome measures for clinical trials in sarcopenia is more difficult; co-primary outcomes, tailored to the specific intervention in question, may be the best way forward in this difficult but clinically important area. PMID:23842964

The opportunities and obstacles in developing a vascular birthmark database for clinical and research use.

PubMed

Sharma, Vishal K; Fraulin, Frankie Og; Harrop, A Robertson; McPhalen, Donald F

2011-01-01

Databases are useful tools in clinical settings. The authors review the benefits and challenges associated with the development and implementation of an efficient electronic database for the multidisciplinary Vascular Birthmark Clinic at the Alberta Children's Hospital, Calgary, Alberta. The content and structure of the database were designed using the technical expertise of a data analyst from the Calgary Health Region. Relevant clinical and demographic data fields were included with the goal of documenting ongoing care of individual patients, and facilitating future epidemiological studies of this patient population. After completion of this database, 10 challenges encountered during development were retrospectively identified. Practical solutions for these challenges are presented. THE CHALLENGES IDENTIFIED DURING THE DATABASE DEVELOPMENT PROCESS INCLUDED: identification of relevant data fields; balancing simplicity and user-friendliness with complexity and comprehensive data storage; database expertise versus clinical expertise; software platform selection; linkage of data from the previous spreadsheet to a new data management system; ethics approval for the development of the database and its utilization for research studies; ensuring privacy and limited access to the database; integration of digital photographs into the database; adoption of the database by support staff in the clinic; and maintaining up-to-date entries in the database. There are several challenges involved in the development of a useful and efficient clinical database. Awareness of these potential obstacles, in advance, may simplify the development of clinical databases by others in various surgical settings.

Identification of potential neuromotor mechanisms of manual therapy in patients with musculoskeletal disablement: rationale and description of a clinical trial.

PubMed

Fisher, Beth E; Davenport, Todd E; Kulig, Kornelia; Wu, Allan D

2009-05-21

Many health care practitioners use a variety of hands-on treatments to improve symptoms and disablement in patients with musculoskeletal pathology.Research to date indirectly suggests a potentially broad effect of manual therapy on the neuromotor processing of functional behavior within the supraspinal central nervous system (CNS) in a manner that may be independent of modification at the level of local spinal circuits. However, the effect of treatment speed, as well as the specific mechanism and locus of CNS changes, remain unclear. We developed a placebo-controlled, randomized study to test the hypothesis that manual therapy procedures directed to the talocrural joint in individuals with post-acute ankle sprain induce a change in corticospinal excitability that is relevant to improve the performance of lower extremity functional behavior. This study is designed to identify potential neuromotor changes associated with manual therapy procedures directed to the appendicular skeleton, compare the relative effect of treatment speed on potential neuromotor effects of manual therapy procedures, and determine the behavioral relevance of potential neuromotor effects of manual therapy procedures. http://www.clinicaltrials.gov identifier NCT00847769.

Identification of potential neuromotor mechanisms of manual therapy in patients with musculoskeletal disablement: rationale and description of a clinical trial

PubMed Central

Fisher, Beth E; Davenport, Todd E; Kulig, Kornelia; Wu, Allan D

2009-01-01

Background Many health care practitioners use a variety of hands-on treatments to improve symptoms and disablement in patients with musculoskeletal pathology. Research to date indirectly suggests a potentially broad effect of manual therapy on the neuromotor processing of functional behavior within the supraspinal central nervous system (CNS) in a manner that may be independent of modification at the level of local spinal circuits. However, the effect of treatment speed, as well as the specific mechanism and locus of CNS changes, remain unclear. Methods/Design We developed a placebo-controlled, randomized study to test the hypothesis that manual therapy procedures directed to the talocrural joint in individuals with post-acute ankle sprain induce a change in corticospinal excitability that is relevant to improve the performance of lower extremity functional behavior. Discussion This study is designed to identify potential neuromotor changes associated with manual therapy procedures directed to the appendicular skeleton, compare the relative effect of treatment speed on potential neuromotor effects of manual therapy procedures, and determine the behavioral relevance of potential neuromotor effects of manual therapy procedures. Trial Registration identifier NCT00847769. PMID:19460169

The Reversal of Direct Oral Anticoagulants in Animal Models

PubMed Central

Honickel, Markus; Akman, Necib; Grottke, Oliver

2017-01-01

ABSTRACT Several direct oral anticoagulants (DOACs), including direct thrombin and factor Xa inhibitors, have been approved as alternatives to vitamin K antagonist anticoagulants. As with any anticoagulant, DOAC use carries a risk of bleeding. In patients with major bleeding or needing urgent surgery, reversal of DOAC anticoagulation may be required, presenting a clinical challenge. The optimal strategy for DOAC reversal is being refined, and may include use of hemostatic agents such as prothrombin complex concentrates (PCCs; a source of concentrated clotting factors), or DOAC-specific antidotes (which bind their target DOAC to abrogate its activity). Though promising, most specific antidotes are still in development. Preclinical animal research is the key to establishing the efficacy and safety of potential reversal agents. Here, we summarize published preclinical animal studies on reversal of DOAC anticoagulation. These studies (n = 26) were identified via a PubMed search, and used rodent, rabbit, pig, and non-human primate models. The larger of these animals have the advantages of similar blood volume/hemodynamics to humans, and can be used to model polytrauma. We find that in addition to varied species being used, there is variability in the models and assays used between studies; we suggest that blood loss (bleeding volume) is the most clinically relevant measure of DOAC anticoagulation-related bleeding and its reversal. The studies covered indicate that both PCCs and specific reversal agents have the potential to be used as part of a clinical strategy for DOAC reversal. For the future, we advocate the development and use of standardized, clinically, and pharmacologically relevant animal models to study novel DOAC reversal strategies. PMID:28471371

Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John's Wort?

PubMed

Mouly, Stéphane; Lloret-Linares, Célia; Sellier, Pierre-Olivier; Sene, Damien; Bergmann, J-F

2017-04-01

An interaction of drug with food, herbs, and dietary supplements is usually the consequence of a physical, chemical or physiologic relationship between a drug and a product consumed as food, nutritional supplement or over-the-counter medicinal plant. The current educational review aims at reminding to the prescribing physicians that the most clinically relevant drug-food interactions may not be strictly limited to those with grapefruit juice and with the Saint John's Wort herbal extract and may be responsible for changes in drug plasma concentrations, which in turn decrease efficacy or led to sometimes life-threatening toxicity. Common situations handled in clinical practice such as aging, concomitant medications, transplant recipients, patients with cancer, malnutrition, HIV infection and those receiving enteral or parenteral feeding may be at increased risk of drug-food or drug-herb interactions. Medications with narrow therapeutic index or potential life-threatening toxicity, e.g., the non-steroidal anti-inflammatory drugs, opioid analgesics, cardiovascular medications, warfarin, anticancer drugs and immunosuppressants may be at risk of significant drug-food interactions to occur. Despite the fact that considerable effort has been achieved to increase patient' and doctor's information and ability to anticipate their occurrence and consequences in clinical practice, a thorough and detailed health history and dietary recall are essential for identifying potential problems in order to optimize patient prescriptions and drug dosing on an individual basis as well as to increase the treatment risk/benefit ratio. Copyright © 2016 Elsevier Ltd. All rights reserved.

Longitudinal Analysis of New Information Types in Clinical Notes

PubMed Central

Zhang, Rui; Pakhomov, Serguei; Melton, Genevieve B.

2014-01-01

It is increasingly recognized that redundant information in clinical notes within electronic health record (EHR) systems is ubiquitous, significant, and may negatively impact the secondary use of these notes for research and patient care. We investigated several automated methods to identify redundant versus relevant new information in clinical reports. These methods may provide a valuable approach to extract clinically pertinent information and further improve the accuracy of clinical information extraction systems. In this study, we used UMLS semantic types to extract several types of new information, including problems, medications, and laboratory information. Automatically identified new information highly correlated with manual reference standard annotations. Methods to identify different types of new information can potentially help to build up more robust information extraction systems for clinical researchers as well as aid clinicians and researchers in navigating clinical notes more effectively and quickly identify information pertaining to changes in health states. PMID:25717418

9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma.

PubMed

Ugolkov, Andrey V; Bondarenko, Gennadiy I; Dubrovskyi, Oleksii; Berbegall, Ana P; Navarro, Samuel; Noguera, Rosa; O'Halloran, Thomas V; Hendrix, Mary J; Giles, Francis J; Mazar, Andrew P

2018-05-25

Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3β (GSK-3β) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3β expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3β inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.

Transbulbar B-Mode Sonography in Multiple Sclerosis: Clinical and Biological Relevance.

PubMed

De Masi, Roberto; Orlando, Stefania; Conte, Aldo; Pasca, Sergio; Scarpello, Rocco; Spagnolo, Pantaleo; Muscella, Antonella; De Donno, Antonella

2016-12-01

Optic nerve sheath diameter quantification by transbulbar B-mode sonography is a recently validated technique, but its clinical relevance in relapse-free multiple sclerosis patients remains unexplored. In an open-label, comparative, cross-sectional study, we aimed to assess possible differences between patients and healthy controls in terms of optic nerve sheath diameter and its correlation with clinical/paraclinical parameters in this disease. Sixty unselected relapse-free patients and 35 matched healthy controls underwent transbulbar B-mode sonography. Patients underwent routine neurologic examination, brain magnetic resonance imaging and visual evoked potential tests. The mean optic nerve sheath diameter 3 and 5 mm from the eyeball was 22-25% lower in patients than controls and correlated with the Expanded Disability Status Scale (r = -0.34, p = 0.048, and r = -0.32, p = 0.042, respectively). We suggest that optic nerve sheath diameter quantified by transbulbar B-mode sonography should be included in routine assessment of the disease as an extension of the neurologic examination. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer

PubMed Central

Siena, S; Sartore-Bianchi, A; Marsoni, S; Hurwitz, H I; McCall, S J; Penault-Llorca, F; Srock, S; Bardelli, A; Trusolino, L

2018-01-01

Abstract Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors is driven by amplification or mutation of HER2. This paper reviews the role of HER2 amplification as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type. While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology. HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients. PMID:29659677

Development of an arthroscopically compatible polymer additive layer manufacture technique.

PubMed

Partridge, Simon W; Benning, Matthew J; German, Matthew J; Dalgarno, Kenneth W

2017-06-01

This article describes a proof of concept study designed to evaluate the potential of an in vivo three-dimensional printing route to support minimally invasive repair of the musculoskeletal system. The study uses a photocurable material to additively manufacture in situ a model implant and demonstrates that this can be achieved effectively within a clinically relevant timescale. The approach has the potential to be applied with a wide range of light-curable materials and with development could be applied to create functionally gradient structures in vivo.

Direct and indirect risk associated with the use of dietary supplements among persons with dementia in a Norwegian memory clinic.

PubMed

Risvoll, Hilde; Giverhaug, Trude; Halvorsen, Kjell H; Waaseth, Marit; Musial, Frauke

2017-05-12

The use of dietary supplements (DS) is common among persons with dementia. Direct risks associated with DS use include adverse events and DS-drug interactions. A direct risk is a risk caused by the treatment itself. Indirect risks are related to the treatment setting, such as the conditions of use, and not to the treatment itself. Because dementia symptoms may reduce a person's ability to cope with the administration of DS, the use of DS may pose a threat to safety as an indirect risk. The aim of this study was to describe the extent of DS use among persons with dementia in ambulatory care and to identify some relevant direct and indirect risks related to DS use. We conducted a survey among 151 persons with dementia attending an outpatient memory clinic in Northern Norway. Study measurements included: the participants' characteristics, cognitive functioning, functioning in the activities of daily living (ADL), and the use of DS and prescription drugs (PD). We assessed direct risks by evaluating potential DS-drug interactions and indirect risks by evaluating the conditions under which it was used. Forty-six percent (n = 70) of the persons with dementia used DS. Ninety-seven percent (n = 147) used PD. We found potentially clinically relevant DS-drug interactions representing a direct risk in eight persons with dementia (11% of users). While only 36% (n = 26) of the participants received assistance with the administration of DS, 73% (n = 106) received assistance with the administration of PD. Persons with dementia living alone were at risk of not receiving assistance, as home care service seldom was involved in DS administration. Data indicated that assistance with DS administration was not provided for all persons with dementia in need, representing an indirect risk to these persons. Only one-third of the persons with dementia and half of the caregivers were aware of the general risks of adverse events and interactions associated with the use of DS. Persons with dementia use DS frequently, yet DS use may be associated with direct and indirect risks to patient safety as potentially clinically relevant interactions were discovered and DS intake often was unsupervised.

Effects of disclosing financial interests on attitudes toward clinical research.

PubMed

Weinfurt, Kevin P; Hall, Mark A; Dinan, Michaela A; DePuy, Venita; Friedman, Joëlle Y; Allsbrook, Jennifer S; Sugarman, Jeremy

2008-06-01

The effects of disclosing financial interests to potential research participants are not well understood. To examine the effects of financial interest disclosures on potential research participants' attitudes toward clinical research. Computerized experiment conducted with 3,623 adults in the United States with either diabetes mellitus or asthma, grouped by lesser and greater severity. Respondents read a description of a hypothetical clinical trial relevant to their diagnosis that included a financial disclosure statement. Respondents received 1 of 5 disclosure statements. Willingness to participate in the hypothetical clinical trial, relative importance of information about the financial interest, change in trust after reading the disclosure statement, surprise regarding the financial interest, and perceived effect of the financial interest on the quality of the clinical trial. Willingness to participate in the hypothetical clinical trial did not differ substantially among the types of financial disclosures. Respondents viewed the disclosed information as less important than other factors in deciding to participate. Disclosures were associated with some respondents trusting the researchers less, although trust among some respondents increased. Most respondents were not surprised to learn of financial interests. Researchers owning equity were viewed as more troubling than researchers who were compensated for the costs of research through per capita payments. Aside from a researcher holding an equity interest, the disclosure to potential research participants of financial interests in research, as recommended in recent policies, is unlikely to affect willingness to participate in research.

Progastrin: a potential predictive marker of liver metastasis in colorectal cancer.

PubMed

Westwood, David A; Patel, Oneel; Christophi, Christopher; Shulkes, Arthur; Baldwin, Graham S

2017-07-01

Staging of colorectal cancer often fails to discriminate outcomes of patients with morphologically similar tumours that exhibit different clinical behaviours. Data from several studies suggest that the gastrin family of growth factors potentiates colorectal cancer tumourigenesis. The aim of this study was to investigate whether progastrin expression may predict clinical outcome in colorectal cancer. Patients with colorectal adenocarcinoma of identical depth of invasion who had not received neoadjuvant therapy were included. The patients either had stage IIa disease with greater than 3-year disease-free survival without adjuvant therapy or stage IV disease with liver metastases on staging CT. Progastrin expression in tumour sections was scored with reference to the intensity and area of immunohistochemical staining. Progastrin expression by stage IV tumours was significantly greater than stage IIa tumours with mean progastrin immunopositivity scores of 2.1 ± 0.2 versus 0.5 ± 0.2, respectively (P < 0.001). This is the first study to show that progastrin expression may be predictive of aggressive tumour behaviour in patients with colorectal cancer and supports its clinical relevance and potential use as a biomarker.

Physiotherapy co-management of rheumatoid arthritis: identification of red flags, significance to clinical practice and management pathways.

PubMed

Briggs, Andrew M; Fary, Robyn E; Slater, Helen; Ranelli, Sonia; Chan, Madelynn

2013-12-01

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease. Physiotherapy interventions for people with RA are predominantly targeted at ameliorating disability resulting from articular and peri-articular manifestations of the disease and providing advice and education to improve functional capacity and quality of life. To ensure safe and effective care, it is critical that physiotherapists are able to identify potentially serious articular and peri-articular manifestations of RA, such as instability of the cervical spine. Additionally, as primary contact professionals, it is essential that physiotherapists are aware of the potentially serious extra-articular manifestations of RA. This paper provides an overview of the practice-relevant manifestations associated with RA that might warrant further investigation by a medical practitioner (red flags), their relevance to physiotherapy practice, and recommended management pathways. Copyright © 2013 Elsevier Ltd. All rights reserved.

Evidence based selection of probiotic strains to promote astronaut health or alleviate symptoms of illness on long duration spaceflight missions.

PubMed

Douglas, G L; Voorhies, A A

2017-10-13

Spaceflight impacts multiple aspects of human physiology, which will require non-invasive countermeasures as mission length and distance from Earth increases and the capability for external medical intervention decreases. Studies on Earth have shown that probiotics have the potential to improve some of the conditions that have manifested during spaceflight, such as gastrointestinal distress, dermatitis, and respiratory infections. The constraints and risks of spaceflight make it imperative that probiotics are carefully selected based on their strain-specific benefits, doses, delivery mechanisms, and relevance to likely crew conditions prior to evaluation in astronauts. This review focuses on probiotics that have been incorporated into healthy human gastrointestinal microbiomes and associated clinically with improvements in inflammatory state or alleviation of symptoms of crew-relevant illness. These studies provide an evidence base for probiotic selection with the greatest potential to support crew health and well-being in spaceflight.

Lack of Impact by SCY-078, a First-in-Class Oral Fungicidal Glucan Synthase Inhibitor, on the Pharmacokinetics of Rosiglitazone, a Substrate for CYP450 2C8, Supports the Low Risk for Clinically Relevant Metabolic Drug-Drug Interactions.

PubMed

Wring, Stephen; Murphy, Gail; Atiee, George; Corr, Christy; Hyman, Michele; Willett, Michael; Angulo, David

2018-05-10

SCY-078, the first in a new class of β 1,3-glucan synthesis inhibitors, is being developed as an oral and intravenous antifungal treatment for Candida and Aspergillus species fungal infections. In vitro, studies indicated SCY-078 is an inhibitor of cytochrome P450 (CYP) 2C8 with markedly lower effect over other CYP isozymes. To examine clinically relevant effects of the potential interaction with SCY-078, this phase 1, open-label, 2-period crossover study evaluated the pharmacokinetic parameters of rosiglitazone, a sensitive substrate of CYP2C8 metabolism, in the absence and presence of SCY-078 dosed to therapeutically relevant SCY-078 concentration exposure after repeat dosing. Healthy adult subjects were randomized to 2 treatment sequences: a single oral 4-mg rosiglitazone dose alone on day 1 or a 1250-mg SCY-078 loading dose on day 1 followed by a once-daily 750-mg SCY-078 dose for an additional 7 days (reflecting the clinical regimen evaluated during phase 2 studies for infections by Candida species) and concurrent administration of a single oral 4-mg rosiglitazone dose on day 3, before alternating following a ≥10-day washout. The exposure to SCY-078 observed in this study was in line with the intended exposure for treatment of invasive fungal infections. The 90% confidence intervals for rosiglitazone exposure geometric mean ratios were within the prespecified no effect interval of 0.70-1.43. Additionally, maximum concentration values for rosiglitazone and its metabolite, N-desmethylrosiglitazone, were not significantly affected by co-administration with SCY-078. Overall, rosiglitazone exposure was not impacted to a clinically meaningful extent with co-administration of therapeutically relevant SCY-078 concentration exposure after repeat dosing. The results are indicative of low risk for interaction of SCY-078 with drugs metabolized via the CYP family of enzymes. © 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

The potentiality of medicinal plants as the source of new contraceptive principles in males

PubMed Central

Ogbuewu, Ifeanyi Princewill; Unamba-Oparah, Ihemdirim Chukwuma; Odoemenam, Victor Udodirim; Etuk, Idorenyin Friday; Okoli, Ifeanyi Charles

2011-01-01

Rising human population throughout the world especially in developing and underdeveloped countries has detrimental effects on life supporting system on earth. Traditionally, plants have been used to treat different kinds of ailments. The growing importance of phytochemicals in males has been reported. Contraceptive ability of plants has been reported in several animal models. The reversibility of the anti-fertility effects of plants and its active compounds are of potential clinical relevance in the development of male contraceptive. This review attempts to discuss the latest reports on the potentiality of medicinal plants as the source of new contraceptive principles in males. PMID:22540095

The role of air pollution in COPD and implications for therapy.

PubMed

Lopez-Campos, J L; Marquez-Martin, E; Soriano, J B

2016-08-01

Exposure to many environmental conditions, apart from tobacco, as a risk factor for developing chronic obstructive pulmonary disease (COPD) has been comprehensively studied. Global estimates of air pollution depict a scenario of a considerable burden on respiratory health. Exposure to biomass smoke and occupational inhaled agents have been described as potentially related to causing or aggravating COPD. A number of emerging natural or accidental disasters have been suggested as a new source of exposure. Management of COPD patients exposed to different substances should include avoidance, especially in the more susceptible populations and proper pharmacological treatment considering potential association with particular clinical presentations. Expert commentary: Altogether, the available information indicates that appraisal of different environmental pollution exposures is clinically relevant, and should be systematically evaluated in COPD.

From Single Nucleotide Polymorphisms to Constant Immunosuppression: Mesenchymal Stem Cell Therapy for Autoimmune Diseases

PubMed Central

Galipeau, Jacques; Nooka, Ajay K.

2013-01-01

The regenerative abilities and the immunosuppressive properties of mesenchymal stromal cells (MSCs) make them potentially the ideal cellular product of choice for treatment of autoimmune and other immune mediated disorders. Although the usefulness of MSCs for therapeutic applications is in early phases, their potential clinical use remains of great interest. Current clinical evidence of use of MSCs from both autologous and allogeneic sources to treat autoimmune disorders confers conflicting clinical benefit outcomes. These varied results may possibly be due to MSC use across wide range of autoimmune disorders with clinical heterogeneity or due to variability of the cellular product. In the light of recent genome wide association studies (GWAS), linking predisposition of autoimmune diseases to single nucleotide polymorphisms (SNPs) in the susceptible genetic loci, the clinical relevance of MSCs possessing SNPs in the critical effector molecules of immunosuppression is largely undiscussed. It is of further interest in the allogeneic setting, where SNPs in the target pathway of MSC's intervention may also modulate clinical outcome. In the present review, we have discussed the known critical SNPs predisposing to disease susceptibility in various autoimmune diseases and their significance in the immunomodulatory properties of MSCs. PMID:24350294

Computer-assisted abdominal surgery: new technologies.

PubMed

Kenngott, H G; Wagner, M; Nickel, F; Wekerle, A L; Preukschas, A; Apitz, M; Schulte, T; Rempel, R; Mietkowski, P; Wagner, F; Termer, A; Müller-Stich, Beat P

2015-04-01

Computer-assisted surgery is a wide field of technologies with the potential to enable the surgeon to improve efficiency and efficacy of diagnosis, treatment, and clinical management. This review provides an overview of the most important new technologies and their applications. A MEDLINE database search was performed revealing a total of 1702 references. All references were considered for information on six main topics, namely image guidance and navigation, robot-assisted surgery, human-machine interface, surgical processes and clinical pathways, computer-assisted surgical training, and clinical decision support. Further references were obtained through cross-referencing the bibliography cited in each work. Based on their respective field of expertise, the authors chose 64 publications relevant for the purpose of this review. Computer-assisted systems are increasingly used not only in experimental studies but also in clinical studies. Although computer-assisted abdominal surgery is still in its infancy, the number of studies is constantly increasing, and clinical studies start showing the benefits of computers used not only as tools of documentation and accounting but also for directly assisting surgeons during diagnosis and treatment of patients. Further developments in the field of clinical decision support even have the potential of causing a paradigm shift in how patients are diagnosed and treated.

Clinical relevance of findings in trials of CBT for depression.

PubMed

Lepping, P; Whittington, R; Sambhi, R S; Lane, S; Poole, R; Leucht, S; Cuijpers, P; McCabe, R; Waheed, W

2017-09-01

Cognitive behavioural therapy (CBT) is beneficial in depression. Symptom scores can be translated into Clinical Global Impression (CGI) scale scores to indicate clinical relevance. We aimed to assess the clinical relevance of findings of randomised controlled trials (RCTs) of CBT in depression. We identified RCTs of CBT that used the Hamilton Rating Scale for Depression (HAMD). HAMD scores were translated into Clinical Global Impression - Change scale (CGI-I) scores to measure clinical relevance. One hundred and seventy datasets from 82 studies were included. The mean percentage HAMD change for treatment arms was 53.66%, and 29.81% for control arms, a statistically significant difference. Combined active therapies showed the biggest improvement on CGI-I score, followed by CBT alone. All active treatments had better than expected HAMD percentage reduction and CGI-I scores. CBT has a clinically relevant effect in depression, with a notional CGI-I score of 2.2, indicating a significant clinical response. The non-specific or placebo effect of being in a psychotherapy trial was a 29% reduction of HAMD. Copyright © 2017. Published by Elsevier Masson SAS.

Development and evaluation of a culture-free microbiota profiling platform (MYcrobiota) for clinical diagnostics.

PubMed

Boers, Stefan A; Hiltemann, Saskia D; Stubbs, Andrew P; Jansen, Ruud; Hays, John P

2018-06-01

Microbiota profiling has the potential to greatly impact on routine clinical diagnostics by detecting DNA derived from live, fastidious, and dead bacterial cells present within clinical samples. Such results could potentially be used to benefit patients by influencing antibiotic prescribing practices or to generate new classical-based diagnostic methods, e.g., culture or PCR. However, technical flaws in 16S rRNA gene next-generation sequencing (NGS) protocols, together with the requirement for access to bioinformatics, currently hinder the introduction of microbiota analysis into clinical diagnostics. Here, we report on the development and evaluation of an "end-to-end" microbiota profiling platform (MYcrobiota), which combines our previously validated micelle PCR/NGS (micPCR/NGS) methodology with an easy-to-use, dedicated bioinformatics pipeline. The newly designed bioinformatics pipeline processes micPCR/NGS data automatically and summarizes the results in interactive, but simple web reports. In order to explore the utility of MYcrobiota in clinical diagnostics, 47 clinical samples (40 "damaged skin" samples and 7 synovial fluids) were investigated using routine bacterial culture as comparator. MYcrobiota confirmed the presence of bacterial DNA in 37/37 culture-positive samples and detected bacterial taxa in 2/10 culture-negative samples. Moreover, 36/38 potentially relevant aerobic bacterial taxa and 3/3 mixtures of anaerobic bacteria were identified using culture and MYcrobiota, with the sensitivity and specificity being 95%. Interestingly, the majority of the 448 bacterial taxa identified using MYcrobiota were not identified using culture, which could potentially have an impact on clinical decision-making. Taken together, the development of MYcrobiota is a promising step towards the introduction of microbiota analysis into clinical diagnostic laboratories.

Update in clinical allergy and immunology.

PubMed

von Gunten, S; Marsland, B J; von Garnier, C; Simon, D

2012-12-01

In the recent years, a tremendous body of studies has addressed a broad variety of distinct topics in clinical allergy and immunology. In this update, we discuss selected recent data that provide clinically and pathogenetically relevant insights or identify potential novel targets and strategies for therapy. The role of the microbiome in shaping allergic immune responses and molecular, as well as cellular mechanisms of disease, is discussed separately and in the context of atopic dermatitis, as an allergic model disease. Besides summarizing novel evidence, this update highlights current areas of uncertainties and debates that, as we hope, shall stimulate scientific discussions and research activities in the field. © 2012 John Wiley & Sons A/S.

Application of Platelet-Rich Plasma to Disorders of the Knee Joint

PubMed Central

Mandelbaum, Bert R.; McIlwraith, C. Wayne

2013-01-01

Importance. The promising therapeutic potential and regenerative properties of platelet-rich plasma (PRP) have rapidly led to its widespread clinical use in musculoskeletal injury and disease. Although the basic scientific rationale surrounding PRP products is compelling, the clinical application has outpaced the research. Objective. The purpose of this article is to examine the current concepts around the basic science of PRP application, different preparation systems, and clinical application of PRP in disorders in the knee. Evidence Acquisition. A systematic search of PubMed for studies that evaluated the basic science, preparation and clinical application of platelet concentrates was performed. The search used terms, including platelet-rich plasma or PRP preparation, activation, use in the knee, cartilage, ligament, and meniscus. Studies found in the initial search and related studies were reviewed. Results. A comprehensive review of the literature supports the potential use of PRP both nonoperatively and intraoperatively, but highlights the absence of large clinical studies and the lack of standardization between method, product, and clinical efficacy. Conclusions and Relevance. In addition to the call for more randomized, controlled clinical studies to assess the clinical effect of PRP, at this point, it is necessary to investigate PRP product composition and eventually have the ability to tailor the therapeutic product for specific indications. PMID:26069674

Drug development in neuropsychopharmacology.

PubMed

Fritze, Jürgen

2008-03-01

Personalized medicine is still in its infancy concerning drug development in neuropsychopharmacology. Adequate biomarkers with clinical relevance to drug response and/or tolerability and safety largely remain to be identified. Possibly, this kind of personalized medicine will first gain clinical relevance in the dementias. The clinical relevance of the genotyping of drug-metabolizing enzymes as suggested by drug licensing authorities for the pharmacokinetic evaluation of medicinal products needs to be proven in sound clinical trials.

The Structured Clinically Relevant Interview for Psychiatrists in Training (SCRIPT): A New Standardized Assessment Tool for Recruitment in the UK

ERIC Educational Resources Information Center

Rao, Rahul

2007-01-01

Objective: The multifaceted nature of training and the diverse backgrounds of potential Senior House Officers (Postgraduate Residents) require a novel approach to the selection of trainees wishing to pursue a career in psychiatry. The author reports the properties of a semi-structured interview (the SCRIPT) for assessing doctors short-listed for a…

Comparative evaluation of the drug interaction screening programs MediQ and ID PHARMA CHECK in neurological inpatients.

PubMed

Zorina, Olesya I; Haueis, Patrick; Semmler, Alexander; Marti, Isabelle; Gonzenbach, Roman R; Guzek, Markus; Kullak-Ublick, Gerd A; Weller, Michael; Russmann, Stefan

2012-08-01

The comparative evaluation of clinical decision support software (CDSS) programs regarding their sensitivity and positive predictive value for the identification of clinically relevant drug interactions. In this research, we used a cross-sectional study that identified potential drug interactions using the CDSS MediQ and the ID PHARMA CHECK in 484 neurological inpatients. Interactions were reclassified according to the Zurich Interaction System, a multidimensional classification that incorporates the Operational Classification of Drug Interactions. In 484 patients with 2812 prescriptions, MediQ and ID PHARMA CHECK generated a total of 1759 and 1082 alerts, respectively. MediQ identified 658 unique potentially interacting combinations, 8 classified as "high danger," 164 as "average danger," and 486 as "low danger." ID PHARMA CHECK detected 336 combinations assigned to one or several of 12 risk and management categories. Altogether, both CDSS issued alerts relating to 808 unique potentially interacting combinations. According to the Zurich Interaction System, 6 of these were contraindicated, 25 were provisionally contraindicated, 190 carried a conditional risk, and 587 had a minimal risk of adverse events. The positive predictive value for alerts having at least a conditional risk was 0.24 for MediQ and 0.48 for ID PHARMA CHECK. CDSS showed major differences in the identification and grading of interactions, and many interactions were only identified by one of the two CDSS. For both programs, only a small proportion of all identified interactions appeared clinically relevant, and the selected display of alerts that imply management changes is a key issue in the further development and local setup of such programs. Copyright © 2012 John Wiley & Sons, Ltd.

Value of 3.0 T MR imaging in refractory partial epilepsy and negative 1.5 T MRI.

PubMed

Nguyen, Dang Khoa; Rochette, Emilie; Leroux, Jean-Maxime; Beaudoin, Gilles; Cossette, Patrick; Lassonde, Maryse; Guilbert, François

2010-10-01

High-field 3.0 T MR scanners provide an improved signal-to-noise ratio which can be translated in higher image resolution, possibly allowing critical detection of subtle epileptogenic lesions missed on standard-field 1.0-1.5 T MRIs. In this study, the authors explore the potential value of re-imaging at 3.0 T patients with refractory partial epilepsy and negative 1.5 T MRI. We retrospectively identified all patients with refractory partial epilepsy candidate for surgery who had undergone a 3.0 T MR study after a negative 1.5 T MR study. High-field 3.0 T MRIs were reviewed qualitatively by neuroradiologists experienced in interpreting epilepsy studies with access to clinical information. Relevance and impact on clinical management were assessed by an epileptologist. Between November 2006 and August 2009, 36 patients with refractory partial epilepsy candidate for surgery underwent 3.0 T MR study after a 1.5 T MR study failed to disclose a relevant epileptogenic lesion. A potential lesion was found only in two patients (5.6%, 95% CI: 1.5-18.1%). Both were found to have hippocampal atrophy congruent with other presurgical localization techniques which resulted in omission of an invasive EEG study and direct passage to surgery. The frequency of detection of a new lesion by re-imaging at 3.0 T patients with refractory partial epilepsy candidate for surgery was found to be low, but seems to offer the potential of a significant clinical impact for selected patients. This finding needs to be validated in a prospective controlled study. Copyright © 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Integration of complementary and alternative medicine information and advice in chronic disease management guidelines.

PubMed

Team, Victoria; Canaway, Rachel; Manderson, Lenore

2011-01-01

The growing evidence on the benefits and risks of complementary and alternative medicine (CAM) and its high rate of use (69% of Australians) - particularly for chronic or recurrent conditions - means increasing attention on CAM. However, few people disclose CAM use to their GP, and health professionals tend to inadequately discuss CAM-related issues with their patients, partly due to insufficient knowledge. As clinical and non-clinical chronic condition management guidelines are a means to educate primary health care practitioners, we undertook a content analysis of guidelines relevant to two common chronic conditions - cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) - to assess their provision of CAM-related information. Ten current Australian guidelines were reviewed, revealing scant CAM content. When available, the CAM-relevant information was brief, in some cases unclear, inconclusive and lacking in direction to the GP or health care provider. Although we focus on CVD and T2DM, we argue the value of all chronic condition management guidelines integrating relevant evidence-informed information and advice on CAM risks, benefits and referrals, to increase GP awareness and knowledge of appropriate CAM therapies, and potentially to facilitate doctor-client discussion about CAM.

An exploratory analysis of PubMed's free full-text limit on citation retrieval for clinical questions.

PubMed

Krieger, Mary M; Richter, Randy R; Austin, Tricia M

2008-10-01

The research sought to determine (1) how use of the PubMed free full-text (FFT) limit affects citation retrieval and (2) how use of the FFT limit impacts the types of articles and levels of evidence retrieved. Four clinical questions based on a research agenda for physical therapy were searched in PubMed both with and without the use of the FFT limit. Retrieved citations were examined for relevancy to each question. Abstracts of relevant citations were reviewed to determine the types of articles and levels of evidence. Descriptive analysis was used to compare the total number of citations, number of relevant citations, types of articles, and levels of evidence both with and without the use of the FFT limit. Across all 4 questions, the FFT limit reduced the number of citations to 11.1% of the total number of citations retrieved without the FFT limit. Additionally, high-quality evidence such as systematic reviews and randomized controlled trials were missed when the FFT limit was used. Health sciences librarians play a key role in educating users about the potential impact the FFT limit has on the number of citations, types of articles, and levels of evidence retrieved.

Religion, Spirituality, and HIV Clinical Outcomes: A Systematic Review of the Literature.

PubMed

Doolittle, B R; Justice, A C; Fiellin, D A

2018-06-01

This systematic review evaluates the association between religion, spirituality and clinical outcomes in HIV-infected individuals. A systematic literature review was conducted for all English language articles published between 1980 and 2016 in relevant databases. Six hundred fourteen studies were evaluated. 15 met inclusion criteria. Ten (67%) studies reported a positive association between religion or spirituality and a clinical HIV outcome. Two (13%) studies failed to detect such an association; and two (13%) demonstrated a negative association. One study (7%) identified features of religiosity and spirituality that had both negative and positive associations with HIV clinical outcomes. Recognizing the religious or spiritual commitments of patients may serve as an important component of patient care. Further longitudinal studies and interventions might be required to further clarify the potential impact of religion and spirituality on HIV clinical outcomes.

[Perioperative onset of sarcoidosis : Rare differential diagnosis of a difficult airway].

PubMed

Jansen, G; Nowak, A

2018-05-01

Sarcoidosis is a rare multisystemic chronic inflammatory condition. Typically, there is a big discrepancy between the patient's subjectively perceived symptoms and the presence of clinical signs. Due to the high number of potential sites of onset (e. g. larynx, lungs, heart, liver, kidneys) the affected organs may show functional restrictions that are relevant for decisions related to anesthesia. Therefore, an anesthetists working in a clinical setting should be familiar with the special needs of this patient collective. This article describes the onset of sarcoidosis in a case of an unexpected difficult airway.

Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations.

PubMed

Tamborero, David; Rubio-Perez, Carlota; Deu-Pons, Jordi; Schroeder, Michael P; Vivancos, Ana; Rovira, Ana; Tusquets, Ignasi; Albanell, Joan; Rodon, Jordi; Tabernero, Josep; de Torres, Carmen; Dienstmann, Rodrigo; Gonzalez-Perez, Abel; Lopez-Bigas, Nuria

2018-03-28

While tumor genome sequencing has become widely available in clinical and research settings, the interpretation of tumor somatic variants remains an important bottleneck. Here we present the Cancer Genome Interpreter, a versatile platform that automates the interpretation of newly sequenced cancer genomes, annotating the potential of alterations detected in tumors to act as drivers and their possible effect on treatment response. The results are organized in different levels of evidence according to current knowledge, which we envision can support a broad range of oncology use cases. The resource is publicly available at http://www.cancergenomeinterpreter.org .

Rethinking Normal: Benefits and Risks of Not Reporting Harmless Incidental Findings.

PubMed

Pandharipande, Pari V; Herts, Brian R; Gore, Richard M; Mayo-Smith, William W; Harvey, H Benjamin; Megibow, Alec J; Berland, Lincoln L

2016-07-01

The authors explore the benefits and risks of not reporting imaging findings that do not have clinical relevance, with the goal of developing recommendations to reduce their reporting. The authors review the example of incidentally detected, simple renal cysts (Bosniak category I), including medicolegal conditions required for such a shift in reporting practices to be acceptable. The authors propose four potential criteria for not reporting clinically unimportant findings and recommend that these criteria be debated in other contexts, so that they can be refined and implemented. Copyright © 2016 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Preliminary clinical results with the ISL laser

NASA Astrophysics Data System (ADS)

Hoppeler, Thomas; Gloor, Balder

1992-08-01

The ISL laser (Intelligent Surgical Lasers, Inc.), a Nd:YLF picosecond pulse laser, is currently being used under investigational device exemption to perform microsurgery of the anterior segment of the eye. At different study sites procedures for cataract fragmentation and iridotomy, as well as for posterior capsulotomy after cataract surgery, are under evaluation. Other potential applications include: sclerostomy ab interno, the cutting of membranes in the anterior and posterior segment of the eye; corneal incisions; and corneal intrastromal effects. We discuss various clinically relevant aspects of the use of this picosecond laser. An overview of different computer controlled laser patterns is given.

Free software to analyse the clinical relevance of drug interactions with antiretroviral agents (SIMARV®) in patients with HIV/AIDS.

PubMed

Giraldo, N A; Amariles, P; Monsalve, M; Faus, M J

Highly active antiretroviral therapy has extended the expected lifespan of patients with HIV/AIDS. However, the therapeutic benefits of some drugs used simultaneously with highly active antiretroviral therapy may be adversely affected by drug interactions. The goal was to design and develop a free software to facilitate analysis, assessment, and clinical decision making according to the clinical relevance of drug interactions in patients with HIV/AIDS. A comprehensive Medline/PubMed database search of drug interactions was performed. Articles that recognized any drug interactions in HIV disease were selected. The publications accessed were limited to human studies in English or Spanish, with full texts retrieved. Drug interactions were analyzed, assessed, and grouped into four levels of clinical relevance according to gravity and probability. Software to systematize the information regarding drug interactions and their clinical relevance was designed and developed. Overall, 952 different references were retrieved and 446 selected; in addition, 67 articles were selected from the citation lists of identified articles. A total of 2119 pairs of drug interactions were identified; of this group, 2006 (94.7%) were drug-drug interactions, 1982 (93.5%) had an identified pharmacokinetic mechanism, and 1409 (66.5%) were mediated by enzyme inhibition. In terms of clinical relevance, 1285 (60.6%) drug interactions were clinically significant in patients with HIV (levels 1 and 2). With this information, a software program that facilitates identification and assessment of the clinical relevance of antiretroviral drug interactions (SIMARV ® ) was developed. A free software package with information on 2119 pairs of antiretroviral drug interactions was designed and developed that could facilitate analysis, assessment, and clinical decision making according to the clinical relevance of drug interactions in patients with HIV/AIDS. Copyright © 2016 Elsevier Inc. All rights reserved.

'Cloud computing' and clinical trials: report from an ECRIN workshop.

PubMed

Ohmann, Christian; Canham, Steve; Danielyan, Edgar; Robertshaw, Steve; Legré, Yannick; Clivio, Luca; Demotes, Jacques

2015-07-29

Growing use of cloud computing in clinical trials prompted the European Clinical Research Infrastructures Network, a European non-profit organisation established to support multinational clinical research, to organise a one-day workshop on the topic to clarify potential benefits and risks. The issues that arose in that workshop are summarised and include the following: the nature of cloud computing and the cloud computing industry; the risks in using cloud computing services now; the lack of explicit guidance on this subject, both generally and with reference to clinical trials; and some possible ways of reducing risks. There was particular interest in developing and using a European 'community cloud' specifically for academic clinical trial data. It was recognised that the day-long workshop was only the start of an ongoing process. Future discussion needs to include clarification of trial-specific regulatory requirements for cloud computing and involve representatives from the relevant regulatory bodies.

Are Randomized Controlled Trials the (G)old Standard? From Clinical Intelligence to Prescriptive Analytics.

PubMed

Van Poucke, Sven; Thomeer, Michiel; Heath, John; Vukicevic, Milan

2016-07-06

Despite the accelerating pace of scientific discovery, the current clinical research enterprise does not sufficiently address pressing clinical questions. Given the constraints on clinical trials, for a majority of clinical questions, the only relevant data available to aid in decision making are based on observation and experience. Our purpose here is 3-fold. First, we describe the classic context of medical research guided by Poppers' scientific epistemology of "falsificationism." Second, we discuss challenges and shortcomings of randomized controlled trials and present the potential of observational studies based on big data. Third, we cover several obstacles related to the use of observational (retrospective) data in clinical studies. We conclude that randomized controlled trials are not at risk for extinction, but innovations in statistics, machine learning, and big data analytics may generate a completely new ecosystem for exploration and validation.

Are Randomized Controlled Trials the (G)old Standard? From Clinical Intelligence to Prescriptive Analytics

PubMed Central

2016-01-01

Despite the accelerating pace of scientific discovery, the current clinical research enterprise does not sufficiently address pressing clinical questions. Given the constraints on clinical trials, for a majority of clinical questions, the only relevant data available to aid in decision making are based on observation and experience. Our purpose here is 3-fold. First, we describe the classic context of medical research guided by Poppers’ scientific epistemology of “falsificationism.” Second, we discuss challenges and shortcomings of randomized controlled trials and present the potential of observational studies based on big data. Third, we cover several obstacles related to the use of observational (retrospective) data in clinical studies. We conclude that randomized controlled trials are not at risk for extinction, but innovations in statistics, machine learning, and big data analytics may generate a completely new ecosystem for exploration and validation. PMID:27383622

Translational research in addiction: toward a framework for the development of novel therapeutics.

PubMed

Paterson, Neil E

2011-06-15

The development of novel substance use disorder (SUD) therapeutics is insufficient to meet the medical needs of a growing SUD patient population. The identification of translatable SUD models and tests is a crucial step in establishing a framework for SUD therapeutic development programs. The present review begins by identifying the clinical features of SUDs and highlights the narrow regulatory end-point required for approval of a novel SUD therapeutic. A conceptual overview of dependence is provided, followed by identification of potential intervention targets in the addiction cycle. The main components of the addiction cycle provide the framework for a discussion of preclinical models and their clinical analogs, all of which are focused on isolated behavioral end-points thought to be relevant to the persistence of compulsive drug use. Thus, the greatest obstacle to successful development is the gap between the multiplicity of preclinical and early clinical end-points and the regulatory end-point of sustained abstinence. This review proposes two pathways to bridging this gap: further development and validation of the preclinical extended access self-administration model; inclusion of secondary end-points comprising all of the measures highlighted in the present discussion in Phase 3 trials. Further, completion of the postdictive validation of analogous preclinical and clinical assays is of high priority. Ultimately, demonstration of the relevance and validity of a variety of end-points to the ultimate goal of abstinence will allow researchers to identify truly relevant therapeutic mechanisms and intervention targets, and establish a framework for SUD therapeutic development that allows optimal decision-making and resource allocation. 2011 Elsevier Inc. All rights reserved.

Altered DNA Methylation Patterns Associated With Clinically Relevant Increases in PTSD Symptoms and PTSD Symptom Profiles in Military Personnel.

PubMed

Martin, Christiana; Cho, Young-Eun; Kim, Hyungsuk; Yun, Sijung; Kanefsky, Rebekah; Lee, Hyunhwa; Mysliwiec, Vincent; Cashion, Ann; Gill, Jessica

2018-05-01

Military personnel experience posttraumatic stress disorder (PTSD), which is associated with differential DNA methylation across the whole genome. However, the relationship between these DNA methylation patterns and clinically relevant increases in PTSD severity is not yet clearly understood. The purpose of this study was to identify differences in DNA methylation associated with PTSD symptoms and investigate DNA methylation changes related to increases in the severity of PTSD in military personnel. In this pilot study, a cross-sectional comparison was made between military personnel with PTSD (n = 8) and combat-matched controls without PTSD (n = 6). Symptom measures were obtained, and genome-wide DNA methylation was measured using methylated DNA immunoprecipitation (MeDIP-seq) from whole blood samples at baseline and 3 months later. A longitudinal comparison measured DNA methylation changes in military personnel with clinically relevant increases in PTSD symptoms between time points (PTSD onset) and compared methylation patterns to controls with no clinical changes in PTSD. In military personnel with elevated PTSD symptoms 3 months following baseline, 119 genes exhibited reduced methylation and 8 genes exhibited increased methylation. Genes with reduced methylation in the PTSD-onset group relate to the canonical pathways of netrin signaling, Wnt/Ca + pathway, and axonal guidance signaling. These gene pathways relate to neurological disorders, and the current findings suggest that these epigenetic changes potentially relate to PTSD symptomology. This study provides some novel insights into the role of epigenetic changes in PTSD symptoms and the progression of PTSD symptoms in military personnel.

Presence and Persistence of Viable, Clinically Relevant Legionella pneumophila Bacteria in Garden Soil in the Netherlands

PubMed Central

van Heijnsbergen, E.; van Deursen, A.; Bouwknegt, M.; Bruin, J. P.; Schalk, J. A. C.

2016-01-01

ABSTRACT Garden soils were investigated as reservoirs and potential sources of pathogenic Legionella bacteria. Legionella bacteria were detected in 22 of 177 garden soil samples (12%) by amoebal coculture. Of these 22 Legionella-positive soil samples, seven contained Legionella pneumophila. Several other species were found, including the pathogenic Legionella longbeachae (4 gardens) and Legionella sainthelensi (9 gardens). The L. pneumophila isolates comprised 15 different sequence types (STs), and eight of these STs were previously isolated from patients according to the European Working Group for Legionella Infections (EWGLI) database. Six gardens that were found to be positive for L. pneumophila were resampled after several months, and in three gardens, L. pneumophila was again isolated. One of these gardens was resampled four times throughout the year and was found to be positive for L. pneumophila on all occasions. IMPORTANCE Tracking the source of infection for sporadic cases of Legionnaires' disease (LD) has proven to be hard. L. pneumophila ST47, the sequence type that is most frequently isolated from LD patients in the Netherlands, is rarely found in potential environmental sources. As L. pneumophila ST47 was previously isolated from a garden soil sample during an outbreak investigation, garden soils were investigated as reservoirs and potential sources of pathogenic Legionella bacteria. The detection of viable, clinically relevant Legionella strains indicates that garden soil is a potential source of Legionella bacteria, and future research should assess the public health implication of the presence of L. pneumophila in garden soil. PMID:27316958

Presence and Persistence of Viable, Clinically Relevant Legionella pneumophila Bacteria in Garden Soil in the Netherlands.

PubMed

van Heijnsbergen, E; van Deursen, A; Bouwknegt, M; Bruin, J P; de Roda Husman, A M; Schalk, J A C

2016-09-01

Garden soils were investigated as reservoirs and potential sources of pathogenic Legionella bacteria. Legionella bacteria were detected in 22 of 177 garden soil samples (12%) by amoebal coculture. Of these 22 Legionella-positive soil samples, seven contained Legionella pneumophila Several other species were found, including the pathogenic Legionella longbeachae (4 gardens) and Legionella sainthelensi (9 gardens). The L. pneumophila isolates comprised 15 different sequence types (STs), and eight of these STs were previously isolated from patients according to the European Working Group for Legionella Infections (EWGLI) database. Six gardens that were found to be positive for L. pneumophila were resampled after several months, and in three gardens, L. pneumophila was again isolated. One of these gardens was resampled four times throughout the year and was found to be positive for L. pneumophila on all occasions. Tracking the source of infection for sporadic cases of Legionnaires' disease (LD) has proven to be hard. L. pneumophila ST47, the sequence type that is most frequently isolated from LD patients in the Netherlands, is rarely found in potential environmental sources. As L. pneumophila ST47 was previously isolated from a garden soil sample during an outbreak investigation, garden soils were investigated as reservoirs and potential sources of pathogenic Legionella bacteria. The detection of viable, clinically relevant Legionella strains indicates that garden soil is a potential source of Legionella bacteria, and future research should assess the public health implication of the presence of L. pneumophila in garden soil. Copyright © 2016 van Heijnsbergen et al.

Clinicomanometric factors associated with clinically relevant esophagogastric junction outflow obstruction from the Sandhill high-resolution manometry system.

PubMed

Song, B G; Min, Y W; Lee, H; Min, B-H; Lee, J H; Rhee, P-L; Kim, J J

2018-03-01

Integrated relaxation pressure (IRP) is a key metric for diagnosing esophagogastric junction outflow obstruction (EGJOO). However, its normal value might be different according to the manufacturer of high-resolution manometry (HRM). This study aimed to investigate optimal value of IRP for diagnosing EGJOO in Sandhill HRM and to find clinicomanometric variables to segregate clinically relevant EGJOO. We analyzed 262 consecutive subjects who underwent HRM between June 2011 and December 2016 showing elevated median IRP (> 15 mm Hg) but did not satisfy criteria for achalasia. Clinically relevant subjects were defined as follows: (i) subsequent HRM met achalasia criteria during follow-up (early achalasia); (ii) Eckardt score was decreased at least two points without exceeding a score of 3 after pneumatic dilatation (variant achalasia); and (iii) significant passage disturbance on esophagogram without structural abnormality (possible achalasia). Seven subjects were clinically relevant, including two subjects with early achalasia, four subjects with variant achalasia, and one subject with possible achalasia. All clinically relevant subjects had IRP 20 mm Hg or above. Among subjects (n = 122) with IRP 20 mm Hg or more, clinically relevant group (n = 7) had significantly higher rate of dysphagia (100% vs 24.3%, P < .001) and compartmentalized pressurization (85.7% vs 21.7%, P = .001) compared to clinically non-relevant group (n = 115). Our results suggest that IRP of 20 mm Hg or higher could segregate clinically relevant subjects showing EGJOO in Sandhill HRM. Additionally, if subjects have both dysphagia and compartmentalized pressurization, careful follow-up is essential. © 2017 John Wiley & Sons Ltd.

The spine in Paget’s disease

PubMed Central

Dell’Atti, C.; Lalam, R. K.; Tins, B. J.; Tyrrell, P. N. M.

2007-01-01

Paget’s disease (PD) is a chronic metabolically active bone disease, characterized by a disturbance in bone modelling and remodelling due to an increase in osteoblastic and osteoclastic activity. The vertebra is the second most commonly affected site. This article reviews the various spinal pathomechanisms and osseous dynamics involved in producing the varied imaging appearances and their clinical relevance. Advanced imaging of osseous, articular and bone marrow manifestations of PD in all the vertebral components are presented. Pagetic changes often result in clinical symptoms including back pain, spinal stenosis and neural dysfunction. Various pathological complications due to PD involvement result in these clinical symptoms. Recognition of the imaging manifestations of spinal PD and the potential complications that cause the clinical symptoms enables accurate assessment of patients prior to appropriate management. PMID:17410356

Applications of mass spectrometry for quantitative protein analysis in formalin-fixed paraffin-embedded tissues

PubMed Central

Steiner, Carine; Ducret, Axel; Tille, Jean-Christophe; Thomas, Marlene; McKee, Thomas A; Rubbia-Brandt, Laura A; Scherl, Alexander; Lescuyer, Pierre; Cutler, Paul

2014-01-01

Proteomic analysis of tissues has advanced in recent years as instruments and methodologies have evolved. The ability to retrieve peptides from formalin-fixed paraffin-embedded tissues followed by shotgun or targeted proteomic analysis is offering new opportunities in biomedical research. In particular, access to large collections of clinically annotated samples should enable the detailed analysis of pathologically relevant tissues in a manner previously considered unfeasible. In this paper, we review the current status of proteomic analysis of formalin-fixed paraffin-embedded tissues with a particular focus on targeted approaches and the potential for this technique to be used in clinical research and clinical diagnosis. We also discuss the limitations and perspectives of the technique, particularly with regard to application in clinical diagnosis and drug discovery. PMID:24339433

Recommendations for Clinical Pathology Data Generation, Interpretation, and Reporting in Target Animal Safety Studies for Veterinary Drug Development.

PubMed

Siska, William; Gupta, Aradhana; Tomlinson, Lindsay; Tripathi, Niraj; von Beust, Barbara

Clinical pathology testing is routinely performed in target animal safety studies in order to identify potential toxicity associated with administration of an investigational veterinary pharmaceutical product. Regulatory and other testing guidelines that address such studies provide recommendations for clinical pathology testing but occasionally contain outdated analytes and do not take into account interspecies physiologic differences that affect the practical selection of appropriate clinical pathology tests. Additionally, strong emphasis is often placed on statistical analysis and use of reference intervals for interpretation of test article-related clinical pathology changes, with limited attention given to the critical scientific review of clinically, toxicologically, or biologically relevant changes. The purpose of this communication from the Regulatory Affairs Committee of the American Society for Veterinary Clinical Pathology is to provide current recommendations for clinical pathology testing and data interpretation in target animal safety studies and thereby enhance the value of clinical pathology testing in these studies.

Facile synthesis, pharmacokinetic and systemic clearance evaluation, and positron emission tomography cancer imaging of 64Cu-Au alloy nanoclusters

NASA Astrophysics Data System (ADS)

Zhao, Yongfeng; Sultan, Deborah; Detering, Lisa; Luehmann, Hannah; Liu, Yongjian

2014-10-01

Gold nanoparticles have been widely used for oncological applications including diagnosis and therapy. However, the non-specific mononuclear phagocyte system accumulation and potential long-term toxicity have significantly limited clinical translation. One strategy to overcome these shortcomings is to reduce the size of gold nanoparticles to allow renal clearance. Herein, we report the preparation of 64Cu alloyed gold nanoclusters (64CuAuNCs) for in vivo evaluation of pharmacokinetics, systemic clearance, and positron emission tomography (PET) imaging in a mouse prostate cancer model. The facile synthesis in acqueous solution allowed precisely controlled 64Cu incorporation for high radiolabeling specific activity and stability for sensitive and accurate detection. Through surface pegylation with 350 Da polyethylene glycol (PEG), the 64CuAuNCs-PEG350 afforded optimal biodistribution and significant renal and hepatobiliary excretion. PET imaging showed low non-specific tumor uptake, indicating its potential for active targeting of clinically relevant biomarkers in tumor and metastatic organs.Gold nanoparticles have been widely used for oncological applications including diagnosis and therapy. However, the non-specific mononuclear phagocyte system accumulation and potential long-term toxicity have significantly limited clinical translation. One strategy to overcome these shortcomings is to reduce the size of gold nanoparticles to allow renal clearance. Herein, we report the preparation of 64Cu alloyed gold nanoclusters (64CuAuNCs) for in vivo evaluation of pharmacokinetics, systemic clearance, and positron emission tomography (PET) imaging in a mouse prostate cancer model. The facile synthesis in acqueous solution allowed precisely controlled 64Cu incorporation for high radiolabeling specific activity and stability for sensitive and accurate detection. Through surface pegylation with 350 Da polyethylene glycol (PEG), the 64CuAuNCs-PEG350 afforded optimal biodistribution and significant renal and hepatobiliary excretion. PET imaging showed low non-specific tumor uptake, indicating its potential for active targeting of clinically relevant biomarkers in tumor and metastatic organs. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr04569f

Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use.

PubMed

Taylor, Charles P; Traynelis, Stephen F; Siffert, Joao; Pope, Laura E; Matsumoto, Rae R

2016-08-01

Dextromethorphan (DM) has been used for more than 50years as an over-the-counter antitussive. Studies have revealed a complex pharmacology of DM with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential. DM is rapidly metabolized to dextrorphan, which has hampered the exploration of DM therapy separate from its metabolites. Coadministration of DM with a low dose of quinidine inhibits DM metabolism, yields greater bioavailability and enables more specific testing of the therapeutic properties of DM apart from its metabolites. The development of the drug combination DM hydrobromide and quinidine sulfate (DM/Q), with subsequent approval by the US Food and Drug Administration for pseudobulbar affect, led to renewed interest in understanding DM pharmacology. This review summarizes the interactions of DM with brain receptors and transporters and also considers its metabolic and pharmacokinetic properties. To assess the potential clinical relevance of these interactions, we provide an analysis comparing DM activity from in vitro functional assays with the estimated free drug DM concentrations in the brain following oral DM/Q administration. The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α3β4 subunits, and cause agonist activity at sigma-1 receptors. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Sequencing of intraductal biopsies is feasible and potentially impacts clinical management of patients with indeterminate biliary stricture and cholangiocarcinoma.

PubMed

Bankov, Katrin; Döring, Claudia; Schneider, Markus; Hartmann, Sylvia; Winkelmann, Ria; Albert, Joerg G; Bechstein, Wolf Otto; Zeuzem, Stefan; Hansmann, Martin Leo; Peveling-Oberhag, Jan; Walter, Dirk

2018-04-30

Definite diagnosis and therapeutic management of cholangiocarcinoma (CCA) remains a challenge. The aim of the current study was to investigate feasibility and potential impact on clinical management of targeted sequencing of intraductal biopsies. Intraductal biopsies with suspicious findings from 16 patients with CCA in later clinical course were analyzed with targeted sequencing including tumor and control benign tissue (n = 55 samples). A CCA-specific sequencing panel containing 41 genes was designed and a dual strand targeted enrichment was applied. Sequencing was successfully performed for all samples. In total, 79 mutations were identified and a mean of 1.7 mutations per tumor sample (range 0-4) as well as 2.3 per biopsy (0-6) were detected and potentially therapeutically relevant genes were identified in 6/16 cases. In 14/18 (78%) biopsies with dysplasia or inconclusive findings at least one mutation was detected. The majority of mutations were found in both surgical specimen and biopsy (68%), while 28% were only present in biopsies in contrast to 4% being only present in the surgical tumor specimen. Targeted sequencing from intraductal biopsies is feasible and potentially improves the diagnostic yield. A profound genetic heterogeneity in biliary dysplasia needs to be considered in clinical management and warrants further investigation. The current study is the first to demonstrate the feasibility of sequencing of intraductal biopsies which holds the potential to impact diagnostic and therapeutical management of patients with biliary dysplasia and neoplasia.

Knowledge discovery for Deep Phenotyping serious mental illness from Electronic Mental Health records.

PubMed

Jackson, Richard; Patel, Rashmi; Velupillai, Sumithra; Gkotsis, George; Hoyle, David; Stewart, Robert

2018-01-01

Background: Deep Phenotyping is the precise and comprehensive analysis of phenotypic features in which the individual components of the phenotype are observed and described. In UK mental health clinical practice, most clinically relevant information is recorded as free text in the Electronic Health Record, and offers a granularity of information beyond what is expressed in most medical knowledge bases. The SNOMED CT nomenclature potentially offers the means to model such information at scale, yet given a sufficiently large body of clinical text collected over many years, it is difficult to identify the language that clinicians favour to express concepts. Methods: By utilising a large corpus of healthcare data, we sought to make use of semantic modelling and clustering techniques to represent the relationship between the clinical vocabulary of internationally recognised SMI symptoms and the preferred language used by clinicians within a care setting. We explore how such models can be used for discovering novel vocabulary relevant to the task of phenotyping Serious Mental Illness (SMI) with only a small amount of prior knowledge.  Results: 20 403 terms were derived and curated via a two stage methodology. The list was reduced to 557 putative concepts based on eliminating redundant information content. These were then organised into 9 distinct categories pertaining to different aspects of psychiatric assessment. 235 concepts were found to be expressions of putative clinical significance. Of these, 53 were identified having novel synonymy with existing SNOMED CT concepts. 106 had no mapping to SNOMED CT. Conclusions: We demonstrate a scalable approach to discovering new concepts of SMI symptomatology based on real-world clinical observation. Such approaches may offer the opportunity to consider broader manifestations of SMI symptomatology than is typically assessed via current diagnostic frameworks, and create the potential for enhancing nomenclatures such as SNOMED CT based on real-world expressions.

Knowledge discovery for Deep Phenotyping serious mental illness from Electronic Mental Health records

PubMed Central

Jackson, Richard; Patel, Rashmi; Velupillai, Sumithra; Gkotsis, George; Hoyle, David; Stewart, Robert

2018-01-01

Background: Deep Phenotyping is the precise and comprehensive analysis of phenotypic features in which the individual components of the phenotype are observed and described. In UK mental health clinical practice, most clinically relevant information is recorded as free text in the Electronic Health Record, and offers a granularity of information beyond what is expressed in most medical knowledge bases. The SNOMED CT nomenclature potentially offers the means to model such information at scale, yet given a sufficiently large body of clinical text collected over many years, it is difficult to identify the language that clinicians favour to express concepts. Methods: By utilising a large corpus of healthcare data, we sought to make use of semantic modelling and clustering techniques to represent the relationship between the clinical vocabulary of internationally recognised SMI symptoms and the preferred language used by clinicians within a care setting. We explore how such models can be used for discovering novel vocabulary relevant to the task of phenotyping Serious Mental Illness (SMI) with only a small amount of prior knowledge.  Results: 20 403 terms were derived and curated via a two stage methodology. The list was reduced to 557 putative concepts based on eliminating redundant information content. These were then organised into 9 distinct categories pertaining to different aspects of psychiatric assessment. 235 concepts were found to be expressions of putative clinical significance. Of these, 53 were identified having novel synonymy with existing SNOMED CT concepts. 106 had no mapping to SNOMED CT. Conclusions: We demonstrate a scalable approach to discovering new concepts of SMI symptomatology based on real-world clinical observation. Such approaches may offer the opportunity to consider broader manifestations of SMI symptomatology than is typically assessed via current diagnostic frameworks, and create the potential for enhancing nomenclatures such as SNOMED CT based on real-world expressions. PMID:29899974

Soft tissue fillers for adipose tissue regeneration: From hydrogel development toward clinical applications.

PubMed

Van Nieuwenhove, I; Tytgat, L; Ryx, M; Blondeel, P; Stillaert, F; Thienpont, H; Ottevaere, H; Dubruel, P; Van Vlierberghe, S

2017-11-01

There is a clear and urgent clinical need to develop soft tissue fillers that outperform the materials currently used for adipose tissue reconstruction. Recently, extensive research has been performed within this field of adipose tissue engineering as the commercially available products and the currently existing techniques are concomitant with several disadvantages. Commercial products are highly expensive and associated with an imposing need for repeated injections. Lipofilling or free fat transfer has an unpredictable outcome with respect to cell survival and potential resorption of the fat grafts. Therefore, researchers are predominantly investigating two challenging adipose tissue engineering strategies: in situ injectable materials and porous 3D printed scaffolds. The present work provides an overview of current research encompassing synthetic, biopolymer-based and extracellular matrix-derived materials with a clear focus on emerging fabrication technologies and developments realized throughout the last decade. Moreover, clinical relevance of the most promising materials will be discussed, together with potential concerns associated with their application in the clinic. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Is it time to introduce repetitive transcranial magnetic stimulation into standard clinical practice for the treatment of depressive disorders?

PubMed

Fitzgerald, Paul

2003-02-01

To examine issues relating to the potential introduction of repetitive transcranial magnetic stimulation (rTMS) into clinical practice as a treatment for depression. A review of the outcomes literature accompanied by an analysis of issues relating to the potential advantages and pitfalls of the introduction of rTMS as a treatment strategy. Evidence is progressively accumulating that rTMS has antidepressant properties that are clinically relevant. These effects are biologically plausible and supported by basic research. Patients with therapy-resistant depression have few treatment alternatives and experience significant suffering, thus justifying the early introduction of a new treatment such as rTMS for this patient group. However, this must be balanced by a need to foster considerable further research and not to raise expectations unreasonably. It is timely for rTMS to be made more available to patients with treatment-resistant mood disorders. This need not be limited to clinical research trials but should only occur in medical settings where continual evaluation and research is conducted.

Mental Health of HIV-Seropositive Women During Pregnancy and Postpartum Period: A Comprehensive Literature Review

PubMed Central

Dass-Brailsford, Priscilla; Nora, Diana; Talisman, Nicholas

2014-01-01

With growing numbers of HIV-seropositive (HIV+) women of child-bearing age and increased access to effective clinical protocols for preventing mother-to-child transmission (MTCT) of HIV, mental health-related factors have become increasingly relevant due to their potential to affect the women’s quality of life, obstetric outcomes and risk of MTCT. This review synthesizes evidence from 53 peer-reviewed publications examining mental health-related variables in pregnant and postpartum HIV+ women. The presentation of results is organized by the level of socioeconomic resources in the countries where studies were conducted (i.e., high-, middle-, and low-income countries). It is concluded that psychiatric symptoms, particularly depression, and mental health vulnerabilities (e.g., inadequate coping skills) are widespread among pregnant HIV+ women globally and have a potential to affect psychological well-being, quality of life and salient clinical outcomes. The current body of evidence provides rationale for developing and evaluating clinical and structural interventions aimed at improving mental health outcomes and their clinical correlates in pregnant HIV+ women. PMID:24584458

Pathophysiological consequences and benefits of HFE mutations: 20 years of research

PubMed Central

Hollerer, Ina; Bachmann, André; Muckenthaler, Martina U.

2017-01-01

Mutations in the HFE (hemochromatosis) gene cause hereditary hemochromatosis, an iron overload disorder that is hallmarked by excessive accumulation of iron in parenchymal organs. The HFE mutation p.Cys282Tyr is pathologically most relevant and occurs in the Caucasian population with a carrier frequency of up to 1 in 8 in specific European regions. Despite this high prevalence, the mutation causes a clinically relevant phenotype only in a minority of cases. In this review, we summarize historical facts and recent research findings about hereditary hemochromatosis, and outline the pathological consequences of the associated gene defects. In addition, we discuss potential advantages of HFE mutations in asymptomatic carriers. PMID:28280078

[Environmental factors and male fertility].

PubMed

Köhn, F-M; Schuppe, H C

2016-07-01

The identification of potential environmental hazards may have clinical relevance for diagnosis of male infertility. Knowledge about these factors will improve prevention of fertility disorders. Apart from drugs or factors related to lifestyle such as alcohol and tobacco smoke, various environmental and occupational agents, both chemical and physical, may impair male reproductive functions. With regard to the complex regulation of the male reproductive system, the available information concerning single exogenous factors and their mechanisms of action in humans is limited. This is also due to the fact that extrapolation of results obtained from experimental animal studies remains difficult. Nevertheless, the assessment of relevant exposures to reproductive toxicants should be carefully evaluated during diagnostic procedures of andrological patients.

Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis.

PubMed

Kim, Soo-Hyun; Redvers, Richard P; Chi, Lap Hing; Ling, Xiawei; Lucke, Andrew J; Reid, Robert C; Fairlie, David P; Baptista Moreno Martin, Ana Carolina; Anderson, Robin L; Denoyer, Delphine; Pouliot, Normand

2018-05-21

Breast cancer brain metastasis remains largely incurable. While several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immune-compromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain-selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo and potent radio-sensitising properties in vitro The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis. © 2018. Published by The Company of Biologists Ltd.

New dimensions and new tools to realize the potential of RDoC: digital phenotyping via smartphones and connected devices.

PubMed

Torous, J; Onnela, J-P; Keshavan, M

2017-03-07

Mobile and connected devices like smartphones and wearable sensors can facilitate the collection of novel naturalistic and longitudinal data relevant to psychiatry at both the personal and population level. The National Institute of Mental Health's Research Domain Criteria framework offers a useful roadmap to organize, guide and lead new digital phenotyping data towards research discoveries and clinical advances.

Corynebacterium tuberculostearicum: a Potentially Misidentified and Multiresistant Corynebacterium Species Isolated from Clinical Specimens

PubMed Central

Hinić, V.; Lang, C.; Weisser, M.; Straub, C.; Frei, R.

2012-01-01

Corynebacterium tuberculostearicum is a lipophilic corynebacterium validly characterized in 2004. We provide clinical information on 18 patients from whom this organism was isolated. The majority of the patients were hospitalized and had a history of prolonged treatment with broad-spectrum antimicrobials. In 7 (38.9%) of the 18 cases, the isolates were found to be clinically relevant. The present report also includes detailed data on the biochemical and molecular identification of C. tuberculostearicum, as well as its identification by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). Our data demonstrate that routine biochemical tests do not provide reliable identification of C. tuberculostearicum. MALDI-TOF MS represents a helpful tool for the identification of this species, since all of the strains matched C. tuberculostearicum as the first choice and 58.3% (7/12) of the strains processed with the full extraction protocol generated scores of >2.000. Nevertheless, partial 16S rRNA gene sequencing still represents the gold standard for the identification of this species. Due to the challenging identification of C. tuberculostearicum, we presume that this organism is often misidentified and its clinical relevance is underestimated. The antimicrobial susceptibility profile of C. tuberculostearicum presented here reveals that 14 (87.5%) of the 16 strains analyzed exhibited multidrug resistance. PMID:22593594

Cell-surface central nervous system autoantibodies: Clinical relevance and emerging paradigms

PubMed Central

Irani, Sarosh R; Gelfand, Jeffrey M; Al-Diwani, Adam; Vincent, Angela

2014-01-01

The recent discovery of several potentially pathogenic autoantibodies has helped identify patients with clinically distinctive central nervous system diseases that appear to benefit from immunotherapy. The associated autoantibodies are directed against the extracellular domains of cell-surface–expressed neuronal or glial proteins such as LGI1, N-methyl-D-aspartate receptor, and aquaporin-4. The original descriptions of the associated clinical syndromes were phenotypically well circumscribed. However, as availability of antibody testing has increased, the range of associated patient phenotypes and demographics has expanded. This in turn has led to the recognition of more immunotherapy-responsive syndromes in patients presenting with cognitive and behavioral problems, seizures, movement disorders, psychiatric features, and demyelinating disease. Although antibody detection remains diagnostically important, clinical recognition of these distinctive syndromes should ensure early and appropriate immunotherapy administration. We review the emerging paradigm of cell-surface–directed antibody–mediated neurological diseases, describe how the associated disease spectrums have broadened since the original descriptions, discuss some of the methodological issues regarding techniques for antibody detection and emphasize considerations surrounding immunotherapy administration. As these disorders continue to reach mainstream neurology and even psychiatry, more cell-surface–directed antibodies will be discovered, and their possible relevance to other more common disease presentations should become more clearly defined. PMID:24930434

Probing consciousness with event-related potentials in the vegetative state

PubMed Central

Faugeras, F.; Rohaut, B.; Weiss, N.; Bekinschtein, T.A.; Galanaud, D.; Puybasset, L.; Bolgert, F.; Sergent, C.; Cohen, L.; Dehaene, S.

2011-01-01

Objective: Probing consciousness in noncommunicating patients is a major medical and neuroscientific challenge. While standardized and expert behavioral assessment of patients constitutes a mandatory step, this clinical evaluation stage is often difficult and doubtful, and calls for complementary measures which may overcome its inherent limitations. Several functional brain imaging methods are currently being developed within this perspective, including fMRI and cognitive event-related potentials (ERPs). We recently designed an original rule extraction ERP test that is positive only in subjects who are conscious of the long-term regularity of auditory stimuli. Methods: In the present work, we report the results of this test in a population of 22 patients who met clinical criteria for vegetative state. Results: We identified 2 patients showing this neural signature of consciousness. Interestingly, these 2 patients showed unequivocal clinical signs of consciousness within the 3 to 4 days following ERP recording. Conclusions: Taken together, these results strengthen the relevance of bedside neurophysiological tools to improve diagnosis of consciousness in noncommunicating patients. PMID:21593438

MicroRNAs as New Biomarkers for Diagnosis and Prognosis, and as Potential Therapeutic Targets in Acute Myeloid Leukemia

PubMed Central

Trino, Stefania; Caivano, Antonella; Laurenzana, Ilaria; Tagliaferri, Daniela; Falco, Geppino; Del Vecchio, Luigi; Musto, Pellegrino; De Luca, Luciana

2018-01-01

Acute myeloid leukemias (AML) are clonal disorders of hematopoietic progenitor cells which are characterized by relevant heterogeneity in terms of phenotypic, genotypic, and clinical features. Among the genetic aberrations that control disease development there are microRNAs (miRNAs). miRNAs are small non-coding RNAs that regulate, at post-transcriptional level, translation and stability of mRNAs. It is now established that deregulated miRNA expression is a prominent feature in AML. Functional studies have shown that miRNAs play an important role in AML pathogenesis and miRNA expression signatures are associated with chemotherapy response and clinical outcome. In this review we summarized miRNA signature in AML with different cytogenetic, molecular and clinical characteristics. Moreover, we reviewed the miRNA regulatory network in AML pathogenesis and we discussed the potential use of cellular and circulating miRNAs as biomarkers for diagnosis and prognosis and as therapeutic targets. PMID:29401684

Biomedically relevant circuit-design strategies in mammalian synthetic biology

PubMed Central

Bacchus, William; Aubel, Dominique; Fussenegger, Martin

2013-01-01

The development and progress in synthetic biology has been remarkable. Although still in its infancy, synthetic biology has achieved much during the past decade. Improvements in genetic circuit design have increased the potential for clinical applicability of synthetic biology research. What began as simple transcriptional gene switches has rapidly developed into a variety of complex regulatory circuits based on the transcriptional, translational and post-translational regulation. Instead of compounds with potential pharmacologic side effects, the inducer molecules now used are metabolites of the human body and even members of native cell signaling pathways. In this review, we address recent progress in mammalian synthetic biology circuit design and focus on how novel designs push synthetic biology toward clinical implementation. Groundbreaking research on the implementation of optogenetics and intercellular communications is addressed, as particularly optogenetics provides unprecedented opportunities for clinical application. Along with an increase in synthetic network complexity, multicellular systems are now being used to provide a platform for next-generation circuit design. PMID:24061539

An 'integrative neuroscience' perspective on ADHD: linking cognition, emotion, brain and genetic measures with implications for clinical support.

PubMed

Williams, Leanne M; Tsang, Tracey W; Clarke, Simon; Kohn, Michael

2010-10-01

There remains a translational gap between research findings and their implementation in clinical practice that applies to attention-deficit/hyperactivity disorder (ADHD), as well as to other major disorders of brain health in childhood, adolescence and adulthood. Research studies have identified potential 'markers' to support diagnostic, functional assessment and treatment decisions, but there is little consensus about these markers. Of these potential markers, cognitive measures of thinking functions, such as sustaining attention and associated electrical brain activity, show promise in complementing the clinical management process. Emerging evidence highlights the relevance of emotional, as well as thinking, functions to ADHD. Here, we outline an integrative neuroscience framework for ADHD that offers one means to bring together cognitive measures of thinking functions with measures of emotion, and their brain and genetic correlates. Understanding these measures and the relationships between them is a first step towards the development of tools that will help to assess the heterogeneity of ADHD, and aid in tailoring treatment choices.

Clinical Applications of Hallucinogens: A Review

PubMed Central

Garcia-Romeu, Albert; Kersgaard, Brennan; Addy, Peter H.

2016-01-01

Hallucinogens fall into several different classes, as broadly defined by pharmacological mechanism of action, and chemical structure. These include psychedelics, entactogens, dissociatives, and other atypical hallucinogens. Although these classes do not share a common primary mechanism of action, they do exhibit important similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes. Such effects likely contribute to their recreational use. However, a growing body of evidence indicates that these drugs may have therapeutic applications beyond their potential for abuse. This review will present data on several classes of hallucinogens with a particular focus on psychedelics, entactogens, and dissociatives, for which clinical utility has been most extensively documented. Information on each class is presented in turn, tracing relevant historical insights, highlighting similarities and differences between the classes from the molecular to the behavioral level, and presenting the most up-to-date information on clinically oriented research with these substances, with important ramifications for their potential therapeutic value. PMID:27454674

Reprogramming the tumor microenvironment to enhance adoptive cellular therapy.

PubMed

Beavis, Paul A; Slaney, Clare Y; Kershaw, Michael H; Gyorki, David; Neeson, Paul J; Darcy, Phillip K

2016-02-01

The frontiers of cancer immunotherapy are extending in terms of both the range of cancer types that can potentially be targeted and the types of therapeutics that are in clinical development. The use of adoptive cellular therapy (ACT) and its derivative, chimeric antigen receptor (CAR) T cells, is currently limited to hematological malignancies and immunogenic cancers such as melanoma and renal cell carcinoma. Although ACT utilizing ex vivo expanded tumor-infiltrating lymphocytes (TIL) or engineered CAR/TCR T cells have undergone clinical trials for other solid cancers, their efficacy to date has been limited. This may be due, in part, to the immunosuppressive nature of the tumor microenvironment. The development of novel combination approaches which target the immunosuppressive network engineered by tumors has raised the possibility of using ACT for a broader range of cancers. This review summarizes the potential of such strategies and outlines the clinical relevance of these observations. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evolving paradigms in multifocal breast cancer.

PubMed

Salgado, Roberto; Aftimos, Philippe; Sotiriou, Christos; Desmedt, Christine

2015-04-01

The 7th edition of the TNM defines multifocal breast cancer as multiple simultaneous ipsilateral and synchronous breast cancer lesions, provided they are macroscopically distinct and measurable using current traditional pathological and clinical tools. According to the College of American Pathologists (CAP), the characterization of only the largest lesion is considered sufficient, unless the grade and/or histology are different between the lesions. Here, we review three potentially clinically relevant aspects of multifocal breast cancers: first, the importance of a different intrinsic breast cancer subtype of the various lesions; second, the emerging awareness of inter-lesion heterogeneity; and last but not least, the potential introduction of bias in clinical trials due to the unrecognized biological diversity of these cancers. Although the current strategy to assess the lesion with the largest diameter has clearly its advantages in terms of costs and feasibility, this recommendation may not be sustainable in time and might need to be adapted to be compliant with new evolving paradigms in breast cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

Prostate Stem Cell Antigen: A Prospective Therapeutic and Diagnostic Target

PubMed Central

Raff, Adam B.; Gray, Andrew; Kast, W. Martin

2009-01-01

The development of novel clinical tools to combat cancer is an intense field of research and recent efforts have been directed at the identification of proteins that may provide diagnostic, prognostic and/or therapeutic applications due to their restricted expression. To date, a number of protein candidates have emerged as potential clinical tools in the treatment of prostate cancer. Discovered over ten year ago, prostate stem cell antigen (PSCA) is a cell surface antigen that belongs to the Ly-6/Thy-1 family of glycosylphosphatidylinositol-anchored proteins. PSCA is highly overexpressed in human prostate cancer, with limited expression in normal tissues, making it an ideal target for both diagnosis and therapy. Several studies have now clearly correlated the expression of PSCA with relevant clinical benchmarks, such as Gleason score and metastasis, while others have demonstrated the efficacy of PSCA targeting in treatment through various modalities. The purpose of this review is to present the current body of knowledge about PSCA and its potential role in the treatment of human prostate cancer. PMID:18838214

Leap motion evaluation for assessment of upper limb motor skills in Parkinson's disease.

PubMed

Butt, A H; Rovini, E; Dolciotti, C; Bongioanni, P; De Petris, G; Cavallo, F

2017-07-01

The main goal of this study is to investigate the potential of the Leap Motion Controller (LMC) for the objective assessment of motor dysfunctioning in patients with Parkinson's disease (PwPD). The most relevant clinical signs in Parkinson's Disease (PD), such as slowness of movements, frequency variation, amplitude variation, and speed, were extracted from the recorded LMC data. Data were clinically quantified using the LMC software development kit (SDK). In this study, 16 PwPD subjects and 12 control healthy subjects were involved. A neurologist assessed the subjects during the task execution, assigning them a score according to the MDS/UPDRS-Section III items. Features of motor performance from both subject groups (patients and healthy controls) were extracted with dedicated algorithms. Furthermore, to find out the significance of such features from the clinical point of view, machine learning based methods were used. Overall, our findings showed the moderate potential of LMC to extract the motor performance of PwPD.

A Narrative Review of Lumbar Fusion Surgery With Relevance to Chiropractic Practice.

PubMed

Daniels, Clinton J; Wakefield, Pamela J; Bub, Glenn A; Toombs, James D

2016-12-01

The purpose of this narrative review was to describe the most common spinal fusion surgical procedures, address the clinical indications for lumbar fusion in degeneration cases, identify potential complications, and discuss their relevance to chiropractic management of patients after surgical fusion. The PubMed database was searched from the beginning of the record through March 31, 2015, for English language articles related to lumbar fusion or arthrodesis or both and their incidence, procedures, complications, and postoperative chiropractic cases. Articles were retrieved and evaluated for relevance. The bibliographies of selected articles were also reviewed. The most typical lumbar fusion procedures are posterior lumbar interbody fusion, anterior lumbar interbody fusion, transforaminal interbody fusion, and lateral lumbar interbody fusion. Fair level evidence supports lumbar fusion procedures for degenerative spondylolisthesis with instability and for intractable low back pain that has failed conservative care. Complications and development of chronic pain after surgery is common, and these patients frequently present to chiropractic physicians. Several reports describe the potential benefit of chiropractic management with spinal manipulation, flexion-distraction manipulation, and manipulation under anesthesia for postfusion low back pain. There are no published experimental studies related specifically to chiropractic care of postfusion low back pain. This article describes the indications for fusion, common surgical practice, potential complications, and relevant published chiropractic literature. This review includes 10 cases that showed positive benefits from chiropractic manipulation, flexion-distraction, and/or manipulation under anesthesia for postfusion lumbar pain. Chiropractic care may have a role in helping patients in pain who have undergone lumbar fusion surgery.

The impact of patents on the development of genome-based clinical diagnostics: an analysis of case studies

PubMed Central

Pierce, Brandon L.; Carlson, Christopher S.; Kuszler, Patricia C.; Stanford, Janet L.; Austin, Melissa A.

2010-01-01

Purpose Fragmented ownership of diagnostic gene patents has the potential to create an ‘anticommons’ in the area of genomic diagnostics, making it difficult and expensive to assemble the patent rights necessary to develop a panel of genetic tests. The objectives of this study were to identify U.S. patents that protect existing panels of genetic tests, describe how (or if) test providers acquired rights to these patents, and determine if fragmented patent ownership has inhibited the commercialization of these panels. Methods As case studies, we selected four clinical applications of genetic testing (cystic fibrosis, maturity-onset diabetes of the young, long QT syndrome, and hereditary breast cancer) that utilize tests protected by ≥3 U.S. patents. We summarized publically available information on relevant patents, test providers, licenses, and litigation. Results For each case study, all tests of major genes/mutations were patented, and at least one party held the collective rights to conduct all relevant tests, often as a result of licensing agreements. Conclusions We did not find evidence that fragmentation of patent rights has inhibited commercialization of genetic testing services. However, as knowledge of genetic susceptibility increases, it will be important to consider the potential consequences of fragmented ownership of diagnostic gene patents. PMID:19367193

Tumors Alter Inflammation and Impair Dermal Wound Healing in Female Mice

PubMed Central

Pyter, Leah M.; Husain, Yasmin; Calero, Humberto; McKim, Daniel B.; Lin, Hsin-Yun; Godbout, Jonathan P.; Sheridan, John F.; Engeland, Christopher G.; Marucha, Phillip T.

2016-01-01

Tissue repair is an integral component of cancer treatment (e.g., due to surgery, chemotherapy, radiation). Previous work has emphasized the immunosuppressive effects of tumors on adaptive immunity and has shown that surgery incites cancer metastases. However, the extent to which and how tumors may alter the clinically-relevant innate immune process of wound healing remains an untapped potential area of improvement for treatment, quality of life, and ultimately, mortality of cancer patients. In this study, 3.5 mm full-thickness dermal excisional wounds were placed on the dorsum of immunocompetent female mice with and without non-malignant flank AT-84 murine oral squamous cell carcinomas. Wound closure rate, inflammatory cell number and inflammatory signaling in wounds, and circulating myeloid cell concentrations were compared between tumor-bearing and tumor-free mice. Tumors delayed wound closure, suppressed inflammatory signaling, and altered myeloid cell trafficking in wounds. An in vitro scratch “wounding” assay of adult dermal fibroblasts treated with tumor cell-conditioned media supported the in vivo findings. This study demonstrates that tumors are sufficient to disrupt fundamental and clinically-relevant innate immune functions. The understanding of these underlying mechanisms provides potential for therapeutic interventions capable of improving the treatment of cancer while reducing morbidities and mortality. PMID:27548621

Systematic reviews of complementary therapies – an annotated bibliography. Part 3: Homeopathy

PubMed Central

Linde, Klaus; Hondras, Maria; Vickers, Andrew; Riet, Gerben ter; Melchart, Dieter

2001-01-01

Background Complementary therapies are widespread but controversial. We aim to provide a comprehensive collection and a summary of systematic reviews of clinical trials in three major complementary therapies (acupuncture, herbal medicine, homeopathy). This article is dealing with homeopathy. Potentially relevant reviews were searched through the register of the Cochrane Complementary Medicine Field, the Cochrane Library, Medline, and bibliographies of articles and books. To be included articles had to review prospective clinical trials of homeopathy; had to describe review methods explicitly; had to be published; and had to focus on treatment effects. Information on conditions, interventions, methods, results and conclusions was extracted using a pretested form and summarized descriptively. Results Eighteen out of 22 potentially relevant reviews preselected in the screening process met the inclusion criteria. Six reviews addressed the question whether homeopathy is effective across conditions and interventions. The majority of available trials seem to report positive results but the evidence is not convincing. For isopathic nosodes for allergic conditions, oscillococcinum for influenza-like syndromes and galphimia for pollinosis the evidence is promising while in other areas reviewed the results are equivocal. Interpretation Reviews on homeopathy often address general questions. While the evidence is promising for some topics the findings of the available reviews are unlikely to end the controversy on this therapy. PMID:11527508

Trustworthiness and relevance in web-based clinical question answering.

PubMed

Cruchet, Sarah; Boyer, Célia; van der Plas, Lonneke

2012-01-01

Question answering systems try to give precise answers to a user's question posed in natural language. It is of utmost importance that the answers returned are relevant to the user's question. For clinical QA, the trustworthiness of answers is another important issue. Limiting the document collection to certified websites helps to improve the trustworthiness of answers. On the other hand, limited document collections are known to harm the relevancy of answers. We show, however, in a comparative evaluation, that promoting trustworthiness has no negative effect on the relevance of the retrieved answers in our clinical QA system. On the contrary, the answers found are in general more relevant.

Comparison of gesture and conventional interaction techniques for interventional neuroradiology.

PubMed

Hettig, Julian; Saalfeld, Patrick; Luz, Maria; Becker, Mathias; Skalej, Martin; Hansen, Christian

2017-09-01

Interaction with radiological image data and volume renderings within a sterile environment is a challenging task. Clinically established methods such as joystick control and task delegation can be time-consuming and error-prone and interrupt the workflow. New touchless input modalities may have the potential to overcome these limitations, but their value compared to established methods is unclear. We present a comparative evaluation to analyze the value of two gesture input modalities (Myo Gesture Control Armband and Leap Motion Controller) versus two clinically established methods (task delegation and joystick control). A user study was conducted with ten experienced radiologists by simulating a diagnostic neuroradiological vascular treatment with two frequently used interaction tasks in an experimental operating room. The input modalities were assessed using task completion time, perceived task difficulty, and subjective workload. Overall, the clinically established method of task delegation performed best under the study conditions. In general, gesture control failed to exceed the clinical input approach. However, the Myo Gesture Control Armband showed a potential for simple image selection task. Novel input modalities have the potential to take over single tasks more efficiently than clinically established methods. The results of our user study show the relevance of task characteristics such as task complexity on performance with specific input modalities. Accordingly, future work should consider task characteristics to provide a useful gesture interface for a specific use case instead of an all-in-one solution.

Emerging Applications of Stem Cell and Regenerative Medicine to Sports Injuries

PubMed Central

Ajibade, David A.; Vance, Danica D.; Hare, Joshua M.; Kaplan, Lee D.; Lesniak, Bryson P.

2014-01-01

Background: The treatment of sports-related musculoskeletal injuries with stem cells has become more publicized because of recent reports of high-profile athletes undergoing stem cell procedures. There has been increased interest in defining the parameters of safety and efficacy and the indications for potential use of stem cells in clinical practice. Purpose: To review the role of regenerative medicine in the treatment of sports-related injuries. Study Design: Review. Method: Relevant studies were identified through a PubMed search combining the terms stem cells and cartilage, ligament, tendon, muscle, and bone from January 2000 to August 2013. Studies and works cited in these studies were also reviewed. Results: Treatment of sports-related injuries with stem cells shows potential for clinical efficacy from the data available from basic science and animal studies. Conclusion: Cell-based therapies and regenerative medicine offer safe and potentially efficacious treatment for sports-related musculoskeletal injuries. Basic science and preclinical studies that support the possibility of enhanced recovery from sports injuries using cell-based therapies are accumulating; however, more clinical evidence is necessary to define the indications and parameters for their use. Accordingly, exposing patients to cell-based therapies could confer an unacceptable risk profile with minimal or no benefit. Continued clinical testing with animal models and clinical trials is necessary to determine the relative risks and benefits as well as the indications and methodology of treatment. PMID:26535296

Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement

PubMed Central

Bianco, Antonio C.; Bauer, Andrew J.; Burman, Kenneth D.; Cappola, Anne R.; Celi, Francesco S.; Cooper, David S.; Kim, Brian W.; Peeters, Robin P.; Rosenthal, M. Sara; Sawka, Anna M.

2014-01-01

Background: A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. Methods: Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force. Results: We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non–levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones. Conclusions: We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine–liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potential therapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (including subgroup effects). Additional research is also needed to develop thyroid hormone analogs with a favorable benefit to risk profile. PMID:25266247

Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement.

PubMed

Jonklaas, Jacqueline; Bianco, Antonio C; Bauer, Andrew J; Burman, Kenneth D; Cappola, Anne R; Celi, Francesco S; Cooper, David S; Kim, Brian W; Peeters, Robin P; Rosenthal, M Sara; Sawka, Anna M

2014-12-01

A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force. We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non-levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones. We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine-liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potential therapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (including subgroup effects). Additional research is also needed to develop thyroid hormone analogs with a favorable benefit to risk profile.

Recent advances in targeting protein arginine methyltransferase enzymes in cancer therapy.

PubMed

Smith, Emily; Zhou, Wei; Shindiapina, Polina; Sif, Said; Li, Chenglong; Baiocchi, Robert A

2018-05-21

Exploration in the field of epigenetics has revealed the diverse roles of the protein arginine methyltransferase (PRMT) family of proteins in multiple disease states. These findings have led to the development of specific inhibitors and discovery of several new classes of drugs with potential to treat both benign and malignant conditions. Areas covered: We provide an overview on the role of PRMT enzymes in healthy and malignant cells, highlighting the role of arginine methylation in specific pathways relevant to cancer pathogenesis. Additionally, we describe structure and catalytic activity of PRMT and discuss the mechanisms of action of novel small molecule inhibitors of specific members of the arginine methyltransferase family. Expert opinion: As the field of PRMT biology advances, it's becoming clear that this class of enzymes is highly relevant to maintaining normal physiologic processes as well and disease pathogenesis. We discuss the potential impact of PRMT inhibitors as a broad class of drugs, including the pleiotropic effects, off target effects the need for more detailed PRMT-centric interactomes, and finally, the potential for targeting this class of enzymes in clinical development of experimental therapeutics for cancer.

DTI measures identify mild and moderate TBI cases among patients with complex health problems: A receiver operating characteristic analysis of U.S. veterans.

PubMed

Main, Keith L; Soman, Salil; Pestilli, Franco; Furst, Ansgar; Noda, Art; Hernandez, Beatriz; Kong, Jennifer; Cheng, Jauhtai; Fairchild, Jennifer K; Taylor, Joy; Yesavage, Jerome; Wesson Ashford, J; Kraemer, Helena; Adamson, Maheen M

2017-01-01

Standard MRI methods are often inadequate for identifying mild traumatic brain injury (TBI). Advances in diffusion tensor imaging now provide potential biomarkers of TBI among white matter fascicles (tracts). However, it is still unclear which tracts are most pertinent to TBI diagnosis. This study ranked fiber tracts on their ability to discriminate patients with and without TBI. We acquired diffusion tensor imaging data from military veterans admitted to a polytrauma clinic (Overall n  = 109; Age: M  = 47.2, SD  = 11.3; Male: 88%; TBI: 67%). TBI diagnosis was based on self-report and neurological examination. Fiber tractography analysis produced 20 fiber tracts per patient. Each tract yielded four clinically relevant measures (fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity). We applied receiver operating characteristic (ROC) analyses to identify the most diagnostic tract for each measure. The analyses produced an optimal cutpoint for each tract. We then used kappa coefficients to rate the agreement of each cutpoint with the neurologist's diagnosis. The tract with the highest kappa was most diagnostic. As a check on the ROC results, we performed a stepwise logistic regression on each measure using all 20 tracts as predictors. We also bootstrapped the ROC analyses to compute the 95% confidence intervals for sensitivity, specificity, and the highest kappa coefficients. The ROC analyses identified two fiber tracts as most diagnostic of TBI: the left cingulum (LCG) and the left inferior fronto-occipital fasciculus (LIF). Like ROC, logistic regression identified LCG as most predictive for the FA measure but identified the right anterior thalamic tract (RAT) for the MD, RD, and AD measures. These findings are potentially relevant to the development of TBI biomarkers. Our methods also demonstrate how ROC analysis may be used to identify clinically relevant variables in the TBI population.

Creation of a Bioengineered Skin Flap Scaffold with a Perfusable Vascular Pedicle.

PubMed

Jank, Bernhard J; Goverman, Jeremy; Guyette, Jacques P; Charest, Jon M; Randolph, Mark; Gaudette, Glenn R; Gershlak, Joshua R; Purschke, Martin; Javorsky, Emilia; Nazarian, Rosalynn M; Leonard, David A; Cetrulo, Curtis L; Austen, William G; Ott, Harald C

2017-07-01

Full-thickness skin loss is a challenging problem due to limited reconstructive options, demanding 75 million surgical procedures annually in the United States. Autologous skin grafting is the gold standard treatment, but results in donor-site morbidity and poor aesthetics. Numerous skin substitutes are available on the market to date, however, none truly functions as full-thickness skin due to lack of a vascular network. The creation of an autologous full-thickness skin analogue with a vascular pedicle would result in a paradigm shift in the management of wounds and in reconstruction of full-thickness skin defects. To create a clinically relevant foundation, we generated an acellular skin flap scaffold (SFS) with a perfusable vascular pedicle of clinically relevant size by perfusion decellularization of porcine fasciocutaneous flaps. We then analyzed the yielded SFS for mechanical properties, biocompatibility, and regenerative potential in vitro and in vivo. Furthermore, we assessed the immunological response using an in vivo model. Finally, we recellularized the vascular compartment of an SFS and reconnected it to a recipient's blood supply to test for perfusability. Perfusion decellularization removed all cellular components with preservation of native extracellular matrix composition and architecture. Biaxial testing revealed preserved mechanical properties. Immunologic response and biocompatibility assessed via implantation and compared with native xenogenic skin and commercially available dermal substitutes revealed rapid neovascularization and complete tissue integration. Composition of infiltrating immune cells showed no evidence of allorejection and resembled the inflammatory phase of wound healing. Implantation into full-thickness skin defects demonstrated good tissue integration and skin regeneration without cicatrization. We have developed a protocol for the generation of an SFS of clinically relevant size, containing a vascular pedicle, which can be utilized for perfusion decellularization and, ultimately, anastomosis to the recipient vascular system after precellularization. The observed favorable immunological response and good tissue integration indicate the substantial regenerative potential of this platform.

Resected Brain Tissue, Seizure Onset Zone and Quantitative EEG Measures: Towards Prediction of Post-Surgical Seizure Control

PubMed Central

Andrzejak, Ralph G.; Hauf, Martinus; Pollo, Claudio; Müller, Markus; Weisstanner, Christian; Wiest, Roland; Schindler, Kaspar

2015-01-01

Background Epilepsy surgery is a potentially curative treatment option for pharmacoresistent patients. If non-invasive methods alone do not allow to delineate the epileptogenic brain areas the surgical candidates undergo long-term monitoring with intracranial EEG. Visual EEG analysis is then used to identify the seizure onset zone for targeted resection as a standard procedure. Methods Despite of its great potential to assess the epileptogenicty of brain tissue, quantitative EEG analysis has not yet found its way into routine clinical practice. To demonstrate that quantitative EEG may yield clinically highly relevant information we retrospectively investigated how post-operative seizure control is associated with four selected EEG measures evaluated in the resected brain tissue and the seizure onset zone. Importantly, the exact spatial location of the intracranial electrodes was determined by coregistration of pre-operative MRI and post-implantation CT and coregistration with post-resection MRI was used to delineate the extent of tissue resection. Using data-driven thresholding, quantitative EEG results were separated into normally contributing and salient channels. Results In patients with favorable post-surgical seizure control a significantly larger fraction of salient channels in three of the four quantitative EEG measures was resected than in patients with unfavorable outcome in terms of seizure control (median over the whole peri-ictal recordings). The same statistics revealed no association with post-operative seizure control when EEG channels contributing to the seizure onset zone were studied. Conclusions We conclude that quantitative EEG measures provide clinically relevant and objective markers of target tissue, which may be used to optimize epilepsy surgery. The finding that differentiation between favorable and unfavorable outcome was better for the fraction of salient values in the resected brain tissue than in the seizure onset zone is consistent with growing evidence that spatially extended networks might be more relevant for seizure generation, evolution and termination than a single highly localized brain region (i.e. a “focus”) where seizures start. PMID:26513359

A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients

PubMed Central

Zandvliet, Maarten L.; Koolen, Stijn L. W.; Mathijssen, Ron H. J.; van der Rijt, Carin C. D.

2016-01-01

Fentanyl is a strong opioid that is available for various administration routes, and which is widely used to treat cancer‐related pain. Many factors influence the fentanyl pharmacokinetics leading to a wide inter‐ and intrapatient variability. This systematic review summarizes multiple studied factors that potentially influence fentanyl pharmacokinetics with a focus on implications for cancer patients. The use of CYP3A4 inhibitors and inducers, impaired liver function, and heating of the patch potentially influence fentanyl pharmacokinetics in a clinically relevant way. In elderly patients, current data suggest that we should carefully dose fentanyl due to alterations in absorption and metabolism. The influence of BMI and gender on fentanyl pharmacokinetics is questionable, most probably due to a large heterogeneity in the published studies. Pharmacogenetics, e.g. the CYP3A5*3 gene polymorphism, may influence fentanyl pharmacokinetics as well, although further study is warranted. Several other factors have been studied but did not show significant and clinically relevant effects on fentanyl pharmacokinetics. Unfortunately, most of the published papers that studied factors influencing fentanyl pharmacokinetics describe healthy volunteers instead of cancer patients. Results from the studies in volunteers may not be simply extrapolated to cancer patients because of multiple confounding factors. To handle fentanyl treatment in a population of cancer patients, it is essential that physicians recognize factors that influence fentanyl pharmacokinetics, thereby preventing potential side‐effects and increasing its efficacy. PMID:27619152

Current evidence of peripheral vestibular symptoms secondary to otitis media.

PubMed

Monsanto, Rafael da Costa; Kasemodel, Ana Luiza Papi; Tomaz, Andreza; Paparella, Michael M; Penido, Norma de Oliveira

2018-05-06

The association between otitis media and vestibular symptoms has been hypothesized in the past. Thus, in this study, we aimed to critically analyze (based in a systematic review of the literature) whether patients who have otitis media are at greater risk of developing vestibular impairment or not. We performed a systematic review of the literature and identified potentially relevant articles reporting vestibular symptoms and results of vestibular function tests in patients with otitis media through searches of the PubMED, Web of Science, Scopus, and Google Scholar databases. The quality of the final set of records was assessed using the "Newcaste-Ottawa Scale". Of the 2334 records searched, 43 met our inclusion and exclusion criteria, and those included 2250 patients. The records comprised 20 longitudinal studies, 21 cross-sectional studies, and 2 case reports. Regarding the type of otitis media studied, 25 examined vestibular impairment in otitis media with effusion, 6 acute otitis media, and 12 chronic otitis media. Results of anamnesis, clinical exams, and several vestibular function tests are reported and critically discussed. Most studies evaluating the association between otitis media and vestibular symptoms have potential methodological flaws. Clinical evidence suggests that patients with otitis media have increased chances for having vestibular symptoms, delayed acquisition of developmental milestones, and abnormalities in several vestibular function tests as compared with controls. Future studies with rigorous methodology aiming to assess the clinical significance (and prognostic factors) of the association between otitis media and vestibular impairment are warranted. Key message Several studies demonstrated long-term sequelae secondary to otitis media. However, the evidence supporting those assumptions are based in low-quality evidence. Thus, better structured studies are warranted to better understand the clinical relevance of such association.

Recurrence, submicroscopic complexity, and potential clinical relevance of copy gains detected by array CGH that are shown to be unbalanced insertions by FISH.

PubMed

Neill, Nicholas J; Ballif, Blake C; Lamb, Allen N; Parikh, Sumit; Ravnan, J Britt; Schultz, Roger A; Torchia, Beth S; Rosenfeld, Jill A; Shaffer, Lisa G

2011-04-01

Insertions occur when a segment of one chromosome is translocated and inserted into a new region of the same chromosome or a non-homologous chromosome. We report 71 cases with unbalanced insertions identified using array CGH and FISH in 4909 cases referred to our laboratory for array CGH and found to have copy-number abnormalities. Although the majority of insertions were non-recurrent, several recurrent unbalanced insertions were detected, including three der(Y)ins(Y;18)(q?11.2;p11.32p11.32)pat inherited from parents carrying an unbalanced insertion. The clinical significance of these recurrent rearrangements is unclear, although the small size, limited gene content, and inheritance pattern of each suggests that the phenotypic consequences may be benign. Cryptic, submicroscopic duplications were observed at or near the insertion sites in two patients, further confounding the clinical interpretation of these insertions. Using FISH, linear amplification, and array CGH, we identified a 126-kb duplicated region from 19p13.3 inserted into MECP2 at Xq28 in a patient with symptoms of Rett syndrome. Our results demonstrate that although the interpretation of most non-recurrent insertions is unclear without high-resolution insertion site characterization, the potential for an otherwise benign duplication to result in a clinically relevant outcome through the disruption of a gene necessitates the use of FISH to determine whether copy-number gains detected by array CGH represent tandem duplications or unbalanced insertions. Further follow-up testing using techniques such as linear amplification or sequencing should be used to determine gene involvement at the insertion site after FISH has identified the presence of an insertion.

The use and impact of quality of life assessment tools in clinical care settings for cancer patients, with a particular emphasis on brain cancer: insights from a systematic review and stakeholder consultations.

PubMed

King, Sarah; Exley, Josephine; Parks, Sarah; Ball, Sarah; Bienkowska-Gibbs, Teresa; MacLure, Calum; Harte, Emma; Stewart, Katherine; Larkin, Jody; Bottomley, Andrew; Marjanovic, Sonja

2016-09-01

Patient-reported data are playing an increasing role in health care. In oncology, data from quality of life (QoL) assessment tools may be particularly important for those with limited survival prospects, where treatments aim to prolong survival while maintaining or improving QoL. This paper examines the use and impact of using QoL measures on health care of cancer patients within a clinical setting, particularly those with brain cancer. It also examines facilitators and challenges, and provides implications for policy and practice. We conducted a systematic literature review, 15 expert interviews and a consultation at an international summit. The systematic review found no relevant intervention studies specifically in brain cancer patients, and after expanding our search to include other cancers, 15 relevant studies were identified. The evidence on the effectiveness of using QoL tools was inconsistent for patient management, but somewhat more consistent in favour of improving patient-physician communication. Interviews identified unharnessed potential and growing interest in QoL tool use and associated challenges to address. Our findings suggest that the use of QoL tools in cancer patients may improve patient-physician communication and have the potential to improve care, but the tools are not currently widely used in clinical practice (in brain cancer nor some other cancer contexts) although they are in clinical trials. There is a need for further research and stakeholder engagement on how QoL tools can achieve most impact across cancer and patient contexts. There is also a need for policy, health professional, research and patient communities to strengthen information exchange and debate, support awareness raising and provide training on tool design, use and interpretation.

A mouse diversity panel approach reveals the potential for clinical kidney injury due to DB289 not predicted by classical rodent models.

PubMed

Harrill, Alison H; Desmet, Kristina D; Wolf, Kristina K; Bridges, Arlene S; Eaddy, J Scott; Kurtz, C Lisa; Hall, J Ed; Paine, Mary F; Tidwell, Richard R; Watkins, Paul B

2012-12-01

DB289 is the first oral drug shown in clinical trials to have efficacy in treating African trypanosomiasis (African sleeping sickness). Mild liver toxicity was noted but was not treatment limiting. However, development of DB289 was terminated when several treated subjects developed severe kidney injury, a liability not predicted from preclinical testing. We tested the hypothesis that the kidney safety liability of DB289 would be detected in a mouse diversity panel (MDP) comprised of 34 genetically diverse inbred mouse strains. MDP mice received 10 days of oral treatment with DB289 or vehicle and classical renal biomarkers blood urea nitrogen (BUN) and serum creatinine (sCr), as well as urine biomarkers of kidney injury were measured. While BUN and sCr remained within reference ranges, marked elevations were observed for kidney injury molecule-1 (KIM-1) in the urine of sensitive mouse strains. KIM-1 elevations were not always coincident with elevations in alanine aminotransferase (ALT), suggesting that renal injury was not linked to hepatic injury. Genome-wide association analyses of KIM-1 elevations indicated that genes participating in cholesterol and lipid biosynthesis and transport, oxidative stress, and cytokine release may play a role in DB289 renal injury. Taken together, the data resulting from this study highlight the utility of using an MDP to predict clinically relevant toxicities, to identify relevant toxicity biomarkers that may translate into the clinic, and to identify potential mechanisms underlying toxicities. In addition, the sensitive mouse strains identified in this study may be useful in screening next-in-class compounds for renal injury.

Battery-free, wireless sensors for full-body pressure and temperature mapping

PubMed Central

Han, Seungyong; Kim, Jeonghyun; Won, Sang Min; Ma, Yinji; Kang, Daeshik; Xie, Zhaoqian; Lee, Kyu-Tae; Chung, Ha Uk; Banks, Anthony; Min, Seunghwan; Heo, Seung Yun; Davies, Charles R.; Lee, Jung Woo; Lee, Chi-Hwan; Kim, Bong Hoon; Li, Kan; Zhou, Yadong; Wei, Chen; Feng, Xue; Huang, Yonggang; Rogers, John A.

2018-01-01

Thin, soft, skin-like sensors capable of precise, continuous measurements of physiological health have broad potential relevance to clinical health care. Use of sensors distributed over a wide area for full-body, spatiotemporal mapping of physiological processes would be a considerable advance for this field. We introduce materials, device designs, wireless power delivery and communication strategies, and overall system architectures for skin-like, battery-free sensors of temperature and pressure that can be used across the entire body. Combined experimental and theoretical investigations of the sensor operation and the modes for wireless addressing define the key features of these systems. Studies with human subjects in clinical sleep laboratories and in adjustable hospital beds demonstrate functionality of the sensors, with potential implications for monitoring of circadian cycles and mitigating risks for pressure-induced skin ulcers. PMID:29618561

Panel 3: Genetics and Precision Medicine of Otitis Media.

PubMed

Lin, Jizhen; Hafrén, Hena; Kerschner, Joseph; Li, Jian-Dong; Brown, Steve; Zheng, Qing Y; Preciado, Diego; Nakamura, Yoshihisa; Huang, Qiuhong; Zhang, Yan

2017-04-01

Objective The objective is to perform a comprehensive review of the literature up to 2015 on the genetics and precision medicine relevant to otitis media. Data Sources PubMed database of the National Library of Medicine. Review Methods Two subpanels were formed comprising experts in the genetics and precision medicine of otitis media. Each of the panels reviewed the literature in their respective fields and wrote draft reviews. The reviews were shared with all panel members, and a merged draft was created. The entire panel met at the 18th International Symposium on Recent Advances in Otitis Media in June 2015 and discussed the review and refined the content. A final draft was made, circulated, and approved by the panel members. Conclusion Many genes relevant to otitis media have been identified in the last 4 years in advancing our knowledge regarding the predisposition of the middle ear mucosa to commensals and pathogens. Advances include mutant animal models and clinical studies. Many signaling pathways are involved in the predisposition of otitis media. Implications for Practice New knowledge on the genetic background relevant to otitis media forms a basis of novel potential interventions, including potential new ways to treat otitis media.

Image acquisition context: procedure description attributes for clinically relevant indexing and selective retrieval of biomedical images.

PubMed

Bidgood, W D; Bray, B; Brown, N; Mori, A R; Spackman, K A; Golichowski, A; Jones, R H; Korman, L; Dove, B; Hildebrand, L; Berg, M

1999-01-01

To support clinically relevant indexing of biomedical images and image-related information based on the attributes of image acquisition procedures and the judgments (observations) expressed by observers in the process of image interpretation. The authors introduce the notion of "image acquisition context," the set of attributes that describe image acquisition procedures, and present a standards-based strategy for utilizing the attributes of image acquisition context as indexing and retrieval keys for digital image libraries. The authors' indexing strategy is based on an interdependent message/terminology architecture that combines the Digital Imaging and Communication in Medicine (DICOM) standard, the SNOMED (Systematized Nomenclature of Human and Veterinary Medicine) vocabulary, and the SNOMED DICOM microglossary. The SNOMED DICOM microglossary provides context-dependent mapping of terminology to DICOM data elements. The capability of embedding standard coded descriptors in DICOM image headers and image-interpretation reports improves the potential for selective retrieval of image-related information. This favorably affects information management in digital libraries.

Ethnic and racial differences in clinically relevant symptoms in active duty military personnel with posttraumatic stress disorder.

PubMed

Kaczkurkin, Antonia N; Asnaani, Anu; Hall-Clark, Brittany; Peterson, Alan L; Yarvis, Jeffrey S; Foa, Edna B

2016-10-01

Previous research has shown racial/ethnic differences in Vietnam veterans on symptoms related to posttraumatic stress disorder (PTSD). The current study explored racial/ethnic differences in PTSD symptoms and clinically relevant symptoms. Resilience and social support were tested as potential moderators of racial/ethnic differences in symptoms. The sample included 303 active duty male service members seeking treatment for PTSD. After controlling for age, education, military grade, and combat exposure, Hispanic/Latino and African American service members reported greater PTSD symptoms compared to non-Hispanic White service members. Higher alcohol consumption was endorsed by Hispanic/Latino service members compared to non-Hispanic White or African American service members, even after controlling for PTSD symptom severity. No racial/ethnic differences were found with regard to other variables. These results suggest that care should be made to thoroughly assess PTSD patients, especially those belonging to minority groups, for concurrent substance use problems that may impede treatment utilization or adherence. Copyright © 2016 Elsevier Ltd. All rights reserved.

Use of Repetitive Transcranial Magnetic Stimulation for Treatment in Psychiatry

PubMed Central

2013-01-01

The potential of noninvasive neurostimulation by repetitive transcranial magnetic stimulation (rTMS) for improving psychiatric disorders has been studied increasingly over the past two decades. This is especially the case for major depression and for auditory-verbal hallucinations in schizophrenia. The present review briefly describes the background of this novel treatment modality and summarizes evidence from clinical trials into the efficacy of rTMS for depression and hallucinations. Evidence for efficacy in depression is stronger than for hallucinations, although a number of studies have reported clinically relevant improvements for hallucinations too. Different stimulation parameters (frequency, duration, location of stimulation) are discussed. There is a paucity of research into other psychiatric disorders, but initial evidence suggests that rTMS may also hold promise for the treatment of negative symptoms in schizophrenia, obsessive compulsive disorder and post-traumatic stress disorder. It can be concluded that rTMS induces alterations in neural networks relevant for psychiatric disorders and that more research is needed to elucidate efficacy and underlying mechanisms of action. PMID:24023548

Use of repetitive transcranial magnetic stimulation for treatment in psychiatry.

PubMed

Aleman, André

2013-08-01

The potential of noninvasive neurostimulation by repetitive transcranial magnetic stimulation (rTMS) for improving psychiatric disorders has been studied increasingly over the past two decades. This is especially the case for major depression and for auditory-verbal hallucinations in schizophrenia. The present review briefly describes the background of this novel treatment modality and summarizes evidence from clinical trials into the efficacy of rTMS for depression and hallucinations. Evidence for efficacy in depression is stronger than for hallucinations, although a number of studies have reported clinically relevant improvements for hallucinations too. Different stimulation parameters (frequency, duration, location of stimulation) are discussed. There is a paucity of research into other psychiatric disorders, but initial evidence suggests that rTMS may also hold promise for the treatment of negative symptoms in schizophrenia, obsessive compulsive disorder and post-traumatic stress disorder. It can be concluded that rTMS induces alterations in neural networks relevant for psychiatric disorders and that more research is needed to elucidate efficacy and underlying mechanisms of action.

Quantum cascade lasers (QCLs) in biomedical spectroscopy.

PubMed

Schwaighofer, Andreas; Brandstetter, Markus; Lendl, Bernhard

2017-10-02

Quantum cascade lasers (QCL) are the first room temperature semiconductor laser source for the mid-IR spectral region, triggering substantial development for the advancement of mid-IR spectroscopy. Mid-IR spectroscopy in general provides rapid, label-free and objective analysis, particularly important in the field of biomedical analysis. Due to their unique properties, QCLs offer new possibilities for development of analytical methods to enable quantification of clinically relevant concentration levels and to support medical diagnostics. Compared to FTIR spectroscopy, novel and elaborated measurement techniques can be implemented that allow miniaturized and portable instrumentation. This review illustrates the characteristics of QCLs with a particular focus on their benefits for biomedical analysis. Recent applications of QCL-based spectroscopy for analysis of a variety of clinically relevant samples including breath, urine, blood, interstitial fluid, and biopsy samples are summarized. Further potential for technical advancements is discussed in combination with future prospects for employment of QCL-based devices in routine and point-of-care diagnostics.

Parenting stress and child behavior problems among clinic-referred youth: cross-cultural differences across the US and Korea.

PubMed

Chung, Kyong-Mee; Ebesutani, Chad; Bang, Hye Min; Kim, Joohee; Chorpita, Bruce F; Weisz, John R; Suh, Dongsoo; Byun, Heejung

2013-06-01

Due to increased multiculturalism in the US and abroad, there is a need for increased understanding of the different ways in which parenting stress is related to child problems across cultures. In the present study, we investigated (a) differences in reported parenting stress and childhood problem behaviors across a Korean (n = 71) and US (n = 71) sample, as well as (b) differences in the ways in which parenting stress and childhood problems were related across Korean and US children based on mothers' reports. Results revealed that Korean mothers reported significantly higher parenting stress yet significantly lower childhood problem behaviors compared to US mothers. In addition, mother-based reports of child problems were significantly associated with parenting stress in the US sample, but not in the Korean sample. Clinical implications and culturally-relevant issues relevant to these findings are addressed, including a potential under-reporting bias of child problems among Asian parents.

Trauma Patient with Fat Embolism Detected on Computed Tomography.

PubMed

Sousa, Isabel; Janeiro, João; Campos, Paula; Távora, Isabel

2017-01-31

Fat embolism is frequent following fractures of long bones, however the development of the clinical syndrome of fat embolism (characterized by progressive respiratory distress, mental status depression and petechial rash) is rare, but relevant because of its potential severity. We report a case of a trauma patient with multiple fractures of the right lower limb in whom an emergency computed tomography scan showed fat emboli within the lumen of the homolateral common femoral vein. The imaging detection of macroscopic fat emboli should alert the clinician to the potential for subsequent fat embolism syndrome.

Bioactive Oligosaccharide Natural Products

PubMed Central

McCranie, Emilianne K.; Bachmann, Brian O.

2016-01-01

Oligosaccharide natural products target a wide spectrum of biological processes including disruption of cell wall biosynthesis, interference of bacterial translation, and inhibition of human α-amylase. Correspondingly, oligosaccharides possess potential for development as treatments of such diverse diseases as bacterial infections and type II diabetes. Despite their potent and selective activities and potential clinical relevance, isolated bioactive secondary metabolic oligosaccharides are less prevalent than other classes of natural products and their biosynthesis has received comparatively less attention. This review highlights the unique modes of action and biosynthesis of four classes of bioactive oligosaccharides: the orthosomycins, moenomycins, saccharomicins, and acarviostatins. PMID:24883430

How good is "evidence" from clinical studies of drug effects and why might such evidence fail in the prediction of the clinical utility of drugs?

PubMed

Naci, Huseyin; Ioannidis, John P A

2015-01-01

Promising evidence from clinical studies of drug effects does not always translate to improvements in patient outcomes. In this review, we discuss why early evidence is often ill suited to the task of predicting the clinical utility of drugs. The current gap between initially described drug effects and their subsequent clinical utility results from deficits in the design, conduct, analysis, reporting, and synthesis of clinical studies-often creating conditions that generate favorable, but ultimately incorrect, conclusions regarding drug effects. There are potential solutions that could improve the relevance of clinical evidence in predicting the real-world effectiveness of drugs. What is needed is a new emphasis on clinical utility, with nonconflicted entities playing a greater role in the generation, synthesis, and interpretation of clinical evidence. Clinical studies should adopt strong design features, reflect clinical practice, and evaluate outcomes and comparisons that are meaningful to patients. Transformative changes to the research agenda may generate more meaningful and accurate evidence on drug effects to guide clinical decision making.

Training interpretation biases among individuals with body dysmorphic disorder symptoms.

PubMed

Premo, Julie E; Sarfan, Laurel D; Clerkin, Elise M

2016-03-01

The current study provided an initial test of a Cognitive Bias Modification for Interpretations (CBM-I) training paradigm among a sample with elevated BDD symptoms (N=86). As expected, BDD-relevant interpretations were reduced among participants who completed a positive (vs. comparison) training program. Results also pointed to the intriguing possibility that modifying biased appearance-relevant interpretations is causally related to changes in biased, socially relevant interpretations. Further, providing support for cognitive behavioral models, residual change in interpretations was associated with some aspects of in vivo stressor responding. However, contrary to expectations there were no significant effects of condition on emotional vulnerability to a BDD stressor, potentially because participants in both training conditions experienced reductions in biased socially-threatening interpretations following training (suggesting that the "comparison" condition was not inert). These findings have meaningful theoretical and clinical implications, and fit with transdiagnostic conceptualizations of psychopathology. Copyright © 2015 Elsevier Ltd. All rights reserved.

Motivating medical students to do research: a mixed methods study using Self-Determination Theory.

PubMed

Rosenkranz, Sara K; Wang, Shaoyu; Hu, Wendy

2015-06-02

It is widely accepted that all medical graduates should understand the uses and methods of rigorous research, with a need to promote research to graduates who will pursue an academic career. This study aimed to explore, identify and explain what motivates and demotivates medical students to do research. A convergent parallel mixed methods study was conducted. Cross-sectional quantitative survey data (n = 579) and qualitative semi-structured interview findings (n = 23) data were separately collected and analysed. Informed by Self-Determination Theory (SDT), quantitative and qualitative findings were integrated to develop a model for the factors associated with medical students' expressed motivation to do research, and related to clinical and research learning activities at different stages in an undergraduate medical program. Only 7.5% of students had research experience prior to entering the program. Survey results revealed that students who had experienced exposure to the uncertainties of clinical practice through clerkships (Pre-Clinical (48%) vs Clinical Years (64%), p < 0.001), and a sense of achievement through supported compulsory research activities which were conducted as a team (Pre- Community Research (51%) vs Post-Community Research (66%), p < 0.001), were more likely to view future research activities positively. When integrated with qualitative findings using the three SDT domains of autonomy, competence and relatedness, eight major themes were identified: Self & Time, Career, Bureaucracy, Financial, Confidence, Clinical Relevance, Research as a Social Activity, and Personal Relevance. The findings suggest that motivation to do research is associated with increasing internalization of intrinsic motivators; in particular those associated with competence (Confidence) and relatedness (Clinical Relevance, Research as a Social Activity). SDT is useful for understanding the motivation of individuals and how curriculum can be designed to optimise motivation. Study findings suggest that well supported compulsory research activities that incorporate group learning and elements of choice may promote motivation to do research, and potentially, careers in research, even in a research naive student body.

Multicentre study highlighting clinical relevance of new high-throughput methodologies in molecular epidemiology of Pneumocystis jirovecii pneumonia.

PubMed

Esteves, F; de Sousa, B; Calderón, E J; Huang, L; Badura, R; Maltez, F; Bassat, Q; de Armas, Y; Antunes, F; Matos, O

2016-06-01

Pneumocystis jirovecii causes severe interstitial pneumonia (PcP) in immunosuppressed patients. This multicentre study assessed the distribution frequencies of epidemiologically relevant genetic markers of P. jirovecii in different geographic populations from Portugal, the USA, Spain, Cuba and Mozambique, and the relationship between the molecular data and the geographical and clinical information, based on a multifactorial approach. The high-throughput typing strategy for P. jirovecii characterization consisted of DNA pooling using quantitative real-time PCR followed by multiplex-PCR/single base extension. The frequencies of relevant P. jirovecii single nucleotide polymorphisms (mt85, SOD110, SOD215, DHFR312, DHPS165 and DHPS171) encoded at four loci were estimated in ten DNA pooled samples representing a total of 182 individual samples. Putative multilocus genotypes of P. jirovecii were shown to be clustered due to geographic differences but were also dependent on clinical characteristics of the populations studied. The haplotype DHFR312T/SOD110C/SOD215T was associated with severe AIDS-related PcP and high P. jirovecii burdens. The frequencies of this genetic variant of P. jirovecii were significantly higher in patients with AIDS-related PcP from Portugal and the USA than in the colonized patients from Portugal, and Spain, and children infected with P. jirovecii from Cuba or Mozambique, highlighting the importance of this haplotype, apparently associated with the severity of the disease and specific clinical groups. Patients from the USA and Mozambique showed higher rates of DHPS mutants, which may suggest the circulation of P. jirovecii organisms potentially related with trimethoprim-sulfamethoxazole resistance in those geographical regions. This report assessed the worldwide distribution of P. jirovecii haplotypes and their epidemiological impact in distinct geographic and clinical populations. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. All rights reserved.

Pharmacological Treatment of Obesity in Children and Adolescents: Present and Future

PubMed Central

Iughetti, Lorenzo; China, Mariachiara; Berri, Rossella; Predieri, Barbara

2011-01-01

The prevalence of overweight and obesity is increasing in children and adolescents worldwide raising the question on the approach to this condition because of the potential morbidity, mortality, and economic tolls. Dietetic and behavioral treatments alone have only limited success; consequently, discussion on strategies for treating childhood and adolescent obesity has been promoted. Considering that our knowledge on the physiological systems regulating food intake and body weight is considerably increased, many studies have underlined the scientific and clinical relevance of potential treatments based on management of peripheral or central neuropeptides signals by drugs. In this paper, we analyze the data on the currently approved obesity pharmacological treatment suggesting the new potential drugs. PMID:21197151

Nontypeable Haemophilus influenzae biofilms: role in chronic airway infections.

PubMed

Swords, W Edward

2012-01-01

Like many pathogens inhabiting mucosal surfaces, nontypeable Haemophilus influenzae (NTHi) forms multicellular biofilm communities both in vitro and in various infection models. In the past 15 years much has been learned about determinants of biofilm formation by this organism and potential roles in bacterial virulence, especially in the context of chronic and recurrent infections. However, this concept has not been without some degree of controversy, and in the past some have expressed doubts about the relevance of NTHi biofilms to disease. In this review, I will summarize the present information on the composition and potential role(s) of NTHi biofilms in different clinical contexts, as well as highlight potential areas for future work.

Nontypeable Haemophilus influenzae biofilms: role in chronic airway infections

PubMed Central

Swords, W. Edward

2012-01-01

Like many pathogens inhabiting mucosal surfaces, nontypeable Haemophilus influenzae (NTHi) forms multicellular biofilm communities both in vitro and in various infection models. In the past 15 years much has been learned about determinants of biofilm formation by this organism and potential roles in bacterial virulence, especially in the context of chronic and recurrent infections. However, this concept has not been without some degree of controversy, and in the past some have expressed doubts about the relevance of NTHi biofilms to disease. In this review, I will summarize the present information on the composition and potential role(s) of NTHi biofilms in different clinical contexts, as well as highlight potential areas for future work. PMID:22919686

Phenotype Instance Verification and Evaluation Tool (PIVET): A Scaled Phenotype Evidence Generation Framework Using Web-Based Medical Literature.

PubMed

Henderson, Jette; Ke, Junyuan; Ho, Joyce C; Ghosh, Joydeep; Wallace, Byron C

2018-05-04

Researchers are developing methods to automatically extract clinically relevant and useful patient characteristics from raw healthcare datasets. These characteristics, often capturing essential properties of patients with common medical conditions, are called computational phenotypes. Being generated by automated or semiautomated, data-driven methods, such potential phenotypes need to be validated as clinically meaningful (or not) before they are acceptable for use in decision making. The objective of this study was to present Phenotype Instance Verification and Evaluation Tool (PIVET), a framework that uses co-occurrence analysis on an online corpus of publically available medical journal articles to build clinical relevance evidence sets for user-supplied phenotypes. PIVET adopts a conceptual framework similar to the pioneering prototype tool PheKnow-Cloud that was developed for the phenotype validation task. PIVET completely refactors each part of the PheKnow-Cloud pipeline to deliver vast improvements in speed without sacrificing the quality of the insights PheKnow-Cloud achieved. PIVET leverages indexing in NoSQL databases to efficiently generate evidence sets. Specifically, PIVET uses a succinct representation of the phenotypes that corresponds to the index on the corpus database and an optimized co-occurrence algorithm inspired by the Aho-Corasick algorithm. We compare PIVET's phenotype representation with PheKnow-Cloud's by using PheKnow-Cloud's experimental setup. In PIVET's framework, we also introduce a statistical model trained on domain expert-verified phenotypes to automatically classify phenotypes as clinically relevant or not. Additionally, we show how the classification model can be used to examine user-supplied phenotypes in an online, rather than batch, manner. PIVET maintains the discriminative power of PheKnow-Cloud in terms of identifying clinically relevant phenotypes for the same corpus with which PheKnow-Cloud was originally developed, but PIVET's analysis is an order of magnitude faster than that of PheKnow-Cloud. Not only is PIVET much faster, it can be scaled to a larger corpus and still retain speed. We evaluated multiple classification models on top of the PIVET framework and found ridge regression to perform best, realizing an average F1 score of 0.91 when predicting clinically relevant phenotypes. Our study shows that PIVET improves on the most notable existing computational tool for phenotype validation in terms of speed and automation and is comparable in terms of accuracy. ©Jette Henderson, Junyuan Ke, Joyce C Ho, Joydeep Ghosh, Byron C Wallace. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 04.05.2018.

Phenotype Instance Verification and Evaluation Tool (PIVET): A Scaled Phenotype Evidence Generation Framework Using Web-Based Medical Literature

PubMed Central

Ke, Junyuan; Ho, Joyce C; Ghosh, Joydeep; Wallace, Byron C

2018-01-01

Background Researchers are developing methods to automatically extract clinically relevant and useful patient characteristics from raw healthcare datasets. These characteristics, often capturing essential properties of patients with common medical conditions, are called computational phenotypes. Being generated by automated or semiautomated, data-driven methods, such potential phenotypes need to be validated as clinically meaningful (or not) before they are acceptable for use in decision making. Objective The objective of this study was to present Phenotype Instance Verification and Evaluation Tool (PIVET), a framework that uses co-occurrence analysis on an online corpus of publically available medical journal articles to build clinical relevance evidence sets for user-supplied phenotypes. PIVET adopts a conceptual framework similar to the pioneering prototype tool PheKnow-Cloud that was developed for the phenotype validation task. PIVET completely refactors each part of the PheKnow-Cloud pipeline to deliver vast improvements in speed without sacrificing the quality of the insights PheKnow-Cloud achieved. Methods PIVET leverages indexing in NoSQL databases to efficiently generate evidence sets. Specifically, PIVET uses a succinct representation of the phenotypes that corresponds to the index on the corpus database and an optimized co-occurrence algorithm inspired by the Aho-Corasick algorithm. We compare PIVET’s phenotype representation with PheKnow-Cloud’s by using PheKnow-Cloud’s experimental setup. In PIVET’s framework, we also introduce a statistical model trained on domain expert–verified phenotypes to automatically classify phenotypes as clinically relevant or not. Additionally, we show how the classification model can be used to examine user-supplied phenotypes in an online, rather than batch, manner. Results PIVET maintains the discriminative power of PheKnow-Cloud in terms of identifying clinically relevant phenotypes for the same corpus with which PheKnow-Cloud was originally developed, but PIVET’s analysis is an order of magnitude faster than that of PheKnow-Cloud. Not only is PIVET much faster, it can be scaled to a larger corpus and still retain speed. We evaluated multiple classification models on top of the PIVET framework and found ridge regression to perform best, realizing an average F1 score of 0.91 when predicting clinically relevant phenotypes. Conclusions Our study shows that PIVET improves on the most notable existing computational tool for phenotype validation in terms of speed and automation and is comparable in terms of accuracy. PMID:29728351

Quality, risk management and governance in mental health: an overview.

PubMed

Callaly, Tom; Arya, Dinesh; Minas, Harry

2005-03-01

To consider the origin, current emphasis and relevance of the concepts of quality, risk management and clinical governance in mental health. Increasingly, health service boards and management teams are required to give attention to clinical governance rather than corporate governance alone. Clinical governance is a unifying quality concept that aims to produce a structure and systems to assure and improve the quality of clinical services by promoting an integrated and organization-wide approach towards continuous quality improvement. Many psychiatrists will find the reduction in clinical autonomy, the need to consider the welfare of the whole population as well as the individual patient for whom they are responsible, and the requirement that they play a part in a complex systems approach to quality improvement to be a challenge. Avoiding or ignoring this challenge will potentially lead to conflict with modern management approaches and increased loss of influence on future developments in mental health services.

Toxicogenomics and clinical toxicology: an example of the connection between basic and applied sciences.

PubMed

Ferrer-Dufol, Ana; Menao-Guillen, Sebastian

2009-04-10

The relationship between basic research and its potential clinical applications is often a difficult subject. Clinical toxicology has always been very dependent on experimental research whose usefulness has been impaired by the existence of huge differences in the toxicity expression of different substances, inter- and intra-species which make it difficult to predict clinical effects in humans. The new methods in molecular biology developed in the last decades are furnishing very useful tools to study some of the more relevant molecules implied in toxicokinetic and toxicodynamic processes. We aim to show some meaningful examples of how recent research developments with genes and proteins have clear applications to understand significant clinical matters, such as inter-individual variations in susceptibility to chemicals, and other phenomena related to the way some substances act to induce variations in the expression and functionality of these targets.

A First Step towards a Clinical Decision Support System for Post-traumatic Stress Disorders.

PubMed

Ma, Sisi; Galatzer-Levy, Isaac R; Wang, Xuya; Fenyö, David; Shalev, Arieh Y

2016-01-01

PTSD is distressful and debilitating, following a non-remitting course in about 10% to 20% of trauma survivors. Numerous risk indicators of PTSD have been identified, but individual level prediction remains elusive. As an effort to bridge the gap between scientific discovery and practical application, we designed and implemented a clinical decision support pipeline to provide clinically relevant recommendation for trauma survivors. To meet the specific challenge of early prediction, this work uses data obtained within ten days of a traumatic event. The pipeline creates personalized predictive model for each individual, and computes quality metrics for each predictive model. Clinical recommendations are made based on both the prediction of the model and its quality, thus avoiding making potentially detrimental recommendations based on insufficient information or suboptimal model. The current pipeline outperforms the acute stress disorder, a commonly used clinical risk factor for PTSD development, both in terms of sensitivity and specificity.

The Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 2A Receptor Activation.

PubMed

Preller, Katrin H; Herdener, Marcus; Pokorny, Thomas; Planzer, Amanda; Kraehenmann, Rainer; Stämpfli, Philipp; Liechti, Matthias E; Seifritz, Erich; Vollenweider, Franz X

2017-02-06

A core aspect of the human self is the attribution of personal relevance to everyday stimuli enabling us to experience our environment as meaningful [1]. However, abnormalities in the attribution of personal relevance to sensory experiences are also critical features of many psychiatric disorders [2, 3]. Despite their clinical relevance, the neurochemical and anatomical substrates enabling meaningful experiences are largely unknown. Therefore, we investigated the neuropharmacology of personal relevance processing in humans by combining fMRI and the administration of the mixed serotonin (5-HT) and dopamine receptor (R) agonist lysergic acid diethylamide (LSD), well known to alter the subjective meaning of percepts, with and without pretreatment with the 5-HT 2A R antagonist ketanserin. General subjective LSD effects were fully blocked by ketanserin. In addition, ketanserin inhibited the LSD-induced attribution of personal relevance to previously meaningless stimuli and modulated the processing of meaningful stimuli in cortical midline structures. These findings point to the crucial role of the 5-HT 2A R subtype and cortical midline regions in the generation and attribution of personal relevance. Our results thus increase our mechanistic understanding of personal relevance processing and reveal potential targets for the treatment of psychiatric illnesses characterized by alterations in personal relevance attribution. Copyright © 2017 Elsevier Ltd. All rights reserved.

Reflections on relevance: Psychotherapy and Psychosomatics in 2004.

PubMed

Balon, Richard

2005-01-01

Relevance of an article is a highly desirable yet hardly predictable quality at the time of its publication. Article relevance is frequently measured by the impact factor of the journal where the article is published. Furthermore, impact factor, citation index and citation analysis are used as a measure of research progress and scientific wealth of a nation. The wisdom and significance of this approach to relevance is debatable and thus discussed here. In 2004, Psychotherapy and Psychosomatics published a variety of articles which, in the author's view, are clinically relevant. Several selected clinically relevant issues reviewed in this article include: the conceptualization of fibromyalgia as a stress disorder; the psychosocial impact and psychosocial interventions in cancer; the impact of alexithymia on patient care; the possible relationship between depression and nutrition (namely intake of folate and pyridoxal phosphate); the significance of hypercoagulability in panic-like anxiety; the questionable value of single isomer drugs, and the relevance and adequacy of clinimetrics versus psychometrics in clinical research. The reviewed issues seem to be relevant to clinical practice, research or both, but also to our critical thinking, and the critical review of the developments in psychiatry and psychology. Copyright 2005 S. Karger AG, Basel.

Diagnostic value of clinical tests for degenerative rotator cuff disease in medical practice.

PubMed

Lasbleiz, S; Quintero, N; Ea, K; Petrover, D; Aout, M; Laredo, J D; Vicaut, E; Bardin, T; Orcel, P; Beaudreuil, J

2014-06-01

To assess the diagnostic value of clinical tests for degenerative rotator cuff disease (DRCD) in medical practice. Patients with DRCD were prospectively included. Eleven clinical tests of the rotator cuff have been done. One radiologist performed ultrasonography (US) of the shoulder. Results of US were expressed as normal tendon, tendinopathy or full-thickness tear (the reference). For each clinical test and each US criteria, sensitivity, specificity, negative predictive value and positive predictive value, accuracy, negative likelihood ratio (NLR) and positive likelihood ratio (PLR) were calculated. Clinical relevance was defined as PLR ≥2 and NLR ≤0.5. For 35 patients (39 shoulders), Jobe (PLR: 2.08, NLR: 0.31) and full-can (2, 0.5) test results were relevant for diagnosis of supraspinatus tears and resisted lateral rotation (2.42, 0.5) for infraspinatus tears, with weakness as response criteria. The lift-off test (8.50, 0.27) was relevant for subscapularis tears with lag sign as response criteria. Yergason's test (3.7, 0.41) was relevant for tendinopathy of the long head of the biceps with pain as a response criterion. There was no relevant clinical test for diagnosis of tendinopathy of supraspinatus, infraspinatus or subscapularis. Five of 11 clinical tests were relevant for degenerative rotator cuff disease. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Update in outpatient general internal medicine: practice-changing evidence published in 2014.

PubMed

Sundsted, Karna K; Wieland, Mark L; Szostek, Jason H; Post, Jason A; Mauck, Karen F

2015-10-01

The practice of outpatient general internal medicine requires a diverse and evolving knowledge base. General internists must identify practice-changing shifts in the literature and reflect on their impact. Accordingly, we conducted a review of practice-changing articles published in outpatient general internal medicine in 2014. To identify high-quality, clinically relevant publications, we reviewed all titles and abstracts published in the following primary data sources in 2014: New England Journal of Medicine, Journal of the American Medical Association (JAMA), Annals of Internal Medicine, JAMA Internal Medicine, and the Cochrane Database of Systematic Reviews. All 2014 primary data summaries from Journal Watch-General Internal Medicine and ACP JournalWise also were reviewed. The authors used a modified Delphi method to reach consensus on inclusion of 8 articles using the following criteria: clinical relevance to outpatient internal medicine, potential for practice change, and strength of evidence. Clusters of important articles around one clinical question were considered as a single-candidate series. The article merits were debated until consensus was reached on the final 8, spanning a variety of topics commonly encountered in outpatient general internal medicine. Copyright © 2015 Elsevier Inc. All rights reserved.

Clinical and Neurobiological Relevance of Current Animal Models of Autism Spectrum Disorders

PubMed Central

Kim, Ki Chan; Gonzales, Edson Luck; Lázaro, María T.; Choi, Chang Soon; Bahn, Geon Ho; Yoo, Hee Jeong; Shin, Chan Young

2016-01-01

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments, as well as repetitive and restrictive behaviors. The phenotypic heterogeneity of ASD has made it overwhelmingly difficult to determine the exact etiology and pathophysiology underlying the core symptoms, which are often accompanied by comorbidities such as hyperactivity, seizures, and sensorimotor abnormalities. To our benefit, the advent of animal models has allowed us to assess and test diverse risk factors of ASD, both genetic and environmental, and measure their contribution to the manifestation of autistic symptoms. At a broader scale, rodent models have helped consolidate molecular pathways and unify the neurophysiological mechanisms underlying each one of the various etiologies. This approach will potentially enable the stratification of ASD into clinical, molecular, and neurophenotypic subgroups, further proving their translational utility. It is henceforth paramount to establish a common ground of mechanistic theories from complementing results in preclinical research. In this review, we cluster the ASD animal models into lesion and genetic models and further classify them based on the corresponding environmental, epigenetic and genetic factors. Finally, we summarize the symptoms and neuropathological highlights for each model and make critical comparisons that elucidate their clinical and neurobiological relevance. PMID:27133257

Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents.

PubMed

Rong, Carola; Carmona, Nicole E; Lee, Yena L; Ragguett, Renee-Marie; Pan, Zihang; Rosenblat, Joshua D; Subramaniapillai, Mehala; Shekotikhina, Margarita; Almatham, Fahad; Alageel, Asem; Mansur, Rodrigo; Ho, Roger C; McIntyre, Roger S

2018-01-01

To determine, via narrative, non-systematic review of pre-clinical and clinical studies, whether the effect of cannabis on hepatic biotransformation pathways would be predicted to result in clinically significant drug-drug interactions (DDIs) with commonly prescribed psychotropic agents. Areas covered: A non-systematic literature search was conducted using the following databases: PubMed, PsycInfo, and Scopus from inception to January 2017. The search term cannabis was cross-referenced with the terms drug interactions, cytochrome, cannabinoids, cannabidiol, and medical marijuana. Pharmacological, molecular, and physiologic studies evaluating the pharmacokinetics of Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD), both in vitro and in vivo, were included. Bibliographies were also manually searched for additional citations that were relevant to the overarching aim of this paper. Expert opinion: Δ 9 -Tetrahydrocannabinol and CBD are substrates and inhibitors of cytochrome P450 enzymatic pathways relevant to the biotransformation of commonly prescribed psychotropic agents. The high frequency and increasing use of cannabis invites the need for healthcare providers to familiarize themselves with potential DDIs in persons receiving select psychotropic agents, and additionally consuming medical marijuana and/or recreational marijuana.

Space for the Prisoner's Point of View.

PubMed

Haupt, Laura

2017-03-01

The lead article in this issue discusses a potentially free metaphorical space-that of decision-making-within the confines, tangible and intangible, of life in jail or prison. By interviewing prisoner-participants from six clinical studies, Paul Christopher and colleagues sought to find out how these men and women would answer open-ended questions about their decision to enroll in the research. What the interviewers heard was that none saw themselves as having been inappropriately pressured to do so. In fact, a significant percentage of the prisoners described being dissuaded from participating in the studies. The authors therefore advise that unfair exploitation poses the more relevant research risk to contemporary prisoners in the United States than does coercion, and they encourage investigations into whether prisoners are unfairly restricted or discouraged from joining clinical studies. Although Keramet Reiter makes no reference to etymology in her commentary responding to the article, her argument suggests that the roots of "coerce"-the Latin for "shut up" or "enclose"-remain relevant. Reiter argues that, under current conditions, the people shut up in prisons in the United States cannot make an unfettered choice to join a clinical trial. © 2017 The Hastings Center.

Stress and Memory: A Selective Review on Recent Developments in the Understanding of Stress Hormone Effects on Memory and Their Clinical Relevance.

PubMed

Wolf, O T; Atsak, P; de Quervain, D J; Roozendaal, B; Wingenfeld, K

2016-08-01

Stress causes a neuroendocrine response cascade, leading to the release of catecholamines and glucocorticoids (GCs). GCs influence learning and memory by acting on mineralocorticoid (MR) and glucocorticoid (GR) receptors. Typically, GCs enhance the consolidation of memory processing at the same time as impairing the retrieval of memory of emotionally arousing experiences. The present selective review addresses four recent developments in this area. First, the role of the endocannabinoid system in mediating the rapid, nongenomic effects of GCs on memory is illustrated in rodents. Subsequently, studies on the impact of the selective stimulation of MRs on different memory processes in humans are summarised. Next, a series of human experiments on the impact of stress or GC treatment on fear extinction and fear reconsolidation is presented. Finally, the clinical relevance of the effects of exogenous GC administration is highlighted by the description of patients with anxiety disorders who demonstrate an enhancement of extinction-based therapies by GC treatment. The review highlights the substantial progress made in our mechanistic understanding of the memory-modulating properties of GCs, as well as their clinical potential. © 2015 British Society for Neuroendocrinology.

Discerning trends in multiplex immunoassay technology with potential for resource-limited settings.

PubMed

Gordon, Julian; Michel, Gerd

2012-04-01

In the search for more powerful tools for diagnoses of endemic diseases in resource-limited settings, we have been analyzing technologies with potential applicability. Increasingly, the process focuses on readily accessible bodily fluids combined with increasingly powerful multiplex capabilities to unambiguously diagnose a condition without resorting to reliance on a sophisticated reference laboratory. Although these technological advances may well have important implications for the sensitive and specific detection of disease, to date their clinical utility has not been demonstrated, especially in resource-limited settings. Furthermore, many emerging technological developments are in fields of physics or engineering, which are not readily available to or intelligible to clinicians or clinical laboratory scientists. This review provides a look at technology trends that could have applicability to high-sensitivity multiplexed immunoassays in resource-limited settings. Various technologies are explained and assessed according to potential for reaching relevant limits of cost, sensitivity, and multiplex capability. Frequently, such work is reported in technical journals not normally read by clinical scientists, and the authors make enthusiastic claims for the potential of their technology while ignoring potential pitfalls. Thus it is important to draw attention to technical hurdles that authors may not be publicizing. Immunochromatographic assays, optical methods including those involving waveguides, electrochemical methods, magnetorestrictive methods, and field-effect transistor methods based on nanotubes, nanowires, and nanoribbons reveal possibilities as next-generation technologies.

The Translational Role of Diffusion Tensor Image Analysis in Animal Models of Developmental Pathologies

PubMed Central

Oguz, Ipek; McMurray, Matthew S.; Styner, Martin; Johns, Josephine M.

2013-01-01

Diffusion Tensor Magnetic Resonance Imaging (DTI) has proven itself a powerful technique for clinical investigation of the neurobiological targets and mechanisms underlying developmental pathologies. The success of DTI in clinical studies has demonstrated its great potential for understanding translational animal models of clinical disorders, and preclinical animal researchers are beginning to embrace this new technology to study developmental pathologies. In animal models, genetics can be effectively controlled, drugs consistently administered, subject compliance ensured, and image acquisition times dramatically increased to reduce between-subject variability and improve image quality. When pairing these strengths with the many positive attributes of DTI, such as the ability to investigate microstructural brain organization and connectivity, it becomes possible to delve deeper into the study of both normal and abnormal development. The purpose of this review is to provide new preclinical investigators with an introductory source of information about the analysis of data resulting from small animal DTI studies to facilitate the translation of these studies to clinical data. In addition to an in depth review of translational analysis techniques, we present a number of relevant clinical and animal studies using DTI to investigate developmental insults in order to further illustrate techniques and to highlight where small animal DTI could potentially provide a wealth of translational data to inform clinical researchers. PMID:22627095

Retrieval of diagnostic and treatment studies for clinical use through PubMed and PubMed's Clinical Queries filters.

PubMed

Lokker, Cynthia; Haynes, R Brian; Wilczynski, Nancy L; McKibbon, K Ann; Walter, Stephen D

2011-01-01

Clinical Queries filters were developed to improve the retrieval of high-quality studies in searches on clinical matters. The study objective was to determine the yield of relevant citations and physician satisfaction while searching for diagnostic and treatment studies using the Clinical Queries page of PubMed compared with searching PubMed without these filters. Forty practicing physicians, presented with standardized treatment and diagnosis questions and one question of their choosing, entered search terms which were processed in a random, blinded fashion through PubMed alone and PubMed Clinical Queries. Participants rated search retrievals for applicability to the question at hand and satisfaction. For treatment, the primary outcome of retrieval of relevant articles was not significantly different between the groups, but a higher proportion of articles from the Clinical Queries searches met methodologic criteria (p=0.049), and more articles were published in core internal medicine journals (p=0.056). For diagnosis, the filtered results returned more relevant articles (p=0.031) and fewer irrelevant articles (overall retrieval less, p=0.023); participants needed to screen fewer articles before arriving at the first relevant citation (p<0.05). Relevance was also influenced by content terms used by participants in searching. Participants varied greatly in their search performance. Clinical Queries filtered searches returned more high-quality studies, though the retrieval of relevant articles was only statistically different between the groups for diagnosis questions. Retrieving clinically important research studies from Medline is a challenging task for physicians. Methodological search filters can improve search retrieval.

Cross Talk: The Microbiota and Neurodevelopmental Disorders

PubMed Central

Kelly, John R.; Minuto, Chiara; Cryan, John F.; Clarke, Gerard; Dinan, Timothy G.

2017-01-01

Humans evolved within a microbial ecosystem resulting in an interlinked physiology. The gut microbiota can signal to the brain via the immune system, the vagus nerve or other host-microbe interactions facilitated by gut hormones, regulation of tryptophan metabolism and microbial metabolites such as short chain fatty acids (SCFA), to influence brain development, function and behavior. Emerging evidence suggests that the gut microbiota may play a role in shaping cognitive networks encompassing emotional and social domains in neurodevelopmental disorders. Drawing upon pre-clinical and clinical evidence, we review the potential role of the gut microbiota in the origins and development of social and emotional domains related to Autism spectrum disorders (ASD) and schizophrenia. Small preliminary clinical studies have demonstrated gut microbiota alterations in both ASD and schizophrenia compared to healthy controls. However, we await the further development of mechanistic insights, together with large scale longitudinal clinical trials, that encompass a systems level dimensional approach, to investigate whether promising pre-clinical and initial clinical findings lead to clinical relevance. PMID:28966571

Peri-operative anaesthetic myocardial preconditioning and protection – cellular mechanisms and clinical relevance in cardiac anaesthesia

PubMed Central

Kunst, G; Klein, A A

2015-01-01

Preconditioning has been shown to reduce myocardial damage caused by ischaemia–reperfusion injury peri-operatively. Volatile anaesthetic agents have the potential to provide myocardial protection by anaesthetic preconditioning and, in addition, they also mediate renal and cerebral protection. A number of proof-of-concept trials have confirmed that the experimental evidence can be translated into clinical practice with regard to postoperative markers of myocardial injury; however, this effect has not been ubiquitous. The clinical trials published to date have also been too small to investigate clinical outcome and mortality. Data from recent meta-analyses in cardiac anaesthesia are also not conclusive regarding intra-operative volatile anaesthesia. These inconclusive clinical results have led to great variability currently in the type of anaesthetic agent used during cardiac surgery. This review summarises experimentally proposed mechanisms of anaesthetic preconditioning, and assesses randomised controlled clinical trials in cardiac anaesthesia that have been aimed at translating experimental results into the clinical setting. PMID:25764404

How Next-Generation Sequencing and Multiscale Data Analysis Will Transform Infectious Disease Management

PubMed Central

Pak, Theodore R.; Kasarskis, Andrew

2015-01-01

Recent reviews have examined the extent to which routine next-generation sequencing (NGS) on clinical specimens will improve the capabilities of clinical microbiology laboratories in the short term, but do not explore integrating NGS with clinical data from electronic medical records (EMRs), immune profiling data, and other rich datasets to create multiscale predictive models. This review introduces a range of “omics” and patient data sources relevant to managing infections and proposes 3 potentially disruptive applications for these data in the clinical workflow. The combined threats of healthcare-associated infections and multidrug-resistant organisms may be addressed by multiscale analysis of NGS and EMR data that is ideally updated and refined over time within each healthcare organization. Such data and analysis should form the cornerstone of future learning health systems for infectious disease. PMID:26251049

Sources of bias in clinical ethics case deliberation.

PubMed

Magelssen, Morten; Pedersen, Reidar; Førde, Reidun

2014-10-01

A central task for clinical ethics consultants and committees (CEC) is providing analysis of, and advice on, prospective or retrospective clinical cases. However, several kinds of biases may threaten the integrity, relevance or quality of the CEC's deliberation. Bias should be identified and, if possible, reduced or counteracted. This paper provides a systematic classification of kinds of bias that may be present in a CEC's case deliberation. Six kinds of bias are discussed, with examples, as to their significance and risk factors. Possible remedies are suggested. The potential for bias is greater when the case deliberation is performed by an individual ethics consultant than when an entire clinical ethics committee is involved. 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.

Clinical relevance of diagnosing COPD by fixed ratio or lower limit of normal: a systematic review.

PubMed

van Dijk, Wouter D; Gupta, Nisha; Tan, Wan C; Bourbeau, Jean

2014-02-01

Different spirometric criteria in diagnosing COPD have been advocated by different groups, debilitating adequate diagnosis and treatment of COPD. We reviewed the clinical relevance of fixed ratio and lower limit of normal (LLN) in diagnosing COPD and explored if modifying factors may affect their clinical relevance. Two reviewers independently searched PubMed and Embase for papers that compared both criteria on any clinically relevant outcome, published before June 1st, 2012, without any language restriction. Two reviewers independently extracted the study characteristics, including study design, population characteristics and diagnostic criteria used, and summarized the results of clinical relevance. Study quality was assessed by scoring forms for bias and level of evidence. Of 394 studies retrieved, 11 studies were included, with a median of 1,258 participants. Although both criteria appeared related with various clinically relevant outcomes, we were unable to prefer one criterion over the other, with various performances of the criteria for different outcomes. Should the criteria disagree on diagnosis, an alternative diagnosis should be suspected, in particular in those (elderly) with less severe airflow limitation for whom the LLN appears a better criterion. The fixed ratio appears to perform better in subjects with more severe airflow limitation. In diagnosing COPD, severity of airflow limitation appears an important factor for choosing whether the fixed ratio or LLN. Disagreement between the criteria is suggestive for an alternative diagnosis. Future studies on clinical relevance should further reveal the criterion of choice, in order to improve adequate diagnosis and consequent treatments.

Modelling Conditions and Health Care Processes in Electronic Health Records: An Application to Severe Mental Illness with the Clinical Practice Research Datalink.

PubMed

Olier, Ivan; Springate, David A; Ashcroft, Darren M; Doran, Tim; Reeves, David; Planner, Claire; Reilly, Siobhan; Kontopantelis, Evangelos

2016-01-01

The use of Electronic Health Records databases for medical research has become mainstream. In the UK, increasing use of Primary Care Databases is largely driven by almost complete computerisation and uniform standards within the National Health Service. Electronic Health Records research often begins with the development of a list of clinical codes with which to identify cases with a specific condition. We present a methodology and accompanying Stata and R commands (pcdsearch/Rpcdsearch) to help researchers in this task. We present severe mental illness as an example. We used the Clinical Practice Research Datalink, a UK Primary Care Database in which clinical information is largely organised using Read codes, a hierarchical clinical coding system. Pcdsearch is used to identify potentially relevant clinical codes and/or product codes from word-stubs and code-stubs suggested by clinicians. The returned code-lists are reviewed and codes relevant to the condition of interest are selected. The final code-list is then used to identify patients. We identified 270 Read codes linked to SMI and used them to identify cases in the database. We observed that our approach identified cases that would have been missed with a simpler approach using SMI registers defined within the UK Quality and Outcomes Framework. We described a framework for researchers of Electronic Health Records databases, for identifying patients with a particular condition or matching certain clinical criteria. The method is invariant to coding system or database and can be used with SNOMED CT, ICD or other medical classification code-lists.

Animal Models in Genomic Research: Techniques, Applications, and Roles for Nurses

PubMed Central

Osier, Nicole D.; Pham, Lan; Savarese, Amanda; Sayles, Kendra

2016-01-01

Animal research has been conducted by scientists for over two millennia resulting in a better understanding of human anatomy, physiology, and pathology, as well as testing of novel therapies. In the molecular genomic era, pre-clinical models represent a key tool for understanding the genomic underpinnings of health and disease and are relevant to precision medicine initiatives. Nurses contribute to improved health by collecting and translating evidence from clinically relevant pre-clinical models. Using animal models, nurses can ask questions that would not be feasible or ethical to address in humans, and establish the safety and efficacy of interventions before translating them to clinical trials. Two advantages of using pre-clinical models are reduced variability between test subjects and the opportunity for precisely controlled experimental exposures. Standardized care controls the effects of diet and environment, while the availability of inbred strains significantly reduces the confounding effects of genetic differences. Outside the laboratory, nurses can contribute to the approval and oversight of animal studies, as well as translation to clinical trials and, ultimately, patient care. This review is intended as a primer on the use of animal models to advance nursing science; specifically, the paper discusses the utility of preclinical models for studying the pathophysiologic and genomic contributors to health and disease, testing interventions, and evaluating effects of environmental exposures. Considerations specifically geared to nurse researchers are also introduced, including discussion of how to choose an appropriate model and controls, potential confounders, as well as legal and ethical concerns. Finally, roles for nurse clinicians in pre-clinical research are also highlighted. PMID:27969037

PRION-1 scales analysis supports use of functional outcome measures in prion disease

PubMed Central

Mead, S.; Ranopa, M.; Gopalakrishnan, G.S.; Thompson, A.G.B.; Rudge, P.; Wroe, S.; Kennedy, A.; Hudson, F.; MacKay, A.; Darbyshire, J.H.; Walker, A.S.

2011-01-01

Objectives: Human prion diseases are heterogeneous but invariably fatal neurodegenerative disorders with no known effective therapy. PRION-1, the largest clinical trial in prion disease to date, showed no effect of the potential therapeutic quinacrine on survival. Although there are several limitations to the usefulness of survival as an outcome measure, there have been no comprehensive studies of alternatives. Methods: To address this we did comparative analyses of neurocognitive, psychiatric, global, clinician-rated, and functional scales, focusing on validity, variability, and impact on statistical power over 77 person-years follow-up in 101 symptomatic patients in PRION-1. Results: Quinacrine had no demonstrable benefit on any of the 8 scales (p > 0.4). All scales had substantial numbers of patients with the worst possible score at enrollment (Glasgow Coma Scale score being least affected) and were impacted by missing data due to disease progression. These effects were more significant for cognitive/psychiatric scales than global, clinician-rated, or functional scales. The Barthel and Clinical Dementia Rating scales were the most valid and powerful in simulated clinical trials of an effective therapeutic. A combination of selected subcomponents from these 2 scales gave somewhat increased power, compared to use of survival, to detect clinically relevant effects in future clinical trials of feasible size. Conclusions: Our findings have implications for the choice of primary outcome measure in prion disease clinical trials. Prion disease presents the unusual opportunity to follow patients with a neurodegenerative disease through their entire clinical course, and this provides insights relevant to designing outcome measures in related conditions. PMID:22013183

Relevance of MICA and other non-HLA antibodies in clinical transplantation.

PubMed

Sumitran-Holgersson, Suchitra

2008-10-01

The clinical importance of HLA-specific antibodies for organ allograft outcome is well established. In the past few years, there has been an increasing interest in non-HLA antigens as targets of injury in organ transplant recipients. This increased interest has been spurred by the fact that HLA-identical kidney transplants also undergo immunological rejections. Polymorphisms within non-HLA genes associated with evoking an immune response to alloantigens are currently being studied for their association with transplant outcome. Non-HLA antigens, such as the polymorphic MHC class I-related chain A (MICA), expressed on endothelial cells have been implicated in the pathogenesis of hyperacute, acute and chronic organ allograft rejections. Use of endothelial cells as targets may clarify the specificities of other clinically relevant non-HLA antibodies in graft rejections. This review summarizes past and current knowledge of the clinical importance and specificities of non-HLA antibodies, and mechanisms by which these antibodies may contribute to graft destruction in clinical transplantation. The aims of current research into the role of non-HLA antigens and their genetics in predicting outcome are to develop an improved insight into the basic science of transplantation and to develop a risk or prognostic index for use in the clinical setting. Non-HLA antibody responses are receiving increasing interest in acute and chronic rejection and specificity, affinity, and pathogenicity need to be investigated to estimate their contribution. Undoubtedly, this will continue to be an area of interest in terms of fully understanding the role of non-HLA antigens as targets of immune-mediated injury and the potential for clinical intervention.

Animal models in genomic research: Techniques, applications, and roles for nurses.

PubMed

Osier, Nicole D; Pham, Lan; Savarese, Amanda; Sayles, Kendra; Alexander, Sheila A

2016-11-01

Animal research has been conducted by scientists for over two millennia resulting in a better understanding of human anatomy, physiology, and pathology, as well as testing of novel therapies. In the molecular genomic era, pre-clinical models represent a key tool for understanding the genomic underpinnings of health and disease and are relevant to precision medicine initiatives. Nurses contribute to improved health by collecting and translating evidence from clinically relevant pre-clinical models. Using animal models, nurses can ask questions that would not be feasible or ethical to address in humans, and establish the safety and efficacy of interventions before translating them to clinical trials. Two advantages of using pre-clinical models are reduced variability between test subjects and the opportunity for precisely controlled experimental exposures. Standardized care controls the effects of diet and environment, while the availability of inbred strains significantly reduces the confounding effects of genetic differences. Outside the laboratory, nurses can contribute to the approval and oversight of animal studies, as well as translation to clinical trials and, ultimately, patient care. This review is intended as a primer on the use of animal models to advance nursing science; specifically, the paper discusses the utility of preclinical models for studying the pathophysiologic and genomic contributors to health and disease, testing interventions, and evaluating effects of environmental exposures. Considerations specifically geared to nurse researchers are also introduced, including discussion of how to choose an appropriate model and controls, potential confounders, as well as legal and ethical concerns. Finally, roles for nurse clinicians in pre-clinical research are also highlighted. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical, Ergonomic, and Economic Outcomes With Multichamber Bags Compared With (Hospital) Pharmacy Compounded Bags and Multibottle Systems: A Systematic Literature Review.

PubMed

Alfonso, Jorge Emilio; Berlana, David; Ukleja, Andrew; Boullata, Joseph

2017-09-01

Multichamber bags (MCBs) may offer potential clinical, ergonomic, and economic advantages compared with (hospital) pharmacy compounded bags (COBs) and multibottle systems (MBSs). A systematic literature review was performed to identify and assess the available evidence regarding advantages of MCBs compared with COBs and MBSs. Medline, Embase, the Cochrane Databases, and EconLit were searched for articles reporting clinical, ergonomic, and economic outcomes for MCBs compared with COBs or MBSs. The search was limited to studies conducted in hospitalized patients >2 years of age that were published in English between January 1990 and November 2014. The Population Intervention Comparison Outcomes Study Design (PICOS) framework was used for the analysis. From 1307 unique citations, 74 potentially relevant publications were identified; review of references identified 2 additional publications. Among the 76 publications, 18 published studies met the inclusion criteria. Most were retrospective in design. Ten studies reported clinical outcomes, including 1 prospective randomized trial and multiple retrospective analyses that reported a lower risk of bloodstream infection for MCBs compared with other delivery systems. Sixteen studies reported ergonomic and/or economic outcomes; most reported a potential cost benefit for MCBs, with consistent reports of reduced time and labor compared with other systems. The largest cost benefit was observed in studies evaluating total hospitalization costs. The systematic literature review identified evidence of potential clinical, ergonomic, and economic benefits for MCBs compared with COBs and MBSs; however, methodological factors limited evidence quality. More prospective studies are required to corroborate existing evidence.

Vitamin Excess and Deficiency.

PubMed

Diab, Liliane; Krebs, Nancy F

2018-04-01

The published literature supports the high prevalence of supplement use in children and adolescents in the United States. Pediatricians today are faced with questions from parents and patients about the benefits, safety, efficacy, and correct dose of vitamins and minerals. In this article, we review 7 vitamins with the most clinical relevance as judged by abundance in food, risks and symptoms of deficiency, and potential for toxicity. Specifically, we focus on possible clinical scenarios that can be indicative of nutritional deficiency. We synthesize and summarize guidelines from nutrition experts, various medical societies, the World Health Organization, and the American Academy of Pediatrics. © American Academy of Pediatrics, 2018. All rights reserved.

Review of near-infrared methods for wound assessment

NASA Astrophysics Data System (ADS)

Sowa, Michael G.; Kuo, Wen-Chuan; Ko, Alex C.-T.; Armstrong, David G.

2016-09-01

Wound management is a challenging and costly problem that is growing in importance as people are living longer. Instrumental methods are increasingly being relied upon to provide objective measures of wound assessment to help guide management. Technologies that employ near-infrared (NIR) light form a prominent contingent among the existing and emerging technologies. We review some of these technologies. Some are already established, such as indocyanine green fluorescence angiography, while we also speculate on others that have the potential to be clinically relevant to wound monitoring and assessment. These various NIR-based technologies address clinical wound management needs along the entire healing trajectory of a wound.

Prostaglandins and Inflammation

PubMed Central

Ricciotti, Emanuela; FitzGerald, Garret A.

2011-01-01

Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase (COX) isoenzymes and their biosynthesis is blocked by nonsteroidal anti-inflammatory drugs (NSAIDs), including those selective for inhibition of COX-2. Despite the clinical efficacy of NSAIDs, prostaglandins may function in both the promotion and resolution of inflammation. This review summarizes insights into the mechanisms of prostaglandin generation and the roles of individual mediators and their receptors in modulating the inflammatory response. Prostaglandin biology has potential clinical relevance for atherosclerosis, the response to vascular injury and aortic aneurysm. PMID:21508345

The user's view of commercially available medical technology

NASA Technical Reports Server (NTRS)

Harrison, D. C.

1975-01-01

The potential user of new medical equipment for imaging the cardiovascular system is often faced with the problem of deciding whether or not to accept a new piece of equipment or a new technological concept into the practice of cardiology. Considerations for acquiring new medical technology are discussed in some detail. Acquisition of new technology should depend on whether the equipment provides more and relevant clinical data, is for research or for limited use, is properly engineered for patient use, presents information in easily storable and retrievable form, is tested and validated clinically, is fabricated by a reliable manufacturer, is cost effective, and may be readily replaced by a new technology.

Magnetic resonance imaging of the vagina: an overview for radiologists with emphasis on clinical decision making*

PubMed Central

Ferreira, Daian Miranda; Bezerra, Régis Otaviano França; Ortega, Cinthia Denise; Blasbalg, Roberto; Viana, Públio César Cavalcante; de Menezes, Marcos Roberto; Rocha, Manoel de Souza

2015-01-01

Magnetic resonance imaging is a method with high contrast resolution widely used in the assessment of pelvic gynecological diseases. However, the potential of such method to diagnose vaginal lesions is still underestimated, probably due to the scarce literature approaching the theme, the poor familiarity of radiologists with vaginal diseases, some of them relatively rare, and to the many peculiarities involved in the assessment of the vagina. Thus, the authors illustrate the role of magnetic resonance imaging in the evaluation of vaginal diseases and the main relevant findings to be considered in the clinical decision making process. PMID:26379324

Insights from clinical research completed during the west Africa Ebola virus disease epidemic

PubMed Central

Rojek, Amanda; Horby, Peter; Dunning, Jake

2018-01-01

The west Africa Ebola virus disease (EVD) epidemic was extraordinary in scale. Now that the epidemic has ended, it is a relevant time to examine published studies with direct relevance to clinical care and, more broadly, to examine the implications of the clinical research response mounted. Clinically relevant research includes literature detailing risk factors for and clinical manifestations of EVD, laboratory and other investigation findings in patients, experimental vaccine and therapeutic clinical trials, and analyses of survivor syndrome. In this Review, we discuss new insights from patient-oriented research completed during the west Africa epidemic, identify ongoing knowledge gaps, and suggest priorities for future research. PMID:28461209

Responsive Biomaterials: Advances in Materials Based on Shape-Memory Polymers.

PubMed

Hardy, John G; Palma, Matteo; Wind, Shalom J; Biggs, Manus J

2016-07-01

Shape-memory polymers (SMPs) are morphologically responsive materials with potential for a variety of biomedical applications, particularly as devices for minimally invasive surgery and the delivery of therapeutics and cells for tissue engineering. A brief introduction to SMPs is followed by a discussion of the current progress toward the development of SMP-based biomaterials for clinically relevant biomedical applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Clinical Utility of Blood Cell Histogram Interpretation

PubMed Central

Bhagya, S.; Majeed, Abdul

2017-01-01

An automated haematology analyser provides blood cell histograms by plotting the sizes of different blood cells on X-axis and their relative number on Y-axis. Histogram interpretation needs careful analysis of Red Blood Cell (RBC), White Blood Cell (WBC) and platelet distribution curves. Histogram analysis is often a neglected part of the automated haemogram which if interpreted well, has significant potential to provide diagnostically relevant information even before higher level investigations are ordered. PMID:29207767

Clinical Utility of Blood Cell Histogram Interpretation.

PubMed

Thomas, E T Arun; Bhagya, S; Majeed, Abdul

2017-09-01

An automated haematology analyser provides blood cell histograms by plotting the sizes of different blood cells on X-axis and their relative number on Y-axis. Histogram interpretation needs careful analysis of Red Blood Cell (RBC), White Blood Cell (WBC) and platelet distribution curves. Histogram analysis is often a neglected part of the automated haemogram which if interpreted well, has significant potential to provide diagnostically relevant information even before higher level investigations are ordered.

Research perspectives in first metatarsal osteotomy and fixation stability.

PubMed

Landsman, A S; Higgins, K R; Lampe, N

1996-07-01

Well-designated research is required to provide clinical guidance by validation of old and new methods. Variables, including technologic advancement in surgical techniques, diagnosis, shoe design, and immobilization all contribute to the challenge of investigating surgical procedures of the foot. This article highlights some of the relevant research pertaining to first metatarsal osteotomies and internal fixation and provides direction for potential, future research. Numerous aspects about the research techniques involved are discussed.

Enzyme potentiated hyposensitization: IV. effect of protamine on the immunological behavior of beta glucuronidase in mice and patients with hay fever.

PubMed

McEwen, L M; Nicholson, M; Kitchen, I; O'Gorman, J; White, S

1975-05-01

The ability of beta glucuronidase and a small dose of antigen to modify the anaphylactic reaction of previously sensitized mice has been further investigated. Protamine has an important effect on the immunological behavior of the enzyme. A trial on hay fever patients shows that the results in mice are relevant and that the method can produce significant clinical hyposensitization.

Prevalence of the prescription of potentially interacting drugs.

PubMed

Tragni, Elena; Casula, Manuela; Pieri, Vasco; Favato, Giampiero; Marcobelli, Alberico; Trotta, Maria Giovanna; Catapano, Alberico Luigi

2013-01-01

The use of multiple medications is becoming more common, with a correspondingly increased risk of untoward effects and drug-related morbidity and mortality. We aimed at estimating the prevalence of prescription of relevant potentially interacting drugs and at evaluating possible predictors of potentially interacting drug exposure. We retrospectively analyzed data on prescriptions dispensed from January 2004 to August 2005 to individuals of two Italian regions with a population of almost 2.1 million individuals. We identified 27 pairs of potentially interacting drugs by examining clinical relevance, documentation, and volume of use in Italy. Subjects who received at least one prescription of both drugs were selected. Co-prescribing denotes "two prescriptions in the same day", and concomitant medication "the prescription of two drugs with overlapping coverage". A logistic regression analysis was conducted to examine the predictors of potential Drug-Drug Interaction (pDDIs). 957,553 subjects (45.3% of study population) were exposed to at least one of the drugs/classes of the 27 pairs. Overall, pDDIs occurred 2,465,819 times. The highest rates of concomitant prescription and of co-prescription were for ACE inhibitors+NSAIDs (6,253 and 4,621/100,000 plan participants). Considering concomitance, the male/female ratio was <1 in 17/27 pairs (from 0.31 for NSAIDs-ASA+SSRI to 0.74 for omeprazole+clopidogrel). The mean age was lowest for methotrexate pairs (+omeprazole, 59.9 years; +NSAIDs-ASA, 59.1 years) and highest for digoxin+verapamil (75.4 years). In 13/27 pairs, the mean ages were ≥70 years. On average, subjects involved in pDDIs received ≥10 drugs. The odds of exposure were more frequently higher for age ≥65 years, males, and those taking a large number of drugs. A substantial number of clinically important pDDIs were observed, particularly among warfarin users. Awareness of the most prevalent pDDIs could help practitioners in preventing concomitant use, resulting in a better quality of drug prescription and potentially avoiding unwanted side effects.

Antecedent thermal injury worsens split-thickness skin graft quality: A clinically relevant porcine model of full-thickness burn, excision and grafting.

PubMed

Carlsson, Anders H; Rose, Lloyd F; Fletcher, John L; Wu, Jesse C; Leung, Kai P; Chan, Rodney K

2017-02-01

Current standard of care for full-thickness burn is excision followed by autologous split-thickness skin graft placement. Skin grafts are also frequently used to cover surgical wounds not amenable to linear closure. While all grafts have potential to contract, clinical observation suggests that antecedent thermal injury worsens contraction and impairs functional and aesthetic outcomes. This study evaluates the impact of antecedent full-thickness burn on split-thickness skin graft scar outcomes and the potential mediating factors. Full-thickness contact burns (100°C, 30s) were created on the backs of anesthetized female Yorkshire Pigs. After seven days, burn eschar was tangentially excised and covered with 12/1000th inch (300μm) split-thickness skin graft. For comparison, unburned wounds were created by sharp excision to fat before graft application. From 7 to 120days post-grafting, planimetric measurements, digital imaging and biopsies for histology, immunohistochemistry and gene expression were obtained. At 120days post-grafting, the Observer Scar Assessment Scale, colorimetry, contour analysis and optical graft height assessments were performed. Twenty-nine porcine wounds were analyzed. All measured metrics of clinical skin quality were significantly worse (p<0.05) in burn injured wounds. Histological analysis supported objective clinical findings with marked scar-like collagen proliferation within the dermis, increased vascular density, and prolonged and increased cellular infiltration. Observed differences in contracture also correlated with earlier and more prominent myofibroblast differentiation as demonstrated by α-SMA staining. Antecedent thermal injury worsens split-thickness skin graft quality, likely by multiple mechanisms including burn-related inflammation, microscopically inadequate excision, and dysregulation of tissue remodeling. A valid, reliable, clinically relevant model of full-thickness burn, excision and skin replacement therapy has been demonstrated. Future research to enhance quality of skin replacement therapies should be directed toward modulation of inflammation and assessments for complete excision. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

Physicians and pharmacists: collaboration to improve the quality of prescriptions in primary care in Mexico.

PubMed

Mino-León, Dolores; Reyes-Morales, Hortensia; Jasso, Luis; Douvoba, Svetlana Vladislavovna

2012-06-01

Inappropriate prescription is a relevant problem in primary health care settings in Mexico, with potentially harmful consequences for patients. To evaluate the effectiveness of incorporating a pharmacist into primary care health team to reduce prescription errors for patients with diabetes and/or hypertension. One Family Medicine Clinic from the Mexican Institute of Social Security in Mexico City. A "pharmacotherapy intervention" provided by pharmacists through a quasi experimental (before-after) design was carried out. Physicians who allowed access to their diabetes and/or hypertensive patients' medical records and prescriptions were included in the study. Prescription errors were classified as "filling", "clinical" or "both". Descriptive analysis, identification of potential drug-drug interactions (pD-DI), and comparison of the proportion of patients with prescriptions with errors detected "before" and "after" intervention were performed. Decrease in the proportion of patients who received prescriptions with errors after the intervention. Pharmacists detected at least one type of error in 79 out of 160 patients. Errors were "clinical", "both" and "filling" in 47, 21 and 11 of these patient's prescriptions respectively. Predominant errors were, in the subgroup of patient's prescriptions with "clinical" errors, pD-DI; in the subgroup of "both" errors, lack of information on dosing interval and pD-DI; and in the "filling" subgroup, lack of information on dosing interval. The pD-DI caused 50 % of the errors detected, from which 19 % were of major severity. The impact of the correction of errors post-intervention was observed in 19 % of patients who had erroneous prescriptions before the intervention of the pharmacist (49.3-30.3 %, p < 0.05). The impact of the intervention was relevant from a clinical point of view for the public health services in Mexico. The implementation of early warning systems of the most widely prescribed drugs is an alternative for reducing prescription errors and consequently the risks they may cause.

Resistant starch: a promising dietary agent for the prevention/treatment of inflammatory bowel disease and bowel cancer.

PubMed

Higgins, Janine A; Brown, Ian L

2013-03-01

Resistant starch represents a diverse range of indigestible starch-based dietary carbohydrates. Resistant starch has been investigated in the past for its effects on bowel health (pH, epithelial thickness, and apoptosis of colorectal cancer cells); reduction in postprandial glycemia; increased insulin sensitivity; and effects on the gut microbiome. This review highlights advances as resistant starch gains clinical relevance as a potential treatment/preventive tool for diseases such as colorectal cancer (CRC) and diabetes. Recent articles have evaluated the comparative physiological effects of different types of resistant starch and investigated the effects of resistant starch on blood lipids, body weight, and defining resistant starch-induced changes to the micriobiome that may be important in health and disease. The most novel and relevant recent data describe a role for resistant starch in ameliorating inflammation; the use of resistant starch for optimal bowel health and prevention of CRC; and, further, that the systemic effects of resistant starch may be important for the treatment of other forms of cancer, such as breast cancer. This review describes advances in resistant starch research highlighting the gastrointestinal effects that are now being linked to systemic, whole body effects with clinical relevance. These effects have important implications for overall health and the prevention or amelioration of various chronic diseases.

Version 3 of the historical-clinical-risk management-20 (HCR-20V3): relevance to violence risk assessment and management in forensic conditional release contexts.

PubMed

Douglas, Kevin S

2014-09-01

The conditional release of insanity acquittees requires decisions both about community risk level and the contextual factors that may mitigate or aggravate risk. This article discusses the potential role of the newly revised Historical-Clinical-Risk Management-20 (HCR-20, Version 3) within the conditional release context. A brief review of the structured professional judgment (SPJ) approach to violence risk assessment and management is provided. Version 2 of the HCR-20, which has been broadly adopted and evaluated, is briefly described. New features of Version 3 of the HCR-20 with particular relevance to conditional release decision-making are reviewed, including: item indicators; ratings of the relevance of risk factors to an individual's violence; risk formulation; scenario planning; and risk management planning. Version 3 of the HCR-20 includes a number of features that should assist evaluators and decision-makers to determine risk level, as well as to anticipate and specify community conditions and contexts that may mitigate or aggravate risk. Research on the HCR-20 Version 3 using approximately 800 participants across three settings (forensic psychiatric, civil psychiatric, correctional) and eight countries is reviewed. Copyright © 2014 John Wiley & Sons, Ltd.

An exploratory analysis of PubMed's free full-text limit on citation retrieval for clinical questions

PubMed Central

Krieger, Mary M.; Richter, Randy R.; Austin, Tricia M.

2008-01-01

Objective: The research sought to determine (1) how use of the PubMed free full-text (FFT) limit affects citation retrieval and (2) how use of the FFT limit impacts the types of articles and levels of evidence retrieved. Methods: Four clinical questions based on a research agenda for physical therapy were searched in PubMed both with and without the use of the FFT limit. Retrieved citations were examined for relevancy to each question. Abstracts of relevant citations were reviewed to determine the types of articles and levels of evidence. Descriptive analysis was used to compare the total number of citations, number of relevant citations, types of articles, and levels of evidence both with and without the use of the FFT limit. Results: Across all 4 questions, the FFT limit reduced the number of citations to 11.1% of the total number of citations retrieved without the FFT limit. Additionally, high-quality evidence such as systematic reviews and randomized controlled trials were missed when the FFT limit was used. Conclusions: Health sciences librarians play a key role in educating users about the potential impact the FFT limit has on the number of citations, types of articles, and levels of evidence retrieved. PMID:18974812

Public health relevance of drug-nutrition interactions.

PubMed

Péter, Szabolcs; Navis, Gerjan; de Borst, Martin H; von Schacky, Clemens; van Orten-Luiten, Anne Claire B; Zhernakova, Alexandra; Witkamp, Renger F; Janse, André; Weber, Peter; Bakker, Stephan J L; Eggersdorfer, Manfred

2017-08-01

The public health relevance of drug-nutrition interactions is currently highly undervalued and overlooked. This is particularly the case for elderly persons where multi-morbidity and consequently polypharmacy is very common. Vitamins and other micronutrients have central functions in metabolism, and their interactions with drugs may result in clinically relevant physiological impairments but possibly also in positive effects. On 12 April 2016, the University Medical Center Groningen (The Netherlands), as part of its Healthy Ageing program, organized a workshop on the public health relevance of drug-nutrient interactions. In this meeting, experts in the field presented results from recent studies on interactions between pharmaceuticals and nutrients, and discussed the role of nutrition for elderly, focusing on those persons receiving pharmaceutical treatment. This paper summarizes the proceedings of the symposium and provides an outlook for future research needs and public health measures. Since food, pharma and health are closely interconnected domains, awareness is needed in the medical community about the potential relevance of drug-nutrition interactions. Experts and stakeholders should advocate for the integration of drug-nutrition evaluations in the drug development process. Strategies for the individual patients should be developed, by installing drug review protocols, screening for malnutrition and integrating this topic into the general medical advice.

Framework to assess the effects of using patient-reported outcome measures in chronic care management.

PubMed

Santana, Maria-Jose; Feeny, David

2014-06-01

The inclusion of patient-reported outcome measures (PROMs) in the routine clinical care of chronically ill patients has the potential to add valuable information about the impact of the disease and its treatment and promotes effective patient self-management in which patients become more active participants in their own care. PROMs provide clinicians with timely information on patients' symptoms as well as functional and emotional status. PROMs are a useful tool for enhancing patient-clinician communication. We develop a conceptual framework describing the potential effects of the use of PROMs in chronic care management. The framework summarizes insights from the methods for evaluating the clinical effectiveness and methods for the health technology assessment of diagnostic technologies and results from the relevant studies. The framework describes potential effects, from proximal to distal, including communication (patient-clinician, patient-relative, clinician-clinician, and clinician-relative), engaging patients in shared clinical decision making, patient management (clinician management and patient self-management), and patient outcomes. Important potential effects also include enhancement in patient activation as well as improvements in clinician and patient satisfaction, and patient adherence to recommended treatment. Previous frameworks have described patient-physician communication, patient satisfaction, and health outcomes. Our framework adds unique domains, including patient engagement, patient activation, shared clinical decision making, and patient self-management. The framework can be used as a tool to guide the development of interventions to improve chronic care management through the use of PROMs.

Identifying Opportunities for Vertical Integration of Biochemistry and Clinical Medicine.

PubMed

Wendelberger, Karen J.; Burke, Rebecca; Haas, Arthur L.; Harenwattananon, Marisa; Simpson, Deborah

1998-01-01

Objectives: Retention of basic science knowledge, as judged by National Board of Medical Examiners' (NBME) data, suffers due to lack of apparent relevance and isolation of instruction from clinical application, especially in biochemistry. However, the literature reveals no systematic process for identifying key biochemical concepts and associated clinical conditions. This study systematically identified difficult biochemical concepts and their common clinical conditions as a critical step towards enhancing relevance and retention of biochemistry.Methods: A multi-step/ multiple stakeholder process was used to: (1) identify important biochemistry concepts; (2) determine students' perceptions of concept difficulty; (3) assess biochemistry faculty, student, and clinical teaching scholars' perceived relevance of identified concepts; and (4) identify associated common clinical conditions for relevant and difficult concepts. Surveys and a modified Delphi process were used to gather data, subsequently analyzed using SPSS for Windows.Results: Sixteen key biochemical concepts were identified. Second year medical students rated 14/16 concepts as extremely difficult while fourth year students rated nine concepts as moderately to extremely difficult. On average, each teaching scholar generated common clinical conditions for 6.2 of the 16 concepts, yielding a set of seven critical concepts and associated clinical conditions.Conclusions: Key stakeholders in the instructional process struggle to identify biochemistry concepts that are critical, difficult to learn and associated with common clinical conditions. However, through a systematic process beginning with identification of concepts and associated clinical conditions, relevance of basic science instruction can be enhanced.

Virus-Bacteria Interactions: Implications and Potential for the Applied and Agricultural Sciences.

PubMed

Moore, Matthew D; Jaykus, Lee-Ann

2018-02-02

Eukaryotic virus-bacteria interactions have recently become an emerging topic of study due to multiple significant examples related to human pathogens of clinical interest. However, such omnipresent and likely important interactions for viruses and bacteria relevant to the applied and agricultural sciences have not been reviewed or compiled. The fundamental basis of this review is that these interactions have importance and deserve more investigation, as numerous potential consequences and applications arising from their discovery are relevant to the applied sciences. The purpose of this review is to highlight and summarize eukaryotic virus-bacteria findings in the food/water, horticultural, and animal sciences. In many cases in the agricultural sciences, mechanistic understandings of the effects of virus-bacteria interactions remain unstudied, and many studies solely focus on co-infections of bacterial and viral pathogens. Given recent findings relative to human viral pathogens, further research related to virus-bacteria interactions would likely result in numerous discoveries and beneficial applications.

Neuroethics, confidentiality, and a cultural imperative in early onset Alzheimer disease: a case study with a First Nation population

PubMed Central

2013-01-01

The meaningful consideration of cultural practices, values and beliefs is a necessary component in the effective translation of advancements in neuroscience to clinical practice and public discourse. Society’s immense investment in biomedical science and technology, in conjunction with an increasingly diverse socio-cultural landscape, necessitates the study of how potential discoveries in neurodegenerative diseases such as Alzheimer disease are perceived and utilized across cultures. Building on the work of neuroscientists, ethicists and philosophers, we argue that the growing field of neuroethics provides a pragmatic and constructive pathway to guide advancements in neuroscience in a manner that is culturally nuanced and relevant. Here we review a case study of one issue in culturally oriented neuroscience research where it is evident that traditional research ethics must be broadened and the values and needs of diverse populations considered for meaningful and relevant research practices. A global approach to neuroethics has the potential to furnish critical engagement with cultural considerations of advancements in neuroscience. PMID:24131854

Investigation of Tear Biomarkers as an Indicator of Human Health

NASA Technical Reports Server (NTRS)

Morton, Stephen; Tucker, Bethany; Crucian, Brian; Steinberg, Susan; Hagan, Suzanne

2017-01-01

Scientific literature suggests that tear biomarkers can be used as a guide towards clinical diagnosis of human health (Hagan et al., 2016). This study will investigate whether tear biomarkers represents a research and clinical opportunity to assess human health prior to, during, and after exposure to the spaceflight environment. The focus of this study is to compare biomarkers previously identified as potentially relevant to both ocular and brain health against unique physiological outcomes of exposure to the space flight environment. Study subjects suffering from terrestrial conditions thought to be similar to Spaceflight Associated Neuro-ocular Syndrome (SANS: formerly VIIP), e.g. patients with idiopathic intracranial hypertension (IIH) and optic neuritis may be relevant to conditions associated with spaceflight. This study will review methodologies, tear biomarkers related to state of ocular and brain health, the strengths and weakness of using tear fluid biomarkers versus other body fluid samples, and will survey current tear fluid biomarker knowledge in research and clinical practice. A strength of using tear biomarkers is that sampling is non-invasive and used as a guide in understanding pathologies, including ocular and systemic inflammatory conditions (Cocho et al., 2016)., Salvisberg et al., 2014). Moreover, tear biomarkers may reflect diseases affecting the central nervous system (CNS) (Salvisberg et al., 2014). For example, in multiple sclerosis (MS), the concordance rate between tear biomarkers versus cerebrospinal fluid (CSF) is approximately 83%, indicating that, in the majority of cases, tears are at least as effective as CSF in potentially identifying novel MS biomarkers (Devos et al., 2001).

Epidemiology and risk factors for drug allergy.

PubMed

Thong, Bernard Y-H; Tan, Teck-Choon

2011-05-01

The aim of this review was to describe the current evidence-based knowledge of the epidemiology, prevalence, incidence, risk factors and genetic associations of drug allergy. Articles published between 1966 and 2010 were identified in MEDLINE using the key words adult, adverse drug reaction reporting systems, age factors, anaphylactoid, anaphylaxis, anaesthetics, antibiotics, child, drug allergy, drug eruptions, ethnic groups, hypersensitivity, neuromuscular depolarizing agents, neuromuscular nondepolarizing agents, sex factors, Stevens Johnson syndrome and toxic epidermal necrolysis. Additional studies were identified from article reference lists. Relevant, peer-reviewed original research articles, case series and reviews were considered for review. Current epidemiological studies on adverse drug reactions (ADRs) have used different definitions for ADR-related terminology, often do not differentiate immunologically and non-immunologically mediated drug hypersensitivity, study different study populations (different ethnicities, inpatients or outpatients, adults or children), utilize different methodologies (spontaneous vs. non-spontaneous reporting, cohort vs. case-control studies), different methods of assessing drug imputability and different methods of data analyses. Potentially life-threatening severe cutaneous adverse reactions (SCAR) are associated with a high risk of morbidity and mortality. HLA associations for SCAR associated with allopurinol, carbamazepine and abacavir have been reported with the potential for clinical use in screening prior to prescription. Identification of risk factors for drug allergy and appropriate genetic screening of at-risk ethnic groups may improve the outcomes of drug-specific SCAR. Research and collaboration are necessary for the generation of clinically-relevant, translational pharmacoepidemiological and pharmacogenomic knowledge, and success of health outcomes research and policies on drug allergies. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Imaging opioid analgesia in the human brain and its potential relevance for understanding opioid use in chronic pain

PubMed Central

Lee, Michael C.; Wanigasekera, Vishvarani; Tracey, Irene

2014-01-01

Opioids play an important role for the management of acute pain and in palliative care. The role of long-term opioid therapy in chronic non-malignant pain remains unclear and is the focus of much clinical research. There are concerns regarding analgesic tolerance, paradoxical pain and issues with dependence that can occur with chronic opioid use in the susceptible patient. In this review, we discuss how far human neuroimaging research has come in providing a mechanistic understanding of pain relief provided by opioids, and suggest avenues for further studies that are relevant to the management of chronic pain with opioids. This article is part of the Special Issue Section entitled ‘Neuroimaging in Neuropharmacology’. PMID:23891639

Retention of knowledge and perceived relevance of basic sciences in an integrated case-based learning (CBL) curriculum

PubMed Central

2013-01-01

Background Knowledge and understanding of basic biomedical sciences remain essential to medical practice, particularly when faced with the continual advancement of diagnostic and therapeutic modalities. Evidence suggests, however, that retention tends to atrophy across the span of an average medical course and into the early postgraduate years, as preoccupation with clinical medicine predominates. We postulated that perceived relevance demonstrated through applicability to clinical situations may assist in retention of basic science knowledge. Methods To test this hypothesis in our own medical student cohort, we administered a paper-based 50 MCQ assessment to a sample of students from Years 2 through 5. Covariates pertaining to demographics, prior educational experience, and the perceived clinical relevance of each question were also collected. Results A total of 232 students (Years 2–5, response rate 50%) undertook the assessment task. This sample had comparable demographic and performance characteristics to the whole medical school cohort. In general, discipline-specific and overall scores were better for students in the latter years of the course compared to those in Year 2; male students and domestic students tended to perform better than their respective counterparts in certain disciplines. In the clinical years, perceived clinical relevance was significantly and positively correlated with item performance. Conclusions This study suggests that perceived clinical relevance is a contributing factor to the retention of basic science knowledge and behoves curriculum planners to make clinical relevance a more explicit component of applied science teaching throughout the medical course. PMID:24099045

Does the choice of display system influence perception and visibility of clinically relevant features in digital pathology images?

NASA Astrophysics Data System (ADS)

Kimpe, Tom; Rostang, Johan; Avanaki, Ali; Espig, Kathryn; Xthona, Albert; Cocuranu, Ioan; Parwani, Anil V.; Pantanowitz, Liron

2014-03-01

Digital pathology systems typically consist of a slide scanner, processing software, visualization software, and finally a workstation with display for visualization of the digital slide images. This paper studies whether digital pathology images can look different when presenting them on different display systems, and whether these visual differences can result in different perceived contrast of clinically relevant features. By analyzing a set of four digital pathology images of different subspecialties on three different display systems, it was concluded that pathology images look different when visualized on different display systems. The importance of these visual differences is elucidated when they are located in areas of the digital slide that contain clinically relevant features. Based on a calculation of dE2000 differences between background and clinically relevant features, it was clear that perceived contrast of clinically relevant features is influenced by the choice of display system. Furthermore, it seems that the specific calibration target chosen for the display system has an important effect on the perceived contrast of clinically relevant features. Preliminary results suggest that calibrating to DICOM GSDF calibration performed slightly worse than sRGB, while a new experimental calibration target CSDF performed better than both DICOM GSDF and sRGB. This result is promising as it suggests that further research work could lead to better definition of an optimized calibration target for digital pathology images resulting in a positive effect on clinical performance.

Evaluation of linear classifiers on articles containing pharmacokinetic evidence of drug-drug interactions.

PubMed

Kolchinsky, A; Lourenço, A; Li, L; Rocha, L M

2013-01-01

Drug-drug interaction (DDI) is a major cause of morbidity and mortality. DDI research includes the study of different aspects of drug interactions, from in vitro pharmacology, which deals with drug interaction mechanisms, to pharmaco-epidemiology, which investigates the effects of DDI on drug efficacy and adverse drug reactions. Biomedical literature mining can aid both kinds of approaches by extracting relevant DDI signals from either the published literature or large clinical databases. However, though drug interaction is an ideal area for translational research, the inclusion of literature mining methodologies in DDI workflows is still very preliminary. One area that can benefit from literature mining is the automatic identification of a large number of potential DDIs, whose pharmacological mechanisms and clinical significance can then be studied via in vitro pharmacology and in populo pharmaco-epidemiology. We implemented a set of classifiers for identifying published articles relevant to experimental pharmacokinetic DDI evidence. These documents are important for identifying causal mechanisms behind putative drug-drug interactions, an important step in the extraction of large numbers of potential DDIs. We evaluate performance of several linear classifiers on PubMed abstracts, under different feature transformation and dimensionality reduction methods. In addition, we investigate the performance benefits of including various publicly-available named entity recognition features, as well as a set of internally-developed pharmacokinetic dictionaries. We found that several classifiers performed well in distinguishing relevant and irrelevant abstracts. We found that the combination of unigram and bigram textual features gave better performance than unigram features alone, and also that normalization transforms that adjusted for feature frequency and document length improved classification. For some classifiers, such as linear discriminant analysis (LDA), proper dimensionality reduction had a large impact on performance. Finally, the inclusion of NER features and dictionaries was found not to help classification.

Interactions of bilastine, a new oral H₁ antihistamine, with human transporter systems.

PubMed

Lucero, Maria Luisa; Gonzalo, Ana; Ganza, Alvaro; Leal, Nerea; Soengas, Itziar; Ioja, Eniko; Gedey, Szilvia; Jahic, Mirza; Bednarczyk, Dallas

2012-06-01

Membrane transporters play a significant role in facilitating transmembrane drug movement. For new pharmacological agents, it is important to evaluate potential interactions (e.g., substrate specificity and/or inhibition) with human transporters that may affect their pharmacokinetics, efficacy, or toxicity. Bilastine is a new nonsedating H₁ antihistamine indicated for the treatment of allergic rhinoconjunctivitis and urticaria. The in vitro inhibitory effects of bilastine were assessed on 12 human transporters: four efflux [multidrug resistance protein 1 (MDR1) or P-glycoprotein, breast cancer resistance protein (BCRP), multidrug resistance associated protein 2 (MRP2), and bile salt export pump) and eight uptake transporters (sodium taurocholate cotransporting polypeptide, organic cation transporter (OCT)1, organic anion transporter (OAT)1, OAT3, OCT2, OATP2B1, OATP1B1, and OATP1B3). Only mild inhibition was found for MDR1-, OCT1-, and OATP2B1-mediated transport of probe substrates at the highest bilastine concentration assayed (300 μM; half-maximal inhibitory concentration: ≥300 μM). Bilastine transport by MDR1, BCRP, OAT1, OAT3, and OCT2 was also investigated in vitro. Only MDR1 active transport of bilastine was relevant, whereas it did not appear to be a substrate of OCT2, OAT1, or OAT3, nor was it transported substantially by BCRP. Drug-drug interactions resulting from bilastine inhibition of drug transporters that would be generally regarded as clinically relevant are unlikely. Additionally, bilastine did not appear to be a substrate of human BCRP, OAT1, OAT3, or OCT2 and thus is not a potential victim of inhibitors of these transporters. On the other hand, based on in vitro evaluation, clinically relevant interactions with MDR1 inhibitors are anticipated.

Messages from the Malaysian Diabetes Registries on Diabetes Care in Malaysian public healthcare facilities.

PubMed

Chew, Boon-How; Lee, Ping-Yein; Cheong, Ai-Theng; Ismail, Mastura; Shariff-Ghazali, Sazlina; Goh, Pik-Pin

2016-10-01

A persistent and increasing prevalence of diagnosed and undiagnosed diabetes mellitus has recently been reported in the National Health and Morbidity Survey 2015. This commentary recapitulates the relevant and valuable lessons in the Malaysian national diabetes registries to inform the healthcare stakeholders and policy makers on potential areas of clinical practice improvement and future researches. Under performance of the process measures and sub-optimal control of HbA1c, blood pressure and lipids profile were prevalent (<40% achieved treatment targets). Although these had improved slightly from 2009 to 2012, diabetes co-morbidities (hypertension and dyslipidaemia) and complications had also increased. Prevalence of insulin use had doubled, and lipid lowering agent use had increased about 50% in 2012 compared to 2009. We identified six clinical areas for urgent attention and improvement, and three potential areas for future research. Copyright © 2016 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Discovery of antitubulin agents with antiangiogenic activity as single entities with multitarget chemotherapy potential.

PubMed

Gangjee, Aleem; Pavana, Roheeth Kumar; Ihnat, Michael A; Thorpe, Jessica E; Disch, Bryan C; Bastian, Anja; Bailey-Downs, Lora C; Hamel, Ernest; Bai, Rouli

2014-05-08

Antiangiogenic agents (AA) are cytostatic, and their utility in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of vascular endothelial growth factor receptor-2 (VEGFR2) inhibitors with antitubulin agents have been particularly successful. We have discovered a novel, potentially important analogue, that combines potent VEGFR2 inhibitory activity (comparable to that of sunitinib) with potent antitubulin activity (comparable to that of combretastatin A-4 (CA)) in a single molecule, with GI50 values of 10(-7) M across the entire NCI 60 tumor cell panel. It potently inhibited tubulin assembly and circumvented the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to antimicrotubule agents. The compound is freely water-soluble as its HCl salt and afforded excellent antitumor activity in vivo, superior to docetaxel, sunitinib, or Temozolomide, without any toxicity.

OTC analgesics and drug interactions: clinical implications

PubMed Central

Fendrick, A Mark; Pan, Deborah E; Johnson, Grace E

2008-01-01

The risk of drug interactions with concurrent use of multiple medications is a clinically relevant issue. Many patients are unaware that over-the-counter (OTC) analgesics can cause potentially serious adverse effects when used in combination with other common medications such as anticoagulants, corticosteroids, or antihypertensive agents. Of particular significance is the increased risk of upper abdominal gastrointestinal adverse events in patients who take traditional nonsteroidal anti-inflammatory drugs (NSAIDs). This risk is dose dependent and further increased in patients who take more than one NSAID or use NSAIDs in combination with certain other medications. Some NSAIDs may also mitigate the antiplatelet benefits of aspirin and may increase blood pressure in patients with hypertension. Clinicians should be aware of potential drug interactions with OTC analgesics when prescribing new medications. Additionally, patients should be properly counseled on the appropriate and safe use of OTC analgesics. PMID:18257920

Consumer sleep monitors: is there a baby in the bathwater?

PubMed Central

Russo, Kathryn; Goparaju, Balaji; Bianchi, Matt T

2015-01-01

The rapid expansion of consumer sleep devices is outpacing the validation data necessary to assess the potential use of these devices in clinical and research settings. Common sleep monitoring devices utilize a variety of sensors to track movement as well as cardiac and respiratory physiology. The variety of sensors and user-specific factors offer the potential, at least theoretically, for clinically relevant information. We describe the current challenges for interpretation of consumer sleep monitoring data, since the devices are mainly used in non-medical contexts (consumer use) although medically-definable sleep disorders may commonly occur in this setting. A framework for addressing questions of how certain devices might be useful is offered. We suggest that multistage validation efforts are crucially needed, from the level of sensor data and algorithm output, to extrapolations beyond healthy adults and into other populations and real-world environments. PMID:26604847

Improving the quality of nurse clinical documentation for chronic patients at primary care clinics: A multifaceted intervention.

PubMed

Mahomed, Ozayr H; Naidoo, Salsohni; Asmall, Shaidah; Taylor, Myra

2015-09-25

Deficiencies in record keeping practices have been reported at primary care level in the public health sector in South Africa. These deficiencies have the potential to negatively impact patient health outcomes as the break in information may hinder continuity of care. This disruption in information management has particular relevance for patients with chronic diseases. The aim of this study was to establish if the implementation of a structured clinical record (SCR) as an adjunct tool to the algorithmic guidelines for chronic disease management improved the quality of clinical records at primary care level. A quasi-experimental study (before and after study with a comparison group) was conducted across 30 primary health care clinics (PHCs) located in three districts in South Africa. Twenty PHCs that received the intervention were selected as intervention clinics and 10 facilities were selected as comparison facilities. The lot quality assurance sampling (LQAS) method was used to determine the number of records required to be reviewed per diagnostic condition per facility. There was a a statistically significant increase in the percentage of clinical records achieving compliance to the minimum criteria from the baseline to six months post-intervention for both HIV patients on antiretroviral treatment and patients with non-communicable diseases (hypertension and diabetes). A multifaceted intervention using a SCR to supplement the educational outreach component (PC 101 training) has demonstrated the potential for improving the quality of clinical records for patients with chronic diseases at primary care clinics in South Africa.

Detecting clinically relevant new information in clinical notes across specialties and settings.

PubMed

Zhang, Rui; Pakhomov, Serguei V S; Arsoniadis, Elliot G; Lee, Janet T; Wang, Yan; Melton, Genevieve B

2017-07-05

Automated methods for identifying clinically relevant new versus redundant information in electronic health record (EHR) clinical notes is useful for clinicians and researchers involved in patient care and clinical research, respectively. We evaluated methods to automatically identify clinically relevant new information in clinical notes, and compared the quantity of redundant information across specialties and clinical settings. Statistical language models augmented with semantic similarity measures were evaluated as a means to detect and quantify clinically relevant new and redundant information over longitudinal clinical notes for a given patient. A corpus of 591 progress notes over 40 inpatient admissions was annotated for new information longitudinally by physicians to generate a reference standard. Note redundancy between various specialties was evaluated on 71,021 outpatient notes and 64,695 inpatient notes from 500 solid organ transplant patients (April 2015 through August 2015). Our best method achieved at best performance of 0.87 recall, 0.62 precision, and 0.72 F-measure. Addition of semantic similarity metrics compared to baseline improved recall but otherwise resulted in similar performance. While outpatient and inpatient notes had relatively similar levels of high redundancy (61% and 68%, respectively), redundancy differed by author specialty with mean redundancy of 75%, 66%, 57%, and 55% observed in pediatric, internal medicine, psychiatry and surgical notes, respectively. Automated techniques with statistical language models for detecting redundant versus clinically relevant new information in clinical notes do not improve with the addition of semantic similarity measures. While levels of redundancy seem relatively similar in the inpatient and ambulatory settings in the Fairview Health Services, clinical note redundancy appears to vary significantly with different medical specialties.

Life events and escape in conversion disorder.

PubMed

Nicholson, T R; Aybek, S; Craig, T; Harris, T; Wojcik, W; David, A S; Kanaan, R A

2016-09-01

Psychological models of conversion disorder (CD) traditionally assume that psychosocial stressors are identifiable around symptom onset. In the face of limited supportive evidence such models are being challenged. Forty-three motor CD patients, 28 depression patients and 28 healthy controls were assessed using the Life Events and Difficulties Schedule in the year before symptom onset. A novel 'escape' rating for events was developed to test the Freudian theory that physical symptoms of CD could provide escape from stressors, a form of 'secondary gain'. CD patients had significantly more severe life events and 'escape' events than controls. In the month before symptom onset at least one severe event was identified in 56% of CD patients - significantly more than 21% of depression patients [odds ratio (OR) 4.63, 95% confidence interval (CI) 1.56-13.70] and healthy controls (OR 5.81, 95% CI 1.86-18.2). In the same time period 53% of CD patients had at least one 'high escape' event - again significantly higher than 14% in depression patients (OR 6.90, 95% CI 2.05-23.6) and 0% in healthy controls. Previous sexual abuse was more commonly reported in CD than controls, and in one third of female patients was contextually relevant to life events at symptom onset. The majority (88%) of life events of potential aetiological relevance were not identified by routine clinical assessments. Nine per cent of CD patients had no identifiable severe life events. Evidence was found supporting the psychological model of CD, the Freudian notion of escape and the potential aetiological relevance of childhood traumas in some patients. Uncovering stressors of potential aetiological relevance requires thorough psychosocial evaluation.

Seventeen Years of Using Flowable Resin Restoratives--A Dental Practitioner's Personal Clinical Review.

PubMed

Firla, Markus Th

2015-04-01

Seen through the author's eyes on the basis of his practising dentistry for almost three decades, light-activated flowable resin restoratives (FRCs) or, in common clinical dental terminology, flowable composites have gradually gained major importance in restorative dentistry. Inputs to this ongoing trend are coming from continuous improvements in material properties and the favourable handling characteristics experienced with this particular group of restoratives. Intended to be used in direct adhesive filling procedures, the number and variety of recent generations of flowable composites for lining, restoration of all cavity classes (I-V), core build-ups and, more recently, 'bulk-fill-restorations', however, necessitates a profound clinical understanding of the selective use of flowable composites to ensure clinical success and guarantee long-term high quality results. Clinical relevance: Today's flowable composites allow for reliable restoration of all kinds of defects. However, both the handling characteristics and the material properties of FRCs must be fully understood before taking advantage of their potentially excellent clinical performance.

Digital pathology in nephrology clinical trials, research, and pathology practice.

PubMed

Barisoni, Laura; Hodgin, Jeffrey B

2017-11-01

In this review, we will discuss (i) how the recent advancements in digital technology and computational engineering are currently applied to nephropathology in the setting of clinical research, trials, and practice; (ii) the benefits of the new digital environment; (iii) how recognizing its challenges provides opportunities for transformation; and (iv) nephropathology in the upcoming era of kidney precision and predictive medicine. Recent studies highlighted how new standardized protocols facilitate the harmonization of digital pathology database infrastructure and morphologic, morphometric, and computer-aided quantitative analyses. Digital pathology enables robust protocols for clinical trials and research, with the potential to identify previously underused or unrecognized clinically useful parameters. The integration of digital pathology with molecular signatures is leading the way to establishing clinically relevant morpho-omic taxonomies of renal diseases. The introduction of digital pathology in clinical research and trials, and the progressive implementation of the modern software ecosystem, opens opportunities for the development of new predictive diagnostic paradigms and computer-aided algorithms, transforming the practice of renal disease into a modern computational science.

The Effects of Clinically Relevant Multiple-Choice Items on the Statistical Discrimination of Physician Clinical Competence.

ERIC Educational Resources Information Center

Downing, Steven M.; Maatsch, Jack L.

To test the effect of clinically relevant multiple-choice item content on the validity of statistical discriminations of physicians' clinical competence, data were collected from a field test of the Emergency Medicine Examination, test items for the certification of specialists in emergency medicine. Two 91-item multiple-choice subscales were…

The Oncopig Cancer Model: An Innovative Large Animal Translational Oncology Platform

PubMed Central

Schachtschneider, Kyle M.; Schwind, Regina M.; Newson, Jordan; Kinachtchouk, Nickolas; Rizko, Mark; Mendoza-Elias, Nasya; Grippo, Paul; Principe, Daniel R.; Park, Alex; Overgaard, Nana H.; Jungersen, Gregers; Garcia, Kelly D.; Maker, Ajay V.; Rund, Laurie A.; Ozer, Howard; Gaba, Ron C.; Schook, Lawrence B.

2017-01-01

Despite an improved understanding of cancer molecular biology, immune landscapes, and advancements in cytotoxic, biologic, and immunologic anti-cancer therapeutics, cancer remains a leading cause of death worldwide. More than 8.2 million deaths were attributed to cancer in 2012, and it is anticipated that cancer incidence will continue to rise, with 19.3 million cases expected by 2025. The development and investigation of new diagnostic modalities and innovative therapeutic tools is critical for reducing the global cancer burden. Toward this end, transitional animal models serve a crucial role in bridging the gap between fundamental diagnostic and therapeutic discoveries and human clinical trials. Such animal models offer insights into all aspects of the basic science-clinical translational cancer research continuum (screening, detection, oncogenesis, tumor biology, immunogenicity, therapeutics, and outcomes). To date, however, cancer research progress has been markedly hampered by lack of a genotypically, anatomically, and physiologically relevant large animal model. Without progressive cancer models, discoveries are hindered and cures are improbable. Herein, we describe a transgenic porcine model—the Oncopig Cancer Model (OCM)—as a next-generation large animal platform for the study of hematologic and solid tumor oncology. With mutations in key tumor suppressor and oncogenes, TP53R167H and KRASG12D, the OCM recapitulates transcriptional hallmarks of human disease while also exhibiting clinically relevant histologic and genotypic tumor phenotypes. Moreover, as obesity rates increase across the global population, cancer patients commonly present clinically with multiple comorbid conditions. Due to the effects of these comorbidities on patient management, therapeutic strategies, and clinical outcomes, an ideal animal model should develop cancer on the background of representative comorbid conditions (tumor macro- and microenvironments). As observed in clinical practice, liver cirrhosis frequently precedes development of primary liver cancer or hepatocellular carcinoma. The OCM has the capacity to develop tumors in combination with such relevant comorbidities. Furthermore, studies on the tumor microenvironment demonstrate similarities between OCM and human cancer genomic landscapes. This review highlights the potential of this and other large animal platforms as transitional models to bridge the gap between basic research and clinical practice. PMID:28879168

Generation of small molecules to interfere with regulated necrosis.

PubMed

Degterev, Alexei; Linkermann, Andreas

2016-06-01

Interference with regulated necrosis for clinical purposes carries broad therapeutic relevance and, if successfully achieved, has a potential to revolutionize everyday clinical routine. Necrosis was interpreted as something that no clinician might ever be able to prevent due to the unregulated nature of this form of cell death. However, given our growing understanding of the existence of regulated forms of necrosis and the roles of key enzymes of these pathways, e.g., kinases, peroxidases, etc., the possibility emerges to identify efficient and selective small molecule inhibitors of pathologic necrosis. Here, we review the published literature on small molecule inhibition of regulated necrosis and provide an outlook on how combination therapy may be most effective in treatment of necrosis-associated clinical situations like stroke, myocardial infarction, sepsis, cancer and solid organ transplantation.

Current Status and Future Development of Cell Transplantation Therapy for Periodontal Tissue Regeneration

PubMed Central

Yoshida, Toshiyuki; Washio, Kaoru; Iwata, Takanori; Okano, Teruo; Ishikawa, Isao

2012-01-01

It has been shown that stem cell transplantation can regenerate periodontal tissue, and several clinical trials involving transplantation of stem cells into human patients have already begun or are in preparation. However, stem cell transplantation therapy is a new technology, and the events following transplantation are poorly understood. Several studies have reported side effects and potential risks associated with stem cell transplantation therapy. To protect patients from such risks, governments have placed regulations on stem cell transplantation therapies. It is important for the clinicians to understand the relevant risks and governmental regulations. This paper describes the ongoing clinical studies, basic research, risks, and governmental controls related to stem cell transplantation therapy. Then, one clinical study is introduced as an example of a government-approved periodontal cell transplantation therapy. PMID:22315604

Ahead of the game: the use of gaming to enhance knowledge of psychopharmacology.

PubMed

Beek, Terra S; Boone, Cheryl; Hubbard, Grace

2014-12-01

Experiential teaching strategies have the potential to more effectively help students with critical thinking than traditional lecture formats. Gaming is an experiential teaching-learning strategy that reinforces teamwork, interaction, and enjoyment and introduces the element of play. Two Bachelor of Science in Nursing students and a clinical instructor created a Jeopardy!(®)-style game to enhance understanding of psychopharmacology, foster student engagement in the learning process, and promote student enjoyment during clinical postconference. The current article evaluates the utility, relevance, and effectiveness of gaming using a Jeopardy!(®)-style format for the psychiatric clinical setting. Students identified the strengths of this learning activity as increased awareness of knowledge deficits, as well as the reinforcement of existing knowledge and the value of teamwork. Copyright 2014, SLACK Incorporated.

[Blastocystis spp.: Advances, controversies and future challenges].

PubMed

Del Coco, Valeria F; Molina, Nora B; Basualdo, Juan A; Córdoba, María A

Blastocystis spp. is the most common protozoan detected in human stool samples. In developing countries, infection rates are higher than 20%. The presence of this parasite in the feces of several host species suggests its zoonotic potential. The clinical relevance and the pathogenic role of Blastocystis spp. in the intestinal tract remain unclear. There are several clinical reports that recognize it as the etiologic agent of several intestinal disorders such as diarrhea, inflammatory bowel disease and ulcerative colitis, although the pathogenicity of this parasite has not been proved yet. This wide range of clinical manifestations could be related to the genetic diversity exhibited by this parasite. Copyright © 2016 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

Consensus and contentious statements on the use of probiotics in clinical practice: a South East Asian Gastro-neuro Motility Association Working Team Report.

PubMed

Gwee, Kok-Ann; Lee, Warren Wei-Rhen; Ling, Khoon Lin; Ooi, Choon Jin; Quak, Seng Hock; Dan, Yock Young; Siah, Kewin Tien-Ho; Huang, James Guoxian; Chua, Andrew Seng Boon; Hilmi, Ida Normiha; Raja Affendi, R A; Ong, Christina; Simadibrata, Marcellus; Abdullah, Murdani; Sollano, Jose D; Leelakusolvong, Somchai; Gonlachanvit, Sutep; Lee, Yeong Yeh; Ricaforte-Campos, Jane D; Yin, Yee Kian; Chong, Kuck-Meng; Wong, Chong Yuen

2018-04-26

The concept of consuming microorganisms in the treatment of a medical condition and in health maintenance has gained much traction, giving rise to an abundance of medical claims, and of health supplements. We identified relevant clinical questions on the therapeutic use of probiotics and reviewed the literature in irritable bowel syndrome, inflammatory bowel disease, impaired intestinal immunity, liver disease, intestinal infections and common childhood digestive disorders. Statements were developed to address these clinical questions. A panel of experienced clinicians was tasked to critically evaluate and debate the available data. Both consensus and contentious statements are presented to provide to clinicians a perspective on the potential of probiotics, and importantly their limitations. This article is protected by copyright. All rights reserved.

Therapeutic Risk and Benefits of Concomitantly Using Herbal Medicines and Conventional Medicines: From the Perspectives of Evidence Based on Randomized Controlled Trials and Clinical Risk Management

PubMed Central

Zhang, Xiu-lai; Chen, Meng; Zhu, Ling-ling

2017-01-01

Despite increased awareness of the potential of herb-drug interactions (HDIs), the lack of rigorous clinical evidence regarding the significance provides a challenge for clinicians and consumers to make rational decisions about the safe combination of herbal and conventional medicines. This review addressed HDIs based on evidence from randomized controlled trials (RCTs). Literature was identified by performing a PubMed search till January 2017. Risk description and clinical risk management were described. Among 74 finally included RCTs, 17 RCTs (22.97%) simply addressed pharmacodynamic HDIs. Fifty-seven RCTs (77.03%) investigated pharmacokinetic HDIs and twenty-eight of them showed potential or actual clinical relevance. The extent of an HDI may be associated with the factors such as pharmacogenomics, dose of active ingredients in herbs, time course of interaction, characteristics of the object drugs (e.g., administration routes and pharmacokinetic profiles), modification of herbal prescription compositions, and coexistence of inducers and inhibitors. Clinical professionals should enhance risk management on HDIs such as increasing awareness of potential changes in therapeutic risk and benefits, inquiring patients about all currently used conventional medicines and herbal medicines and supplements, automatically detecting highly substantial significant HDI by computerized reminder system, selecting the alternatives, adjusting dose, reviewing the appropriateness of physician orders, educating patients to monitor for drug-interaction symptoms, and paying attention to follow-up visit and consultation. PMID:28491115

The long tail of molecular alterations in non-small cell lung cancer: a single-institution experience of next-generation sequencing in clinical molecular diagnostics.

PubMed

Fumagalli, Caterina; Vacirca, Davide; Rappa, Alessandra; Passaro, Antonio; Guarize, Juliana; Rafaniello Raviele, Paola; de Marinis, Filippo; Spaggiari, Lorenzo; Casadio, Chiara; Viale, Giuseppe; Barberis, Massimo; Guerini-Rocco, Elena

2018-03-13

Molecular profiling of advanced non-small cell lung cancers (NSCLC) is essential to identify patients who may benefit from targeted treatments. In the last years, the number of potentially actionable molecular alterations has rapidly increased. Next-generation sequencing allows for the analysis of multiple genes simultaneously. To evaluate the feasibility and the throughput of next-generation sequencing in clinical molecular diagnostics of advanced NSCLC. A single-institution cohort of 535 non-squamous NSCLC was profiled using a next-generation sequencing panel targeting 22 actionable and cancer-related genes. 441 non-squamous NSCLC (82.4%) harboured at least one gene alteration, including 340 cases (63.6%) with clinically relevant molecular aberrations. Mutations have been detected in all but one gene ( FGFR1 ) of the panel. Recurrent alterations were observed in KRAS , TP53 , EGFR , STK11 and MET genes, whereas the remaining genes were mutated in <5% of the cases. Concurrent mutations were detected in 183 tumours (34.2%), mostly impairing KRAS or EGFR in association with TP53 alterations. The study highlights the feasibility of targeted next-generation sequencing in clinical setting. The majority of NSCLC harboured mutations in clinically relevant genes, thus identifying patients who might benefit from different targeted therapies. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Application of a diagnosis-based clinical decision guide in patients with low back pain.

PubMed

Murphy, Donald R; Hurwitz, Eric L

2011-10-21

Low back pain (LBP) is common and costly. Development of accurate and efficacious methods of diagnosis and treatment has been identified as a research priority. A diagnosis-based clinical decision guide (DBCDG; previously referred to as a diagnosis-based clinical decision rule) has been proposed which attempts to provide the clinician with a systematic, evidence-based means to apply the biopsychosocial model of care. The approach is based on three questions of diagnosis. The purpose of this study is to present the prevalence of findings using the DBCDG in consecutive patients with LBP. Demographic, diagnostic and baseline outcome measure data were gathered on a cohort of LBP patients examined by one of three examiners trained in the application of the DBCDG. Data were gathered on 264 patients. Signs of visceral disease or potentially serious illness were found in 2.7%. Centralization signs were found in 41%, lumbar and sacroiliac segmental signs in 23% and 27%, respectively and radicular signs were found in 24%. Clinically relevant myofascial signs were diagnosed in 10%. Dynamic instability was diagnosed in 63%, fear beliefs in 40%, central pain hypersensitivity in 5%, passive coping in 3% and depression in 3%. The DBCDG can be applied in a busy private practice environment. Further studies are needed to investigate clinically relevant means to identify central pain hypersensitivity, poor coping and depression, correlations and patterns among the diagnostic components of the DBCDG as well as inter-examiner reliability and efficacy of treatment based on the DBCDG.

[Medical aspects of common non-lethal weapons].

PubMed

Kunz, Sebastian Niko; Grove, Christina; Monticelli, Fabio

2014-03-01

The development and provision of non-lethal weapons (NLW) allow military and law enforcement personnel to exploit gradual engagement in countering potentially hazardous threats. Chemical, kinetic and electrical weapons systems are used to curb violence in civilian crowds. With inappropriate usage, these technologies can cause potentially fatal injuries that are not only of clinical, but also of legal relevance. In this context, the practicing physician is faced with treatment as well as assessment issues of new forms of injuries. In order to assure medical care and to be able to draw competent expert's conclusions, a detailed knowledge of the medical effects of these NLW is necessary. The review at hand presents today's most popular NLW and gives an overview of their possible injury potential and required treatments.

Potential Benefits of Non-Pharmacological Therapies in Fibromyalgia

PubMed Central

Sueiro Blanco, F.; Estévez Schwarz, I.; Ayán, C.; Cancela, JM.; Martín, V.

2008-01-01

Fibromyalgia (FM) is an incurable common syndrome of non-articular origin, and with no effective treatment by now. A great deal of research has sought to assess the efficacy of different therapies, especially non-pharmacological and low-cost ones, in the reduction of the intensity of symptoms. Despite the availability of a wide range of alternative therapies nowadays, there is little scientific evidence of the potential benefits of most of them, with results being contradictories. The purpose of this paper is to review some of the less well known alternative therapies in FM treatment, to describe the more relevant clinical studies published in this matter, and to analyze the potential effects of the main alternative therapies, in order to verify their efficacy. PMID:19088863

Standardized Computer-based Organized Reporting of EEG: SCORE

PubMed Central

Beniczky, Sándor; Aurlien, Harald; Brøgger, Jan C; Fuglsang-Frederiksen, Anders; Martins-da-Silva, António; Trinka, Eugen; Visser, Gerhard; Rubboli, Guido; Hjalgrim, Helle; Stefan, Hermann; Rosén, Ingmar; Zarubova, Jana; Dobesberger, Judith; Alving, Jørgen; Andersen, Kjeld V; Fabricius, Martin; Atkins, Mary D; Neufeld, Miri; Plouin, Perrine; Marusic, Petr; Pressler, Ronit; Mameniskiene, Ruta; Hopfengärtner, Rüdiger; Emde Boas, Walter; Wolf, Peter

2013-01-01

The electroencephalography (EEG) signal has a high complexity, and the process of extracting clinically relevant features is achieved by visual analysis of the recordings. The interobserver agreement in EEG interpretation is only moderate. This is partly due to the method of reporting the findings in free-text format. The purpose of our endeavor was to create a computer-based system for EEG assessment and reporting, where the physicians would construct the reports by choosing from predefined elements for each relevant EEG feature, as well as the clinical phenomena (for video-EEG recordings). A working group of EEG experts took part in consensus workshops in Dianalund, Denmark, in 2010 and 2011. The faculty was approved by the Commission on European Affairs of the International League Against Epilepsy (ILAE). The working group produced a consensus proposal that went through a pan-European review process, organized by the European Chapter of the International Federation of Clinical Neurophysiology. The Standardised Computer-based Organised Reporting of EEG (SCORE) software was constructed based on the terms and features of the consensus statement and it was tested in the clinical practice. The main elements of SCORE are the following: personal data of the patient, referral data, recording conditions, modulators, background activity, drowsiness and sleep, interictal findings, “episodes” (clinical or subclinical events), physiologic patterns, patterns of uncertain significance, artifacts, polygraphic channels, and diagnostic significance. The following specific aspects of the neonatal EEGs are scored: alertness, temporal organization, and spatial organization. For each EEG finding, relevant features are scored using predefined terms. Definitions are provided for all EEG terms and features. SCORE can potentially improve the quality of EEG assessment and reporting; it will help incorporate the results of computer-assisted analysis into the report, it will make possible the build-up of a multinational database, and it will help in training young neurophysiologists. PMID:23506075

An evaluation of the pharmacokinetics of methylphenidate for the treatment of attention-deficit/ hyperactivity disorder.

PubMed

Frölich, Jan; Banaschewski, Tobias; Döpfner, Manfred; Görtz-Dorten, Anja

2014-08-01

Methylphenidate (MPH) plays a principal role in the multimodal treatment of attention-deficit/hyperactivity disorder (ADHD). Controlled studies have demonstrated an effective reduction in the core symptoms of the disorder following MPH therapy, although long-term studies also demonstrate that the therapeutic benefits dissipate in the absence of combined psychosocial interventions. This review article focuses on the pharmacological characteristics of MPH, examining its effects on brain metabolism and the neurotransmitter system. Neuropsychological and clinical effects of different immediate and extended release MPH formulations are discussed to aid clinicians in choosing the appropriate formulation. The drug's addictive potency and abuse potential is also discussed. Data came from a literature search of relevant studies performed using the PubMed database up to June 2013. MPH is effective in the treatment of the core symptoms of ADHD. Considerable clinical expertise is required to identify an individually well-adapted dosage which will produce the optimal clinical effects with potential side effects minimized. Due to low adherence to medication, especially in adolescents, motivation to treatment and attentive clinical monitoring is mandatory, as is the consideration of risks of abuse or the presence of a comorbid addictive disorder.

Construction and Potential Applications of Biosensors for Proteins in Clinical Laboratory Diagnosis

PubMed Central

Liu, Xuan

2017-01-01

Biosensors for proteins have shown attractive advantages compared to traditional techniques in clinical laboratory diagnosis. In virtue of modern fabrication modes and detection techniques, various immunosensing platforms have been reported on basis of the specific recognition between antigen-antibody pairs. In addition to profit from the development of nanotechnology and molecular biology, diverse fabrication and signal amplification strategies have been designed for detection of protein antigens, which has led to great achievements in fast quantitative and simultaneous testing with extremely high sensitivity and specificity. Besides antigens, determination of antibodies also possesses great significance for clinical laboratory diagnosis. In this review, we will categorize recent immunosensors for proteins by different detection techniques. The basic conception of detection techniques, sensing mechanisms, and the relevant signal amplification strategies are introduced. Since antibodies and antigens have an equal position to each other in immunosensing, all biosensing strategies for antigens can be extended to antibodies under appropriate optimizations. Biosensors for antibodies are summarized, focusing on potential applications in clinical laboratory diagnosis, such as a series of biomarkers for infectious diseases and autoimmune diseases, and an evaluation of vaccine immunity. The excellent performances of these biosensors provide a prospective space for future antibody-detection-based disease serodiagnosis. PMID:29207528

Construction and Potential Applications of Biosensors for Proteins in Clinical Laboratory Diagnosis.

PubMed

Liu, Xuan; Jiang, Hui

2017-12-04

Biosensors for proteins have shown attractive advantages compared to traditional techniques in clinical laboratory diagnosis. In virtue of modern fabrication modes and detection techniques, various immunosensing platforms have been reported on basis of the specific recognition between antigen-antibody pairs. In addition to profit from the development of nanotechnology and molecular biology, diverse fabrication and signal amplification strategies have been designed for detection of protein antigens, which has led to great achievements in fast quantitative and simultaneous testing with extremely high sensitivity and specificity. Besides antigens, determination of antibodies also possesses great significance for clinical laboratory diagnosis. In this review, we will categorize recent immunosensors for proteins by different detection techniques. The basic conception of detection techniques, sensing mechanisms, and the relevant signal amplification strategies are introduced. Since antibodies and antigens have an equal position to each other in immunosensing, all biosensing strategies for antigens can be extended to antibodies under appropriate optimizations. Biosensors for antibodies are summarized, focusing on potential applications in clinical laboratory diagnosis, such as a series of biomarkers for infectious diseases and autoimmune diseases, and an evaluation of vaccine immunity. The excellent performances of these biosensors provide a prospective space for future antibody-detection-based disease serodiagnosis.

Establishment and Characterization of Primary Glioblastoma Cell Lines from Fresh and Frozen Material: A Detailed Comparison

PubMed Central

Mullins, Christina Susanne; Schneider, Björn; Stockhammer, Florian; Krohn, Mathias; Classen, Carl Friedrich; Linnebacher, Michael

2013-01-01

Background Development of clinically relevant tumor model systems for glioblastoma multiforme (GBM) is important for advancement of basic and translational biology. High molecular heterogeneity of GBM tumors is well recognized, forming the rationale for molecular tests required before administration of several of the novel therapeutics rapidly entering the clinics. One model that has gained wide acceptance is the primary cell culture model. The laborious and time consuming process is rewarded with a relative high success rate (about 60%). We here describe and evaluate a very simple cryopreservation procedure for GBM tissue prior to model establishment that will considerably reduce the logistic complexity. Methods Twenty-seven GBM samples collected ad hoc were prepared for primary cell culture freshly from surgery (#1) and after cryopreservation (#2). Results Take rates after cryopreservation (59%) were as satisfactory as from fresh tissue (63%; p = 1.000). We did not observe any relevant molecular or phenotypic differences between cell lines established from fresh or vitally frozen tissue. Further, sensitivity both towards standard chemotherapeutic agents (Temozolomide, BCNU and Vincristine) and novel agents like the receptor tyrosine kinase inhibitor Imatinib did not differ. Conclusions Our simple cryopreservation procedure facilitates collection, long-time storage and propagation (modeling) of clinical GBM specimens (potentially also from distant centers) for basic research, (pre-) clinical studies of novel therapies and individual response prediction. PMID:23951083

Clinical Development of VEGF Signaling Pathway Inhibitors in Childhood Solid Tumors

PubMed Central

Yamashiro, Darrell J.; Fox, Elizabeth

2011-01-01

Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers. PMID:22042784

Herbs with potential nephrotoxic effects according to traditional Persian medicine: Review and assessment of scientific evidence.

PubMed

Kolangi, Fatemeh; Memariani, Zahra; Bozorgi, Mahboubeh; Mozaffarpur, Seyyed Ali; Mirzapour, Mohaddeseh

2018-04-03

The increased use of herbal remedies particularly in patients with kidney diseases indicated the importance of studies which focused on nephrotoxic plants. The present study aimed to review and assess the kidney-damaging herbs mentioned in the Persian medicine [PM] books. The main PM books were searched for nephrotoxic herbs and their relevant reformers traditionally proposed for preventing renal damage. PubMed, Scopus and Google Scholar were investigated for evaluation of the scientific evidence relating to the nephrotoxicity of herbs. A total of 64 plants with kidney damage potential and their reformer medicaments were recorded in 7 sources included in this review. Allium schoenoprasum and Marrubium vulgare were the most repeated and emphasized nephrotoxic plants in PM books, but there was not any relevant scientific evidence. Despite the lack of clinical studies, some evidence was found for 38% of plants that were related to renal damage. The most repeated reformers for reducing the renal side effects mainly consisted of gum tragacanth, gum Arabic, mastic gum, anise, jujube and honey and some evidence was found for their nephroprotective activities. The present study reviewed and assessed the herbs with adverse renal effects in the main PM books. Some evidence was in line with the potential nephrotoxicity of plants and their ‎reformers. Despite the lack of clinical research for evaluation of their renal damage, the herbs may be focused in term of their nephrotoxicity; and there is a need for further studies on the scientific basis of their nephrotoxicity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Criteria for choosing an intravenous infusion line intended for multidrug infusion in anaesthesia and intensive care units.

PubMed

Maiguy-Foinard, Aurélie; Genay, Stéphanie; Lannoy, Damien; Barthélémy, Christine; Lebuffe, Gilles; Debaene, Bertrand; Odou, Pascal; Décaudin, Bertrand

2017-02-01

The aims are to identify critical parameters influencing the drug mass flow rate of infusion delivery to patients during multidrug infusion and to discuss their clinical relevance. A review of literature was conducted in January 2016 using Medline, Google Scholar, ScienceDirect, Web of Science and Scopus online databases. References relating to the accuracy of fluid delivery via gravity-flow intravenous (IV) infusion systems and positive displacement pumps, components of IV administration sets, causes of flow rate variability, potential complications due to flow rate variability, IV therapies especially at low flow rates and drug compatibilities were considered relevant. Several parameters impact the delivery of drugs and fluids by IV infusion. Among them are the components of infusion systems that particularly influence the flow rate of medications and fluids being delivered. By their conception, they may generate significant start-up delays and flow rate variability. Performing multidrug infusion requires taking into account two main points: the common dead volume of drugs delivered simultaneously with potential consequences on the accuracy and amount of drug delivery and the prevention of drug incompatibilities and their clinical effects. To prevent the potentially serious effects of flow rate variability on patients, clinicians should receive instruction on the fluid dynamics of an IV administration set and so be able to take steps to minimise flow rate changes during IV therapy. Copyright © 2016 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.

Frailty and sarcopenia: From theory to clinical implementation and public health relevance.

PubMed

Cesari, Matteo; Nobili, Alessandro; Vitale, Giovanni

2016-11-01

The sustainability of healthcare systems is threatened by the increasing (absolute and relative) number of older persons referring to clinical services. Such global phenomenon is questioning the traditional paradigms of medicine, pushing towards the need of new criteria at the basis of clinical decision algorithms. In this context, frailty has been advocated as a geriatric condition potentially capable of overcoming the weakness of chronological age in the identification of individuals requiring adapted care due to their increased vulnerability to stressors. Interestingly, frailty poses itself beyond the concept of nosological conditions due to the difficulties at correctly framing traditional diseases in the complex and heterogeneous scenario of elders. Thus, frailty may play a key role in public health policies for promoting integrated care towards biologically aged individuals, currently presenting multiple unmet clinical needs. At the same time, the term frailty has also been frequently used in the literature for framing a physical condition of risk for (mainly functional) negative endpoints. The combination of such physical impairment with an organ-specific phenotype (e.g., the age-related skeletal muscle decline or sarcopenia) may determine the assumptions for the development of a clinical condition to be used as potential target for ad hoc interventions against physical disability. In the present article, we present the background of frailty and sarcopenia, and discuss their potentialities for reshaping current clinical and research practice in order to promote holistic approach to older patients, solicit personalization of care, and develop new targets for innovative interventions. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Polymer coating embolism from intravascular medical devices - a clinical literature review.

PubMed

Chopra, Amitabh M; Mehta, Monik; Bismuth, Jean; Shapiro, Maksim; Fishbein, Michael C; Bridges, Alina G; Vinters, Harry V

Over the past three decades, lubricious (hydrophobic and/or hydrophilic) polymer-coated devices have been increasingly adopted by interventional physicians and vascular surgeons to access and treat a wider range of clinical presentations. Recent clinical literature highlights the presence of polymer coating emboli within the anatomy - a result of coating separation from an intravascular device - and associates it with a range of adverse clinical sequelae. The 2015 U.S. Food and Drug Administration safety communication titled "Lubricious Coating Separation from Intravascular Medical Devices" acknowledges these concerns and concludes that it will work with stakeholders to develop nonclinical test methodologies, establish performance criteria, and identify gaps in current national and international device standards for coating integrity performance. Despite this communication and multiple case reports from interventional physicians, pathologists, dermatologists and other involved physician specialties, polymer coating embolism remains clinically underrecognized. This article consolidates the available literature on polymer coating embolism (1986-2016) and highlights the following relevant information for the physician: (a) the history and elusive nature of polymer coating embolism; (b) potential incidence rates of this phenomenon; (c) reported histologic findings and clinical effects of polymer emboli in the anatomy; (d) the importance of the collaborative clinician-pathologist partnership to report polymer embolism findings; and (e) the importance to study particulate release from intravascular devices so as to further understand and potentially evolve coated interventional technologies. Preliminary research on coatings highlights the potential of using iterations of coatings on medical devices that attain the desired therapeutic result and mitigate or eliminate particulates altogether. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

False Alarms and Overmonitoring: Major Factors in Alarm Fatigue Among Labor Nurses.

PubMed

Simpson, Kathleen Rice; Lyndon, Audrey

2018-06-08

Nurses can be exposed to hundreds of alarms during their shift, contributing to alarm fatigue. The purposes were to explore similarities and differences in perceptions of clinical alarms by labor nurses caring for generally healthy women compared with perceptions of adult intensive care unit (ICU) and neonatal ICU nurses caring for critically ill patients and to seek nurses' suggestions for potential improvements. Nurses were asked via focus groups about the utility of clinical alarms from medical devices. There was consensus that false alarms and too many devices generating alarms contributed to alarm fatigue, and most alarms lacked clinical relevance. Nurses identified certain types of alarms that they responded to immediately, but the vast majority of the alarms did not contribute to their clinical assessment or planned nursing care. Monitoring only those patients who need it and only those physiologic values that are warranted, based on patient condition, may decrease alarm burden.

Translating basic research into clinical practice or what else do we have to learn about olfactory ensheathing cells?

PubMed

Radtke, Christine; Wewetzer, Konstantin

2009-06-12

Olfactory ensheathing cells (OECs) are Schwann cell-like glial cells of the olfactory system that have been shown to promote axonal regeneration and remyelination in a variety of different lesion paradigms. It is still a matter of debate in how far OECs differ from Schwann cells regarding their regenerative potential and molecular setup. The fact that OECs have been already used for transplantation in humans may imply that the need of the hour is the fine-tuning of clinical application details rather than to cross the bridge between laboratory animal and man. Considering the therapeutic transplantation of OECs, however, the basic question to date is not 'how' to translate but rather 'what' to translate into clinical practice. The aim of the present article is to provide a summary of the current literature and to define the open issues relevant for translating basic research on OECs into clinical practice.

Prescription Drug Monitoring Programs: Ethical Issues in the Emergency Department.

PubMed

Marco, Catherine A; Venkat, Arvind; Baker, Eileen F; Jesus, John E; Geiderman, Joel M

2016-11-01

Prescription drug monitoring programs are statewide databases available to clinicians to track prescriptions of controlled medications. These programs may provide valuable information to assess the history and use of controlled substances and contribute to clinical decisionmaking in the emergency department (ED). The widespread availability of the programs raises important ethical issues about beneficence, nonmaleficence, respect for persons, justice, confidentiality, veracity, and physician autonomy. In this article, we review the ethical issues surrounding prescription drug monitoring programs and how those issues might be addressed to ensure the proper application of this tool in the ED. Clinical decisionmaking in regard to the appropriate use of opioids and other controlled substances is complex and should take into account all relevant clinical factors, including age, sex, clinical condition, medical history, medication history and potential drug-drug interactions, history of addiction or diversion, and disease state. Copyright © 2016 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

Infiltrative cervical lesions causing symptomatic occipital neuralgia.

PubMed

Sierra-Hidalgo, F; Ruíz, J; Morales-Cartagena, A; Martínez-Salio, A; Serna, J de la; Hernández-Gallego, J

2011-10-01

Occipital neuralgia is a well-recognized cause of posterior head and neck pain that may associate mild sensory changes in the cutaneous distribution of the occipital nerves, lacking a recognizable local structural aetiology in most cases. Atypical clinical features or an abnormal neurological examination are alerts for a potential underlying cause of pain, although cases of clinically typical occipital neuralgia as isolated manifestation of lesions of the cervical spinal cord, cervical roots, or occipital nerves have been increasingly reported. We describe two cases (one with typical and another one with atypical clinical features) of occipital neuralgia secondary to paravertebral pyomyositis and vertebral relapse of multiple myeloma in patients with relevant medical history that aroused the possibility of an underlying structural lesion. We discuss the need for cranio-cervical magnetic resonance imaging in all patients with occipital neuralgia, even when typical clinical features are present and neurological examination is completely normal.

How next-generation sequencing and multiscale data analysis will transform infectious disease management.

PubMed

Pak, Theodore R; Kasarskis, Andrew

2015-12-01

Recent reviews have examined the extent to which routine next-generation sequencing (NGS) on clinical specimens will improve the capabilities of clinical microbiology laboratories in the short term, but do not explore integrating NGS with clinical data from electronic medical records (EMRs), immune profiling data, and other rich datasets to create multiscale predictive models. This review introduces a range of "omics" and patient data sources relevant to managing infections and proposes 3 potentially disruptive applications for these data in the clinical workflow. The combined threats of healthcare-associated infections and multidrug-resistant organisms may be addressed by multiscale analysis of NGS and EMR data that is ideally updated and refined over time within each healthcare organization. Such data and analysis should form the cornerstone of future learning health systems for infectious disease. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Method for Phenotypic Detection of Extended-Spectrum Beta-Lactamases in Enterobacter Species in the Routine Clinical Setting ▿

PubMed Central

Stuart, James Cohen; Diederen, Bram; al Naiemi, Nashwan; Fluit, Ad; Arents, Niek; Thijsen, Steven; Vlaminckx, Bart; Mouton, Johan W.; Leverstein-van Hall, Maurine

2011-01-01

In 271 Enterobacter blood culture isolates from 12 hospitals, extended-spectrum beta-lactamase (ESBL) prevalence varied between 0% and 30% per hospital. High prevalence was associated with dissemination, indicating the potential relevance of infection control measures. Screening with cefepime or Vitek 2, followed by a cefepime/cefepime-clavulanate Etest, was an accurate strategy for ESBL detection in Enterobacter isolates (positive predictive value, 100%; negative predictive value, 99%). PMID:21562100

Time to connect: bringing social context into addiction neuroscience

PubMed Central

Heilig, Markus; Epstein, David H.; Nader, Michael A.; Shaham, Yavin

2017-01-01

Research on the neural substrates of drug reward, withdrawal and relapse has yet to be translated into significant advances in the treatment of addiction. One potential reason is that this research has not captured a common feature of human addiction: progressive social exclusion and marginalization. We propose that research aimed at understanding the neural mechanisms that link these processes to drug seeking and drug taking would help to make addiction neuroscience research more clinically relevant. PMID:27277868

Time to connect: bringing social context into addiction neuroscience.

PubMed

Heilig, Markus; Epstein, David H; Nader, Michael A; Shaham, Yavin

2016-09-01

Research on the neural substrates of drug reward, withdrawal and relapse has yet to be translated into significant advances in the treatment of addiction. One potential reason is that this research has not captured a common feature of human addiction: progressive social exclusion and marginalization. We propose that research aimed at understanding the neural mechanisms that link these processes to drug seeking and drug taking would help to make addiction neuroscience research more clinically relevant.

Butyric acid – a well-known molecule revisited

PubMed Central

Banasiewicz, Tomasz; Rydzewska, Grażyna

2017-01-01

The properties of butyric acid, and the role it plays in the gastrointestinal tract, have been known for many years. However, the newest research shows that butyric acid still remains a molecule with a potential that has not as yet been fully exploited. The article provides an outline of relevant up-to-date knowledge about butyric acid, and presents the expert position on the clinical benefits of using butyric acid products in the therapy of gastrointestinal diseases. PMID:28702095

Butyric acid - a well-known molecule revisited.

PubMed

Borycka-Kiciak, Katarzyna; Banasiewicz, Tomasz; Rydzewska, Grażyna

2017-01-01

The properties of butyric acid, and the role it plays in the gastrointestinal tract, have been known for many years. However, the newest research shows that butyric acid still remains a molecule with a potential that has not as yet been fully exploited. The article provides an outline of relevant up-to-date knowledge about butyric acid, and presents the expert position on the clinical benefits of using butyric acid products in the therapy of gastrointestinal diseases.

Dysphagia and dentistry.

PubMed

Curl, Charlotte; Boyle, Carole

2014-06-01

Dysphagia is defined as a 'difficulty in swallowing' and is commonly found in the general population, particularly in the elderly. This article gives an overview of the more frequently encountered swallowing disorders and provides advice on how to manage the dysphagic patient in the dental surgery. Clinical Relevance: By identifying patients with dysphagia and being aware of the potential problems that the clinician may experience when treating them, the risk of aspiration, choking and healthcare-acquired upper respiratory tract infections may be reduced.

An ecological model of intimate partner violence perpetration at different levels of severity.

PubMed

Smith Slep, Amy M; Foran, Heather M; Heyman, Richard E

2014-08-01

Intimate partner violence (IPV) is a significant public health concern. This study proposed and tested an ecological model of both general and clinically significant (i.e., injurious or fear-evoking) IPV perpetration (IPVPerp). Risk and promotive factors from multiple ecological levels of influence (i.e., individual, family, workplace, community) were hypothesized to be important in the prediction of IPVPerp. Although clinically significant IPVPerp and general IPVPerp were hypothesized to relate, specific risks for clinically significant IPVPerp were hypothesized. U.S. Air Force active duty members and civilian spouses (N = 34,861 men; 24,331 women) from 82 sites worldwide completed the 2006 Community Assessment, an anonymous online survey assessing IPVPerp along with a variety of potential risk and promotive factors. Final structural equation models for men and women, cross-validated in holdout samples, clearly supported the relevance of an ecological approach to IPVPerp. Factors from all 4 levels were associated with both general IPVPerp and clinically significant IPVPerp, with relatively distal community and workplace factors operating via more proximal individual and family level variables (e.g., relationship satisfaction). The results suggest a variety of both established and novel potential targets for indirectly targeting general and clinically significant IPVPerp by improving risk profiles at the individual, family, workplace, and community levels.

Serious gaming in women's health care.

PubMed

de Wit-Zuurendonk, L D; Oei, S G

2011-11-01

Computer-based (serious) gaming is a new field in medical education, which has the potential to become an important tool for healthcare professionals for learning a range of clinical skills. To evaluate the current status of serious gaming in medicine, we performed a systematic literature review. In June 2011, we undertook a search in PubMed and Embase databases with the MeSH terms video games, education, training, gaming and healthcare. Thirty relevant papers were identified, reviewed and summarised. The studies showed that serious gaming is a stimulating learning method and that students are enthusiastic about its use. Studies have shown that previous recreational gaming is associated with greater surgical skill, especially for laparoscopy. In addition to surgical skills, serious gaming is potentially a good method for learning clinical decision-making and patient interaction. Games are already being developed for teaching specific clinical skills, for example in cardiology and orthopaedics for example. Initial studies suggest that serious gaming is likely to be an effective training method; however, there is a paucity of studies showing the conclusive clinical benefit of serious gaming. Future studies should focus on demonstrating the clinical effectiveness of serious gaming on skills used in patient care. © 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2011 RCOG.

Vessel calibre—a potential MRI biomarker of tumour response in clinical trials

PubMed Central

Emblem, Kyrre E.; Farrar, Christian T.; Gerstner, Elizabeth R.; Batchelor, Tracy T.; Borra, Ronald J. H.; Rosen, Bruce R.; Sorensen, A. Gregory; Jain, Rakesh K.

2015-01-01

Our understanding of the importance of blood vessels and angiogenesis in cancer has increased considerably over the past decades, and the assessment of tumour vessel calibre and structure has become increasingly important for in vivo monitoring of therapeutic response. The preferred method for in vivo imaging of most solid cancers is MRI, and the concept of vessel-calibre MRI has evolved since its initial inception in the early 1990s. Almost a quarter of a century later, unlike traditional contrast-enhanced MRI techniques, vessel-calibre MRI remains widely inaccessible to the general clinical community. The narrow availability of the technique is, in part, attributable to limited awareness and a lack of imaging standardization. Thus, the role of vessel-calibre MRI in early phase clinical trials remains to be determined. By contrast, regulatory approvals of antiangiogenic agents that are not directly cytotoxic have created an urgent need for clinical trials incorporating advanced imaging analyses, going beyond traditional assessments of tumour volume. To this end, we review the field of vessel-calibre MRI and summarize the emerging evidence supporting the use of this technique to monitor response to anticancer therapy. We also discuss the potential use of this biomarker assessment in clinical imaging trials and highlight relevant avenues for future research. PMID:25113840

Rapid review shows that probiotics and fermented infant formulas do not cause d-lactic acidosis in healthy children.

PubMed

Łukasik, J; Salminen, S; Szajewska, H

2018-03-30

Extensive ongoing research on probiotics and infant formulas raises a number of safety questions. One concern is the potential influence of d-lactic acid-containing preparations on the health of infants and children. The aim of this review was to summarise the available knowledge on the ingestion of d-lactic acid-producing bacteria, acidified infant formulas and fermented infant formulas as a potential cause of paediatric d-lactic acidosis. A Medline database search was performed in July 2017, with no restrictions on the language, article type or publication date. The 1715 search results were screened for clinical trials, review articles, case series and case reports of relevance to the topic. We identified five randomised controlled trials from 2005 to 2017 covering 544 healthy infants and some case reports and experimental studies. No clinically relevant adverse effects of d-lactic acid-producing probiotics and fermented infant formulas were described in healthy children. However, a harmless, subclinical accumulation of d-lactate was theoretically possible. The only known cases of paediatric d-lactic acidosis occurred in patients with short bowel syndrome or, historically, in infants fed with acidified formulas. Our main finding was that probiotics and fermented formulas did not cause d-lactic acidosis in healthy children. ©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

The Impact of eHealth on the Quality and Safety of Healthcare

NASA Astrophysics Data System (ADS)

Majeed, Azeem; Black, Ashly; Car, Josip; Anandan, Chantelle; Cresswell, Kathrin; McKinstry, Brian; Pagliari, Claudia; Procter, Rob; Sheikh, Aziz

There is considerable interest in using information technology (IT) to enhance the quality and safety of healthcare. We undertook a systematic literature review to assess the impact of eHealth applications on the quality and safety of healthcare. We retrieved 46,349 potentially relevant publications, from which we selected 67 relevant systematic reviews for inclusion. The literature was found to be poorly collated and of variable quality in its methodology, reporting and utility. We categorised eHealth applications into three main areas: i). storing, managing and transmission of data; ii). supporting clinical decision-making; and iii). facilitating care from a distance. We found that relative to the potential benefits noted within the literature, little empirical evidence exists in support of these applications. Of the few studies revealing the clearest evidence of benefits, many are from academic clinical centres where developers of new applications have also been directly associated with their evaluation. It is therefore unclear how effective these applications would be if deployed outside the environment in which they were developed. Our review of the impact of eHealth applications on quality and safety of healthcare demonstrated a vast gap between the postulated and empirically demonstrated benefits. In addition, there is a lack of robust research on risks and costs. Consequently, the cost-effectiveness of these interventions has yet to be demonstrated.

Systematic reviews of complementary therapies – an annotated bibliography. Part 2: Herbal medicine

PubMed Central

Linde, Klaus; ter Riet, Gerben; Hondras, Maria; Vickers, Andrew; Saller, Reinhard; Melchart, Dieter

2001-01-01

Background Complementary therapies are widespread but controversial. We aim to provide a comprehensive collection and a summary of systematic reviews of clinical trials in three major complementary therapies (acupuncture, herbal medicine, homeopathy). This article is dealing with herbal medicine. Potentially relevant reviews were searched through the register of the Cochrane Complementary Medicine Field, the Cochrane Library, Medline, and bibliographies of articles and books. To be included articles had to review prospective clinical trials of herbal medicines; had to describe review methods explicitly; had to be published; and had to focus on treatment effects. Information on conditions, interventions, methods, results and conclusions was extracted using a pre-tested form and summarized descriptively. Results From a total of 79 potentially relevant reviews pre-selected in the screening process 58 met the inclusion criteria. Thirty of the reports reviewed ginkgo (for dementia, intermittent claudication, tinnitus, and macular degeneration), hypericum (for depression) or garlic preparations (for cardiovascular risk factors and lower limb atherosclerosis). The quality of primary studies was criticized in the majority of the reviews. Most reviews judged the available evidence as promising but definitive conclusions were rarely possible. Conclusions Systematic reviews are available on a broad range of herbal preparations prescribed for defined conditions. There is very little evidence on the effectiveness of herbalism as practised by specialist herbalists who combine herbs and use unconventional diagnosis. PMID:11518548

Impact of a novel teaching method based on feedback, activity, individuality and relevance on students' learning.

PubMed

Edafe, Ovie; Brooks, William S; Laskar, Simone N; Benjamin, Miles W; Chan, Philip

2016-03-20

This study examines the perceived impact of a novel clinical teaching method based on FAIR principles (feedback, activity, individuality and relevance) on students' learning on clinical placement. This was a qualitative research study. Participants were third year and final year medical students attached to one UK vascular firm over a four-year period (N=108). Students were asked to write a reflective essay on how FAIRness approach differs from previous clinical placement, and its advantages and disadvantages. Essays were thematically analysed and globally rated (positive, negative or neutral) by two independent researchers. Over 90% of essays reported positive experiences of feedback, activity, individuality and relevance model. The model provided multifaceted feedback; active participation; longitudinal improvement; relevance to stage of learning and future goals; structured teaching; professional development; safe learning environment; consultant involvement in teaching. Students perceived preparation for tutorials to be time intensive for tutors/students; a lack of teaching on medical sciences and direct observation of performance; more than once weekly sessions would be beneficial; some issues with peer and public feedback, relevance to upcoming exam and large group sizes. Students described negative experiences of "standard" clinical teaching. Progressive teaching programmes based on the FAIRness principles, feedback, activity, individuality and relevance, could be used as a model to improve current undergraduate clinical teaching.

From days to hours: reporting clinically actionable variants from whole genome sequencing.

PubMed

Middha, Sumit; Baheti, Saurabh; Hart, Steven N; Kocher, Jean-Pierre A

2014-01-01

As the cost of whole genome sequencing (WGS) decreases, clinical laboratories will be looking at broadly adopting this technology to screen for variants of clinical significance. To fully leverage this technology in a clinical setting, results need to be reported quickly, as the turnaround rate could potentially impact patient care. The latest sequencers can sequence a whole human genome in about 24 hours. However, depending on the computing infrastructure available, the processing of data can take several days, with the majority of computing time devoted to aligning reads to genomics regions that are to date not clinically interpretable. In an attempt to accelerate the reporting of clinically actionable variants, we have investigated the utility of a multi-step alignment algorithm focused on aligning reads and calling variants in genomic regions of clinical relevance prior to processing the remaining reads on the whole genome. This iterative workflow significantly accelerates the reporting of clinically actionable variants with no loss of accuracy when compared to genotypes obtained with the OMNI SNP platform or to variants detected with a standard workflow that combines Novoalign and GATK.

Risk for Clinically Relevant Adverse Cardiac Events in Patients With Chest Pain at Hospital Admission.

PubMed

Weinstock, Michael B; Weingart, Scott; Orth, Frank; VanFossen, Douglas; Kaide, Colin; Anderson, Judy; Newman, David H

2015-07-01

Patients with potentially ischemic chest pain are commonly admitted to the hospital or observed after a negative evaluation in the emergency department (ED) owing to concern about adverse events. Previous studies have looked at 30-day mortality, but no current large studies have examined the most important information regarding ED disposition: the short-term risk for a clinically relevant adverse cardiac event (including inpatient ST-segment elevation myocardial infarction, life-threatening arrhythmia, cardiac or respiratory arrest, or death). To determine the incidence of clinically relevant adverse cardiac events in patients hospitalized for chest pain with 2 troponin-negative findings, nonconcerning initial ED vital signs, and nonischemic, interpretable electrocardiographic findings. We conducted a blinded data review of 45,416 encounters obtained from a prospectively collected database enrolling adult patients admitted or observed with the following inclusion criteria: (1) primary presenting symptom of chest pain, chest tightness, chest burning, or chest pressure and (2) negative findings for serial biomarkers. Data were collected and analyzed from July 1, 2008, through June 30, 2013, from the EDs of 3 community teaching institutions with an aggregate census of more than 1 million visits. We analyzed data extracted by hypothesis-blinded abstractors. The primary outcome was a composite of life-threatening arrhythmia, inpatient ST-segment elevation myocardial infarction, cardiac or respiratory arrest, or death during hospitalization. Of the 45,416 encounters, 11,230 met criteria for inclusion. Mean patient age was 58.0 years. Of the 11 230 encounters, 44.83% of patients arrived by ambulance and 55.00% of patients were women. Relevant history included hypertension in 46.00%, diabetes mellitus in 19.72%, and myocardial infarction in 13.16%. The primary end point occurred in 20 of the 11 230 patients (0.18% [95% CI, 0.11%-0.27%]). After excluding patients with abnormal vital signs, electrocardiographic ischemia, left bundle branch block, or a pacemaker rhythm, we identified a primary end point event in 4 of 7266 patients (0.06% [95% CI, 0.02%-0.14%]). Of these events, 2 were noncardiac and 2 were possibly iatrogenic. In adult patients with chest pain admitted with 2 negative findings for serial biomarkers, nonconcerning vital signs, and nonischemic electrocardiographic findings, short-term clinically relevant adverse cardiac events were rare and commonly iatrogenic, suggesting that routine inpatient admission may not be a beneficial strategy for this group.

Clinical Interpretation and Implications of Whole-Genome Sequencing

PubMed Central

Dewey, Frederick E.; Grove, Megan E.; Pan, Cuiping; Goldstein, Benjamin A.; Bernstein, Jonathan A.; Chaib, Hassan; Merker, Jason D.; Goldfeder, Rachel L.; Enns, Gregory M.; David, Sean P.; Pakdaman, Neda; Ormond, Kelly E.; Caleshu, Colleen; Kingham, Kerry; Klein, Teri E.; Whirl-Carrillo, Michelle; Sakamoto, Kenneth; Wheeler, Matthew T.; Butte, Atul J.; Ford, James M.; Boxer, Linda; Ioannidis, John P. A.; Yeung, Alan C.; Altman, Russ B.; Assimes, Themistocles L.; Snyder, Michael; Ashley, Euan A.; Quertermous, Thomas

2014-01-01

IMPORTANCE Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication. OBJECTIVES To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings. DESIGN, SETTING, AND PARTICIPANTS An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings. MAIN OUTCOMES AND MEASURES Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up. RESULTS Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95%CI, 0.40-0.64), and reclassified 69%of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001). CONCLUSIONS AND RELEVANCE In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine. PMID:24618965

Altered Mitochondrial Membrane Potential, Mass, and Morphology in the Mononuclear Cells of Humans with Type 2 Diabetes

PubMed Central

Widlansky, Michael E.; Wang, Jingli; Shenouda, Sherene M.; Hagen, Tory M.; Smith, Anthony R.; Kizhakekuttu, Tinoy J.; Kluge, Matthew A.; Weihrauch, Dorothee; Gutterman, David D.; Vita, Joseph A.

2010-01-01

Mitochondrial membrane hyperpolarization and morphological changes are important in inflammatory cell activation. Despite the pathophysiological relevance, no valid and reproducible method for measuring mitochondrial homeostasis in human inflammatory cells is currently available. This study's purpose was to define and validate reproducible methods for measuring relevant mitochondrial perturbations and to determine whether these methods could discern mitochondrial perturbations in type 2 diabetes mellitus (T2DM), a condition associated with altered mitochondrial homeostasis. We employed 5,5',6,6'-tetrachloro-1,1'3,3'-tetraethylbenzamidazol-carboncyanine (JC-1) to estimate mitochondrial membrane potential (ψm) and acridine orange 10-nonyl bromide (NAO) to assess mitochondrial mass in human mononuclear cells isolated from blood. Both assays were reproducible. We validated our findings by electron microscopy and pharmacological manipulation of ψm. We measured JC-1 and NAO fluorescence in the mononuclear cells of 27 T2DM patients and 32 controls. Mitochondria were more polarized (P=0.02) and mitochondrial mass was lower in T2DM (P=0.008). Electron microscopy demonstrated diabetic mitochondria were smaller, more spherical, and occupied less cellular area in T2DM. Mitochondrial superoxide production was higher in T2DM (P=0.01). Valid and reproducible measurements of mitochondrial homeostasis can be made in human mononuclear cells using these fluorophores. Further, potential clinically relevant perturbations in mitochondrial homeostasis in T2DM human mononuclear cells can be detected. PMID:20621033

Potentiation of apoptosis by histone deacetylase inhibitors and doxorubicin combination: cytoplasmic cathepsin B as a mediator of apoptosis in multiple myeloma.

PubMed

Cheriyath, V; Kuhns, M A; Kalaycio, M E; Borden, E C

2011-03-15

Although inhibitors of histone deacetylase inhibitors (HDACis) in combination with genotoxins potentiate apoptosis, the role of proteases other than caspases in this process remained elusive. Therefore, we examined the potentiation of apoptosis and related mechanisms of HDACis and doxorubicin combination in a panel of myeloma cell lines and in 25 primary myelomas. At IC(50) concentrations, sodium butyrate (an HDACi) or doxorubicin alone caused little apoptosis. However, their combination potentiated apoptosis and synergistically reduced the viability of myeloma cells independent of p53 and caspase 3-7 activation. Potentiated apoptosis correlated with nuclear translocation of apoptosis-inducing factor, suggesting the induction of caspase 3- and 7-independent pathways. Consistent with this, butyrate and doxorubicin combination significantly increased the activity of cytoplasmic cathepsin B. Inhibition of cathepsin B either with a small-molecule inhibitor or downregulation with a siRNA reversed butyrate- and doxorubicin-potentiated apoptosis. Finally, ex vivo, clinically relevant concentrations of butyrate or SAHA (suberoylanilide hydroxamic acid, vorinostat, an HDACi in clinical testing) in combination with doxorubicin significantly (P<0.0001) reduced the survival of primary myeloma cells. Cathepsin B has a prominent function in mediating apoptosis potentiated by HDACi and doxorubicin combinations in myeloma. Our results support a molecular model of lysosomal-mitochondrial crosstalk in HDACi- and doxorubicin-potentiated apoptosis through the activation of cathepsin B.

A randomized trial comparing INR monitoring devices in patients with anticoagulation self-management: evaluation of a novel error-grid approach.

PubMed

Hemkens, Lars G; Hilden, Kristian M; Hartschen, Stephan; Kaiser, Thomas; Didjurgeit, Ulrike; Hansen, Roland; Bender, Ralf; Sawicki, Peter T

2008-08-01

In addition to the metrological quality of international normalized ratio (INR) monitoring devices used in patients' self-management of long-term anticoagulation, the effectiveness of self-monitoring with such devices has to be evaluated under real-life conditions with a focus on clinical implications. An approach to evaluate the clinical significance of inaccuracies is the error-grid analysis as already established in self-monitoring of blood glucose. Two anticoagulation monitors were compared in a real-life setting and a novel error-grid instrument for oral anticoagulation has been evaluated. In a randomized crossover study 16 patients performed self-management of anticoagulation using the INRatio and the CoaguChek S system. Main outcome measures were clinically relevant INR differences according to established criteria and to the error-grid approach. A lower rate of clinically relevant disagreements according to Anderson's criteria was found with CoaguChek S than with INRatio without statistical significance (10.77% vs. 12.90%; P = 0.787). Using the error-grid we found principally consistent results: More measurement pairs with discrepancies of no or low clinical relevance were found with CoaguChek S, whereas with INRatio we found more differences with a moderate clinical relevance. A high rate of patients' satisfaction with both of the point of care devices was found with only marginal differences. A principal appropriateness of the investigated point-of-care devices to adequately monitor the INR is shown. The error-grid is useful for comparing monitoring methods with a focus on clinical relevance under real-life conditions beyond assessing the pure metrological quality, but we emphasize that additional trials using this instrument with larger patient populations are needed to detect differences in clinically relevant disagreements.

Interpreting the biological relevance of bioinformatic analyses with T-DNA sequence for protein allergenicity.

PubMed

Harper, B; McClain, S; Ganko, E W

2012-08-01

Global regulatory agencies require bioinformatic sequence analysis as part of their safety evaluation for transgenic crops. Analysis typically focuses on encoded proteins and adjacent endogenous flanking sequences. Recently, regulatory expectations have expanded to include all reading frames of the inserted DNA. The intent is to provide biologically relevant results that can be used in the overall assessment of safety. This paper evaluates the relevance of assessing the allergenic potential of all DNA reading frames found in common food genes using methods considered for the analysis of T-DNA sequences used in transgenic crops. FASTA and BLASTX algorithms were used to compare genes from maize, rice, soybean, cucumber, melon, watermelon, and tomato using international regulatory guidance. Results show that BLASTX for maize yielded 7254 alignments that exceeded allergen similarity thresholds and 210,772 alignments that matched eight or more consecutive amino acids with an allergen; other crops produced similar results. This analysis suggests that each nontransgenic crop has a much greater potential for allergenic risk than what has been observed clinically. We demonstrate that a meaningful safety assessment is unlikely to be provided by using methods with inherently high frequencies of false positive alignments when broadly applied to all reading frames of DNA sequence. Copyright © 2012 Elsevier Inc. All rights reserved.

Clinically Relevant Levels of 4-Aminopyridine Strengthen Physiological Responses in Intact Motor Circuits in Rats, Especially After Pyramidal Tract Injury.

PubMed

Sindhurakar, Anil; Mishra, Asht M; Gupta, Disha; Iaci, Jennifer F; Parry, Tom J; Carmel, Jason B

2017-04-01

4-Aminopyridine (4-AP) is a Food and Drug Administration-approved drug to improve motor function in people with multiple sclerosis. Preliminary results suggest the drug may act on intact neural circuits and not just on demyelinated ones. To determine if 4-AP at clinically relevant levels alters the excitability of intact motor circuits. In anesthetized rats, electrodes were placed over motor cortex and the dorsal cervical spinal cord for electrical stimulation, and electromyogram electrodes were inserted into biceps muscle to measure responses. The motor responses to brain and spinal cord stimulation were measured before and for 5 hours after 4-AP administration both in uninjured rats and rats with a cut lesion of the pyramidal tract. Blood was collected at the same time as electrophysiology to determine drug plasma concentration with a goal of 20 to 100 ng/mL. We first determined that a bolus infusion of 0.32 mg/kg 4-AP was optimal: it produced on average 61.5 ± 1.8 ng/mL over the 5 hours after infusion. This dose of 4-AP increased responses to spinal cord stimulation by 1.3-fold in uninjured rats and 3-fold in rats with pyramidal tract lesion. Responses to cortical stimulation also increased by 2-fold in uninjured rats and up to 4-fold in the injured. Clinically relevant levels of 4-AP strongly augment physiological responses in intact circuits, an effect that was more robust after partial injury, demonstrating its broad potential in treating central nervous system injuries.

The Relevance of Sex Differences in Performance Fatigability

PubMed Central

Hunter, Sandra K.

2016-01-01

Performance fatigability differs between men and women for a range of fatiguing tasks. Women are usually less fatigable than men and this is most widely described for isometric fatiguing contractions, and some dynamic tasks. The sex difference in fatigability is specific to the task demands so that one mechanism is not universal, including any sex differences in skeletal muscle physiology, muscle perfusion and voluntary activation. However, there are substantial knowledge gaps about the task dependency of the sex differences in fatigability, the involved mechanisms and the relevance to clinical populations and with advanced age. The knowledge gaps are in part due to the significant deficits in the number of women included in performance fatigability studies despite a gradual increase in the inclusion of women over the last 20 years. Therefore, this review 1) provides a rationale for the limited knowledge about sex differences in performance fatigability, 2) summarizes the current knowledge on sex differences in fatigability and the potential mechanisms across a range of tasks, 3) highlights emerging areas of opportunity in clinical populations, and 4) suggests strategies to close the knowledge gap and understanding the relevance of sex differences in performance fatigability. The limited understanding about sex differences in fatigability in healthy and clinical populations, presents as a field ripe with opportunity for high impact studies. Such studies will inform on the limitations of men and women during athletic endeavors, ergonomic tasks and daily activities. Because fatigability is required for effective neuromuscular adaptation, sex differences in fatigability studies will also inform on optimal strategies for training and rehabilitation in both men and women. PMID:27015385

Potential for treatment of severe autism in tuberous sclerosis complex

PubMed Central

Gipson, Tanjala T; Gerner, Gwendolyn; Wilson, Mary Ann; Blue, Mary E; Johnston, Michael V

2013-01-01

The Food and Drug Administration (FDA) has approved two mechanism-based treatments for tuberous sclerosis complex (TSC)-everolimus and vigabatrin. However, these treatments have not been systematically studied in individuals with TSC and severe autism. The aim of this review is to identify the clinical features of severe autism in TSC, applicable preclinical models, and potential barriers that may warrant strategic planning in the design phase of clinical trial development. A comprehensive search strategy was formed and searched across PubMed, Embase and SCOPUS from their inception to 2/21/12, 3/16/12, and 3/12/12 respectively. After the final search date, relevant, updated articles were selected from PubMed abstracts generated electronically and emailed daily from PubMed. The references of selected articles were searched, and relevant articles were selected. A search of clinicaltrials.gov was completed using the search term “TSC” and “tuberous sclerosis complex”. Autism has been reported in as many as 60% of individuals with TSC; however, review of the literature revealed few data to support clear classification of the severity of autism in TSC. Variability was identified in the diagnostic approach, assessment of cognition, and functional outcome among the reviewed studies and case reports. Objective outcome measures were not used in many early studies; however, diffusion tensor imaging of white matter, neurophysiologic variability in infantile spasms, and cortical tuber subcategories were examined in recent studies and may be useful for objective classification of TSC in future studies. Mechanism-based treatments for TSC are currently available. However, this literature review revealed two potential barriers to successful design and implementation of clinical trials in individuals with severe autism-an unclear definition of the population and lack of validated outcome measures. Recent studies of objective outcome measures in TSC and further study of applicable preclinical models present an opportunity to overcome these barriers. PMID:25254170

Antimicrobial activity of extracts from macroalgae Ulva lactuca against clinically important Staphylococci is impacted by lunar phase of macroalgae harvest.

PubMed

Deveau, A M; Miller-Hope, Z; Lloyd, E; Williams, B S; Bolduc, C; Meader, J M; Weiss, F; Burkholder, K M

2016-05-01

Staphylococcus aureus is a common human bacterial pathogen that causes skin and soft tissue infections. Methicillin-resistant Staph. aureus (MRSA) are increasingly drug-resistant, and thus there is great need for new therapeutics to treat Staph. aureus infections. Attention has focused on potential utility of natural products, such as extracts of marine macroalgae, as a source of novel antimicrobial compounds. The green macroalgae Ulva lactuca produces compounds inhibitory to human pathogens, although the effectiveness of U. lactuca extracts against clinically relevant strains of Staph. aureus is poorly understood. In addition, macroalgae produce secondary metabolites that may be influenced by exogenous factors including lunar phase, but whether lunar phase affects U. lactuca antimicrobial capacity is unknown. We sought to evaluate the antibacterial properties of U. lactuca extracts against medically important Staphylococci, and to determine the effect of lunar phase on antimicrobial activity. We report that U. lactuca methanolic extracts inhibit a range of Staphylococci, and that lunar phase of macrolagae harvest significantly impacts antimicrobial activity, suggesting that antimicrobial properties can be maximized by manipulating time of algal harvest. These findings provide useful parameters for future studies aimed at isolating and characterizing U. lactuca anti-Staphylococcal agents. The growing prevalence of antibiotic-resistant human pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) has intensified efforts towards discovery and development of novel therapeutics. Marine macroalgae like Ulva lactuca are increasingly recognized as potential sources of antimicrobials, but the efficacy of U. lactuca extracts against common, virulent strains of Staph. aureus is poorly understood. We demonstrate that U. lactuca methanolic extracts inhibit a variety of clinically relevant Staphylococcus strains, and that the antimicrobial activity can be maximized by optimizing time of algal harvest. These findings provide potentially useful parameters for future work of isolating and identifying novel antimicrobial agents from macroalgae. © 2016 The Society for Applied Microbiology.

Integration of somatic mutation, expression and functional data reveals potential driver genes predictive of breast cancer survival.

PubMed

Suo, Chen; Hrydziuszko, Olga; Lee, Donghwan; Pramana, Setia; Saputra, Dhany; Joshi, Himanshu; Calza, Stefano; Pawitan, Yudi

2015-08-15

Genome and transcriptome analyses can be used to explore cancers comprehensively, and it is increasingly common to have multiple omics data measured from each individual. Furthermore, there are rich functional data such as predicted impact of mutations on protein coding and gene/protein networks. However, integration of the complex information across the different omics and functional data is still challenging. Clinical validation, particularly based on patient outcomes such as survival, is important for assessing the relevance of the integrated information and for comparing different procedures. An analysis pipeline is built for integrating genomic and transcriptomic alterations from whole-exome and RNA sequence data and functional data from protein function prediction and gene interaction networks. The method accumulates evidence for the functional implications of mutated potential driver genes found within and across patients. A driver-gene score (DGscore) is developed to capture the cumulative effect of such genes. To contribute to the score, a gene has to be frequently mutated, with high or moderate mutational impact at protein level, exhibiting an extreme expression and functionally linked to many differentially expressed neighbors in the functional gene network. The pipeline is applied to 60 matched tumor and normal samples of the same patient from The Cancer Genome Atlas breast-cancer project. In clinical validation, patients with high DGscores have worse survival than those with low scores (P = 0.001). Furthermore, the DGscore outperforms the established expression-based signatures MammaPrint and PAM50 in predicting patient survival. In conclusion, integration of mutation, expression and functional data allows identification of clinically relevant potential driver genes in cancer. The documented pipeline including annotated sample scripts can be found in http://fafner.meb.ki.se/biostatwiki/driver-genes/. yudi.pawitan@ki.se Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Methodology for the in vitro evaluation of the delivery efficiency from valved holding chambers with facemasks.

PubMed

Xu, Zhen; Hsu, Wenchi; von Hollen, Dirk; Viswanath, Ashwin; Nikander, Kurt; Dalby, Richard

2014-08-01

In vitro performance studies of valved holding chamber (VHC)-facemask systems are a cost-effective means of circumventing potentially confounding clinical variables. This article reports results of an in vitro investigation into VHC-facemask performance, using three age-specific soft anatomical model (SAM) faces, under clinically relevant conditions. A potentially standardized method was developed to assess VHC-facemask seal leakage, and evaluate the in vitro delivery efficiency of conventional and antistatic VHC-facemask systems. A custom-built test rig and VHC cradles were used to position the VHC-facemask systems against the SAM faces, with a constant, reproducible force. A standardized simulated pediatric breathing pattern (tidal volume = 155 mL; inhalation:exhalation ratio = 40:60; 25 breaths/min) was utilized. Percent facemask seal leakage, percent delivered dose, and the effect of different numbers of simulated breaths (2 to 8) were investigated. Of the VHC-facemask systems tested, the OptiChamber Diamond VHC with LiteTouch facemask (Diamond) system had the lowest percent seal leakage with each SAM face. Percent seal leakage from the other VHC-facemask systems was similar with SAM0 and SAM2 faces; the AeroChamber Plus Z-Stat VHC with ComfortSeal facemask (AC Z-Stat) system had a substantially greater percent seal leakage with the SAM1 face. Regardless of the number of simulated breaths, the Diamond system delivered the greatest mean percent delivered dose, with the lowest coefficient of variation, with each SAM face. Percent delivered dose did not correlate well with seal leakage, particularly for VHC-facemask systems with high seal leakage. The electrostatic properties of the VHCs appeared to influence drug delivery. This study describes a potentially standardized method for the evaluation of VHC-facemask systems. Use of this method enabled a comprehensive investigation into the influence of clinically relevant variables, including age-specific facial anatomy, number of simulated breaths, and seal leakage, on the delivery efficiency of several commercially available VHC-facemask systems.

Evaluating the potential effect on fetal tissue after exposure to granisetron during pregnancy.

PubMed

Smith, Judith A; Julius, Justin M; Gaikwad, Anjali; Berens, Pamela D; Alcorn, Joseph; Moise, Kenneth J; Refuerzo, Jerrie S

2015-06-01

The objective of this study was to elucidate the possible toxic effects on the fetal tissues after exposure to two clinically relevant concentrations of granisetron. Primary cells were isolated from human fetal organs of 16-19 weeks gestational age and treated with 3 ng/mL or 30 ng/mL of granisetron. Cell cycle progression was evaluated by flow cytometry. ELISA was used to detect alterations in major apoptotic proteins. Up to 10% apoptosis in cardiac tissue was observed following treatment with 30 ng/mL granisetron. Neither concentration of granisetron caused alteration in cell cycle progression or alterations in apoptotic proteins in any of the other tissues. At 30 ng/mL granisetron concentration had the potential to induce up to 10% apoptosis in cardiac tissue; clinical significance needs further evaluation. At granisetron 3 ng/mL there was no detectable toxicity or on any fetal tissue in this study. Further research is needed to confirm these preliminary findings and determine if clinically significant. Copyright © 2015 Elsevier Inc. All rights reserved.

FGFR-targeted therapeutics for the treatment of breast cancer.

PubMed

De Luca, Antonella; Frezzetti, Daniela; Gallo, Marianna; Normanno, Nicola

2017-03-01

Breast cancer is a complex disease and several molecular drivers regulate its progression. Fibroblast growth factor receptor (FGFR) signaling is frequently deregulated in many cancers, including breast cancer. Due the involvement of the FGFR/FGF axis in the pathogenesis and progression of tumors, FGFR-targeted agents might represent a potential therapeutic option for breast cancer patients. Areas covered: This review offers an overview of targeted agents against FGFRs and their clinical development in breast cancer. The most relevant literature and the latest studies in the Clinicaltrial.com database have been discussed. Expert opinion: FGFR inhibition has been recently considered as a promising therapeutic option for different tumor types. However, preliminary results of clinical trials of FGFR inhibitors in breast cancer have been quite disappointing. In order to increase the clinical benefit of FGFR therapies in breast cancer, future studies should focus on: understanding the role of the various FGFR aberrations in cancer progression; identifying potential biomarkers to select patients that could benefit of FGFR inhibitors and developing therapeutic strategies that improve the efficacy of these agents and minimize toxicities.

Multifunctional Skin-like Electronics for Quantitative, Clinical Monitoring of Cutaneous Wound Healing

PubMed Central

Hattori, Yoshiaki; Falgout, Leo; Lee, Woosik; Jung, Sung-Young; Poon, Emily; Lee, Jung Woo; Na, Ilyoun; Geisler, Amelia; Sadhwani, Divya; Zhang, Yihui; Su, Yewang; Wang, Xiaoqi; Liu, Zhuangjian; Xia, Jing; Cheng, Huanyu; Webb, R. Chad; Bonifas, Andrew P.; Won, Philip; Jeong, Jae-Woong; Jang, Kyung-In; Song, Young Min; Nardone, Beatrice; Nodzenski, Michael; Fan, Jonathan A.; Huang, Yonggang; West, Dennis P.; Paller, Amy S.; Alam, Murad

2014-01-01

Non-invasive, biomedical devices have the potential to provide important, quantitative data for the assessment of skin diseases and wound healing. Traditional methods either rely on qualitative visual and tactile judgments of a professional and/or data obtained using instrumentation with forms that do not readily allow intimate integration with sensitive skin near a wound site. Here we report a skin-like electronics platform that can softly and reversibly laminate perilesionally at wounds to provide highly accurate, quantitative data of relevance to the management of surgical wound healing. Clinical studies on patients using thermal sensors and actuators in fractal layouts provide precise time-dependent mapping of temperature and thermal conductivity of the skin near the wounds. Analytical and simulation results establish the fundamentals of the sensing modalities, the mechanics of the system, and strategies for optimized design. The use of this type of ‘epidermal’ electronics system in a realistic, clinical setting with human subjects establishes a set of practical procedures in disinfection, reuse, and protocols for quantitative measurement. The results have the potential to address important unmet needs in chronic wound management. PMID:24668927

Clinical applications of hallucinogens: A review.

PubMed

Garcia-Romeu, Albert; Kersgaard, Brennan; Addy, Peter H

2016-08-01

Hallucinogens fall into several different classes, as broadly defined by pharmacological mechanism of action, and chemical structure. These include psychedelics, entactogens, dissociatives, and other atypical hallucinogens. Although these classes do not share a common primary mechanism of action, they do exhibit important similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes. Such effects likely contribute to their recreational use. However, a growing body of evidence indicates that these drugs may have therapeutic applications beyond their potential for abuse. This review will present data on several classes of hallucinogens with a particular focus on psychedelics, entactogens, and dissociatives, for which clinical utility has been most extensively documented. Information on each class is presented in turn, tracing relevant historical insights, highlighting similarities and differences between the classes from the molecular to the behavioral level, and presenting the most up-to-date information on clinically oriented research with these substances, with important ramifications for their potential therapeutic value. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Short-term intensive insulin therapy at diagnosis in type 2 diabetes: plan for filling the gaps.

PubMed

Weng, Jianping; Retnakaran, Ravi; Ariachery C, Ammini; Ji, Linong; Meneghini, Luigi; Yang, Wenying; Woo, Jeong-Taek

2015-09-01

Short-term intensive insulin therapy is unique amongst therapies for type 2 diabetes because it offers the potential to preserve and improve beta-cell function without additional pharmacological treatment. On the basis of clinical experience and the promising results of a series of studies in newly diagnosed patients, mostly in Asian populations, an expert workshop was convened to assess the available evidence and the potential application of short-term intensive insulin therapy should it be advocated for inclusion in clinical practice. Participants included primary care physicians and endocrinologists. We endorse the concept of short-term intensive insulin therapy as an option for some patients with type 2 diabetes at the time of diagnosis and have identified the following six areas where additional knowledge could help clarify optimal use in clinical practice: (1) generalizability to primary care, (2) target population and biomarkers, (3) follow-up treatment, (4) education of patients and providers, (5) relevance of ethnicity, and (6) health economics. © 2014 The Authors. Diabetes Metabolism Research and Reviews published by John Wiley & Sons, Ltd.

Antidiabetic Properties of Germinated Brown Rice: A Systematic Review

PubMed Central

Bhanger, Muhammad Iqbal; Ismail, Norsharina; Ismail, Maznah

2012-01-01

Diet is an important variable in the course of type 2 diabetes, which has generated interest in dietary options like germinated brown rice (GBR) for effective management of the disease among rice-consuming populations. In vitro data and animal experiments show that GBR has potentials as a functional diet for managing this disease, and short-term clinical studies indicate encouraging results. Mechanisms for antidiabetic effects of GBR due to bioactive compounds like γ-aminobutyric acid (GABA), γ-oryzanol, dietary fibre, phenolics, vitamins, acylated steryl β-glucoside, and minerals include antihyperglycemia, low insulin index, antioxidative effect, antithrombosis, antihypertensive effect, hypocholesterolemia, and neuroprotective effects. The evidence so far suggests that there may be enormous benefits for diabetics in rice-consuming populations if white rice is replaced with GBR. However, long-term clinical studies are still needed to verify these findings on antidiabetic effects of GBR. Thus, we present a review on the antidiabetic properties of GBR from relevant preclinical and clinical studies, in order to provide detailed information on this subject for researchers to review the potential of GBR in combating this disease. PMID:23304216

A Real-Time Clinical Endoscopic System for Intraluminal, Multiplexed Imaging of Surface-Enhanced Raman Scattering Nanoparticles

PubMed Central

Garai, Ellis; Loewke, Nathan O.; Rogalla, Stephan; Mandella, Michael J.; Felt, Stephen A.; Friedland, Shai; Liu, Jonathan T. C.; Gambhir, Sanjiv S.; Contag, Christopher H.

2015-01-01

The detection of biomarker-targeting surface-enhanced Raman scattering (SERS) nanoparticles (NPs) in the human gastrointestinal tract has the potential to improve early cancer detection; however, a clinically relevant device with rapid Raman-imaging capability has not been described. Here we report the design and in vivo demonstration of a miniature, non-contact, opto-electro-mechanical Raman device as an accessory to clinical endoscopes that can provide multiplexed molecular data via a panel of SERS NPs. This device enables rapid circumferential scanning of topologically complex luminal surfaces of hollow organs (e.g., colon and esophagus) and produces quantitative images of the relative concentrations of SERS NPs that are present. Human and swine studies have demonstrated the speed and simplicity of this technique. This approach also offers unparalleled multiplexing capabilities by simultaneously detecting the unique spectral fingerprints of multiple SERS NPs. Therefore, this new screening strategy has the potential to improve diagnosis and to guide therapy by enabling sensitive quantitative molecular detection of small and otherwise hard-to-detect lesions in the context of white-light endoscopy. PMID:25923788

Astaxanthin: A Potential Therapeutic Agent in Cardiovascular Disease

PubMed Central

Fassett, Robert G.; Coombes, Jeff S.

2011-01-01

Astaxanthin is a xanthophyll carotenoid present in microalgae, fungi, complex plants, seafood, flamingos and quail. It is an antioxidant with anti-inflammatory properties and as such has potential as a therapeutic agent in atherosclerotic cardiovascular disease. Synthetic forms of astaxanthin have been manufactured. The safety, bioavailability and effects of astaxanthin on oxidative stress and inflammation that have relevance to the pathophysiology of atherosclerotic cardiovascular disease, have been assessed in a small number of clinical studies. No adverse events have been reported and there is evidence of a reduction in biomarkers of oxidative stress and inflammation with astaxanthin administration. Experimental studies in several species using an ischaemia-reperfusion myocardial model demonstrated that astaxanthin protects the myocardium when administered both orally or intravenously prior to the induction of the ischaemic event. At this stage we do not know whether astaxanthin is of benefit when administered after a cardiovascular event and no clinical cardiovascular studies in humans have been completed and/or reported. Cardiovascular clinical trials are warranted based on the physicochemical and antioxidant properties, the safety profile and preliminary experimental cardiovascular studies of astaxanthin. PMID:21556169

Inflammation in Depression and the Potential for Anti-Inflammatory Treatment

PubMed Central

Köhler, Ole; Krogh, Jesper; Mors, Ole; Benros, Michael Eriksen

2016-01-01

Accumulating evidence supports an association between depression and inflammatory processes, a connection that seems to be bidirectional. Clinical trials have indicated antidepressant treatment effects for anti-inflammatory agents, both as add-on treatment and as monotherapy. In particular, nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine-inhibitors have shown antidepressant treatment effects compared to placebo, but also statins, poly-unsaturated fatty acids, pioglitazone, minocycline, modafinil, and corticosteroids may yield antidepressant treatment effects. However, the complexity of the inflammatory cascade, limited clinical evidence, and the risk for side effects stress cautiousness before clinical application. Thus, despite proof-of-concept studies of anti-inflammatory treatment effects in depression, important challenges remain to be investigated. Within this paper, we review the association between inflammation and depression together with the current evidence on use of anti-inflammatory treatment in depression. Based on this, we address the questions and challenges that seem most important and relevant to future studies, such as timing, most effective treatment lengths and identification of subgroups of patients potentially responding better to different anti-inflammatory treatment regimens. PMID:27640518

Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.

PubMed

Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

2016-01-01

MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.

Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction

PubMed Central

Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

2016-01-01

MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results. PMID:26105141

Leveraging biodiversity knowledge for potential phyto-therapeutic applications

PubMed Central

Sharma, Vivekanand; Sarkar, Indra Neil

2013-01-01

Objective To identify and highlight the feasibility, challenges, and advantages of providing a cross-domain pipeline that can link relevant biodiversity information for phyto-therapeutic assessment. Materials and methods A public repository of clinical trials information (ClinicalTrials.gov) was explored to determine the state of plant-based interventions under investigation. Results The results showed that ∼15% of drug interventions in ClinicalTrials.gov were potentially plant related, with about 60% of them clustered within 10 taxonomic families. Further analysis of these plant-based interventions identified ∼3.7% of associated plant species as endangered as determined from the International Union for the Conservation of Nature Red List. Discussion The diversity of the plant kingdom has provided human civilization with life-sustaining food and medicine for centuries. There has been renewed interest in the investigation of botanicals as sources of new drugs, building on traditional knowledge about plant-based medicines. However, data about the plant-based biodiversity potential for therapeutics (eg, based on genetic or chemical information) are generally scattered across a range of sources and isolated from contemporary pharmacological resources. This study explored the potential to bridge biodiversity and biomedical knowledge sources. Conclusions The findings from this feasibility study suggest that there is an opportunity for developing plant-based drugs and further highlight taxonomic relationships between plants that may be rich sources for bioprospecting. PMID:23518859

Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence.

PubMed

Rohleder, Cathrin; Müller, Juliane K; Lange, Bettina; Leweke, F M

2016-01-01

There is urgent need for the development of mechanistically different and less side-effect prone antipsychotic compounds. The endocannabinoid system has been suggested to represent a potential new target in this indication. While the chronic use of cannabis itself has been considered a risk factor contributing to the development of schizophrenia, triggered by the phytocannabinoid delta-9-tetrahydrocannabinol (Δ 9 -THC), cannabidiol, the second most important phytocannabinoid, appears to have no psychotomimetic potential. Although, results from animal studies are inconsistent to a certain extent and seem to depend on behavioral paradigms, treatment duration and experimental conditions applied, cannabidiol has shown antipsychotic properties in both rodents and rhesus monkeys. After some individual treatment attempts, the first randomized, double-blind controlled clinical trial demonstrated that in acute schizophrenia cannabidiol exerts antipsychotic properties comparable to the antipsychotic drug amisulpride while being accompanied by a superior, placebo-like side effect profile. As the clinical improvement by cannabidiol was significantly associated with elevated anandamide levels, it appears likely that its antipsychotic action is based on mechanisms associated with increased anandamide concentrations. Although, a plethora of mechanisms of action has been suggested, their potential relevance for the antipsychotic effects of cannabidiol still needs to be investigated. The clarification of these mechanisms as well as the establishment of cannabidiol's antipsychotic efficacy and its hopefully benign side-effect profile remains the subject of a number of previously started clinical trials.

Sensitivity and Predictive Value of 15 PubMed Search Strategies to Answer Clinical Questions Rated Against Full Systematic Reviews

PubMed Central

Merglen, Arnaud; Courvoisier, Delphine S; Combescure, Christophe; Garin, Nicolas; Perrier, Arnaud; Perneger, Thomas V

2012-01-01

Background Clinicians perform searches in PubMed daily, but retrieving relevant studies is challenging due to the rapid expansion of medical knowledge. Little is known about the performance of search strategies when they are applied to answer specific clinical questions. Objective To compare the performance of 15 PubMed search strategies in retrieving relevant clinical trials on therapeutic interventions. Methods We used Cochrane systematic reviews to identify relevant trials for 30 clinical questions. Search terms were extracted from the abstract using a predefined procedure based on the population, interventions, comparison, outcomes (PICO) framework and combined into queries. We tested 15 search strategies that varied in their query (PIC or PICO), use of PubMed’s Clinical Queries therapeutic filters (broad or narrow), search limits, and PubMed links to related articles. We assessed sensitivity (recall) and positive predictive value (precision) of each strategy on the first 2 PubMed pages (40 articles) and on the complete search output. Results The performance of the search strategies varied widely according to the clinical question. Unfiltered searches and those using the broad filter of Clinical Queries produced large outputs and retrieved few relevant articles within the first 2 pages, resulting in a median sensitivity of only 10%–25%. In contrast, all searches using the narrow filter performed significantly better, with a median sensitivity of about 50% (all P < .001 compared with unfiltered queries) and positive predictive values of 20%–30% (P < .001 compared with unfiltered queries). This benefit was consistent for most clinical questions. Searches based on related articles retrieved about a third of the relevant studies. Conclusions The Clinical Queries narrow filter, along with well-formulated queries based on the PICO framework, provided the greatest aid in retrieving relevant clinical trials within the 2 first PubMed pages. These results can help clinicians apply effective strategies to answer their questions at the point of care. PMID:22693047

Sensitivity and predictive value of 15 PubMed search strategies to answer clinical questions rated against full systematic reviews.

PubMed

Agoritsas, Thomas; Merglen, Arnaud; Courvoisier, Delphine S; Combescure, Christophe; Garin, Nicolas; Perrier, Arnaud; Perneger, Thomas V

2012-06-12

Clinicians perform searches in PubMed daily, but retrieving relevant studies is challenging due to the rapid expansion of medical knowledge. Little is known about the performance of search strategies when they are applied to answer specific clinical questions. To compare the performance of 15 PubMed search strategies in retrieving relevant clinical trials on therapeutic interventions. We used Cochrane systematic reviews to identify relevant trials for 30 clinical questions. Search terms were extracted from the abstract using a predefined procedure based on the population, interventions, comparison, outcomes (PICO) framework and combined into queries. We tested 15 search strategies that varied in their query (PIC or PICO), use of PubMed's Clinical Queries therapeutic filters (broad or narrow), search limits, and PubMed links to related articles. We assessed sensitivity (recall) and positive predictive value (precision) of each strategy on the first 2 PubMed pages (40 articles) and on the complete search output. The performance of the search strategies varied widely according to the clinical question. Unfiltered searches and those using the broad filter of Clinical Queries produced large outputs and retrieved few relevant articles within the first 2 pages, resulting in a median sensitivity of only 10%-25%. In contrast, all searches using the narrow filter performed significantly better, with a median sensitivity of about 50% (all P < .001 compared with unfiltered queries) and positive predictive values of 20%-30% (P < .001 compared with unfiltered queries). This benefit was consistent for most clinical questions. Searches based on related articles retrieved about a third of the relevant studies. The Clinical Queries narrow filter, along with well-formulated queries based on the PICO framework, provided the greatest aid in retrieving relevant clinical trials within the 2 first PubMed pages. These results can help clinicians apply effective strategies to answer their questions at the point of care.

Exome Sequencing in the Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia

PubMed Central

Fogel, Brent L.; Lee, Hane; Deignan, Joshua L.; Strom, Samuel P.; Kantarci, Sibel; Wang, Xizhe; Quintero-Rivera, Fabiola; Vilain, Eric; Grody, Wayne W.; Perlman, Susan; Geschwind, Daniel H.; Nelson, Stanley F.

2015-01-01

IMPORTANCE Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established. OBJECTIVE To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia. DESIGN, SETTING, AND PARTICIPANTS We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia. MAIN OUTCOMES AND MEASURES Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation. RESULTS We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias. CONCLUSIONS AND RELEVANCE This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia. PMID:25133958

Modelling Conditions and Health Care Processes in Electronic Health Records: An Application to Severe Mental Illness with the Clinical Practice Research Datalink

PubMed Central

Olier, Ivan; Springate, David A.; Ashcroft, Darren M.; Doran, Tim; Reeves, David; Planner, Claire; Reilly, Siobhan; Kontopantelis, Evangelos

2016-01-01

Background The use of Electronic Health Records databases for medical research has become mainstream. In the UK, increasing use of Primary Care Databases is largely driven by almost complete computerisation and uniform standards within the National Health Service. Electronic Health Records research often begins with the development of a list of clinical codes with which to identify cases with a specific condition. We present a methodology and accompanying Stata and R commands (pcdsearch/Rpcdsearch) to help researchers in this task. We present severe mental illness as an example. Methods We used the Clinical Practice Research Datalink, a UK Primary Care Database in which clinical information is largely organised using Read codes, a hierarchical clinical coding system. Pcdsearch is used to identify potentially relevant clinical codes and/or product codes from word-stubs and code-stubs suggested by clinicians. The returned code-lists are reviewed and codes relevant to the condition of interest are selected. The final code-list is then used to identify patients. Results We identified 270 Read codes linked to SMI and used them to identify cases in the database. We observed that our approach identified cases that would have been missed with a simpler approach using SMI registers defined within the UK Quality and Outcomes Framework. Conclusion We described a framework for researchers of Electronic Health Records databases, for identifying patients with a particular condition or matching certain clinical criteria. The method is invariant to coding system or database and can be used with SNOMED CT, ICD or other medical classification code-lists. PMID:26918439

Recommendations for an update of the 2010 European regulatory guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis and reflections about related clinically relevant outcomes: expert consensus statement.

PubMed

Reginster, J-Y; Reiter-Niesert, S; Bruyère, O; Berenbaum, F; Brandi, M-L; Branco, J; Devogelaer, J-P; Herrero-Beaumont, G; Kanis, J; Maggi, S; Maheu, E; Richette, P; Rizzoli, R; Cooper, C

2015-12-01

The European Society on Clinical and Economic aspects of Osteoporosis and Osteoarthritis (ESCEO) organised a working group to evaluate the need for updating the current European guideline on clinical investigation of drugs used in the treatment of osteoarthritis (OA). Areas of potential attention were identified and the need for modifications, update or clarification was examined. Proposals were then developed based on literature reviews and through a consensus process. It was agreed that the current guideline overall still reflects the current knowledge in OA, although two possible modifications were identified. The first relates to the number and timing of measurements required as primary endpoints during clinical trials of symptom-relieving drugs, either drugs with rapid onset of action or slow acting drugs. The suggested modifications are intended to take into consideration the time related clinical need and expected time response to these drugs - i.e., a more early effect for the first category in addition to the maintenance of effect, a more continuous benefit over the long-term for the latter - in the timing of assessments. Secondly, values above which a benefit over placebo should be considered clinically relevant were considered. Based on literature reviews, the most consensual values were determined for primary endpoints of both symptom-relieving drugs (i.e., pain intensity on a visual analogue scale (VAS)) and disease-modifying drugs (i.e., radiographic joint-space narrowing). This working document might be considered by the European regulatory authorities in a future update of the guideline for the registration of drugs in OA. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Clinical progression of ocular injury following arsenical vesicant lewisite exposure.

PubMed

Tewari-Singh, Neera; Croutch, Claire R; Tuttle, Richard; Goswami, Dinesh G; Kant, Rama; Peters, Eric; Culley, Tara; Ammar, David A; Enzenauer, Robert W; Petrash, J Mark; Casillas, Robert P; Agarwal, Rajesh

2016-12-01

Ocular injury by lewisite (LEW), a potential chemical warfare and terrorist agent, results in edema of eyelids, inflammation, massive corneal necrosis and blindness. To enable screening of effective therapeutics to treat ocular injury from LEW, useful clinically-relevant endpoints are essential. Hence, we designed an efficient exposure system capable of exposing up to six New-Zealand white rabbits at one time, and assessed LEW vapor-induced progression of clinical ocular lesions mainly in the cornea. The right eye of each rabbit was exposed to LEW (0.2 mg/L) vapor for 2.5, 5.0, 7.5 and 10.0 min and clinical progression of injury was observed for 28 days post-exposure (dose-response study), or exposed to same LEW dose for 2.5 and 7.5 min and clinical progression of injury was observed for up to 56 days post-exposure (time-response study); left eye served as an unexposed control. Increasing LEW exposure caused corneal opacity within 6 h post-exposure, which increased up to 3 days, slightly reduced thereafter till 3 weeks, and again increased thereafter. LEW-induced corneal ulceration peaked at 1 day post-exposure and its increase thereafter was observed in phases. LEW exposure induced neovascularization starting at 7 days which peaked at 22-35 days post-exposure, and remained persistent thereafter. In addition, LEW exposure caused corneal thickness, iris redness, and redness and swelling of the conjunctiva. Together, these findings provide clinical sequelae of ocular injury following LEW exposure and for the first time establish clinically-relevant quantitative endpoints, to enable the further identification of histopathological and molecular events involved in LEW-induced ocular injury.

The effectiveness of the bone bridge transtibial amputation technique: A systematic review of high-quality evidence.

PubMed

Kahle, Jason T; Highsmith, M Jason; Kenney, John; Ruth, Tim; Lunseth, Paul A; Ertl, Janos

2017-06-01

This literature review was undertaken to determine if commonly held views about the benefits of a bone bridge technique are supported by the literature. Four databases were searched for articles pertaining to surgical strategies specific to a bone bridge technique of the transtibial amputee. A total of 35 articles were identified as potential articles. Authors included methodology that was applied to separate topics. Following identification, articles were excluded if they were determined to be low quality evidence or not pertinent. Nine articles were identified to be pertinent to one of the topics: Perioperative Care, Acute Care, Subjective Analysis and Function. Two articles sorted into multiple topics. Two articles were sorted into the Perioperative Care topic, 4 articles sorted into the Acute Care topic, 2 articles into the Subjective Analysis topic and 5 articles into the Function topic. There are no high quality (level one or two) clinical trials reporting comparisons of the bone bridge technique to traditional methods. There is limited evidence supporting the clinical outcomes of the bone bridge technique. There is no agreement supporting or discouraging the perioperative and acute care aspects of the bone bridge technique. There is no evidence defining an interventional comparison of the bone bridge technique. Current level III evidence supports a bone bridge technique as an equivalent option to the non-bone bridge transtibial amputation technique. Formal level I and II clinical trials will need to be considered in the future to guide clinical practice. Clinical relevance Clinical Practice Guidelines are evidence based. This systematic literature review identifies the highest quality evidence to date which reports a consensus of outcomes agreeing bone bridge is as safe and effective as alternatives. The clinical relevance is understanding bone bridge could additionally provide a mechanistic advantage for the transtibial amputee.

Comprehensive Genomic Profiling of Esthesioneuroblastoma Reveals Additional Treatment Options.

PubMed

Gay, Laurie M; Kim, Sungeun; Fedorchak, Kyle; Kundranda, Madappa; Odia, Yazmin; Nangia, Chaitali; Battiste, James; Colon-Otero, Gerardo; Powell, Steven; Russell, Jeffery; Elvin, Julia A; Vergilio, Jo-Anne; Suh, James; Ali, Siraj M; Stephens, Philip J; Miller, Vincent A; Ross, Jeffrey S

2017-07-01

Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit. We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions). Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), with GA in PIK3CA , NF1 , CDKN2A , and CDKN2C occurring in 7% of samples. We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB. Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), and alterations in PIK3CA , NF1 , CDKN2A , or CDKN2C were identified in 7% of samples. Responses to treatment with the kinase inhibitors sunitinib, everolimus, and pazopanib are presented in conjunction with tumor genomics. © AlphaMed Press 2017.

Global analysis of serum microRNAs as potential biomarkers for lung adenocarcinoma.

PubMed

Rani, Sweta; Gately, Kathy; Crown, John; O'Byrne, Ken; O'Driscoll, Lorraine

2013-12-01

Early diagnosis and the ability to predict the most relevant treatment option for individuals is essential to improve clinical outcomes for non-small cell lung cancer (NSCLC) patients. Adenocarcinoma (ADC), a subtype of NSCLC, is the single biggest cancer killer and therefore an urgent need to identify minimally invasive biomarkers to enable early diagnosis. Recent studies, by ourselves and others, indicate that circulating miRNAs have potential as biomarkers. Here we applied global profiling approaches in serum from patients with ADC of the lung to explore if miRNAs have potential as diagnostic biomarkers. This study involved RNA isolation from 80 sera specimens including those from ADC patients (equal numbers of stages 1, 2, 3, and 4) and age- and gender-matched controls (n = 40 each). Six hundred and sixty-seven miRNAs were co-analyzed in these specimens using TaqMan low density arrays and qPCR validation using individual miRNAs. Overall, approximately 390 and 370 miRNAs were detected in ADC and control sera, respectively. A group of 6 miRNAs, miR-30c-1* (AUC = 0.74; P<0.002), miR-616* (AUC = 0.71; P = 0.001), miR-146b-3p (AUC = 0.82; P<0.0001), miR-566 (AUC = 0.80; P<0.0001), miR-550 (AUC = 0.72; P = 0.0006), and miR-939 (AUC = 0.82; P<0.0001) was found to be present at substantially higher levels in ADC compared with control sera. Conversely, miR-339-5p and miR-656 were detected at substantially lower levels in ADC sera (co-analysis resulting in AUC = 0.6; P = 0.02). Differences in miRNA profile identified support circulating miRNAs having potential as diagnostic biomarkers for ADC. More extensive studies of ADC and control serum specimens are warranted to independently validate the potential clinical relevance of these miRNAs as minimally invasive biomarkers for ADC.

LoC-SERS toward clinical application: quantification of antibiotics in human urine samples

NASA Astrophysics Data System (ADS)

Hidi, I. J.; Jahn, M.; Weber, K.; Pletz, M. W.; Bocklitz, T. W.; Cialla-May, D.; Popp, J.

2017-02-01

The determination of the concentration of xenobiotics in biological matrix followed by the change of the prescribing procedure plays a major role in the transition from general to personalized medicine. For this contribution, human urine samples collected from healthy volunteers and from patients having urinary tract infection were used as biological matrix to assess the potential and limitation of LoC-SERS to detected levofloxacin and nitroxoline. The determination of both antibiotics at clinically relevant concentrations, 1.38 mM +/- 0.68 mM for levofloxacin and 10-40 µM for nitroxoline, will be presented. For quantification purposes the standard addition method is combined with LoC-SERS.

Human Trafficking, Mental Illness, and Addiction: Avoiding Diagnostic Overshadowing.

PubMed

Stoklosa, Hanni; MacGibbon, Marti; Stoklosa, Joseph

2017-01-01

This article reviews an emergency department-based clinical vignette of a trafficked patient with co-occurring pregnancy-related, mental health, and substance use disorder issues. The authors, including a survivor of human trafficking, draw on their backgrounds in addiction care, human trafficking, emergency medicine, and psychiatry to review the literature on relevant general health and mental health consequences of trafficking and propose an approach to the clinical complexities this case presents. In their discussion, the authors explicate the deleterious role of implicit bias and diagnostic overshadowing in trafficked patients with co-occurring addiction and mental illness. Finally, the authors propose a trauma-informed, multidisciplinary response to potentially trafficked patients. © 2017 American Medical Association. All Rights Reserved.

Adrenomedullin and Pregnancy: Perspectives from Animal Models to Humans

PubMed Central

Lenhart, Patricia M.; Caron, Kathleen M.

2012-01-01

A healthy pregnancy requires strict coordination of genetic, physiologic, and environmental factors. The relatively common incidence of infertility and pregnancy complications has resulted in increased interest in understanding the mechanisms that underlie normal versus abnormal pregnancy. The peptide hormone adrenomedullin has recently been the focus of some exciting breakthroughs in the pregnancy field. Supported by mechanistic studies in genetic animal models, there continues to be a growing body of evidence demonstrating the importance of adrenomedullin protein levels in a variety of human pregnancy complications. With more extensive mechanistic studies and improved consistency in clinical measurements of adrenomedullin, there is great potential for the development of adrenomedullin as a clinically-relevant biomarker in pregnancy and pregnancy complications. PMID:22425034

In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems

PubMed Central

Beedie, Shaunna L.; Rore, Holly M.; Barnett, Shelby; Chau, Cindy H.; Luo, Weiming; Greig, Nigel H.; Figg, William D.; Vargesson, Neil

2016-01-01

Thalidomide, a drug known for its teratogenic side-effects, is used successfully to treat a variety of clinical conditions including leprosy and multiple myeloma. Intense efforts are underway to synthesize and identify safer, clinically relevant analogs. Here, we conduct a preliminary in vivo screen of a library of new thalidomide analogs to determine which agents demonstrate activity, and describe a cohort of compounds with anti-angiogenic properties, anti-inflammatory properties and some compounds which exhibited both. The combination of the in vivo zebrafish and chicken embryo model systems allows for the accelerated discovery of new, potential therapies for cancerous and inflammatory conditions. PMID:27120781

Improving Atrial Fibrillation Therapy: Is There a Gene for That?

PubMed Central

Hucker, William J.; Hanley, Alan; Ellinor, Patrick T.

2017-01-01

Atrial fibrillation (AF) is an all-too-common and often challenging reality of clinical care. AF leads to significant morbidity and mortality; however, currently available treatments for AF have modest efficacy and high recurrence rates. In recent years, genetic therapy approaches have been explored in preclinical models of AF, and offer potential as a treatment modality with targeted delivery, tissue specificity, and therapy tailored to address mechanisms underlying the arrhythmia. However, many challenges remain before gene therapy can advance to a clinically relevant AF treatment. In this review, we will summarize the available published data on gene therapy and discuss the challenges, opportunities, and limitations of this approach. PMID:28427583

Rabies virus vaccine as an immune adjuvant against cancers and glioblastoma: new studies may resurrect a neglected potential.

PubMed

Altinoz, M A; Guloksuz, S; Elmaci, I

2017-07-01

To review the literature about the use of Rabies Virus-Vaccine (RV-V) as an anticancer immunotherapeutic modality in the light of recent findings. The literature search in relevant databases with the following key words: Rabies virus, cancer, remission. Remissions occured following RV-V injections in patients with cervical cancer and melanoma. Pilot clinical studies showed that RV-V injections enhanced survival in glioblastoma patients, which is supported by findings in GL261 mouse glioma model. If public health studies demonstrate protective role of RV-V against certain types of cancers, it can be benefitted as a novel immune adjuvant in clinic.

Epithelial plasticity in prostate cancer: principles and clinical perspectives.

PubMed

Das, Rajdeep; Gregory, Philip A; Hollier, Brett G; Tilley, Wayne D; Selth, Luke A

2014-11-01

Over the past decade, the capacity of cancer cells to oscillate between epithelial and mesenchymal phenotypes, termed epithelial plasticity (EP), has been demonstrated to play a critical role in metastasis. This phenomenon may be particularly important for prostate cancer (PC) progression, since recent studies have revealed interplay between EP and signaling by the androgen receptor (AR) oncoprotein. Moreover, EP appears to play a role in dictating the response to therapies for metastatic PC. This review will evaluate preclinical and clinical evidence for the relevance of EP in PC progression and consider the potential of targeting and measuring EP as a means to treat and manage lethal forms of the disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

The 2013 Gerard W. Ostheimer Lecture: What's New in Obstetric Anesthesia?

PubMed

Palanisamy, A

2014-02-01

The "What's New in Obstetric Anesthesia?" lecture is delivered annually in honor of the eminent obstetric anesthesiologist Gerard. W. Ostheimer. This lecture summarizes topics of importance and clinical relevance published in the fields of obstetric anesthesia, obstetrics, and perinatology in the preceding year. The review is a redacted version of the lecture delivered at the Society for Obstetric Anesthesia and Perinatology's Annual Meeting in April 2013. Special emphasis is placed on non-invasive technologies and biomarkers that have the potential to improve clinical care of the pregnant woman. Furthermore, sufficient attention is focused on medical diseases that have their onset or are worsened during pregnancy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Big data from electronic health records for early and late translational cardiovascular research: challenges and potential.

PubMed

Hemingway, Harry; Asselbergs, Folkert W; Danesh, John; Dobson, Richard; Maniadakis, Nikolaos; Maggioni, Aldo; van Thiel, Ghislaine J M; Cronin, Maureen; Brobert, Gunnar; Vardas, Panos; Anker, Stefan D; Grobbee, Diederick E; Denaxas, Spiros

2018-04-21

Cohorts of millions of people's health records, whole genome sequencing, imaging, sensor, societal and publicly available data present a rapidly expanding digital trace of health. We aimed to critically review, for the first time, the challenges and potential of big data across early and late stages of translational cardiovascular disease research. We sought exemplars based on literature reviews and expertise across the BigData@Heart Consortium. We identified formidable challenges including: data quality, knowing what data exist, the legal and ethical framework for their use, data sharing, building and maintaining public trust, developing standards for defining disease, developing tools for scalable, replicable science and equipping the clinical and scientific work force with new inter-disciplinary skills. Opportunities claimed for big health record data include: richer profiles of health and disease from birth to death and from the molecular to the societal scale; accelerated understanding of disease causation and progression, discovery of new mechanisms and treatment-relevant disease sub-phenotypes, understanding health and diseases in whole populations and whole health systems and returning actionable feedback loops to improve (and potentially disrupt) existing models of research and care, with greater efficiency. In early translational research we identified exemplars including: discovery of fundamental biological processes e.g. linking exome sequences to lifelong electronic health records (EHR) (e.g. human knockout experiments); drug development: genomic approaches to drug target validation; precision medicine: e.g. DNA integrated into hospital EHR for pre-emptive pharmacogenomics. In late translational research we identified exemplars including: learning health systems with outcome trials integrated into clinical care; citizen driven health with 24/7 multi-parameter patient monitoring to improve outcomes and population-based linkages of multiple EHR sources for higher resolution clinical epidemiology and public health. High volumes of inherently diverse ('big') EHR data are beginning to disrupt the nature of cardiovascular research and care. Such big data have the potential to improve our understanding of disease causation and classification relevant for early translation and to contribute actionable analytics to improve health and healthcare.

Tenofovir alafenamide (TAF) does not deplete mitochondrial DNA in human T-cell lines at intracellular concentrations exceeding clinically relevant drug exposures.

PubMed

Stray, Kirsten M; Park, Yeojin; Babusis, Darius; Callebaut, Christian; Cihlar, Tomas; Ray, Adrian S; Perron, Michel

2017-04-01

HIV-infected patients treated with certain nucleoside reverse transcriptase inhibitors (NRTIs) have experienced adverse effects due to drug-related mitochondrial toxicity. Tenofovir alafenamide (TAF) is a novel prodrug of the NRTI tenofovir (TFV) with an improved safety profile compared to tenofovir disoproxil fumarate (TDF). Prior in vitro studies have demonstrated that the parent nucleotide TFV has no significant effects on mtDNA synthesis. This study investigated whether clinically relevant TAF and TDF exposures affect mtDNA content in human lymphocytes. First, activated or resting peripheral blood mononuclear cells (PBMCs), as well as MT-2 and Jurkat T-cell lines, were continuously treated with ddC for 10 days to establish their susceptibility to mtDNA depletion. PBMCs had low sensitivity to NRTI-mediated mtDNA depletion in vitro. In contrast, ddC treatment of rapidly dividing MT-2 and Jurkat cells resulted in a dose-dependent decrease in mtDNA. Therefore, these two T-cell lines were selected for evaluating TAF and TDF treatment effects. MT-2 and Jurkat cells were pulse-treated with TAF or TDF every 24 h for 10 days to mimic pharmacologically relevant drug exposures. Pulse treatment of cells with 3.3 μM TAF or 1.1 μM TDF for 10 days resulted in 2- to 7-fold greater steady-state intracellular TFV-diphosphate (TFV-DP) levels than those observed clinically in TAF- or TDF-treated patients. At these concentrations, no significant TAF- (106.7% and 84.1% of control; p = 0.77 and 0.12 for MT-2 and Jurkat, respectively) or TDF- (100.6% and 91.0% of control; p = 0.91 and 0.37, respectively) associated reduction in mtDNA content was observed compared with untreated control cells. This study demonstrates that, despite delivering higher intracellular levels of TFV-DP than TDF, TAF does not inhibit mtDNA synthesis in vitro at concentrations exceeding the clinically relevant intracellular drug exposures. Thus, TAF has a low potential for mitochondrial toxicity in T-cells of HIV-infected patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Myocardium distribution of sertindole and its metabolite dehydrosertindole in guinea-pigs.

PubMed

Canal-Raffin, Mireille; Titier, Karine; Déridet, Evelyne; Martinez, Béatrice; Abouelfath, Abdelilah; Miras, Alain; Gromb, Sophie; Molimard, Mathieu; Moore, Nicholas

2006-05-01

Sertindole, like other atypical antipsychotics, has been shown to increase the action potential duration and QT interval in a concentration dependent manner, in in vitro electrophysiological studies. However, this does not always translate into increased duration of the QT interval, increased risk of torsade de pointes or sudden death in clinical practice. The reasons for these apparent discrepancies are unclear and many studies have underscored the importance of the interpretation of in vitro electrophysiological data in the context of other pharmacodynamic (e.g. cardiac ion channels target, receptor affinity) and pharmacokinetic parameters (total plasma drug concentration and drug distribution). To address the possible relevance of the concentrations used in experimental studies, the myocardium distribution of sertindole and its metabolite was determined after single and repeated intraperitoneal administration to guinea-pigs. The data suggest that the plasma concentration appears to predict the concentration in the myocardium and that the myocardium concentrations of sertindole are 3.1 times higher than plasma concentrations. Using these data, the relevance of in vitro electrophysiological studies to clinical plasma concentrations has been appraised. Copyright 2006 John Wiley & Sons, Ltd.

A Case for the Standardized Assessment of Testamentary Capacity

PubMed Central

Brenkel, Megan; Whaley, Kimberley; Herrmann, Nathan; Crawford, Kerri; Hazan, Elias; Cardiff, Laura; Owen, Adrian M.

2018-01-01

Background With an increasingly aged, frail population that holds a disproportionate amount of wealth, clinicians (especially those with expertise in older adults) may be asked with more frequency to offer a clinical opinion on testamentary capacity (TC), the mental capacity to make a will. Method This paper reviews the legal criteria as well as the empirical research on assessment tools for determining testamentary capacity (TC). We also review the relevance of instruments used for the assessment of other decisional capacities in order to evince the potential value of developing a standardized assessment of TC for clinician experts. Results The legal criteria, often referred to as a “test”, for determining requisite TC (Banks v. Goodfellow) have remained much the same since 1870 with minimal clinical input and, as such, there has been little development in TC assessment instruments. Decisional instruments designed to assess Consent to Treatment may have relevance for TC. Conclusion We make the case for a semi-structured interview that includes standardized criteria for the legal test for TC, supplemented by a validated brief neuropsychological assessment, which together comprise a Contemporaneous Assessment Instrument (CAI) for TC. PMID:29581818

Sugammadex, a Neuromuscular Blockade Reversal Agent, Causes Neuronal Apoptosis in Primary Cultures

PubMed Central

Palanca, José M.; Aguirre-Rueda, Diana; Granell, Manuel V.; Aldasoro, Martin; Garcia, Alma; Iradi, Antonio; Obrador, Elena; Mauricio, Maria Dolores; Vila, Jose; Gil-Bisquert, Anna; Valles, Soraya L.

2013-01-01

Sugammadex, a γ-cyclodextrin that encapsulates selectively steroidal neuromuscular blocking agents, such as rocuronium or vecuronium, has changed the face of clinical neuromuscular pharmacology. Sugammadex allows a rapid reversal of muscle paralysis. Sugammadex appears to be safe and well tolerated. Its blood-brain barrier penetration is poor (< 3% in rats), and thus no relevant central nervous toxicity is expected. However the blood brain barrier permeability can be altered under different conditions (i.e. neurodegenerative diseases, trauma, ischemia, infections, or immature nervous system). Using MTT, confocal microscopy, caspase-3 activity, cholesterol quantification and Western-blot we determine toxicity of Sugammadex in neurons in primary culture. Here we show that clinically relevant sugammadex concentrations cause apoptotic/necrosis neuron death in primary cultures. Studies on the underlying mechanism revealed that sugammadex-induced activation of mitochondria-dependent apoptosis associates with depletion of neuronal cholesterol levels. Furthermore SUG increase CytC, AIF, Smac/Diablo and CASP-3 protein expression in cells in culture. Potential association of SUG-induced alteration in cholesterol homeostasis with oxidative stress and apoptosis activation occurs. Furthermore, resistance/sensitivity to oxidative stress differs between neuronal cell types. PMID:23983586