Evidence-based recommendations for antibiotic usage to treat endodontic infections and pain: A systematic review of randomized controlled trials.

PubMed

Aminoshariae, Anita; Kulild, James C

2016-03-01

The purpose of this investigation was to identify evidence-based scientific methodologies to aid dental clinicians in establishing the indications for prescribing antibiotics for endodontic infection or pain. The authors prepared and registered a protocol on PROSPERO. They conducted electronic searches in MEDLINE, Scopus, Cochrane Library, and ClinicalTrials.gov. In addition, the authors hand searched the bibliographies of all relevant articles, the gray literature, and textbooks for randomized controlled clinical studies. The authors independently selected the relevant articles. The overall quality of the studies was fair with a low risk of bias, but 2 studies had a moderate risk of bias. The best available clinical evidence signals no indications for prescribing antibiotics preoperatively or postoperatively to prevent endodontic infection or pain unless the spread of infection is systemic, the patient is febrile, or both. Generally, an accurate diagnosis coupled with effective endodontic treatment will decrease microbial flora enough for healing to occur. To help decrease the number of drug-resistant microbes, oral health care providers should not prescribe antibiotics when they are not indicated. Copyright © 2016 American Dental Association. Published by Elsevier Inc. All rights reserved.

Infrared sauna in patients with rheumatoid arthritis and ankylosing spondylitis. A pilot study showing good tolerance, short-term improvement of pain and stiffness, and a trend towards long-term beneficial effects.

PubMed

Oosterveld, Fredrikus G J; Rasker, Johannes J; Floors, Mark; Landkroon, Robert; van Rennes, Bob; Zwijnenberg, Jan; van de Laar, Mart A F J; Koel, Gerard J

2009-01-01

To study the effects of infrared (IR) Sauna, a form of total-body hyperthermia in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients were treated for a 4-week period with a series of eight IR treatments. Seventeen RA patients and 17 AS patients were studied. IR was well tolerated, and no adverse effects were reported, no exacerbation of disease. Pain and stiffness decreased clinically, and improvements were statistically significant (p < 0.05 and p < 0.001 in RA and AS patients, respectively) during an IR session. Fatigue also decreased. Both RA and AS patients felt comfortable on average during and especially after treatment. In the RA and AS patients, pain, stiffness, and fatigue also showed clinical improvements during the 4-week treatment period, but these did not reach statistical significance. No relevant changes in disease activity scores were found, indicating no exacerbation of disease activity. In conclusion, infrared treatment has statistically significant short-term beneficial effects and clinically relevant period effects during treatment in RA and AS patients without enhancing disease activity. IR has good tolerability and no adverse effects.

The Behavioral Actions of Lithium in Rodent Models

PubMed Central

O’Donnell, Kelley C.; Gould, Todd D.

2007-01-01

For nearly as long as lithium has been in clinical use for the treatment of bipolar disorder, depression, and other conditions, investigators have attempted to characterize its effects on behaviors in rodents. Lithium consistently decreases exploratory activity, rearing, aggression, and amphetamine-induced hyperlocomotion; and it increases the sensitivity to pilocarpine-induced seizures, decreases immobility time in the forced swim test, and attenuates reserpine-induced hypolocomotion. Lithium also predictably induces conditioned taste aversion and alterations in circadian rhythms. The modulation of stereotypy, sensitization, and reward behavior are less consistent actions of the drug. These behavioral models may be relevant to human symptoms and to clinical endophenotypes. It is likely that the actions of lithium in a subset of these animal models are related to the therapeutic efficacy, as well the side effects, of the drug. We conclude with a brief discussion of various molecular mechanisms by which these lithium-sensitive behaviors may be mediated, and comment on the ways in which rat and mouse models can be used more effectively in the future to address persistent questions about the therapeutically relevant molecular actions of lithium. PMID:17532044

The impact of written information and counseling (WOMAN-PRO II Program) on symptom outcomes in women with vulvar neoplasia: A multicenter randomized controlled phase II study.

PubMed

Raphaelis, Silvia; Mayer, Hanna; Ott, Stefan; Mueller, Michael D; Steiner, Enikö; Joura, Elmar; Senn, Beate

2017-07-01

To determine whether written information and/or counseling based on the WOMAN-PRO II Program decreases symptom prevalence in women with vulvar neoplasia by a clinically relevant degree, and to explore the differences between the 2 interventions in symptom prevalence, symptom distress prevalence, and symptom experience. A multicenter randomized controlled parallel-group phase II trial with 2 interventions provided to patients after the initial diagnosis was performed in Austria and Switzerland. Women randomized to written information received a predefined set of leaflets concerning wound care and available healthcare services. Women allocated to counseling were additionally provided with 5 consultations by an Advanced Practice Nurse (APN) between the initial diagnosis and 6months post-surgery that focused on symptom management, utilization of healthcare services, and health-related decision-making. Symptom outcomes were simultaneously measured 5 times to the counseling time points. A total of 49 women with vulvar neoplasia participated in the study. Symptom prevalence decreased in women with counseling by a clinically relevant degree, but not in women with written information. Sporadically, significant differences between the 2 interventions could be observed in individual items, but not in the total scales or subscales of the symptom outcomes. The results indicate that counseling may reduce symptom prevalence in women with vulvar neoplasia by a clinically relevant extent. The observed group differences between the 2 interventions slightly favor counseling over written information. The results justify testing the benefit of counseling thoroughly in a comparative phase III trial. Copyright © 2017 Elsevier Inc. All rights reserved.

Treatment of painful bone metastases in prostate and breast cancer patients with the therapeutic radiopharmaceutical rhenium-188-HEDP. Clinical benefit in a real-world study.

PubMed

Lange, Rogier; Overbeek, Floor; de Klerk, John M H; Pasker-de Jong, Pieternel C M; van den Berk, Alexandra M; Ter Heine, Rob; Rodenburg, Cees J; Kooistra, Anko; Hendrikse, N Harry; Bloemendal, Haiko J

2016-09-26

Rhenium-188-HEDP ((188)Re-HEDP) is an effective radiopharmaceutical for the palliative treatment of osteoblastic bone metastases. However, only limited data on its routine use are available and its effect on quality of life (QoL) has not been studied. Therefore, we evaluated the clinical benefit of (188)Re-HEDP in routine clinical care. Prostate or breast cancer patients with painful bone metastases receiving (188)Re-HEDP as a routine clinical procedure were eligible for evaluation. Clinical benefit was assessed in terms of efficacy and toxicity. Pain palliation and QoL were monitored using the visual analogue scale (VAS), corrected for opioid intake, and the EORTC QLQ-C30 Global health status/QoL-scale. Thrombocyte and leukocyte nadirs were used to assess haematological toxicity. 45 and 47 patients were evaluable for pain palliation and QoL, respectively. After a single injection of (188)Re-HEDP, the overall pain response rate was 69% and mean VAS-scores decreased relevantly and significantly (p < 0.05). Repeated treatment resulted in similar pain response. The overall QoL response rate was 68% and mean Global health status/QoL-scores increased relevantly and significantly. Haematological side effects were mild and transient. The clinically relevant response on pain and quality of life and the limited adverse events prove clinical benefit of treatment with (188)Re-HEDP and support its use in routine clinical care. Its effectiveness appears comparable to that of external beam radiotherapy.

Selective and Protracted Effect of Nifedipine on Fear Memory Extinction Correlates with Induced Stress Response

ERIC Educational Resources Information Center

Waltereit, Robert; Mannhardt, Sonke; Nescholta, Sabine; Maser-Gluth, Christiane; Bartsch, Dusan

2008-01-01

Memory extinction, defined as a decrease of a conditioned response as a function of a non-reinforced conditioned stimulus presentation, has high biological and clinical relevance. Extinction is not a passive reversing or erasing of the plasticity associated with acquisition, but a novel, active learning process. Nifedipine blocks L-type voltage…

An exploration of the relationship between fatigue and physical functioning in patients with end stage renal disease receiving haemodialysis.

PubMed

O'Sullivan, Dawn; McCarthy, Geraldine

2007-11-01

To measure fatigue and physical functioning in patients with end stage renal disease (ESRD) receiving haemodialysis and to investigate the relationships between fatigue and physical functioning. Fatigue and reduced physical functioning are among the most bothersome symptoms experienced by individuals receiving haemodialysis for ESRD. Research has shown that increasing activity levels has resulted in decreased fatigue levels and improved physical functioning in individuals with cancer. Establishing whether or not a relationship exists between both concepts in haemodialysis patients is a preliminary step in identifying potential fatigue reducing strategies necessary for improved wellbeing. A quantitative exploratory correlational design was used with 46 individuals completing the Multi-dimensional Fatigue Inventory, the Medical Outcomes Study Short-Form 36-item questionnaire and a Demographic Questionnaire. Results indicated fatigue was prevalent with highest scores achieved for physical fatigue; reduced activity and general fatigue. Substantial limitations in physical functioning were found. A significant moderate negative relationship between general fatigue and physical functioning indicated that, as physical functioning levels increased, fatigue levels decreased. A significant difference was also found between general fatigue scores for males and females. Significant relationships were found between overall physical functioning, older age and employment status. The research indicates the prevalence of fatigue and limitations in physical functioning in individuals with ESRD. However, as physical functioning increased fatigue decreased; a finding relevant to clinical nursing. Understanding the levels of fatigue and the value of exercise is of relevance to clinical practice thus assessment of fatigue and physical functioning ability in the clinical setting is necessary.

Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [(11)C]MADAM PET study.

PubMed

Finnema, Sjoerd J; Halldin, Christer; Bang-Andersen, Benny; Bundgaard, Christoffer; Farde, Lars

2015-11-01

A number of serotonin receptor positron emission tomography (PET) radioligands have been shown to be sensitive to changes in extracellular serotonin concentration, in a generalization of the well-known dopamine competition model. High doses of selective serotonin reuptake inhibitors (SSRIs) decrease serotonin receptor availability in monkey brain, consistent with increased serotonin concentrations. However, two recent studies on healthy human subjects, using a single, lower and clinically relevant SSRI dose, showed increased cortical serotonin receptor radioligand binding, suggesting potential decreases in serotonin concentration in projection regions when initiating treatment. The cross-species differential SSRI effect may be partly explained by serotonin transporter (SERT) occupancy in monkey brain being higher than is clinically relevant. We here determine SERT occupancy after single doses of escitalopram or citalopram by conducting PET measurements with [(11)C]MADAM in monkeys. Relationships between dose, plasma concentration and SERT occupancy were estimated by one-site binding analyses. Binding affinity was expressed as dose (ID50) or plasma concentration (K i) where 50 % SERT occupancy was achieved. Estimated ID50 and K i values were 0.020 mg/kg and 9.6 nmol/L for escitalopram and 0.059 mg/kg and 9.7 nmol/L for citalopram, respectively. Obtained K i values are comparable to values reported in humans. Escitalopram or citalopram doses nearly saturated SERT in previous monkey studies which examined serotonin sensitivity of receptor radioligands. PET-measured cross-species differential effects of SSRI on cortical serotonin concentration may thus be related to SSRI dose. Future monkey studies using SSRI doses inducing clinically relevant SERT occupancy may further illuminate the delayed onset of SSRI therapeutic effects.

Encapsulated Stem Cells Loaded With Hyaluronidase-expressing Oncolytic Virus for Brain Tumor Therapy

PubMed Central

Martinez-Quintanilla, Jordi; He, Derek; Wakimoto, Hiroaki; Alemany, Ramon; Shah, Khalid

2015-01-01

Despite the proven safety of oncolytic viruses (OV) in clinical trials for glioblastoma (GBM), their efficacy has been hindered by suboptimal spreading within the tumor. We show that hyaluronan or hyaluronic acid (HA), an important component of extracellular matrix (ECM), is highly expressed in a majority of tumor xenografts established from patient-derived GBM lines that present both invasive and nodular phenotypes. Intratumoral injection of a conditionally replicating adenovirus expressing soluble hyaluronidase (ICOVIR17) into nodular GBM, mediated HA degradation and enhanced viral spread, resulting in a significant antitumor effect and mice survival. In an effort to translate OV-based therapeutics into clinical settings, we encapsulated human adipose-derived mesenchymal stem cells (MSC) loaded with ICOVIR17 in biocompatible synthetic extracellular matrix (sECM) and tested their efficacy in a clinically relevant mouse model of GBM resection. Compared with direct injection of ICOVIR17, sECM-MSC loaded with ICOVIR17 resulted in a significant decrease in tumor regrowth and increased mice survival. This is the first report of its kind revealing the expression of HA in GBM and the role of OV-mediated HA targeting in clinically relevant mouse model of GBM resection and thus has clinical implications. PMID:25352242

Therapeutic horticulture in clinical depression: a prospective study.

PubMed

Gonzalez, Marianne Thorsen; Hartig, Terry; Patil, Grete Grindal; Martinsen, Egil W; Kirkevold, Marit

2009-01-01

Clinically depressed persons suffer from impaired mood and distortion of cognition. This study assessed changes in depression severity and perceived attentional capacity of clinically depressed adults (N=18) during a 12-week therapeutic horticulture program. The Beck Depression Inventory (BDI) and Attentional Function Index (AFI) were administered at baseline, twice during (4 and 8 weeks), and immediately after the intervention (12 weeks), and at a 3-month follow-up. Experiences of being away and fascination related to the intervention were measured at 4, 8, and 12 weeks. The mean BDI score declined 9.7 points from pretest (27.3) to posttest (p < .001) and were clinically relevant (deltaBDI > or =6) for 72% of the cases. The mean AFI score increased 10.2 points from pretest (68.8) to posttest (p = .06). The greatest change in BDI and AFI scores occurred in the initial weeks of the intervention. The reduction in BDI scores remained significant and clinically relevant at the 3-month follow-up (N=16). The decline in depression severity during the intervention correlated strongly with the degree to which the participants found that it captured their attention. Therapeutic horticulture may decrease depression severity and improve perceived attentional capacity by engaging effortless attention and interrupting rumination.

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.

Technological Advances in Cardiovascular Safety Assessment Decrease Preclinical Animal Use and Improve Clinical Relevance.

PubMed

Berridge, Brian R; Schultze, A Eric; Heyen, Jon R; Searfoss, George H; Sarazan, R Dustan

2016-12-01

Cardiovascular (CV) safety liabilities are significant concerns for drug developers and preclinical animal studies are predominately where those liabilities are characterized before patient exposures. Steady progress in technology and laboratory capabilities is enabling a more refined and informative use of animals in those studies. The application of surgically implantable and telemetered instrumentation in the acute assessment of drug effects on CV function has significantly improved historical approaches that involved anesthetized or restrained animals. More chronically instrumented animals and application of common clinical imaging assessments like echocardiography and MRI extend functional and in-life structural assessments into the repeat-dose setting. A growing portfolio of circulating CV biomarkers is allowing longitudinal and repeated measures of cardiac and vascular injury and dysfunction better informing an understanding of temporal pathogenesis and allowing earlier detection of undesirable effects. In vitro modeling systems of the past were limited by their lack of biological relevance to the in vivo human condition. Advances in stem cell technology and more complex in vitro modeling platforms are quickly creating more opportunity to supplant animals in our earliest assessments for liabilities. Continuing improvement in our capabilities in both animal and nonanimal modeling should support a steady decrease in animal use for primary liability identification and optimize the translational relevance of the animal studies we continue to do. © The Author 2016. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

The effect of clinically relevant thermocycling on the flexural properties of endodontic post materials.

PubMed

Stewardson, Dominic A; Shortall, Adrian C; Marquis, Peter M

2010-05-01

It is suggested that fibre-reinforced composite (FRC) posts have lower elastic moduli than metal posts and this will reduce the incidence of root fracture. However, the mechanical properties may be altered in the oral environment. The aims of this study were to determine the effect on the flexural properties of FRC and metal post materials produced by: (1) a thermocycling regime which was clinically relevant and representative of that which would occur during 1 year in the mouth and (2) storage for 1 year at body temperature. Nine FRC and two metal post material samples were sealed in polythene sleeves and thermocycled between 10 degrees C and 50 degrees C for 10,000 cycles. Additional samples were stored dry at 37 degrees C for 1 year. The flexural strength and moduli were determined by three-point bending and compared with untreated control samples. Thermocycling and storage at 37 degrees C for 1 year decreased the mean flexural modulus of all materials. This was statistically significant for 8 of 11 materials after thermocycling, and 4 of 11 materials after storage at 37 degrees C (p<0.05). Thermocycling and storage at 37 degrees C produced a non-significant increase in yield strength for both metal post materials. Thermocycling significantly increased the flexural strength of Postec while it decreased for the other FRC materials. Storage at 37 degrees C increased the flexural strength of three FRC materials (significantly for Postec) while it was decreased among the other materials. Although some of the changes noticed in flexural properties were statistically significant, it is doubtful that they are of sufficient magnitude to affect clinical performance.

Pain relief is associated with decreasing postural sway in patients with non-specific low back pain.

PubMed

Ruhe, Alexander; Fejer, René; Walker, Bruce

2012-03-21

Increased postural sway is well documented in patients suffering from non-specific low back pain, whereby a linear relationship between higher pain intensities and increasing postural sway has been described. No investigation has been conducted to evaluate whether this relationship is maintained if pain levels change in adults with non-specific low back pain. Thirty-eight patients with non-specific low back pain and a matching number of healthy controls were enrolled. Postural sway was measured by three identical static bipedal standing tasks of 90 sec duration with eyes closed in narrow stance on a firm surface. The perceived pain intensity was assessed by a numeric rating scale (NRS-11). The patients received three manual interventions (e.g. manipulation, mobilization or soft tissue techniques) at 3-4 day intervals, postural sway measures were obtained at each occasion. A clinically relevant decrease of four NRS scores in associated with manual interventions correlated with a significant decrease in postural sway. In contrast, if no clinically relevant change in intensity occurred (≤ 1 level), postural sway remained similar compared to baseline. The postural sway measures obtained at follow-up sessions 2 and 3 associated with specific NRS level showed no significant differences compared to reference values for the same pain score. Alterations in self-reported pain intensities are closely related to changes in postural sway. The previously reported linear relationship between the two variables is maintained as pain levels change. Pain interference appears responsible for the altered sway in pain sufferers. This underlines the clinical use of sway measures as an objective monitoring tool during treatment or rehabilitation.

Clinical Relevance of Ceramide Metabolism in the Pathogenesis of Human Head and Neck Squamous Cell Carcinoma (HNSCC): Attenuation of C18-ceramide in HNSCC Tumors Correlates with Lymphovascular Invasion and Nodal Metastasis

PubMed Central

Karahatay, Serdar; Thomas, Kesha; Koybasi, Serap; Senkal, Can E.; ElOjeimy, Saeed; Liu, Xiang; Bielawski, Jacek; Day, Terry A.; Boyd Gillespie, M; Sinha, Debajyoti; Norris, James S.; Hannun, Yusuf A.; Ogretmen, Besim

2007-01-01

It has been documented previously that defects in the generation of C18-ceramide, a product of ceramide synthase 1 (CerS1), also known as longevity assurance gene 1 (hLASS1), play important roles in the pathogenesis and/or progression of HNSCC. However, whether altered levels of ceramide generation in HNSCC tumors have any clinical relevance remains unknown. In this study, the levels of endogenous ceramides were measured in tumor tissues of 45 HNSCC patients as compared to their normal tissues using high-pressure liquid chromatography/mass spectrometry (LC/MS), and then possible link between ceramide levels and the clinical parameters of HNSCC were examined. The data showed that the levels of C16-, C24-, C24:1-ceramide were significantly elevated in the majority of tumor tissues compared to their normal tissues, while the levels of only C18-ceramide were significantly decreased in HNSCC tumors, especially in tumor tissues of male patients. Importantly, it was also shown here that decreased C18-ceramide levels in HNSCC tumor tissues were significantly associated with the higher incidences of lymphovascular invasion, and pathologic nodal metastasis. Importantly, attenuation of C18-ceramide was also positively linked to the higher overall stages of the primary HNSCC tumors. Therefore, these data suggest, for the first time, that the defects in the generation/accumulation of C18-ceramide might have important clinical roles in HNSCC, especially in lymphovascular invasion and nodal disease. PMID:17619081

Nasal carriage of Staphylococcus aureus in Australian (pre-clinical and clinical) medical students.

PubMed

Stubbs, E; Pegler, M; Vickery, A; Harbour, C

1994-06-01

The nasal carriage of Staphylococcus aureus in 808 Australian medical students was studied. Five groups of students experienced varying degrees of clinical exposure in a hospital environment ranging from 0 to 42 months. The overall percentage of carriers among the five groups did not vary. However, with increasing clinical exposure there was a decrease in the percentage of isolates sensitive to all antibiotics tested, and an increase in the carriage of S. aureus resistant to three or more antibiotics. No carriers of methicillin-resistant S. aureus (MRSA) were detected. The comparative rates of S. aureus carriage between female and male students varied. The relevance of medical students as nasal carriers of S. aureus in the hospital environment today is discussed.

Predictive Accuracy of Calf Circumference Measurements to Detect Decreased Skeletal Muscle Mass and European Society for Clinical Nutrition and Metabolism-Defined Malnutrition in Hospitalized Older Patients.

PubMed

Maeda, Keisuke; Koga, Takayuki; Nasu, Tomomi; Takaki, Miki; Akagi, Junji

2017-01-01

The ability to readily diagnose sarcopenia and malnutrition in a clinical setting is essential. This study is aimed at clarifying the calf circumference (CC) cut-off values for decreased skeletal muscle mass (SMM), according to the Asian Work Group for Sarcopenia's criteria definition of sarcopenia, and those for European Society for Clinical Nutrition and Metabolism-defined malnutrition, in hospitalized Japanese patients. The study involved 1,164 patients aged ≥65 years. Predictive CC cut-off values were determined using receiver operating curve (ROC) analyses. The predictive validity of the cut-off values was confirmed against in-hospital mortality. There were 654 females and 510 males (mean age, 83.5 ± 8.2 years). Decreased SMM and malnutrition were observed in 80.4 and 32.8% of all patients, respectively. ROC analyses identified CCs of ≤29 cm (female, area under the curve [AUC] 0.791) and ≤30 cm (male, AUC 0.832) as cut-off values for decreased SMM, and CCs of ≤26 cm (female, AUC 0.798) and ≤28 cm (male, AUC 0.837) for malnutrition. CC cut-off values for SMM and malnutrition were independently correlated with in-hospital mortality. The study determined appropriate cut-off values for CC to identify decreased SMM and malnutrition according to the relevant guidelines. © 2017 S. Karger AG, Basel.

Fat-soluble vitamins and atopic disease: what is the evidence?

PubMed

Litonjua, Augusto A

2012-02-01

The prevalence of asthma and other atopic disorders continues to increase worldwide. Examination of the epidemiologic patterns has revealed that this rise has occurred primarily in western, industrialised countries and countries transitioning to this lifestyle. While many changes have occurred in human populations over the years, it has been hypothesised that some of the relevant changes that have led to the rise in asthma and atopic disorders have been the changes from a traditional diet to a more western diet consisting of decreased intake of fruits and vegetables (sources of antioxidant vitamins and carotenoids) leading to decreased intakes of vitamins E and A, and a decrease in sun exposure (e.g. greater time spent indoors and heavy use of sunscreen) leading to decreased circulating levels of vitamin D. This review will examine the evidence for an effect of fat-soluble vitamins (vitamins A, D and K) on the development and severity of asthma and allergies. While observational studies suggest that these vitamins may play a salutary role in asthma and allergies, large, well-designed clinical trials are lacking. Of the fat-soluble vitamins, vitamin D holds great promise as an agent for primary and secondary prevention of disease. Ongoing clinical trials will help determine whether results of observational studies can be applied to the clinical setting.

Fat-soluble vitamins and atopic disease: what is the evidence?

PubMed Central

Litonjua, Augusto A.

2012-01-01

The prevalence of asthma and other atopic disorders continues to increase worldwide. Examination of the epidemiologic patterns has revealed that this rise has occurred primarily in western, industrialised countries and countries transitioning to this lifestyle. While many changes have occurred in human populations over the years, it has been hypothesised that some of the relevant changes that have led to the rise in asthma and atopic disorders have been the changes from a traditional diet to a more western diet consisting of decreased intake of fruits and vegetables (sources of antioxidant vitamins and carotenoids) leading to decreased intakes of vitamins E and A, and a decrease in sun exposure (e.g. greater time spent indoors and heavy use of sunscreen) leading to decreased circulating levels of vitamin D. This review will examine the evidence for an effect of fat-soluble vitamins (vitamins A, D and K) on the development and severity of asthma and allergies. While observational studies suggest that these vitamins may play a salutary role in asthma and allergies, large, well-designed clinical trials are lacking. Of the fat-soluble vitamins, vitamin D holds great promise as an agent for primary and secondary prevention of disease. Ongoing clinical trials will help determine whether results of observational studies can be applied to the clinical setting. PMID:22114947

Effect of the Putative Lithium Mimetic Ebselen on Brain Myo-Inositol, Sleep, and Emotional Processing in Humans.

PubMed

Singh, Nisha; Sharpley, Ann L; Emir, Uzay E; Masaki, Charles; Herzallah, Mohammad M; Gluck, Mark A; Sharp, Trevor; Harmer, Catherine J; Vasudevan, Sridhar R; Cowen, Philip J; Churchill, Grant C

2016-06-01

Lithium remains the gold standard in treating bipolar disorder but has unwanted toxicity and side effects. We previously reported that ebselen inhibits inositol monophosphatase (IMPase) and exhibits lithium-like effects in animal models through lowering of inositol. Ebselen has been tested in clinical trials for other disorders, enabling us to determine for the first time the effect of a blood-brain barrier-penetrant IMPase inhibitor on human central nervous system (CNS) function. We now report that in a double-blind, placebo-controlled trial with healthy participants, acute oral ebselen reduced brain myo-inositol in the anterior cingulate cortex, consistent with CNS target engagement. Ebselen decreased slow-wave sleep and affected emotional processing by increasing recognition of some emotions, decreasing latency time in the acoustic startle paradigm, and decreasing the reinforcement of rewarding stimuli. In summary, ebselen affects the phosphoinositide cycle and has CNS effects on surrogate markers that may be relevant to the treatment of bipolar disorder that can be tested in future clinical trials.

Topical Vitamin C and the Skin: Mechanisms of Action and Clinical Applications.

PubMed

Al-Niaimi, Firas; Chiang, Nicole Yi Zhen

2017-07-01

OBJECTIVE: This review article details the main mechanisms of action and clinical applications of topical vitamin C on the skin, including its antioxidative, photoprotective, antiaging, and antipigmentary effects. DESIGN: A PubMed search for the relevant articles on vitamin C and the skin was conducted using the following key words: "vitamin C," "ascorbic acid," "ascorbyl-6-palmitate,"and "magnesium ascorbyl phosphate." RESULTS: As one of the most powerful antioxidants in the skin, vitamin C has been shown to protect against photoaging, ultraviolet-induced immunosuppression, and photocarcinogenesis. It also has an antiaging effect by increasing collagen synthesis, stabilizing collagen fibers, and decreasing collagen degradation. It decreases melanin formation, thereby reducing pigmentation. Vitamin C is the primary replenisher of vitamin E and works synergistically with vitamin E in the protection against oxidative damage. CONCLUSION: Topical vitamin C has a wide range of clinical applications, from antiaging and antipigmentary to photoprotective. Currently, clinical studies on the efficacy of topical formulations of vitamin C remain limited, and the challenge lies in finding the most stable and permeable formulation in achieving the optimal results.

Mepolizumab for Treating Severe Eosinophilic Asthma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

PubMed

Bermejo, Iñigo; Stevenson, Matt; Cooper, Katy; Harnan, Sue; Hamilton, Jean; Clowes, Mark; Carroll, Christopher; Harrison, Tim; Saha, Shironjit

2018-02-01

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the company (GlaxoSmithKline) that manufactures mepolizumab (Nucala ® ) to submit evidence on the clinical and cost effectiveness of mepolizumab for the treatment of severe eosinophilic asthma. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). The ERG produced a review of the evidence for the clinical and cost effectiveness of mepolizumab as add-on to standard of care (SoC) compared with SoC and omalizumab, based upon the company's submission to NICE. The clinical-effectiveness evidence in the company's submission was based predominantly on three randomised controlled trials (DREAM, MENSA and SIRIUS) comparing add-on mepolizumab with placebo plus SoC. The relevant population was defined in terms of degree of asthma severity (four or more exacerbations in the previous year and/or dependency on maintenance oral corticosteroids [mOCS]) and degree of eosinophilia (a blood eosinophil count of ≥ 300 cells/µl in the previous year) based on post hoc subgroup analyses of the pivotal trials. Other subpopulations were considered throughout the appraisal, defined by different eosinophil measurements, number of exacerbations and dependency (or lack thereof) on mOCS. Statistically significant reductions in clinically significant exacerbations were observed in patients receiving mepolizumab compared with SoC meta-analysed across MENSA and DREAM in the modified intention-to-treat (ITT) population (rate ratio [RR] 0.51; 95% confidence interval [CI] 0.42-0.62) as well as in the relevant population (RR 0.47; 95% CI 0.36-0.62). In terms of quality of life, differences on the St. George's Respiratory Questionnaire in MENSA for add-on subcutaneous mepolizumab 100 mg vs. placebo were 7 and 7.5 units in the modified ITT and relevant populations, respectively. A number of issues in the clinical evidence base warrant caution in its interpretation. The ERG noted that the definition of SoC used in the trials differed from that in clinical practice, where patients with severe uncontrolled asthma start treatment with a mOCS. The company's economic post-consultation analysis incorporating a confidential patient access scheme (PAS) estimated that the incremental cost-effectiveness ratio (ICER) for add-on mepolizumab compared with SoC was £27,418 per quality-adjusted life-year (QALY) gained in the relevant population if patients stopped mepolizumab after 1 year unless (1) the number of exacerbations decreased at least 50% or (2) a reduction in corticosteroids dose was achieved whilst maintaining asthma control. The ERG applied an age adjustment to all utilities and corrected the post-continuation assessment utilities, which resulted in an ICER for add-on mepolizumab compared with SoC of £29,163 per QALY gained. The ERG noted that this ICER was not robust for patients who continued treatment due to a corticosteroid dose reduction where exacerbations had decreased by less than 50%, because corticosteroid dose reduction was not allowed in the main trial in which the evidence was gathered (MENSA). The NICE appraisal committee (AC) concluded that add-on mepolizumab could be recommended as an option for treating severe refractory eosinophilic asthma in adults for the relevant population when the stopping rule suggested by the company was applied. The AC also concluded that the comparison between mepolizumab and omalizumab was not clinically relevant or methodologically robust.

Female Pattern Hair Loss: a clinical and pathophysiological review*

PubMed Central

Ramos, Paulo Müller; Miot, Hélio Amante

2015-01-01

Female Pattern Hair Loss or female androgenetic alopecia is the main cause of hair loss in adult women and has a major impact on patients' quality of life. It evolves from the progressive miniaturization of follicles that lead to a subsequent decrease of the hair density, leading to a non-scarring diffuse alopecia, with characteristic clinical, dermoscopic and histological patterns. In spite of the high frequency of the disease and the relevance of its psychological impact, its pathogenesis is not yet fully understood, being influenced by genetic, hormonal and environmental factors. In addition, response to treatment is variable. In this article, authors discuss the main clinical, epidemiological and pathophysiological aspects of female pattern hair loss. PMID:26375223

Food for Thought Look Back in Anger – What Clinical Studies Tell Us About Preclinical Work

PubMed Central

Hartung, Thomas

2013-01-01

Summary Misled by animal studies and basic research? Whenever we take a closer look at the outcome of clinical trials in a field such as, most recently, stroke or septic shock, we see how limited the value of our preclinical models was. For all indications, 95% of drugs that enter clinical trials do not make it to the market, despite all promise of the (animal) models used to develop them. Drug development has started already to decrease its reliance on animal models: In Europe, for example, despite increasing R&D expenditure, animal use by pharmaceutical companies dropped by more than 25% from 2005 to 2008. In vitro studies are likewise limited: questionable cell authenticity, over-passaging, mycoplasma infections, and lack of differentiation as well as non-homeostatic and non-physiologic culture conditions endanger the relevance of these models. The standards of statistics and reporting often are poor, further impairing reliability. Alarming studies from industry show miserable reproducibility of landmark studies. This paper discusses factors contributing to the lack of reproducibility and relevance of pre-clinical research. The conclusion: Publish less but of better quality and do not rely on the face value of animal studies. PMID:23861075

Need assessment of enhancing the weightage of applied biochemistry in the undergraduate curriculum at MGIMS, sevagram.

PubMed

Kumar, Satish; Jena, Lingaraja; Vagha, Jayant

2016-05-06

In order to review the need assessment of enhancing the weightage of Applied Biochemistry in the undergraduate curriculum at Mahatma Gandhi Institute of Medical Sciences (MGIMS), Sevagram, a validated questionnaire was sent to 453 participants which include 387 undergraduate students, 11 interns, 23 postgraduate students, and 32 faculty members. A web-based data collection and analysis tool was designed for online questionnaire distribution, data collection, and analysis. Response rate was 100%. Most of the respondents agreed that the subject Biochemistry has relevance in clinical practice (81.24%) and applied based learning of Biochemistry by medical undergraduates would help in overall improvement in the health standards/patients care (83.44%). According to 65.12% respondents, most of the medical undergraduates read Biochemistry just for examination purpose only. Nearly half of the respondents agreed that minute details of biochemical reactions were not much useful in clinical practice (53.86%) and the vast majority of diagrammatic cycles memorized by the medical undergraduates had no relevance in clinical practice (51.21%), the decreased interest in learning the Applied Biochemistry was due to more amount of clinically irrelevant information taught to medical undergraduates (73.51%), there was a need to rethink for removing the diagrammatic biochemical cycles from curriculum for medical undergraduates (48.12%), the less learning of Applied Biochemistry or competencies would affect the clinical skills and knowledge of medical undergraduates (70.42%). The result of this study suggests that there is need for restructuring the Biochemistry curriculum with more clinical relevance. © 2016 by The International Union of Biochemistry and Molecular Biology, 44:230-240, 2016. © 2016 The International Union of Biochemistry and Molecular Biology.

What is the effect of chest physiotherapy in hospitalized children with pneumonia?

PubMed

Damiani, Felipe; Adasme, Rodrigo

2015-10-19

Chest physiotherapy is applied in clinical practice for the treatment of pneumonia. However, its use is still controversial. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified one systematic review including two relevant randomized controlled trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded it is unclear whether chest physiotherapy increases or decreases the length of hospitalization, severity, or the time to clinical improvement in children with pneumonia because the certainty of the evidence is very low.

Animal model of neuropathic tachycardia syndrome

NASA Technical Reports Server (NTRS)

Carson, R. P.; Appalsamy, M.; Diedrich, A.; Davis, T. L.; Robertson, D.

2001-01-01

Clinically relevant autonomic dysfunction can result from either complete or partial loss of sympathetic outflow to effector organs. Reported animal models of autonomic neuropathy have aimed to achieve complete lesions of sympathetic nerves, but incomplete lesions might be more relevant to certain clinical entities. We hypothesized that loss of sympathetic innervation would result in a predicted decrease in arterial pressure and a compensatory increase in heart rate. Increased heart rate due to loss of sympathetic innervation is seemingly paradoxical, but it provides a mechanistic explanation for clinical autonomic syndromes such as neuropathic postural tachycardia syndrome. Partially dysautonomic animals were generated by selectively lesioning postganglionic sympathetic neurons with 150 mg/kg 6-hydroxydopamine hydrobromide in male Sprague-Dawley rats. Blood pressure and heart rate were monitored using radiotelemetry. Systolic blood pressure decreased within hours postlesion (Delta>20 mm Hg). Within 4 days postlesion, heart rate rose and remained elevated above control levels. The severity of the lesion was determined functionally and pharmacologically by spectral analysis and responsiveness to tyramine. Low-frequency spectral power of systolic blood pressure was reduced postlesion and correlated with the diminished tyramine responsiveness (r=0.9572, P=0.0053). The tachycardia was abolished by treatment with the beta-antagonist propranolol, demonstrating that it was mediated by catecholamines acting on cardiac beta-receptors. Partial lesions of the autonomic nervous system have been hypothesized to underlie many disorders, including neuropathic postural tachycardia syndrome. This animal model may help us better understand the pathophysiology of autonomic dysfunction and lead to development of therapeutic interventions.

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.

[Relevance of drug use in clinical manifestations of schizophrenia].

PubMed

Arias Horcajadas, F; Sánchez Romero, S; Padín Calo, J J

2002-01-01

To study the association between drugs use with schizophrenia clinical manifestations. The sample consists of 82 out-patients with schizophrenia, between 18 and 45 years old. They were evaluated with Addiction Severity Index (ASI) and with Positive and Negative Syndrome Scale (PANSS). A 6 months follow up was carried out. 37,8% patients had lifetime drug dependence (including alcohol and others drugs except for tobacco). The prevalence of dependence for the different drugs were: opioids 9,8%, cocaine 11%, alcohol 29,3%, cannabis 24,4%, tobacco 68,3%, caffeine 15,9%. Drug dependent had more family and legal problems. At the multiple regression analysis it was observed that cannabis and tobacco dependence was associated with a decrease in the PANSS negative symptoms subscale, and on the contrary, alcohol dependence produces a similar intensity increase at that scoring. We don't detect any clinical relevance effects over positive symptoms. Cannabis and tobacco may improve schizophrenia negative symptoms or neuroleptic secondary effects or patients with few negative symptoms may have more predisposition to the use, on the contrary alcohol use can impairment those symptoms.

Efficacy and safety profile of LCR35 complete freeze-dried culture in irritable bowel syndrome: a randomized, double-blind study.

PubMed

Dapoigny, Michel; Piche, Thierry; Ducrotte, Philippe; Lunaud, Bernard; Cardot, Jean-Michel; Bernalier-Donadille, Annick

2012-05-07

To assess the effects and safety of Lactobacillus casei rhamnosus LCR35 complete freeze-dried culture (LCR35) in patients suffering from irritable bowel syndrome (IBS). A randomized, double-blind pilot study was performed in 50 patients complaining of IBS symptoms complying with Rome III criteria. Patients were allocated to receive either LCR35 (n = 25) at a minimum daily dose of 6 × 10(8) colony forming units or placebo (n = 25) for 4 wk. At inclusion, after treatment and 2 wk later, patients completed the IBS severity scale. Change from baseline in the IBS severity score at the end of treatment was the primary efficacy criterion. Changes were compared between groups in the whole population and in IBS subtypes (IBS with predominance of constipation, IBS with predominance of diarrhoea, mixed IBS, unsubtyped IBS). The presence of lactobacillus casei rhamnosus in stools was investigated at inclusion and at the end of treatment. The gastrointestinal quality of life questionnaire and the hospital anxiety and depression (HAD) scale were also completed. Both groups were balanced for baseline characteristics. In 85% of patients, stool analyses showed that lactobacillus casei rhamnosus able to survive in the digestive tract. In the whole population, improvements in the IBS severity score did not differ significantly between treatments with a 25% decrease after 4-wk treatment, and a 15% decrease from baseline 2 wk later in both groups. In IBS subgroups, statistical analysis could not be performed due to small sample size, but a clinical response in favour of LCR35 was observed in IBS patients with predominance of diarrhoea: no change in the symptom severity score was seen with the placebo after 4 wk treatment, whereas a clinically relevant decrease occurred with LCR35 (-37% vs -3%). Furthermore, in spite of an increase in symptom intensity, the IBS severity score was maintained below the baseline value 2 wk later with LCR35 (-19% from baseline), whilst a slight 5% increase from baseline was observed with placebo. In the IBS subgroup with predominance of diarrhoea only, a clinically relevant decrease in abdominal pain severity score (-36%) was observed with LCR35, whereas no change occurred with placebo. In mixed IBS patients, the 20% and 30% decreases in the IBS severity score observed after treatment with LCR35 and placebo, respectively, were maintained 2 wk later in both groups. A clinical response slightly in favour of placebo was observed at the end of the treatment period in IBS patients with predominance of constipation (-41% vs -20%) and unsubtyped IBS patients (-47% vs -17%), with the same value maintained 2 wk later. In both groups, no clinically relevant changes were observed either for the gastrointestinal quality of life index or HAD score. Thus, these results suggest that sub-grouping of IBS patients may be important for optimizing treatment responses by the physician. This pilot study suggests that LCR35 could have some efficacy in IBS patients complaining of diarrhoea. These preliminary results need to be confirmed in larger studies.

Effect of guaifenesin on mucin production, rheology, and mucociliary transport in differentiated human airway epithelial cells.

PubMed

Seagrave, JeanClare; Albrecht, Helmut; Park, Yong Sung; Rubin, Bruce; Solomon, Gail; Kim, K Chul

2011-12-01

Guaifenesin is widely used to alleviate symptoms of excessive mucus accumulation in the respiratory tract. However, its mechanism of action is poorly understood. The authors hypothesized that guaifenesin improves mucociliary clearance in humans by reducing mucin release, by decreasing mucus viscoelasticity, and by increasing mucociliary transport. To test these hypotheses, human differentiated airway epithelial cells, cultured at an air-liquid interface, were treated with clinically relevant concentrations of guaifenesin by addition to the basolateral medium. To evaluate the effect on mucin secretion, the authors used an anzyme-linked immunosorbent assay (ELISA) to measure the amounts of MUC5AC protein in apical surface fluid and cell lysates. To measure mucociliary transportability, additional cultures were treated for 1 or 6 hours with guaifenesin, and the movement of cell debris was measured from video data. Further, the authors measured mucus dynamic viscoelasticity using a micro cone and plate rheometer with nondestructive creep transformation. Guaifenesin suppressed mucin production in a dose-dependent manner at clinically relevant concentrations. The reduced mucin production was associated with increased mucociliary transport and decreased viscoelasticity of the mucus. Viability of the cultures was not significantly affected. These results suggest that guaifenesin could improve mucociliary clearance in humans by reducing the release and/or production of mucins, thereby altering mucus rheology.

[Evaluation of pain during mobilization and endotracheal aspiration in critical patients].

PubMed

Robleda, G; Roche-Campo, F; Membrilla-Martínez, L; Fernández-Lucio, A; Villamor-Vázquez, M; Merten, A; Gich, I; Mancebo, J; Català-Puigbó, E; Baños, J E

2016-03-01

1) To assess the prevalence of pain during nursing care procedures, and 2) to evaluate the usefulness of certain vital signs and the bispectral index (BIS) in detecting pain. A prospective, observational analytical study was made of procedures (endotracheal aspiration and mobilization with turning) in critically ill sedated patients on mechanical ventilation. The Behavioral Pain Scale was used to assess pain, with scores of ≥3 indicating pain. Various physiological signs and BIS values were recorded, with changes of >10% being considered clinically relevant. A total of 146 procedures in 70 patients were analyzed. Pain prevalence during the procedures was 94%. Vital signs and BIS values increased significantly during the procedures compared to resting conditions, but only the changes in BIS were considered clinically relevant. In the subgroup of patients receiving preemptive analgesia prior to the procedure, pain decreased significantly compared to the group of patients who received no such analgesia (-2 [IQR: {-5}-0] vs. 3 [IQR: 1-4]; P<.001, respectively). The procedures evaluated in this study are painful. Changes in vital signs are not good indicators of pain. Changes in BIS may provide useful information about pain, but more research is needed. The administration of preemptive analgesia decreases pain during the procedures. Copyright © 2015 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.

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.

Quality Control of Next-generation Sequencing-based In vitro Diagnostic Test for Onco-relevant Mutations Using Multiplex Reference Materials in Plasma.

PubMed

Liu, Donglai; Zhou, Haiwei; Shi, Dawei; Shen, Shu; Tian, Yabin; Wang, Lin; Lou, Jiatao; Cong, Rong; Lu, Juan; Zhang, Henghui; Zhao, Meiru; Zhu, Shida; Cao, Zhisheng; Jin, Ruilin; Wang, Yin; Zhang, Xiaoni; Yang, Guohua; Wang, Youchun; Zhang, Chuntao

2018-01-01

Background: Widespread clinical implementation of next-generation sequencing (NGS)-based cancer in vitro diagnostic tests (IVDs) highlighted the urgency to establish reference materials which could provide full control of the process from nucleic acid extraction to test report generation. The formalin-fixed, paraffin-embedded (FFPE) tissue and blood plasma containing circulating tumor deoxyribonucleic acid (ctDNA) were mostly used for clinically detecting onco-relevant mutations. Methods: We respectively developed multiplex FFPE and plasma reference materials covering three clinically onco-relevant mutations within the epidermal growth factor receptor ( EGFR ) gene at serial allelic frequencies. All reference materials were quantified and validated via droplet digital polymerase chain reaction (ddPCR), and then were distributed to eight domestic manufacturers for the collaborative evaluation of the performance of several domestic NGS-based cancer IVDs covering four major NGS platforms (NextSeq, HiSeq, Ion Proton and BGISEQ). Results: All expected mutations except one at extremely low allelic frequencies were detected, despite some differences in coefficient of variation (CV) which increased with the decrease of allelic frequency (CVs ranging from 18% to 106%). It was worth noting that the CV value seemed to correlate with a particular mutation as well. The repeatability of determination of different mutations was L858R>T790M>19del. Conclusions: The results indicated our reference materials would be pivotal for quality control of NGS-based cancer IVDs and would guide the further development of reference materials covering more onco-relevant mutations.

Depression of home cage wheel running: a reliable and clinically relevant method to assess migraine pain in rats.

PubMed

Kandasamy, Ram; Lee, Andrea T; Morgan, Michael M

2017-12-01

The development of new anti-migraine treatments is limited by the difficulty inassessing migraine pain in laboratory animals. Depression of activity is one of the few diagnostic criteria formigraine that can be mimicked in rats. The goal of the present study was to test the hypothesis thatdepression of home cage wheel running is a reliable and clinically relevant method to assess migraine painin rats. Adult female rats were implanted with a cannula to inject allyl isothiocyanate (AITC) onto the dura to induce migraine pain, as has been shown before. Rats recovered from implantation surgery for 8 days in cages containing a running wheel. Home cage wheel running was recorded 23 h a day. AITC and the migraine medication sumatriptan were administered in the hour prior to onset of the dark phase. Administration of AITC caused a concentration-dependent decrease in wheel running that lasted 3 h. The duration and magnitude of AITC-induced depression of wheel running was consistent following three repeated injections spaced 48 h apart. Administration of sumatriptan attenuated AITC-induced depressionof wheel running when a large dose (1 mg/kg) was administered immediately following AITC administration. Wheel running patterns did not change when sumatriptan was given to naïve rats. These data indicate that home cage wheel running is a sensitive, reliable, and clinically relevant method to assess migraine pain in the rat.

Curtailing the high rate of late-stage attrition of investigational therapeutics against unprecedented targets in patients with lung and other malignancies.

PubMed

Rowinsky, Eric K

2004-06-15

A greater understanding of the pathogenesis and biology of cancer coupled with major advances in biotechnology has resulted in the identification of rationally designed, target-based (RDTB) anticancer therapeutics, ushering in new therapeutic opportunities and high expectations for the future as well as developmental challenges. Because these agents appear to principally target malignant cells, it is expected that they will produce less toxicity at clinically effective doses than nonspecific cytotoxic agents, but their target requirements are likely to be much more stringent. The innate complexity of the networks that contain elements targeted by these agents also decreases the probability that any single therapeutic manipulation will result in robust clinical activity and success when used alone, particularly in patients with solid malignancies that have multiple relevant signaling aberrations. In contrast, proof of principle and robust antitumor activity may be most efficiently demonstrated in nonrandomized evaluations involving tumors that are principally driven by aberrations of the specific target. The predominant therapeutic manifestation of RDTB agents in preclinical studies is due to decreased tumor growth rates and will likely be similar in the clinic; however, such manifestations are not readily detectable and quantifiable using nonrandomized clinical evaluations. To curtail the increasing rate of late-stage attrition of RDTB agents, which, if maintained, will stymie progress in cancer therapy, the design of initial nonrandomized evaluations, particularly the selection of tumors and patients, must be guided by the principal biological features of the agents. Next, evaluations, some of which must be randomized, can be performed in a wide range of tumor types, depending on the presence and relevance of the target. To validate the concept of RDTB therapeutics and to realize their full potential, radically different development, evaluation, and regulatory paradigms must be adopted.

Severe community-acquired pneumonia: timely management measures in the first 24 hours.

PubMed

Phua, Jason; Dean, Nathan C; Guo, Qi; Kuan, Win Sen; Lim, Hui Fang; Lim, Tow Keang

2016-08-28

Mortality rates for severe community-acquired pneumonia (CAP) range from 17 to 48 % in published studies.In this review, we searched PubMed for relevant papers published between 1981 and June 2016 and relevant files. We explored how early and aggressive management measures, implemented within 24 hours of recognition of severe CAP and carried out both in the emergency department and in the ICU, decrease mortality in severe CAP.These measures begin with the use of severity assessment tools and the application of care bundles via clinical decision support tools. The bundles include early guideline-concordant antibiotics including macrolides, early haemodynamic support (lactate measurement, intravenous fluids, and vasopressors), and early respiratory support (high-flow nasal cannulae, lung-protective ventilation, prone positioning, and neuromuscular blockade for acute respiratory distress syndrome).While the proposed interventions appear straightforward, multiple barriers to their implementation exist. To successfully decrease mortality for severe CAP, early and close collaboration between emergency medicine and respiratory and critical care medicine teams is required. We propose a workflow incorporating these interventions.

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.

[Analysis of clinical relevance applied to 3methods of reducing weight in overweight or obesity followed-up for one year].

PubMed

Tárraga Marcos, M L; Panisello Royo, J M; Carbayo Herencia, J A; Rosich Domenech, N; Alins Presas, J; Castell Panisello, E; Tárraga López, P J

To analyse the effect of the use/implementation of 3methods to reduce weight in overweight or obese patients during one year of follow up. The design corresponds to a double-blind, randomised, controlled clinical trial with 3arms, and 12 months of follow-up. Patients were randomised into 3intervention groups: obesity motivational intervention, with a nurse previously trained in motivational intervention by expert psychologists (G1; n=60); lower intensity consultation, non-motivational group, with digital platform support (G2; N=61), and a third group that received recommendations for weight loss and follow-up in Primary Care Clinic (G3; n=59). Anthropometric variables (weight, height, and abdominal-waist circumference) were measured, and the percentage of patients who managed to reduce their weight ≥5% was considered as the main measurement of treatment effectiveness. All groups significantly decreased body weight at the end of the study, with a reduction in G1 (-5.6kg) followed by G2 (-4.3kg), and G3 (-1.7kg), with an overall mean: -3.9kg. The indicators of clinical relevance were in G1/G3: relative risk (RR): 4.99 (95% CI: from 2.71 to 9.18); relative risk reduction (RRR): 399.1% (171.3 to 818.0); Absolute risk reduction (RAR): 65.3% (from 51.5 to 79.1) and NNT: 2 (from 2 to 2). In the G2/G3 groups: RR: 3.01 (from 1.57 to 5.76); RRR: 200.5% (from 57.0 to 475.5); RAR: 32.8% (from 16.9 to 48.7) and NNT: 4 (from 3 to 6). In the G1/G2 groups: RR: 1.66 (from 1.25 to 2.20); RRR: 66.1% (from 25.3 to 120.1); RAR: 32.5% (from 16.6 to 48.4) and NNT: 4 (from 3 to 7). All 3groups were able to reduce weight. Although the group with motivational intervention achieved the greatest decrease, as well as the most favourable clinical relevance indicators. Copyright © 2017 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

The effect of normobaric oxygen in patients with acute stroke: a systematic review and meta-analysis.

PubMed

Ding, Jiayue; Zhou, Da; Sui, Meng; Meng, Ran; Chandra, Ankush; Han, Jie; Ding, Yuchuan; Ji, Xunming

2018-03-30

Background Normobaric oxygen (NBO) has received considerable attention due to controversial data in brain protection in patients with acute stroke. This study aims to analyze current data of NBO on brain protection as used in the clinic. Methods We searched for and reviewed relevant articles and references from Pubmed, Medline, Embase, Cochrane, and Clincialtrials.gov that were published prior to October 2017. Data from prospective studies were processed using RevMan5.0 software, provided by Cochrane collaboration and transformed using relevant formulas. Results A total of 11 prospective RCT studies including 6366 patients with acute stroke (NBO group, 3207; control group, 3159) were enrolled in this analysis. △NIHSS represented the values of NIHSS at 4, 24 h, or 7 days post-stroke minus baseline NIHSS. Compared to controls, there was a minor trend toward NBO benefits in short-term prognostic indices, as indicated by decreased ΔNIHSS at our defined time points. By contrast, NBO decreased Barthel Index scores between 3 and 7 months, and increased death rates at 3, 6 months, and 1 year, whereas, modified Rankin Scale scores between 3 and 6 months were unchanged. Conclusions The existing trends toward benefits revealed in this meta-analysis help us appreciate the promising value of NBO, although current evidence of NBO on improving clinical outcomes of stroke is insufficient. Well-designed multi-center clinical trials are encouraged and urgently needed to further explore the efficacy of NBO on brain protection.

Effect of the Putative Lithium Mimetic Ebselen on Brain Myo-Inositol, Sleep, and Emotional Processing in Humans

PubMed Central

Singh, Nisha; Sharpley, Ann L; Emir, Uzay E; Masaki, Charles; Herzallah, Mohammad M; Gluck, Mark A; Sharp, Trevor; Harmer, Catherine J; Vasudevan, Sridhar R; Cowen, Philip J; Churchill, Grant C

2016-01-01

Lithium remains the gold standard in treating bipolar disorder but has unwanted toxicity and side effects. We previously reported that ebselen inhibits inositol monophosphatase (IMPase) and exhibits lithium-like effects in animal models through lowering of inositol. Ebselen has been tested in clinical trials for other disorders, enabling us to determine for the first time the effect of a blood–brain barrier-penetrant IMPase inhibitor on human central nervous system (CNS) function. We now report that in a double-blind, placebo-controlled trial with healthy participants, acute oral ebselen reduced brain myo-inositol in the anterior cingulate cortex, consistent with CNS target engagement. Ebselen decreased slow-wave sleep and affected emotional processing by increasing recognition of some emotions, decreasing latency time in the acoustic startle paradigm, and decreasing the reinforcement of rewarding stimuli. In summary, ebselen affects the phosphoinositide cycle and has CNS effects on surrogate markers that may be relevant to the treatment of bipolar disorder that can be tested in future clinical trials. PMID:26593266

Biofield therapies: helpful or full of hype? A best evidence synthesis.

PubMed

Jain, Shamini; Mills, Paul J

2010-03-01

Biofield therapies (such as Reiki, therapeutic touch, and healing touch) are complementary medicine modalities that remain controversial and are utilized by a significant number of patients, with little information regarding their efficacy. This systematic review examines 66 clinical studies with a variety of biofield therapies in different patient populations. We conducted a quality assessment as well as a best evidence synthesis approach to examine evidence for biofield therapies in relevant outcomes for different clinical populations. Studies overall are of medium quality, and generally meet minimum standards for validity of inferences. Biofield therapies show strong evidence for reducing pain intensity in pain populations, and moderate evidence for reducing pain intensity hospitalized and cancer populations. There is moderate evidence for decreasing negative behavioral symptoms in dementia and moderate evidence for decreasing anxiety for hospitalized populations. There is equivocal evidence for biofield therapies' effects on fatigue and quality of life for cancer patients, as well as for comprehensive pain outcomes and affect in pain patients, and for decreasing anxiety in cardiovascular patients. There is a need for further high-quality studies in this area. Implications and future research directions are discussed.

Topical Vitamin C and the Skin: Mechanisms of Action and Clinical Applications

PubMed Central

Al-Niaimi, Firas

2017-01-01

OBJECTIVE: This review article details the main mechanisms of action and clinical applications of topical vitamin C on the skin, including its antioxidative, photoprotective, antiaging, and antipigmentary effects. DESIGN: A PubMed search for the relevant articles on vitamin C and the skin was conducted using the following key words: “vitamin C,” “ascorbic acid,” “ascorbyl-6-palmitate,”and “magnesium ascorbyl phosphate.” RESULTS: As one of the most powerful antioxidants in the skin, vitamin C has been shown to protect against photoaging, ultraviolet-induced immunosuppression, and photocarcinogenesis. It also has an antiaging effect by increasing collagen synthesis, stabilizing collagen fibers, and decreasing collagen degradation. It decreases melanin formation, thereby reducing pigmentation. Vitamin C is the primary replenisher of vitamin E and works synergistically with vitamin E in the protection against oxidative damage. CONCLUSION: Topical vitamin C has a wide range of clinical applications, from antiaging and antipigmentary to photoprotective. Currently, clinical studies on the efficacy of topical formulations of vitamin C remain limited, and the challenge lies in finding the most stable and permeable formulation in achieving the optimal results. PMID:29104718

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.

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.

No clinically relevant CYP3A induction after St. John's wort with low hyperforin content in healthy volunteers.

PubMed

Mueller, Silke C; Majcher-Peszynska, Jolanta; Mundkowski, Ralf G; Uehleke, Bernhard; Klammt, Sebastian; Sievers, Hartwig; Lehnfeld, Romanus; Frank, Bruno; Thurow, Kerstin; Kundt, Guenther; Drewelow, Bernd

2009-01-01

Induction of CYP3A by St. John's wort (SJW) products with high hyperforin content is well described. Since CYP3A induction is mediated by hyperforin in a concentration-dependent manner, and SJW preparations differ significantly in hyperforin content, the aim of the study was to evaluate the effect of an SJW powder with low hyperforin content on CYP3A function. Twenty healthy male volunteers received an SJW powder with low hyperforin content for 2 weeks. Midazolam plasma concentration time profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication. Midazolam AUC(0-infinity) slightly decreased from 124.0 +/- 62.5 ng/ml.h at baseline to 105.6 +/- 53.2 ng/ml.h after SJW (P < 0.05), representing a mean 11.3% decrease (95% CI: -22.8 to 0.21). No significant change in midazolam C(max), t(1/2) and t(max) was observed. For all pharmacokinetic parameters, the 90% CI for the geometric mean ratio of treatment over baseline were within the no-effect boundaries of 0.70-1.43. Administration of an SJW product with low hyperforin content resulted in a mild induction of CYP3A not considered clinically relevant.

Direct effects of diazepam on emotional processing in healthy volunteers

PubMed Central

Murphy, S. E.; Downham, C.; Cowen, P. J.

2008-01-01

Rationale Pharmacological agents used in the treatment of anxiety have been reported to decrease threat relevant processing in patients and healthy controls, suggesting a potentially relevant mechanism of action. However, the effects of the anxiolytic diazepam have typically been examined at sedative doses, which do not allow the direct actions on emotional processing to be fully separated from global effects of the drug on cognition and alertness. Objectives The aim of this study was to investigate the effect of a lower, but still clinically effective, dose of diazepam on emotional processing in healthy volunteers. Materials and methods Twenty-four participants were randomised to receive a single dose of diazepam (5 mg) or placebo. Sixty minutes later, participants completed a battery of psychological tests, including measures of non-emotional cognitive performance (reaction time and sustained attention) and emotional processing (affective modulation of the startle reflex, attentional dot probe, facial expression recognition, and emotional memory). Mood and subjective experience were also measured. Results Diazepam significantly modulated attentional vigilance to masked emotional faces and significantly decreased overall startle reactivity. Diazepam did not significantly affect mood, alertness, response times, facial expression recognition, or sustained attention. Conclusions At non-sedating doses, diazepam produces effects on attentional vigilance and startle responsivity that are consistent with its anxiolytic action. This may be an underlying mechanism through which benzodiazepines exert their therapeutic effects in clinical anxiety. PMID:18581100

The importance of mean time in therapeutic range for complication rates in warfarin therapy of patients with atrial fibrillation: A systematic review and meta-regression analysis.

PubMed

Vestergaard, Anne Sig; Skjøth, Flemming; Larsen, Torben Bjerregaard; Ehlers, Lars Holger

2017-01-01

\\Anticoagulation is used for stroke prophylaxis in non-valvular atrial fibrillation, amongst other by use of the vitamin K antagonist, warfarin. Quality in warfarin therapy is often summarized by the time patients spend within the therapeutic range (percent time in therapeutic range, TTR). The correlation between TTR and the occurrence of complications during warfarin therapy has been established, but the influence of patient characteristics in that respect remains undetermined. The objective of the present papers was to examine the association between mean TTR and complication rates with adjustment for differences in relevant patient cohort characteristics. A systematic literature search was conducted in MEDLINE and Embase (2005-2015) to identify eligible studies reporting on use of warfarin therapy by patients with non-valvular atrial fibrillation and the occurrence of hemorrhage and thromboembolism. Both randomized controlled trials and observational cohort studies were included. The association between the reported mean TTR and major bleeding and stroke/systemic embolism was analyzed by random-effects meta-regression with and without adjustment for relevant clinical cohort characteristics. In the adjusted meta-regressions, the impact of mean TTR on the occurrence of hemorrhage was adjusted for the mean age and the proportion of populations with prior stroke or transient ischemic attack. In the adjusted analyses on thromboembolism, the proportion of females was, furthermore, included. Of 2169 papers, 35 papers met pre-specified inclusion criteria, holding relevant information on 31 patient cohorts. In univariable meta-regression, increasing mean TTR was significantly associated with a decreased rate of both major bleeding and stroke/systemic embolism. However, after adjustment mean TTR was no longer significantly associated with stroke/systemic embolism. The proportion of residual variance composed by between-study heterogeneity was substantial for all analyses. Although higher mean TTR in warfarin therapy was associated with lower complication rates in atrial fibrillation, the strength of the association was decreased when adjusting for differences in relevant clinical characteristics of the patient cohorts. This study suggests that mainly the safety of warfarin therapy increases with higher mean TTR, whereas effectiveness appears not to be substantially improved. Due to the limitations immanent in the meta-regression methods, the results of the present study should be interpreted with caution. Further research on the association between the quality of warfarin therapy and risk of complications is warranted with adjustment for clinically relevant characteristics.

Evaluating Change in Beliefs About the Importance/Control of Thoughts as a Mediator of CBM-I and Responses to an ICT Stressor.

PubMed

Clerkin, Elise M; Magee, Joshua C; Parsons, E Marie

2014-10-01

This study evaluated an adaptation of a Cognitive Bias Modification-Interpretation (CBM-I) procedure designed to shift interpretations of intrusive thoughts related to beliefs about the Importance and Control of Thoughts (ICT). Individuals high in the ICT belief domain were randomly assigned to one of two conditions: (a) a positive (n = 38) condition in which scenarios about intrusive thoughts were repeatedly paired with benign interpretations; or (b) a control (n = 39) condition in which scenarios about intrusive thoughts were paired with 50% benign and 50% threatening interpretations. Further, participants engaged in an ICT stressor task. Structural equation modeling with bias-corrected bootstrapping was used to examine the effects of training on ICT-relevant interpretations, beliefs, and ICT stressor responding. As predicted, individuals in a positive (vs. control) training condition reported decreases in ICT-relevant interpretations and beliefs. Further, there was a small, statistically significant indirect (i.e., mediated) effect of training on measures of ICT stressor responding, which occurred via decreases in ICT-relevant beliefs. In sum, results indicate that training was effective in influencing interpretations and beliefs tied to Importance/Control of Thoughts and that there may be clinical utility to shifting this belief domain.

Evaluating Change in Beliefs About the Importance/Control of Thoughts as a Mediator of CBM-I and Responses to an ICT Stressor

PubMed Central

Clerkin, Elise M.; Magee, Joshua C.; Parsons, E. Marie

2014-01-01

This study evaluated an adaptation of a Cognitive Bias Modification-Interpretation (CBM-I) procedure designed to shift interpretations of intrusive thoughts related to beliefs about the Importance and Control of Thoughts (ICT). Individuals high in the ICT belief domain were randomly assigned to one of two conditions: (a) a positive (n = 38) condition in which scenarios about intrusive thoughts were repeatedly paired with benign interpretations; or (b) a control (n = 39) condition in which scenarios about intrusive thoughts were paired with 50% benign and 50% threatening interpretations. Further, participants engaged in an ICT stressor task. Structural equation modeling with bias-corrected bootstrapping was used to examine the effects of training on ICT-relevant interpretations, beliefs, and ICT stressor responding. As predicted, individuals in a positive (vs. control) training condition reported decreases in ICT-relevant interpretations and beliefs. Further, there was a small, statistically significant indirect (i.e., mediated) effect of training on measures of ICT stressor responding, which occurred via decreases in ICT-relevant beliefs. In sum, results indicate that training was effective in influencing interpretations and beliefs tied to Importance/Control of Thoughts and that there may be clinical utility to shifting this belief domain. PMID:25414811

Clinical and Para Clinical Information Needs of Infertility Electronic Health Records in Iran: A Delphi Study.

PubMed

Farzandipour, Mehrdad; Jeddi, Fateme Rangraz; Gilasi, Hamid Reza; Shirzadi, Diana

2017-09-01

infertility is referred to the person's inability to conceive pregnancy after one year of intercourse without using protection. This study paves the ground for creating a complete, united, and coherent source of patients' medical information. this is an applied research of descriptive-cross sectional type which has been carried out through qualitative - quantitative methods. The sample of the present study was 50 specialists in the field of infertility which has been chosen based on purposive sampling method. Designing the questionnaire was done based on library studies and Gathering experts' views was done based on Delphi technique. 261 items from clinical and Para clinical information of infertile patients' electronic health records were subjected to an opinion poll by experts. During this process 223 items were accepted and 38 items have been rejected after two sessions of surveys by infertility experts. Para clinical information section consisted of 57 items that all of them have been accepted by the experts. Also, clinical information section consisted of 242 items from which 204 items were accepted and 38 items were rejected by the experts. existence of a structured electronic record system of infertile patients' information leads to the integration of patients' information, improvement of health care services and a decrease in treatment costs: all working to increase information safety. Furthermore, only essential and relevant information would be provided for the specialists and it will facilitate and direct the future infertility related studies due to the coherence, unity and relevance of the information.

Assessment of the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia and neuropathic pain. A pilot study.

PubMed

Keizer, D; van Wijhe, M; Post, W J; Uges, D R A; Wierda, J M K H

2007-08-01

Allodynia is a common and disabling symptom in many patients with neuropathic pain. Whereas quantification of pain mostly depends on subjective pain reports, allodynia can also be measured objectively with quantitative sensory testing. In this pilot study, we investigated the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia as a consequence of a neuropathic pain syndrome, by means of correlating subjective pain scores with pain thresholds obtained with quantitative sensory testing. During a 4-week trial, we administered a cannabis extract to 17 patients with allodynia. We quantified the severity of the allodynia with Von Frey monofilaments before, during and after the patients finished the trial. We also asked the patients to rate their pain on a numeric rating scale at these three moments. We found that most of the effect of the cannabis occurred in the last 2 weeks of the trial. In this phase, we observed that the pain thresholds, as measured with Von Frey monofilaments, were inversely correlated with a decrease of the perceived pain intensity. These preliminary findings indicate clinical relevance of quantitative sensory testing with Von Frey monofilaments in the quantification of allodynia in patients with neuropathic pain, although confirmation of our data is still required in further studies to position this method of quantitative sensory testing as a valuable tool, for example, in the evaluation of therapeutic interventions for neuropathic pain.

Hypercalcemic crisis: a clinical review.

PubMed

Ahmad, Shazia; Kuraganti, Gayatri; Steenkamp, Devin

2015-03-01

Hypercalcemia is a common metabolic perturbation. However, hypercalcemic crisis is an unusual endocrine emergency, with little clinical scientific data to support therapeutic strategy. We review the relevant scientific English literature on the topic and review current management strategies after conducting a PubMed, MEDLINE, and Google Scholar search for articles published between 1930 and June 2014 using specific keywords: "hypercalcemic crisis," "hyperparathyroid crisis," "parathyroid storm," "severe primary hyperparathyroidism," "acute hyperparathyroidism," and "severe hypercalcemia" for articles pertaining to the diagnosis, epidemiology, clinical presentation, and treatment strategies. Despite extensive clinical experience, large and well-designed clinical studies to direct appropriate clinical care are lacking. Nonetheless, morbidity and mortality rates have substantially decreased since early series reported almost universal fatality. Improved outcomes can be attributed to modern diagnostic capabilities, leading to earlier diagnosis, along with the recognition that primary hyperparathyroidism is the most common etiology for hypercalcemic crisis. Hypercalcemic crisis is an unusual endocrine emergency that portends excellent outcomes if rapid diagnosis, medical treatment, and definitive surgical treatment are expedited. Copyright © 2015 Elsevier Inc. All rights reserved.

A systematic review of the evidence of reduced allergenicity and clinical benefit of food hydrolysates in dogs with cutaneous adverse food reactions.

PubMed

Olivry, Thierry; Bizikova, Petra

2010-02-01

Several hydrolysate-based diets have been commercialized for helping diagnose or treat dogs with cutaneous adverse food reactions (CAFR). This systematic review was performed to examine the evidence in favour of reduced immunological and clinical allergenicity of hydrolysates in dogs with CAFR. Citation databases, meeting abstracts and article bibliographies were scanned for relevant citations, and companies were contacted to provide unpublished reports. Eleven studies relevant to this study were identified. Some evidence of reduced serum IgE binding to a soy hydrolysate (1 study) and decreased intradermal test reactivity to hydrolysed proteins (three studies) was found. In four reports, the feeding of dogs suspected of having CAFR with hydrolysate-based diets reduced or eliminated clinical signs in a variable proportion of subjects. The percentage of dogs with CAFR that still reacted to these hydrolysate-based diets could not be assessed, however. Importantly, up to 50% of dogs with CAFR enrolled in three controlled studies exhibited increases in clinical signs after ingesting partial hydrolysates derived from foods to which they were hypersensitive. In conclusion, the limited number of studies undertaken point to reduced - but not eliminated - immunological and clinical allergenicity of hydrolysate-based commercial diets. A variable proportion of dogs with CAFR will exhibit a worsening of clinical signs when fed partial hydrolysates. Clinicians must weigh the clinical benefit of these diets versus their high cost and low risk of reduced appetence or gastrointestinal sign development. At this time, hydrolysate-containing diets are probably best used in dogs suspected not to be hypersensitive to their individual components.

Clinical associations of white matter damage in cART-treated HIV-positive children in South Africa.

PubMed

Hoare, Jacqueline; Fouche, Jean-Paul; Phillips, Nicole; Joska, John A; Donald, Kirsten A; Thomas, Kevin; Stein, Dan J

2015-04-01

A range of factors contributes to white matter damage in vertically infected HIV-positive children. These may include combination antiretroviral treatment (cART) regimen, sociodemographic factors, nutritional-hematological status, HIV-relevant clinical variables, and cognitive functioning. We explored associations between a number of these factors and diffusion tensor imaging (DTI) measures in 50 cART-treated children aged 6 to 15 years. Fractional anisotropy (FA), mean diffusion (MD), radial diffusion (RD), and axial diffusion (AD) were derived from 48 cerebral white matter regions. Significant associations between a number of the clinical variables and white matter integrity were found. Decreased FA, a measure of neuronal damage, was associated with being on second-line cART, low hemoglobin, and younger age. Children with increased MD, a measure of neuronal damage, were younger, had reduced albumin and hemoglobin, and increased viral load. Decreased AD, a measure of axonal damage, was associated with increased viral load and total protein, decreased albumin and hemoglobin, younger age, poorer fronto-striatal cognition, and being on second-line cART. Increased RD, a measure of myelin loss, was associated with younger age, low current CD4 count, low albumin and hemoglobin, and higher viral load and total protein. The current findings underline the possible association of first-line treatment failure with white matter brain dysfunction in pediatric neuroHIV and the importance of examining the effects of HIV disease in the context of treatable clinical variables such as anemia and nutritional status.

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.

Design and testing of classroom and clinical teaching evaluation tools for nursing education.

PubMed

Emerson, Roberta J; Records, Kathie

2007-01-01

Student evaluations of teaching provide administrators an overall picture of the effectiveness of personnel and contribute data for promotion and merit decisions. These evaluations must be assessed for their relevance, validity, and reliability. This paper describes the development process and psychometric testing for clinical (n = 149) and didactic (n = 148) student evaluation of teaching forms for undergraduate and graduate courses in one college of nursing. Validity and reliability results were quite strong for the instruments, both of which evidenced a one-factor solution with factor loadings ranging from .68-.88 and Cronbach's alphas of .96 (Classroom) and .95 (Clinical). The clinical and classroom evaluation tools are relatively short, decreasing the burden on students who need to complete the instruments for multiple instructors in any one semester. Initial testing of the psychometric properties of the tools supports their continued use in colleges of nursing.

Differential diagnosis of apneas in preterm infants.

PubMed

Paul, Karel; Melichar, Jan; Miletín, Jan; Dittrichová, Jaroslava

2009-02-01

Clinically relevant apneas, which are common in preterm infants, may adversely affect later neuropsychological condition in this group of patients. Pharmacotherapy to stimulate respiratory functions may be unsuccessful. Polygraphic recording may help in the differential diagnosis of these clinically relevant events. Twenty-nine preterm neonates born before 36 weeks of gestational age were examined using polygraphic recording (respiration--two channels, perioral electromyography, oxygen saturation, heart rate, electroencephalography, electrocardiography, electrooculography). The examination was ordered by the attending physician after an unsuccessful treatment of apnea by Aminophylline, and it should contribute to the clarification of the causes of these events. In the course of the polygraphic examinations, altogether 63 episodes were recorded during which the pulse oximeter alarm signal was set off. In 42 cases, the alarm signal was set off in events during which SaO(2) fell below 85%. In the remaining 21 cases, the alarm signal was set off in episodes during which early bradycardia below 90/min occurred. The onset of apnea was very often associated with the phasic increase of the perioral electromyography and with electroencephalography arousal reaction. Because of suspicion that these apneas may be triggered by episodes of gastroesophageal reflux, the interruption of the Aminophylline treatment and setting up an antireflux regimen were recommended. These therapeutic measures had a positive effect: The frequency of alarm signals decreased within 48 h by a statistically significant 50%. In cases where the pharmacotherapy of apnea by stimulation of respiratory functions is not successful, differential diagnostic analysis should be performed. Polygraphy may contribute to the clarification of the causes underlying clinically relevant apneas in a view of newly described polygraphic signs. It is feasible to suspect, based on these signs, that gastroesophageal reflux is the cause for clinically significant apneas in that case.

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.

Bicruciate retaining

PubMed Central

2016-01-01

Total knee replacement (TKR) is a procedure used to treat knee arthropathy. Patients’ dissatisfaction is still relevant (literature reports dissatisfaction rates as high as 40%). The anterior cruciate ligament is usually removed while performing a total knee arthroplasty, thus changing knee biomechanics. As patients’ mean age to surgery is decreasing, bicruciate retaining models, which preserve normal biomechanics, may be useful in increasing patients’ outcomes. Limited data concerning bicruciate retaining arthroplasty is available; although clinical results are encouraging, there are concerns regarding surgical exposure, anterior cruciate integrity evaluation, and implant fixation. PMID:27162778

Treatment with a Clinically-Relevant Dose of Methylphenidate Alters NMDA Receptor Composition and Synaptic Plasticity in the Juvenile Rat Prefrontal Cortex

PubMed Central

Urban, Kimberly R.; Li, Yan-Chun; Gao, Wen-Jun

2013-01-01

Methylphenidate (Ritalin, MPH) is the most commonly prescribed psychoactive drug for children. Used to treat attention-deficit/hyperactivity disorder (ADHD) and for cognitive enhancement in healthy individuals, its cellular mechanisms of action and potential long-term effects are poorly understood. We recently reported that a clinically relevant (1 mg/kg i.p., single injection) dose of MPH significantly decreased neuronal excitability in the juvenile rat prefrontal cortical neurons. Here we further explore the actions of acute treatment with MPH on the level of NMDA receptor subunits and NMDA receptor-mediated short- and long-term synaptic plasticity in the juvenile rat prefrontal cortical neurons. We found that a single dose of MPH treatment (1 mg/kg, intraperitoneal) significantly decreased the surface and total protein levels of NMDA receptor subunits NR1 and NR2B, but not NR2A, in the juvenile prefrontal cortex. In addition, the amplitude, decay time and charge transfer of NMDA receptor-mediated EPSCs were significantly decreased whereas the amplitude and short-term depression of AMPA receptor-mediated EPSCs were significantly increased in the prefrontal neurons. Furthermore, MPH treatment also significantly increased the probability and magnitude of LTP induction, but had only a small effect on LTD induction in juvenile rat prefrontal cortical neurons. Our data thus present a novel mechanism of action of MPH, i.e., changes in glutamatergic receptor-mediated synaptic plasticity following early-life treatment. Furthermore, since a single dosage resulted in significant changes in NMDA receptors, off-label usage by healthy individuals, especially children and adolescents, may result in altered potential for plastic learning. PMID:23333502

Combination of Emricasan with Ponatinib Synergistically Reduces Ischemia/Reperfusion Injury in Rat Brain Through Simultaneous Prevention of Apoptosis and Necroptosis.

PubMed

Tian, Jing; Guo, Shu; Chen, Heng; Peng, Jing-Jie; Jia, Miao-Miao; Li, Nian-Sheng; Zhang, Xiao-Jie; Yang, Jie; Luo, Xiu-Ju; Peng, Jun

2017-11-04

Apoptosis and receptor-interacting protein kinase 1/3(RIPK1/3)-mediated necroptosis contribute to the cerebral ischemia/reperfusion (I/R) injury. Emricasan is an inhibitor of caspases in clinical trials for liver diseases while ponatinib could be a potential inhibitor for RIPK1/3. This study aims to investigate the effect of emricasan and/or ponatinib on cerebral I/R injury and the underlying mechanisms. Firstly, we evaluated the status of apoptosis and necroposis in a rat model of cerebral I/R under different conditions, which showed noticeable apoptosis and necroptosis under condition of 2-h ischemia and 24-h reperfusion; next, the preventive or therapeutic effect of emricasan or ponatinib on cerebral I/R injury was tested. Administration of emricasan or ponatinib either before or after ischemia could decrease the neurological deficit score and infarct volume; finally, the combined therapeutic effect of emricasan with ponatinib on I/R injury was examined. Combined application of emricasan and ponatinib could further decrease the I/R injury compared to single application. Emricasan decreased the activities of capase-8/-3 in the I/R-treated brain but not the protein levels of necroptosis-relevant proteins: RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL), whereas ponatinib suppressed the expressions of these proteins but not the activities of capase-8/-3. Combination of emricasan with ponatinib could suppress both capase-8/-3 and necroptosis-relevant proteins. Based on these observations, we conclude that combination of emricasan with ponatinib could synergistically reduce I/R injury in rat brain through simultaneous prevention of apoptosis and necroptosis. Our findings might lay a basis on extension of the clinical indications for emricasan and ponatinib in treating ischemic stroke.

Efficacy of the early administration of valacyclovir hydrochloride for the treatment of neuropathogenic equine herpesvirus type-1 infection in horses.

PubMed

Maxwell, Lara K; Bentz, Bradford G; Gilliam, Lyndi L; Ritchey, Jerry W; Pusterla, Nicola; Eberle, R; Holbrook, Todd C; McFarlane, Dianne; Rezabek, Grant B; Meinkoth, James; Whitfield, Chase; Goad, Carla L; Allen, George P

2017-10-01

OBJECTIVE To determine whether prophylactic administration of valacyclovir hydrochloride versus initiation of treatment at the onset of fever would differentially protect horses from viral replication and clinical disease attributable to equine herpesvirus type-1 (EHV-1) infection. ANIMALS 18 aged mares. PROCEDURES Horses were randomly assigned to receive an oral placebo (control), treatment at detection of fever, or prophylactic treatment (initiated 1 day prior to viral challenge) and then inoculated intranasally with a neuropathogenic strain of EHV-1. Placebo or valacyclovir was administered orally for 7 or 14 days after EHV-1 inoculation or detection of fever (3 horses/group). Effects of treatment on viral replication and clinical disease were evaluated. Plasma acyclovir concentrations and viremia were assessed to determine inhibitory concentrations of valacyclovir. RESULTS Valacyclovir administration decreased shedding of virus and viremia, compared with findings for control horses. Rectal temperatures and clinical disease scores in horses that received valacyclovir prophylactically for 2 weeks were lower than those in control horses. The severity of but not the risk for ataxia was decreased by valacyclovir administration. Viremia was decreased when steady-state trough plasma acyclovir concentrations were > 0.8 μg/mL, supporting the time-dependent activity of acyclovir. CONCLUSIONS AND CLINICAL RELEVANCE Valacyclovir treatment significantly decreased viral replication and signs of disease in EHV-1-infected horses; effects were greatest when treatment was initiated before viral inoculation, but treatment was also effective when initiated as late as 2 days after inoculation. During an outbreak of equine herpesvirus myeloencephalopathy, antiviral treatment may be initiated in horses at various stages of infection, including horses that have not yet developed signs of viral disease.

In vitro cross-resistance profile of nucleoside reverse transcriptase inhibitor (NRTI) BMS-986001 against known NRTI resistance mutations.

PubMed

Li, Zhufang; Terry, Brian; Olds, William; Protack, Tricia; Deminie, Carol; Minassian, Beatrice; Nowicka-Sans, Beata; Sun, Yongnian; Dicker, Ira; Hwang, Carey; Lataillade, Max; Hanna, George J; Krystal, Mark

2013-11-01

BMS-986001 is a novel HIV nucleoside reverse transcriptase inhibitor (NRTI). To date, little is known about its resistance profile. In order to examine the cross-resistance profile of BMS-986001 to NRTI mutations, a replicating virus system was used to examine specific amino acid mutations known to confer resistance to various NRTIs. In addition, reverse transcriptases from 19 clinical isolates with various NRTI mutations were examined in the Monogram PhenoSense HIV assay. In the site-directed mutagenesis studies, a virus containing a K65R substitution exhibited a 0.4-fold change in 50% effective concentration (EC50) versus the wild type, while the majority of viruses with the Q151M constellation (without M184V) exhibited changes in EC50 versus wild type of 0.23- to 0.48-fold. Susceptibility to BMS-986001 was also maintained in an L74V-containing virus (0.7-fold change), while an M184V-only-containing virus induced a 2- to 3-fold decrease in susceptibility. Increasing numbers of thymidine analog mutation pattern 1 (TAM-1) pathway mutations correlated with decreases in susceptibility to BMS-986001, while viruses with TAM-2 pathway mutations exhibited a 5- to 8-fold decrease in susceptibility, regardless of the number of TAMs. A 22-fold decrease in susceptibility to BMS-986001 was observed in a site-directed mutant containing the T69 insertion complex. Common non-NRTI (NNRTI) mutations had little impact on susceptibility to BMS-986001. The results from the site-directed mutants correlated well with the more complicated genotypes found in NRTI-resistant clinical isolates. Data from clinical studies are needed to determine the clinically relevant resistance cutoff values for BMS-986001.

What is the most relevant standard of success in assisted reproduction? Defining outcome in ART: a Gordian knot of safety, efficacy and quality.

PubMed

Land, Jolande A; Evers, Johannes L H

2004-05-01

In the course of the present Debate series, several new outcome measures for assisted reproduction have been proposed to encourage the transfer of fewer embryos, in order to diminish the number of multiple pregnancies. The implementation of these recommendations, however, is hampered by the perception that safety and efficacy are communicating vessels: it is presumed that by decreasing the number of embryos transferred, pregnancy rates will decrease as well. Data from national and international registries, however, do not confirm the assumption of the communicating vessels: pregnancy rates tend to be low in countries in which many embryos are transferred, and the highest pregnancy rates occur where the number of embryos per transfer is low. Only top-level clinics (where treatment efficacy is guaranteed) are able to decrease the number of embryos transferred without compromising their pregnancy rate, and to vouch for safety in this way. Elective single embryo transfer (eSET) can never be mandatory in all patients, but the percentage of eSETs performed by a particular assisted reproduction treatment centre does reflect its quality: the ultimate outcome measure of efficacy ánd safety. Therefore, the eSET rate is the most relevant qualifier of performance in assisted reproduction.

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.

Cold physical plasma treated buffered saline solution as effective agent against pancreatic cancer cells.

PubMed

Bekeschus, Sander; Kading, Andre; Schroder, Tim; Wende, Kristian; Hackbarth, Christine; Liedtke, Kim Rouven; van der Linde, Julia; von Woedtke, Thomas; Heidecke, Claus-Dieter; Partecke, Lars-Ivo

2018-05-07

Cold physical plasma has been suggested as a new anticancer tool recently. However, direct use of plasma is limited to visible tumors and in some clinical situations not feasible. This includes repetitive treatment of peritoneal metastases which commonly occur in advanced gastrointestinal cancer and in pancreatic cancer in particular. In case of diffuse intraperitoneal metastatic spread Hyperthermic Intraperitoneal Intraoperative Chemotherapy (HIPEC) is used as therapeutic approach. Plasma treated solutions may combine their suspected systemic non-toxic characteristics with the anticancer effects of HIPEC. Previous work has provided evidence for an anti-cancer efficacy of plasma treated cell culture medium but the clinical relevance of such an approach is low due to its complex formulation and lack of medical accreditation. Therefore, plasma treated phosphate-buffered saline (PBS) which closely resembles medically certified solutions was investigated for its cytotoxic effect on 2D monolayer murine pancreatic cancer cells in vitro. It significantly decreased cancer cell metabolisms and proliferation whereas plasma treated Dulbecco's Modified Eagle Medium had no effect. Moreover, tumor cell growth attenuation was significantly higher when compared to syngeneic primary murine fibroblasts. Both results were confirmed in a human pancreatic cancer cell line. Finally, plasma treated PBS also decreased tumor sizes of pancreatic tumors in the TUM-CAM model in a three-dimensional manner, and induction of apoptosis was found to be responsible for all anticancer effects identified. Altogether, plasma treated PBS inhibited cell growth in 2D and 3D models of cancer. These results may help facilitating the development of new plasma derived anticancer agent with clinical relevance in the future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Suppressive effects of ketamine on macrophage functions

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

Chang Yi; Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; Chen, T.-L.

2005-04-01

Ketamine is an intravenous anesthetic agent. Clinically, induction of anesthesia with ketamine can cause immunosuppression. Macrophages play important roles in host defense. In this study, we attempted to evaluate the effects of ketamine on macrophage functions and its possible mechanism using mouse macrophage-like Raw 264.7 cells as the experimental model. Exposure of macrophages to 10 and 100 {mu}M ketamine, which correspond to 0.1 and 1 times the clinically relevant concentration, for 1, 6, and 24 h had no effect on cell viability or lactate dehydrogenase release. When the administered concentration reached 1000 {mu}M, ketamine caused a release of lactate dehydrogenasemore » and cell death. Ketamine, at 10 and 100 {mu}M, did not affect the chemotactic activity of macrophages. Administration of 1000 {mu}M ketamine in macrophages resulted in a decrease in cell migration. Treatment of macrophages with ketamine reduced phagocytic activities. The oxidative ability of macrophages was suppressed by ketamine. Treatment with lipopolysaccharide induced TNF-{alpha}, IL-1{beta}, and IL-6 mRNA in macrophages. Administration of ketamine alone did not influence TNF-{alpha}, IL-1{beta}, or IL-6 mRNA production. Meanwhile, cotreatment with ketamine and lipopolysaccharide significantly inhibited lipopolysaccharide-induced TNF-{alpha}, IL-1{beta}, and IL-6 mRNA levels. Exposure to ketamine led to a decrease in the mitochondrial membrane potential. However, the activity of mitochondrial complex I NADH dehydrogenase was not affected by ketamine. This study shows that a clinically relevant concentration of ketamine (100 {mu}M) can suppress macrophage function of phagocytosis, its oxidative ability, and inflammatory cytokine production possibly via reduction of the mitochondrial membrane potential instead of direct cellular toxicity.« less

Effectiveness and Tolerability of THC/CBD Oromucosal Spray for Multiple Sclerosis Spasticity in Italy: First Data from a Large Observational Study.

PubMed

Trojano, Maria; Vila, Carlos

2015-01-01

The prospective, non-interventional Mobility Improvement (MOVE) 2 study was designed to provide real life data on clinical outcomes of patients with treatment-resistant multiple sclerosis (MS) spasticity receiving routine treatment with tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex®), subsequent to its approval in European countries. This interim analysis reports on MOVE 2 patients from Italy. Interim data from 322 patients (58.3% female; mean age 51.1 ± 10.2 years) were analyzed. From baseline to month 3 of treatment (Visit 3), the mean 0-10 Numerical Rating Scale (NRS) score decreased by -19.1% (-1.6 points, p < 0.0001) and the mean modified Ashworth score decreased from 2.6 to 2.3 points (p < 0.0001). At Visit 3, 24.6% of 203 patients with available data were clinically relevant responders (≥30% improvement from baseline NRS score; p < 0.001 vs. baseline). The mean reported dose of THC:CBD oromucosal spray was 6.1 ± 2.5 sprays/day at Visit 1 (1 month) and 5.1 ± 2.6 sprays/day at Visit 3 (range 1-12 sprays/day at both timepoints). Forty-one (13.1%) patients reported at least one adverse event (AE), which included 3 serious AEs (1 unrelated). AEs with an incidence ≥1% were dizziness (5.6%), confusion (2.5%), nausea (1.25%) and somnolence (1.25%). In everyday clinical practice in Italy, THC:CBD oromucosal spray provided symptomatic relief of MS spasticity with good tolerability in a relevant number of previously resistant patients. © 2015 S. Karger AG, Basel.

How does multilevel upper airway surgery influence the lives of dogs with severe brachycephaly? Results of a structured pre- and postoperative owner questionnaire.

PubMed

Pohl, Sabine; Roedler, Frauke S; Oechtering, Gerhard U

2016-04-01

Brachycephalic airway syndrome in dogs is typified by a variety of anatomical abnormalities causing a diverse spectrum of clinical signs of varying intensity. This variability makes the assessment of the surgical outcome after upper airway surgery difficult. Using a structured questionnaire, the present study investigated the dog owner-perceived severity and frequency of a broad spectrum of welfare-relevant impairments 2 weeks before and 6 months after brachycephalic dogs underwent a recently developed multi-level upper airway surgery. All dogs underwent surgical treatment of stenotic nares (ala-vestibuloplasty), the nasal cavity (laser-assisted turbinectomy, LATE), the pharynx (palatoplasty and tonsillotomy), and if indicated, laryngeal surgery (laser-assisted ablation of everted ventricles and partial cuneiformectomy). Owners of brachycephalic dogs (n = 102) referred for upper airway surgery were eligible to participate. Questionnaire data from owners of 37 Pugs and 25 French bulldogs were evaluated. In all dogs, the clinical signs associated with brachycephaly improved markedly after surgery. Most encouraging was the striking reduction in life-threatening events by 90% (choking fits decreased from 60% to 5% and collapse from 27% to 3%). The incidence of sleeping problems decreased from 55% to 3%, and the occurrence of breathing sounds declined by approximately 50%. There was a marked improvement in exercise tolerance and a modest improvement in heat tolerance. Dogs with severe brachycephaly benefitted substantially from multi-level surgery, and there were particular improvements in the incidences of severe impairment and life-threatening events. However, despite the marked improvement perceived by dog owners, these dogs remained clinically affected and continued to show welfare-relevant impairments caused by these hereditary disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

The effect of a high protein diet on leucine and alanine turnover in acid maltase deficiency.

PubMed Central

Umpleby, A M; Trend, P S; Chubb, D; Conaglen, J V; Williams, C D; Hesp, R; Scobie, I N; Wiles, C M; Spencer, G; Sönksen, P H

1989-01-01

Leucine and alanine production rate was measured in 5 patients with acid maltase deficiency in the postabsorptive state, following 6 months on a normal diet with placebo and 6 months on an isocaloric high protein diet (16-22% protein). Whole body leucine production rate, a measure of protein degradation, expressed in terms of lean body mass was significantly greater than in five control subjects. Following the high protein diet, leucine production rate was decreased in four of the five patients but this was not statistically significant. Alanine production rate expressed in terms of lean body mass was significantly greater than in control subjects. After the high protein diet, alanine production rate and concentration were significantly decreased (p less than 0.05). There were no significant improvements in any of the clinically relevant variables measured in these patients. It is possible that a larger increase in protein intake over a longer time period may have a clinical effect. PMID:2507747

Hemimegalencephaly: Clinical, EEG, neuroimaging, and IMP-SPECT correlation

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

Konkol, R.J.; Maister, B.H.; Wells, R.G.

1990-11-01

Iofetamine-single photon emission computed tomography (IMP-SPECT) was performed on 2 girls (5 1/2 and 6 years of age) with histories of intractable seizures, developmental delay, and unilateral hemiparesis secondary to hemimegalencephaly. Electroencephalography (EEG) revealed frequent focal discharges in 1 patient, while a nearly continuous burst suppression pattern over the malformed hemisphere was recorded in the other. IMP-SPECT demonstrated a good correlation with neuroimaging studies. In spite of the different EEG patterns, which had been proposed to predict contrasting clinical outcomes, both IMP-SPECT scans disclosed a similar decrease in tracer uptake in the malformed hemisphere. These results are consistent with themore » pattern of decreased tracer uptake found in other interictal studies of focal seizures without cerebral malformations. In view of recent recommendations for hemispherectomy in these patients, we suggest that the IMP-SPECT scan be used to compliment EEG as a method to define the extent of abnormality which may be more relevant to long-term prognosis than EEG alone.« less

Summary of studies on the blue-green autofluorescence and light transmission of the ocular lens

NASA Astrophysics Data System (ADS)

Van Best, Jaap A.; Kuppens, Esmeralda V.

1996-07-01

This paper reviews previous work done to demonstrate the clinical relevance of the measurement of blue-green autofluorescence and light transmission of the ocular lens. These can be determined quantitatively with fluorophotometry in a few seconds. Autofluorescence and transmission values are determined in healthy volunteers, in patients with insulin-dependent diabetes mellitus, and in patients with untreated glaucoma or untreated ocular hypertension. The lens autofluorescence of healthy volunteers increased linearly and transmission decreased exponentially with age. Each year of diabetes induced an increase of autofluorescence equal to one extra year of age. Untreated glaucoma or ocular hypertension had no significant effect on lens autofluorescence and transmission. Increased autofluorescence and decreased transmission values in comparison with values of a healthy population are proved to be indicative for an increased risk of developing cataract and the clinical usefulness of these measures is demonstrated. Diabetes is a risk factor for developing cataracts while untreated glaucoma or ocular hypertension is not.

[Drug-food interactions in internal medicine: What physicians should know?].

PubMed

Mouly, S; Morgand, M; Lopes, A; Lloret-Linares, C; Bergmann, J-F

2015-08-01

Orally administered medications may interact with various fruits, vegetables, herbal medicines, functional foods or dietary supplements. Drug-food interactions, which are mostly unknown from prescribers, including internists, may be responsible for changes in drug plasma concentrations, which may decrease efficacy or led to sometimes life-threatening toxicity. Aging, concomitant medications, transplant recipients, patients with cancer, malnutrition, HIV infection and those receiving enteral or parenteral feeding are at increased risk of drug-food interactions. This review focused on the most clinically relevant drug-food interactions, including those with grapefruit juice, Saint-John's Wort, enteral or parenteral nutrition, their respective consequences in the clinical setting in order to provide thoughtful information for internists in their routine clinical practice. Specific clinical settings are also detailed, such as the Ramadan or multiple medications especially in elderly patients. Drug-food interactions are also presented with respect to the main therapeutic families, including the non-steroidal anti-inflammatory drugs, analgesics, cardiovascular medications, warfarin as well as new oral anticoagulants, anticancer drugs and immunosuppressant medications. Considerable effort has been achieved to a better understanding of food-drug interactions and increase clinicians' ability to anticipate their occurrence and consequences in clinical practice. Describing the frequency of relevant food-drug interactions in internal medicine is paramount in order to optimize patient care and drug dosing on an individual basis as well as to increase patients and doctors information. Copyright © 2015 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

The effects of repeated nitroglycerin administrations in rats; modeling migraine-related endpoints and chronification.

PubMed

Harris, Hannah M; Carpenter, Jessica M; Black, Jonathan R; Smitherman, Todd A; Sufka, Kenneth J

2017-06-01

Rodent models typically use a single nitroglycerin injection to induce migraine, yet migraine in clinical populations presents as recurrent episodes. Further, these models quantify behavioral endpoints that do not align with the clinical features of episodic migraine or migraine chronification and therefore may limit translational relevance. Rats received 5 nitroglycerin (10mg/kg/2ml), propylene glycol/ethanol vehicle, or saline injections every third day over 15days. Behavioral endpoints were assessed 110min post nitroglycerin administration and included time spent light/dark chambers for photophobia as well as activity, facial pain expressions, and tactile allodynia. Animals administered nitroglycerin displayed photophobia, decreased activity, and increased facial pain expression. Similar alterations in photophobia and activity were seen in the vehicle treated animals, but these tended to diminish by the 4th or 5th injection. The presentation of spontaneous tactile allodynia was observed in the nitroglycerin group by the 5th episode. Most NTG migraine models entail a single NTG administration and quantification of evoked allodynia. This paradigm employs recurring NTG episodes and clinically-relevant measures of photophobia, hypoactivity and facial grimace endpoints as well as introduces a novel arena apparatus to quantify spontaneous allodynia. This repeated NTG procedure and endpoint measures aligns with the frequency and clinical presentation of episodic migraine and its chronification, respectively. Further, propylene glycol ethanol vehicle contributes to migraine endpoints. Copyright © 2017 Elsevier B.V. All rights reserved.

Triclosan Decreases Rat Thyroxine: Mode-of-Action, Developmental Susceptibility and Human Relevance

EPA Science Inventory

Triclosan (TCS) decreases serum thyroxine (T4) in the rat. In vivo and in vitro approaches were used to address three uncertainties: by what mode-of-action (MOA) does TCS decrease T4; does TCS decrease T4 developmentally; and, are effects observed in rats relevant to humans? To t...

Immunological, anti-angiogenic and clinical effects of intratumoral interleukin 12 electrogene therapy combined with metronomic cyclophosphamide in dogs with spontaneous cancer: A pilot study.

PubMed

Cicchelero, Laetitia; Denies, Sofie; Vanderperren, Katrien; Stock, Emmelie; Van Brantegem, Leen; de Rooster, Hilde; Sanders, Niek N

2017-08-01

The immunological, anti-angiogenic and clinical effects of metronomic cyclophosphamide and 3 consecutive intratumoral interleukin (IL)-12 gene therapy (electrogene therapy (EGT)) treatments were evaluated in 6 dogs with spontaneous cancer. In all dogs, a decrease in peripheral leukocytes 2 days after IL-12 EGT coincided with erythema and swelling of the tumor. In the tumor, a transient increase in IL-12 levels was measured, whereas a continuous increase in interferon γ (IFNγ) and thrombospondin 1 (TSP-1) were determined in contrast to a continuous decrease in vascular endothelial growth factor (VEGF). In the serum, a transient increase in IL-12 and IL-10 levels were noted in contrast to a transient decrease in VEGF and TSP-1. The treatment resulted in a significant anti-angiogenic effect. Although all primary tumors continued to progress in time, this progression was slower than before treatment according to the contrast-enhanced ultrasound data. Besides the encouraging immunostimulatory and anti-angiogenic effects observed in all dogs we also noticed in 4 out of 6 dogs clinically relevant improvements in quality of life and weight. These results hold great promise for combinatorial strategies of IL-12 EGT and metronomic chemotherapy with conventional antitumor (immuno)therapies. Copyright © 2016 Elsevier Ireland Ltd. 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...

Human-relevant Levels of Added Sugar Consumption Increase Female Mortality and Lower Male Fitness in Mice

PubMed Central

Ruff, James S.; Suchy, Amanda K.; Hugentobler, Sara A.; Sosa, Mirtha M.; Schwartz, Bradley L.; Morrison, Linda C.; Gieng, Sin H.; Shigenaga, Mark K.; Potts, Wayne K.

2013-01-01

Consumption of added sugar has increased over recent decades and is correlated with numerous diseases. Rodent models have elucidated mechanisms of toxicity, but only at concentrations beyond typical human exposure. Here we show that comparatively low levels of added sugar consumption have substantial negative effects on mouse survival, competitive ability, and reproduction. Using Organismal Performance Assays (OPAs) – in which mice fed human-relevant concentrations of added sugar (25% Kcal from a mixture of fructose and glucose [F/G]) and control mice compete in seminatural enclosures for territories, resources and mates – we demonstrate that F/G-fed females experience a two-fold increase in mortality while F/G-fed males control 26% fewer territories and produce 25% less offspring. These findings represent the lowest level of sugar consumption shown to adversely affect mammalian health. Clinical defects of F/G-fed mice were decreased glucose clearance and increased fasting cholesterol. Our data highlight that physiological adversity can exist when clinical disruptions are minor, and suggest that OPAs represent a promising technique for unmasking negative effects of toxicants. PMID:23941916

Evaluation of perceived and actual competency in a family medicine objective structured clinical examination

PubMed Central

Graves, Lisa; Lalla, Leonora; Young, Meredith

2017-01-01

Abstract Objective To examine the relationship between objective assessment of performance and self-rated competence immediately before and after participation in a required summative family medicine clerkship objective structured clinical examination (OSCE). Design Learners rated their competence (on a 7-point Likert scale) before and after an OSCE along 3 dimensions: general, specific, and professional competencies relevant to family medicine. Setting McGill University in Montreal, Que. Participants All 168 third-year clinical clerks completing their mandatory family medicine rotation in 2010 to 2011 were invited to participate. Main outcome measures Self-ratings of competence and objective performance scores were compared, and were examined to determine if OSCEs could be a “corrective” tool for self-rating perceived competence (ie, if the experience of undergoing an assessment might assist learners in recalibrating their understanding of their own performance). Results A total of 140 (83%) of the third-year clinical clerks participated. Participating in an OSCE decreased learners’ ratings of perceived competence (pre-OSCE score = 4.9, post-OSCE score = 4.7; F1,3192 = 4.2; P < .05). Learners’ mean self-rated competence for all categories of behaviour (before and after) showed no relationship to OSCE performance (r < 0.12 and P > .08 for all), nor did ratings of station-relevant competence (before and after) (r < 0.19 and P > .09 for all). Ratings of competence before and after the OSCE were correlated for individual students (r > 0.40 and P < .001 for all). Conclusion After the OSCE, students’ self-ratings of perceived competence had decreased, and these ratings had little relationship to actual performance, regardless of the specificity of the rated competency. Discordance between perceived and actual competence is neither novel nor unique to family medicine. However, this discordance is an important consideration for the development of competency-based curricula. PMID:28404722

Crystalline glucosamine sulfate in the management of knee osteoarthritis: efficacy, safety, and pharmacokinetic properties

PubMed Central

Girolami, Federica; Persiani, Stefano

2012-01-01

Glucosamine is an amino monosaccharide and a natural constituent of glycosaminoglycans in articular cartilage. When administered exogenously, it is used for the treatment of osteoarthritis as a prescription drug or a dietary supplement. The latter use is mainly supported by its perception as a cartilage building block, but it actually exerts specific pharmacologic effects, mainly decreasing interleukin 1-induced gene expression by inhibiting the cytokine intracellular signaling cascade in general and nuclear factor-kappa B (NF-kB) activation in particular. As a whole, the use of glucosamine in the management of osteoarthritis is supported by the clinical trials performed with the original prescription product, that is, crystalline glucosamine sulfate. This is the stabilized form of glucosamine sulfate, while other formulations or different glucosamine salts (e.g. hydrochloride) have never been shown to be effective. In particular, long-term pivotal trials of crystalline glucosamine sulfate 1500 mg once daily have shown significant and clinically relevant improvement of pain and function limitation (symptom-modifying effect) in knee osteoarthritis. Continuous administration for up to 3 years resulted in significant reduction in the progression of joint structure changes compared with placebo as assessed by measuring radiologic joint space narrowing (structure-modifying effect). The two effects combined may suggest a disease-modifying effect that was postulated based on an observed decrease in the risk of undergoing total joint replacement in the follow up of patients receiving the product for at least 12 months in the pivotal trials. The safety of the drug was good in clinical trials and in the postmarketing surveillance. Crystalline glucosamine sulfate 1500 mg once daily is therefore recommended in the majority of clinical practice guidelines and was found to be cost effective in pharmacoeconomic analyses. Compared with other glucosamine formulations, salts, or dosage forms, the prescription product achieves higher plasma and synovial fluid concentrations that are above the threshold for a pharmacologically relevant effect, and may therefore justify its distinct therapeutic characteristics. PMID:22850875

Evaluation of perceived and actual competency in a family medicine objective structured clinical examination.

PubMed

Graves, Lisa; Lalla, Leonora; Young, Meredith

2017-04-01

To examine the relationship between objective assessment of performance and self-rated competence immediately before and after participation in a required summative family medicine clerkship objective structured clinical examination (OSCE). Learners rated their competence (on a 7-point Likert scale) before and after an OSCE along 3 dimensions: general, specific, and professional competencies relevant to family medicine. McGill University in Montreal, Que. All 168 third-year clinical clerks completing their mandatory family medicine rotation in 2010 to 2011 were invited to participate. Self-ratings of competence and objective performance scores were compared, and were examined to determine if OSCEs could be a "corrective" tool for self-rating perceived competence (ie, if the experience of undergoing an assessment might assist learners in recalibrating their understanding of their own performance). A total of 140 (83%) of the third-year clinical clerks participated. Participating in an OSCE decreased learners' ratings of perceived competence (pre-OSCE score = 4.9, post-OSCE score = 4.7; F 1,3192 = 4.2; P  < .05). Learners' mean self-rated competence for all categories of behaviour (before and after) showed no relationship to OSCE performance ( r < 0.12 and P > .08 for all), nor did ratings of station-relevant competence (before and after) ( r < 0.19 and P > .09 for all). Ratings of competence before and after the OSCE were correlated for individual students ( r > 0.40 and P < .001 for all). After the OSCE, students' self-ratings of perceived competence had decreased, and these ratings had little relationship to actual performance, regardless of the specificity of the rated competency. Discordance between perceived and actual competence is neither novel nor unique to family medicine. However, this discordance is an important consideration for the development of competency-based curricula. Copyright© the College of Family Physicians of Canada.

Total MRI Small Vessel Disease Burden Correlates with Cognitive Performance, Cortical Atrophy, and Network Measures in a Memory Clinic Population.

PubMed

Banerjee, Gargi; Jang, Hyemin; Kim, Hee Jin; Kim, Sung Tae; Kim, Jae Seung; Lee, Jae Hong; Im, Kiho; Kwon, Hunki; Lee, Jong Min; Na, Duk L; Seo, Sang Won; Werring, David John

2018-01-01

Recent evidence suggests that combining individual imaging markers of cerebral small vessel disease (SVD) may more accurately reflect its overall burden and better correlate with clinical measures. We wished to establish the clinical relevance of the total SVD score in a memory clinic population by investigating the association with SVD score and cognitive performance, cortical atrophy, and structural network measures, after adjusting for amyloid-β burden. We included 243 patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease dementia, subcortical vascular MCI, or subcortical vascular dementia. All underwent MR and [11C] PiB-PET scanning and had standardized cognitive testing. Multiple linear regression was used to evaluate the relationships between SVD score and cognition, cortical thickness, and structural network measures. Path analyses were performed to evaluate whether network disruption mediates the effects of SVD score on cortical thickness and cognition. Total SVD score was associated with the performance of frontal (β - 4.31, SE 2.09, p = 0.040) and visuospatial (β - 0.95, SE 0.44, p = 0.032) tasks, and with reduced cortical thickness in widespread brain regions. Total SVD score was negatively correlated with nodal efficiency, as well as changes in brain network organization, with evidence of reduced integration and increasing segregation. Path analyses showed that the associations between SVD score and frontal and visuospatial scores were partially mediated by decreases in their corresponding nodal efficiency and cortical thickness. Total SVD burden has clinical relevance in a memory clinic population and correlates with cognition, and cortical atrophy, as well as structural network disruption.

Susceptibility based upon Chemical Interaction with Disease ...

EPA Pesticide Factsheets

One of the challenges facing toxicology and risk assessment is that numerous host and environmental factors may modulate vulnerability and risk. An area of increasing interest is the potential for chemicals to interact with background aging and disease processes, an interaction that may yield cumulative damage, altered chemical potency, and increased disease incidence. This review outlines the interactions possible between chemicals and background disease and identifies the type of information needed to evaluate such interactions. Key among these is the existence of a clinically relevant and easy to measure biomarker of disease risk which allows the identification of vulnerable individuals based upon the level of risk biomarker. The impact of toxic chemicals on this biomarker can then be used to predict how the chemical modifies disease risk as long as related mechanistic and toxicological data are consistent with toxicant effect on the disease process. Several case studies are briefly presented which describe the toxic chemical, the clinical biomarker and the impacted disease including: fine particulate matter/decreased heart rate variability/increased cardiopulmonary events; cadmium/decreased glomerular filtration rate/increased chronic kidney disease; methyl mercury/decreased paraoxonase-1/increased cardiovascular risk; trichloroethylene/increased anti-nuclear antibody/autoimmunity; dioxin/increased CYP1A1/hypertension. These case studies point o

Mobile phone interference with medical equipment and its clinical relevance: a systematic review.

PubMed

Lawrentschuk, Nathan; Bolton, Damien M

2004-08-02

To conduct a systematic review of studies on clinically relevant digital mobile phone electromagnetic interference with medical equipment. MEDLINE and SUMSEARCH were searched for the period 1966-2004. The Cochrane Library and Database of Abstracts of Reviews of Effects were also searched for systematic reviews. Studies were eligible if published in a peer-reviewed journal in English, and if they included testing of digital mobile phones for clinically relevant interference with medical equipment used to monitor or treat patients, but not implantable medical devices. As there was considerable heterogeneity in medical equipment studied and the conduct of testing, results were summarised rather than subjected to meta-analysis. Clinically relevant electromagnetic interference (EMI) secondary to mobile phones potentially endangering patients occurred in 45 of 479 devices tested at 900 MHz and 14 of 457 devices tested at 1800 MHz. However, in the largest studies, the prevalence of clinically relevant EMI was low. Most clinically relevant EMI occurred when mobile phones were used within 1 m of medical equipment. Although testing was not standardised between studies and equipment tested was not identical, it is of concern that at least 4% of devices tested in any study were susceptible to clinically relevant EMI. All studies recommend some type of restriction of mobile phone use in hospitals, with use greater than 1 m from equipment and restrictions in clinical areas being the most common.

Pediatric Allergic Contact Dermatitis: Clinical and Epidemiological Study in a Tertiary Hospital.

PubMed

Ortiz Salvador, J M; Esteve Martínez, A; Subiabre Ferrer, D; Victoria Martínez, A M; de la Cuadra Oyanguren, J; Zaragoza Ninet, V

Few epidemiological studies have investigated the incidence of allergic contact dermatitis in children. Underdiagnosis has been observed in some studies, with many cases in which the condition is not suspected clinically and patch tests are not performed. However, the prevalence of pediatric sensitization to allergens has been reported to be as high as 20%, and the diagnosis should therefore be contemplated as a possibility in this age group. We performed a retrospective analysis of the skin allergy database of the Dermatology Department of Consorcio Hospital General Universitario de Valencia. Children between 0 and 16 years of age diagnosed with allergic contact dermatitis in the previous 15 years (between 2000 and 2015) were included in the analysis. Epidemiological (age, sex, history of atopy) and clinical (site of the lesions, allergen series applied, positive reactions, and their relevance) variables were gathered. Patch tests had been performed on 4,593 patients during the study period. Of these, 265 (6%) were children aged between 0 and 16 years. A positive reaction to at least one of the allergens tested was observed in 144 (54.3%) patients in that group. The allergens most frequently identified were the following (in decreasing order of frequency): thiomersal, cobalt chloride, colophony, paraphenylenediamine, potassium dichromate, mercury, and nickel. The sensitization was considered relevant in 177 (61.3%) cases. More than half of the children studied showed sensitization to 1 or more allergens, with a high percentage of relevant sensitizations. All children with a clinical suspicion of allergic contact dermatitis should be referred for patch testing. As no standardized test series have been developed for this age group, a high level of clinical suspicion and knowledge of the allergens most commonly involved are required when selecting the allergens to be tested. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Supporting deployed operations: are military nurses gaining the relevant experience from MDHUs to be competent in deployed operations?

PubMed

Beaumont, Steven P; Allan, Helen T

2014-01-01

To explore how peacetime employment of military nurses in the UK National Health Service Medical Defence Hospital Units prepares them to be competent to practise in their role on deployment. Military secondary care nurses are employed within UK National Health Service Trusts to gain clinical experience that will be relevant to their military nursing role. A two-stage grounded theory study using mixed methods: postal questionnaire survey and in-depth interviews. In stage one a postal questionnaire was distributed to all serving military nurses. Stage two involved 12 semi-structured interviews. The data from both parts of the study were analysed using grounded theory. Four categories and one core category were identified, which suggested that participants did not feel fully prepared for deployment. Their feelings of preparedness increased with deployment experience and decreased when the nature of injuries seen on deployment changed. Respondents argued that even when unprepared, they did not feel incompetent. The findings suggest that the peacetime clinical experience gained in the National Health Service did not always develop the necessary competencies to carry out roles as military nurses on deployment. This study highlights the unique role of military nurses. We discuss these findings in the light of the literature on competency and expertise. The military nurses in this study did not feel fully prepared for deployed operations. We propose a new model for how military nurses could gain relevant experience from their National Health Service placements. National Health Service clinical placements need to be reassessed regularly to ensure that they are meeting military nurses' clinical requirements. Experiences of nurses returning from deployment could be shared and used as a basis for reflection and learning within National Health Service Trusts and also inform decisions regarding the appropriateness of clinical placements for qualified military nurses. © 2012 Blackwell Publishing Ltd.

Sphincter of Oddi botulinum toxin injection to prevent pancreatic fistula after distal pancreatectomy.

PubMed

Hackert, Thilo; Klaiber, Ulla; Hinz, Ulf; Kehayova, Tzveta; Probst, Pascal; Knebel, Phillip; Diener, Markus K; Schneider, Lutz; Strobel, Oliver; Michalski, Christoph W; Ulrich, Alexis; Sauer, Peter; Büchler, Markus W

2017-05-01

Postoperative pancreatic fistula represents the most important complication after distal pancreatectomy. The aim of this study was to evaluate the use of a preoperative endoscopic injection of botulinum toxin into the sphincter of Oddi to prevent postoperative pancreatic fistula (German Clinical Trials Register number: DRKS00007885). This was an investigator-initiated, prospective clinical phase I/II trial with an exploratory study design. We included patients who underwent preoperative endoscopic sphincter botulinum toxin injection (100 units of Botox). End points were the feasibility, safety, and postoperative outcomes, including postoperative pancreatic fistula within 30 days after distal pancreatectomy. Botulinum toxin patients were compared with a control collective of patients undergoing distal pancreatectomy without botulinum toxin injection by case-control matching in a 1:1 ratio. Between February 2015 and February 2016, 29 patients were included. All patients underwent successful sphincter of Oddi botulinum toxin injection within a median of 6 (range 0-10) days before operation. One patient had an asymptomatic, self-limiting (48 hours) increase in serum amylase and lipase after injection. Distal pancreatectomy was performed in 24/29 patients; 5 patients were not resectable. Of the patients receiving botulinum toxin, 7 (29%) had increased amylase levels in drainage fluid on postoperative day 3 (the International Study Group of Pancreatic Surgery definition of postoperative pancreatic fistula grade A) without symptoms or need for reintervention. Importantly, no clinically relevant fistulas (International Study Group of Pancreatic Surgery grades B/C) were observed in botulinum toxin patients compared to 33% postoperative pancreatic fistula grade B/C in case-control patients (P < .004). Preoperative sphincter of Oddi botulinum toxin injection is a novel and safe approach to decrease the incidence of clinically relevant postoperative pancreatic fistula after distal pancreatectomy. The results of the present trial suggest its efficacy in the prevention of clinically relevant postoperative pancreatic fistula and are validated currently in the German Federal Government-sponsored, multicenter, randomized controlled PREBOT trial. Copyright © 2016 Elsevier Inc. All rights reserved.

Viability of primary osteoblasts after treatment with tenofovir alafenamide: Lack of cytotoxicity at clinically relevant drug concentrations

PubMed Central

Callebaut, Christian; Liu, Yang; Babusis, Darius; Ray, Adrian; Miller, Michael; Kitrinos, Kathryn

2017-01-01

Tenofovir alafenamide (TAF) is a phosphonoamidate prodrug of the nucleotide HIV reverse transcriptase inhibitor tenofovir (TFV). TAF is approved for the treatment of HIV-1 infection as part of the single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and TAF. When dosed once-daily, TAF results in approximately 90% lower levels of plasma TFV and a 4-fold increase in intracellular TFV-diphosphate (TFV-DP) in PBMCs compared with the TFV prodrug tenofovir disoproxil fumarate (TDF). Several antiretrovirals, including TDF, have been associated with bone mineral density decreases in patients; the effect of clinically relevant TAF concentrations on primary osteoblast viability was therefore assessed in vitro. Studies in PBMCs determined that a 2-hour TAF exposure at concentrations similar to human plasma Cmax achieved intracellular TFV-DP levels comparable to those observed after the maximum recommended human dose of 25 mg TAF. Comparable intracellular TFV-DP levels were achieved in primary osteoblasts with 2-hour TAF exposure daily for 3 days at concentrations similar to those used for PBMCs (100–400 nM). No change in cell viability was observed in either primary osteoblasts or PBMCs. The mean TAF CC50 in primary osteoblasts after 3 days of daily 2-hour pulses was >500 μM, which is >1033 times higher than the TAF maximum recommended human dose plasma Cmax. In summary, primary osteoblasts were not preferentially loaded by TAF compared with PBMCs, with comparable TFV-DP levels achieved in both cell types. Furthermore, there was no impact on osteoblast cell viability at clinically relevant TAF concentrations. PMID:28182625

Viability of primary osteoblasts after treatment with tenofovir alafenamide: Lack of cytotoxicity at clinically relevant drug concentrations.

PubMed

Callebaut, Christian; Liu, Yang; Babusis, Darius; Ray, Adrian; Miller, Michael; Kitrinos, Kathryn

2017-01-01

Tenofovir alafenamide (TAF) is a phosphonoamidate prodrug of the nucleotide HIV reverse transcriptase inhibitor tenofovir (TFV). TAF is approved for the treatment of HIV-1 infection as part of the single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and TAF. When dosed once-daily, TAF results in approximately 90% lower levels of plasma TFV and a 4-fold increase in intracellular TFV-diphosphate (TFV-DP) in PBMCs compared with the TFV prodrug tenofovir disoproxil fumarate (TDF). Several antiretrovirals, including TDF, have been associated with bone mineral density decreases in patients; the effect of clinically relevant TAF concentrations on primary osteoblast viability was therefore assessed in vitro. Studies in PBMCs determined that a 2-hour TAF exposure at concentrations similar to human plasma Cmax achieved intracellular TFV-DP levels comparable to those observed after the maximum recommended human dose of 25 mg TAF. Comparable intracellular TFV-DP levels were achieved in primary osteoblasts with 2-hour TAF exposure daily for 3 days at concentrations similar to those used for PBMCs (100-400 nM). No change in cell viability was observed in either primary osteoblasts or PBMCs. The mean TAF CC50 in primary osteoblasts after 3 days of daily 2-hour pulses was >500 μM, which is >1033 times higher than the TAF maximum recommended human dose plasma Cmax. In summary, primary osteoblasts were not preferentially loaded by TAF compared with PBMCs, with comparable TFV-DP levels achieved in both cell types. Furthermore, there was no impact on osteoblast cell viability at clinically relevant TAF concentrations.

The effect of cisatracurium and rocuronium on lung function in anesthetized children.

PubMed

Yang, Charles I; Fine, Gavin F; Jooste, Edmund H; Mutich, Rebecca; Walczak, Stephen A; Motoyama, Etsuro K

2013-12-01

Neuromuscular blocking drugs have been implicated in intraoperative bronchoconstrictive episodes. We examined the effects of clinically relevant doses of cisatracurium and rocuronium on the lung mechanics of pediatric subjects. We hypothesized that cisatracurium and rocuronium would have bronchoconstrictive effects. We studied ASA physical status I and II pediatric subjects having elective dental or urological procedures, requiring general anesthesia with endotracheal intubations with either cisatracurium or rocuronium. Pulmonary function tests were performed before and after neuromuscular blocking drug dosing and again after albuterol administration. Using forced deflation and passive deflation techniques, forced vital capacity (FVC) and maximum expiratory flow rate at 10% (MEF10) of FVC were obtained. Fractional changes from the baseline were used to compare subjects. Changes in MEF10 of >30% were considered clinically significant. A Shapiro-Wilk test, paired t test, and Wilcoxon rank sum test were used to analyze the data. Twenty-five subjects (median age = 5.25 years; range = 9 months-9.9 years) were studied; 12 subjects received cisatracurium and 13 subjects received rocuronium. Data are shown as mean proportional change ± SD or, in the case of not normally distributed, median proportional change (first, third quartile) with P values. In the cisatracurium group, there were no differences between baseline and postneuromuscular blocker administration in the fractional change from the baselines of FVC (1.00 ± 0.04, P = 0.5), but there was a significant decrease in MEF10 (0.80 ± 0.18, P = 0.002). In the rocuronium group, there were small yet significant decreases of FVC (0.99 [first quartile 0.97, third quartile 1], P = 0.02) and significant decreases in MEF10 (0.78 ± 0.26, P = 0.008). After administration of albuterol in the cisatracurium group, FVC increased slightly but significantly from baseline values (1.02 ± 0.02, P = 0.005). MEF10 increased significantly beyond baseline values (1.24 ± 0.43, P =0.04). In the rocuronium group, there were also significant differences between baseline and postalbuterol administration from the baseline value of FVC (1.02 ± 0.02, P = 0.004) and MEF10 (1.23 ± 0.29, P = 0.01). At clinically relevant doses, both cisatracurium and rocuronium caused changes in lung function, indicating constriction of smaller airways. In general, these changes were mild and not clinically detectable. However, in the rocuronium group, 3 of 13 patients showed more noticeable decreases in MEF10 (≤50%), demonstrating the potential for significant broncho-bronchiolar constriction in susceptible patients.

Imagery Rescripting: The Impact of Conceptual and Perceptual Changes on Aversive Autobiographical Memories

PubMed Central

Slofstra, Christien; Nauta, Maaike H.; Holmes, Emily A.; Bockting, Claudi L. H.

2016-01-01

Background Imagery rescripting (ImRs) is a process by which aversive autobiographical memories are rendered less unpleasant or emotional. ImRs is thought only to be effective if a change in the meaning-relevant (semantic) content of the mental image is produced, according to a cognitive hypothesis of ImRs. We propose an additional hypothesis: that ImRs can also be effective by the manipulation of perceptual features of the memory, without explicitly targeting meaning-relevant content. Methods In two experiments using a within-subjects design (both N = 48, community samples), both Conceptual-ImRs—focusing on changing meaning-relevant content—and Perceptual-ImRs—focusing on changing perceptual features—were compared to Recall-only of aversive autobiographical image-based memories. An active control condition, Recall + Attentional Breathing (Recall+AB) was added in the first experiment. In the second experiment, a Positive-ImRs condition was added—changing the aversive image into a positive image that was unrelated to the aversive autobiographical memory. Effects on the aversive memory’s unpleasantness, vividness and emotionality were investigated. Results In Experiment 1, compared to Recall-only, both Conceptual-ImRs and Perceptual-ImRs led to greater decreases in unpleasantness, and Perceptual-ImRs led to greater decreases in emotionality of memories. In Experiment 2, the effects on unpleasantness were not replicated, and both Conceptual-ImRs and Perceptual-ImRs led to greater decreases in emotionality, compared to Recall-only, as did Positive-ImRs. There were no effects on vividness, and the ImRs conditions did not differ significantly from Recall+AB. Conclusions Results suggest that, in addition to traditional forms of ImRs, targeting the meaning-relevant content of an image during ImRs, relatively simple techniques focusing on perceptual aspects or positive imagery might also yield benefits. Findings require replication and extension to clinical samples. PMID:27486966

Baseline predictors of persistence to first disease-modifying treatment in multiple sclerosis.

PubMed

Zettl, U K; Schreiber, H; Bauer-Steinhusen, U; Glaser, T; Hechenbichler, K; Hecker, M

2017-08-01

Patients with multiple sclerosis (MS) require lifelong therapy. However, success of disease-modifying therapies is dependent on patients' persistence and adherence to treatment schedules. In the setting of a large multicenter observational study, we aimed at assessing multiple parameters for their predictive power with respect to discontinuation of therapy. We analyzed 13 parameters to predict discontinuation of interferon beta-1b treatment during a 2-year follow-up period based on data from 395 patients with MS who were treatment-naïve at study onset. Besides clinical characteristics, patient-related psychosocial outcomes were assessed as well. Among patients without clinically relevant fatigue, males showed a higher persistence rate than females (80.3% vs 64.7%). Clinically relevant fatigue scores decreased the persistence rate in men and especially in women (71.4% and 51.2%). Besides gender and fatigue, univariable and multivariable analyses revealed further factors associated with interferon beta-1b therapy discontinuation, namely lower quality of life, depressiveness, and higher relapse rate before therapy initiation, while higher education, living without a partner, and higher age improved persistence. Patients with higher grades of fatigue and depressiveness are at higher risk to prematurely discontinue MS treatment; especially, women suffering from fatigue have an increased discontinuation rate. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Future of electronic health records: implications for decision support.

PubMed

Rothman, Brian; Leonard, Joan C; Vigoda, Michael M

2012-01-01

The potential benefits of the electronic health record over traditional paper are many, including cost containment, reductions in errors, and improved compliance by utilizing real-time data. The highest functional level of the electronic health record (EHR) is clinical decision support (CDS) and process automation, which are expected to enhance patient health and healthcare. The authors provide an overview of the progress in using patient data more efficiently and effectively through clinical decision support to improve health care delivery, how decision support impacts anesthesia practice, and how some are leading the way using these systems to solve need-specific issues. Clinical decision support uses passive or active decision support to modify clinician behavior through recommendations of specific actions. Recommendations may reduce medication errors, which would result in considerable savings by avoiding adverse drug events. In selected studies, clinical decision support has been shown to decrease the time to follow-up actions, and prediction has proved useful in forecasting patient outcomes, avoiding costs, and correctly prompting treatment plan modifications by clinicians before engaging in decision-making. Clinical documentation accuracy and completeness is improved by an electronic health record and greater relevance of care data is delivered. Clinical decision support may increase clinician adherence to clinical guidelines, but educational workshops may be equally effective. Unintentional consequences of clinical decision support, such as alert desensitization, can decrease the effectiveness of a system. Current anesthesia clinical decision support use includes antibiotic administration timing, improved documentation, more timely billing, and postoperative nausea and vomiting prophylaxis. Electronic health record implementation offers data-mining opportunities to improve operational, financial, and clinical processes. Using electronic health record data in real-time for decision support and process automation has the potential to both reduce costs and improve the quality of patient care. © 2012 Mount Sinai School of Medicine.

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.

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.

[Moderate hypoglycemia in the preterm infant: is it relevant?].

PubMed

Wayenberg, J-L; Pardou, A

2008-02-01

Glucose monitoring and management of hypoglycaemia in preterm infants remain controversial. However, recent animal studies have shown that hypoglycaemia is associated to increased generation of reactive oxygen and nitrogen species, to inhibition of cellular maturation and to apoptosis in brain. Despite potential consequences of hypoglycaemia on brain development in preterm infants, only few studies are available on this topic. Available clinical studies on neurological development of hypoglycaemic preterm infants are not conclusive but suggest detrimental effect of repeated mild hypoglycaemia on brain development. Both experimental and clinical arguments are sufficient to mind to this problem with great awareness. Therefore, routine repeated measurements of blood glucose concentration are necessary and active intervention is proposed if glucose plasma level decreases below 2.5 mmol/l.

Multidisciplinary Team Contributions Within a Dedicated Outpatient Palliative Radiotherapy Clinic: A Prospective Descriptive Study

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

Pituskin, Edith, E-mail: pituskin@ualberta.c; University of Alberta, Edmonton, AB; Fairchild, Alysa

Purpose: Patients with bone metastases may experience pain, fatigue, and decreased mobility. Multiple medications for analgesia are often required, each with attendant side effects. Although palliative-intent radiotherapy (RT) is effective in decreasing pain, additional supportive care interventions may be overlooked. Our objective was to describe the feasibility of multidisciplinary assessment of patients with symptomatic bone metastases attending a dedicated outpatient palliative RT clinic. Methods and Materials: Consecutive patients referred for RT for painful bone metastases were screened for symptoms and needs relevant to their medications, nutritional intake, activities of daily living, and psychosocial and spiritual concerns from January 1 tomore » December 31, 2007. Consultations by appropriate team members and resulting recommendations were collected prospectively. Patients who received RT were contacted by telephone 4 weeks later to assess symptom outcomes. Results: A total of 106 clinic visits by 82 individual patients occurred. As determined by screening form responses, the clinical Pharmacist, Occupational Therapist, Registered Dietician and Social Worker were consulted to provide assessments and recommendations within the time constraints presented by 1-day palliative RT delivery. In addition to pain relief, significant improvements in tiredness, depression, anxiety, drowsiness and overall well-being were reported at 4 weeks. Conclusions: Systematic screening of this population revealed previously unmet needs, addressed in the form of custom verbal and written recommendations. Multidisciplinary assessment is associated with a high number of recommendations and decreased symptom distress. Our findings lend strong support to the routine assessment by multiple supportive care professionals for patients with advanced cancer being considered for palliative RT.« less

Bleeding risk in patients with atrial fibrillation: the AMADEUS study.

PubMed

Lane, Deirdre A; Kamphuisen, Pieter W; Minini, Pascal; Büller, Harry R; Lip, Gregory Y H

2011-07-01

This study aimed to assess the impact of combination antithrombotic therapy on stroke and bleeding risk compared with anticoagulation therapy only in patients with atrial fibrillation (AF). Post hoc analysis of 4,576 patients with AF (mean ± SD age, 70.1 ± 9.1 years; men, 66.5%) enrolled in the Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation (AMADEUS) trial were randomized to receive either subcutaneous idraparinux (2.5 mg weekly) (n = 2,283) or dose-adjusted vitamin K antagonists (VKAs) (international normalized ratio, 2.0-3.0) (n = 2,293). Of these patients, 848 (18.5%) received antiplatelet therapy (aspirin, clopidogrel, ticlopidine, etc) in addition to anticoagulation treatment (combination antithrombotic therapy). A total of 572 (15.3% per year) clinically relevant bleeding and 103 (2.6% per year) major bleeding events occurred. Patients receiving combination antithrombotic therapy had a 2.3- to 2.5-fold increased risk of clinically relevant bleeding events and major bleeding events, respectively, compared with those receiving anticoagulation therapy only. Multivariate analyses (hazard ratio, 95% CI) revealed that the risk of clinically relevant bleeding was significantly increased by age 65 to 74 years (1.44, 1.14-1.82) and ≥ 75 years (1.59, 1.24-2.04, P = .001) and by combination antithrombotic therapy (2.47, 2.07-2.96, P < .0001). The same held true for major bleeding events, with analogous figures for age 65 to 74 years (2.26, 1.08-4.71) and ≥ 75 years (4.19, 1.98-8.87, P = .0004) and for combination antithrombotic therapy (2.23, 1.49-3.34, P < .0001). Combination antithrombotic therapy was not associated with a decrease in ischemic stroke risk compared with anticoagulation therapy only (11 [1.4% per year] vs 22 [0.7% per year]; adjusted hazard ratio, 2.01; 95% CI, 0.94-4.30; P = .07). Combination antithrombotic therapy increases the risk of clinically relevant bleeding and major bleeding in patients with AF and does not appear to reduce the risk of stroke.

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.

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.

Thrombelastography is Better Than PT, aPTT, and Activated Clotting Time in Detecting Clinically Relevant Clotting Abnormalities After Hypothermia, Hemorrhagic Shock and Resuscitation in Pigs

DTIC Science & Technology

2008-09-01

hypothermia group using a cold blanket with 4°C circulating water. In the combined group, hemorrhagic shock and LR re- suscitation were induced the same... circulation and a decrease in platelet counts. Fibrinogen levels, in con- trast, were not changed significantly from baseline by hypo- thermia in this...et al. Effect of skin temperature on platelet function in patients undergoing extracorporeal bypass. J Thorac Cardiovasc Surg. 1992;104:108–116. The

Resilience in Aging Mice

PubMed Central

Kirkland, James L.; Stout, Michael B.

2016-01-01

Abstract Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance health span and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context. The preliminary set of tests ranked by the participants is discussed here, recognizing that this is a first attempt. PMID:27535963

Critical illness polyneuropathy and myopathy: a systematic review

PubMed Central

Zhou, Chunkui; Wu, Limin; Ni, Fengming; Ji, Wei; Wu, Jiang; Zhang, Hongliang

2014-01-01

Critical illness polyneuropathy and critical illness myopathy are frequent complications of severe illness that involve sensorimotor axons and skeletal muscles, respectively. Clinically, they manifest as limb and respiratory muscle weakness. Critical illness polyneuropathy/myopathy in isolation or combination increases intensive care unit morbidity via the inability or difficulty in weaning these patients off mechanical ventilation. Many patients continue to suffer from decreased exercise capacity and compromised quality of life for months to years after the acute event. Substantial progress has been made lately in the understanding of the pathophysiology of critical illness polyneuropathy and myopathy. Clinical and ancillary test results should be carefully interpreted to differentiate critical illness polyneuropathy/myopathy from similar weaknesses in this patient population. The present review is aimed at providing the latest knowledge concerning the pathophysiology of critical illness polyneuropathy/myopathy along with relevant clinical, diagnostic, differentiating, and treatment information for this debilitating neurological disease. PMID:25206749

[RAAS and insulin resistance].

PubMed

Motoshima, Hiroyuki; Araki, Eiichi

2012-09-01

The role of the renin-angiotensin-aldosterone system (RAAS) on the development of insulin resistance and type 2 diabetes (T2DM) is an area of growing interest. Most of the deleterious actions of the RAAS on insulin signals appear to be mediated through activation of the serine/threonine kinase, oxidative stress and tissue-inflammation in insulin-sensitive organs. Both experimental and clinical studies demonstrated that angiotensin II (Ang II) and aldosterone could play a role in the development of insulin resistance, diabetes and cardiovascular diseases. Large randomized clinical trials revealed that blockade of the RAAS with either angiotensin I converting enzyme inhibitors or AT1 receptor blockers results in decreased T2DM incidence, with a minor attenuation of markers for insulin resistance. This review focuses on the role of RAAS in the pathogenesis of insulin resistance, as well as on clinical relevance of RAAS blockade in the prevention and treatment of the metabolic syndrome and pre-diabetes.

Quantitative Assessment of the Safety Benefits Associated with Increasing Clinical Peanut Thresholds Through Immunotherapy.

PubMed

Baumert, Joseph L; Taylor, Steve L; Koppelman, Stef J

Peanut immunotherapy studies are conducted with the aim to decrease the sensitivity of patients to peanut exposure with the outcome evaluated by testing the threshold for allergic response in a double-blind placebo-controlled food challenge. The clinical relevance of increasing this threshold is not well characterized. We aimed to quantify the clinical benefit of an increased threshold for peanut-allergic patients. Quantitative risk assessment was performed by matching modeled exposure to peanut protein with individual threshold levels. Exposure was modeled by pairing US consumption data for various food product categories with potential contamination levels of peanut that have been demonstrated to be present on occasion in such food products. Cookies, ice cream, doughnuts/snack cakes, and snack chip mixes were considered in the risk assessment. Increasing the baseline threshold before immunotherapy from 100 mg or less peanut protein to 300 mg peanut protein postimmunotherapy reduces the risk of experiencing an allergic reaction by more than 95% for all 4 food product categories that may contain trace levels of peanut residue. Further increase in the threshold to 1000 mg of peanut protein had an additional quantitative benefit in risk reduction for all patients reacting to 300 mg or less at baseline. We conclude that achieving thresholds of 300 mg and 1000 mg of peanut protein by peanut immunotherapy is clinically relevant, and that the risk for peanut-allergic patients who have achieved this increased threshold to experience an allergic reaction is reduced in a clinically meaningful way. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Lidocaine and ropivacaine, but not bupivacaine, demethylate deoxyribonucleic acid in breast cancer cells in vitro.

PubMed

Lirk, P; Hollmann, M W; Fleischer, M; Weber, N C; Fiegl, H

2014-07-01

Lidocaine demethylates deoxyribonucleic acid (DNA) in breast cancer cells. This modification of epigenetic information may be of therapeutic relevance in the perioperative period, because a decrease in methylation can reactivate tumour suppressor genes and inhibit tumour growth. The objectives of this study were to determine the effect of two amide local anaesthetics, ropivacaine and bupivacaine, on methylation in two breast cancer cell lines and to detect whether the combination of lidocaine with the chemotherapy agent 5-aza-2'-deoxycytidine (DAC) would result in additive demethylating effects. Breast cancer cell lines BT-20 [oestrogen receptor (ER)-negative] and MCF-7 (ER-positive) were incubated with lidocaine, bupivacaine, and ropivacaine to assess demethylating properties. Then, we tested varying concentrations of lidocaine and DAC to assess whether their demethylating effects were additive. Cell numbers and global methylation status were analysed. Lidocaine decreased methylation in BT-20 and MCF-7 cells, ropivacaine decreased methylation in BT-20 cells, and bupivacaine had no demethylating effect. When combined, lidocaine and DAC had additive demethylating effects. At clinically relevant doses, lidocaine and ropivacaine exert demethylating effects on specific breast cancer cell lines, but bupivacaine does not. The demethylating effects of lidocaine and DAC are indeed additive. © The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Aplasia cutis congenita associated with epidermolysis bullosa].

PubMed

Muñoz-Guerrero, Félix; Muñoz-Solís, Adrián Antonio; Ornelas-Aguirre, José Manuel

2017-12-01

Aplasia cutis congenita (ACC) is a skin condition of rare presentation, this disease is characterized by absence of skin at birth and associated with facial, skin and bone skull deformities. The diagnosis is mainly clinical. Male 5 days after birth, unique product of primigravida mother and no family history of relevance. Physical examination revealed bilateral and symmetrical skin defects of both lower extremities, the disease is characterized by skin fragility, scabs, and coated pseudomembrane ulcers, decreased interdigital space between toes of the left foot, retraction of the foot and genu varum. It was handled with allograft of epidermis cultured in vitro, general wound care and clinical follow-up. ACC associated with epidermolysis bullosa is one of the rarer forms of presentation. It is necessary to rule out other skin diseases. Clinical management is recommended with biological or synthetic skin cover, infection prevention, early treatment of complications and clinical follow. Copyright © 2016 Academia Mexicana de Cirugía A.C. Publicado por Masson Doyma México S.A. All rights reserved.

Interpretation of Blood Microbiology Results - Function of the Clinical Microbiologist.

PubMed

Kristóf, Katalin; Pongrácz, Júlia

2016-04-01

The proper use and interpretation of blood microbiology results may be one of the most challenging and one of the most important functions of clinical microbiology laboratories. Effective implementation of this function requires careful consideration of specimen collection and processing, pathogen detection techniques, and prompt and precise reporting of identification and susceptibility results. The responsibility of the treating physician is proper formulation of the analytical request and to provide the laboratory with complete and precise patient information, which are inevitable prerequisites of a proper testing and interpretation. The clinical microbiologist can offer advice concerning the differential diagnosis, sampling techniques and detection methods to facilitate diagnosis. Rapid detection methods are essential, since the sooner a pathogen is detected, the better chance the patient has of getting cured. Besides the gold-standard blood culture technique, microbiologic methods that decrease the time in obtaining a relevant result are more and more utilized today. In the case of certain pathogens, the pathogen can be identified directly from the blood culture bottle after propagation with serological or automated/semi-automated systems or molecular methods or with MALDI-TOF MS (matrix-assisted laser desorption-ionization time of flight mass spectrometry). Molecular biology methods are also suitable for the rapid detection and identification of pathogens from aseptically collected blood samples. Another important duty of the microbiology laboratory is to notify the treating physician immediately about all relevant information if a positive sample is detected. The clinical microbiologist may provide important guidance regarding the clinical significance of blood isolates, since one-third to one-half of blood culture isolates are contaminants or isolates of unknown clinical significance. To fully exploit the benefits of blood culture and other (non- culture based) diagnoses, the microbiologist and the clinician should interact directly.

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.

Direct toxic effects of aqueous extract of cigarette smoke on cardiac myocytes at clinically relevant concentrations

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

Yamada, Shigeyuki; Zhang Xiuquan; Kadono, Toshie

Aims: Our goal was to determine if clinically relevant concentrations of aqueous extract of cigarette smoke (CSE) have direct deleterious effects on ventricular myocytes during simulated ischemia, and to investigate the mechanisms involved. Methods: CSE was prepared with a smoking chamber. Ischemia was simulated by metabolic inhibition (MI) with cyanide (CN) and 0 glucose. Adult rabbit and mouse ventricular myocyte [Ca{sup 2+}]{sub i} was measured by flow cytometry using fluo-3. Mitochondrial [Ca{sup 2+}] was measured with confocal microscopy, and Rhod-2 fluorescence. The mitochondrial permeability transition (MPT) was detected by TMRM fluorescence and myocyte contracture. Myocyte oxidative stress was quantified bymore » dichlorofluorescein (DCF) fluorescence with confocal microscopy. Results: CSE 0.1% increased myocyte contracture caused by MI. The nicotine concentration (HPLC) in 0.1% CSE was 15 ng/ml, similar to that in humans after smoking cigarettes. CSE 0.1% increased mitochondrial Ca{sup 2+} uptake, and increased the susceptibility of mitochondria to the MPT. CSE 0.1% increased DCF fluorescence in isolated myocytes, and increased [Ca{sup 2+}]{sub i} in paced myocytes exposed to 2.0 mM CN, 0 glucose (P-MI). These effects were inhibited by the superoxide scavenger Tiron. The effect of CSE on [Ca{sup 2+}]{sub i} during P-MI was also prevented by ranolazine. Conclusions: CSE in clinically relevant concentrations increases myocyte [Ca{sup 2+}]{sub i} during simulated ischemia, and increases myocyte susceptibility to the MPT. These effects appear to be mediated at least in part by oxidative radicals in CSE, and likely contribute to the effects of cigarette smoke to increase myocardial infarct size, and to decrease angina threshold.« less

The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse.

PubMed

Jacobsen, Jacob P R; Plenge, Per; Sachs, Benjamin D; Pehrson, Alan L; Cajina, Manuel; Du, Yunzhi; Roberts, Wendy; Rudder, Meghan L; Dalvi, Prachiti; Robinson, Taylor J; O'Neill, Sharon P; Khoo, King S; Morillo, Connie Sanchez; Zhang, Xiaodong; Caron, Marc G

2014-12-01

Escitalopram appears to be a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inhibition of the SERT, there by curtailing the elevation of extracellular 5-hydroxytryptamine (5-HTExt), and hence anti-depressant efficacy. Further, it has been suggested that a putative allosteric binding site is important for binding of escitalopram to the primary, orthosteric, site, and for R-citalopram's inhibition here of. Primary: Investigate at the human (h)SERT, at clinical relevant doses, whether R-citalopram antagonizes escitalopram-induced 5-HTExt elevation. Secondary: Investigate whether abolishing the putative allosteric site affects escitalopram-induced 5-HTExt elevation and/or modulates the effect of R-citalopram. Recombinant generation of hSERT transgenic mice; in vivo microdialysis; SERT binding; pharmacokinetics; 5-HT sensitive behaviors (tail suspension, marble burying). We generated mice expressing either the wild-type human SERT (hSERT(WT)) or hSERT carrying amino acid substitutions (A505V, L506F, I507L, S574T and I575T) collectively abolishing the putative allosteric site (hSERT(ALI/VFL+SI/TT)). One mg/kg escitalopram yielded clinical relevant plasma levels and brain levels consistent with therapeutic SERT occupancy. The hSERT mice showed normal basal 5-HTExt levels. Escitalopram-induced 5-HTExt elevation was not decreased by R-citalopram co-treatment and was unaffected by loss of the allosteric site. The behavioral effects of the clinically relevant escitalopram dose were small and tended to be enhanced by R-citalopram co-administration. We find no evidence that R-citalopram directly antagonizes escitalopram or that the putative allosteric site is important for hSERT inhibition by escitalopram.

Shear lag sutures: Improved suture repair through the use of adhesives

PubMed Central

Linderman, Stephen W.; Kormpakis, Ioannis; Gelberman, Richard H.; Birman, Victor; Wegst, Ulrike G. K.; Genin, Guy M.; Thomopoulos, Stavros

2015-01-01

Suture materials and surgical knot tying techniques have improved dramatically since their first use over five millennia ago. However, the approach remains limited by the ability of the suture to transfer load to tissue at suture anchor points. Here, we predict that adhesive-coated sutures can improve mechanical load transfer beyond the range of performance of existing suture methods, thereby strengthening repairs and decreasing the risk of failure. The mechanical properties of suitable adhesives were identified using a shear lag model. Examination of the design space for an optimal adhesive demonstrated requirements for strong adhesion and low stiffness to maximize the strength of the adhesive-coated suture repair construct. To experimentally assess the model, we evaluated single strands of sutures coated with highly flexible cyanoacrylates (Loctite 4903 and 4902), cyanoacrylate (Loctite QuickTite Instant Adhesive Gel), rubber cement, rubber/gasket adhesive (1300 Scotch-Weld Neoprene High Performance Rubber & Gasket Adhesive), an albumin-glutaraldehyde adhesive (BioGlue), or poly(dopamine). As a clinically relevant proof-of-concept, cyanoacrylate-coated sutures were then used to perform a clinically relevant flexor digitorum tendon repair in cadaver tissue. The repair performed with adhesive-coated suture had significantly higher strength compared to the standard repair without adhesive. Notably, cyanoacrylate provides strong adhesion with high stiffness and brittle behavior, and is therefore not an ideal adhesive for enhancing suture repair. Nevertheless, the improvement in repair properties in a clinically relevant setting, even using a non-ideal adhesive, demonstrates the potential for the proposed approach to improve outcomes for treatments requiring suture fixation. Further study is necessary to develop a strongly adherent, compliant adhesive within the optimal design space described by the model. PMID:26022966

Intracranial current density (LORETA) differences in QEEG frequency bands between depressed and non-depressed alcoholic patients.

PubMed

Coutin-Churchman, Pedro; Moreno, Rocío

2008-04-01

To assess possible differences in intracranial source distribution of surface QEEG power between depressed and non-depressed alcoholic patients in order to find any symptom-related topographic features of physiopathologic relevance. Low-Resolution Electromagnetic Tomography (LORETA) for the delta, theta, alpha and beta bands of EEG spectra was estimated from 38 alcoholic patients, 20 with and 18 without clinical depression, in which QEEG showed decreased slow and increased beta activity diffusely. Statistical non-parametric mapping was used to compare depressed and non-depressed groups. Measures of intracranial current density in individual patients at areas of significant differences were correlated with BDI scores. Patients with clinical depression showed areas of significantly lower current density than non-depressed patients in delta band at left anterior temporal, left midtemporal (including amygdala and hippocampus), and both frontopolar cortices mostly on the right; and in theta band at bilateral parietal lobe, anterior cingulate and medial frontal cortex. No differences were found at alpha and beta band. Intracranial current density in delta band at left parahippocampal, left midfrontal cortex and right frontopolar cortex was negatively correlated with BDI score. Theta band also showed negative correlations with BDI at sites of significant differences. Diffusely decreased delta and theta activity in the surface QEEG of alcoholic patients has a different intracranial distribution linked to the presence or not of clinical depression that seems to reveal a dysfunctional neuronal state at several specific limbic and other cortical locations that have been related to a specific clinical disorder such as depression. These results provided further evidence on the effects of depression in the context of alcohol dependence, in this case decreased slow activity as a possible marker of neuronal damage secondary to alcohol toxicity, clinically expressed as depressive symptoms when present in structures that are known to be related to clinical depression.

Evaluation and Management of Vaginitis

PubMed Central

Carr, Phyllis L; Felsenstein, Donna; Friedman, Robert H

1998-01-01

OBJECTIVE To evaluate recent advances in our understanding of the clinical relevance, diagnosis, and treatment of vaginal infections, and to determine an efficient and effective method of evaluating this clinical problem in the outpatient setting. DATA SOURCES Relevant papers on vaginitis limited to the English language obtained through a MEDLINE search for the years 1985 to 1997 were reviewed. DATA SYNTHESIS Techniques that enable the identification of the various strains of candida have helped lead to a better understanding of the mechanisms of recurrent candida infection. From this information a rationale for the treatment of recurrent disease can be developed. Bacterial vaginosis has been associated with complications, including upper genital tract infection, preterm delivery, and wound infection. Women undergoing pelvic surgery, procedures in pregnancy, or pregnant women at risk of preterm delivery should be evaluated for bacterial vaginosis to decrease the rate of complications associated with this condition. New, more standardized criteria for the diagnosis of bacterial vaginosis may improve diagnostic consistency among clinicians and comparability of study results. Use of topical therapies in the treatment of bacterial vaginosis are effective and associated with fewer side effects than systemic medication. Trichomonas vaginalis, although decreasing in incidence, has been associated with upper genital tract infection. Therapy of T. vaginalis infection has been complicated by an increasing incidence of resistance to metronidazole. CONCLUSIONS Vaginitis is a common medical problem in women that is associated with significant morbidity and previously unrecognized complications. Research in recent years has improved diagnostic tools as well as treatment modalities for all forms of vaginitis. PMID:9613891

The Oral Histone Deacetylase Inhibitor ITF2357 Reduces Cytokines and Protects Islet β Cells In Vivo and In Vitro

PubMed Central

Lewis, Eli C; Blaabjerg, Lykke; Størling, Joachim; Ronn, Sif G; Mascagni, Paolo; Dinarello, Charles A; Mandrup-Poulsen, Thomas

2011-01-01

In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1β (IL-1β), IL-12, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ); each contribute to β-cell destruction, mediated in part by nitric oxide. Inhibitors of histone deacetylases (HDAC) are used commonly in humans but also possess antiinflammatory and cytokine-suppressing properties. Here we show that oral administration of the HDAC inhibitor ITF2357 to mice normalized streptozotocin (STZ)-induced hyperglycemia at the clinically relevant doses of 1.25–2.5 mg/kg. Serum nitrite levels returned to nondiabetic values, islet function improved and glucose clearance increased from 14% (STZ) to 50% (STZ + ITF2357). In vitro, at 25 and 250 nmol/L, ITF2357 increased islet cell viability, enhanced insulin secretion, inhibited MIP-1α and MIP-2 release, reduced nitric oxide production and decreased apoptosis rates from 14.3% (vehicle) to 2.6% (ITF2357). Inducible nitric oxide synthase (iNOS) levels decreased in association with reduced islet-derived nitrite levels. In peritoneal macrophages and splenocytes, ITF2357 inhibited the production of nitrite, as well as that of TNFα and IFNγ at an IC50 of 25–50 nmol/L. In the insulin-producing INS cells challenged with the combination of IL-1β plus IFNγ, apoptosis was reduced by 50% (P < 0.01). Thus at clinically relevant doses, the orally active HDAC inhibitor ITF2357 favors β-cell survival during inflammatory conditions. PMID:21193899

Acute effects of alemtuzumab infusion in patients with active relapsing-remitting MS

PubMed Central

Thomas, Katja; Eisele, Judith; Rodriguez-Leal, Francisco Alejandro; Hainke, Undine

2016-01-01

Objective: Alemtuzumab exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cells. Beyond long-term immunologic and clinical data, little is known about acute changes in immunologic and routine laboratory parameters and their clinical relevance during the initial alemtuzumab infusion. Methods: Fifteen patients with highly active MS were recruited. In addition to parameters including heart rate, blood pressure, body temperature, and monitoring of adverse events, complete blood cell count, liver enzymes, kidney function, acute-phase proteins, serum cytokine profile, complement activation, peripheral immune cell distribution, and their potential of cytokine release were investigated prior to and after methylprednisolone and after alemtuzumab on each day of alemtuzumab infusion. Results: After the first alemtuzumab infusion, both the total leukocyte and granulocyte counts markedly increased, whereas lymphocyte counts dramatically decreased. In addition to lymphocyte depletion, cell subtypes important for innate immunity also decreased within the first week after alemtuzumab infusion. Although patients reported feeling well, C-reactive protein and procalcitonin peaked at serum levels consistent with septic conditions. Increases in liver enzymes were detected, although kidney function remained stable. Proinflammatory serum cytokine levels clearly rose after the first alemtuzumab infusion. Alemtuzumab led to impaired cytokine release ex vivo in nondepleted cells. Normal clinical parameters and mild adverse events were presented. Conclusions: Dramatic immunologic effects were observed. Standardized infusion procedure and pretreatment management attenuated infusion-related reactions. Alemtuzumab-mediated effects led to artificially altered parameters in standard blood testing. We recommend clinical decision-making based on primarily clinical symptoms within the first alemtuzumab treatment week. PMID:27213173

Increased Susceptibility to Chemical Toxicity with Pre-existing ...

EPA Pesticide Factsheets

Numerous host and environmental factors may modulate vulnerability and risk. An area of increasing interest to risk assessors is the potential for chemicals to interact with pre-existing diseases and aging that may yield cumulative damage, altered chemical response, and increased disease susceptibility. We evaluated the relationships between chemicals and pre-existing disease and identify the type of information needed to evaluate the relationships of interest. Key among these is the existence of a clinically relevant and easy to measure biomarker of disease risk which is also modulated by a particular chemical of interest. This biomarker may be a physiological, biochemical, or genetic indicator that corresponds to a phase of the disease process and may be an indicator of where an individual is on the continuum of disease or health status. The relationship between chemical exposure and a biomarker may then be used to predict how preexisting conditions may modify health risks of chemical exposures. Several case studies are explored to describe the toxic chemical, the clinical biomarker, the impacted disease and the evidence that the chemical enhances disease risk: fine particulate matter/decreased heart rate variability/increased cardiopulmonary events; cadmium/decreased glomerular filtration ate/increased chronic kidney disease; methyl mercury/decreased paraoxonase-1/increased cardiovascular risk; Trichloroethylene/increased anti-nuclear antibody/autoimmunit

Hyaluronic Acid Decreases Lipid Synthesis in Sebaceous Glands.

PubMed

Jung, Yu Ra; Hwang, Chul; Ha, Jeong-Min; Choi, Dae-Kyoung; Sohn, Kyung-Cheol; Lee, Young; Seo, Young-Joon; Lee, Young-Ho; Kim, Chang-Deok; Lee, Jeung-Hoon; Im, Myung

2017-06-01

Hyaluronic acid (HA) is the major glycosaminoglycan in the extracellular matrix and has been implicated in several functions in skin cells. However, evidence is lacking regarding the HA signaling in sebaceous glands, and its potential role needs to be clarified. We investigated the role of HA in lipid production in sebaceous glands in an experimental study of human sebocytes followed by a clinical study. We first examined the effects of HA on sebaceous glands in hamsters and intradermal injection of HA into hamster auricles decreased both the size of sebaceous glands and the level of lipid production. We demonstrated that human skin sebaceous glands in vivo and sebocytes in vitro express CD44 (HA binding receptor) and that HA downregulates lipid synthesis in a dose-dependent manner. To evaluate the clinical relevance of HA in human skin, 20 oily participants were included in a double-blind, placebo-controlled, split-face study, and the HA-treated side showed a significant decrease in sebum production. The results of this study indicate that HA plays a functional role in human sebaceous gland biology and HA signaling is an effective candidate in the management of disorders in which sebum production is increased. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Fractal Dimension of EEG Activity Senses Neuronal Impairment in Acute Stroke

PubMed Central

Zappasodi, Filippo; Olejarczyk, Elzbieta; Marzetti, Laura; Assenza, Giovanni; Pizzella, Vittorio; Tecchio, Franca

2014-01-01

The brain is a self-organizing system which displays self-similarities at different spatial and temporal scales. Thus, the complexity of its dynamics, associated to efficient processing and functional advantages, is expected to be captured by a measure of its scale-free (fractal) properties. Under the hypothesis that the fractal dimension (FD) of the electroencephalographic signal (EEG) is optimally sensitive to the neuronal dysfunction secondary to a brain lesion, we tested the FD’s ability in assessing two key processes in acute stroke: the clinical impairment and the recovery prognosis. Resting EEG was collected in 36 patients 4–10 days after a unilateral ischemic stroke in the middle cerebral artery territory and 19 healthy controls. National Health Institute Stroke Scale (NIHss) was collected at T0 and 6 months later. Highuchi FD, its inter-hemispheric asymmetry (FDasy) and spectral band powers were calculated for EEG signals. FD was smaller in patients than in controls (1.447±0.092 vs 1.525±0.105) and its reduction was paired to a worse acute clinical status. FD decrease was associated to alpha increase and beta decrease of oscillatory activity power. Larger FDasy in acute phase was paired to a worse clinical recovery at six months. FD in our patients captured the loss of complexity reflecting the global system dysfunction resulting from the structural damage. This decrease seems to reveal the intimate nature of structure-function unity, where the regional neural multi-scale self-similar activity is impaired by the anatomical lesion. This picture is coherent with neuronal activity complexity decrease paired to a reduced repertoire of functional abilities. FDasy result highlights the functional relevance of the balance between homologous brain structures’ activities in stroke recovery. PMID:24967904

Fractal dimension of EEG activity senses neuronal impairment in acute stroke.

PubMed

Zappasodi, Filippo; Olejarczyk, Elzbieta; Marzetti, Laura; Assenza, Giovanni; Pizzella, Vittorio; Tecchio, Franca

2014-01-01

The brain is a self-organizing system which displays self-similarities at different spatial and temporal scales. Thus, the complexity of its dynamics, associated to efficient processing and functional advantages, is expected to be captured by a measure of its scale-free (fractal) properties. Under the hypothesis that the fractal dimension (FD) of the electroencephalographic signal (EEG) is optimally sensitive to the neuronal dysfunction secondary to a brain lesion, we tested the FD's ability in assessing two key processes in acute stroke: the clinical impairment and the recovery prognosis. Resting EEG was collected in 36 patients 4-10 days after a unilateral ischemic stroke in the middle cerebral artery territory and 19 healthy controls. National Health Institute Stroke Scale (NIHss) was collected at T0 and 6 months later. Highuchi FD, its inter-hemispheric asymmetry (FDasy) and spectral band powers were calculated for EEG signals. FD was smaller in patients than in controls (1.447±0.092 vs 1.525±0.105) and its reduction was paired to a worse acute clinical status. FD decrease was associated to alpha increase and beta decrease of oscillatory activity power. Larger FDasy in acute phase was paired to a worse clinical recovery at six months. FD in our patients captured the loss of complexity reflecting the global system dysfunction resulting from the structural damage. This decrease seems to reveal the intimate nature of structure-function unity, where the regional neural multi-scale self-similar activity is impaired by the anatomical lesion. This picture is coherent with neuronal activity complexity decrease paired to a reduced repertoire of functional abilities. FDasy result highlights the functional relevance of the balance between homologous brain structures' activities in stroke recovery.

Four-week dietary supplementation with 10- and/or 15-fold basal choline caused decreased body weight in Sprague Dawley rats.

PubMed

Bagley, Bradford D; Chang, Shu-Ching; Ehresman, David J; Eveland, Alan; Parker, George A; Peters, Jeffrey M; Butenhoff, John L

2017-10-01

Choline is an essential nutrient utilized for phosphatidylcholine biosynthesis and lipoprotein packaging and secretion. Recently, choline supplementation has been used by athletes and the public for weight loss. However, the potential toxicological impact of choline dietary supplementation requires further investigation. This study examined the effects of choline dietary supplementation in Sprague Dawley rats for 4 weeks. Rats were fed diets containing basal choline levels (control) or 5-, 10-, or 15-fold (5×, 10×, or 15×) basal diet concentration. In groups fed choline-supplemented diets, there were no toxicologically relevant findings in clinical observations, food intake, clinical chemistry, liver weights, or liver histopathology. However, decreased mean body weights (8.5-10.2%) and body weight gains (24-31%) were noted for the 10× choline-supplemented (females only) and 15× choline-supplemented (both sexes) groups relative to the control groups from day 3 onward. These body weight effects were not related to a persistent reduction in average food intake. Serum cholesterol was increased in the 15× choline-supplemented male rats relative to the controls, an expected effect of choline supplementation; however, there were no changes in the serum cholesterol of female rats. Serum choline concentrations were increased in female rats relative to the male rats across all treatment groups. The maximum tolerated dose for male and female rats were the 15× and 10× choline supplements, respectively, based on decreased mean body weight and body weight gains. This study supported the conclusions of a clinical trial that showed a high choline diet can decrease body weight in humans.

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.

Development of an indexed integrated neuroradiology reports for teaching file creation

NASA Astrophysics Data System (ADS)

Tameem, Hussain Z.; Morioka, Craig; Bennett, David; El-Saden, Suzie; Sinha, Usha; Taira, Ricky; Bui, Alex; Kangarloo, Hooshang

2007-03-01

The decrease in reimbursement rates for radiology procedures has placed even more pressure on radiology departments to increase their clinical productivity. Clinical faculties have less time for teaching residents, but with the advent and prevalence of an electronic environment that includes PACS, RIS, and HIS, there is an opportunity to create electronic teaching files for fellows, residents, and medical students. Experienced clinicians, who select the most appropriate radiographic image, and clinical information relevant to that patient, create these teaching files. Important cases are selected based on the difficulty in determining the diagnosis or the manifestation of rare diseases. This manual process of teaching file creation is time consuming and may not be practical under the pressure of increased demands on the radiologist. It is the goal of this research to automate the process of teaching file creation by manually selecting key images and automatically extracting key sections from clinical reports and laboratories. The text report is then processed for indexing to two standard nomenclatures UMLS and RADLEX. Interesting teaching files can then be queried based on specific anatomy and findings found within the clinical reports.

Sacubitril/Valsartan in Clinical Practice: A Report of 2 Cases.

PubMed

Cosentino, Eugenio

Following the results of the PARADIGM-HF trial, the European Society of Cardiology (ESC) guidelines recommend sacubitril/valsartan to replace ACE inhibitors in ambulatory patients with heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal therapy and who fit trial criteria. However, the optimal use of sacubitril/valsartan in clinical practice needs further investigation. We report here the cases of 2 patients with HFrEH successfully treated with sacubitril/valsartan in our daily practice. Both subjects presented multiple comorbidities and received an implantable cardioverter defibrillator in primary prevention. In both patients, therapy with sacubitril/valsartan led to prompt (30 days) amelioration of heart function, with a corresponding decrease in NHYA class and without any relevant safety issue. © 2017 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.

Age-dependent metabolic and immunosuppressive effects of Tacrolimus

PubMed Central

Krenzien, Felix; Quante, Markus; Heinbokel, Timm; Seyda, Midas; Minami, Koichiro; Uehara, Hirohito; Biefer, Hector Rodriguez Cetina; Schuitenmaker, Jeroen M.; Gabardi, Steven; Splith, Katrin; Schmelzle, Moritz; Petrides, Athena K.; Azuma, Haruhito; Pratschke, Johann; Li, Xian C.; ElKhal, Abdallah; Tullius, Stefan G.

2016-01-01

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor Tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T-cells. Old recipient mice exhibited prolonged skin graft survival when compared to young animals following TAC administration. More importantly, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce pro-inflammatory IFN-γ cytokine production and promote IL-10 production in old CD4+ T-cells. In addition, TAC administration decreased IL-2 secretion in old CD4+ T-cells more effectively while inhibiting the proliferation of CD4+ T-cells in old mice. Both, TAC treated murine and human CD4+ T-cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca2+-influx, two critical pathways in T-cell activation. Of note, depletion of CD8+ T-cells did not alter allograft survival outcome in old TAC treated mice, suggesting that TAC age-specific effects were mainly CD4+ T-cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4+ T-cell mediated. The suppression of calcineurin levels and Ca2+-influx in both, old murine and human T-cells emphasizes on the clinical relevance of age-specific effects when utilizing TAC. PMID:27754593

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.

The effect of grapefruit juice on drug disposition

PubMed Central

Hanley, Michael J.; Cancalon, Paul; Widmer, Wilbur W.; Greenblatt, David J.

2011-01-01

Introduction Since their initial discovery in 1989, grapefruit juice-drug interactions have received extensive interest from the scientific, medical, regulatory, and lay communities. Although knowledge regarding the effects of grapefruit juice on drug disposition continues to expand, the list of drugs studied in the clinical setting remains relatively limited. Areas covered This article reviews the in vitro effects of grapefruit juice and its constituents on the activity of cytochrome P450 enzymes, organic anion-transporting polypeptides, P-glycoprotein, esterases and sulfotransferases. The translational applicability of the in vitro findings to the clinical setting is discussed for each drug metabolizing enzyme and transporter. Reported area under the plasma concentration-time curve ratios for available grapefruit juice-drug interaction studies are also provided. Relevant investigations were identified by searching the Pubmed electronic database from 1989 to 2010. Expert opinion Grapefruit juice increases the bioavailability of some orally-administered drugs that are metabolized by CYP3A and normally undergo extensive presystemic extraction. In addition, grapefruit juice can decrease the oral absorption of a few drugs that rely on organic anion-transporting polypeptides in the gastrointestinal tract for their uptake. The number of drugs shown to interact with grapefruit juice in vitro is far greater than the number of clinically relevant grapefruit juice-drug interactions. For the majority of patients, complete avoidance of grapefruit juice is unwarranted. PMID:21254874

Factors influencing adherence to psychopharmacological medications in psychiatric patients: a structural equation modeling approach.

PubMed

De Las Cuevas, Carlos; de Leon, Jose; Peñate, Wenceslao; Betancort, Moisés

2017-01-01

To evaluate pathways through which sociodemographic, clinical, attitudinal, and perceived health control variables impact psychiatric patients' adherence to psychopharmacological medications. A sample of 966 consecutive psychiatric outpatients was studied. The variables were sociodemographic (age, gender, and education), clinical (diagnoses, drug treatment, and treatment duration), attitudinal (attitudes toward psychopharmacological medication and preferences regarding participation in decision-making), perception of control over health (health locus of control, self-efficacy, and psychological reactance), and level of adherence to psychopharmacological medications. Structural equation modeling was applied to examine the nonstraightforward relationships and the interactive effects among the analyzed variables. Structural equation modeling demonstrated that psychiatric patients' treatment adherence was associated: 1) negatively with cognitive psychological reactance (adherence decreased as cognitive psychological reactance increased), 2) positively with patients' trust in their psychiatrists (doctors' subscale), 3) negatively with patients' belief that they are in control of their mental health and that their mental health depends on their own actions (internal subscale), and 4) positively (although weakly) with age. Self-efficacy indirectly influenced treatment adherence through internal health locus of control. This study provides support for the hypothesis that perceived health control variables play a relevant role in psychiatric patients' adherence to psychopharmacological medications. The findings highlight the importance of considering prospective studies of patients' psychological reactance and health locus of control as they may be clinically relevant factors contributing to adherence to psychopharmacological medications.

Er:YAG laser in the treatment of periodontal sites with recurring chronic inflammation: a 12-month randomized, controlled clinical trial.

PubMed

Krohn-Dale, Ivar; Bøe, Olav E; Enersen, Morten; Leknes, Knut N

2012-08-01

The objective of this randomized, controlled clinical trial was to compare the clinical and microbiological effects of pocket debridement using erbium-doped: yttrium, aluminium and garnet (Er:YAG) laser with conventional debridement in maintenance patients. Fifteen patients, all smokers, having at least four teeth with residual probing depth (PD) ≥ 5 mm were recruited. Two pockets in two jaw quadrants were randomly assigned to subgingival debridement using an Er:YAG laser (test) or ultrasonic scaler/curette (control) at 3-month intervals. Relative attachment level (RAL), PD, bleeding on probing and dental plaque were recorded at baseline and at 6 and 12 months. Microbiological subgingival samples were taken at the same time points and analysed using a checkerboard DNA-DNA hybridization technique. A significant decrease in PD took place in both treatments from baseline to 12 months (p < 0.01). In the control, the mean initial PD decreased from 5.4 to 4.0 mm at 12 months. For the test, a similar decrease occurred. No significant between-treatment differences were shown at any time point. The mean RAL showed no overall significant inter- or intra-treatment differences (p > 0.05). No significant between-treatment differences were observed in subgingival microbiological composition or total pathogens. The results failed to support that an Er:YAG laser may be superior to conventional debridement in the treatment of smokers with recurring chronic inflammation. This appears to be the first time that repeated Er-YAG laser instrumentation has been compared with mechanical instrumentation of periodontal sites with recurring chronic inflammation over a clinically relevant time period. © 2012 John Wiley & Sons A/S.

Improved blood utilization using real-time clinical decision support.

PubMed

Goodnough, Lawrence T; Shieh, Lisa; Hadhazy, Eric; Cheng, Nathalie; Khari, Paul; Maggio, Paul

2014-05-01

We analyzed blood utilization at Stanford Hospital and Clinics after implementing real-time clinical decision support (CDS) and best practice alerts (BPAs) into physician order entry (POE) for blood transfusions. A clinical effectiveness (CE) team developed consensus with a suggested transfusion threshold of a hemoglobin (Hb) level of 7 g/dL, or 8 g/dL for patients with acute coronary syndromes. The CDS was implemented in July 2010 and consisted of an interruptive BPA at POE, a link to relevant literature, and an "acknowledgment reason" for the blood order. The percentage of blood ordered for patients whose most recent Hb level exceeded 8 g/dL ranged at baseline from 57% to 66%; from the education intervention by the CE team August 2009 to July 2010, the percentage decreased to a range of 52% to 56% (p = 0.01); and after implementation of CDS and BPA, by end of December 2010 the percentage of patients transfused outside the guidelines decreased to 35% (p = 0.02) and has subsequently remained below 30%. For the most recent interval, only 27% (767 of 2890) of transfusions occurred in patients outside guidelines. Comparing 2009 to 2012, despite an increase in annual case mix index from 1.952 to 2.026, total red blood cell (RBC) transfusions decreased by 7186 units, or 24%. The estimated net savings for RBC units (at $225/unit) in purchase costs for 2012 compared to 2009 was $1,616,750. Real-time CDS has significantly improved blood utilization. This system of concurrent review can be used by health care institutions, quality departments, and transfusion services to reduce blood transfusions. © 2013 American Association of Blood Banks.

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.

Clinical efficacy and safety of mesenchymal stem cell transplantation for osteoarthritis treatment: A meta-analysis

PubMed Central

Li, Li; Tao, Sun; Bo, Lin; Lin, Chen

2017-01-01

Purpose The aim of this study was to evaluate the therapeutic efficacy and safety of mesenchymal stem cells (MSCs) for the treatment of patients with knee osteoarthritis (OA). Materials We performed a meta-analysis of relevant published clinical studies. An electronic search was conducted for randomized controlled trials (RCTs) of MSC-based therapy in knee OA. The visual analogue scale (VAS), International Knee Documentation Committee (IKDC) form, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne algofunctional indices (Lequesne), Lysholm knee scale (Lysholm), Tegner activity scale (Tegner) and adverse events (AEs) were evaluated. Results Eleven eligible trials with 582 knee OA patients were included in the present meta-analysis. We demonstrated that MSC treatment could significantly decrease VAS and increase IKDC scoresafter a 24-month follow-up compared with controls (P<0.05). MSC therapy also showed significant decreases in WOMAC and Lequesne scores after the 12-month follow-up (P<0.01). Analysis of Lysholm (24-month) and Tegner (12- and 24-month) scores also demonstrated favorable results for MSC treatment (P<0.05). Conclusion Overall, MSC transplantation treatment was shown to be safe and has great potential as an efficacious clinical therapy for patients with knee OA. PMID:28448518

Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration.

PubMed

Teixeira-da-Cunha, Mariana G A; Gomes, Rachel N; Roehrs, Nathassia; Bozza, Fernando A; Prescott, Stephen M; Stafforini, Diana; Zimmerman, Guy A; Bozza, Patricia T; Castro-Faria-Neto, Hugo C

2013-01-01

Current evidence indicates that dysregulation of the host inflammatory response to infectious agents is central to the mortality of patients with sepsis. Strategies to block inflammatory mediators such as PAF have been investigated as adjuvant therapies for sepsis. PAF-AH, the enzyme responsible for PAF degradation, showed positive results in pre-clinical studies and phase II clinical trials, but the results of a phase III study were disappointing. In this study, we investigated the potential protective mechanism of PAF-AH in sepsis using the murine model of cecal ligation and puncture (CLP). Treatment with rPAF-AH increased peritoneal fluid levels of the anti-inflammatory mediators MCP-1/CCL2 after CLP. The numbers of bacteria (CFU) in the peritoneal cavity were decreased in the rPAF-AH-treated group, indicating more efficient bacterial clearance after rPAF-AH treatment. Interestingly, we observed increased levels of nitric oxide (NO) after PAF-AH administration, and rPAF-AH treatment did not decrease CFU numbers either in iNOS-deficient mice or in CCR2-deficient mice. We concluded that administration of exogenous rPAF-AH reduced inflammatory injury, altered cytokine levels and favored bacterial clearance with a clear impact on mortality through modulation of MCP-1/CCL2 and NO levels in a clinically relevant sepsis model.

Gemfibrozil in Combination with Statins-Is It Really Contraindicated?

PubMed

Wiggins, Barbara S; Saseen, Joseph J; Morris, Pamela B

2016-04-01

Gemfibrozil is a lipid-modifying agent that belongs to the fibric acid derivative class. Fibric acid derivatives activate peroxisome proliferator activated receptor α (PPAR-α). The primary role of these agents in clinical practice is for the management of hypertriglyceridemia. Triglycerides may be reduced by as much as 74 % in some patients. In addition to lowering triglycerides, these agents can also decrease very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) as well as raise high-density lipoprotein cholesterol (HDL-C). Based on the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults and the National Lipid Association, pharmacologic therapy to reduce triglycerides should be considered when triglyceride levels are ≥500 mg/dL. While the use of gemfibrozil has decreased over the years for a variety of reasons, muscle-associated adverse effects is the predominant reason and the one that is most clinically relevant. However, despite these concerns, there are situations in which the use of gemfibrozil in combination with a statin may be necessary. Understanding the metabolism of gemfibrozil and the degree of interaction with the various statins will assist health-care providers to optimize safety when this combination is clinically indicated.

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.

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.

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

Teaching surgical exposures to undergraduate medical students: an integration concept for anatomical and surgical education.

PubMed

Hammer, Niels; Hepp, Pierre; Löffler, Sabine; Schleifenbaum, Stefan; Steinke, Hanno; Klima, Stefan

2015-06-01

Decreasing numbers of students are interested in starting a surgical career, posing substantial challenges to patient care in the next years. The anatomy course is one of the key subjects in medical training, especially in surgical disciplines. Innovative teaching concepts that integrate surgically relevant anatomy and manual dexterity might help boost student interest in surgery. A preclinical workshop entitled "Surgical exposures" was developed. A team of anatomists and surgeons introduced the surgical exposures, demonstrating the procedures on Thiel-fixed body donors. Following this introduction, students practiced the exposures in an operating room-like manner. A six-point Likert scale was used to evaluate the workshop and to compare it to the first-year dissection course. The overall evaluation result for the surgical exposures was excellent, proving to be a significantly better result when compared to the first-year dissection course. The students were more satisfied with the teaching time invested by the peers and regarded the workshop as clinically highly relevant. Furthermore, they felt that questions were addressed better and that the overall atmosphere was better than in the gross anatomy course. Subject to criticism was the course size and practicing time in both cases. The surgical exposures workshop provides preclinical students with clinically relevant anatomy and manual dexterity. It may positively influence the decision to follow a surgical career. This course, however, requires extensive teaching resources. The given concept may help implement practical medical skills in the preclinical curriculum, strengthening the professional identity of surgeons and anatomists.

Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects.

PubMed

Gan, Lu; Jiang, Xuemin; Mendonza, Anisha; Swan, Therese; Reynolds, Christine; Nguyen, Joanne; Pal, Parasar; Neelakantham, Srikanth; Dahlke, Marion; Langenickel, Thomas; Rajman, Iris; Akahori, Mizuki; Zhou, Wei; Rebello, Sam; Sunkara, Gangadhar

2016-01-01

LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 μg single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions. © 2015, The American College of Clinical Pharmacology.

Preliminary development of a diabetic foot ulcer database from a wound electronic medical record: a tool to decrease limb amputations.

PubMed

Golinko, Michael S; Margolis, David J; Tal, Adit; Hoffstad, Ole; Boulton, Andrew J M; Brem, Harold

2009-01-01

Our objective was to create a practical standardized database of clinically relevant variables in the care of patients with diabetes and foot ulcers. Numerical clinical variables such as age, baseline laboratory values, and wound area were extracted from the wound electronic medical record (WEMR). A coding system was developed to translate narrative data, culture, and pathology reports into discrete, quantifiable variables. Using data extracted from the WEMR, a diabetic foot ulcer-specific database incorporated the following tables: (1) demographics, medical history, and baseline laboratory values; (2) vascular testing data; (3) radiology data; (4) wound characteristics; and (5) wound debridement data including pathology, culture results, and amputation data. The database contains variables that can be easily exported for analysis. Amputation was studied in 146 patients who had at least two visits (e.g., two entries in the database). Analysis revealed that 19 (13%) patients underwent 32 amputations (nine major and 23 minor) in 23 limbs. There was a decreased risk of amputation, 0.87 (0.78, 1.00), using a proportional hazards model, associated with an increased number of visits and entries in the WEMR. Further analysis revealed no significant difference in age, gender, HbA1c%, cholesterol, white blood cell count, or prealbumin at baseline, whereas hemoglobin and albumin were significantly lower in the amputee group (p<0.05) than the nonamputee group. Fifty-nine percent of amputees had histological osteomyelitis based on operating room biopsy vs. 45% of nonamputees. In conclusion, tracking patients with a WEMR is a tool that could potentially increase patient safety and quality of care, allowing clinicians to more easily identify a nonhealing wound and intervene. This report describes a method of capturing data relevant to clinical care of a patient with a diabetic foot ulcer, and may enable clinicians to adapt such a system to their own patient population.

SURFACTANT DYSFUNCTION IN LUNG CONTUSION WITH AND WITHOUT SUPERIMPOSED GASTRIC ASPIRATION IN A RAT MODEL

PubMed Central

Raghavendran, Krishnan; Davidson, Bruce A.; Knight, Paul R.; Wang, Zhengdong; Helinski, Jadwiga; Chess, Patricia R.; Notter, Robert H.

2009-01-01

This study investigates surfactant dysfunction in rats with lung contusion (LC) induced by blunt chest trauma. Rats at 24 h postcontusion had a decreased percent content of large surfactant aggregates in cell-free bronchoalveolar lavage (BAL) and altered large-aggregate composition with decreased phosphatidylcholine (PC), increased lyso-PC, and increased protein compared with uninjured controls. The surface activity of large aggregates on a pulsating bubble surfactometer was also severely impaired at 24 h postcontusion. Decreases in large surfactant aggregate content and surface activity were improved, but still apparent, at 48 and 72 h postcontusion compared with uninjured control rats and returned to normal by 96 h postcontusion. The functional importance of surfactant abnormalities in LC injury was documented in pilot studies showing that exogenous surfactant replacement at 24 h postcontusion improved inflation/deflation lung volumes. Additional experiments investigated a clinically relevant combination of LC plus gastric aspiration (combined acid and small gastric food particles) and found reductions in large surfactant aggregates in BAL similar to those for LC. However, rats given LC + combined acid and small gastric food particles versus LC had more severe surfactant dysfunction based on decreases in surface activity and alterations in large aggregate composition. Combined data for all animal groups had strong statistical correlations between surfactant dysfunction (increased minimum surface tension, decreased large aggregates in BAL, decreased aggregate PC, and increased aggregate lyso-PC) and the severity of inflammatory lung injury (increased total protein, albumin, protein/phospholipid ratio, neutrophils, and erythrocytes in BAL plus increased whole lung myeloperoxidase activity). These results show that surfactant dysfunction is important in the pathophysiology of LC with or without concurrent gastric aspiration and provides a rationale for surfactant replacement therapy in these prevalent clinical conditions. PMID:18323743

Peripheral White Blood Cell Subsets in Metastatic Colorectal Cancer Patients Treated with Cetuximab: The Potential Clinical Relevance.

PubMed

Matić, Ivana Z; Kolundžija, Branka; Damjanović, Ana; Spasić, Jelena; Radosavljević, Davorin; Đorđić Crnogorac, Marija; Grozdanić, Nađa; Juranić, Zorica D

2017-01-01

It was demonstrated that cetuximab-induced tumor regression is based on the effects exerted by immune cells included mainly in the innate immune response. Therefore, the focus of this study was to explore the alterations in the percentages of CD16+, and/or CD56+ lymphocytes, which are comprised of NK cells, and minority of CD56+CD3+ cells, in patients with metastatic colorectal cancer before or 2 months after the treatment with cetuximab-based regimens associated with the response to therapy. The changes in the percentages of lymphocytes and granulocytes in these patients were evaluated as well. We enrolled 50 patients with wild-type KRAS metastatic colorectal cancer. Disease progression was observed in 11/50 patients (non-responders), while other patients achieved partial response or stable disease (responders). Control groups included up to 72 healthy individuals. A significant decrease in the percentages of CD56+ and CD16+CD56+ lymphocytes together with a significant decrease in the percentage of lymphocytes and an increase in the ratio of granulocyte to lymphocyte percentages were observed in patients with metastatic colorectal cancer before therapy, compared with those in the healthy individuals. In contrast to those in the responders, the percentage of CD16+ lymphocytes in the overall white blood cell pool was shown to be significantly decreased in the non-responders, together with a significantly decreased percentage of lymphocytes, a significantly increased percentage of granulocytes, and an increased ratio of granulocyte to lymphocyte percentages before treatment compared with those in the healthy controls. Two months after the initiation of the treatment, significantly decreased percentages of CD16+, CD56+, and CD16+CD56+ lymphocytes were observed in patients, compared with those determined in the healthy controls. The same changes in the amounts of circulating immune cells were also observed in the responder subgroup, but the percentages of CD16+, CD56+, and CD16+CD56+ lymphocytes 2 months after treatment in the non-responder group did not differ significantly in comparison with healthy individuals. Considerable alterations of immune cell percentages observed in patients with metastatic colorectal cancer with disease progression indicate that the assessment of peripheral white blood cell architecture before treatment initiation may be clinically relevant.

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.

Clindamycin phosphate-tretinoin combination gel revisited: status report on a specific formulation used for acne treatment.

PubMed

Del Rosso, James Q

2017-03-01

Topical agents, including retinoids and antibiotics, are commonly used to treat acne vulgaris (AV) and remain as components of acne treatment guidelines. Approved topical combination formulations offer the advantages of established efficacy, decreased frequency of application, and improved convenience for patients. This article discusses both clindamycin phosphate (CP) and tretinoin (Tret) as components of a topical aqueous-based combination gel that has been shown to be effective, safe, and well tolerated for treatment of facial AV. Clinically relevant considerations with use of this treatment are also discussed, including therapeutic advantages and potential limitations.

Herb-drug interaction: a case study of effect of ginger on the pharmacokinetic of metronidazole in rabbit.

PubMed

Okonta, J M; Uboh, M; Obonga, W O

2008-01-01

The effect of ginger on the pharmacokinectic of metronidazole was studied using rabbits in a crossover study method. The relevance of this study borders on the wide use of ginger for culinary and phytotherapeutic purposes, and metronidazole that is commonly used for every gastrointestinal complain in our communities without prescription. Ginger significantly increased the absorption and plasma half-life, and significantly decreased the elimination rate constant and clearance of metronidazole (P<0.05). Thus, in clinical practice, the patients should be advised on the serious implication of using both items together.

Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach

PubMed Central

Klimant, E.; Wright, H.; Rubin, D.; Seely, D.; Markman, M.

2018-01-01

This article reviews intravenous vitamin C (IV C) in cancer care and offers a rational approach to enable medical oncologists and integrative practitioners to safely provide IV C combined with oral vitamin C to patients. The use of IV C is a safe supportive intervention to decrease inflammation in the patient and to improve symptoms related to antioxidant deficiency, disease processes, and side effects of standard cancer treatments. A proposed rationale, together with relevant clinical safety considerations for the application of IV C in oncologic supportive care, is provided. PMID:29719430

[The blood-brain barrier in ageing persons].

PubMed

Haaning, Nina; Damsgaard, Else Marie; Moos, Torben

2018-03-26

Brain capillary endothelial cells (BECs) form the ultra-tight blood-brain barrier (BBB). The permeability of the BBB increases with increasing age and neurovascular and neurodegenerative diseases. Major defects of the BBB can be initiated by increased permeability to plasma proteins in small arteriosclerotic arteries and release of proteins from degenerating neurons into the brain extracellular space. These proteins deposit in perivascular spaces, and subsequently negatively influence the BECs leading to decreased expression of barrier proteins. Detection of BBB defects by the use of non-invasive techniques is relevant for clinical use in settings with advanced age and severe brain disorders.

Classic and nonclassic HLA class I expression in penile cancer and relation to HPV status and clinical outcome.

PubMed

Djajadiningrat, Rosa S; Horenblas, Simon; Heideman, Daniëlle A M; Sanders, Joyce; de Jong, Jeroen; Jordanova, Ekaterina S

2015-04-01

Loss of expression of HLA class I is a mechanism of immune evasion in various cancers that is often associated with a worse patient outcome. We analyzed HLA expression in a large cohort with penile cancer in relation to clinical outcome. We used penile cancer tissue blocks from 168 patients who underwent surgical resection between 2000 and 2009 to construct tissue microarrays. Immunohistochemical staining was done with antibodies directed against classic and nonclassic HLA molecules. HLA expression was scored semiquantitatively, divided into 3 expression groups and correlated with clinicopathological variables, including HPV and survival. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards models. Complete and partial loss of total classic HLA class I was observed in 32% and 50% of cases, and up-regulation of HLA-E and G in 16% and 13%, respectively. When corrected for relevant clinical parameters, partial HLA-A loss was significantly associated with decreased survival overall (HR 2.3, 95% CI 1.1-4.6) and in HPV negative patients alone (HR 3.4, 95% CI 1.4-8.4). Abnormal HLA-B/C, E or G expression levels were not associated with survival. To our knowledge this is the first study to describe a link between HLA expression and the clinical outcome of penile cancer. HLA down-regulation occurs frequently and partial loss of HLA-A is an independent predictor of poor survival in HPV negative patients. Complete understanding of the mechanisms and relevance of HLA down-regulation and immune evasion in regard to the clinical outcome will contribute to the future design of immunotherapy interventions. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

An open-label tolerability study of BL-1020 antipsychotic: a novel gamma aminobutyric acid ester of perphenazine.

PubMed

Anand, Ravi; Geffen, Yona; Vasile, Daniel; Dan, Irina

2010-01-01

BL-1020, a novel gamma aminobutyric acid (GABA) ester of perphenazine, is a new oral antipsychotic with a strong affinity for dopamine and serotonin receptors. Unlike first- and second-generation antipsychotics, it has agonist activity at GABA(A). This is the first study to examine tolerability and safety of BL-1020 in schizophrenia. This was a phase-II, open-label, multicenter, 6-week study treating patients (n = 36) with chronic schizophrenia. Dosing started at 20 mg/d and increased over 7 days to 40 mg/d. Weekly assessments were conducted. All but 1 patient was titrated to 30 mg/d at day 4; on day 7, 30 were titrated to 40 mg/d. Four patients discontinued the study prematurely. There was no clinically relevant increase in vital signs, sedation, dizziness, or other central nervous system effects or electrocardiogram or laboratory abnormalities and a small increase in weight. Ten patients experienced extrapyramidal symptoms (EPS) requiring treatment with an anticholinergic; 4 patients were unable to reach maximum dose because of EPS. Extrapyramidal Symptom Rating Scale did not indicate clinically significant changes in EPS. The most common adverse event was insomnia (6 patients); other frequent adverse effects (all n = 3) were extrapyramidal disorder, headache, parkinsonism, tremor, and hyperprolactinemia. There was improvement on Positive and Negative Syndrome Scale and Clinical Global Impression of Change with 22 patients showing at least 20% decrease by end point on Positive and Negative Syndrome Scale and 31 patients showing at least minimal improvement on Clinical Global Impression of Change. These data suggest that 20 to 40 mg/d of BL-1020 is associated with clinically relevant improvement of psychosis with no worsening of EPS and support further testing in randomized controlled trials.

Truly selective primary IgM deficiency is probably very rare.

PubMed

Janssen, L M A; Macken, T; Creemers, M C W; Pruijt, J F M; Eijk, J J J; de Vries, E

2018-02-01

Isolated decreased serum-immunoglobulin (Ig)M has been associated with severe and/or recurrent infections, atopy and autoimmunity. However, the reported high prevalence of clinical problems in IgM-deficient patients may reflect the skewed tertiary centre population studied so far. Also, many papers on IgM deficiency have included patients with more abnormalities than simply IgM-deficiency. We studied truly selective primary IgM deficiency according to the diagnostic criteria of the European Society for Immunodeficiencies (ESID) (true sIgMdef) by reviewing the literature (261 patients with primary decreased serum-IgM in 46 papers) and analysing retrospectively all patients with decreased serum-IgM in a large teaching hospital in 's-Hertogenbosch, the Netherlands [1 July 2005-23 March 2016; n = 8049 IgM < 0·4 g/l; n = 2064 solitary (IgG+IgA normal/IgM < age-matched reference)]. A total of 359 of 2064 (17%) cases from our cohort had primary isolated decreased serum-IgM, proven persistent in 45 of 359 (13%) cases; their medical charts were reviewed. Our main finding is that true sIgMdef is probably very rare. Only six of 261 (2%) literature cases and three of 45 (7%) cases from our cohort fulfilled the ESID criteria completely; 63 of 261 (24%) literature cases also had other immunological abnormalities and fulfilled the criteria for unclassified antibody deficiencies (unPAD) instead. The diagnosis was often uncertain (possible sIgMdef): data on IgG subclasses and/or vaccination responses were lacking in 192 of 261 (74%) literature cases and 42 of 45 (93%) cases from our cohort. Our results also illustrate the clinical challenge of determining the relevance of a serum sample with decreased IgM; a larger cohort of true sIgMdef patients is needed to explore fully its clinical consequences. The ESID online Registry would be a useful tool for this. © 2017 British Society for Immunology.

Limited stability of thiopurine metabolites in blood samples: relevant in research and clinical practise.

PubMed

de Graaf, P; Vos, R M; de Boer, N H K; Sinjewel, A; Jharap, B; Mulder, C J J; van Bodegraven, A A; Veldkamp, A I

2010-06-01

Monitoring of thiopurine metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) is used to assess compliance and explain adverse reactions in IBD-patients. Correlations between dosage, metabolite concentrations and therapeutic efficacy or toxicity are contradictive. Research is complicated by analytical problems as matrices analyzed and analytical procedures vary widely. Moreover, stability of thiopurine metabolites is not well documented, yet pivotal for interpretation of analytical outcomes. Therefore, we prospectively investigated metabolite stability in blood samples under standard storage conditions. Stability at room temperature and refrigeration (22 degrees C, 4 degrees C) was investigated during 1 week and frozen samples (-20 degrees C, -80 degrees C) were analyzed during 6 months storage. Ten patient samples were analyzed for each study period. Median 6-TGN concentrations on day 7 decreased significantly to 53% and 90% during storage at ambient temperature or refrigeration. Median 6-MMP concentrations on day 7 decreased significantly to 55% and 86%, respectively. Samples stored at -20 degrees C also showed significant decreases in both 6-TGN and 6-MMP in comparison with baseline values. At -80 degrees C, only 6-MMP showed a significant decrease in values compared to baseline. The stability of thiopurine metabolites is clearly a limiting factor in studies investigating utilisation of TDM and correlations with therapeutic outcome in IBD-patients. This has to be accounted for in clinical practice and (multi-center) trials investigating thiopurine drugs. Copyright 2010. Published by Elsevier B.V.

Clinical study on the unloading effect of hip bracing on gait in patients with hip osteoarthritis.

PubMed

Nérot, Agathe; Nicholls, Micah

2017-04-01

Internal hip abduction moment is a major indicator for hip loading. A new hip bracing concept was designed to unload the cartilaginous area in hip osteoarthritis via an abduction and external rotation force intended to alter the weight bearing area and reduce compression through the joint. To assess the effect of a novel brace on hip rotation in the transverse and coronal planes and on the hip abduction moment. Repeated measures. Gait analysis was performed on 14 subjects with unilateral symptomatic hip osteoarthritis. Pain, joint motion, moments and vertical ground reaction force were compared between the braced and the unbraced (control), randomly assigned, conditions. Nine participants felt an immediate reduction in pain while walking with the hip brace. Peak hip abduction moment significantly decreased on the osteoarthritis side ( p = 0.017). Peak hip adduction ( p = 0.004) and internal rotation ( p = 0.0007) angles significantly decreased at stance with the brace. Wearing the brace would appear to reduce the compressive joint reaction force at the femuroacetabular interface as indicated by a reduction in internal hip abduction moment along with immediate pain reduction in nine participants. Further long-term studies are warranted. Clinical relevance The brace rotates the hip in the transverse and coronal planes, possibly resulting in a decrease in load through the diseased area of cartilage. In some patients, an immediate decrease in pain was experienced. The brace offers an alternative solution for hip osteoarthritis patients not ready for a hip replacement.

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.

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.

Antiproliferative and Apoptotic Effects of Lidocaine on Human Hepatocarcinoma Cells. A preliminary study.

PubMed

Jurj, Ancuta; Tomuleasa, Ciprian; Tat, Tiberiu T; Berindan-Neagoe, Ioana; Vesa, Stefan V; Ionescu, Daniela C

2017-03-01

It is now well documented that certain anesthetic techniques may influence long term outcome in cancer patients undergoing surgery. More recently, local anesthetics proved certain antiproliferative effects in cancer cells. In our study, we aimed to investigate if lidocaine has antiproliferative effects in human hepatocarcinoma cells and to identify possible mechanisms of these effects. We investigated the inhibitory effect of different concentrations of lidocaine on the proliferation of cultured HepG2 human hepatocarcinoma cells and LX2 normal liver fibroblasts. Cells were exposed to nine different concentrations of lidocaine for 72h. MTT assay was used to investigate HepG2 and LX2 proliferation while Western blotting was used for detection of p53 expression level. Our data showed that lidocaine inhibited cell proliferation in a concentration-dependent manner in both HepG2 and LX2. The antiproliferative effects of lidocaine in LX2 were significantly diminished as compared with those in HepG2 (p< 0.001). Similarly, the expression level of p53 was significant decreased in HepG2 lines treated with lidocaine as compared with control and LX2 (p = 0.0241). In clinically relevant concentrations, lidocaine had significant antiproliferative effects on human hepatocarcinoma cells. These effects were time and dose-dependent. One of the possible mechanisms of these effects is by modifying the P53 expression level. The relevance of these findings in clinical practice is limited; clinical impact of these effects on the outcome of patients with hepatocarcinoma undergoing surgery or minimal invasive procedures needs to be demonstrated in future animal models and clinical studies.

Challenges and promises in the development of neurotrophic factor-based therapies for Parkinson's disease.

PubMed

Rodrigues, Tiago Martins; Jerónimo-Santos, André; Outeiro, Tiago Fleming; Sebastião, Ana Maria; Diógenes, Maria José

2014-04-01

Parkinson's disease (PD) is a chronic movement disorder typically coupled to progressive degeneration of dopaminergic neurons in the substantia nigra (SN). The treatments currently available are satisfactory for symptomatic management, but the efficacy tends to decrease as neuronal loss progresses. Neurotrophic factors (NTFs) are endogenous proteins known to promote neuronal survival, even in degenerating states. Therefore, the use of these factors is regarded as a possible therapeutic approach, which would aim to prevent PD or to even restore homeostasis in neurodegenerative disorders. Intriguingly, although favorable results in in vitro and in vivo models of the disease were attained, clinical trials using these molecules have failed to demonstrate a clear therapeutic benefit. Therefore, the development of animal models that more closely reproduce the mechanisms known to underlie PD-related neurodegeneration would be a major step towards improving the capacity to predict the clinical usefulness of a given NTF-based approach in the experimental setting. Moreover, some adjustments to the design of clinical trials ought to be considered, which include recruiting patients in the initial stages of the disease, improving the efficacy of the delivery methods, and combining synergetic NTFs or adding NTF-boosting drugs to the already available pharmacological approaches. Despite the drawbacks on the road to the use of NTFs as pharmacological tools for PD, very relevant achievements have been reached. In this article, we review the current status of the potential relevance of NTFs for treating PD, taking into consideration experimental evidence, human observational studies, and data from clinical trials.

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.

Propofol preferentially relaxes neurokinin receptor-2-induced airway smooth muscle contraction in guinea pig trachea.

PubMed

Gleason, Neil R; Gallos, George; Zhang, Yi; Emala, Charles W

2010-06-01

Propofol is the anesthetic of choice for patients with reactive airway disease and is thought to reduce intubation- or irritant-induced bronchoconstriction by decreasing the cholinergic component of vagal nerve activation. However, additional neurotransmitters, including neurokinins, play a role in irritant-induced bronchoconstriction. We questioned the mechanistic assumption that the clinically recognized protective effect of propofol against irritant-induced bronchoconstriction during intubation was due to attenuation of airway cholinergic reflexes. Muscle force was continuously recorded from isolated guinea pig tracheal rings in organ baths. Rings were subjected to exogenous contractile agonists (acetylcholine, histamine, endothelin-1, substance P, acetyl-substance P, and neurokinin A) or to electrical field stimulation (EFS) to differentiate cholinergic or nonadrenergic, noncholinergic nerve-mediated contraction with or without cumulatively increasing concentrations of propofol, thiopental, etomidate, or ketamine. Propofol did not attenuate the cholinergic component of EFS-induced contraction at clinically relevant concentrations. In contrast, propofol relaxed nonadrenergic, noncholinergic-mediated EFS contraction at concentrations within the clinical range (20-100 mum, n = 9; P < 0.05), and propofol was more potent against an exogenous selective neurokinin-2 receptor versus neurokinin-1 receptor agonist contraction (n = 6, P < 0.001). Propofol, at clinically relevant concentrations, relaxes airway smooth muscle contracted by nonadrenergic, noncholinergic-mediated EFS and exogenous neurokinins but not contractions elicited by the cholinergic component of EFS. These findings suggest that the mechanism of protective effects of propofol against irritant-induced bronchoconstriction involves attenuation of tachykinins released from nonadrenergic, noncholinergic nerves acting at neurokinin-2 receptors on airway smooth muscle.

A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.

PubMed

Pawluk, Shane Ashley; Roels, Craig Allan; Wilby, Kyle John; Ensom, Mary H H

2015-04-01

Medications indicated for helminthes and other parasitic infections are frequently being used in mass populations in endemic areas. Currently, there is a lack of guidance for clinicians on how to appropriately manage drug interactions when faced with patients requiring short-term anthelmintic therapy with albendazole or mebendazole while concurrently taking other agents. The objective of this review was to systematically summarize and evaluate published literature on the pharmacokinetics of albendazole or mebendazole when taken with other interacting medications. A search of MEDLINE (1946 to October 2014), EMBASE (1974 to October 2014), International Pharmaceutical Abstracts (1970 to October 2014), Google, and Google Scholar was conducted for articles describing the pharmacokinetics of albendazole or mebendazole when given with other medications (and supplemented by a bibliographic review of all relevant articles). Altogether, 17 articles were included in the review. Studies reported data on pharmacokinetic parameters for albendazole or mebendazole when taken with cimetidine, dexamethasone, ritonavir, phenytoin, carbamazepine, phenobarbital, ivermectin, praziquantel, diethylcarbamazine, azithromycin, and levamisole. Cimetidine increased the elimination half-life of albendazole and maximum concentration (Cmax) of mebendazole; dexamethasone increased the area under the plasma concentration-time curve (AUC) of albendazole; levamisole decreased the Cmax of albendazole; anticonvulsants (phenytoin, phenobarbital, carbamazepine) decreased the AUC of albendazole; praziquantel increased the AUC of albendazole; and ritonavir decreased the AUC of both albendazole and mebendazole. No major interactions were found with ivermectin, azithromycin, or diethylcarbamazine. Future research is required to clarify the clinical relevance of the interactions observed.

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…

Clinical Detection of Pre-Cataractous Lens Protein Changes using Dynamic Light Scattering

PubMed Central

Datiles, Manuel B.; Ansari, Rafat R.; Suh, Kwang I.; Vitale, Susan; Reed, George F.; Zigler, J. Samuel; Ferris., Frederick L.

2008-01-01

Purpose To use Dynamic Light Scattering (DLS) to clinically assess early pre-cataractous lens protein changes. Methods We performed a cross sectional study in 380 eyes of 235 subjects aged 7–86 years with AREDS clinical lens nuclear grades ranging from 0–3.8. A DLS device was used to assess α-crystallin, a molecular chaperone protein shown to bind other damaged lens proteins, preventing their aggregation. The outcome measure was the α-crystallin index (ACI), a measure of unbound α-crystallin in each lens. The association of ACI with increasing nuclear opacity and aging was determined. Results There was a significant decrease in ACI associated with increasing grades of lens nuclear opacity (p<0.0001). There are significant losses of α-crystallin even in clinically clear lenses associated with aging (p<0.0001). The standard error of measurement was 3%. Conclusions DLS clinically detects loss of α-crystallin proteins even in clinically clear lenses. ACI measurements may be useful in identifying patients at high risk for developing cataract, and as an outcome variable in clinical lens studies. Clinical Relevance Our studies suggest that the ACI may be a useful measure of the protective α-crystallin molecular chaperone reserve present in a lens, analogous to creatinine clearance in estimating renal function reserve. PMID:19064850

Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug-drug interactions.

PubMed

Rietjens, Saskia J; Hondebrink, Laura; Westerink, Remco H S; Meulenbelt, Jan

2012-11-01

Clinical outcome following 3,4-methylenedioxymethamphetamine (MDMA) intake ranges from mild entactogenic effects to a life-threatening intoxication. Despite ongoing research, the clinically most relevant mechanisms causing acute MDMA-induced adverse effects remain largely unclear. This complicates the triage and treatment of MDMA users needing medical care. The user's genetic profile and interactions resulting from polydrug use are key factors that modulate the individual response to MDMA and influence MDMA pharmacokinetics and dynamics, and thus clinical outcome. Polymorphisms in CYP2D6, resulting in poor metabolism status, as well as co-exposure of MDMA with specific substances (e.g. selective serotonin reuptake inhibitors (SSRIs)) can increase MDMA plasma levels, but can also decrease the formation of toxic metabolites and subsequent cellular damage. While pre-exposure to e.g. SSRIs can increase MDMA plasma levels, clinical effects (e.g. blood pressure, heart rate, body temperature) can be reduced, possibly due to a pharmacodynamic interaction at the serotonin reuptake transporter (SERT). Pretreatment with inhibitors of the dopamine or norepinephrine reuptake transporter (DAT or NET), 5-HT(2A) or α-β adrenergic receptor antagonists or antipsychotics prior to MDMA exposure can also decrease one or more MDMA-induced physiological and/or subjective effects. Carvedilol, ketanserin and haloperidol can reduce multiple MDMA-induced clinical and neurotoxic effects. Thus besides supportive care, i.e. sedation using benzodiazepines, intravenous hydration, aggressive cooling and correction of electrolytes, it is worthwhile to investigate the usefulness of carvedilol, ketanserin and haloperidol in the treatment of MDMA-intoxicated patients.

Efficacy and tolerability of paliperidone ER in patients with unsatisfactorily controlled schizophrenia by other antipsychotics: a flexible-dose approach

PubMed Central

Mauri, Massimo C.; Adami, Marina; Reggiardo, Giorgio; Giulio, Corrivetti

2015-01-01

This study evaluates the effectiveness of paliperidone ER in patients with symptomatic but not highly acute schizophrenia in terms of efficacy, safety, and patients’ perception of their social functioning and well-being. This is a multicenter, open-label prospective study with a flexible-dose approach; 133 patients were enrolled and followed for 13 weeks after switching to paliperidone ER. Outcome efficacy measures were as follows: the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity (CGI-S) scale, and the Personal and Social Performance (PSP) scale; in addition, the Subjective Well-being under Neuroleptics (SWN-20) scale, the Drug Attitude Inventory (DAI-30), and the sleep evaluation scale were used. Symptom Rating Scale (ESRS), adverse events, and subjective side effects were recorded. 118/133(88.7%) patients completed the study. The mean PANSS score decreased (88.98±10.09 to 66.52±16.29; P<0.001); 40.5% of the patients achieved improvement of at least 30%. PSP and CGI-S scores as well as DAI-30 and SWN-20 decreased (P<0.001). ESRS (P<0.001) decreased significantly from the baseline. Throughout the trial, no deaths occurred and only one serious adverse event was reported. Paliperidone ER has proved to be efficacious, safe, and well tolerated also with this approach more closely resembling actual clinical practice. Patient-relevant outcome parameters such as social functioning and quality of life improved, which is crucial for treatment adherence in clinical practice. PMID:26230269

Efficacy and tolerability of paliperidone ER in patients with unsatisfactorily controlled schizophrenia by other antipsychotics: a flexible-dose approach.

PubMed

Mauri, Mauro; Mauri, Massimo C; Adami, Marina; Reggiardo, Giorgio; Giulio, Corrivetti

2015-11-01

This study evaluates the effectiveness of paliperidone ER in patients with symptomatic but not highly acute schizophrenia in terms of efficacy, safety, and patients' perception of their social functioning and well-being. This is a multicenter, open-label prospective study with a flexible-dose approach; 133 patients were enrolled and followed for 13 weeks after switching to paliperidone ER. Outcome efficacy measures were as follows: the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity (CGI-S) scale, and the Personal and Social Performance (PSP) scale; in addition, the Subjective Well-being under Neuroleptics (SWN-20) scale, the Drug Attitude Inventory (DAI-30), and the sleep evaluation scale were used. Symptom Rating Scale (ESRS), adverse events, and subjective side effects were recorded. 118/133(88.7%) patients completed the study. The mean PANSS score decreased (88.98 ± 10.09 to 66.52 ± 16.29; P < 0.001); 40.5% of the patients achieved improvement of at least 30%. PSP and CGI-S scores as well as DAI-30 and SWN-20 decreased (P < 0.001). ESRS (P < 0.001) decreased significantly from the baseline. Throughout the trial, no deaths occurred and only one serious adverse event was reported. Paliperidone ER has proved to be efficacious, safe, and well tolerated also with this approach more closely resembling actual clinical practice. Patient-relevant outcome parameters such as social functioning and quality of life improved, which is crucial for treatment adherence in clinical practice.

Effects of therapeutic plasma exchange on serum immunoglobulin concentrations in a dog with refractory immune-mediated hemolytic anemia.

PubMed

Scagnelli, Alyssa M; Walton, Stuart A; Liu, Chin-Chi; Acierno, Mark J

2018-05-01

CASE DESCRIPTION A 9-year-old 8.3-kg (18.3-lb) neutered male Miniature Schnauzer was referred for diagnosis and treatment of a sudden onset of lethargy, anorexia, vomiting, and pallor. CLINICAL FINDINGS On physical examination, the dog was lethargic with pale mucous membranes and a capillary refill time ≥ 2 seconds. Skin and sclera were mildly icteric. Signs of pain were elicited during abdominal palpation, and an enlarged spleen was noted. Results of agglutination testing and cytologic findings were consistent with immune-mediated hemolytic anemia (IMHA). No contributing factors for development of IMHA were identified. TREATMENT AND OUTCOME Initial treatment included management with immunosuppressant medications. Three packed RBC transfusions were administered, but clinical signs continued to progress. Therefore, therapeutic plasma exchange (TPE) was performed 5 and 9 days after admission. Following each TPE procedure, the dog had an appreciable clinical improvement and decrease in RBC autoagglutination, and the Hct stabilized. Serum IgG and IgM concentrations were measured during and after both TPE procedures. Despite anticoagulative treatment, the dog developed a thrombus in the splenic vein, necessitating a splenectomy. CLINICAL RELEVANCE The decrease and rebound in serum IgG and IgM concentrations following TPE provided evidence that TPE may have the same immunomodulatory effects in dogs as have been proposed to occur in people. Further, findings suggested that TPE may be a useful alternative in dogs with refractory IMHA when traditional treatments fail.

Does prolonged β-lactam infusions improve clinical outcomes compared to intermittent infusions? A meta-analysis and systematic review of randomized, controlled trials

PubMed Central

2011-01-01

Background The emergence of multi-drug resistant Gram-negatives (MDRGNs) coupled with an alarming scarcity of new antibiotics has forced the optimization of the therapeutic potential of available antibiotics. To exploit the time above the minimum inhibitory concentration mechanism of β-lactams, prolonging their infusion may improve outcomes. The primary objective of this meta-analysis was to determine if prolonged β-lactam infusion resulted in decreased mortality and improved clinical cure compared to intermittent β-lactam infusion. Methods Relevant studies were identified from searches of MEDLINE, EMBASE, and CENTRAL. Heterogeneity was assessed qualitatively, in addition to I2 and Chi-square statistics. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated using Mantel-Haenszel random-effects models. Results Fourteen randomized controlled trials (RCTs) were included. Prolonged infusion β-lactams were not associated with decreased mortality (n= 982; RR 0.92; 95% CI:0.61-1.37) or clinical cure (n = 1380; RR 1.00 95% CI:0.94-1.06) compared to intermittent infusions. Subgroup analysis for β-lactam subclasses and equivalent total daily β-lactam doses yielded similar results. Most studies had notable methodological flaws. Conclusions No clinical advantage was observed for prolonged infusion β-lactams. The limited number of studies with MDRGNs precluded evaluation of prolonged infusion of β-lactams for this subgroup. A large, multicenter RCT with critically ill patients infected with MDRGNs is needed. PMID:21696619

Evaluation of the Environmental Bias on Accelerometer-Measured Total Daily Activity Counts and Owner Survey Responses in Dogs with Osteoarthritis.

PubMed

Katz, Erin M; Scott, Ruth M; Thomson, Christopher B; Mesa, Eileen; Evans, Richard; Conzemius, Michael G

2017-11-01

Objective  To determine if environmental variables affect the average daily activity counts (AC) of dogs with osteoarthritis (OA) and/or owners' perception of their dog's clinical signs or quality of life. Methods  The AC and Canine Brief Pain Inventory (CBPI) owner questionnaires of 62 dogs with OA were compared with daily environmental variables including the following: average temperature (°C), high temperature (°C), low temperature (°C), relative humidity (%), total precipitation (mm), average barometric pressure (hPa) and total daylight hours. Results  Daily AC significantly correlated with average temperature and total daylight hours, but average temperature and total daylight hours accounted for less than 1% of variation in AC. No other significant relationships were found between daily AC and daily high temperature, low temperature, relative humidity, total precipitation or average barometric pressure. No statistical relationship was found between daily AC and the CBPI, nor between environmental variables and the CBPI. Canine Brief Pain Inventory scores for pain severity and pain interference decreased significantly over the test period. Clinical Significance  The relationship between daily AC and average temperature and total daylight hours was significant, but unlikely to be clinically significant. Thus, environmental variables do not appear to have a clinically relevant bias on AC or owner CBPI questionnaires. The decrease over time in CBPI pain severity and pain interference values suggests owners completing the CBPI in this study were influenced by a caregiver placebo effect. Schattauer GmbH Stuttgart.

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.

Convergent Evolution Driven by Rifampin Exacerbates the Global Burden of Drug-Resistant Staphylococcus aureus

PubMed Central

2018-01-01

ABSTRACT Mutations in the beta-subunit of bacterial RNA polymerase (RpoB) cause resistance to rifampin (Rifr), a critical antibiotic for treatment of multidrug-resistant Staphylococcus aureus. In vitro studies have shown that RpoB mutations confer decreased susceptibility to other antibiotics, but the clinical relevance is unknown. Here, by analyzing 7,099 S. aureus genomes, we demonstrate that the most prevalent RpoB mutations promote clinically relevant phenotypic plasticity resulting in the emergence of stable S. aureus lineages, associated with increased risk of therapeutic failure through generation of small-colony variants (SCVs) and coresistance to last-line antimicrobial agents. We found eight RpoB mutations that accounted for 93% (469/505) of the total number of Rifr mutations. The most frequently selected amino acid substitutions affecting residue 481 (H481N/Y) were associated with worldwide expansions of Rifr clones spanning decades. Recreating the H481N/Y mutations confirmed no impact on S. aureus growth, but the H481N mutation promoted the emergence of a subpopulation of stable Rifr SCVs with reduced susceptibility to vancomycin and daptomycin. Recreating the other frequent RpoB mutations showed similar impacts on resistance to these last-line agents. We found that 86% of all Rifr isolates in our global sample carried the mutations promoting cross-resistance to vancomycin and 52% to both vancomycin and daptomycin. As four of the most frequent RpoB mutations confer only low-level Rifr, equal to or below some international breakpoints, we recommend decreasing these breakpoints and reconsidering the appropriate use of rifampin to reduce the fixation and spread of these clinically deleterious mutations. IMPORTANCE Increasing antibiotic resistance in the major human pathogen Staphylococcus aureus is threatening the ability to treat patients with these infections. Recent laboratory studies suggest that mutations in the gene commonly associated with rifampin resistance may also impact susceptibility to other last-line antibiotics in S. aureus; however, the overall frequency and clinical impact of these mutations are unknown. By mining a global collection of clinical S. aureus genomes and by mutagenesis experiments, this work reveals that common rifampin-induced rpoB mutations promote phenotypic plasticity that has led to the global emergence of stable, multidrug-resistant S. aureus lineages that are associated with increased risk of therapeutic failure through coresistance to other last-line antimicrobials. We recommend decreasing susceptibility breakpoints for rifampin to allow phenotypic detection of critical rpoB mutations conferring low resistance to rifampin and reconsidering the appropriate use of rifampin to reduce the fixation and spread of these deleterious mutations globally. PMID:29404415

Rivastigmine for Alzheimer's disease: Canadian interpretation of intermediate outcome measures and cost implications.

PubMed

Baladi, J F; Bailey, P A; Black, S; Bouchard, R W; Farcnik, K D; Gauthier, S; Kertesz, A; Mohr, E; Robillard, A

2000-12-01

Clinical studies have shown that patients with Alzheimer's disease (AD) who are treated with rivastigmine have statistically significantly better scores on 5 scales used to assess AD than control patients receiving placebo. However, the clinical meaning and cost implications of these differences are not clear. The purpose of this study was to assess the clinical meaning and cost implications of statistically significant results obtained in clinical trials of rivastigmine for the treatment of AD. Potential cost implications for the health care system, caregivers, and society are considered. Data on clinical effects of rivastigmine were obtained from published North American and European clinical studies of patients with mild to moderately severe AD receiving rivastigmine 6 to 12 mg/d (n = 828) or placebo (n = 647). Differences in scores on the Alzheimer's Disease Assessment Scale-Cognitive Function, Clinician's Interview-Based Impression of Change with both clinical and caregiver information considered, Progressive Deterioration Scale, Mini-Mental State Examination (MMSE), and Global Deterioration Scale were assessed. A convenience panel of 9 Canadian specialists experienced in the treatment of AD provided their opinions on the clinical importance of the trial results. Chart review was performed to identify specific behaviors that improved, and cost implications of improvements were assessed. The panel determined that statistically significant differences in scores on all scales except the MMSE were likely associated with functional or cognitive differences that were clinically relevant for patients, reflecting stabilization that would have beneficial consequences for caregivers and health care resource use. Subsequent chart review showed that improvement on specific scale items confirmed the physician panel's opinion. Analysis of possible cost implications to society indicated that medication expenditures would be offset largely by delays in the need for paid home care and institutionalization, positive effects on caregiver health, and less time lost from work for the caregiver. From the perspective of a Canadian specialist panel, rivastigmine treatment for AD produces clinically relevant effects for patients that are beneficial to caregivers. These effects suggest decreased use of caregiver resources and delays in the need for institutionalization, both of which reduce societal costs.

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.

The prevalence of chromium allergy in Denmark is currently increasing as a result of leather exposure.

PubMed

Thyssen, J P; Jensen, P; Carlsen, B C; Engkilde, K; Menné, T; Johansen, J D

2009-12-01

Chromium allergy has traditionally been caused by occupational skin contact with cement. In 1983, Danish legislation made the addition of ferrous sulphate compulsory in cement to reduce the water-soluble chromium content to not more than 2 ppm. An effect from this intervention has previously been demonstrated among Danish construction workers. To investigate the development of chromium allergy among patients with dermatitis tested between 1985 and 2007 in Denmark. Furthermore, to determine causative exposures in patients with chromium allergy. A retrospective analysis of patch test data was performed (n = 16,228) and charts from patients with chromium allergy were reviewed. Comparisons were made using a chi(2) test. Logistic regression analyses were used to test for associations. The prevalence of chromium allergy decreased significantly from 3.6% in 1985 to 1% in 1995 (P(trend) < 0.001) but increased to 3.3% in 2007 (P(trend) < 0.001). The frequency of clinically relevant cement exposure decreased significantly among patients with chromium allergy from 12.7% in 1989-1994 to 3.0% (P < 0.01) in 1995-2007, whereas the frequency of relevant leather exposure increased significantly from 24.1% during 1989-1994 to 45.5% during 1995-2007 (P < 0.02). Chromium allergy is currently increasing in Denmark due to leather exposure.

Surgical management of vesicoureteral reflux with recurrent urinary tract infection after renal transplantation in a dog.

PubMed

Park, Kyung-Mee; Nam, Hyun-Suk; Hussein, Kamal Hany; Woo, Heung-Myong

2016-02-01

CASE DESCRIPTION A 3-year-old male Cocker Spaniel renal transplant recipient was readmitted 39 weeks after transplantation because of acute clinical signs of pollakiuria, intermittent vomiting, decreased appetite, lethargy, and mild fever. CLINICAL FINDINGS Hydronephrosis and hydroureter were observed with ultrasonography and contrast cystography, and a diagnosis of vesicoureteral reflux (VUR) was made. Urinary tract infection (UTI) caused by Escherichia coli was also diagnosed on the basis of results of urine culture. TREATMENT AND OUTCOME Despite treatment of the UTI with an appropriate antimicrobial for 6 weeks, the VUR persisted and the UTI recurred 9 weeks after cessation of antimicrobial treatment. Therefore, surgical correction by means of revision extravesicular ureteroneocytostomy was performed. Both VUR and hydronephrosis resolved after surgery. No recurrences of clinical signs of urinary tract complications were observed during the subsequent 22-month follow-up period. CLINICAL RELEVANCE Results suggested that ureteral reimplantation with an extravesicular technique incorporating a long submucosal tunnel may be an effective treatment for VUR when medical management fails in canine renal transplant recipients with recurrent UTIs.

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.

Characterization of equine vitamin D-binding protein, development of an assay, and assessment of plasma concentrations of the protein in healthy horses and horses with gastrointestinal disease.

PubMed

Pihl, Tina H; Jacobsen, Stine; Olsen, Dorthe T; Højrup, Peter; Grosche, Astrid; Freeman, David E; Andersen, Pia H; Houen, Gunnar

2017-06-01

OBJECTIVE To purify and characterize equine vitamin D-binding protein (VDBP) from equine serum and to evaluate plasma concentrations of VDBP in healthy horses and horses with gastrointestinal injury or disease. ANIMALS 13 healthy laboratory animals (8 mice and 5 rabbits), 61 healthy horses, 12 horses with experimentally induced intestinal ischemia and reperfusion (IR), and 59 horses with acute gastrointestinal diseases. PROCEDURES VDBP was purified from serum of 2 healthy horses, and recombinant equine VDBP was obtained through a commercial service. Equine VDBP was characterized by mass spectrometry. Monoclonal and polyclonal antibodies were raised against equine VDBP, and a rocket immunoelectrophoresis assay for equine VDBP was established. Plasma samples from 61 healthy horses were used to establish working VDBP reference values for study purposes. Plasma VDBP concentrations were assessed at predetermined time points in horses with IR and in horses with naturally occurring gastrointestinal diseases. RESULTS The working reference range for plasma VDBP concentration in healthy horses was 531 to 1,382 mg/L. Plasma VDBP concentrations were significantly decreased after 1 hour of ischemia in horses with IR, compared with values prior to induction of ischemia, and were significantly lower in horses with naturally occurring gastrointestinal diseases with a colic duration of < 12 hours than in healthy horses. CONCLUSIONS AND CLINICAL RELEVANCE Plasma VDBP concentrations were significantly decreased in horses with acute gastrointestinal injury or disease. Further studies and the development of a clinically relevant assay are needed to establish the reliability of VDBP as a diagnostic and prognostic marker in horses.

Serum potassium decline during hospitalization for acute decompensated heart failure is a predictor of 6-month mortality, independent of N-terminal pro-B-type natriuretic peptide levels: An individual patient data analysis.

PubMed

Salah, Khibar; Pinto, Yigal M; Eurlings, Luc W; Metra, Marco; Stienen, Susan; Lombardi, Carlo; Tijssen, Jan G; Kok, Wouter E

2015-09-01

Limited data exist for the role of serum potassium changes during hospitalization for acute decompensated heart failure (ADHF). The present study investigated the long-term prognostic value of potassium changes during hospitalization in patients admitted for ADHF. Our study is a pooled individual patient data analysis assembled from 3 prospective cohorts comprising 754 patients hospitalized for ADHF. The endpoint was all-cause mortality within 180 days after discharge. Serum potassium levels and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were measured at admission and at discharge. A percentage decrease >15% in serum potassium levels occurred in 96 (13%) patients, and an absolute decrease of >0.7 mmol/L in serum potassium levels occurred in 85 (12%) patients; and both were predictors of poor outcome independent of admission or discharge serum potassium. After the addition of other strong predictors of mortality-a 30% change in NT-proBNP during hospitalization, discharge levels of NT-proBNP, renal markers, and other relevant clinical variables-the multivariate hazard ratio of serum potassium percentage reduction of >15% remained an independent predictor of 180-day mortality (hazard ratio 2.06, 95% CI 1.14-3.73). A percentage serum potassium decline of >15% is an independent predictor of 180-day all-cause mortality on top of baseline potassium levels, NT-proBNP levels, renal variables, and other relevant clinical variables. This suggest that patients hospitalized for ADHF with a decline of >15% in serum potassium levels are at risk and thus monitoring and regulating of serum potassium level during hospitalization are needed in these patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Vasopeptidase inhibition with omapatrilat increases fluid and protein microvascular permeability in cat skeletal muscle.

PubMed

Persson, Johan; Morsing, Peter; Grände, Per-Olof

2004-03-01

Vasopeptidase inhibition is a new antihypertensive approach combining inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), but severe oedema, mainly angio-oedema, has been reported. As ACE and NEP catalyse degradation of the permeability-increasing peptide bradykinin, and NEP also catalyses degradation of permeability-increasing peptides such as atrial natriuretic peptide, substance P, endothelin-1 and angiotensin II, vasopeptidase inhibition may increase microvascular permeability. To analyse the effects of vasopeptidase inhibition on permeability. The study was performed on the autoperfused cat calf skeletal muscle, evaluating the effects on fluid and protein permeability of a clinically relevant dose of the vasopeptidase inhibitor, omapatrilat. The effects were compared with those of the vehicle, of selective ACE and NEP inhibition, and of omapatrilat during bradykinin receptor blockade. Effects on fluid permeability were determined with a capillary filtration coefficient (CFC) technique, and effects on protein permeability were assessed from changes in the osmotic reflection coefficient for albumin. After 1.5 h of intravenous infusion of omapatrilat (0.35 mg/kg per hour), mean arterial pressure was reduced from 114 mmHg to 86 mmHg (P < 0.01) and skeletal muscle vascular resistance was reduced from 14.5 peripheral resistance units (PRU) to 11.5 PRU (P < 0.05). CFC was increased by 22% (P < 0.01) and the reflection coefficient was decreased by 17% (P < 0.01). Infusion of vehicle had no effects. Inhibition of NEP increased permeability without affecting blood pressure, whereas ACE inhibition decreased blood pressure without affecting permeability. The increase in permeability associated with omapatrilat was reduced by bradykinin blockade. A clinically relevant antihypertensive dose of omapatrilat reduces vascular resistance and increases fluid and protein permeability, the permeability effect more by inhibition of NEP than by inhibition of ACE, by a mechanism involving bradykinin.

Cognitive Analysis of Decision Support for Antibiotic Prescribing at the Point of Ordering in a Neonatal Intensive Care Unit

PubMed Central

Sheehan, Barbara; Kaufman, David; Stetson, Peter; Currie, Leanne M.

2009-01-01

Computerized decision support systems have been used to help ensure safe medication prescribing. However, the acceptance of these types of decision support has been reported to be low. It has been suggested that decreased acceptance may be due to lack of clinical relevance. Additionally, cognitive fit between the user interface and clinical task may impact the response of clinicians as they interact with the system. In order to better understand clinician responses to such decision support, we used cognitive task analysis methods to evaluate clinical alerts for antibiotic prescribing in a neonatal intensive care unit. Two methods were used: 1) a cognitive walkthrough; and 2) usability testing with a ‘think-aloud’ protocol. Data were analyzed for impact on cognitive effort according to categories of cognitive distance. We found that responses to alerts may be context specific and that lack of screen cues often increases cognitive effort required to use a system. PMID:20351922

Pregabalin Modulation of Neurotransmitter Release Is Mediated by Change in Intrinsic Activation/Inactivation Properties of Cav2.1 Calcium ChannelsS⃞

PubMed Central

Di Guilmi, Mariano N.; Urbano, Francisco J.; Inchauspe, Carlota Gonzalez

2011-01-01

In this work, we studied the effects of the anticonvulsant and analgesic drug pregabalin (PGB) on excitatory postsynaptic currents (EPSCs) at principal neurons of the mouse medial nucleus of the trapezoid body and on presynaptic calcium currents at the calyx of Held. We found that the acute application of PGB reduced the amplitude of EPSCs in a dose-dependent manner with a maximal blocking effect of approximately 30%. A clinical high-concentration dose of PGB (e.g., 500 μM) blocked Cav2.1 channel-mediated currents and decreased their facilitation during a 100-Hz train, without changing their voltage-dependent activation. Furthermore, PGB also removed the inactivation of Cav2.1 channels at a clinically relevant low concentration of 100 μM. These results suggest novel modulatory mechanisms mediated by the acute administration of PGB on fast excitatory synaptic transmission and might contribute to better understanding PGB anticonvulsant/analgesic clinical effects. PMID:21177783

Computer-Aided Nodule Assessment and Risk Yield Risk Management of Adenocarcinoma: The Future of Imaging?

PubMed

Foley, Finbar; Rajagopalan, Srinivasan; Raghunath, Sushravya M; Boland, Jennifer M; Karwoski, Ronald A; Maldonado, Fabien; Bartholmai, Brian J; Peikert, Tobias

2016-01-01

Increased clinical use of chest high-resolution computed tomography results in increased identification of lung adenocarcinomas and persistent subsolid opacities. However, these lesions range from very indolent to extremely aggressive tumors. Clinically relevant diagnostic tools to noninvasively risk stratify and guide individualized management of these lesions are lacking. Research efforts investigating semiquantitative measures to decrease interrater and intrarater variability are emerging, and in some cases steps have been taken to automate this process. However, many such methods currently are still suboptimal, require validation and are not yet clinically applicable. The computer-aided nodule assessment and risk yield software application represents a validated tool for the automated, quantitative, and noninvasive tool for risk stratification of adenocarcinoma lung nodules. Computer-aided nodule assessment and risk yield correlates well with consensus histology and postsurgical patient outcomes, and therefore may help to guide individualized patient management, for example, in identification of nodules amenable to radiological surveillance, or in need of adjunctive therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

CANARY Risk Management of Adenocarcinoma: The Future of Imaging?

PubMed Central

Foley, Finbar; Rajagopalan, Srinivasan; Raghunath, Sushravya M; Boland, Jennifer M; Karwoski, Ronald A.; Maldonado, Fabien; Bartholmai, Brian J; Peikert, Tobias

2016-01-01

Increased clinical utilization of chest high resolution computed tomography results in increased identification of lung adenocarcinomas and persistent sub-solid opacities. However, these lesions range from very indolent to extremely aggressive tumors. Clinically relevant diagnostic tools to non-invasively risk stratify and guide individualized management of these lesions are lacking. Research efforts investigating semi-quantitative measures to decrease inter- and intra-rater variability are emerging, and in some cases steps have been taken to automate this process. However, many such methods currently are still sub-optimal, require validation and are not yet clinically applicable. The Computer-Aided Nodule Assessment and Risk Yield (CANARY) software application represents a validated tool for the automated, quantitative, non-invasive tool for risk stratification of adenocarcinoma lung nodules. CANARY correlates well with consensus histology and post-surgical patient outcomes and therefore may help to guide individualized patient management e.g. in identification of nodules amenable to radiological surveillance, or in need of adjunctive therapy. PMID:27568149

Optimal utilization of a breast care advanced practice clinician.

PubMed

Russell, Katie W; Mone, Mary C; Serpico, Victoria J; Ward, Cori; Lynch, Joanna; Neumayer, Leigh A; Nelson, Edward W

2014-12-01

Incorporation of "lean" business philosophy within health care has the goal of adding value by reducing cost and improving quality. Applying these principles to the role of Advance Practice Clinicians (APCs) is relevant because they have become essential members of the healthcare team. An independent surgical breast care clinic directed by an APC was created with measurements of success to include the following: time to obtain an appointment, financial viability, and patient/APC/MD satisfaction. During the study period, there was a trend toward a decreased median time to obtain an appointment. Monthly APC charges increased from $388 to $30,800. The mean provider satisfaction score by Press Ganey was 96% for the APC and 95.8% for the surgeon. Both clinicians expressed significant satisfaction with clinic development. Overall, initiation of an APC breast clinic met the proposed goals of success. The use of lean philosophy demonstrates that implementation of change can result in added value in patient care. Copyright © 2014 Elsevier Inc. All rights reserved.

Personalized prescribing: a new medical model for clinical implementation of psychotropic drugs

PubMed Central

Eap, Chin B.

2016-01-01

The use of pharmacogenetic tests was already being proposed in psychiatry in the early 2000s because genetic factors were known to influence drug pharmacokinetics and pharmacodynamics. However, sufficient levels of evidence to justify routine use have been achieved for only a few tests (eg, major histocompatibility complex, class I, B, allele 1502 [HLA-B*1502] for carbamazepine in epilepsy and bipolar disorders); many findings are too preliminary or, when replicated, of low clinical relevance because of a small effect size. Although drug selection and dose adaptation according to cytochrome P450 genotypes are sound, a large number of patients need to be genotyped in order to prevent one case of severe side effect and/or nonresponse. The decrease in cost for genetic analysis shifts the cost: benefit ratio toward increasing use of pharmacogenetic tests. However, they have to be combined with careful clinical evaluations and other tools (eg, therapeutic drug monitoring and phenotyping) to contribute to the general aim of providing the best care for psychiatric patients. PMID:27757065

Personalized prescribing: a new medical model for clinical implementation of psychotropic drugs.

PubMed

Eap, Chin B

2016-09-01

The use of pharmacogenetic tests was already being proposed in psychiatry in the early 2000s because genetic factors were known to influence drug pharmacokinetics and pharmacodynamics. However, sufficient levels of evidence to justify routine use have been achieved for only a few tests (eg, major histocompatibility complex, class I, B, allele 1502 [HLA-B*1502] for carbamazepine in epilepsy and bipolar disorders); many findings are too preliminary or, when replicated, of low clinical relevance because of a small effect size. Although drug selection and dose adaptation according to cytochrome P450 genotypes are sound, a large number of patients need to be genotyped in order to prevent one case of severe side effect and/or nonresponse. The decrease in cost for genetic analysis shifts the cost: benefit ratio toward increasing use of pharmacogenetic tests. However, they have to be combined with careful clinical evaluations and other tools (eg, therapeutic drug monitoring and phenotyping) to contribute to the general aim of providing the best care for psychiatric patients.

Medical research in Israel and the Israel biomedical database.

PubMed

Berns, D S; Rager-Zisman, B

2000-11-01

The data collected for the second edition of the Directory of Medical Research in Israel and the Israel Biomedical Database have yielded very relevant information concerning the distribution of investigators, publication activities and funding sources. The aggregate data confirm the findings of the first edition published in 1996 [2]. Those facts endorse the highly concentrated and extensive nature of medical research in the Jerusalem area, which is conducted at the Hebrew University and its affiliated hospitals. In contrast, Tel Aviv University, whose basic research staff is about two-thirds the size of the Hebrew University staff, has a more diffuse relationship with its clinical staff who are located at more than half a dozen hospitals. Ben-Gurion University in Beer Sheva and the Technion in Haifa are smaller in size, but have closer geographic contact between their clinical and basic research staff. Nonetheless, all the medical schools and affiliated hospitals have good publication and funding records. It is important to note that while some aspects of the performance at basic research institutions seem to be somewhat better than at hospitals, the records are actually quite similar despite the greater burden of clinical services at the hospitals as compared to teaching responsibilities in the basic sciences. The survey also indicates the substantial number of young investigators in the latest survey who did not appear in the first survey. While this is certainly encouraging, it is also disturbing that the funding sources are apparently decreasing at a time when young investigators are attempting to become established and the increasing burden of health care costs precludes financial assistance from hospital sources. The intensity and undoubtedly the quality of medical research in Israel remains at a level consistent with many of the more advanced western countries. This conclusion is somewhat mitigated by the fact that there is a decrease in available funding and a measurable decrease in scholarly activity at a time when a new, younger generation of investigators is just beginning to become productive. In closing, we wish to stress that the collection of data for the Biomedical Database is a continuing project and we encourage all medical researches who may not have contributed relevant information to write to the Office of the Chief Scientist or contact the office by email.

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.

Biofield Therapies: Helpful or Full of Hype? A Best Evidence Synthesis

PubMed Central

Mills, Paul J.

2009-01-01

Background Biofield therapies (such as Reiki, therapeutic touch, and healing touch) are complementary medicine modalities that remain controversial and are utilized by a significant number of patients, with little information regarding their efficacy. Purpose This systematic review examines 66 clinical studies with a variety of biofield therapies in different patient populations. Method We conducted a quality assessment as well as a best evidence synthesis approach to examine evidence for biofield therapies in relevant outcomes for different clinical populations. Results Studies overall are of medium quality, and generally meet minimum standards for validity of inferences. Biofield therapies show strong evidence for reducing pain intensity in pain populations, and moderate evidence for reducing pain intensity hospitalized and cancer populations. There is moderate evidence for decreasing negative behavioral symptoms in dementia and moderate evidence for decreasing anxiety for hospitalized populations. There is equivocal evidence for biofield therapies' effects on fatigue and quality of life for cancer patients, as well as for comprehensive pain outcomes and affect in pain patients, and for decreasing anxiety in cardiovascular patients. Conclusion There is a need for further high-quality studies in this area. Implications and future research directions are discussed. Electronic supplementary material The online version of this article (doi:10.1007/s12529-009-9062-4) contains supplementary material, which is available to authorized users. PMID:19856109

Clinical audit of diabetes management can improve the quality of care in a resource-limited primary care setting.

PubMed

Govender, Indira; Ehrlich, Rodney; Van Vuuren, Unita; De Vries, Elma; Namane, Mosedi; De Sa, Angela; Murie, Katy; Schlemmer, Arina; Govender, Strini; Isaacs, Abdul; Martell, Rob

2012-12-01

To determine whether clinical audit improved the performance of diabetic clinical processes in the health district in which it was implemented. Patient folders were systematically sampled annually for review. Primary health-care facilities in the Metro health district of the Western Cape Province in South Africa. Health-care workers involved in diabetes management. Clinical audit and feedback. The Skillings-Mack test was applied to median values of pooled audit results for nine diabetic clinical processes to measure whether there were statistically significant differences between annual audits performed in 2005, 2007, 2008 and 2009. Descriptive statistics were used to illustrate the order of values per process. A total of 40 community health centres participated in the baseline audit of 2005 that decreased to 30 in 2009. Except for two routine processes, baseline medians for six out of nine processes were below 50%. Pooled audit results showed statistically significant improvements in seven out of nine clinical processes. The findings indicate an association between the application of clinical audit and quality improvement in resource-limited settings. Co-interventions introduced after the baseline audit are likely to have contributed to improved outcomes. In addition, support from the relevant government health programmes and commitment of managers and frontline staff contributed to the audit's success.

Structure-based approach for identification of novel phenylboronic acids as serine-β-lactamase inhibitors

NASA Astrophysics Data System (ADS)

Sgrignani, Jacopo; De Luca, Filomena; Torosyan, Hayarpi; Docquier, Jean-Denis; Duan, Da; Novati, Beatrice; Prati, Fabio; Colombo, Giorgio; Grazioso, Giovanni

2016-10-01

β-Lactamases are bacterial enzymes conferring resistance to β-lactam antibiotics in clinically-relevant pathogens, and represent relevant drug targets. Recently, the identification of new boronic acids (i.e. RPX7009) paved the way to the clinical application of these molecules as potential drugs. Here, we screened in silico a library of 1400 boronic acids as potential AmpC β-lactamase inhibitors. Six of the most promising candidates were evaluated in biochemical assays leading to the identification of potent inhibitors of clinically-relevant β-lactamases like AmpC, KPC-2 and CTX-M-15. One of the selected compounds showed nanomolar K i value with the clinically-relevant KPC-2 carbapenemase, while another one exhibited broad spectrum inhibition, being also active on Enterobacter AmpC and the OXA-48 class D carbapenemase.

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.

PubMed

Krenzien, F; Quante, M; Heinbokel, T; Seyda, M; Minami, K; Uehara, H; Biefer, H R C; Schuitenmaker, J M; Gabardi, S; Splith, K; Schmelzle, M; Petrides, A K; Azuma, H; Pratschke, J; Li, X C; ElKhal, A; Tullius, S G

2017-05-01

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4 + T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4 + T cells more effectively while inhibiting the proliferation of CD4 + T cells in old mice. Both TAC-treated murine and human CD4 + T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca 2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8 + T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4 + T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4 + T cell mediated. The suppression of calcineurin levels and Ca 2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Team clinician variability in return-to-play decisions.

PubMed

Shultz, Rebecca; Bido, Jennifer; Shrier, Ian; Meeuwisse, Willem H; Garza, Daniel; Matheson, Gordon O

2013-11-01

To describe the variability in the return-to-play (RTP) decisions of experienced team clinicians and to assess their clinical opinion as to the relevance of 19 factors described in a RTP decision-making model. Survey questionnaire. Advanced Team Physician Course. Sixty-seven of 101 sports medicine clinicians completed the questionnaire. Results were analyzed using descriptive statistics. For categorical variables, we report percentage and frequency. For continuous variables, we report mean (SD) if data were approximately normally distributed and frequencies for clinically relevant categories for skewed data. The average number of years of clinical sports medicine experience was 13.6 (9.8). Of the 62 clinicians who responded fully, 35% (n = 22) would "clear" (vs "not clear") an athlete to participate in sport even if the risk of an acute reinjury or long-term sequelae is increased. When respondents were given 6 different RTP options rather than binary choices, there were increased discrepancies across some injury risk scenarios. For example, 8.1% to 16.1% of respondents who chose to clear an athlete when presented with binary choices, later chose to "not clear" an athlete when given 6 graded RTP options. The respondents often considered factors of potential importance to athletes as nonimportant to the RTP decision process if risk of reinjury was unaffected (range, n = 4 [10%] to n = 19 [45%]). There is a high degree of variability in how different clinicians weight the different factors related to RTP decision making. More precise definitions decrease but do not eliminate this variability.

Circulating intact and cleaved forms of the urokinase-type plasminogen activator receptor: biological variation, reference intervals and clinical useful cut-points.

PubMed

Thurison, Tine; Christensen, Ib J; Lund, Ida K; Nielsen, Hans J; Høyer-Hansen, Gunilla

2015-01-15

High levels of circulating forms of the urokinase-type plasminogen activator receptor (uPAR) are significantly associated to poor prognosis in cancer patients. Our aim was to determine biological variations and reference intervals of the uPAR forms in blood, and in addition, to test the clinical relevance of using these as cut-points in colorectal cancer (CRC) prognosis. uPAR forms were measured in citrated and EDTA plasma samples using time-resolved fluorescence immunoassays. Diurnal, intra- and inter-individual variations were assessed in plasma samples from cohorts of healthy individuals. Reference intervals were determined in plasma from healthy individuals randomly selected from a Danish multi-center cross-sectional study. A cohort of CRC patients was selected from the same cross-sectional study. The reference intervals showed a slight increase with age and women had ~20% higher levels. The intra- and inter-individual variations were ~10% and ~20-30%, respectively and the measured levels of the uPAR forms were within the determined 95% reference intervals. No diurnal variation was found. Applying the normal upper limit of the reference intervals as cut-point for dichotomizing CRC patients revealed significantly decreased overall survival of patients with levels above this cut-point of any uPAR form. The reference intervals for the different uPAR forms are valid and the upper normal limits are clinically relevant cut-points for CRC prognosis. Copyright © 2014 Elsevier B.V. All rights reserved.

Clinical Relevance and Cost-Savings of Levocarnitine Versus Ammonul in the Management Of Hyperammonemia in a Cancer Patient: The Impact of a Clinical Pharmacist.

PubMed

Anyanwu, Chukwuma; Ezeudu, Chinonso; Le, Hoa; Egwim, Oliver

2018-01-01

Hyperammonemia, a relatively uncommon condition characterized by elevated ammonia levels in the blood, presents with varied physiological etiologies that may send patients to the intensive care unit (ICU) with encephalopathy. An immediate decrease in ammonia levels is necessary to avert neurological damage. However, due to the multifaceted nature of hyperammonemia, a definite determination of etiology is not always possible. This case report examines the clinical and economic impact of a pharmacist in managing acute hyperammonemia of unknown etiology in a 62-year-old Hispanic man who had recently been diagnosed with metastatic medullary thyroid cancer and associated hypercalcemia. The patient was treated with levocarnitine after the failure of several other treatments. Levocarnitine therapy controlled the patient's ammonia levels, which had progressively reached extremely high levels. His mental status, which had deteriorated severely, returned to baseline. This case illustrates the importance of having a clinical pharmacist in the ICU. The pharmacist's expertise and knowledge helped avert adverse clinical consequences and promoted considerable cost-savings. This case also shows that levocarnitine may be an effective treatment for certain cases of hyperammonia-induced encephalopathy with unknown etiology.

Modeling systolic pressure variation due to positive pressure ventilation.

PubMed

Messerges, Joanne

2006-01-01

Although many clinical techniques have been proposed to assess blood volume none have been established as an undisputed standard practice, Volume studies suggest systolic pressure variation (SPV) as a promising volume indicator but underlying influences on SPV are not well understood. Successful modeling of SPV will reveal the major SPV influencers, guide algorithm development to accommodate these influencers, and potentially lead to a more clinically relevant interpretation of SPV values, thus improving upon current clinical methods for assessing blood volume. This study takes a first step towards identifying SPV influencers by investigating three variations of an existing pressure-flow cardiovascular model. Each successive version introduces an additional modification in attempt to model SPV under normovolemic and hypovolemic conditions, where the last model accounts for positive pressure ventilation, venous compression, and a rightward septum shift. Under normovolemic conditions, each model yields SPV values of 5.8, 6.4, and 6.7 mmHg, respectively. Under hypovolemic conditions the results do not agree with clinical findings, suggesting these three mechanisms alone do not dictate the clinical SPV response to a decrease in volume. Model results are used to suggest improvements for future work.

Resilience in Aging Mice.

PubMed

Kirkland, James L; Stout, Michael B; Sierra, Felipe

2016-11-01

Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance health span and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context. The preliminary set of tests ranked by the participants is discussed here, recognizing that this is a first attempt. Published by Oxford University Press on behalf of The Gerontological Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Implementation of an automated system for monitoring adherence to hemodialysis treatment: a report of seven years of experience.

PubMed

Bellazzi, Riccardo; Sacchi, Lucia; Caffi, Ezio; de Vincenzi, Amedeo; Nai, Maurizio; Manicone, Francesco; Larizza, Cristiana; Bellazzi, Roberto

2012-05-01

In this paper we present the clinical deployment and evaluation of a computerized system, EMOSTAT, aimed at improving the quality of hemodialysis sessions. EMOSTAT automatically imports data from the hemodialysis monitoring software tools and analyzes the delivered treatment looking at six clinically relevant parameters. Failures-to-adhere (FtAs) to the planned treatment are detected and reported to the care-givers. EMOSTAT has been used for more than seven years in the management of a dialysis service located in Mede, Italy. A total of 72 patients were monitored and 21251 dialyses were collected. Data analysis is performed on the periods 2002-2005 and 2005-2008, corresponding to two different software releases. The system had been exploited into everyday clinical practice for the entire considered period. The number of FtAs significantly decreased along the first period: the bulk blood flow FtAs decreased after the introduction of the system. Hemodialysis sessions lasted longer in the second period. Co-occurring FtAs, highlighting the presence of complex FtAs patterns, were also detected. EMOSTAT provides an effective way to re-focus the attention of the dialysis department on the treatment plan and on its implementation. The automatic data collection and the design philosophy of EMOSTAT allowed the routine use of the system. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Microbiological contamination of cubicle curtains in an out-patient podiatry clinic

PubMed Central

2010-01-01

Background Exposure to potential pathogens on contaminated healthcare garments and curtains can occur through direct or indirect contact. This study aimed to identify the microorganisms present on podiatry clinic curtains and measure the contamination pre and post a standard hospital laundry process. Method Baseline swabs were taken to determine colony counts present on cubical curtains before laundering. Curtains were swabbed again immediately after, one and three weeks post laundering. Total colony counts were calculated and compared to baseline, with identification of micro-organisms. Results Total colony counts increased very slightly by 3% immediately after laundry, which was not statistically significant, and declined significantly (p = 0.0002) by 56% one-week post laundry. Three weeks post laundry colony counts had increased by 16%; although clinically relevant, this was not statistically significant. The two most frequent microorganisms present throughout were Coagulase Negative Staphylococcus and Micrococcus species. Laundering was not completely effective, as both species demonstrated no significant change following laundry. Conclusion This work suggests current laundry procedures may not be 100% effective in killing all microorganisms found on curtains, although a delayed decrease in total colony counts was evident. Cubicle curtains may act as a reservoir for microorganisms creating potential for cross contamination. This highlights the need for additional cleaning methods to decrease the risk of cross infection and the importance of maintaining good hand hygiene. PMID:21087486

Impact of a cystic fibrosis transmembrane conductance regulator (CFTR) modulator on high-dose ibuprofen therapy in pediatric cystic fibrosis patients.

PubMed

Bruch, Brittany A; Singh, Sachinkumar B; Ramsey, Laura J; Starner, Timothy D

2018-05-01

This study was undertaken to determine if a clinically relevant drug-drug interaction occurred between ibuprofen and lumacaftor/ivacaftor. Peak ibuprofen plasma concentrations were measured prior to and after lumacaftor/ivacaftor initiation. A Wilcoxon signed rank sum test was used to compare the values. Nine patients were included in the final analysis. Peak ibuprofen plasma concentrations decreased an average of 36.4 mcg/mL after initiation of lumacaftor/ivacaftor with a relative reduction of 41.7%. The average peak plasma concentration was 84.2 mcg/mL (SD = 10.9) prior to lumacaftor/ivacaftor initiation and 47.9 mcg/mL (SD = 16.4) following initiation (P = 0.0039). Peak concentrations occurred at an average of 100 min (SD = 30) and 107 min (SD = 40) prior to and following lumacaftor/ivacaftor initiation, respectively. We suggest a clinically relevant drug-drug interaction exists between ibuprofen and lumacaftor/ivacaftor. Lumacaftor may cause subtherapeutic ibuprofen plasma concentrations due to the induction of CYP enzymes and increased metabolism of ibuprofen. Based on this analysis, we have modified our use of ibuprofen in several patients after evaluation of this drug-drug interaction. © 2018 Wiley Periodicals, Inc.

Anxiety Sensitivity and Interoceptive Exposure: A Transdiagnostic Construct and Change Strategy

PubMed Central

Boswell, James F.; Farchione, Todd J.; Sauer-Zavala, Shannon; Murray, Heather W.; Fortune, Meghan R.; Barlow, David H.

2013-01-01

Recent findings support the relevance of anxiety sensitivity (AS) and interoceptive exposure (IE) across emotional disorders. This study (a) evaluated levels of AS across different anxiety disorders, (b) examined change in AS over the course of transdiagnostic psychological intervention, and its relationship with outcome, and (c) described the implementation of IE to address AS with patients with different anxiety disorders. Participants (N = 54) were patients who received treatment with the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) in two consecutive treatment trials. Participants completed a measure of AS at pre- and posttreatment, and multiple occasions during treatment. Symptom severity was assessed at pre- and posttreatment, and clinical information related to physical symptoms and IE were collected as part of routine clinical practice. Elevated AS was observed at pretreatment across diagnoses and decreases in AS were observed from pre- to posttreatment. Similar changes occurred across the diagnostic categories, notably coinciding with the introduction of IE. Change in AS was correlated with reduced symptom levels at posttreatment and 6-month follow-up. Patients with different anxiety disorders endorsed similar physical symptoms and practiced similar IE exercises with similar effects. Results provide preliminary support for the usefulness of IE as a treatment strategy across the spectrum of anxiety disorders, and additional support for the transdiagnostic relevance of AS. PMID:23768669

Hypocalcaemia after total thyroidectomy: could intact parathyroid hormone be a predictive factor for transient postoperative hypocalcemia?

PubMed

Puzziello, Alessandro; Gervasi, Rita; Orlando, Giulio; Innaro, Nadia; Vitale, Mario; Sacco, Rosario

2015-02-01

Hypocalcemia, the most common complication of thyroidectomy, is a transient condition in up to 27% of patients and a permanent condition approximately 1% of patients. The aim of this prospective study was to evaluate reliability of postoperative intact parathyroid hormone (iPTH) assessment for predicting clinically relevant postthyroidectomy hypocalcemia for a safe early discharge of patients with no overtreatment. Seventy-five consecutive patients (age 51 ± 13 years [mean ± SD]) undergoing total or completion thyroidectomy with no concomitant parathyroid diseases or renal failure were included in the present study. Serum iPTH level was determined before and 2 hours after thyroidectomy. Serum calcium concentration was determined 1 day before and 2 days postoperatively. The occurrence of postoperative hypocalcemia was correlated both with the absolute and relative iPTH decrease, determined as a ratio of the preoperative value (P < .0001). There was a greater difference in relative decrease in iPTH between patients remaining normocalcemic and those with hypocalcemia present on the second postoperative day. Hypocalcemic patients on the second postoperative day had a 62% relative decrease in iPTH 2 hours after thyroidectomy. The relative decrease in serum iPTH was greater in patients with hypocalcemia arising on the second postoperative day rather than in patients who remained normocalcemic. The relative decrease in iPTH determined 2 hours after total thyroidectomy together with the serum calcium concentration 24 hours after thyroidectomy proved to be useful predictors of sustained hypocalcemia and might change the clinical management of patients after thyroid surgery to support a longer hospitalization in these selected patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Micrometastases in neuroblastoma: are they clinically important?

PubMed Central

Burchill, S A

2004-01-01

Despite advances in the treatment of neuroblastoma (NBL), recurrence and metastases continue to pose major problems in clinical management. The relation between micrometastases and the development of secondary disease is not fully understood. However, accurate methods to detect low numbers of tumour cells may allow the evaluation of their role in the disease process, and by implication the possible benefits of eliminating them. Although there is substantial evidence for the increased sensitivity of current molecular methods for the detection of NBL cells compared with more conventional cytology, the clinical relevance and usefulness of detecting this disease remain controversial. The primary goal of current translational research must be to evaluate the clinical relevance of micrometastatic disease detected by these methods in multicentre prospective clinical outcome studies. Only then can the clinical usefulness of these methods be defined so that they may be introduced into relevant clinical practice. PMID:14693828

Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

PubMed

Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

2015-12-01

Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

Physicians' perspective on the clinical meaningfulness of inflammatory bowel disease trial results: an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) survey.

PubMed

Olivera, P; Sandborn, W J; Panés, J; Baumann, C; D'Haens, G; Vermeire, S; Danese, S; Peyrin-Biroulet, L

2018-03-01

Several novel compounds are being developed for inflammatory bowel diseases (IBD). In addition, biosimilar drugs are being approved. An increasing number of head-to-head, superiority and non-inferiority trials in patients with IBD are expected in the future. The clinical relevance of the magnitude of the effect size is often debated. To better understand physicians' perspectives on the clinical meaningfulness of IBD trial results. We conducted an online survey among all IOIBD (International Organization for the Study of Inflammatory Bowel Diseases) members, asking their opinion on the clinical relevance of the results of IBD trials. Forty-six IOIBD members responded to the survey (52.3%). In biologic-naïve ulcerative colitis (UC) and Crohn's disease (CD) patients, most of the participants considered a 15% difference with placebo for clinical remission and endoscopic remission to be clinically relevant. In head-to-head trials, most of participants considerer a 10% difference between groups for clinical remission and endoscopic remission to be clinically relevant. Half of respondents considered 10% to be an adequate margin in non-inferiority trials. In bioequivalence studies, most of the participants considered adequate a ± 5% difference between a biosimilar and the originator for pharmacokinetic parameters, efficacy, safety and immunogenicity. Regarding safety, the difference between two drugs considered clinically relevant varied from 1% to 5%, depending on the type of adverse event. This is the first survey exploring how physicians perceive IBD trial results, providing an estimation of the magnitude of the difference between treatment arms that may directly influence clinical practice. © 2018 John Wiley & Sons Ltd.

Role of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus.

PubMed

Solini, Anna

2016-12-01

In the last ten years, knowledge on pathophysiology of type 2 diabetes (T2DM) has significantly increased, with multiple failures (decreased incretin effect, increased lipolysis, increased glucagon secretion, neurotransmitters dysfunction) recognized as important contributors, together with decreased insulin secretion and reduced peripheral glucose uptake. As a consequence, the pharmacologic therapy of T2DM has been progressively enriched by several novel classes of drugs, trying to overcome these defects. The last, intriguing compounds come into the market are SGLT2 inhibitors, framing the kidney in a different scenario, not as site of a harmful disease complication, but rather as the means to correct hyperglycemia and fight the disease. This review aims to offer a short, updated overview of the role of these compounds in the treatment of T2DM, focusing on efficacy, ancillary albeit relevant clinical effects, safety, potential cardiovascular protection, positioning in common therapeutic algorithms.

How do microclimate factors affect the risk for superficial pressure ulcers: a mathematical modeling study.

PubMed

Gefen, Amit

2011-08-01

In this study, a mathematical model is developed for analyzing the effects of the microclimate on skin tolerance to superficial pressure ulcers (SPUs). The modeling identified the following factors as such that decrease the tolerance of skin to SPUs: (i) increase in the skin temperature, (ii) increase in the ambient temperature, (iii) increase in the relative humidity, (iv) increase in the skin-support (or skin-clothing-support) contact pressures, and (v) decrease in permeabilities of the materials contacting the skin or being close to it, e.g. the covering sheet of the support and clothing. The modeling is consistent with relevant empirical findings and clinical observations documented in the literature, explains them from a basic science aspect, and can be further developed for design of interventions, safer patient clothing and supports that consider the optimization of microclimate factors. Copyright © 2010 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.

[Radial Approach for Percutaneous Coronary Interventions in Patients With Ischemic Heart Disease: Advantages and Disadvantages, Complications Rate in Comparison With Femoral Approach].

PubMed

Fettser, D V; Batyraliev, T A; Pershukov, I V; Vanyukov, A E; Sidorenko, B A

2017-05-01

During recent 10-15 years, percutaneous coronary interventions (PCI) have reached a new level of efficacy and safety. Rate of serious coronary complications has decreased. That to a greater degree exposes the problem of peripheral complications at the site of arterial approach. At the same time portion of patients older than 75 years in the total pool of PCI constantly increases. Number of patients with pronounced obesity also grows each year. Radial approach for PCI allows to substantially decrease rate of peripheral complications at the account of lowered rate of bleedings, and to shorten duration of hospitalization. In this literature review we present results of a number of relevant clinical studies including those which contained groups of elderly patients and of patients with obesity. We also have summarized main advantages and disadvantages of radial approach as compared with femoral approach for coronary angiography and PCI.

In vitro cytotoxicity of orthodontic primers.

PubMed

D'Antò, Vincenzo; Spagnuolo, Gianrico; Polito, Ilaria; Paduano, Sergio; Ambrosio, Luigi; Valletta, Rosa

2009-01-01

The aim of this study was to evaluate the cytotoxicity of four orthodontic primers: Transbond XT and Transbond MIP (3M, USA), Eagle Fluorsure (American Orthodontics, USA) and Ortho Solo (Ormco, USA). Balb 3T3 cells were exposed to different concentrations of primers (0-0.25 mg/ml). Mitochondrial dehydrogenase activity was evaluated by MTT assay and cell necrosis was measured by flow cytometry (propidium iodide staining). All the materials decreased cell viability in a dose related manner. Cytotoxicity of orthodontic primers based on concentrations which caused a 50% decrease of mitochondrial activity was ranked as follows: Transbond XT (45.57 mg/ml) > Eagle Fluorsure (49.27 mg/ml) > Transbond MIP (64.35 mg/ml) > Ortho solo (70.09 mg/ml). Our results suggest that the cytotoxic potencies demonstrated by orthodontic primers might be of clinical relevance since they disturbed cell metabolism and induced cell death in monolayer cultures.

Association of weight loss with improved disease activity in patients with rheumatoid arthritis: A retrospective analysis using electronic medical record data

PubMed Central

Kreps, David J.; Halperin, Florencia; Desai, Sonali P.; Zhang, Zhi Z.; Losina, Elena; Olson, Amber T.; Karlson, Elizabeth W.; Bermas, Bonnie L.; Sparks, Jeffrey A.

2018-01-01

Objective To evaluate the association between weight loss and rheumatoid arthritis (RA) disease activity. Methods We conducted a retrospective cohort study of RA patients seen at routine clinic visits at an academic medical center, 2012–2015. We included patients who had ≥2 clinical disease activity index (CDAI) measures. We identified visits during follow-up where the maximum and minimum weights occurred and defined weight change and CDAI change as the differences of these measures at these visits. We defined disease activity improvement as CDAI decrease of ≥5 and clinically relevant weight loss as ≥5 kg. We performed logistic regression analyses to establish the association between improved disease activity and weight loss and baseline BMI category (≥25 kg/m2 or <25 kg/m2). We built linear regression models to investigate the association between continuous weight loss and CDAI change among patients who were overweight/obese at baseline and who lost weight during follow-up. Results We analyzed data from 174 RA patients with a median follow-up of 1.9 years (IQR 1.3–2.4); 117 (67%) were overweight/obese at baseline, and 53 (31%) lost ≥5 kg during follow-up. Patients who were overweight/obese and lost ≥5 kg had three-fold increased odds of disease activity improvement compared to those who did not (OR 3.03, 95%CI 1.18–7.83). Among those who were overweight/obese at baseline, each kilogram weight loss was associated with CDAI improvement of 1.15 (95%CI 0.42–1.88). Our study was limited by using clinical data from a single center without fixed intervals for assessments. Conclusion Clinically relevant weight loss (≥5 kg) was associated with improved RA disease activity in the routine clinical setting. Further studies are needed for replication and to evaluate the effect of prospective weight loss interventions on RA disease activity. PMID:29606976

Impact of a novel teaching method based on feedback, activity, individuality and relevance on students’ learning

PubMed Central

Brooks, William S.; Laskar, Simone N.; Benjamin, Miles W.; Chan, Philip

2016-01-01

Objectives 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. Methods 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. Results 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. Conclusions 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. PMID:26995588

The Hypothesis-Driven Physical Examination.

PubMed

Garibaldi, Brian T; Olson, Andrew P J

2018-05-01

The physical examination remains a vital part of the clinical encounter. However, physical examination skills have declined in recent years, in part because of decreased time at the bedside. Many clinicians question the relevance of physical examinations in the age of technology. A hypothesis-driven approach to teaching and practicing the physical examination emphasizes the performance of maneuvers that can alter the likelihood of disease. Likelihood ratios are diagnostic weights that allow clinicians to estimate the post-probability of disease. This hypothesis-driven approach to the physical examination increases its value and efficiency, while preserving its cultural role in the patient-physician relationship. Copyright © 2017 Elsevier Inc. All rights reserved.

Virtual reality simulator: demonstrated use in neurosurgical oncology.

PubMed

Clarke, David B; D'Arcy, Ryan C N; Delorme, Sebastien; Laroche, Denis; Godin, Guy; Hajra, Sujoy Ghosh; Brooks, Rupert; DiRaddo, Robert

2013-04-01

The overriding importance of patient safety, the complexity of surgical techniques, and the challenges associated with teaching surgical trainees in the operating room are all factors driving the need for innovative surgical simulation technologies. Despite these issues, widespread use of virtual reality simulation technology in surgery has not been fully implemented, largely because of the technical complexities in developing clinically relevant and useful models. This article describes the successful use of the NeuroTouch neurosurgical simulator in the resection of a left frontal meningioma. The widespread application of surgical simulation technology has the potential to decrease surgical risk, improve operating room efficiency, and fundamentally change surgical training.

Clinically Relevant Outcome Measures Following Limb Osseointegration; Systematic Review of the Literature.

PubMed

Al Muderis, Munjed M; Lu, William Y; Li, Jiao Jiao; Kaufman, Kenton; Orendurff, Michael; Highsmith, M Jason; Lunseth, Paul A; Kahle, Jason T

2018-02-01

The current standard of care for an amputee is a socket-based prostheses. An osseointegrated implant (OI) is an alternative for prosthetic attachment. Osseointegration addresses reported problems related to wearing a socket interface, such as skin issues, discomfort, diminished function, quality of life, prosthetic use, and abandonment. The purpose of this report is to systematically review current literature regarding OI to identify and categorize the reported clinically relevant outcome measures, rate the quality of available evidence, and synthesize the findings. A multidisciplinary team used PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methods. Search methodology was based on identifying clinically relevant articles. Three databases were searched: PubMed, CINAHL, and Web of Science. Clinical studies with aggregated data reporting at least 1 clinically relevant outcome measure were included. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criterion was used for critical appraisal and recommendations. This review identified 21 clinically relevant observational studies. Outcome measures were categorized into the following 9 categories: vibratory stimulation, complications, biomechanics, economics, patient-reported outcome measures, electromyography, x-ray, physical functional performance, and energy consumption. This systematic review consisted of Level III and IV observational studies. Homogeneous outcome measures with strong psychometric properties across prospective studies do not exist to date. Higher-level, prospective, randomized, long-term, clinically relevant trials are needed to prove efficacy of OI compared with socket prosthetic attachment. Osseointegration was at least equivalent to sockets in most studies. In some cases, it was superior. Osseointegration represents a promising alternative to socket prosthetic attachments for extremity amputees. Therapeutic Level III. See Instructions for Authors for a complete description of levels of 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.

Hypocaloric high-protein diet improves clinical and biochemical markers in patients with nonalcoholic fatty liver disease (NAFLD).

PubMed

Bezerra Duarte, Sebastião Mauro; Faintuch, Joel; Stefano, José Tadeu; Sobral de Oliveira, Maria Beatriz; de Campos Mazo, Daniel Ferraz; Rabelo, Fabiola; Vanni, Denise; Nogueira, Monize Aydar; Carrilho, Flair José; Marques Souza de Oliveira, Claudia Pinto

2014-01-01

To investigate the role of hypocaloric highprotein diet, a prospective clinical study was conducted in NAFLD patients. Pre-versus post-interventional data were analyzed in 48 stable NAFLD patients (submitted to a hypocaloric high-protein diet during 75 days. Variables included anthropometrics (body mass index/ BMI and waist circumference/WC), whole-body and segmental bioimpedance analysis and biochemical tests. Diet compliance was assessed by interviews every two weeks. BMI, WC and body fat mass remained relatively stable (-1.3%, -1.8% and -2.5% respectively, no significance). HDL- cholesterol increased (P < 0.05) whereas total, LDL and VLDL cholesterol, triglycerides, aspartate aminotransferase/ AST, gamma glutamyltransferase/GGT, alkaline phosphatase/ AP, fasting blood glucose and glycated hemoglobin/ HbA1c decreased (P < 0.05). When patients were stratified according to increase (22/48, 45.8%) and decrease (21/48, 43.8%) of BMI, association between weight decrease and liver benefit could be elicited in such circumstances for ALT, AP and AST/ALT ratio. No change could be demonstrated in patients who gained weight. Multivariate assessment confirmed that waist circumference, ferritin, triacylglycerol, and markers of glucose homeostasis were the most relevant associated with liver enzymes. Ours results are consistent with the literature of calorie restriction in the management of NAFLD. Changes in lifestyle and weight loss are recommended for NAFLD patients. European guidelines also support this recommendation. This is the first study that demonstrated that a high protein, hypocaloric diet were associated with improvement of lipid profile, glucose homeostasis and liver enzymes in NAFLD independent on BMI decrease or body fat mass reduction.

Accelerated autoantibody clearance by intravenous immunoglobulin therapy: studies in experimental models to determine the magnitude and time course of the effect.

PubMed

Bleeker, W K; Teeling, J L; Hack, C E

2001-11-15

Recently, it has been postulated that the beneficial effect of intravenous immunoglobulins (IVIGs) in antibody-mediated autoimmune disorders is based on accelerated catabolism of autoantibodies. In the current study, in vivo experiments were performed with mice in which autoantibody production was mimicked by continuous infusion of monoclonal antibodies. In this model, a single dose of IVIG reduced the plasma concentrations of the infused immunoglobulin (Ig)G1 monoclonal antibody (mAb) by approximately 40% after 3 days, whereas the concentration of an IgA mAb was not affected. To extrapolate these findings to humans, a computational model for IgG clearance was established that accurately predicted the time course and magnitude of the decrease in IgG plasma levels observed in mice. Adapted for humans, this model predicted a gradually occurring decrease in autoantibody levels after IVIG administration (2 g/kg), with a maximum reduction of approximately 25% after 3 to 4 weeks and a continued decrease of several months. In conclusion, a single high dose of IVIG induces a relatively small but long-lasting reduction of autoantibody levels by accelerated IgG clearance. This mechanism has clinical relevance in the sense that it can fully explain, as the sole mechanism, the gradual decrease in autoantibody levels observed in several patient studies. However, in some clinical studies, larger or more rapid effects have been observed that cannot be explained by accelerated clearance. Hence, IVIG can also reduce autoantibody levels through mechanisms such as down-regulation of antibody production or neutralization by anti-idiotypic antibodies.

Preliminary description of aging cats and dogs presented to a New Zealand first-opinion veterinary clinic at end-of-life.

PubMed

Gates, M C; Hinds, H J; Dale, A

2017-11-01

AIMS To conduct a preliminary investigation into the chronic disease conditions and clinical signs present in aging New Zealand companion animals at end-of-life and to describe the timing, circumstances, and manner of death. METHODS The medical records database of a first-opinion, companion animal, veterinary practice in Auckland, New Zealand was searched to identify all canine and feline patients ≥7 years of age that were subjected to euthanasia or cremated in the period between July 2012-June 2014. The free-text medical notes were analysed for information on the circumstances surrounding the death, previous diagnoses of chronic disease conditions, and the presence of clinical signs associated with decreased quality-of-life at the time of euthanasia. RESULTS The median age at death was 15 (max 22) years for the 130 cats and 12 (max 17) years for the 68 dogs in the study sample. Euthanasia at the clinic was carried out for 119/130 (91%) cats and 62/68 (91%) dogs, with the remainder recorded as having an unassisted death. The frequency of deaths was highest during December for both cats and dogs. Cost was mentioned as an issue in the medical records for 39/181 (21.6%) patients that were subjected to euthanasia. At the time of euthanasia, 92/119 (77.3%) cats and 43/62 (69.4%) dogs were recorded as having >1 clinical sign associated with a decreased quality-of-life. Inappetence and non-specific decline were the two most commonly recorded clinical signs for both dogs and cats. Cardiovascular disease (44/130, 34%), renal failure (40/130, 31%), and malignant neoplasia (36/130, 28%) were the most common chronic disease conditions recorded for cats. Degenerative joint disease (22/68, 32%), malignant neoplasia (14/68, 21%), and cardiovascular disease (8/68, 12%) were the most common chronic disease conditions recorded for dogs. CONCLUSIONS AND CLINICAL RELEVANCE These preliminary findings highlight that aging companion animals in New Zealand frequently have chronic disease conditions and clinical signs that may potentially be associated with decreased quality-of-life at the time of death. Further in-depth studies are required to determine whether there is a greater role for veterinarians in counselling owners about end-of-life care and euthanasia decisions.

Mechanisms and disease relevance of neutrophil extracellular trap formation.

PubMed

Van Avondt, Kristof; Hartl, Dominik

2018-03-15

While the microscopic appearance of neutrophil extracellular traps (NETs) has fascinated basic researchers since its discovery, the (patho)physiological mechanisms triggering NET release, the disease relevance and clinical translatability of this unconventional cellular mechanism remained poorly understood. Here, we summarize and discuss current concepts of the mechanisms and disease relevance of NET formation. © 2018 Stichting European Society for Clinical Investigation Journal Foundation.

Parylene MEMS patency sensor for assessment of hydrocephalus shunt obstruction.

PubMed

Kim, Brian J; Jin, Willa; Baldwin, Alexander; Yu, Lawrence; Christian, Eisha; Krieger, Mark D; McComb, J Gordon; Meng, Ellis

2016-10-01

Neurosurgical ventricular shunts inserted to treat hydrocephalus experience a cumulative failure rate of 80 % over 12 years; obstruction is responsible for most failures with a majority occurring at the proximal catheter. Current diagnosis of shunt malfunction is imprecise and involves neuroimaging studies and shunt tapping, an invasive measurement of intracranial pressure and shunt patency. These patients often present emergently and a delay in care has dire consequences. A microelectromechanical systems (MEMS) patency sensor was developed to enable direct and quantitative tracking of shunt patency in order to detect proximal shunt occlusion prior to the development of clinical symptoms thereby avoiding delays in treatment. The sensor was fabricated on a flexible polymer substrate to eventually allow integration into a shunt. In this study, the sensor was packaged for use with external ventricular drainage systems for clinical validation. Insights into the transduction mechanism of the sensor were obtained. The impact of electrode size, clinically relevant temperatures and flows, and hydrogen peroxide (H2O2) plasma sterilization on sensor function were evaluated. Sensor performance in the presence of static and dynamic obstruction was demonstrated using 3 different models of obstruction. Electrode size was found to have a minimal effect on sensor performance and increased temperature and flow resulted in a slight decrease in the baseline impedance due to an increase in ionic mobility. However, sensor response did not vary within clinically relevant temperature and flow ranges. H2O2 plasma sterilization also had no effect on sensor performance. This low power and simple format sensor was developed with the intention of future integration into shunts for wireless monitoring of shunt state and more importantly, a more accurate and timely diagnosis of shunt failure.

Are age-appropriate antibiotic formulations missing from the WHO list of essential medicines for children? A comparison study.

PubMed

Ivanovska, Verica; Leufkens, Hubert G; Rademaker, Carin Ma; Zisovska, Elizabeta; Pijnenburg, Mariëlle W; van Dijk, Liset; Mantel-Teeuwisse, Aukje K

2017-04-01

There is a global call for formulations, which are better suited for children of different age categories and in a variety of settings. One key public health area of interest is age-appropriate paediatric antibiotics. We aimed to identify clinically relevant paediatric formulations of antibiotics listed on pertinent formularies that were not on the WHO Essential Medicines List for Children (EMLc). We compared four medicines lists versus the EMLc and contrasted paediatric antibiotic formulations in relation to administration routes, dosage forms and/or drug strengths. The additional formulations on comparator lists that differed from the EMLc formulations were evaluated for their added clinical values and costs. The analysis was based on 26 EMLc antibiotics. Seven oral and two parenteral formulations were considered clinically relevant for paediatric use. Frequently quoted benefits of oral formulations included: filling the gap of unmet therapeutic needs in certain age/weight groups (phenoxymethylpenicillin and metronidazole oral liquids, and nitrofurantoin capsules), and simplified administration and supply advantages (amoxicillin dispersible tablets, clyndamycin capsules, cloxacillin tablets, and sulfamethoxazole+trimethoprim tablets). Lower doses of ampicillin and cefazolin powder for injection could simplify the dosing in newborns and infants, reduce the risk of medical errors, and decrease the waste of medicines, but may target only narrow age/weight groups. The identified additional formulations of paediatric antibiotics on comparator lists may offer clinical benefits for low-resource settings, including simplified administration and increased dosing accuracy. The complexity of both procuring and managing multiple strengths and formulations also needs to be considered. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Type D patients report poorer health status prior to and after cardiac rehabilitation compared to non-type D patients.

PubMed

Pelle, Aline J; Erdman, Ruud A M; van Domburg, Ron T; Spiering, Marquita; Kazemier, Marten; Pedersen, Susanne S

2008-10-01

Type D personality is an emerging risk factor in coronary artery disease (CAD). Cardiac rehabilitation (CR) improves outcomes, but little is known about the effects of CR on Type D patients. We examined (1) variability in Type D caseness following CR, (2) Type D as a determinant of health status, and (3) the clinical relevance of Type D as a determinant of health status compared to cardiac history. CAD patients (n = 368) participating in CR completed the Type D Scale, the Short-Form Health Survey 36 pre- and post-CR, and the Hospital Anxiety and Depression Scale pre-CR, to assess health status and depressive and anxious symptomatology, respectively. The prevalence of Type D decreased from 26.6% to 20.7% (p = 0.012) following CR, but Type D caseness remained stable in 81% of patients. Health status significantly improved following CR [F(1,359) = 17.48, p < 0.001], adjusting for demographic and clinical factors and anxious and depressive symptoms. Type D patients reported poorer health status [F(1,359) = 10.40, p = 0.001], with the effect of Type D being stable over time [F(1,359) = 0.49, p = 0.48]. Patients with a cardiac history benefited less from CR [F(1,359) = 5.76, p = 0.02]. The influence of Type D on health status was larger compared to that for cardiac history, as indicated by Cohen's effect size index. Type D patients reported poorer health status compared to non-Type D patients pre- and post-CR. In the majority of patients, CR did not change Type D caseness, with Type D being associated with a stable and clinically relevant effect on outcome. These high-risk patients should be identified in clinical practice and may require adjunctive interventions.

The selective estrogen receptor alpha agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: a phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine.

PubMed

van Vollenhoven, Ronald F; Houbiers, Jos G A; Buttgereit, Frank; In 't Hout, Joanna; Boers, Maarten; Leij, Susanne; Kvien, Tore K; Dijkmans, Ben A C; Szczepański, Leszek; Szombati, Istvan; Sierakowski, Stanislaw; Miltenburg, André M M

2010-02-01

Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor alpha (ERalpha) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity. A 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-finding, proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28). Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose-related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial. The observed lack of clinical benefit in RA patients treated with an ERalpha agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERalpha-mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.

A Multifactorial Weight Reduction Programme for Children with Overweight and Asthma: A Randomized Controlled Trial

PubMed Central

Willeboordse, Maartje; van de Kant, Kim D. G.; Tan, Frans E. S.; Mulkens, Sandra; Schellings, Julia; Crijns, Yvonne; van der Ploeg, Liesbeth; van Schayck, Constant P.; Dompeling, Edward

2016-01-01

Background There is increasing evidence that obesity is related to asthma development and severity. However, it is largely unknown whether weight reduction can influence asthma management, especially in children. Objective To determine the effects of a multifactorial weight reduction intervention on asthma management in overweight/obese children with (a high risk of developing) asthma. Methods An 18-month weight-reduction randomized controlled trial was conducted in 87 children with overweight/obesity and asthma. Every six months, measurements of anthropometry, lung function, lifestyle parameters and inflammatory markers were assessed. Analyses were performed with linear mixed models for longitudinal analyses. Results After 18 months, the body mass index-standard deviation score decreased by -0.14±0.29 points (p<0.01) in the intervention group and -0.12±0.34 points (p<0.01) in the control group. This change over time did not differ between groups (p>0.05). Asthma features (including asthma control and asthma-related quality of life) and lung function indices (static and dynamic) improved significantly over time in both groups. The FVC% predicted improved over time by 10.1 ± 8.7% in the intervention group (p<0.001), which was significantly greater than the 6.1 ± 8.4% in the control group (p<0.05). Conclusions & clinical relevance Clinically relevant improvements in body weight, lung function and asthma features were found in both the intervention and control group, although some effects were more pronounced in the intervention group (FVC, asthma control, and quality of life). This implies that a weight reduction intervention could be clinically beneficial for children with asthma. Trial Registration ClinicalTrials.gov NCT00998413 PMID:27294869

Clinical Relevance of IgE to Profilin and/or Polcalcin in Pollen-Sensitized Patients.

PubMed

San Nicoló, Marion; Braun, Thomas; Eder, Katharina; Berghaus, Alexander; Gröger, Moritz

2016-01-01

Component-resolved diagnostics is gaining importance in allergy diagnostics. Allergen extracts contain components with different rates of prevalence and clinical relevance, which can be subdivided at molecular level into major and minor allergens. Clinical complaints are usually triggered by major allergens, while the role of sensitization to the panallergens profilin and polcalcin still remains unclear. Eighty-six patients from southern Bavaria with sensitization to the panallergens profilin (Bet v 2/Phl p 12) and/or polcalcin (Bet v 4/Phl p 7) were examined in regard to their sensitization to the 4 main botanic denominations Betulaceae, Oleaceae, Poaceae and Asteraceae by skin prick test and measurement of specific immunoglobulin E antibodies to natural allergen extracts as well as major allergen components rPhl p 1/5, rBet v 1, rOle e 1 and nArt v 1. Sensitization was rated as clinically relevant or irrelevant depending on anamnesis or intranasal allergen challenge. Regarding the 4 botanic denominations, there was no significant difference in the incidence of sensitization to the panallergens profilin, polcalcin or both. The sensitization pattern does not alter when subdividing the cohort into clinically relevant and silent sensitization. We did not find clinically symptomatic sensitization to panallergens without cosensitization to a major allergen. Our results suggest that sole sensitization to panallergens seems to have no clinical relevance in allergic rhinoconjunctivitis. Clinical complaints seem to be triggered manly by major allergens. Thus, component-resolved allergy diagnostics is crucial in the diagnosis and treatment of polysensitized patients. © 2016 S. Karger AG, Basel.

The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse

PubMed Central

Jacobsen, Jacob P.R.; Plenge, Per; Sachs, Benjamin D.; Pehrson, Alan L.; Cajina, Manuel; Du, Yunzhi; Roberts, Wendy; Rudder, Meghan L.; Dalvi, Prachiti; Robinson, Taylor J.; O’Neill, Sharon P.; Khoo, King S.; Morillo, Connie Sanchez; Zhang, Xiaodong; Caron, Marc G.

2015-01-01

Rationale Escitalopram is a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inhibition of the SERT, curtailing the elevation of extracellular 5-hydroxytryptamine (5-HTExt), and antidepressant efficacy. Further, it has been suggested that a putative allosteric binding site is important for binding of escitalopram to the primary, orthosteric, site, and for R-citalopram’s inhibition hereof. Objectives Primary: Investigate at the human (h)SERT, at clinical relevant doses, whether R-citalopram antagonizes escitalopram-induced 5-HTExt elevation. Secondary: Investigate whether abolishing the putative allosteric site affects escitalopram-induced 5-HTExt elevation and/or modulates the effect of R-citalopram. Methods Recombinant technology; in vivo microdialysis; receptor binding; pharmacokinetics; 5-HT sensitive behaviors (tail suspension, marble burying). Results We generated mice expressing either the wild-type human SERT (hSERTWT) or hSERT carrying amino acid substitutions (A505V, L506F, I507L, S574T and I575T) collectively abolishing the putative allosteric site (hSERTALI/VFL+SI/TT). One mg/kg escitalopram yielded clinical relevant plasma levels and brain levels consistent with therapeutic SERT occupancy. Importantly, escitalopram-induced 5-HTExt elevation was not decreased by R-citalopram co-treatment. Further, escitalopram-induced 5-HTExt elevation was not affected by loss of the allosteric site. The behavioral effects of the clinically relevant escitalopram dose were small, tending to be enhanced by R-citalopram co-administration. Conclusions We find no evidence that R-citalopram directly antagonizes escitalopram or that the putative allosteric site is important for hSERT inhibition by escitalopram. Our findings points to mechanisms for R-citalopram antagonism of escitalopram’s antidepressant action other than direct antagonistic binding interactions at the hSERT. PMID:24810106

TARGETING POLYMER THERAPEUTICS TO BONE

PubMed Central

Low, Stewart; Kopeček, Jindřich

2012-01-01

An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides an unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drug-carrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems. PMID:22316530

Update on GH therapy in adults.

PubMed

Boguszewski, Cesar Luiz

2017-01-01

Over the last three decades, short- and long-term observational studies, clinical trials, systematic reviews, and meta-analyses have provided relevant information on the efficacy and safety of growth hormone (GH) replacement therapy in adults with GH deficiency (AGHD). The knowledge acquired during this time has been compiled into different guidelines that offer clinicians an evidence-based, practical approach for the management of AGHD. There are, however, still open questions in some key areas in which recommendations are supported by only moderate or weak evidence. In the last recent years, the development of long-acting GH preparations has created new therapeutic possibilities by decreasing injection frequency, improving adherence and thereby potentially maximizing clinical outcomes. The aims of this review are to advance our understanding on the diagnosis and treatment of AGHD and to present an update and future perspectives on the use of long-acting GH preparations.

[Protocol for peripheral parenteral nutrition management ready to use in surgical patients].

PubMed

Pinzón Espitia, Olga Lucia; Varón Vega, Martha Liliana

2014-10-03

Patients undergoing elective surgery, require a comprehensive clinical treatment that tends to maintain or prevent deterioration of nutritional status and promote clinical outcomes, and in turn improve the safety of parenteral nutrition therapy through optimization of technology, as a option aimed at minimizing risk and lower operating costs in institutions providing health services. To review the literature in order to study the requirements and recommendations of peripheral parenteral nutritional support and / or complementary ready to use in people undergoing surgery. Data synthesis after reviewing the relevant literature, to allow the protocol design. The search was conducted in the following databases: PubMed, Medline, Embase and ScienceDirect. Peripheral parenteral nutrition is a ready to use alternative nutritional support that improves the contribution Protein-Energy and demonstrate improvements in patient safety, decrease costs and increase patient satisfaction. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Technology as friend or foe? Do electronic health records increase burnout?

PubMed

Ehrenfeld, Jesse M; Wanderer, Jonathan P

2018-06-01

To summarize recent relevant studies regarding the use of electronic health records and physician burnout. Recently acquired knowledge regarding the relationship between electronic health record use, professional satisfaction, burnout, and desire to leave clinical practice are discussed. Adoption of electronic health records has increased across the United States and worldwide. Although electronic health records have many benefits, there is growing concern about the adverse consequences of their use on physician satisfaction and burnout. Poor usability, incongruent workflows, and the addition of clerical tasks to physician documentation requirements have been previously highlighted as ongoing concerns with electronic health record adoption. In multiple recent studies, electronic health records have been shown to decrease professional satisfaction, increase burnout, and the likelihood that a physician will reduce or leave clinical practice. One interventional study demonstrated a positive effect of a dedicated electronic health record entry clerk on physicians working in an outpatient practice.

Microfluidics and Coagulation Biology

PubMed Central

Colace, Thomas V.; Tormoen, Garth W.

2014-01-01

The study of blood ex vivo can occur in closed or open systems, with or without flow. Microfluidic devices facilitate measurements of platelet function, coagulation biology, cellular biorheology, adhesion dynamics, pharmacology, and clinical diagnostics. An experimental session can accommodate 100s to 1000s of unique clotting events. Using microfluidics, thrombotic events can be studied on defined surfaces of biopolymers, matrix proteins, and tissue factor under constant flow rate or constant pressure drop conditions. Distinct shear rates can be created on a device with a single perfusion pump. Microfluidic devices facilitated the determination of intraluminal thrombus permeability and the discovery that platelet contractility can be activated by a sudden decrease in flow. Microfluidics are ideal for multicolor imaging of platelets, fibrin, and phosphatidylserine and provide a human blood analog to the mouse injury models. Overall, microfluidic advances offer many opportunities for research, drug testing under relevant hemodynamic conditions, and clinical diagnostics. PMID:23642241

Nanoengineered implant as a new platform for regenerative nanomedicine using 3D well-organized human cell spheroids

PubMed Central

Keller, Laetitia; Idoux-Gillet, Ysia; Wagner, Quentin; Eap, Sandy; Brasse, David; Schwinté, Pascale; Arruebo, Manuel; Benkirane-Jessel, Nadia

2017-01-01

In tissue engineering, it is still rare today to see clinically transferable strategies for tissue-engineered graft production that conclusively offer better tissue regeneration than the already existing technologies, decreased recovery times, and less risk of complications. Here a novel tissue-engineering concept is presented for the production of living bone implants combining 1) a nanofibrous and microporous implant as cell colonization matrix and 2) 3D bone cell spheroids. This combination, double 3D implants, shows clinical relevant thicknesses for the treatment of an early stage of bone lesions before the need of bone substitutes. The strategy presented here shows a complete closure of a defect in nude mice calvaria after only 31 days. As a novel strategy for bone regenerative nanomedicine, it holds great promises to enhance the therapeutic efficacy of living bone implants. PMID:28138241

Protein-targeted corona phase molecular recognition

PubMed Central

Bisker, Gili; Dong, Juyao; Park, Hoyoung D.; Iverson, Nicole M.; Ahn, Jiyoung; Nelson, Justin T.; Landry, Markita P.; Kruss, Sebastian; Strano, Michael S.

2016-01-01

Corona phase molecular recognition (CoPhMoRe) uses a heteropolymer adsorbed onto and templated by a nanoparticle surface to recognize a specific target analyte. This method has not yet been extended to macromolecular analytes, including proteins. Herein we develop a variant of a CoPhMoRe screening procedure of single-walled carbon nanotubes (SWCNT) and use it against a panel of human blood proteins, revealing a specific corona phase that recognizes fibrinogen with high selectivity. In response to fibrinogen binding, SWCNT fluorescence decreases by >80% at saturation. Sequential binding of the three fibrinogen nodules is suggested by selective fluorescence quenching by isolated sub-domains and validated by the quenching kinetics. The fibrinogen recognition also occurs in serum environment, at the clinically relevant fibrinogen concentrations in the human blood. These results open new avenues for synthetic, non-biological antibody analogues that recognize biological macromolecules, and hold great promise for medical and clinical applications. PMID:26742890

Cryotherapy and ankle motion in chronic venous disorders

PubMed Central

Kelechi, Teresa J.; Mueller, Martina; Zapka, Jane G.; King, Dana E.

2013-01-01

This study compared ankle range of motion (AROM) including dorsiflexion, plantar flexion, inversion and eversion, and venous refill time (VRT) in leg skin inflamed by venous disorders, before and after a new cryotherapy ulcer prevention treatment. Fifty-seven-individuals participated in the randomized clinical trial; 28 in the experimental group and 29 received usual care only. Results revealed no statistically significant differences between the experimental and usual care groups although AROM measures in the experimental group showed a consistent, non-clinically relevant decrease compared to the usual care group except for dorsiflexion. Within treatment group comparisons of VRT results showed a statistically significant increase in both dorsiflexion and plantar flexion for patients with severe VRT in the experimental group (6.9 ± 6.8; p = 0.002 and 5.8 ± 12.6; p = 0.02, respectively). Cryotherapy did not further restrict already compromised AROM, and in some cases, there were minor improvements. PMID:23516043

Syphilis: The Renaissance of an Old Disease with Oral Implications

PubMed Central

Carlos, Roman

2009-01-01

Syphilis is caused by Treponema pallidum an anaerobic filamentous spirochete. In recent years, striking outbreaks have occurred in USA, Canada, Russia, China and some areas of Central and Eastern Europe. Main epidemiology changes reflect sex industry, sexual promiscuity, decreasing use of barrier protection (i.e. condoms) due to false sense of security that nowadays sexually transmitted diseases are curable and lack of pertinent knowledge. Considering that the initial presentation of syphilis may be the oral cavity, it is of great relevance to include this disease in the differential diagnosis of unusual oral ulcerations and white patches. Primary syphilis is a highly infectious disease in which inappropriate treatment may be apparently curative while the patient remains highly infectious. It is then of pivotal importance that clinicians maintain a high clinical index of suspicion. At the present time, clinical-pathologic correlation together with serologic studies remain essential in establishing the diagnosis of syphilis. PMID:20596972

Interviews with children about their mental health problems: The congruence and validity of information that children report.

PubMed

Macleod, Emily; Woolford, June; Hobbs, Linda; Gross, Julien; Hayne, Harlene; Patterson, Tess

2017-04-01

To obtain a child's perspective during a mental health assessment, he or she is usually interviewed. Although researchers and clinicians generally agree that it is beneficial to hear a child's account of his or her presenting issues, there is debate about whether children provide reliable or valid clinical information during these interviews. Here, we examined whether children provide clinically and diagnostically relevant information in a clinical setting. In all, 31 children aged 5-12-years undergoing mental health assessments were asked open-ended questions about their presenting problems during a semi-structured interview. We coded the information that children reported to determine whether it was clinically relevant and could be used to diagnose their problems and to formulate and plan treatment. We also coded children's information to determine whether it was congruent with the children's presenting problems and their eventual clinical diagnoses. Most of the information that children reported was clinically relevant and included information about behaviour, affect, temporal details, thoughts, people, the environment, and the child's physical experiences. The information that children reported was also clinically valid; it was congruent with the problems that were discussed (84%) and also with the eventual diagnosis that the child received after a complete assessment (74%). We conclude that children can contribute relevant, clinically useful, valid information during clinical psychological assessments.

New Perspectives on the Diagnosis of Allergy to Anisakis spp.

PubMed

Moneo, Ignacio; Carballeda-Sangiao, Noelia; González-Muñoz, Miguel

2017-05-01

To compare the prevalence of sensitization in different countries based on specific IgE values and to evaluate the use of isolated native or recombinant allergens for diagnosis. Isolated allergens help in the diagnosis of truly sensitized patients avoiding false positives due to cross-reactions. Their use is therefore highly recommended, especially when used as a combination of several relevant allergens. The use of purified allergens allows an accurate diagnosis and this has led to three important findings: (1) in addition to the digestive route of sensitization, occupational and non-digestive exposure seems to be clinically relevant. (2) The parasite appears as an important agent for chronic urticaria. And (3) in endemic countries, the amount of highly sensitized subjects in the general population could be as high as 7%. Adequate information to asymptomatic patients on fish consumption habits would avoid new contacts with parasite allergens and decrease their specific IgE levels and consequently the appearance of acute or chronic episodes induced by the parasite.

Methylphenidate-Elicited Dopamine Increases in Ventral Striatum Are Associated with Long-Term Symptom Improvement in Adults with Attention Deficit Hyperactivity Disorder

PubMed Central

Volkow, Nora D.; Wang, Gene-Jack; Tomasi, Dardo; Kollins, Scott H.; Wigal, Tim L.; Newcorn, Jeffrey H.; Telang, Frank W.; Fowler, Joanna S.; Logan, Jean; Wong, Christopher T.; Swanson, James M.

2012-01-01

Stimulant medications, such as methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and [11C]raclopride (D2/D3 receptor radioligand sensitive to competition with endogenous dopamine). Clinical responses were assessed using the Conners' Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous methylphenidate significantly increased dopamine in striatum (assessed as decreases in D2/D3 receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response. PMID:22262882

Development of a family functioning scale for major depressive disorder.

PubMed

DiBenedetti, Dana Britt; Danchenko, Natalya; François, Clement; Lewis, Sandra; Davis, Kimberly H; Fehnel, Sheri E

2012-03-01

To better understand depression's impact on family functioning from the perspectives of patients with major depressive disorder (MDD) and their partners; to develop and test patient and partner versions of a new self-reported measure, the Depression and Family Functioning Scale (DFFS), for use in clinical trials. Concept elicitation interviews were conducted with 32 adults with clinician-diagnosed moderate-to-severe MDD and their respective partners. Twenty-six items were drafted to address relevant aspects of family functioning and were then tested and refined through two iterative sets of cognitive debriefing interviews, each conducted by the same pair of highly experienced researchers, including a licensed clinical psychologist. Depression negatively affects family functioning through poorer communication, increased conflicts, decreased family interaction, and decreased intimacy. No existing instrument measured all domains of interest, or had been rigorously developed and psychometrically validated in the target populations. The draft DFFS items generally tested well and only minor modifications were made to the items after the second set of interviews. Both patients and partners indicated that the final set of 15 DFFS items addresses all concepts of importance. The DFFS evaluates the impact of depression on family functioning and has the potential to provide important information that can facilitate a more comprehensive evaluation of new treatments in clinical trial settings. Although MDD severity was not confirmed with a standardized interview, in clinical practice in the US, MDD is generally not diagnosed with the use of a structured clinical interview or clinician-administered tool. In the current study, depression severity had little (if any) impact on the specific concepts elicited as being important to family functioning. In fact, patients with milder depression had more insight and were able to better articulate changes in family functioning with treatment.

Methylphenidate-Elicited Dopamine Increases in Ventral Striatum Are Associated with Long-Term Symptom Improvement in Adults with Attention Deficit Hyperactivity Disorder

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

Volkow N. D.; Wang G.; Volkow, N.D.

Stimulant medications, such as methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and [{sup 11}C]raclopride (D{sub 2}/D{sub 3} receptor radioligand sensitivemore » to competition with endogenous dopamine). Clinical responses were assessed using the Conners Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous methylphenidate significantly increased dopamine in striatum (assessed as decreases in D{sub 2}/D{sub 3} receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response.« less

Short-term changes in neck pain, widespread pressure pain sensitivity, and cervical range of motion after the application of trigger point dry needling in patients with acute mechanical neck pain: a randomized clinical trial.

PubMed

Mejuto-Vázquez, María J; Salom-Moreno, Jaime; Ortega-Santiago, Ricardo; Truyols-Domínguez, Sebastián; Fernández-de-Las-Peñas, César

2014-04-01

Randomized clinical trial. To determine the effects of trigger point dry needling (TrPDN) on neck pain, widespread pressure pain sensitivity, and cervical range of motion in patients with acute mechanical neck pain and active trigger points in the upper trapezius muscle. TrPDN seems to be effective for decreasing pain in individuals with upper-quadrant pain syndromes. Potential effects of TrPDN for decreasing pain and sensitization in individuals with acute mechanical neck pain are needed. Methods Seventeen patients (53% female) were randomly assigned to 1 of 2 groups: a single session of TrPDN or no intervention (waiting list). Pressure pain thresholds over the C5-6 zygapophyseal joint, second metacarpal, and tibialis anterior muscle; neck pain intensity; and cervical spine range-of-motion data were collected at baseline (pretreatment) and 10 minutes and 1 week after the intervention by an assessor blinded to the treatment allocation of the patient. Mixed-model analyses of variance were used to examine the effects of treatment on each outcome variable. Patients treated with 1 session of TrPDN experienced greater decreases in neck pain, greater increases in pressure pain threshold, and higher increases in cervical range of motion than those who did not receive an intervention at both 10 minutes and 1 week after the intervention (P<.01 for all comparisons). Between-group effect sizes were medium to large immediately after the TrPDN session (standardized mean score differences greater than 0.56) and large at the 1-week follow-up (standardized mean score differences greater than 1.34). The results of the current randomized clinical trial suggest that a single session of TrPDN may decrease neck pain intensity and widespread pressure pain sensitivity, and also increase active cervical range of motion, in patients with acute mechanical neck pain. Changes in pain, pressure pain threshold, and cervical range of motion surpassed their respective minimal detectable change values, supporting clinically relevant treatment effects. Level of Evidence Therapy, level 1b-.

Locating relevant patient information in electronic health record data using representations of clinical concepts and database structures.

PubMed

Pan, Xuequn; Cimino, James J

2014-01-01

Clinicians and clinical researchers often seek information in electronic health records (EHRs) that are relevant to some concept of interest, such as a disease or finding. The heterogeneous nature of EHRs can complicate retrieval, risking incomplete results. We frame this problem as the presence of two gaps: 1) a gap between clinical concepts and their representations in EHR data and 2) a gap between data representations and their locations within EHR data structures. We bridge these gaps with a knowledge structure that comprises relationships among clinical concepts (including concepts of interest and concepts that may be instantiated in EHR data) and relationships between clinical concepts and the database structures. We make use of available knowledge resources to develop a reproducible, scalable process for creating a knowledge base that can support automated query expansion from a clinical concept to all relevant EHR data.

[Laser biostimulation in the treatment of pleurisy].

PubMed

Milojević, Momir; Kuruc, Vesna

2003-01-01

Low-intensity lasers have been utilized in medicine in two ways: for local stimulation and for stimulation of acupuncture points. Literature data reveal that this method has been indiscriminately applied in psychiatry, rheumatology, gynecology, dermatology, otorhinolaryngology, in diverse acute and chronic pains, inflammations, vascular disorders, angina pectoris, bronchial asthma. Most commonly reported clinical effects are analgesia, spasmolytic and anti-inflammatory effects, as well as faster wound and bone healing. This prospective study analyses effects of laser biostimulation on patients with pleurisy. The analysis included 25 patients treated at the Institute of Lung Diseases in Sremska Kamenica during 2000, 2001 and 2002. Apart from conservative treatment, these patients were treated with laser biostimulation of acupuncture points and local region for ten days. During treatment, changes of present clinical signs, general symptoms, radiological findings, as well as changes of some relevant biochemical parameters were recorded. Results were compared with the control group which included the same number of patients, who differed from the examined group only by not being exposed to laser biostimulation. The examined group of patients with pleuritis presented with quicker resorption of pleural effusion, less pleural adhesions, more significant decrease of clinical symptoms, especially pain, as well as more significant increase of cortisol and immunoglobulin A and decrease of circulating immune complexes (CIC), leukocytes and sedimentation rate than the control group. Mechanisms of laser biostimulation in treatment of pleurisy were described in detail and the obtained results were correlated to those reported by other authors. 1. Patients with pleurisy undergoing laser stimulation presented with faster resorption of effusion and remission of the subjective symptoms, as well as significant decrease of biochemical acute inflammation parameters in the peripheral blood and therefore with faster recovery. 2. In patients with pleurisy laser treatment increases regenerative mechanisms of the pleural surface, thus decreasing the quantity of formed adhesions and resulting in better mobility of the diaphragm.

Selecting relevant and feasible measurement instruments for the revised Dutch clinical practice guideline for physical therapy in patients after stroke.

PubMed

Otterman, Nicoline; Veerbeek, Janne; Schiemanck, Sven; van der Wees, Philip; Nollet, Frans; Kwakkel, Gert

2017-07-01

To select relevant and feasible instruments for the revision of the Dutch clinical practice guideline for physical therapy in patients with stroke. In this implementation study a comprehensive proposal for ICF categories and matching instruments was developed, based on reliability and validity. Relevant instruments were then selected in a consensus round by 11 knowledge brokers who were responsible for the implementation of the selected instruments. The feasibility of the selected instruments was tested by 36 physical therapists at different work settings within stroke services. Finally, instruments that were deemed relevant and feasible were included in the revised guideline. A total of 28 instruments were recommended for inclusion in the revised guideline. Nineteen instruments were retained from the previous guideline. Ten new instruments were tested in clinical practice, seven of which were found feasible. Two more instruments were added after critical appraisal of the set of the measurement instruments. The revised guideline contains 28 relevant and feasible instrument selected and tested in clinical practice by physical therapists. Further education and implementation is needed to integrate instruments in clinical practice. Further research is proposed for developing and implementing a core set of measurement instruments to be used at fixed time points to establish data registries that allow for continuous improvement of rehabilitation for stroke patients. Implications for Rehabilitation The revised Dutch Stroke Physical Therapy Guideline recommends a total of 28 instruments, that are relevant and feasible for clinical practice of physical therapist in the different settings of stroke rehabilitation. The selection of instrument in daily practice should be part of the clinical reasoning process of PTs and be tailored to individual patients' needs and the degree of priority of the affected ICF category. Suggested education strategies for further integration of instruments in of the daily practice of PTs in Stroke Rehabilitation are: 'Training on the job' and 'peer assessment in clinical situations'.

Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture

PubMed Central

Malik, Deepika; Tarek, Mohamed; Caceres del Carpio, Javier; Ramirez, Claudio; Boyer, David; Kenney, M Cristina; Kuppermann, Baruch D

2014-01-01

Purpose To compare the safety profiles of antivascular endothelial growth factor (VEGF) drugs ranibizumab, bevacizumab, aflibercept and ziv-aflibercept on retinal pigment epithelium cells in culture. Methods Human retinal pigment epithelium cells (ARPE-19) were exposed for 24 h to four anti-VEGF drugs at 1/2×, 1×, 2× and 10× clinical concentrations. Cell viability and mitochondrial membrane potential assay were performed to evaluate early apoptotic changes and rate of overall cell death. Results Cell viability decreased at 10× concentrations in bevacizumab (82.38%, p=0.0001), aflibercept (82.68%, p=0.0002) and ziv-aflibercept (77.25%, p<0.0001), but not at lower concentrations. However, no changes were seen in cell viability in ranibizumab-treated cells at all concentrations including 10×. Mitochondrial membrane potential was slightly decreased in 10× ranibizumab-treated cells (89.61%, p=0.0006) and 2× and 10× aflibercept-treated cells (88.76%, 81.46%; p<0.01, respectively). A larger reduction in mitochondrial membrane potential was seen at 1×, 2× and 10× concentrations of bevacizumab (86.53%, 74.38%, 66.67%; p<0.01) and ziv-aflibercept (73.50%, 64.83% and 49.65% p<0.01) suggestive of early apoptosis at lower doses, including the clinical doses. Conclusions At clinical doses, neither ranibizumab nor aflibercept produced evidence of mitochondrial toxicity or cell death. However, bevacizumab and ziv-aflibercept showed mild mitochondrial toxicity at clinically relevant doses. PMID:24836865

Phlebotomy-induced anemia alters hippocampal neurochemistry in neonatal mice

PubMed Central

Wallin, Diana J.; Tkac, Ivan; Stucker, Sara; Ennis, Kathleen M.; Sola-Visner, Martha; Rao, Raghavendra; Georgieff, Michael K.

2015-01-01

Background Phlebotomy-induced anemia (PIA) is common in preterm infants. The hippocampus undergoes rapid differentiation during late fetal/early neonatal life and relies on adequate oxygen and iron to support oxidative metabolism necessary for development. Anemia shortchanges these two critical substrates, potentially altering hippocampal development and function. Methods PIA (hematocrit <25%) was induced in neonatal mice pups from postnatal day (P)3 to P14. Neurochemical concentrations in the hippocampus were determined using in vivo 1H NMR spectroscopy at 9.4T and compared with control animals at P14. Gene expression was assessed using qRT-PCR. Results PIA decreased brain iron concentration, increased hippocampal lactate and creatine concentrations, and decreased phosphoethanolamine (PE) concentration and the phosphocreatine/creatine ratio. Hippocampal transferrin receptor (Tfrc) gene expression was increased, while the expression of calcium/calmodulin-dependent protein kinase type II alpha (CamKIIα) was decreased in PIA mice. Conclusion This clinically relevant model of neonatal anemia alters hippocampal energy and phospholipid metabolism and gene expression during a critical developmental period. Low target hematocrits for preterm neonates in the NICU may have potential adverse neural implications. PMID:25734245

Complications and posttreatment care following invasive laser skin resurfacing: A review.

PubMed

Li, Dan; Lin, Shi-Bin; Cheng, Biao

2018-06-01

Laser skin resurfacing (LSR) has been used for facial rejuvenation for the last 20 years. Posttreatment care after LSR is essential to decrease the risk of complications. Currently, no unified standards or criteria exist for invasive LSR posttreatment care. We aimed to identify the optimal wound care timing and choice of specific local, systemic, and general medical measures required to decrease complications. We performed a systematic search of the PubMed/MEDLINE electronic databases and included only articles written and published in the English language, with no restrictions on the publication time (year). The search yielded 316 potentially relevant articles, 133 of which met our review criteria. Most of the studies on this topic have focused on wound care during the early stage, typically the first 2 weeks. Closed dressings may offer a more ideal, moist wound environment. The use of medications must be judicious. The ongoing emergence of new methods and products warrants evaluation in future large clinical trials. Familiarity with the complications following invasive LSR and the provision of optimal, effective, and timely posttreatment care may substantially decrease the risks associated with the treatment modality.

Total body water and total body potassium in anorexia nervosa

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

Dempsey, D.T.; Crosby, L.O.; Lusk, E.

1984-08-01

In the ill hospitalized patient with clinically relevant malnutrition, there is a measurable decrease in the ratio of the total body potassium to total body water (TBK/TBW) and a detectable increase in the ratio of total exchangeable sodium to total exchangeable potassium (Nae/Ke). To evaluate body composition analyses in anorexia nervosa patients with chronic uncomplicated semistarvation, TBK and TBW were measured by whole body K40 counting and deuterium oxide dilution in 10 females with stable anorexia nervosa and 10 age-matched female controls. The ratio of TBK/TBW was significantly (p less than 0.05) higher in anorexia nervosa patients than controls. Themore » close inverse correlation found in published studies between TBK/TBW and Nae/Ke together with our results suggest that in anorexia nervosa, Nae/Ke may be low or normal. A decreased TBK/TBW is not a good indicator of malnutrition in the anorexia nervosa patient. The use of a decreased TBK/TBW ratio or an elevated Nae/Ke ratio as a definition of malnutrition may result in inappropriate nutritional management in the patient with severe nonstressed chronic semistarvation.« less

The Relevance of Dietary Polyphenols in Cardiovascular Protection.

PubMed

Murillo, Ana G; Fernandez, Maria L

2017-01-01

The chemical structure of polyphenols consisting of aromatic rings, capable of quenching free radicals, makes them ideal candidates to protect against oxidation. Polyphenols are present in a variety of foods including grapes, berries, dark chocolate, coffee and tea to mention a few. A number of studies have shown that dietary polyphenols exert a protective effect against hypertension, dyslipidemias, inflammation, endothelial function and atherosclerosis, conditions associated with increased risk for cardiovascular disease. Studies indicate that by decreasing cholesterol absorption, polyphenols alter hepatic cholesterol homeostasis resulting in decreases in plasma lipids and reduction in atherogenic lipoproteins thus having a protective effect against atherosclerosis; polyphenols have also been shown to decrease the activity of enzymes involved in the renin-angiotensinaldosterone system and improve blood pressure. Further, they have been recognized to increase nitric oxide production and to improve endothelial function. In this review we will present some of the evidence derived from epidemiological studies, clinical interventions as well as animal and cell studies supporting the cardioprotective effects of dietary polyphenols. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers | Office of Cancer Genomics

Cancer.gov

Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions.

The effects of detomidine, romifidine or acepromazine on echocardiographic measurements and cardiac function in normal horses.

PubMed

Buhl, Rikke; Ersbøll, Annette K; Larsen, Nanna H; Eriksen, Lis; Koch, Jørgen

2007-01-01

To evaluate by echo- and electrocardiography the cardiac effects of sedation with detomidine hydrochloride, romifidine hydrochloride or acepromazine maleate in horses. An experimental study using a cross-over design without randomization. Eight clinically normal Standardbred trotters. Echocardiographic examinations (two-dimensional, guided M-mode and colour Doppler) were recorded on five different days. Heart rate (HR) and standard limb lead electrocardiograms were also obtained. Subsequently, horses were sedated with detomidine (0.01 mg kg(-1)), romifidine (0.04 mg kg(-1)) or acepromazine (0.1 mg kg(-1)) administered intravenously and all examinations repeated. Heart rate before treatment with the three drugs did not differ significantly (p = 0.98). Both detomidine and romifidine induced a significant decrease (p < 0.001) in HR during the first 25 minutes after sedation; while acepromazine had a varying effect on HR. For detomidine, there was a significant increase in LVIDd (left ventricular internal diameter in diastole; p = 0.034) and LVIDs (left ventricular internal diameter in systole; p < 0.001). In addition, a significant decrease was found in IVSs (the interventricular septum in systole; p < 0.001), LVFWs (the left ventricular free wall in systole; p = 0.002) and FS% (fractional shortening; p < 0.001). The frequency of pulmonary regurgitation was increased significantly (p < 0.001). Romifidine induced a significant increase in LVIDs (p < 0.001) and a significant decrease in IVSs (p < 0.001) and FS% (p = 0.002). Acepromazine had no significant effect upon any of the measured values. and clinical relevance The results indicate that sedation of horses with detomidine and to a lesser extent romifidine at the doses given in this study has a significant effect on heart function, echocardiographic measurements of heart dimensions and the occurrence of valvular regurgitation. Although the clinical significance of these results may be minimal, the potential effects of sedative drugs should be taken into account when echocardiographic variables are interpreted in clinical cases.

In vitro and clinical evaluation of OATP-mediated drug interaction potential of sacubitril/valsartan (LCZ696).

PubMed

Ayalasomayajula, S; Han, Y; Langenickel, T; Malcolm, K; Zhou, W; Hanna, I; Alexander, N; Natrillo, A; Goswami, B; Hinder, M; Sunkara, G

2016-08-01

Sacubitril/valsartan (LCZ696) has been recently approved for the treatment of heart failure (HF) patients with reduced ejection fraction. Several HF patients receive statins as co-medication. Because clearance of statins is meditated via OATP1B1/1B3, the inhibition potential of these transporters by LCZ696 analytes was evaluated in vitro. Furthermore, an open-label, fixed-sequence clinical study was conducted to determine the effect of LCZ696 on the exposure of simvastatin and its active metabolite simvastatin acid. In this clinical study, 26 healthy subjects received simvastatin 40 mg alone or in combination with LCZ696 or after 1 or 2 h of LCZ696 dosing. Although no significant inhibition by LBQ657 (an active metabolite of sacubitril) and valsartan was observed, sacubitril inhibited OATP1B1 and OATP1B3 in vitro, with IC50 of 1·91 and 3·81 μm, respectively. Upon co-administration of simvastatin with LCZ696, the Cmax of simvastatin and simvastatin acid decreased by 7% and 13%, respectively. When administered 1 h after LCZ696 dosing, the corresponding Cmax of simvastatin and simvastatin acid decreased by 16% and 4%, respectively. When administered 2 h after LCZ696 dosing, the Cmax of simvastatin decreased by 33% and that of simvastatin acid increased by 16%. However, no notable changes were observed in the AUCs of simvastatin or simvastatin acid upon co-administration or time-separated administration with LCZ696. No notable impact of simvastatin co-administration was observed on the pharmacokinetics of LCZ696 analytes. LCZ696 and simvastatin were generally well tolerated when administered alone or in combination. Overall, the results of this study suggest that although sacubitril inhibited OATP1B1 and OATP1B3 in vitro, it does not translate into any clinically relevant in vivo effect. © 2016 John Wiley & Sons Ltd.

Retrieving clinical evidence: a comparison of PubMed and Google Scholar for quick clinical searches.

PubMed

Shariff, Salimah Z; Bejaimal, Shayna Ad; Sontrop, Jessica M; Iansavichus, Arthur V; Haynes, R Brian; Weir, Matthew A; Garg, Amit X

2013-08-15

Physicians frequently search PubMed for information to guide patient care. More recently, Google Scholar has gained popularity as another freely accessible bibliographic database. To compare the performance of searches in PubMed and Google Scholar. We surveyed nephrologists (kidney specialists) and provided each with a unique clinical question derived from 100 renal therapy systematic reviews. Each physician provided the search terms they would type into a bibliographic database to locate evidence to answer the clinical question. We executed each of these searches in PubMed and Google Scholar and compared results for the first 40 records retrieved (equivalent to 2 default search pages in PubMed). We evaluated the recall (proportion of relevant articles found) and precision (ratio of relevant to nonrelevant articles) of the searches performed in PubMed and Google Scholar. Primary studies included in the systematic reviews served as the reference standard for relevant articles. We further documented whether relevant articles were available as free full-texts. Compared with PubMed, the average search in Google Scholar retrieved twice as many relevant articles (PubMed: 11%; Google Scholar: 22%; P<.001). Precision was similar in both databases (PubMed: 6%; Google Scholar: 8%; P=.07). Google Scholar provided significantly greater access to free full-text publications (PubMed: 5%; Google Scholar: 14%; P<.001). For quick clinical searches, Google Scholar returns twice as many relevant articles as PubMed and provides greater access to free full-text articles.

Standing Height as a Prevention Measure for Overuse Injuries of the Back in Alpine Ski Racing: A Kinematic and Kinetic Study of Giant Slalom

PubMed Central

Spörri, Jörg; Kröll, Josef; Fasel, Benedikt; Aminian, Kamiar; Müller, Erich

2018-01-01

Background: In alpine ski racing, typical loading patterns of the back include a combined occurrence of spinal bending, torsion, and high peak loads. These factors are known to be associated with high spinal disc loading and have been suggested to be attributable to different types of spine deterioration. However, little is known about the effect of standing height (ie, the distance between the bottom of the running surface of the ski and the ski boot sole) on the aforementioned back loading patterns. Purpose: To investigate the effect of reduced standing height on the skier’s overall trunk kinematics and the acting ground-reaction forces in giant slalom (GS) from an overuse injury prevention perspective. Study Design: Controlled laboratory study. Methods: Seven European Cup–level athletes skied a total of 224 GS turns with 2 different pairs of skis varying in standing height. Their overall trunk movement (frontal bending, lateral bending, and torsion angles) was measured based on 2 inertial measurement units located at the sacrum and sternum. Pressure insoles were used to determine the total ground-reaction force. Results: During the turn phase in which the greatest spinal disc loading is expected to occur, significantly lower total ground-reaction forces were observed for skis with a decreased standing height. Simultaneously, the skier’s overall trunk movement (ie, frontal bending, lateral bending, and torsion angles) remained unwaveringly high. Conclusion: Standing height is a reasonable measure to reduce the skier’s overall back loading in GS. Yet, when compared with the effects achievable by increased gate offsets in slalom, for instance, the preventative benefits of decreased standing height seem to be rather small. Clinical Relevance: To reduce the magnitude of overall back loading in GS and to prevent overuse injuries of the back, decreasing standing height might be an efficient approach. Nevertheless, the clinical relevance of the current findings, as well as the effectiveness of the measure “reduced standing height,” must be verified by epidemiological studies before its preventative potential can be judged as conclusive. PMID:29344540

Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post- chemotherapy tissues

PubMed Central

Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

2015-01-01

Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens. PMID:26515599

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.

Urokinase-receptor (u-PAR): an essential player in multiple games of cancer: a review on its role in tumor progression, invasion, metastasis, proliferation/dormancy, clinical outcome and minimal residual disease.

PubMed

Laufs, Stephanie; Schumacher, Jens; Allgayer, Heike

2006-08-01

The relevance of the u-PA system in mediating tumor-associated proteolysis, invasion and metastasis, amongst other phenomena associated with tumor progression, has been clearly demonstrated in diverse cancer entities. This review will update on the biological and clinical relevance of the urokinase-receptor (u-PAR). Specifically, the article focuses on the potential importance of u-PAR for the development of minimal residual disease in solid cancer, and in this context reviews the biological relevance of the u-PAR for tumor cell dormancy. Furthermore, transcriptional mechanisms regulating u-PAR in vitro and in vivo, and their potential clinical and therapeutic relevance in gastrointestinal cancers, are elucidated.

A Vietnamese man with selective mutism: the relevance of multiple interacting 'cultures' in clinical psychiatry.

PubMed

Hollifield, Michael; Geppert, Cynthia; Johnson, Yuam; Fryer, Carol

2003-09-01

Multiple cultural variables have effects on the psychobiology and behavioral manifestations of illness, as do patient and physician perceptions of illness. The interaction among these variables is at the heart of clinical psychiatry. This case of a Vietnamese man with selective mutism underscores the relevance of the 'cultures' of medicine, psychiatry, and war and trauma on the manifestations of illness and illness perceptions by patient and physician. The discussion focuses on how these cultures interact and play a crucial role in formulating diagnosis and treatment planning. Suggestions are given for shifts in medical education that will encourage relevant cultural paradigms to make their way into educational and clinical systems, which in turn should improve cultural competence in clinical psychiatry.

77 FR 32975 - AHRQ Workgroups on ICD-10-CM/PCS Conversion of Quality Indicators (QIs)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-04

... relevant clinical expertise (e.g., cardiovascular disease, neurologic disease, orthopedic and musculoskeletal disease, obstetrics and gynecologic disease, surgery, critical care and pulmonary disease... measurement using administrative data in specific, relevant clinical domains (e.g., cardiovascular disease...

Barriers to Retrieving Patient Information from Electronic Health Record Data: Failure Analysis from the TREC Medical Records Track

PubMed Central

Edinger, Tracy; Cohen, Aaron M.; Bedrick, Steven; Ambert, Kyle; Hersh, William

2012-01-01

Objective: Secondary use of electronic health record (EHR) data relies on the ability to retrieve accurate and complete information about desired patient populations. The Text Retrieval Conference (TREC) 2011 Medical Records Track was a challenge evaluation allowing comparison of systems and algorithms to retrieve patients eligible for clinical studies from a corpus of de-identified medical records, grouped by patient visit. Participants retrieved cohorts of patients relevant to 35 different clinical topics, and visits were judged for relevance to each topic. This study identified the most common barriers to identifying specific clinic populations in the test collection. Methods: Using the runs from track participants and judged visits, we analyzed the five non-relevant visits most often retrieved and the five relevant visits most often overlooked. Categories were developed iteratively to group the reasons for incorrect retrieval for each of the 35 topics. Results: Reasons fell into nine categories for non-relevant visits and five categories for relevant visits. Non-relevant visits were most often retrieved because they contained a non-relevant reference to the topic terms. Relevant visits were most often infrequently retrieved because they used a synonym for a topic term. Conclusions: This failure analysis provides insight into areas for future improvement in EHR-based retrieval with techniques such as more widespread and complete use of standardized terminology in retrieval and data entry systems. PMID:23304287

Barriers to retrieving patient information from electronic health record data: failure analysis from the TREC Medical Records Track.

PubMed

Edinger, Tracy; Cohen, Aaron M; Bedrick, Steven; Ambert, Kyle; Hersh, William

2012-01-01

Secondary use of electronic health record (EHR) data relies on the ability to retrieve accurate and complete information about desired patient populations. The Text Retrieval Conference (TREC) 2011 Medical Records Track was a challenge evaluation allowing comparison of systems and algorithms to retrieve patients eligible for clinical studies from a corpus of de-identified medical records, grouped by patient visit. Participants retrieved cohorts of patients relevant to 35 different clinical topics, and visits were judged for relevance to each topic. This study identified the most common barriers to identifying specific clinic populations in the test collection. Using the runs from track participants and judged visits, we analyzed the five non-relevant visits most often retrieved and the five relevant visits most often overlooked. Categories were developed iteratively to group the reasons for incorrect retrieval for each of the 35 topics. Reasons fell into nine categories for non-relevant visits and five categories for relevant visits. Non-relevant visits were most often retrieved because they contained a non-relevant reference to the topic terms. Relevant visits were most often infrequently retrieved because they used a synonym for a topic term. This failure analysis provides insight into areas for future improvement in EHR-based retrieval with techniques such as more widespread and complete use of standardized terminology in retrieval and data entry systems.

Assessing clinically meaningful treatment effects in controlled trials: chronic migraine as an example.

PubMed

Dodick, David W; Turkel, Catherine C; DeGryse, Ronald E; Diener, Hans-Christoph; Lipton, Richard B; Aurora, Sheena K; Nolan, Marissa E; Silberstein, Stephen D

2015-02-01

In addition to headache, persons with chronic migraine (CM) experience multiple symptoms, both ictal and interictal, that may contribute to their suffering. Translating clinical trial results into practice requires assessment of the results' clinical meaningfulness. When examining treatment benefit in this disabled patient population, multiple headache-symptom measures should be considered to fully reflect clinical relevance. Currently, only onabotulinumtoxinA is approved specifically for headache prophylaxis in adults with CM. Topiramate is the only other therapeutic agent with double-blind, placebo-controlled evidence in this population. Herein we evaluate the clinical meaningfulness of onabotulinumtoxinA and topiramate as headache prophylaxis in CM by comparing primary endpoints from the placebo-controlled, double-blind phase of the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program and the topiramate clinical trial (frequency of headache days [primary endpoint in PREEMPT; secondary in topiramate trial] and migraine/migrainous days [primary in topiramate trial, or "migraine/probable-migraine days"; secondary in PREEMPT]). Additionally, outcome measures such as responder rates, health-related quality of life, discontinuation rates, safety, and tolerability profiles are important clinical considerations. The clinical data indicate that statistically significant, clinically relevant treatment benefits exist for both onabotulinumtoxinA and topiramate. These data support these treatments as meaningful headache prophylaxis in adults with CM. CM is a chronic pain condition. We sought to determine the clinical relevance of recent trials in this disabled population. Clinical data indicate that statistically significant, clinically relevant treatment benefits exist for both onabotulinumtoxinA and topiramate, and support use of these treatments as meaningful headache prophylaxis in CM. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Moderate efficiency of clinicians' predictions decreased for blurred clinical conditions and benefits from the use of BRASS index. A longitudinal study on geriatric patients' outcomes.

PubMed

Signorini, Giulia; Dagani, Jessica; Bulgari, Viola; Ferrari, Clarissa; de Girolamo, Giovanni

2016-01-01

Accurate prognosis is an essential aspect of good clinical practice and efficient health services, particularly for chronic and disabling diseases, as in geriatric populations. This study aims to examine the accuracy of clinical prognostic predictions and to devise prediction models combining clinical variables and clinicians' prognosis for a geriatric patient sample. In a sample of 329 consecutive older patients admitted to 10 geriatric units, we evaluated the accuracy of clinicians' prognosis regarding three outcomes at discharge: global functioning, length of stay (LoS) in hospital, and destination at discharge (DD). A comprehensive set of sociodemographic, clinical, and treatment-related information were also collected. Moderate predictive performance was found for all three outcomes: area under receiver operating characteristic curve of 0.79 and 0.78 for functioning and LoS, respectively, and moderate concordance, Cohen's K = 0.45, between predicted and observed DD. Predictive models found the Blaylock Risk Assessment Screening Score together with clinicians' judgment relevant to improve predictions for all outcomes (absolute improvement in adjusted and pseudo-R(2) up to 19%). Although the clinicians' estimates were important factors in predicting global functioning, LoS, and DD, more research is needed regarding both methodological aspects and clinical measurements, to improve prognostic clinical indices. Copyright © 2016 Elsevier Inc. All rights reserved.

Lime powder treatment reduces urinary excretion of total protein and transferrin but increases uromodulin excretion in patients with urolithiasis.

PubMed

Tosukhowong, Piyaratana; Kulpradit, Pimsuda; Chaiyarit, Sakdithep; Ungjareonwattana, Wattanachai; Kalpongnukul, Nuttiya; Ratchanon, Supoj; Thongboonkerd, Visith

2018-06-01

Our previous study has shown that lime powder (LP) had an inhibitory effect against calcium oxalate stone formation. However, the precise mechanisms underlying such beneficial effect remained unclear. Our present study thus aimed to address the effect of LP on excretory level and compositions of urinary proteins using a proteomics approach. From a total of 80 calcium oxalate stone formers recruited into our 2-year randomized clinical trial of LP effect, 10 patients with comparable age and clinical parameters were selected for this proteomic study. 24-h urine specimens were collected from all subjects, at baseline (before) and after LP treatment for 6 months, and then subjected to quantitative proteomics analysis and subsequent validation by ELISA. Total urinary protein excretion was significantly decreased by LP treatment, but unaffected by placebo. Nanoflow liquid chromatography coupled to tandem mass spectrometry (nanoLC-MS/MS) followed by quantitative analysis revealed 17 proteins whose levels were significantly altered (16 decreased and 1 increased) exclusively by LP treatment. Among these, the decrease of transferrin and increase of uromodulin were validated by ELISA. Moreover, there was a significant correlation between microalbuminuria and urinary transferrin level by Pearson's correlation test. In summary, LP treatment caused significant reduction in total urinary protein excretion and changes in urinary protein compositions that could be linked to stone inhibitory effects and might be relevant mechanisms responsible for the beneficial effects of LP to prevent kidney stone formation and recurrence.

Lipolytic effect of a polyphenolic citrus dry extract of red orange, grapefruit, orange (SINETROL) in human body fat adipocytes. Mechanism of action by inhibition of cAMP-phosphodiesterase (PDE).

PubMed

Dallas, Constantin; Gerbi, Alain; Tenca, Guillaume; Juchaux, Franck; Bernard, François-Xavier

2008-10-01

The present study investigated the lipolytic (break of fat stored) effect of a citrus-based polyphenolic dietary supplement (SINETROL) at human adipocytes (ex vivo), body fat (clinical) and biochemical levels (inhibition of phosphodiesterase). Free fatty acids (FFA) release was used as indicator of human adipocyte lipolysis and SINETROL activity has been compared with known lipolytic products (isoproterenol, theopylline and caffeine). SINETROL stimulated significantly the lipolytic activity in a range of 6 fold greater than the control. Moreover, SINETROL has 2.1 greater activity than guarana 12% caffeine while its content in caffeine is 3 times lower. Clinically, two groups of 10 volunteers with BMI relevant of overweight were compared during 4 and 12 weeks with 1.4 g/day SINETROL and placebo supplementation. In the SINETROL Group the body fat (%) decreased with a significant difference of 5.53% and 15.6% after 4 and 12 weeks, respectively, while the body weight (kg) decreased with a significant difference of 2.2 and 5.2 kg after 4 and 12 weeks, respectively. These observed effects are linked to SINETROL polyphenolic composition and its resulting synergistic activity. SINETROL is a potent inhibitor of cAMP-phosphodiesterase (PDE) (97%) compared to other purified compounds (cyanidin-3 glycoside, narangin, caffeine). These results suggest that SINETROL has a strong lipolytic effect mediated by cAMP-PDE inhibition. SINETROL may serve to prevent obesity by decreasing BMI.

Clinically relevant pharmacokinetic herb-drug interactions in antiretroviral therapy

USDA-ARS?s Scientific Manuscript database

For healthcare professionals, the volume of literature available on herb-drug interactions often makes it difficult to separate experimental/potential interactions from those deemed clinically relevant. There is a need for concise and conclusive information to guide pharmacotherapy in HIV/AIDS. In t...

Influence of the Acidic Beverage Cola on the Absorption of Erlotinib in Patients With Non-Small-Cell Lung Cancer.

PubMed

van Leeuwen, Roelof W F; Peric, Robert; Hussaarts, Koen G A M; Kienhuis, Emma; IJzerman, Nikki S; de Bruijn, Peter; van der Leest, Cor; Codrington, Henk; Kloover, Jeroen S; van der Holt, Bronno; Aerts, Joachim G; van Gelder, Teun; Mathijssen, Ron H J

2016-04-20

Erlotinib depends on stomach pH for its bioavailability. When erlotinib is taken concurrently with a proton pump inhibitor (PPI), stomach pH increases, which results in a clinically relevant decrease of erlotinib bioavailability. We hypothesized that this drug-drug interaction is reversed by taking erlotinib with the acidic beverage cola. The effects of cola on erlotinib bioavailability in patients not treated with a PPI were also studied. In this randomized, cross-over, pharmacokinetic study in patients with non-small-cell lung cancer, we studied intrapatient differences in absorption (area under the plasma concentration time curve [AUC0-12h]) after a 7-day period of concomitant treatment with erlotinib, with or without esomeprazole, with either cola or water. At the 7th and 14th day, patients were hospitalized for 1 day for pharmacokinetic sampling. Twenty-eight evaluable patients were included in the analysis. In patients treated with erlotinib and esomeprazole with cola, the mean AUC0-12h increased 39% (range, -12% to 136%; P = .004), whereas in patients not treated with the PPI, the mean AUC0-12h was only slightly higher (9%; range, -10% to +30%; P = .03) after erlotinib intake with cola. Cola intake led to a clinically relevant and statistically significant increase in the bioavailability of erlotinib during esomeprazole treatment. In patients not treated with the PPI, the effects of cola were marginal. These findings can be used to optimize the management of drug-drug interactions between PPIs and erlotinib. © 2016 by American Society of Clinical Oncology.

Porous titanium bases for osteochondral tissue engineering

PubMed Central

Nover, Adam B.; Lee, Stephanie L.; Georgescu, Maria S.; Howard, Daniel R.; Saunders, Reuben A.; Yu, William T.; Klein, Robert W.; Napolitano, Anthony P.; Ateshian, Gerard A.

2015-01-01

Tissue engineering of osteochondral grafts may offer a cell-based alternative to native allografts, which are in short supply. Previous studies promote the fabrication of grafts consisting of a viable cell-seeded hydrogel integrated atop a porous, bone-like metal. Advantages of the manufacturing process have led to the evaluation of porous titanium as the bone-like base material. Here, porous titanium was shown to support the growth of cartilage to produce native levels of Young’s modulus, using a clinically relevant cell source. Mechanical and biochemical properties were similar or higher for the osteochondral constructs compared to chondral-only controls. Further investigation into the mechanical influence of the base on the composite material suggests that underlying pores may decrease interstitial fluid pressurization and applied strains, which may be overcome by alterations to the base structure. Future studies aim to optimize titanium-based tissue engineered osteochondral constructs to best match the structural architecture and strength of native grafts. Statement of Significance The studies described in this manuscript follow up on previous studies from our lab pertaining to the fabrication of osteochondral grafts that consist of a bone-like porous metal and a chondrocyte-seeded hydrogel. Here, tissue engineered osteochondral grafts were cultured to native stiffness using adult chondrocytes, a clinically relevant cell source, and a porous titanium base, a material currently used in clinical implants. This porous titanium is manufactured via selective laser melting, offering the advantages of precise control over shape, pore size, and orientation. Additionally, this manuscript describes the mechanical influence of the porous base, which may have applicability to porous bases derived from other materials. PMID:26320541

Porous titanium bases for osteochondral tissue engineering.

PubMed

Nover, Adam B; Lee, Stephanie L; Georgescu, Maria S; Howard, Daniel R; Saunders, Reuben A; Yu, William T; Klein, Robert W; Napolitano, Anthony P; Ateshian, Gerard A; Hung, Clark T

2015-11-01

Tissue engineering of osteochondral grafts may offer a cell-based alternative to native allografts, which are in short supply. Previous studies promote the fabrication of grafts consisting of a viable cell-seeded hydrogel integrated atop a porous, bone-like metal. Advantages of the manufacturing process have led to the evaluation of porous titanium as the bone-like base material. Here, porous titanium was shown to support the growth of cartilage to produce native levels of Young's modulus, using a clinically relevant cell source. Mechanical and biochemical properties were similar or higher for the osteochondral constructs compared to chondral-only controls. Further investigation into the mechanical influence of the base on the composite material suggests that underlying pores may decrease interstitial fluid pressurization and applied strains, which may be overcome by alterations to the base structure. Future studies aim to optimize titanium-based tissue engineered osteochondral constructs to best match the structural architecture and strength of native grafts. The studies described in this manuscript follow up on previous studies from our lab pertaining to the fabrication of osteochondral grafts that consist of a bone-like porous metal and a chondrocyte-seeded hydrogel. Here, tissue engineered osteochondral grafts were cultured to native stiffness using adult chondrocytes, a clinically relevant cell source, and a porous titanium base, a material currently used in clinical implants. This porous titanium is manufactured via selective laser melting, offering the advantages of precise control over shape, pore size, and orientation. Additionally, this manuscript describes the mechanical influence of the porous base, which may have applicability to porous bases derived from other materials. Copyright © 2015. Published by Elsevier Ltd.

Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats

PubMed Central

Curtis, Ryan C.; Custis, James T.; Ehrhart, Nicole P.; Ehrhart, E. J.; Condon, Keith W.; Gookin, Sara E.; Donahue, Seth W.

2016-01-01

Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma. PMID:27332712

Home cage wheel running is an objective and clinically relevant method to assess inflammatory pain in male and female rats

PubMed Central

Kandasamy, Ram; Calsbeek, Jonas J.; Morgan, Michael M.

2016-01-01

Background The assessment of nociception in preclinical studies is undergoing a transformation from pain-evoked to pain-depressed tests to more closely mimic the effects of clinical pain. Many inflammatory pain-depressed behaviors (reward seeking, locomotion) have been examined, but these tests are limited because of confounds such as stress and difficulties in quantifying behavior. New Method The present study evaluates home cage wheel running as an objective method to assess the magnitude and duration of inflammatory pain in male and female rats. Results Injection of Complete Freund’s Adjuvant (CFA) into the right hindpaw to induce inflammatory pain almost completely inhibited wheel running for 2 days in males and females. Wheel running gradually returned to baseline levels within 12 days despite persistent mechanical hypersensitivity (von Frey test). Comparison with Existing Methods Continuously monitoring home cage wheel running improves on previous studies examining inflammatory pain-depressed wheel running because it is more sensitive to noxious stimuli, avoids the stress of removing the rat from its cage for testing, and provides a complete analysis of the time course for changes in nociception. Conclusions The present data indicate that home cage wheel running is a clinically relevant method to assess inflammatory pain in the rat. The decrease in activity caused by inflammatory pain and subsequent gradual recovery mimics the changes in activity caused by pain in humans. The tendency for pain-depressed wheel running to be greater in female than male rats is consistent with the tendency for women to be at greater risk of chronic pain than men. PMID:26891874

Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats.

PubMed

Curtis, Ryan C; Custis, James T; Ehrhart, Nicole P; Ehrhart, E J; Condon, Keith W; Gookin, Sara E; Donahue, Seth W

2016-01-01

Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma.

Bottlenecks in the development of topical analgesics: molecule, formulation, dose-finding, and phase III design.

PubMed

Keppel Hesselink, Jan M; Kopsky, David J; Stahl, Stephen M

2017-01-01

Topical analgesics can be defined as topical formulations containing analgesics or co-analgesics. Since 2000, interest in such formulations has been on the rise. There are, however, four critical issues in the research and development phases of topical analgesics: 1) The selection of the active pharmaceutical ingredient. Analgesics and co-analgesics differ greatly in their mechanism of action, and it is required to find the most optimal fit between such mechanisms of action and the pathogenesis of the targeted (neuropathic) pain. 2) Issues concerning the optimized formulation. For relevant clinical efficacy, specific characteristics for the selected vehicle (eg, cream base or gel base) are required, depending on the physicochemical characteristics of the active pharmaceutical ingredient(s) to be delivered. 3) Well-designed phase II dose-finding studies are required, and, unfortunately, such trials are missing. In fact, we will demonstrate that underdosing is one of the major hurdles to detect meaningful and statistically relevant clinical effects of topical analgesics. 4) Selection of clinical end points and innovatively designed phase III trials. End point selection can make or break a trial. For instance, to include numbness together with tingling as a composite end point for neuropathic pain seems stretching the therapeutic impact of an analgesic too far. Given the fast onset of action of topical analgesics (usually within 30 minutes), enrichment designs might enhance the chances for success, as the placebo response might decrease. Topical analgesics may become promising inroads for the treatment of neuropathic pain, once sufficient attention is given to these four key aspects.

Using mixed methods to identify and answer clinically relevant research questions.

PubMed

Shneerson, Catherine L; Gale, Nicola K

2015-06-01

The need for mixed methods research in answering health care questions is becoming increasingly recognized because of the complexity of factors that affect health outcomes. In this article, we argue for the value of using a qualitatively driven mixed method approach for identifying and answering clinically relevant research questions. This argument is illustrated by findings from a study on the self-management practices of cancer survivors and the exploration of one particular clinically relevant finding about higher uptake of self-management in cancer survivors who had received chemotherapy treatment compared with those who have not. A cross-sectional study generated findings that formed the basis for the qualitative study, by informing the purposive sampling strategy and generating new qualitative research questions. Using a quantitative research component to supplement a qualitative study can enhance the generalizability and clinical relevance of the findings and produce detailed, contextualized, and rich answers to research questions that would be unachievable through quantitative or qualitative methods alone. © The Author(s) 2015.

The Role of Clinical Proteomics, Lipidomics, and Genomics in the Diagnosis of Alzheimer's Disease.

PubMed

Martins, Ian James

2016-03-31

The early diagnosis of Alzheimer's disease (AD) has become important to the reversal and treatment of neurodegeneration, which may be relevant to premature brain aging that is associated with chronic disease progression. Clinical proteomics allows the detection of various proteins in fluids such as the urine, plasma, and cerebrospinal fluid for the diagnosis of AD. Interest in lipidomics has accelerated with plasma testing for various lipid biomarkers that may with clinical proteomics provide a more reproducible diagnosis for early brain aging that is connected to other chronic diseases. The combination of proteomics with lipidomics may decrease the biological variability between studies and provide reproducible results that detect a community's susceptibility to AD. The diagnosis of chronic disease associated with AD that now involves genomics may provide increased sensitivity to avoid inadvertent errors related to plasma versus cerebrospinal fluid testing by proteomics and lipidomics that identify new disease biomarkers in body fluids, cells, and tissues. The diagnosis of AD by various plasma biomarkers with clinical proteomics may now require the involvement of lipidomics and genomics to provide interpretation of proteomic results from various laboratories around the world.

Thrombin generation correlates with disease duration in multiple sclerosis (MS): Novel insights into the MS-associated prothrombotic state.

PubMed

Parsons, Martin Em; O'Connell, Karen; Allen, Seamus; Egan, Karl; Szklanna, Paulina B; McGuigan, Christopher; Ní Áinle, Fionnuala; Maguire, Patricia B

2017-01-01

Thrombin is well recognised for its role in the coagulation cascade but it also plays a role in inflammation, with enhanced thrombin generation observed in several inflammatory disorders. Although patients with multiple sclerosis (MS) have a higher incidence of thrombotic disease, thrombin generation has not been studied to date. The aim of this study was to characterise calibrated automated thrombography parameters in patients with relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) in comparison to healthy controls (HCs). Calibrated automated thrombography was performed on platelet poor plasma from 15 patients with RRMS, 15 with PPMS and 19 HCs. We found that patients with RRMS generate thrombin at a significantly faster rate than the less inflammatory subtype, PPMS or HCs. In addition, the speed of thrombin generation was significantly correlated with time from clinical diagnosis in both subtypes. However, in RRMS the rate of thrombin generation was increased with increased time from clinical diagnosis, while in PPMS the rate of thrombin generation decreased with increased time from clinical diagnosis. These data likely reflect the differential active proinflammatory states in each MS subtype and provide novel mechanistic insights into the clinically relevant prothrombotic state observed in these patients.

Alexithymia is associated with attenuated automatic brain response to facial emotion in clinical depression.

PubMed

Suslow, Thomas; Kugel, Harald; Rufer, Michael; Redlich, Ronny; Dohm, Katharina; Grotegerd, Dominik; Zaremba, Dario; Dannlowski, Udo

2016-02-04

Alexithymia is a clinically relevant personality trait related to difficulties in recognizing and describing emotions. Previous studies examining the neural correlates of alexithymia have shown mainly decreased response of several brain areas during emotion processing in healthy samples and patients suffering from autism or post-traumatic stress disorder. In the present study, we examined the effect of alexithymia on automatic brain reactivity to negative and positive facial expressions in clinical depression. Brain activation in response to sad, happy, neutral, and no facial expression (presented for 33 ms and masked by neutral faces) was measured by functional magnetic resonance imaging at 3 T in 26 alexithymic and 26 non-alexithymic patients with major depression. Alexithymic patients manifested less activation in response to masked sad and happy (compared to neutral) faces in right frontal regions and right caudate nuclei than non-alexithymic patients. Our neuroimaging study provides evidence that the personality trait alexithymia has a modulating effect on automatic emotion processing in clinical depression. Our findings support the idea that alexithymia could be associated with functional deficits of the right hemisphere. Future research on the neural substrates of emotion processing in depression should assess and control alexithymia in their analyses.

[The Nutritional Care Experience of a Post-Operative Periampullary Cancer Patient With Cachexia].

PubMed

Liou, Yan-Ting; Chiang, Pin-Yi; Shun, Shiow-Ching

2016-04-01

Cachexia is one of the most widely overlooked of the syndromes that are experienced by cancer patients. This syndrome is especially prevalent among patients with gastroenterology tract cancer. Although the National Comprehensive Cancer Network (NCCN) issued palliative-care practice guidelines for cachexia in 2015, guidelines have yet to be issued for the clinical setting. The authors reviewed the literature and applied their clinical experience to create an approach for identifying the degree of cachexia in a post-operative patient with periampullary cancer. This approach assesses the nutritional status, physical status, laboratory results, and gastrointestinal system functions of the patient using the Cachexia Assessment Scale (CAS) and NCCN Practice Guidelines for Cachexia. The patient improved under nursing care with an increase in nutritional intake and physical activity facilitating their process of post-surgical physical recovery. The authors hope that this experience using the combined CAS-NCCN Practice Guidelines will help clinical caregivers better understand how to apply the relevant guidelines in clinical settings. The developed approach may help nurses assess the comprehensive nutrition status of patients and related factors in order to provide interventions that will decrease the progression of cachexia effectively and promote quality of life.

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

PubMed Central

Leibson, Tom; Carls, Alexandra; Ito, Shinya; Koren, Gideon

2016-01-01

Background Women are commonly prescribed a variety of medications during pregnancy. As most organ systems are affected by the substantial anatomical and physiological changes that occur during pregnancy, it is expected that pharmacokinetics (PK) (absorption, distribution, metabolism, and excretion of drugs) would also be affected in ways that may necessitate changes in dosing schedules. The objective of this study was to systematically identify existing clinically relevant evidence on PK changes during pregnancy. Methods and Findings Systematic searches were conducted in MEDLINE (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), and Web of Science (Thomson Reuters), from database inception to August 31, 2015. An update of the search from September 1, 2015, to May 20, 2016, was performed, and relevant data were added to the present review. No language or date restrictions were applied. All publications of clinical PK studies involving a group of pregnant women with a comparison to nonpregnant participants or nonpregnant population data were eligible to be included in this review. A total of 198 studies involving 121 different medications fulfilled the inclusion criteria. In these studies, commonly investigated drug classes included antiretrovirals (54 studies), antiepileptic drugs (27 studies), antibiotics (23 studies), antimalarial drugs (22 studies), and cardiovascular drugs (17 studies). Overall, pregnancy-associated changes in PK parameters were often observed as consistent findings among many studies, particularly enhanced drug elimination and decreased exposure to total drugs (bound and unbound to plasma proteins) at a given dose. However, associated alterations in clinical responses and outcomes, or lack thereof, remain largely unknown. Conclusion This systematic review of pregnancy-associated PK changes identifies a significant gap between the accumulating knowledge of PK changes in pregnant women and our understanding of their clinical impact for both mother and fetus. It is essential for clinicians to be aware of these unique pregnancy-related changes in PK, and to critically examine their clinical implications. PMID:27802281

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.

Clinical Utility of Preoperative Computed Tomography in Patients With Endometrial Cancer.

PubMed

Bogani, Giorgio; Gostout, Bobbie S; Dowdy, Sean C; Multinu, Francesco; Casarin, Jvan; Cliby, William A; Frigerio, Luigi; Kim, Bohyun; Weaver, Amy L; Glaser, Gretchen E; Mariani, Andrea

2017-10-01

The aim of this study was to determine the clinical utility of routine preoperative pelvic and abdominal computed tomography (CT) examinations in patients with endometrial cancer (EC). We retrospectively reviewed records from patients with EC who underwent a preoperative endometrial biopsy and had surgery at our institution from January 1999 through December 2008. In the subset with an abdominal CT scan obtained within 3 months before surgery, we evaluated the clinical utility of the CT scan. Overall, 224 patients (18%) had a preoperative endometrial biopsy and an available CT scan. Gross intra-abdominal disease was observed in 10% and 20% of patients with preoperative diagnosis of endometrioid G3 and type II EC, respectively, whereas less than 5% of patients had a preoperative diagnosis of hyperplasia or low-grade EC. When examining retroperitoneal findings, we observed that a negative CT scan of the pelvis did not exclude the presence of pelvic node metastasis. Alternately, a negative CT scan in the para-aortic area generally reduced the probability of finding para-aortic dissemination but with an overall low sensitivity (42%). However, the sensitivity for para-aortic dissemination was as high as 67% in patients with G3 endometrioid cancer. In the case of negative para-aortic nodes in the CT scan, the risk of para-aortic node metastases decreased from 18.8% to 7.5% in patients with endometrioid G3 EC. Up to 15% of patients with endometrioid G3 cancer had clinically relevant incidental findings that necessitated medical or surgical intervention. In patients with endometrioid G3 and type II EC diagnosed by the preoperative biopsy, CT scans may help guide the operative plan by facilitating preoperative identification of gross intra-abdominal disease and enlarged positive para-aortic nodes that are not detectable during physical examinations. In addition, CT may reveal other clinically relevant incidental findings.

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review.

PubMed

Pariente, Gali; Leibson, Tom; Carls, Alexandra; Adams-Webber, Thomasin; Ito, Shinya; Koren, Gideon

2016-11-01

Women are commonly prescribed a variety of medications during pregnancy. As most organ systems are affected by the substantial anatomical and physiological changes that occur during pregnancy, it is expected that pharmacokinetics (PK) (absorption, distribution, metabolism, and excretion of drugs) would also be affected in ways that may necessitate changes in dosing schedules. The objective of this study was to systematically identify existing clinically relevant evidence on PK changes during pregnancy. Systematic searches were conducted in MEDLINE (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), and Web of Science (Thomson Reuters), from database inception to August 31, 2015. An update of the search from September 1, 2015, to May 20, 2016, was performed, and relevant data were added to the present review. No language or date restrictions were applied. All publications of clinical PK studies involving a group of pregnant women with a comparison to nonpregnant participants or nonpregnant population data were eligible to be included in this review. A total of 198 studies involving 121 different medications fulfilled the inclusion criteria. In these studies, commonly investigated drug classes included antiretrovirals (54 studies), antiepileptic drugs (27 studies), antibiotics (23 studies), antimalarial drugs (22 studies), and cardiovascular drugs (17 studies). Overall, pregnancy-associated changes in PK parameters were often observed as consistent findings among many studies, particularly enhanced drug elimination and decreased exposure to total drugs (bound and unbound to plasma proteins) at a given dose. However, associated alterations in clinical responses and outcomes, or lack thereof, remain largely unknown. This systematic review of pregnancy-associated PK changes identifies a significant gap between the accumulating knowledge of PK changes in pregnant women and our understanding of their clinical impact for both mother and fetus. It is essential for clinicians to be aware of these unique pregnancy-related changes in PK, and to critically examine their clinical implications.

[Identification of mycobacteria by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry--using reference strains and clinical isolates of Mycobacterium].

PubMed

Niitsuma, Katsunao; Saito, Miwako; Koshiba, Shizuko; Kaneko, Michiyo

2014-05-01

Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS) method is being played an important role for the inspection of clinical microorganism as a rapid and the price reduction. Mass spectra obtained by measuring become points of identification whether the peak pattern match any species mass spectral pattern. We currently use MALDI-TOF MS for rapid and accurate diagnosis of inactivated reference and clinical isolates of Mycobacterium because of the improved pretreatment techniques compared with former inspection methods that pose a higher risk of infection to the operator. The identification matching rate of score value (SV) peak pattern spectra was compared with that of conventional methods such as strain diffusion/amplification. Also, cultures were examined after a fixed number of days. Compared with the initial inspection technique, the pretreatment stage of current MALDI-TOF MS inspection techniques can improve the analysis of inactivated acid-fast bacteria that are often used as inspection criteria strains of clinical isolates. Next, we compared the concordance rate for identification between MALDI-TOF MS and conventional methods such as diffusion/amplification by comparison of peak pattern spectra and evaluated SV spectra to identify differences in the culture media after the retention period. In examination of 158 strains of clinical isolated Mycobacterium tuberculosis complex (MTC), the identification coincidence rate in the genus level in a matching pattern was 99.4%, when the species level was included 94.9%. About 37 strains of nontuberculous mycobacteria (NTM), the identification coincidence rate in the genus level was 94.6%. M. bovis BCG (Tokyo strain) in the reference strain was judged by the matching pattern to be MTC, and it suggested that they are M. tuberculosis and affinity species with high DNA homology. Nontuberculous mycobacterial M. gordonae strain JATA 33-01 shared peak pattern spectra, excluding the isolates, with each clinically isolated strain. However, the mass spectra of six M. gordonae clinical isolates suggested polymorphisms with similar mass-to-charge ratios compared with those of the reference strains. The peak pattern spectra of the clinical isolates and reference strains, excluding the NTM M. gordonae strain JATA33-01, were consistent with the peak pattern characteristics of each isolate. However, a comparison between the peak patterns of the reference strains and those of the six clinically isolated M. gordonae strains revealed a similar mass-to-charge ratio, which may indicate few polymorphisms. The SV spectrum of the improved inspection technique showed no fidelity, but it was acceptable after days of culture as indicated by the decrease in SV (0.3 degree). Also, the reproducibility of this method was good, but no difference was observed from the SV of the improved inspection technique, which decreased by approximately 0.3 because of the number of days of culture storage. In addition, expansion of the database and dissemination of regional specificity by genotype analysis of clinical isolates was relevant to the accumulated data, as expected. In future studies, the relevance and regional specificity of clinical isolates by genotype analysis can be determined by stacking the solid media and database penetration.

Clinical pharmacokinetics: perceptions of hospital pharmacists in Qatar about how it was taught and how it is applied.

PubMed

Kheir, Nadir; Awaisu, Ahmed; Gad, Hoda; Elazzazy, Shereen; Jibril, Farah; Gajam, Mawadda

2015-12-01

The application of clinical pharmacokinetics (PK) is essential when providing pharmaceutical care. Appropriate application of PK monitoring results in improved patient outcomes including decreased mortality, length of treatment, length of hospital stay, and adverse effects of drug therapy. Despite the well-documented evidence of benefits of clinical PK services, many pharmacists find it challenging to apply PK in clinical practice. To evaluate pharmacists' training backgrounds, attitude, practices, and perceived barriers pertaining to the application of PK in clinical practice in Qatar. All hospitals under Hamad Medical Corporation, the main healthcare provider in Qatar. This was a cross-sectional, descriptive study that was conducted between October 2012 and January 2013, using a self-administered web-based survey. Pharmacists were eligible to participate if they: (1) were working as full-time hospital pharmacists and; (2) have been in practice for at least 1 year. PK contents learned in undergraduate curriculum; perception towards the PK contents and instructions received in the undergraduate curriculum and; application of PK in current clinical practice. A total of 112 pharmacists responded to the questionnaire. The majority of the respondents (n = 91; 81.3 %) reported that they had received PK course(s) in their undergraduate curriculum. Similarly, the majority (70-80 %) of them agreed that the undergraduate PK courses or contents they received were important and relevant to their current practice. The pharmacists identified spending more time on dispensing and inventory issues rather than clinical practice, scarce resources, and manual rather than computerized PK calculations as some of the barriers they encountered in learning about PK and its application. The characteristics of the surveyed pharmacists such as gender, age, highest academic degree, and country of graduation did not influence the pharmacists' perception and attitudes towards PK teaching and application (p > 0.05). PK course contents were perceived to lack depth and relevance to practice, and pharmacist had no experiential training that included aspects of PK. These, and other issues, result in poor application of PK in practice.

A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior

PubMed Central

Thanos, Panayotis K.; Robison, Lisa S.; Steier, Jessica; Hwang, Yu Fen; Cooper, Thomas; Swanson, James M.; Komatsu, David E.; Hadjiargyrou, Michael; Volkow, Nora D.

2015-01-01

Most animal studies using methylphenidate (MP) do not administer it the same way it is administered clinically (orally), but rather by injection, resulting in an altered pharmacokinetic profile (i.e. quicker and higher peak concentrations). Here, we evaluated several oral-dosing regimens in rats, including dual-dose drinking, to mimic the clinical drug delivery profile. Using an 8-hour-limited-access-drinking-paradigm, MP solutions were delivered at different doses (20, 30, or 60 mg/kg/day; as well as dual-dosages of 4 and 10 mg/kg/day, 20 and 30 mg/kg/day, or 30 and 60 mg/kg/day, in which the low dose was administered in the first hour of drinking followed by 7 h of drinking the high dose). Blood was sampled and plasma was assayed for MP levels at many time points. Results showed that an 8-hour limited drinking of a dual-dosage 30/60 mg/kg MP solution achieved a pharmacokinetic profile similar to clinically administered doses of MP at the high end of the spectrum (peaking at ~30 ng/mL), while the 4/10 mg/kg MP dual-dosage produced plasma levels in the range produced by typically prescribed clinical doses of MP (peaking at ~8 ng/mL). Treatment with the higher dual-dosage (HD: 30/60 mg/kg) resulted in hyperactivity, while the lower (LD: 4/10 mg/kg) had no effect. Next, chronic effects of these dual-dosages were assessed on behavior throughout three months of treatment and one month of abstinence, beginning in adolescence. MP dose-dependently decreased body weight, which remained attenuated throughout abstinence. MP decreased food intake during early treatment, suggesting that MP may be an appetite suppressant and may also speed metabolism and/or suppress growth. Chronic HD MP resulted in hyperactivity limited during the dark cycle; decreased exploratory behavior; and increased anxiolytic behavior. These findings suggest that this dual-dosage-drinking-paradigm can be used to examine the effects of clinically relevant pharmacokinetic doses of MP, and that chronic treatment with such dosages can result in long-lasting developmental and behavioral changes. PMID:25641666

A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior.

PubMed

Thanos, Panayotis K; Robison, Lisa S; Steier, Jessica; Hwang, Yu Fen; Cooper, Thomas; Swanson, James M; Komatsu, David E; Hadjiargyrou, Michael; Volkow, Nora D

2015-04-01

Most animal studies using methylphenidate (MP) do not administer it the same way it is administered clinically (orally), but rather by injection, resulting in an altered pharmacokinetic profile (quicker and higher peak concentrations). We evaluated several oral-dosing regimens in rats, including dual-dose drinking, to mimic clinical drug delivery. Using an 8-hour-limited-access-drinking-paradigm, MP solutions were delivered at different doses (20, 30, or 60mg/kg/day; as well as dual-dosages of 4 and 10mg/kg/day, 20 and 30mg/kg/day, or 30 and 60mg/kg/day, in which the low dose was administered in the first hour of drinking followed by 7 h of drinking the high dose). Plasma was assayed for MP levels at many time points. Results showed that an 8-hour limited drinking of a dual-dosage 30/60mg/kg MP solution achieved a pharmacokinetic profile similar to clinically administered doses of MP at the high end of the spectrum (peaking at ~30ng/mL), while the 4/10mg/kg MP dual-dosage produced plasma levels in the range produced by typically prescribed clinical doses of MP (peaking at ~8ng/mL). Treatment with the higher dual-dosage (HD: 30/60mg/kg) resulted in hyperactivity, while the lower (LD: 4/10mg/kg) had no effect. Chronic effects of these dual-dosages were assessed throughout three months of treatment and one month of abstinence, beginning in adolescence. MP dose-dependently decreased body weight, which remained attenuated throughout abstinence. MP decreased food intake during early treatment, suggesting that MP may be an appetite suppressant and may also speed metabolism and/or suppress growth. Chronic HD MP resulted in hyperactivity limited during the dark cycle, decreased exploratory behavior, and increased anxiolytic behavior. Findings suggest that these dual-dosage-drinking-paradigms can be used to examine the effects of clinically relevant pharmacokinetic doses of MP and that chronic treatment with such dosages can result in long-lasting developmental and behavioral changes. Copyright © 2015 Elsevier Inc. All rights reserved.

157 Pathogenesis of Epstein-Barr Virus-driven lymphomas of HIV+ patients: new insights of potential clinical relevance

PubMed Central

Dolcetti, Riccardo

2014-01-01

Human Immunodeficiency Virus (HIV)+ patients have an increased risk to develop lymphomas, including a significant fraction of histotypes associated with Epstein-Barr Virus (EBV) infection. Although restoration of EBV-specific T-cell function induced by HAART has led to a decreased incidence of the more immunogenic EBV-associated lymphomas, such as immunoblastic and primary central nervous system lymphomas, other EBV+ histotypes are still prevalent in the HAART era, particularly Hodgkin’s lymphoma. Therefore, factors other than HIV-induced immune suppression are probably required for the development of EBV-related lymphomas in this setting. Particular attention is being given to the identification of microenvironmental stimuli able to up-regulate critical EBV latency proteins or to induce/enhance EBV replication. In fact, recent evidence indicates that, although latency programs predominate in EBV-driven tumors, lytic EBV replication may also be of pathogenic relevance, at least in the early phases of cell transformation. This is particularly relevant for HIV-related lymphomagenesis since the underlying impairment of immune responses may favour uncontrolled activation of EBV lytic replication in latently-infected B lymphocytes. Available data indicate that local expression of distinct cytokines, including IL-4 and IL-13, may up-regulate the expression of the LMP-1 oncoprotein in B cells, thus favoring lymphomagenesis. In the search of microenvironmental factors that may promote the development of EBV-driven lymphomas in HIV+ patients, we obtained evidence supporting a pathogenic role for HIV matrix protein p17, which accumulates in lymphoid tissues of HIV+ individuals, even during HAART. Our findings support a direct contribution of HIV p17 to the development of EBV-driven lymphomagenesis and may provide the rationale for new strategies of clinical intervention in this setting.

A prospective dual-energy X-ray absorptiometry study of bone remodeling after implantation of the Nanos short-stemmed prosthesis.

PubMed

Zeh, Alexander; Pankow, Franziska; Röllinhoff, Marc; Delank, Stefan; Wohlrab, David

2013-04-01

The aim of this study was to analyze the bone remodeling around the Nanos stem (Smith & Nephew, Marl, Germany) after primary total hip arthroplasty for coxarthrosis. In 25 patients (15 male, 10 female, mean age 59.9 years) with the diagnosis of coxarthrosis, a DEXA scan was performed immediately after surgery, 97 days (SD 6.1 days) and 368 days (SD 6.2 days) after implantation of a Nanos prosthesis. Plain radiographs were analyzed digitally for radiolucent lines, varus-valgus femoral stem alignment, measurement of stem migration and changes in varus-valgus femoral stem alignment. The position of the center of rotation (COR) and the offset were assessed pre- and postoperatively. Harris Hip Score was used to evaluate the clinical outcome. The DEXA scan showed a significant and relevant increase in BMD (Bone Mineral Density) in Gruen-Zone 6 (12%) and a decrease in Zone 1 (15%), 2 (5%) and 7 (12%), which was interpreted as reflecting a distal load transfer in the metaphysis of the femur. There was no clinically relevant migration or tilting of the Nanos stem. Radiolucent lines were noted in 12 cases, mainly at the polished tip area of the prosthesis; this was not regarded as a sign of impaired osseointegration. There was no significant difference between the position of the COR and the pre- and postoperative offset. The absence of stem migration, angulation, or relevant radiolucent lines is seen as evidence for an unimpaired osseointegration of the Nanos stem approximately 12 months after implantation. It is concluded that the Nanos prosthesis can reduce loss of BMD of the proximal femur composed with conventional stems or other short-stemmed implants.

Differential effects of synthetic progestagens on neuron survival and estrogen neuroprotection in cultured neurons.

PubMed

Jayaraman, Anusha; Pike, Christian J

2014-03-25

Progesterone and other progestagens are used in combination with estrogens for clinical purposes, including contraception and postmenopausal hormone therapy. Progesterone and estrogens have interactive effects in brain, however interactions between synthetic progestagens and 17β-estradiol (E2) in neurons are not well understood. In this study, we investigated the effects of seven clinically relevant progestagens on estrogen receptor (ER) mRNA expression, E2-induced neuroprotection, and E2-induced BDNF mRNA expression. We found that medroxyprogesterone acetate decreased both ERα and ERβ expression and blocked E2-mediated neuroprotection and BDNF expression. Conversely, levonorgestrel and nesterone increased ERα and or ERβ expression, were neuroprotective, and failed to attenuate E2-mediated increases in neuron survival and BDNF expression. Other progestagens tested, including norethindrone, norethindrone acetate, norethynodrel, and norgestimate, had variable effects on the measured endpoints. Our results demonstrate a range of qualitatively different actions of progestagens in cultured neurons, suggesting significant variability in the neural effects of clinically utilized progestagens. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Current insights into the laboratory diagnosis of HIT.

PubMed

Bakchoul, T; Zöllner, H; Greinacher, A

2014-06-01

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction and prothrombotic disorder caused by immunization against platelet factor 4 (PF4) after complex formation with heparin or other polyanions. After antibody binding to PF4/heparin complexes, HIT antibodies are capable of intravascular platelet activation by cross-linking Fc gamma receptor IIa (FcγRIIa) on the platelet surface leading to a platelet count decrease and/or thrombosis. In contrast to most other immune-mediated disorders, the currently available laboratory tests for anti-PF4/heparin antibodies show a high sensitivity also for clinically irrelevant antibodies. This makes the diagnosis of HIT challenging and bears the risk to substantially overdiagnose HIT. The strength of the antigen assays for HIT is in ruling out HIT when the test is negative. Functional assays have a higher specificity for clinically relevant antibodies, but they are restricted to specialized laboratories. Currently, a Bayesian approach combining the clinical likelihood estimation for HIT with laboratory tests is the most appropriate approach to diagnose HIT. In this review, we give an overview on currently available diagnostic procedures and discuss their limitations. © 2014 John Wiley & Sons Ltd.

Clinical relevance is associated with allergen-specific wheal size in skin prick testing.

PubMed

Haahtela, T; Burbach, G J; Bachert, C; Bindslev-Jensen, C; Bonini, S; Bousquet, J; Bousquet-Rouanet, L; Bousquet, P J; Bresciani, M; Bruno, A; Canonica, G W; Darsow, U; Demoly, P; Durham, S R; Fokkens, W J; Giavi, S; Gjomarkaj, M; Gramiccioni, C; Kowalski, M L; Losonczy, G; Orosz, M; Papadopoulos, N G; Stingl, G; Todo-Bom, A; von Mutius, E; Köhli, A; Wöhrl, S; Järvenpää, S; Kautiainen, H; Petman, L; Selroos, O; Zuberbier, T; Heinzerling, L M

2014-03-01

Within a large prospective study, the Global Asthma and Allergy European Network (GA(2) LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings. To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points. The GA(2) LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated. Depending on the allergen, from 40% (blatella) to 87-89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen. These 'reading keys' for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use. © 2013 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.

Preterm piglets are a clinically relevant model of pediatric GI disease

USDA-ARS?s Scientific Manuscript database

The goal of our research is to establish how nutritional support, enteral versus parenteral, affects gut function and susceptibility to disease in early development. We and others have used the neonatal pig to establish unique models of clinically relevant problems in pediatric gastroenterology, esp...

77 FR 40620 - AHRQ Workgroups on ICD-10-CM/PCS Conversion of Quality Indicators (QIs) - Extension Date for...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-10

... with relevant clinical expertise (e.g., cardiovascular disease, neurologic disease, orthopedic and... measurement using administrative data in specific, relevant clinical domains (e.g., cardiovascular disease... (e.g., cardiovascular disease, neurologic disease, orthopedic and musculoskeletal disease, obstetrics...

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.

Variations in the sonographic measurement techniques of BI-RADS 3 breast masses.

PubMed

Francisco, Juliana; Jales, Rodrigo Menezes; de Oliveira, André Desuó Bueno; Arguello, Carlos Henrique Francisco; Derchain, Sophie

2017-06-01

To evaluate the differences in sonographic (US) distance and volume measurements from different sonologists and identify the optimal parameters to avoid clinically relevant variations in the measurement of BI-RADS 3 breast masses. For this cross-sectional study with prospectively collected data, four physicians with various levels of experience in US, herein called sonologists, performed distance and volume US measurements of 80 masses classified as BI-RADS 3. The Cochran Q test was used to compare the matched sets of rates of clinically relevant variability between all pairs of sonologists' measurements. There were clinically relevant differences between sonologists in the measurements of the longest diameter (range, 17.5-43.7%, p = 0.003), the longest diameter perpendicular to the previous one (anteroposterior diameter) (17.5-33.7%, p = 0.06), the third diameter orthogonal to the plane defined by the previous two (transverse diameter) (28.7-55%, p = 0.001), and at least two of those three diameters (18.7-38.7%, p = 0.015). The smallest clinically relevant differences were observed with volume measurements (range of differences, 6.2-13.7%, p = 0.51). Volume measurement technique was associated with the least variations, whereas distance measurements, which are used routinely, were associated with unacceptable rates of clinically relevant variations. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:252-260, 2017. © 2017 Wiley Periodicals, Inc.

Augmentation in the treatment of restless legs syndrome with transdermal rotigotine.

PubMed

Beneš, Heike; García-Borreguero, Diego; Ferini-Strambi, Luigi; Schollmayer, Erwin; Fichtner, Andreas; Kohnen, Ralf

2012-06-01

To assess the risk of augmentation under treatment with the transdermally delivered dopamine agonist rotigotine for restless legs syndrome (RLS). Experts in RLS augmentation retrospectively reviewed data from two double-blind, placebo-controlled 6-month trials (745 rotigotine and 214 placebo subjects, NCT00136045 and NCT00135993) and from two open-label 1-year trials (620 rotigotine subjects, NCT00498108 and NCT00263068). All study visits were systematically evaluated applying the Max Planck Institute (MPI) criteria for the diagnosis of both augmentation and clinically relevant augmentation. MPI criteria for augmentation were met on at least one visit by 8.2% of all subjects in the double-blind trials with 12 subjects meeting the criteria for clinically relevant augmentation: 11 under rotigotine (1.5%) and one under placebo treatment. In the open-label trials, 9.7% of all subjects met the MPI criteria for augmentation and 2.9% met the criteria for clinically relevant augmentation. None of the patients treated with rotigotine for up to 1.5 years (double-blind plus open-label trial) discontinued prematurely owing to augmentation. Neither could dose-dependency or a time pattern for clinically relevant augmentation episodes be detected. Our analyses suggest that the risk for clinically relevant augmentation for the duration of up to 18 months of rotigotine treatment is low. Copyright © 2012 Elsevier B.V. All rights reserved.

Retrieving Clinical Evidence: A Comparison of PubMed and Google Scholar for Quick Clinical Searches

PubMed Central

Bejaimal, Shayna AD; Sontrop, Jessica M; Iansavichus, Arthur V; Haynes, R Brian; Weir, Matthew A; Garg, Amit X

2013-01-01

Background Physicians frequently search PubMed for information to guide patient care. More recently, Google Scholar has gained popularity as another freely accessible bibliographic database. Objective To compare the performance of searches in PubMed and Google Scholar. Methods We surveyed nephrologists (kidney specialists) and provided each with a unique clinical question derived from 100 renal therapy systematic reviews. Each physician provided the search terms they would type into a bibliographic database to locate evidence to answer the clinical question. We executed each of these searches in PubMed and Google Scholar and compared results for the first 40 records retrieved (equivalent to 2 default search pages in PubMed). We evaluated the recall (proportion of relevant articles found) and precision (ratio of relevant to nonrelevant articles) of the searches performed in PubMed and Google Scholar. Primary studies included in the systematic reviews served as the reference standard for relevant articles. We further documented whether relevant articles were available as free full-texts. Results Compared with PubMed, the average search in Google Scholar retrieved twice as many relevant articles (PubMed: 11%; Google Scholar: 22%; P<.001). Precision was similar in both databases (PubMed: 6%; Google Scholar: 8%; P=.07). Google Scholar provided significantly greater access to free full-text publications (PubMed: 5%; Google Scholar: 14%; P<.001). Conclusions For quick clinical searches, Google Scholar returns twice as many relevant articles as PubMed and provides greater access to free full-text articles. PMID:23948488

[To see the future development of burn medicine from the view of holistic integrative medicine].

PubMed

Hu, D H; Tao, K

2017-04-20

The therapeutic methods and effects have been improved greatly in the past few decades for burn care and management with several important advancements which have resulted in more effective patient stabilization and significantly decreased mortality in China. However, the challenges still exist, such as how to further improve the recovery of the patients' appearance and function, and how to advance the treatment of severe deep extensive burn injury, etc. The theory of holistic integrative medicine (HIM) provides a new opportunity for the development of clinical medicine. This article emphasizes the important roles of HIM in exploration of burn medicine, considering the advanced development of modern life sciences and relevant techniques.

Variation of semen parameters in healthy medical students due to exam stress.

PubMed

Lampiao, Fanuel

2009-12-01

This study was aimed at investigating semen parameters that vary most in samples of healthy donors undergoing stressful examination period. Samples were left to liquefy in an incubator at 37 degrees C, 5% CO2 for 30 minutes before volume was measured. Concentration and motility parameters were measured by means of computer assisted semen analysis (CASA) using Sperm Class Analyzer (Microptic S.L, Madrid, Spain). Sperm concentration was significantly decreased in samples donated close to the exam period as well as samples donated during the exam period when compared to samples donated at the beginning of the semester. Stress levels of donors might prove to be clinically relevant and important when designing experiment protocols.

Chemotherapeutic drug-specific alteration of microvascular blood flow in murine breast cancer as measured by diffuse correlation spectroscopy

PubMed Central

Ramirez, Gabriel; Proctor, Ashley R.; Jung, Ki Won; Wu, Tong Tong; Han, Songfeng; Adams, Russell R.; Ren, Jingxuan; Byun, Daniel K.; Madden, Kelley S.; Brown, Edward B.; Foster, Thomas H.; Farzam, Parisa; Durduran, Turgut; Choe, Regine

2016-01-01

The non-invasive, in vivo measurement of microvascular blood flow has the potential to enhance breast cancer therapy monitoring. Here, longitudinal blood flow of 4T1 murine breast cancer (N=125) under chemotherapy was quantified with diffuse correlation spectroscopy based on layer models. Six different treatment regimens involving doxorubicin, cyclophosphamide, and paclitaxel at clinically relevant doses were investigated. Treatments with cyclophosphamide increased blood flow as early as 3 days after administration, whereas paclitaxel induced a transient blood flow decrease at 1 day after administration. Early blood flow changes correlated strongly with the treatment outcome and distinguished treated from untreated mice individually for effective treatments. PMID:27699124

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.

The effect of empagliflozin on muscle sympathetic nerve activity in patients with type II diabetes mellitus.

PubMed

Jordan, Jens; Tank, Jens; Heusser, Karsten; Heise, Tim; Wanner, Christoph; Heer, Martina; Macha, Sreeraj; Mattheus, Michaela; Lund, Søren S; Woerle, Hans J; Broedl, Uli C

2017-09-01

Inhibition of sodium glucose cotransporter 2 with empagliflozin results in caloric loss by increasing urinary glucose excretion and has a mild diuretic effect. Diuretic effects are usually associated with reflex-mediated increases in sympathetic tone, whereas caloric loss is associated with decreased sympathetic tone. In an open-label trial, muscle sympathetic nerve activity (MSNA) (burst frequency, burst incidence, and total MSNA) was assessed using microneurography performed off-treatment and on day 4 of treatment with empagliflozin 25 mg once daily in 22 metformin-treated patients with type II diabetes (mean [range] age 54 [40-65] years). Systolic and diastolic blood pressure (BP), heart rate, urine volume, and body weight were assessed before and on day 4 (BP, heart rate), day 5 (urine volume), or day 6 (body weight) of treatment with empagliflozin. After 4 days of treatment with empagliflozin, no significant changes in MSNA were apparent despite a numerical increase in urine volume, numerical reductions in BP, and significant weight loss. There were no clinically relevant changes in heart rate. Empagliflozin is not associated with clinically relevant reflex-mediated sympathetic activation in contrast to increases observed with diuretics in other studies. Our study suggests a novel mechanism through which sodium glucose cotransporter 2 inhibition affects human autonomic cardiovascular regulation. Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

The effect of propofol on plasma membrane ultrastructure in the intact cells

NASA Astrophysics Data System (ADS)

Jin, Weixiang; Pralle, Arnd

The mechanism of general anesthesia is still unknown. One drug used for human anesthesia, propofol, has been shown to interact with some ligand gated ion-channels, but also easily dissolves in the lipid bilayer and alters fluidity. Which mechanism dominates or even how anesthesia arises are unclear. We study the influence of propofol on plasma membrane (PM) ultrastructure in intact cells. In the PM, transient submicroscopic nanodomains form by interactions between lipid-acyl-chains or lipid head groups, stabilized by cholesterol. In addition, membrane cytoskeleton further regulates the nanodomains, which then regulate signaling. We study transient propofol effects on these domains from low to clinically relevant propofol concentrations by analyzing diffusion of GFP-tagged outer leaflet/inner leaflet membrane proteins. Using bimFCS we measure diffusion on multiple length scales simultaneously. We observe that at low propofol concentrations, the nanodomains trap GPI-mGFP less, consistent with studies showing that propofol decreases the phase transition temperature of membrane derived vesicles. Interestingly, at clinical relevant concentrations of propofol, the nanodomains trap GPI-mGFP more strongly. This is only observed at 37C. By inhibiting myosin activity or actin filaments (de-)polymerization, we find that the activity of actin filaments further alters the behavior of cholesterol nanodomains due to propofol. We compare the effect of propofol and its analog confirming specificity.

Clinical relevance of IgG antibodies against food antigens in Crohn's disease: a double-blind cross-over diet intervention study.

PubMed

Bentz, S; Hausmann, M; Piberger, H; Kellermeier, S; Paul, S; Held, L; Falk, W; Obermeier, F; Fried, M; Schölmerich, J; Rogler, G

2010-01-01

Environmental factors are thought to play an important role in the development of Crohn's disease (CD). Immune responses against auto-antigens or food antigens may be a reason for the perpetuation of inflammation. In a pilot study, 79 CD patients and 20 healthy controls were examined for food immunoglobulin G (IgG). Thereafter, the clinical relevance of these food IgG antibodies was assessed in a double-blind cross-over study with 40 patients. Based on the IgG antibodies, a nutritional intervention was planned. The interferon (IFN)gamma secretion of T cells was measured. Eosinophil-derived neurotoxin was quantified in stool. The pilot study resulted in a significant difference of IgG antibodies in serum between CD patients and healthy controls. In 84 and 83% of the patients, respectively, IgG antibodies against processed cheese and yeast were detected. The daily stool frequency significantly decreased by 11% during a specific diet compared with a sham diet. Abdominal pain reduced and general well-being improved. IFNgamma secretion of T cells increased. No difference for eosinophil-derived neurotoxin in stool was detected. A nutritional intervention based on circulating IgG antibodies against food antigens showed effects with respect to stool frequency. The mechanisms by which IgG antibodies might contribute to disease activity remain to be elucidated.

Alternating magnetic field optimization for IONP hyperthermia cancer treatment

NASA Astrophysics Data System (ADS)

Kastner, Elliot J.; Reeves, Russell; Bennett, William; Misra, Aditi; Petryk, Jim D.; Petryk, Alicia A.; Hoopes, P. Jack

2015-03-01

Iron oxide nanoparticles (IONP) have therapeutic potential to deliver a thermal dose to tumors when activated in an alternating magnetic field (AMF). Through various targeting methods such as antibody labeling or injection site choice, delivery of IONPs to tumors yields enhanced treatment accuracy and efficacy. Despite this advantage, delivery an AMF, which is sufficient to result in clinically relevant IONP heating, can result in nonspecific tissue heating via the generation of eddy currents and tissue permeated by local electric fields (joule heating). The production of eddy current heating is a function of tissue size, geometry and composition as well as coil design and operation. The purpose of this research is to increase the level of energy deposited into the IONPs versus the non-target tissue (power ratio/PR)1 in order to improve target heating and reduce nonspecific tissue damage. We propose to improve the PR using two primary concepts: (1) reduce power deposition into non-target tissue by manipulating the fields and eddy current flow and (2) enhance heat removal from non-target tissue. We have shown that controlling tissue placement within the AMF field, accounting for tissue geometry, utilizing external cooling devices, and modifying the field properties can decrease non-target heating by more than 50%, at clinically relevant AMF levels, thereby allowing for an increase in thermal dose to the tumor and increasing the therapeutic ratio.

Safety studies conducted on pecan shell fiber, a food ingredient produced from ground pecan shells.

PubMed

Dolan, Laurie; Matulka, Ray; Worn, Jeffrey; Nizio, John

2016-01-01

Use of pecan shell fiber in human food is presently limited, but could increase pending demonstration of safety. In a 91-day rat study, pecan shell fiber was administered at dietary concentrations of 0 (control), 50 000, 100 000 or 150 000 ppm. There was no effect of the ingredient on body weight of males or females or food consumption of females. Statistically significant increases in food consumption were observed throughout the study in 100 000 and 150 000 ppm males, resulting in intermittent decreases in food efficiency (150 000 ppm males only) that were not biologically relevant. All animals survived and no adverse clinical signs or functional changes were attributable to the test material. There were no toxicologically relevant changes in hematology, clinical chemistry or urinalysis parameters or organ weights in rats ingesting pecan shell fiber. Any macroscopic or microscopic findings were incidental, of normal variation and/or of minimal magnitude for test substance association. Pecan shell fiber was non-mutagenic in a bacterial reverse mutation test and non-clastogenic in a mouse peripheral blood micronucleus test. Based on these results, pecan shell fiber has an oral subchronic (13-week) no observable adverse effect level (NOAEL) of 150 000 ppm in rats and is not genotoxic at the doses analyzed.

Characterization of blunt chest trauma in a long-term porcine model of severe multiple trauma

PubMed Central

Horst, K.; Simon, T. P.; Pfeifer, R.; Teuben, M.; Almahmoud, K.; Zhi, Q.; Santos, S. Aguiar; Wembers, C. Castelar; Leonhardt, S.; Heussen, N.; Störmann, P.; Auner, B.; Relja, B.; Marzi, I.; Haug, A. T.; van Griensven, M.; Kalbitz, M.; Huber-Lang, M.; Tolba, R.; Reiss, L. K.; Uhlig, S.; Marx, G.; Pape, H. C.; Hildebrand, F.

2016-01-01

Chest trauma has a significant relevance on outcome after severe trauma. Clinically, impaired lung function typically occurs within 72 hours after trauma. However, the underlying pathophysiological mechanisms are still not fully elucidated. Therefore, we aimed to establish an experimental long-term model to investigate physiological, morphologic and inflammatory changes, after severe trauma. Male pigs (sus scrofa) sustained severe trauma (including unilateral chest trauma, femur fracture, liver laceration and hemorrhagic shock). Additionally, non-injured animals served as sham controls. Chest trauma resulted in severe lung damage on both CT and histological analyses. Furthermore, severe inflammation with a systemic increase of IL-6 (p = 0.0305) and a local increase of IL-8 in BAL (p = 0.0009) was observed. The pO2/FiO2 ratio in trauma animals decreased over the observation period (p < 0.0001) but not in the sham group (p = 0.2967). Electrical Impedance Tomography (EIT) revealed differences between the traumatized and healthy lung (p < 0.0001). In conclusion, a clinically relevant, long-term model of blunt chest trauma with concomitant injuries has been developed. This reproducible model allows to examine local and systemic consequences of trauma and is valid for investigation of potential diagnostic or therapeutic options. In this context, EIT might represent a radiation-free method for bedside diagnostics. PMID:28000769

Human Adipose Mesenchymal Cells Inhibit Melanocyte Differentiation and the Pigmentation of Human Skin via Increased Expression of TGF-β1.

PubMed

Klar, Agnes S; Biedermann, Thomas; Michalak, Katarzyna; Michalczyk, Teresa; Meuli-Simmen, Claudia; Scherberich, Arnaud; Meuli, Martin; Reichmann, Ernst

2017-12-01

There is accumulating evidence that interactions between epidermal melanocytes and stromal cells play an important role in the regulation of skin pigmentation. In this study we established a pigmented dermo-epidermal skin model, melDESS, of human origin to investigate the effects of distinct stromal cells on melanogenesis. melDESS is a complex, clinically relevant skin equivalent composed of an epidermis containing both melanocytes and keratinocytes. Its dermal compartment consists either of adipose tissue-derived stromal cells, dermal fibroblasts (Fbs), or a mixture of both cell types. These skin substitutes were transplanted for 5 weeks on the backs of immuno-incompetent rats and analyzed. Gene expression and Western blot analyses showed a significantly higher expression of transforming growth factor-β1 by adipose tissue-derived stromal cells compared with dermal Fbs. In addition, we showed that melanocytes responded to the increased levels of transforming growth factor-β1 by down-regulating the expression of key melanogenic enzymes such as tyrosinase. This caused decreased melanin synthesis and, consequently, greatly reduced pigmentation of melDESS. The conclusions are of utmost clinical relevance, namely that adipose tissue-derived stromal cells derived from the hypodermis fail to appropriately interact with epidermal melanocytes, thus preventing the sustainable restoration of the patient's native skin color in bioengineered skin grafts. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Low-level laser therapy on MCF-7 cells: a micro-Fourier transform infrared spectroscopy study

NASA Astrophysics Data System (ADS)

Magrini, Taciana D.; dos Santos, Nathalia Villa; Milazzotto, Marcella Pecora; Cerchiaro, Giselle; da Silva Martinho, Herculano

2012-10-01

Low-level laser therapy (LLLT) is an emerging therapeutic approach for several clinical conditions. The clinical effects induced by LLLT presumably scale from photobiostimulation/photobioinhibition at the cellular level to the molecular level. The detailed mechanism underlying this effect remains unknown. This study quantifies some relevant aspects of LLLT related to molecular and cellular variations. Malignant breast cells (MCF-7) were exposed to spatially filtered light from a He-Ne laser (633 nm) with fluences of 5, 28.8, and 1000 mJ/cm2. The cell viability was evaluated by optical microscopy using the Trypan Blue viability test. The micro-Fourier transform infrared technique was employed to obtain the vibrational spectra of each experimental group (control and irradiated) and identify the relevant biochemical alterations that occurred due to the process. It was observed that the red light influenced the RNA, phosphate, and serine/threonine/tyrosine bands. We found that light can influence cell metabolism depending on the laser fluence. For 5 mJ/cm2, MCF-7 cells suffer bioinhibition with decreased metabolic rates. In contrast, for the 1 J/cm2 laser fluence, cells present biostimulation accompanied by a metabolic rate elevation. Surprisingly, at the intermediate fluence, 28.8 mJ/cm2, the metabolic rate is increased despite the absence of proliferative results. The data were interpreted within the retrograde signaling pathway mechanism activated with light irradiation.

Features of lymphatic dysfunction in compressed skin tissues - Implications in pressure ulcer aetiology.

PubMed

Gray, Robert J; Voegeli, David; Bader, Dan L

2016-02-01

Impaired lymph formation and clearance has previously been proposed as a contributory factor in the development of pressure ulcers. The present study has been designed to trial fluorescence lymphangiography for establishing how lymphatic function is altered under a clinically relevant form of mechanical loading. Lymph formation and clearance was traced in both forearms by an intradermal injection of indocyanine green (ICG) (50 μl, 0.05%w/v), imaged using a commercial near-infrared fluorescence imaging unit (Fluobeam(®) 800). External uniaxial loading equivalent to a pressure of 60 mmHg was applied for 45 min in one arm using a custom-built indenter. Loading was associated with a decreased frequency of normal directional drainage (DD) of ICG within delineated vessels, both immediately after loading and 45 min thereafter. Loading was also associated with non-directional drainage (NDD) of ICG within the interstitium. Signal intensity within NDD was often greatest at areas of stress concentration, producing a 'halo pattern', corresponding to the rounded edges of the indenter. These results suggest that loading skin with a clinically relevant magnitude of pressure alters both lymph formation and clearance. Further work to quantify impaired clearance under mechanical loading could provide valuable insight into their involvement in the development of pressure ulcers. Copyright © 2016 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.

Ventilation and cardiac related impedance changes in children undergoing corrective open heart surgery.

PubMed

Schibler, Andreas; Pham, Trang M T; Moray, Amol A; Stocker, Christian

2013-10-01

Electrical impedance tomography (EIT) can determine ventilation and perfusion relationship. Most of the data obtained so far originates from experimental settings and in healthy subjects. The aim of this study was to demonstrate that EIT measures the perioperative changes in pulmonary blood flow after repair of a ventricular septum defect in children with haemodynamic relevant septal defects undergoing open heart surgery. In a 19 bed intensive care unit in a tertiary children's hospital ventilation and cardiac related impedance changes were measured using EIT before and after surgery in 18 spontaneously breathing patients. The EIT signals were either filtered for ventilation (ΔZV) or for cardiac (ΔZQ) related impedance changes. Impedance signals were then normalized (normΔZV, normΔZQ) for calculation of the global and regional impedance related ventilation perfusion relationship (normΔZV/normΔZQ). We observed a trend towards increased normΔZV in all lung regions, a significantly decreased normΔZQ in the global and anterior, but not the posterior lung region. The normΔZV/normΔZQ was significantly increased in the global and anterior lung region. Our study qualitatively validates our previously published modified EIT filtration technique in the clinical setting of young children with significant left-to-right shunt undergoing corrective open heart surgery, where perioperative assessment of the ventilation perfusion relation is of high clinical relevance.

Application of HRV-CD for estimation of life expectancy in various clinical disorders.

PubMed

Almoznino-Sarafian, Dorit; Sarafian, Gideon; Zyssman, Itzhak; Shteinshnaider, Miriam; Tzur, Irma; Kaplan, Ben-Zion; Berman, Sylvia; Cohen, Natan; Gorelik, Oleg

2009-12-01

Low heart rate variability (HRV) was found in various medical conditions including heart failure and acute myocardial infarction. Decreased HRV in these conditions predicted poor prognosis. HRV was estimated in 133 unselected inpatients with relevant clinical bedside conditions by non-linear analysis derived from chaos theory, which calculates the correlation dimension (CD) of the cardiac electrophysiologic system (HRV-CD). Mean HRV-CD in the entire group was 3.75+/-0.45. Heart failure, coronary artery disease, cardiac arrhythmia, low serum potassium, renal dysfunction, and diabetes mellitus were significantly associated with reduced HRV-CD compared to their counterparts [3.6 vs. 3.9 (P<.001), 3.65 vs. 3.87 (P=.005), 3.58 vs. 3.8 (P=.01), 3.38 vs. 3.81 (P=.02), 3.59 vs. 3.8 (P=.04), and 3.66 vs. 3.82 (P=.04), respectively]. Stepwise logistic regression showed heart failure to be the condition most significantly associated with low HRV-CD (odds ratio 4.2, 95% confidence interval 1.90-9.28, P<.001). In the entire group, decreased HRV-CD (< or =3.75 vs. >3.75) was associated with lower survival (P=.01). Mortality of diabetic patients with HRV-CD < or =3.75 exceeded the mortality in patients with HRV-CD >3.75 (P=.02). Heart failure, renal dysfunction or age over 70 combined with HRV-CD < or =3.75 also appeared to be associated with augmented mortality. Diminished HRV-CD is associated with heart failure, coronary artery disease, cardiac arrhythmia, renal dysfunction, diabetes mellitus and low serum potassium. Among the latter, heart failure is most significantly associated with decreased HRV-CD. Decreased HRV-CD values, especially in diabetics, are also associated with lower survival.

Radiation Dose Reduction by Indication-Directed Focused z-Direction Coverage for Neck CT.

PubMed

Parikh, A K; Shah, C C

2016-06-01

The American College of Radiology-American Society of Neuroradiology-Society for Pediatric Radiology Practice Parameter for a neck CT suggests that coverage should be from the sella to the aortic arch. It also recommends using CT scans judiciously to achieve the clinical objective. Our purpose was to analyze the potential dose reduction by decreasing the scan length of a neck CT and to assess for any clinically relevant information that might be missed from this modified approach. This retrospective study included 126 children who underwent a neck CT between August 1, 2013, and September 30, 2014. Alteration of the scan length for the modified CT was suggested on the topographic image on the basis of the indication of the study, with the reader blinded to the images and the report. The CT dose index volume of the original scan was multiplied by the new scan length to calculate the dose-length product of the modified study. The effective dose was calculated for the original and modified studies by using age-based conversion factors from the American Association of Physicists in Medicine Report No. 96. Decreasing the scan length resulted in an average estimated dose reduction of 47%. The average reduction in scan length was 10.4 cm, decreasing the overall coverage by 48%. The change in scan length did not result in any missed findings that altered management. Of the 27 abscesses in this study, none extended to the mediastinum. All of the lesions in question were completely covered. Decreasing the scan length of a neck CT according to the indication provides a significant savings in radiation dose, while not altering diagnostic ability or management. © 2016 by American Journal of Neuroradiology.

The impact of different types of talus deformation after treatment of clubfeet.

PubMed

Kolb, Alexander; Willegger, Madeleine; Schuh, Reinhard; Kaider, Alexandra; Chiari, Catharina; Windhager, Reinhard

2017-01-01

Deformation of the talus in idiopathic congenital clubfeet is a known problem after treatment. However evidence on types of talus deformation and clinical relevance is rare. The aims of this study were first to define different types of talus deformation, and second, to evaluate the impact of these types on long-term results. At a minimum follow-up of ten years 40 idiopathic clubfeet treated by a modified dorsomedial release were analyzed. Based on morphological appearance and the widened range of radius to length ratios (R/L-ratio) in treated clubfeet deformed tali were divided into two groups: tali with decreased R/L-ratios were classified as small-dome talus deformation (SD), tali with increased R/L-ratios were classified as flat-top talus deformation (FT). The impact on degree of arthrosis in the ankle joint, clinical outcome, and ankle range of motion was analyzed. Small-dome talus deformation (SD) was found in nine feet. This group showed decreased R/L-ratios and increased talus opening angles, which were linked to an increased range of motion of the ankle joint (p = 0.033). The impact on onset of arthrosis was not significant for this group (p = 0.056). The group of flat top talus deformation (nine feet) showed increased R/L-ratios and decreased talus opening angles, decreased range of motion (p = 0.019), and a significant impact on onset of arthrosis (p = 0.010). Our study defines a new subgroup of talus deformation: the small dome talus deformation tends to show a better ankle joint range of motion and a lower risk of arthrosis compared to the classical flat dome talus deformation.

Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease.

PubMed

Black, Kevin J; Koller, Jonathan M; Campbell, Meghan C; Gusnard, Debra A; Bandak, Stephen I

2010-12-01

Adenosine A(2a) receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. Rodent studies support the hypothesis that A(2a) antagonists produce this benefit by reducing the inhibitory output of the basal ganglia indirect pathway. One way to test this hypothesis in humans is to quantify regional pharmacodynamic responses with cerebral blood flow (CBF) imaging. That approach has also been proposed as a tool to accelerate pharmaceutical dose finding, but has not yet been applied in humans to drugs in development. We successfully addressed both these aims with a perfusion magnetic resonance imaging (MRI) study of the novel adenosine A(2a) antagonist SYN115. During a randomized, double-blind, placebo-controlled, crossover study in 21 PD patients on levodopa but no agonists, we acquired pulsed arterial spin labeling MRI at the end of each treatment period. SYN115 produced a highly significant decrease in thalamic CBF, consistent with reduced pallidothalamic inhibition via the indirect pathway. Similar decreases occurred in cortical regions whose activity decreases with increased alertness and externally focused attention, consistent with decreased self-reported sleepiness on SYN115. Remarkably, we also derived quantitative pharmacodynamic parameters from the CBF responses to SYN115. These results suggested that the doses tested were on the low end of the effective dose range, consistent with clinical data reported separately. We conclude that (1) SYN115 enters the brain and exerts dose-dependent regional effects, (2) the most prominent of these effects is consistent with deactivation of the indirect pathway as predicted by preclinical studies; and (3) perfusion MRI can provide rapid, quantitative, clinically relevant dose-finding information for pharmaceutical development.

Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease

PubMed Central

Black, Kevin J.; Koller, Jonathan M.; Campbell, Meghan C.; Gusnard, Debra A.; Bandak, Stephen I.

2010-01-01

Adenosine A2a receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. Rodent studies support the hypothesis that A2a antagonists produce this benefit by reducing the inhibitory output of the basal ganglia indirect pathway. One way to test this hypothesis in humans is to quantify regional pharmacodynamic responses with cerebral blood flow (CBF) imaging. That approach has also been proposed as a tool to accelerate pharmaceutical dose-finding, but has not yet been applied in humans to drugs in development. We successfully addressed both these aims with a perfusion MRI study of the novel adenosine A2a antagonist SYN115. During a randomized, double-blind, placebo-controlled, crossover study in 21 PD patients on levodopa but no agonists, we acquired pulsed arterial spin labeling MRI at the end of each treatment period. SYN115 produced a highly significant decrease in thalamic CBF, consistent with reduced pallidothalamic inhibition via the indirect pathway. Similar decreases occurred in cortical regions whose activity decreases with increased alertness and externally-focused attention, consistent with decreased self-reported sleepiness on SYN115. Remarkably, we also derived quantitative pharmacodynamic parameters from the CBF responses to SYN115. These results suggested that the doses tested were on the low end of the effective dose range, consistent with clinical data reported separately. We conclude that (1) SYN115 enters the brain and exerts dose-dependent regional effects, (2) the most prominent of these effects is consistent with deactivation of the indirect pathway as predicted by preclinical studies; and (3) perfusion MRI can provide rapid, quantitative, clinically relevant dose-finding information for pharmaceutical development. PMID:21123574

Whole body vibration training improves vibration perception threshold in healthy young adults: A randomized clinical trial pilot study.

PubMed

Hernandez-Mocholi, M A; Dominguez-Muñoz, F J; Corzo, H; Silva, S Cs; Adsuar, J C; Gusi, N

2016-03-01

Loss of foot sensitivity is a relevant parameter to assess and prevent in several diseases. It is crucial to determine the vibro-tactile sensitivity threshold response to acute conditions to explore innovative monitor tools and interventions to prevent and treat this challenge. The aims were: 1) to analyze the acute effects of a single whole body vibration session (4min-18Hz-4mm) on vibro-tactile perception threshold in healthy young adults. 2) to analyze the 48 hours effects of 3 whole body vibration sessions on vibro-tactile perception threshold in healthy young adults. A randomized controlled clinical trial over 3 sessions of whole body vibration intervention or 3 sessions of placebo intervention. Twenty-eight healthy young adults were included: 11 experimental group and 12 placebo group. The experimental group performed 3 sessions of WBV while the placebo group performed 3 sessions of placebo intervention. The vibro-tactile threshold increased right after a single WBV session in comparison with placebo. Nevertheless, after 3 whole body vibration sessions and 48 hours, the threshold decreased to values lower than the initial. The acute response of the vibro-tactile threshold to one whole body vibration session increased, but the 48 hours short-term response of this threshold decreased in healthy young adults.

Increased Bisecting N-Acetylglucosamine and Decreased Branched Chain Glycans of N-linked Glycoproteins in Expressed Prostatic Secretions Associated with Prostate Cancer Progression

PubMed Central

Nyalwidhe, Julius O.; Betesh, Lucy R.; Powers, Thomas W.; Jones, E. Ellen; White, Krista Y.; Burch, Tanya C.; Brooks, Jasmin; Watson, Megan T.; Lance, Raymond S.; Troyer, Dean A.; Semmes, O. John; Mehta, Anand; Drake, Richard R.

2013-01-01

Purpose Using prostatic fluids rich in glycoproteins like prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) , the goal of this study was to identify the structural types and relative abundance of glycans associated with prostate cancer status for subsequent use in emerging mass spectrometry-based glycopeptide analysis platforms. Experimental Design A series of pooled samples of expressed prostatic secretions (EPS) and exosomes reflecting different stages of prostate cancer disease were used for N-linked glycan profiling by three complementary methods, MALDI-TOF profiling, normal-phase HPLC separation, and triple quadropole MS analysis of PAP glycopeptides. Results Glycan profiling of N-linked glycans from different EPS fluids indicated a global decrease in larger branched tri- and tetra-antennary glycans. Differential exoglycosidase treatments indicated a substantial increase in bisecting N-acetylglucosamines correlated with disease severity. A triple quadrupole MS analysis of the N-linked glycopeptides sites from PAP in aggressive prostate cancer pools was done to cross-reference with the glycan profiling data. Conclusion and clinical relevance Changes in glycosylation as detected in EPS fluids reflect the clinical status of prostate cancer. Defining these molecular signatures at the glycopeptide level in individual samples could improve current approaches of diagnosis and prognosis. PMID:23775902

Xuezhikang Capsule for Type 2 Diabetes with Hyperlipemia: A Systematic Review and Meta-Analysis of Randomized Clinical Trails

PubMed Central

Li, Min; He, Qingyong; Chen, Yinfeng; Li, Bo; Feng, Bo; Zhang, Zhenpeng; Wang, Jie

2015-01-01

Objective. To evaluate the efficacy and safety of Xuezhikang capsule treating type 2 diabetes with hyperlipidemia. Methods. We searched six databases to identify relevant studies published before January 2015. Two review authors independently extracted data and assessed the Cochrane risk of bias tool. We resolved disagreements with this assessment through discussion and a decision was achieved by consensus. Results. We included 21 studies (1548 participants). Treatment courses were at least 8 weeks. Overall, the risk of bias of included trials was unclear. Among them, 16 studies could conduct meta-analysis. The result showed that compared with routine group (5 studies), Xuezhikang group had more effect on decreasing TC, TG, LDL-C, and rising HDL-C. However, compared with statins group (11 studies), Xuezhikang group has less effect on decreasing TC, TG, and rising HDL-C. Meanwhile, two groups had no statistical differences of LDL-C level. Conclusion. Xuezhikang capsule may be effective for treating type 2 diabetes with hyperlipemia. Our findings should be considered cautiously due to unclear risk of bias of the included studies and low methodological quality. Therefore, more strictly designed large-scale randomized clinical trials are needed to evaluate the efficacy of Xuezhikang capsule in type 2 diabetes with hyperlipemia. PMID:26246836

A randomized, open-label 3-way crossover study to investigate the relative bioavailability and bioequivalence of crushed sildenafil 20 mg tablets mixed with apple sauce, extemporaneously prepared suspension (EP), and intact sildenafil 20 mg tablets in healthy volunteers under fasting conditions.

PubMed

Gao, Xiang; Ndongo, Marie-Noella; Checchio, Tina M; Cook, Jack; Duncan, Barbara; LaBadie, Robert R

2015-01-01

The relative bioavailability and bioequivalence of 20-mg doses of a pediatric formulation of sildenafil extemporaneous preparation suspension (EP; 10 mg/mL), the sildenafil 20-mg intact tablet and the crushed sildenafil 20-mg tablet mixed with apple sauce were assessed in a single-dose, randomized, open-label, 3-way crossover study with 18 healthy adult volunteers. Blood samples were collected at predefined times and analyzed for sildenafil plasma concentrations. Natural log-transformed sildenafil pharmacokinetic parameters (Cmax , AUClast , and AUCinf ) were used to estimate relative bioavailability and construct 90% confidence intervals (CI) using a mixed-effects model. Bioequivalence was concluded among the three formulations with one exception, in which the EP suspension showed a 15% decrease in Cmax with a lower 90% CI of 76% compared with the intact tablet. The 15% decrease in sildenafil Cmax is not considered to be clinically relevant. Therefore, the EP suspension is considered to be an appropriate pediatric formulation. All 3 formulations were well tolerated in healthy adult volunteers. © 2014, The American College of Clinical Pharmacology.

Rapid high resolution T1 mapping as a marker of brain development: Normative ranges in key regions of interest.

PubMed

Eminian, Sylvain; Hajdu, Steven David; Meuli, Reto Antoine; Maeder, Philippe; Hagmann, Patric

2018-01-01

We studied in a clinical setting the age dependent T1 relaxation time as a marker of normal late brain maturation and compared it to conventional techniques, namely the apparent diffusion coefficient (ADC). Forty-two healthy subjects ranging from ages 1 year to 20 years were included in our study. T1 brain maps in which the intensity of each pixel corresponded to T1 relaxation times were generated based on MR imaging data acquired using a MP2RAGE sequence. During the same session, diffusion tensor imaging data was collected. T1 relaxation times and ADC in white matter and grey matter were measured in seven clinically relevant regions of interest and were correlated to subjects' age. In the basal ganglia, there was a small, yet significant, decrease in T1 relaxation time (-0.45 ≤R≤-0.59, p<10-2) and ADC (-0.60≤R≤-0.65, p<10-4) as a function of age. In the frontal and parietal white matter, there was a significant decrease in T1 relaxation time (-0.62≤R≤-0.68, p<10-4) and ADC (-0.81≤R≤-0.85, p<10-4) as a function of age. T1 relaxation time changes in the corpus callosum and internal capsule were less relevant for this age range. There was no significant difference between the correlation of T1 relaxation time and ADC with respect to age (p-value = 0.39). The correlation between T1 relaxation and ADC is strong in the white matter but only moderate in basal ganglia over this age period. T1 relaxation time is a marker of brain maturation or myelination during late brain development. Between the age of 1 and 20 years, T1 relaxation time decreases as a function of age in the white matter and basal ganglia. The greatest changes occur in frontal and parietal white matter. These regions are known to mature in the final stage of development and are mainly composed of association circuits. Age-correlation is not significantly different between T1 relaxation time and ADC. Therefore, T1 relaxation time does not appear to be a superior marker of brain maturation than ADC but may be considered as complementary owing the intrinsic differences in bio-physical sensitivity. This work may serve as normative ranges in clinical imaging routines.

Families with burn injury: application in the clinically relevant continuum model.

PubMed

Lehna, Carlee

2011-06-01

This article incorporates the findings from a predominantly qualitative, mixed-method study examining sibling survivors' experiences of a major childhood burn injury into the clinically relevant continuum model as a means of promoting culturally competent and family-centered care. Copyright © 2011 Elsevier Inc. All rights reserved.

Clinical Relevance of Discourse Characteristics after Right Hemisphere Brain Damage

ERIC Educational Resources Information Center

Blake, Margaret Lehman

2006-01-01

Purpose: Discourse characteristics of adults with right hemisphere brain damage are similar to those reported for healthy older adults, prompting the question of whether changes are due to neurological lesions or normal aging processes. The clinical relevance of potential differences across groups was examined through ratings by speech-language…

Gatekeepers for Pragmatic Clinical Trials

PubMed Central

Whicher, Danielle M.; Miller, Jennifer E.; Dunham, Kelly M.; Joffe, Steven

2015-01-01

To successfully implement a pragmatic clinical trial, investigators need access to numerous resources, including financial support, institutional infrastructure (e.g., clinics, facilities, staff), eligible patients, and patient data. Gatekeepers are people or entities who have the ability to allow or deny access to the resources required to support the conduct of clinical research. Based on this definition, gatekeepers relevant to the United States clinical research enterprise include research sponsors, regulatory agencies, payers, health system and other organizational leadership, research team leadership, human research protections programs, advocacy and community groups, and clinicians. This manuscript provides a framework to help guide gatekeepers’ decision-making related to the use of resources for pragmatic clinical trials. These include (1) concern for the interests of individuals, groups, and communities affected by the gatekeepers’ decisions, including protection from harm and maximization of benefits, (2) advancement of organizational mission and values, and (3) stewardship of financial, human, and other organizational resources. Separate from these ethical considerations, gatekeepers’ actions will be guided by relevant federal, state, and local regulations. This framework also suggests that to further enhance the legitimacy of their decision-making, gatekeepers should adopt transparent processes that engage relevant stakeholders when feasible and appropriate. We apply this framework to the set of gatekeepers responsible for making decisions about resources necessary for pragmatic clinical trials in the United States, describing the relevance of the criteria in different situations and pointing out where conflicts among the criteria and relevant regulations may affect decision-making. Recognition of the complex set of considerations that should inform decision-making will guide gatekeepers in making justifiable choices regarding the use of limited and valuable resources. PMID:26374683

A clinical decision support system algorithm for intravenous to oral antibiotic switch therapy: validity, clinical relevance and usefulness in a three-step evaluation study.

PubMed

Akhloufi, H; Hulscher, M; van der Hoeven, C P; Prins, J M; van der Sijs, H; Melles, D C; Verbon, A

2018-04-26

To evaluate a clinical decision support system (CDSS) based on consensus-based intravenous to oral switch criteria, which identifies intravenous to oral switch candidates. A three-step evaluation study of a stand-alone CDSS with electronic health record interoperability was performed at the Erasmus University Medical Centre in the Netherlands. During the first step, we performed a technical validation. During the second step, we determined the sensitivity, specificity, negative predictive value and positive predictive value in a retrospective cohort of all hospitalized adult patients starting at least one therapeutic antibacterial drug between 1 and 16 May 2013. ICU, paediatric and psychiatric wards were excluded. During the last step the clinical relevance and usefulness was prospectively assessed by reports to infectious disease specialists. An alert was considered clinically relevant if antibiotics could be discontinued or switched to oral therapy at the time of the alert. During the first step, one technical error was found. The second step yielded a positive predictive value of 76.6% and a negative predictive value of 99.1%. The third step showed that alerts were clinically relevant in 53.5% of patients. For 43.4% it had already been decided to discontinue or switch the intravenous antibiotics by the treating physician. In 10.1%, the alert resulted in advice to change antibiotic policy and was considered useful. This prospective cohort study shows that the alerts were clinically relevant in >50% (n = 449) and useful in 10% (n = 85). The CDSS needs to be evaluated in hospitals with varying activity of infectious disease consultancy services as this probably influences usefulness.

Evaluation of health alerts from an early illness warning system in independent living.

PubMed

Rantz, Marilyn J; Scott, Susan D; Miller, Steven J; Skubic, Marjorie; Phillips, Lorraine; Alexander, Greg; Koopman, Richelle J; Musterman, Katy; Back, Jessica

2013-06-01

Passive sensor networks were deployed in independent living apartments to monitor older adults in their home environments to detect signs of impending illness and alert clinicians so they can intervene and prevent or delay significant changes in health or functional status. A retrospective qualitative deductive content analysis was undertaken to refine health alerts to improve clinical relevance to clinicians as they use alerts in their normal workflow of routine care delivery to older adults. Clinicians completed written free-text boxes to describe actions taken (or not) as a result of each alert; they also rated the clinical significance (relevance) of each health alert on a scale of 1 to 5. Two samples of the clinician's written responses to the health alerts were analyzed after alert algorithms had been adjusted based on results of a pilot study using health alerts to enhance clinical decision-making. In the first sample, a total of 663 comments were generated by seven clinicians in response to 385 unique alerts; there are more comments than alerts because more than one clinician rated the same alert. The second sample had a total of 142 comments produced by three clinicians in response to 88 distinct alerts. The overall clinical relevance of the alerts, as judged by the content of the qualitative comments by clinicians for each alert, improved from 33.3% of the alerts in the first sample classified as clinically relevant to 43.2% in the second. The goal is to produce clinically relevant alerts that clinicians find useful in daily practice. The evaluation methods used are described to assist others as they consider building and iteratively refining health alerts to enhance clinical decision making.

The Quality of Clinical Information in Adverse Drug Reaction Reports by Patients and Healthcare Professionals: A Retrospective Comparative Analysis.

PubMed

Rolfes, Leàn; van Hunsel, Florence; van der Linden, Laura; Taxis, Katja; van Puijenbroek, Eugène

2017-07-01

Clinical information is needed to assess the causal relationship between a drug and an adverse drug reaction (ADR) in a reliable way. Little is known about the level of relevant clinical information about the ADRs reported by patients. The aim was to determine to what extent patients report relevant clinical information about an ADR compared with their healthcare professional. A retrospective analysis of all ADR reports on the same case, i.e., cases with a report from both the patient and the patient's healthcare professional, selected from the database of the Dutch Pharmacovigilance Center Lareb, was conducted. The extent to which relevant clinical information was reported was assessed by trained pharmacovigilance assessors, using a structured tool. The following four domains were assessed: ADR, chronology, suspected drug, and patient characteristics. For each domain, the proportion of reported information in relation to information deemed relevant was calculated. An average score of all relevant domains was determined and categorized as poorly (≤45%), moderately (from 46 to 74%) or well (≥75%) reported. Data were analyzed using a paired sample t test and Wilcoxon signed rank test. A total of 197 cases were included. In 107 cases (54.3%), patients and healthcare professionals reported a similar level of clinical information. Statistical analysis demonstrated no overall differences between the groups (p = 0.126). In a unique study of cases of ADRs reported by patients and healthcare professionals, we found that patients report clinical information at a similar level as their healthcare professional. For an optimal pharmacovigilance, both healthcare professionals and patient should be encouraged to report.

Research methodology in Dentistry: Part I – The essentials and relevance of research

PubMed Central

Krithikadatta, Jogikalmat

2012-01-01

The need for scientific evidence should be the basis of clinical practice. The field of restorative dentistry and endodontics is evolving at a rapid pace, with the introduction of several materials, instruments, and equipments. However, there is minimal information of their relevance in clinical practice. On the one hand, material and laboratory research is critical, however; its translation into clinical practice is not being substantiated enough with clinical research. This four part review series focuses on methods to improve evidence-based practice, by improving methods to integrate laboratory and clinical research. PMID:22368327

Valerian: no evidence for clinically relevant interactions.

PubMed

Kelber, Olaf; Nieber, Karen; Kraft, Karin

2014-01-01

In recent popular publications as well as in widely used information websites directed to cancer patients, valerian is claimed to have a potential of adverse interactions with anticancer drugs. This questions its use as a safe replacement for, for example, benzodiazepines. A review on the interaction potential of preparations from valerian root (Valeriana officinalis L. root) was therefore conducted. A data base search and search in a clinical drug interaction data base were conducted. Thereafter, a systematic assessment of publications was performed. Seven in vitro studies on six CYP 450 isoenzymes, on p-glycoprotein, and on two UGT isoenzymes were identified. However, the methodological assessment of these studies did not support their suitability for the prediction of clinically relevant interactions. In addition, clinical studies on various valerian preparations did not reveal any relevant interaction potential concerning CYP 1A2, 2D6, 2E1, and 3A4. Available animal and human pharmacodynamic studies did not verify any interaction potential. The interaction potential of valerian preparations therefore seems to be low and thereby without clinical relevance. We conclude that there is no specific evidence questioning their safety, also in cancer patients.

Valerian: No Evidence for Clinically Relevant Interactions

PubMed Central

Nieber, Karen; Kraft, Karin

2014-01-01

In recent popular publications as well as in widely used information websites directed to cancer patients, valerian is claimed to have a potential of adverse interactions with anticancer drugs. This questions its use as a safe replacement for, for example, benzodiazepines. A review on the interaction potential of preparations from valerian root (Valeriana officinalis L. root) was therefore conducted. A data base search and search in a clinical drug interaction data base were conducted. Thereafter, a systematic assessment of publications was performed. Seven in vitro studies on six CYP 450 isoenzymes, on p-glycoprotein, and on two UGT isoenzymes were identified. However, the methodological assessment of these studies did not support their suitability for the prediction of clinically relevant interactions. In addition, clinical studies on various valerian preparations did not reveal any relevant interaction potential concerning CYP 1A2, 2D6, 2E1, and 3A4. Available animal and human pharmacodynamic studies did not verify any interaction potential. The interaction potential of valerian preparations therefore seems to be low and thereby without clinical relevance. We conclude that there is no specific evidence questioning their safety, also in cancer patients. PMID:25093031

Transient and sustained neural responses to death-related linguistic cues

PubMed Central

Shi, Zhenhao

2013-01-01

Recent research showed that perception of death-related vs death-unrelated linguistic cues produced increased frontoparietal activity but decreased insular activity. This study investigated (i) whether the increased frontoparietal and decreased insular activities are, respectively, associated with transient trial-specific processes of death-related linguistic cues and sustained death-related thought during death-relevance judgments on linguistic cues and (ii) whether the neural activity underlying death-related thought can predict individuals’ dispositional death anxiety. Participants were presented with death-related/unrelated words, life-related/unrelated words, and negative-valence/neutral words in separate sessions. Participants were scanned using functional magnetic resonance imaging while performing death-relevance, life-relevance, and valence judgments on the words, respectively. The contrast of death-related vs death-unrelated words during death-relevance judgments revealed transient increased activity in the left inferior parietal lobule, the right frontal eye field, and the right superior parietal lobule. The contrast of death-relevance judgments vs life-relevance/valence judgments showed decreased activity in the bilateral insula. The sustained insular activity was correlated with dispositional death anxiety, but only in those with weak transient frontoparietal responses to death-related words. Our results dissociate the transient and sustained neural responses to death-related linguistic cues and suggest that the combination of the transient and sustained neural activities can predict dispositional death anxiety. PMID:22422804

Contraceptive efficacy and safety of estradiol valerate/dienogest in a healthy female population: a multicenter, open-label, uncontrolled Phase III study.

PubMed

Yu, Qi; Huang, Zirong; Ren, Mulan; Chang, Qing; Zhang, Zhongqi; Parke, Susanne

2018-01-01

To investigate the efficacy and safety of a combined oral contraceptive containing estradiol valerate and dienogest (EV/DNG) in healthy Asian women. In this multicenter Phase III study, women received oral EV/DNG in a 28-day regimen for 13 cycles. The primary efficacy endpoint was the number of unintended pregnancies, measured by the Pearl Index (PI); secondary efficacy endpoints included bleeding pattern and cycle control parameters. Adverse events were monitored during the study and overall satisfaction with treatment was determined on completion of the study. A total of 954 Asian women (97.7% of subjects assigned to study medication; mean age 33.4 years) were treated. Five pregnancies were reported during EV/DNG treatment over 796.34 relevant woman-years of exposure, giving an unadjusted PI of 0.63 and a cumulative failure rate of 0.0049; 3 pregnancies during EV/DNG treatment over 760.35 relevant woman-years of exposure gave an adjusted PI of 0.39. The bleeding pattern improved during the reporting periods within the study. The proportion of women who experienced withdrawal bleeding decreased with treatment (84.9% of women during Cycle 1 vs 79.3% in Cycle 13), and the mean length of withdrawal bleeding decreased with treatment (4.2 vs 3.4 days). The number and maximum length of intracyclic bleeding/spotting episodes also decreased with EV/DNG. EV/DNG was well tolerated, and 92% of women included in the study were very satisfied or somewhat satisfied with EV/DNG. EV/DNG showed high contraceptive efficacy, was well tolerated in Asian women, and may be effectively used in this population. ClinicalTrials.gov identifier: NCT01638910.

Grey matter alterations in migraine: A systematic review and meta-analysis.

PubMed

Jia, Zhihua; Yu, Shengyuan

2017-01-01

To summarize and meta-analyze studies on changes in grey matter (GM) in patients with migraine. We aimed to determine whether there are concordant structural changes in the foci, whether structural changes are concordant with functional changes, and provide further understanding of the anatomy and biology of migraine. We searched PubMed and Embase for relevant articles published between January 1985 and November 2015, and examined the references within relevant primary articles. Following exclusion of unsuitable studies, meta-analysis were performed using activation likelihood estimation (ALE). Eight clinical studies were analyzed for structural changes, containing a total of 390 subjects (191 patients and 199 controls). Five functional studies were enrolled, containing 93 patients and 96 controls. ALE showed that the migraineurs had concordant decreases in the GM volume (GMV) in the bilateral inferior frontal gyri, the right precentral gyrus, the left middle frontal gyrus and the left cingulate gyrus. GMV decreases in right claustrum, left cingulated gyrus, right anterior cingulate, amygdala and left parahippocampal gyrus are related to estimated frequency of headache attack . Activation was found in the somatosensory, cingulate, limbic lobe, basal ganglia and midbrain in migraine patients. GM changes in migraineurs may indicate the mechanism of pain processing and associated symptoms. Changes in the frontal gyrus may predispose a person to pain conditions. The limbic regions may be accumulated damage due to the repetitive occurrence of pain-related processes. Increased activation in precentral gyrus and cingulate opposed to GMV decrease might suggest increased effort duo to disorganization of these areas and/or the use of compensatory strategies involving pain processing in migraine. Knowledge of these structural and functional changes may be useful for monitoring disease progression as well as for therapeutic interventions.

The muscle contraction mode determines lymphangiogenesis differentially in rat skeletal and cardiac muscles by modifying local lymphatic extracellular matrix microenvironments.

PubMed

Greiwe, L; Vinck, M; Suhr, F

2016-05-01

Lymphatic vessels are of special importance for tissue homeostasis, and increases of their density may foster tissue regeneration. Exercise could be a relevant tool to increase lymphatic vessel density (LVD); however, a significant lack of knowledge remains to understand lymphangiogenesis in skeletal muscles upon training. Interestingly, training-induced lymphangiogenesis has never been studied in the heart. We studied lymphangiogenesis and LVD upon chronic concentric and chronic eccentric muscle contractions in both rat skeletal (Mm. Edl and Sol) and cardiac muscles. We found that LVD decreased in both skeletal muscles specifically upon eccentric training, while this contraction increased LVD in cardiac tissue. These observations were supported by opposing local remodelling of lymphatic vessel-specific extracellular matrix components in skeletal and cardiac muscles and protein levels of lymphatic markers (Lyve-1, Pdpn, Vegf-C/D). Confocal microscopy further revealed transformations of lymphatic vessels into vessels expressing both blood (Cav-1) and lymphatic (Vegfr-3) markers upon eccentric training specifically in skeletal muscles. In addition and phenotype supportive, we found increased inflammation (NF-κB/p65, Il-1β, Ifn-γ, Tnf-α and MPO(+) cells) in eccentrically stressed skeletal, but decreased levels in cardiac muscles. Our data provide novel mechanistic insights into lymphangiogenic processes in skeletal and cardiac muscles upon chronic muscle contraction modes and demonstrate that both tissues adapt in opposing manners specifically to eccentric training. These data are highly relevant for clinical applications, because eccentric training serves as a sufficient strategy to increase LVD and to decrease inflammation in cardiac tissue, for example in order to reduce tissue abortion in transplantation settings. © 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Clinical relevance is associated with allergen-specific wheal size in skin prick testing

PubMed Central

Haahtela, T; Burbach, G J; Bachert, C; Bindslev-Jensen, C; Bonini, S; Bousquet, J; Bousquet-Rouanet, L; Bousquet, P J; Bresciani, M; Bruno, A; Canonica, G W; Darsow, U; Demoly, P; Durham, S R; Fokkens, W J; Giavi, S; Gjomarkaj, M; Gramiccioni, C; Kowalski, M L; Losonczy, G; Orosz, M; Papadopoulos, N G; Stingl, G; Todo-Bom, A; von Mutius, E; Köhli, A; Wöhrl, S; Järvenpää, S; Kautiainen, H; Petman, L; Selroos, O; Zuberbier, T; Heinzerling, L M

2014-01-01

Background Within a large prospective study, the Global Asthma and Allergy European Network (GA2LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings. Objective To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points. Methods The GA2LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated. Results Depending on the allergen, from 40% (blatella) to 87–89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen. Conclusion These ‘reading keys’ for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use. PMID:24283409

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

PubMed

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

2015-03-01

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

Association Between Medicare Accountable Care Organization Implementation and Spending Among Clinically Vulnerable Beneficiaries

PubMed Central

Colla, Carrie H.; Lewis, Valerie A.; Kao, Lee-Sien; O’Malley, A. James; Chang, Chiang-Hua; Fisher, Elliott S.

2016-01-01

IMPORTANCE Accountable care contracts hold physician groups financially responsible for the quality and cost of health care delivered to patients. Focusing on clinically vulnerable patients, those with serious conditions who are responsible for the greatest proportion of spending, may result in the largest effects on both patient outcomes and financial rewards for participating physician groups. OBJECTIVE To estimate the effect of Medicare accountable care organization (ACO) contracts on spending and high-cost institutional use for all Medicare beneficiaries and for clinically vulnerable beneficiaries. DESIGN, SETTING, AND PARTICIPANTS For this cohort study, 2 study populations were defined: the overall Medicare population and the clinically vulnerable subgroup of Medicare beneficiaries. The overall Medicare population was based on a random 40% sample drawn from continuously enrolled fee-for-service beneficiaries with at least 1 evaluation and management visit in a calendar year. The clinically vulnerable study population included all Medicare beneficiaries 66 years or older who had at least 3 Hierarchical Condition Categories (HCCs). Beneficiaries entered the cohort during the quarter between January 2009 to December 2011 when they first had at least 3 HCCs and remained in the cohort until death. Cohort entry was restricted to the preperiod to account for potential changes in coding practices after ACO implementation. Difference-in-difference estimations were used to compare changes in health care outcomes for Medicare beneficiaries attributed to physicians in ACOs with those attributed to non-ACO physicians from January 2009 to December 2013. EXPOSURES Medicare ACOs beginning contracts in January 2012, April 2012, July 2012, and January 2013 through the Pioneer and Medicare Shared Savings Programs. MAIN OUTCOMES AND MEASURES Total spending per beneficiary-quarter, spending categories, use of hospitals and emergency departments, ambulatory care sensitive admissions, and 30-day readmissions. RESULTS Total spending decreased by $34 (95% CI, −$52 to −$15) per beneficiary-quarter after ACO contract implementation across the overall Medicare population (n = 15 592 600) and decreased $114 in clinically vulnerable patients (n = 8 673 823) (95% CI, −$178 to −$50). In the overall Medicare cohort, hospitalizations and emergency department visits decreased by 1.3 and 3.0 events per 1000 beneficiaries per quarter, respectively (95% CIs: −2.1 to −0.4 and −4.8 to −1.3), and hospitalizations and emergency department visits decreased in the clinically vulnerable cohort by 2.9 and 4.1 events per 1000 beneficiaries per quarter, respectively (95% CIs: −5.2 to −0.7 and −7.1 to −1.2). Changes in total spending associated with ACOs did not vary by clinical condition of beneficiaries. CONCLUSIONS AND RELEVANCE Medicare ACO programs are associated with modest reductions in spending and use of hospitals and emergency departments. Savings were realized through reductions in use of institutional settings in clinically vulnerable patients. PMID:27322485

Effects of xylitol on xylitol-sensitive versus xylitol-resistant Streptococcus mutans strains in a three-species in vitro biofilm.

PubMed

Marttinen, Aino M; Ruas-Madiedo, Patricia; Hidalgo-Cantabrana, Claudio; Saari, Markku A; Ihalin, Riikka A; Söderling, Eva M

2012-09-01

We studied the effects of xylitol on biofilms containing xylitol-resistant (Xr) and xylitol-sensitive (Xs) Streptococcus mutans, Actinomyces naeslundii and S. sanguinis. The biofilms were grown for 8 and 24 h on hydroxyapatite discs. The viable microorganisms were determined by plate culturing techniques and fluorescence in situ hybridization (FISH) was performed using a S. mutans-specific probe. Extracellular cell-bound polysaccharides (EPS) were determined by spectrofluorometry from single-species S. mutans biofilms. In the presence of 5 % xylitol, the counts of the Xs S. mutans decreased tenfold in the young (8 h) biofilm (p < 0.05) but no effect was seen in the mature (24 h) biofilm. No decrease was observed for the Xr strains, and FISH confirmed these results. No differences were detected in the EPS production of the Xs S. mutans grown with or without xylitol, nor between Xr and Xs S. mutans strains. Thus, it seems that xylitol did not affect the EPS synthesis of the S. mutans strains. Since the Xr S. mutans strains, not inhibited by xylitol, showed no xylitol-induced decrease in the biofilms, we conclude that growth inhibition could be responsible for the decrease of the counts of the Xs S. mutans strains in the clinically relevant young biofilms.

Three months of simvastatin therapy vs. placebo for severe portal hypertension in cirrhosis: A randomized controlled trial.

PubMed

Pollo-Flores, Priscila; Soldan, Mônica; Santos, Ubiratan Cassano; Kunz, Danielle Gobbi; Mattos, Denise Espindola; da Silva, Alexandre Cerqueira; Marchiori, Roberta Cabral; Rezende, Guilherme Ferreira da Motta

2015-11-01

Pleiotropic effects of statins decrease intrahepatic resistance and portal hypertension. We evaluated the effects of simvastatin on hepatic venous pressure gradient (HVPG) and azygos vein blood flow in cirrhotic patients. A 3-month prospective, randomized, triple-blind trial with simvastatin (40 mg/day) vs. placebo was conducted in patients with cirrhotic portal hypertension. HVPG and azygos blood flow, measured by colour Doppler endoscopic ultrasound, were assessed before and after treatment. The primary endpoint was a decrease in the HVPG of at least 20% from baseline or to ≤12 mmHg after the treatment. 34 patients were prospectively enrolled, and 24 completed the protocol. In the simvastatin group 6/11 patients (55%) presented a clinically relevant decrease in the HVPG; no decrease was observed in the placebo group (p=0.036). Patients with medium/large oesophageal varices and previous variceal bleeding had a higher response rate to simvastatin. HVPG and azygos blood flow values were not correlated. No significant adverse events occurred. Simvastatin lowers portal pressure and may even improve liver function. The haemodynamic effect appears to be more evident in patients with severe portal hypertension. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Healing of Postextraction Sockets Preserved With Autologous Platelet Concentrates. A Systematic Review and Meta-Analysis.

PubMed

Del Fabbro, Massimo; Bucchi, Cristina; Lolato, Alessandra; Corbella, Stefano; Testori, Tiziano; Taschieri, Silvio

2017-08-01

The true benefit of autologous platelet concentrates (APCs) for enhancing the healing of postextraction sites is still a matter of debate, and in recent years several clinical trials have addressed this issue. The purpose of this study was to determine the effectiveness of an APC adjunct in the preservation of fresh extraction sockets. An electronic search was performed on Medline, Embase, Scopus, and the Cochrane Central Register of Controlled Trials. Only controlled clinical trials or randomized clinical trials were included. Selected articles underwent risk-of-bias assessment. The outcomes were complications and adverse events, discomfort and quality of life, bone healing and remodeling assessed by histologic and radiographic techniques, and soft tissue healing. Thirty-three comparative studies were included. Nine articles had a parallel design and 24 had a split-mouth design. Twenty studies were considered to have a low risk of bias and 13 were considered to have a high risk. Overall, 1,193 teeth were extracted from 911 patients. Meta-analysis showed that soft tissue healing, probing depth at 3 months, and bone density at 1, 3, and 6 months were statistically better for the APC group. Qualitative analysis suggested that APCs might be associated with a decrease in swelling and trismus. However, no relevant difference among groups was found for probing depth at 1 month, incidence of alveolar osteitis, acute inflammation or infection, percentage of new bone, and indirect measurement of bone metabolism. APCs should be used in postextraction sites to improve clinical and radiographic outcomes such as bone density and soft tissue healing and postoperative symptoms. The actual benefit of APCs on decreasing pain in extraction sockets is still not quantifiable. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Entyvio lengthen dose-interval study: lengthening vedolizumab dose interval and the risk of clinical relapse in inflammatory bowel disease.

PubMed

Chan, Webber; Lynch, Nicole; Bampton, Peter; Chang, Jeff; Chung, Alvin; Florin, Timothy; Hetzel, David J; Jakobovits, Simon; Moore, Gregory; Pavli, Paul; Radford-Smith, Graham; Thin, Lena; Baraty, Brandon; Haifer, Craig; Yau, Yunki; Leong, Rupert W L

2018-07-01

Vedolizumab (VDZ), an α4β7 anti-integrin antibody, is efficacious in the induction and maintenance of remission in ulcerative colitis (UC) and Crohn's disease (CD). In the GEMINI long-term safety study, enrolled patients received 4-weekly VDZ. Upon completion, patients were switched to 8-weekly VDZ in Australia. The clinical success rate of treatment de-escalation for patients in remission on VDZ has not been described previously. To determine the proportion of patients who relapsed after switching from 4 to 8-weekly VDZ, the mean time to relapse, and the recapture rate when switching back to 8-weekly dosing. This was a retrospective, observational, multicenter study of patients previously recruited into GEMINI long-term safety in Australia. Data on the demographics and biochemical findings were collected. There were 34 patients [23 men, mean age 49.1 (±13.1) years] and their mean disease duration was 17.6 (±8.5) years. The mean 4-weekly VDZ infusion duration was 286.5 (±48.8) weeks. A total of five (15%) patients relapsed on dose-interval increase (4/17 UC, 1/17 CD) at a median duration from dose interval lengthening to flare of 14 weeks (interquartile range=6-25). Eighty percent (4/5) of patients re-entered remission following dose-interval decrease back to 4-weekly. No clinical predictors of relapse could be determined because of the small cohort size. The risk of patients relapsing when switching from 4 to 8-weekly VDZ ∼15% and is similar between CD and UC. Dose-interval decrease recaptures 80% of patients who relapsed. Therapeutic drug monitoring of VDZ may be of clinical relevance.

New therapies for chronic hepatitis C infection: a systematic review of evidence from clinical trials.

PubMed

Lee, L Y; Tong, C Y W; Wong, T; Wilkinson, M

2012-04-01

Hepatitis C virus (HCV) affects approximately 3% of the world population. The current standard of care for treatment of HCV is a combination of pegylated interferon and ribavirin. Approximately 10% of patients will stop treatment and 30% of patients require dose reduction because of side effects. For genotype 1 HCV-infected patients, only 40% of patients will achieve undetectable viral load 26 weeks posttreatment. The objectives of this review were to identify new treatments that are in clinical trials. These include boceprevir and telaprevir which are in routine clinical use and form part of the American Association for the Study of Liver Diseases (AASLD) 2011 guidelines as well as drugs based on observational studies, improving/modifying ribavirin or interferon-based therapies, modifying the host response and finally the use of direct-acting antiviral agents (DAA).   MEDLINE and EMBASE databases were searched from 2008 to 2011 for treatments for hepatitis C. Furthermore, abstracts and poster presentations for the annual European Association Study of the Liver, AASLD, Digestive Disease Week and Asian Pacific Association for the study of the Liver were searched for relevant material. All four classes of DAA; NS3/NS4a serine protease inhibitors, cyclophilin inhibitors, NS5b polymerase inhibitors and NS5a inhibitors, show good success rates. Trials have been performed without ribavirin or interferon and demonstrate good antiviral activity with a decreased side effect profile. Combinations of DAA are a promising area of research with a high success rate. Clinical trials show that future HCV therapy could be personalised, achieve higher success rates with decreased adverse incidents. © 2012 Blackwell Publishing Ltd.

Point-of-Care Diagnostics for Niche Applications

PubMed Central

Cummins, Brian M.; Ligler, Frances S.; Walker, Glenn M.

2016-01-01

Point-of-care or point-of-use diagnostics are analytical devices that provide clinically relevant information without the need for a core clinical laboratory. In this review we define point-of-care diagnostics as portable versions of assays performed in a traditional clinical chemistry laboratory. This review discusses five areas relevant to human and animal health where increased attention could produce significant impact: veterinary medicine, space travel, sports medicine, emergency medicine, and operating room efficiency. For each of these areas, clinical need, available commercial products, and ongoing research into new devices are highlighted. PMID:26837054

Cumulative trauma disorders: A review.

PubMed

Iqbal, Zaheen A; Alghadir, Ahmad H

2017-08-03

Cumulative trauma disorder (CTD) is a term for various injuries of the musculoskeletal and nervous systems that are caused by repetitive tasks, forceful exertions, vibrations, mechanical compression or sustained postures. Although there are many studies citing incidence of CTDs, there are fewer articles about its etiology, pathology and management. The aim of our study was to discuss the etiology, pathogenesis, prevention and management of CTDs. A literature search was performed using various electronic databases. The search was limited to articles in English language pertaining to randomized clinical trials, cohort studies and systematic reviews of CTDs. A total of 180 papers were identified to be relevant published since 1959. Out of these, 125 papers reported about its incidence and 50 about its conservative treatment. Workplace environment, same task repeatability and little variability, decreased time for rest, increase in expectations are major factors for developing CTDs. Prevention of its etiology and early diagnosis can be the best to decrease its incidence and severity. For effective management of CTDs, its treatment should be divided into Primordial, Primary, Secondary and Tertiary prevention.

Workflow Optimization in Vertebrobasilar Occlusion

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

Kamper, Lars, E-mail: lars.kamper@helios-kliniken.de; Meyn, Hannes; Rybacki, Konrad

2012-06-15

Objective: In vertebrobasilar occlusion, rapid recanalization is the only substantial means to improve the prognosis. We introduced a standard operating procedure (SOP) for interventional therapy to analyze the effects on interdisciplinary time management. Methods: Intrahospital time periods between hospital admission and neuroradiological intervention were retrospectively analyzed, together with the patients' outcome, before (n = 18) and after (n = 20) implementation of the SOP. Results: After implementation of the SOP, we observed statistically significant improvement of postinterventional patient neurological status (p = 0.017). In addition, we found a decrease of 5:33 h for the mean time period from hospital admissionmore » until neuroradiological intervention. The recanalization rate increased from 72.2% to 80% after implementation of the SOP. Conclusion: Our results underscore the relevance of SOP implementation and analysis of time management for clinical workflow optimization. Both may trigger awareness for the need of efficient interdisciplinary time management. This could be an explanation for the decreased time periods and improved postinterventional patient status after SOP implementation.« less

Selective testing of women based on age for genital Chlamydia trachomatis and Neisseria gonorrhoeae infection in a centralized regional microbiology laboratory.

PubMed

Church, Deirdre L; Amante, L; Semeniuk, H; Gregson, D B

2007-04-01

Calgary Laboratory Services, Alberta, Canada, provides microbiology services via a centralized laboratory to the Calgary Health Region. A selective genital Chlamydia trachomatis (CT)/Neisseria gonorrhoeae (GC) testing policy for women >35 years was implemented. The changes in physician ordering practice, the rate of detection of infections, and the test turnaround times were monitored. The volume of tests, the cost/test, and the total service costs accrued in the year before and after this policy change were compared. An immediate impact was a 30% decrease in tests performed due to the laboratory rejecting samples from older women. Subsequently, physicians' practice changed so that tests were ordered when test criteria were met. Detection rates did not change in any age group. A 27.9% decrease in the total service costs resulted in a labor reduction of 0.2 FTE. Selective testing of women >35 years with a low prevalence of CT/GC infection is clinically relevant and cost-effective.

Discovery of a novel glucose metabolism in cancer: The role of endoplasmic reticulum beyond glycolysis and pentose phosphate shunt

PubMed Central

Marini, Cecilia; Ravera, Silvia; Buschiazzo, Ambra; Bianchi, Giovanna; Orengo, Anna Maria; Bruno, Silvia; Bottoni, Gianluca; Emionite, Laura; Pastorino, Fabio; Monteverde, Elena; Garaboldi, Lucia; Martella, Roberto; Salani, Barbara; Maggi, Davide; Ponzoni, Mirco; Fais, Franco; Raffaghello, Lizzia; Sambuceti, Gianmario

2016-01-01

Cancer metabolism is characterized by an accelerated glycolytic rate facing reduced activity of oxidative phosphorylation. This “Warburg effect” represents a standard to diagnose and monitor tumor aggressiveness with 18F-fluorodeoxyglucose whose uptake is currently regarded as an accurate index of total glucose consumption. Studying cancer metabolic response to respiratory chain inhibition by metformin, we repeatedly observed a reduction of tracer uptake facing a marked increase in glucose consumption. This puzzling discordance brought us to discover that 18F-fluorodeoxyglucose preferentially accumulates within endoplasmic reticulum by exploiting the catalytic function of hexose-6-phosphate-dehydrogenase. Silencing enzyme expression and activity decreased both tracer uptake and glucose consumption, caused severe energy depletion and decreased NADPH content without altering mitochondrial function. These data document the existence of an unknown glucose metabolism triggered by hexose-6-phosphate-dehydrogenase within endoplasmic reticulum of cancer cells. Besides its basic relevance, this finding can improve clinical cancer diagnosis and might represent potential target for therapy. PMID:27121192

Assessment of induced rat mammary tumour response to chemotherapy using the apparent diffusion coefficient of tissue water as determined by diffusion-weighted 1H-NMR spectroscopy in vivo.

PubMed

Lemaire, L; Howe, F A; Rodrigues, L M; Griffiths, J R

1999-03-01

Chemosensitivity of N-methyl-N-nitrosourea-induced rat mammary tumours treated with 5-fluorouracil at a dose of 100 mg kg(-1) i.p. was assessed by using diffusion-weighted 1H-MRS to measure the average diffusion coefficient (ADC) of water in the tumour tissue. ADC measurements prior to any therapy correlated positively with necrotic fraction. Tumours with low initial ADC (< 0.95 x 10(9) m2 s(-1)) showed an increase in ADC 7 days after treatment, whereas tumours with a high initial ADC (> 1.2 x 10(9) m2 s(-1)) showed a decrease. All tumours decreased significantly in volume (P < 0.05) 2, 5 and 7 days after treatment. At day 7 post-treatment, tumours with a high pre-treatment ADC started to regrow. The initial ADC value, as well as changes after treatment predict tumour chemosensitivity, which could be clinically relevant.

Acetaminophen and Metamizole Induce Apoptosis in HT 29 and SW 480 Colon Carcinoma Cell Lines In Vitro.

PubMed

Bundscherer, Anika C; Malsy, Manuela; Gruber, Michael A; Graf, Bernhard M; Sinner, Barbara

2018-02-01

The perioperative phase is supposed to be a period with high vulnerability for cancer dissemination. Acetaminophen and metamizole are common analgesics administered during this phase. We investigated the effect of acetaminophen, metamizole and 4-methylaminoantipyrine (MAA) on proliferation and apoptosis of colon carcinoma cell lines (SW 480 and HT 29). Proliferation was detected by cell proliferation ELISA BrdU, and apoptosis by Annexin V staining. Cytochrome c and caspase 3, 8 and 9 expression levels were detected by western blot. Acetaminophen, metamizole or MAA caused slight changes in proliferation. Acetaminophen, metamizole or the combination increased apoptosis in both cell lines. All agents decreased caspase 3 and 8 expression in SW480. Acetaminophen decreased caspase 9 expression in both cell lines. In clinically relevant doses, acetaminophen and/or metamizole induce apoptosis in both colon cancer cell lines. Both mitochondrial and death receptor pathways might be involved in acetaminophen-induced apoptosis. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Should athletes return to sport after applying ice? A systematic review of the effect of local cooling on functional performance.

PubMed

Bleakley, Chris M; Costello, Joseph T; Glasgow, Philip D

2012-01-01

Applying ice or other forms of topical cooling is a popular method of treating sports injuries. It is commonplace for athletes to return to competitive activity, shortly or immediately after the application of a cold treatment. In this article, we examine the effect of local tissue cooling on outcomes relating to functional performance and to discuss their relevance to the sporting environment. A computerized literature search, citation tracking and hand search was performed up to April, 2011. Eligible studies were trials involving healthy human participants, describing the effects of cooling on outcomes relating to functional performance. Two reviewers independently assessed the validity of included trials and calculated effect sizes. Thirty five trials met the inclusion criteria; all had a high risk of bias. The mean sample size was 19. Meta-analyses were not undertaken due to clinical heterogeneity. The majority of studies used cooling durations > 20 minutes. Strength (peak torque/force) was reported by 25 studies with approximately 75% recording a decrease in strength immediately following cooling. There was evidence from six studies that cooling adversely affected speed, power and agility-based running tasks; two studies found this was negated with a short rewarming period. There was conflicting evidence on the effect of cooling on isolated muscular endurance. A small number of studies found that cooling decreased upper limb dexterity and accuracy. The current evidence base suggests that athletes will probably be at a performance disadvantage if they return to activity immediately after cooling. This is based on cooling for longer than 20 minutes, which may exceed the durations employed in some sporting environments. In addition, some of the reported changes were clinically small and may only be relevant in elite sport. Until better evidence is available, practitioners should use short cooling applications and/or undertake a progressive warm up prior to returning to play.

Prevalence and relevance of the positivity of skin prick testing in patients with chronic urticaria.

PubMed

Kulthanan, Kanokvalai; Jiamton, Sukhum; Rutnin, Ni-on; Insawang, Metavee; Pinkaew, Sumrauy

2008-06-01

Many patients with chronic urticaria (CU) worry that foods or other allergens are responsible for their urticaria. Skin prick testing (SPT) may be one of the investigations used to provide a clear illustration. The purpose of our study was to assess the prevalence of positivity of SPT to food allergens and aeroallergens and their relevance in patients with CU, in order to demonstrate the diagnostic value of SPT in CU. We retrospectively reviewed case record forms of patients with chronic ordinary urticaria who underwent SPT in the Urticaria Clinic, Siriraj Hospital, during the period 2000-2004. The studied allergens included 16 food allergens and 12 aeroallergens. Eighty-eight patients were enrolled. The prevalence of positive SPT among patients with CU was 47.7%. Patients who had personal histories of atopy had statistically significant positive SPT results compared with patients who had negative SPT. Of 88 patients, 26 patients (30%) gave positive results to food allergens, 36 patients (41%) gave positive results to aeroallergens and 20 patients (22.7%) gave positive results to both food and aeroallergens. One-third of the subjects (34.6%) who had positive SPT results to food allergens had clinical relevance of food allergy in some systems but only one patient had clinical relevance of food-induced urticaria. Half of the patients who had a history of aeroallergen sensitivity gave a positive SPT response for aeroallergens; however, there was no clinical relevance to their CU. Our study showed that the prevalence of positive SPT to food allergens and aeroallergens in patients with CU was common but had little clinical relevance to CU.

The efficacy and safety of novel oral anticoagulants for the preventive treatment in atrial fibrillation patients: a systematic review and meta-analysis.

PubMed

Liu, Guang Jian; Wang, Yun Fu; Chen, Ping You; Chang, Wei; Tu, Ming Li; Chang, Li Ying; Cheng, Ping; Luo, Jie

2014-09-01

Novel oral anticoagulants, including direct factor Xa inhibitors and direct factor IIa inhibitors, have been used to prevent stroke in patients with atrial fibrillation (AF) for a decade. In this study, the efficacy and safety of the novel oral anticoagulants were assessed in AF patients. No language restrictions were applied. Study selection and data extraction were carried out by searching PubMed, EMBASE, OVID, the BIOSIS, the Web of Science, Clinical Trials Registers, Cochrane Central Register of Controlled Trials and the China Academic Library and Information System. Each database was searched from its inception date to June 2013. Using odds ratio (OR) as an indicator, we systematically evaluated the primary efficacy endpoints and safety endpoints, as well as 10 secondary endpoints. Compared to the control drugs, the novel oral anticoagulants showed an OR decreased by 26% (OR: 0.74, 95% confidence interval (CI): 0.62-0.88) for stroke or systemic embolism, decreased by 24% (OR: 0.76, 95% CI: 0.64-0.90) for major bleeding, decreased by 10% (OR: 0.90, 95% CI: 0.84-0.95) for death from any cause, decreased by 27% for disabling or fatal stroke (OR: 0.73, 95% CI: 0.54-0.97), decreased by 31% (OR: 0.69, 95% CI: 0.60-0.8) for fatal bleeding, and decreased by 8% (OR: 0.92, 95% CI: 0.88-0.95) for serious adverse events. However, there was no significant difference in acute myocardial infarction, systemic embolism, major bleeding or clinically relevant non-major, all bleeding events, all adverse events and liver function disorder, between the novel oral anticoagulants and control drugs (p > 0.05). Compared to the control drugs, the novel oral anticoagulants showed higher efficiency and safety in patients with AF, as evidenced by their superior performance not only in reducing the risk of stroke or systemic embolism with a lower risk of major bleeding but also in decreasing the incidence of death from any cause, disabling or fatal stroke, serious adverse events and fatal bleeding.

THE GAP BETWEEN ECONOMIC EVALUATIONS AND CLINICAL PRACTICE: A SYSTEMATIC REVIEW OF ECONOMIC EVALUATIONS ON DABIGATRAN FOR ATRIAL FIBRILLATION.

PubMed

Rolden, Herbert J A; van der Wilt, Gert Jan; Maas, Angela H E M; Grutters, Janneke P C

2018-06-18

As model-based economic evaluations (MBEEs) are widely used to make decisions in the context of policy, it is imperative that they represent clinical practice. Here, we assess the relevance of MBEEs on dabigatran for the prevention of stroke in patients with atrial fibrillation (AF). We performed a systematic review on the basis of a developed questionnaire, tailored to oral anticoagulation in patients with AF. Included studies had a full body text in English, compared dabigatran with a vitamin K antagonist, were not dedicated to one or more subgroup(s), and yielded an incremental cost-effectiveness ratio. The relevance of all MBEEs was assessed on the basis of ten context-independent factors, which encompassed clinical outcomes and treatment duration. The MBEEs performed for the United States were assessed on the basis of seventeen context-dependent factors, which were related to the country's target population and clinical environment. The search yielded twenty-nine MBEEs, of which six were performed for the United States. On average, 54 percent of the context-independent factors were included per study, and 37 percent of the seventeen context-dependent factors in the U.S. The share of relevant factors per study did not increase over time. MBEEs on dabigatran leave out several relevant factors, limiting their usefulness to decision makers. We strongly urge health economic researchers to improve the relevance of their MBEEs by including context-independent relevance factors, and modeling context-dependent factors befitting the decision context concerned.

Clinical relevance of pharmacist intervention in an emergency department.

PubMed

Pérez-Moreno, Maria Antonia; Rodríguez-Camacho, Juan Manuel; Calderón-Hernanz, Beatriz; Comas-Díaz, Bernardino; Tarradas-Torras, Jordi

2017-08-01

To evaluate the clinical relevance of pharmacist intervention on patient care in emergencies, to determine the severity of detected errors. Second, to analyse the most frequent types of interventions and type of drugs involved and to evaluate the clinical pharmacist's activity. A 6-month observational prospective study of pharmacist intervention in the Emergency Department (ED) at a 400-bed hospital in Spain was performed to record interventions carried out by the clinical pharmacists. We determined whether the intervention occurred in the process of medication reconciliation or another activity, and whether the drug involved belonged to the High-Alert Medications Institute for Safe Medication Practices (ISMP) list. To evaluate the severity of the errors detected and clinical relevance of the pharmacist intervention, a modified assessment scale of Overhage and Lukes was used. Relationship between clinical relevance of pharmacist intervention and the severity of medication errors was assessed using ORs and Spearman's correlation coefficient. During the observation period, pharmacists reviewed the pharmacotherapy history and medication orders of 2984 patients. A total of 991 interventions were recorded in 557 patients; 67.2% of the errors were detected during medication reconciliation. Medication errors were considered severe in 57.2% of cases and 64.9% of pharmacist intervention were considered relevant. About 10.9% of the drugs involved are in the High-Alert Medications ISMP list. The severity of the medication error and the clinical significance of the pharmacist intervention were correlated (Spearman's ρ=0.728/p<0.001). In this single centre study, the clinical pharmacists identified and intervened on a high number of severe medication errors. This suggests that emergency services will benefit from pharmacist-provided drug therapy services. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

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.

Clinical-decision support based on medical literature: A complex network approach

NASA Astrophysics Data System (ADS)

Jiang, Jingchi; Zheng, Jichuan; Zhao, Chao; Su, Jia; Guan, Yi; Yu, Qiubin

2016-10-01

In making clinical decisions, clinicians often review medical literature to ensure the reliability of diagnosis, test, and treatment because the medical literature can answer clinical questions and assist clinicians making clinical decisions. Therefore, finding the appropriate literature is a critical problem for clinical-decision support (CDS). First, the present study employs search engines to retrieve relevant literature about patient records. However, the result of the traditional method is usually unsatisfactory. To improve the relevance of the retrieval result, a medical literature network (MLN) based on these retrieved papers is constructed. Then, we show that this MLN has small-world and scale-free properties of a complex network. According to the structural characteristics of the MLN, we adopt two methods to further identify the potential relevant literature in addition to the retrieved literature. By integrating these potential papers into the MLN, a more comprehensive MLN is built to answer the question of actual patient records. Furthermore, we propose a re-ranking model to sort all papers by relevance. We experimentally find that the re-ranking model can improve the normalized discounted cumulative gain of the results. As participants of the Text Retrieval Conference 2015, our clinical-decision method based on the MLN also yields higher scores than the medians in most topics and achieves the best scores for topics: #11 and #12. These research results indicate that our study can be used to effectively assist clinicians in making clinical decisions, and the MLN can facilitate the investigation of CDS.

Is Dysfunctional Use of the Mobile Phone a Behavioural Addiction? Confronting Symptom-Based Versus Process-Based Approaches.

PubMed

Billieux, Joël; Philippot, Pierre; Schmid, Cécile; Maurage, Pierre; De Mol, Jan; Van der Linden, Martial

2015-01-01

Dysfunctional use of the mobile phone has often been conceptualized as a 'behavioural addiction' that shares most features with drug addictions. In the current article, we challenge the clinical utility of the addiction model as applied to mobile phone overuse. We describe the case of a woman who overuses her mobile phone from two distinct approaches: (1) a symptom-based categorical approach inspired from the addiction model of dysfunctional mobile phone use and (2) a process-based approach resulting from an idiosyncratic clinical case conceptualization. In the case depicted here, the addiction model was shown to lead to standardized and non-relevant treatment, whereas the clinical case conceptualization allowed identification of specific psychological processes that can be targeted with specific, empirically based psychological interventions. This finding highlights that conceptualizing excessive behaviours (e.g., gambling and sex) within the addiction model can be a simplification of an individual's psychological functioning, offering only limited clinical relevance. The addiction model, applied to excessive behaviours (e.g., gambling, sex and Internet-related activities) may lead to non-relevant standardized treatments. Clinical case conceptualization allowed identification of specific psychological processes that can be targeted with specific empirically based psychological interventions. The biomedical model might lead to the simplification of an individual's psychological functioning with limited clinical relevance. Copyright © 2014 John Wiley & Sons, Ltd.

The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease.

PubMed

Hendriksz, Christian J; Anheim, Mathieu; Bauer, Peter; Bonnot, Olivier; Chakrapani, Anupam; Corvol, Jean-Christophe; de Koning, Tom J; Degtyareva, Anna; Dionisi-Vici, Carlo; Doss, Sarah; Duning, Thomas; Giunti, Paola; Iodice, Rosa; Johnston, Tracy; Kelly, Dierdre; Klünemann, Hans-Hermann; Lorenzl, Stefan; Padovani, Alessandro; Pocovi, Miguel; Synofzik, Matthis; Terblanche, Alta; Then Bergh, Florian; Topçu, Meral; Tranchant, Christine; Walterfang, Mark; Velten, Christian; Kolb, Stefan A

2017-05-01

Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups ("clinical niches") have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes. Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included. Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches. Several clinical niches have been identified that harbor patients at increased risk of NP-C.

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

PubMed Central

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

2017-01-01

Background 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. Objective The purpose of this study was to inventory and assess the entry, growth, sources, and content of clinically relevant social media in dentistry. Methods 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. Results 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. Conclusions 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. PMID:28747291

Subclinical hypothyroidism: to treat or not to treat, that is the question! A systematic review with meta-analysis on lipid profile

PubMed Central

Lau, Eva; de Sousa Pinto, Bernardo; Carvalho, Davide

2017-01-01

Previous studies suggested that subclinical hypothyroidism has a detrimental effect on cardiovascular risk factors, and that its effective treatment may have a beneficial impact on overall health. The main purpose of this review and meta-analysis was to assess whether subclinical hypothyroidism treatment is of clinical relevance, based on cardiovascular risk parameters correction. A systemic research of the literature using MEDLINE tool was performed to identify the relevant studies. Only placebo-controlled randomized control trials were included. A quantitative analysis was also performed. This systematic review and meta-analysis of randomized placebo-controlled trials assess the different impact of levothyroxine vs placebo treatment. A significant decrease in serum thyroid-stimulating hormone and total and low-density lipoprotein cholesterol was obtained with levothyroxine therapy (66, 9 and 14%, respectively) and, although modest, this could be significant in terms of reduction of the incidence of coronary artery disease. Other significant results of lipid parameters were not obtained. This systematic review provides a strong evidence-based data in favour of specific changes and beneficial effects of levothyroxine treatment. PMID:28249936

A Systematic Approach for Discovering Novel, Clinically Relevant Bacteria

PubMed Central

Simmon, Keith E.; Fisher, Mark A.

2012-01-01

Sequencing of the 16S rRNA gene (16S) is a reference method for bacterial identification. Its expanded use has led to increased recognition of novel bacterial species. In most clinical laboratories, novel species are infrequently encountered, and their pathogenic potential is often difficult to assess. We reviewed partial 16S sequences from >26,000 clinical isolates, analyzed during February 2006–June 2010, and identified 673 that have <99% sequence identity with valid reference sequences and are thus possibly novel species. Of these 673 isolates, 111 may represent novel genera (<95% identity). Isolates from 95 novel taxa were recovered from multiple patients, indicating possible clinical relevance. Most repeatedly encountered novel taxa belonged to the genera Nocardia (14 novel taxa, 42 isolates) and Actinomyces (12 novel taxa, 52 isolates). This systematic approach for recognition of novel species with potential diagnostic or therapeutic relevance provides a basis for epidemiologic surveys and improvement of sequence databases and may lead to identification of new clinical entities. PMID:22377371

A systematic approach for discovering novel, clinically relevant bacteria.

PubMed

Schlaberg, Robert; Simmon, Keith E; Fisher, Mark A

2012-03-01

Sequencing of the 16S rRNA gene (16S) is a reference method for bacterial identification. Its expanded use has led to increased recognition of novel bacterial species. In most clinical laboratories, novel species are infrequently encountered, and their pathogenic potential is often difficult to assess. We reviewed partial 16S sequences from >26,000 clinical isolates, analyzed during February 2006-June 2010, and identified 673 that have <99% sequence identity with valid reference sequences and are thus possibly novel species. Of these 673 isolates, 111 may represent novel genera (<95% identity). Isolates from 95 novel taxa were recovered from multiple patients, indicating possible clinical relevance. Most repeatedly encountered novel taxa belonged to the genera Nocardia (14 novel taxa, 42 isolates) and Actinomyces (12 novel taxa, 52 isolates). This systematic approach for recognition of novel species with potential diagnostic or therapeutic relevance provides a basis for epidemiologic surveys and improvement of sequence databases and may lead to identification of new clinical entities.

Relevance of randomised controlled trials in oncology.

PubMed

Tannock, Ian F; Amir, Eitan; Booth, Christopher M; Niraula, Saroj; Ocana, Alberto; Seruga, Bostjan; Templeton, Arnoud J; Vera-Badillo, Francisco

2016-12-01

Well-designed randomised controlled trials (RCTs) can prevent bias in the comparison of treatments and provide a sound basis for changes in clinical practice. However, the design and reporting of many RCTs can render their results of little relevance to clinical practice. In this Personal View, we discuss the limitations of RCT data and suggest some ways to improve the clinical relevance of RCTs in the everyday management of patients with cancer. RCTs should ask questions of clinical rather than commercial interest, avoid non-validated surrogate endpoints in registration trials, and have entry criteria that allow inclusion of all patients who are fit to receive treatment. Furthermore, RCTs should be reported with complete accounting of frequency and management of toxicities, and with strict guidelines to ensure freedom from bias. Premature reporting of results should be avoided. The bar for clinical benefit should be raised for drug registration, which should require publication and review of mature data from RCTs, post-marketing health outcome studies, and value-based pricing. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ezetimibe decreased nonalcoholic fatty liver disease activity score but not hepatic steatosis.

PubMed

Lee, Hyo Young; Jun, Dae Won; Kim, Hyun Jung; Oh, Hyunwoo; Saeed, Waqar Khalid; Ahn, Hyeongsik; Cheung, Ramsey C; Nguyen, Mindie H

2018-03-20

A number of clinical trials reported varying effects of cholesterol lowering agents in nonalcoholic fatty liver disease (NAFLD) patients. We, therefore, assessed the changes in hepatic steatosis and NAFLD activity score (NAS) after treatment with cholesterol lowering agents in NAFLD patients by metaanalysis. The Cochrane Library, the MEDLINE, and the Embase databases were searched until May 2015, without any language restrictions, for randomized controlled trials (RCTs) and nonrandomized studies (NRSs). Additional references were obtained from review of bibliography of relevant articles. The quality of evidence was assessed using the grading of recommendations assessment, development and evaluation guidelines. Three RCTs (n = 98) and two NRSs (n = 101) met our study inclusion criteria (adult, NAFLD, liver biopsy). Liver biopsy was performed in all five studies, but only the three studies reported NAS. Ezetimibe significantly decreased NAS (standardized mean difference [SMD], -0.30; 95% confidence interval [CI], -0.57 to -0.03) but not hepatic steatosis in RCT (SMD, -0.1; 95% CI, -0.53 to 0.32), while the effect was significant for both NAS and intrahepatic content in NRSs (SMD, -3.0; 95% CI, -6.9 to 0.91). Ezetimibe decreased NAS without improving hepatic steatosis.

Ghrelin-induced hypothermia: A Physiological basis but no clinical risk

PubMed Central

Wiedmer, Petra; Strasser, Florian; Horvath, Tamas L.; Blum, David; DiMarchi, Richard; Lutz, Thomas; Schürmann, Annette; Joost, Hans-Georg; Tschöp, Matthias H.; Tong, Jenny

2011-01-01

Ghrelin increases food intake and decreases energy expenditure, promoting a positive energy balance. We observed a single case of serious hypothermia during sustained ghrelin treatment in a male subject, suggesting that ghrelin may play a role in the regulation of body temperature. We therefore investigated the effect of ghrelin treatment on body temperature in rodents and humans under controlled conditions. Intriguingly, we could demonstrate ghrelin binding in axon terminals of the medial preoptic area of the hypothalamus located in the vicinity of cold-sensitive neurons. This localization of ghrelin receptors provides a potential anatomical basis for the regulation of body temperature by ghrelin. However, our follow-up studies also indicated that neither a chronic i.c.v. application of ghrelin in rats, nor a single s.c. injection under cold exposure in mice resulted in a relevant decrease in body core temperature. In addition, a four-hour intravenous ghrelin infusion did not decrease body surface temperature in healthy humans. We concluded that while there is a theoretical molecular basis for ghrelin to modify body temperature in mammals, its magnitude is irrelevant under physiologic circumstances. Hypothermia is not likely to represent a serious risk associated with this agent and pathway. PMID:21513721

Biomolecular aspects of depression: A retrospective analysis.

PubMed

Peacock, Brandon N; Scheiderer, David J; Kellermann, Gottfried H

2017-02-01

The effects of psychological stress, oxidative stress, and chronic low grade inflammation on the neuro-immune connection have been implicated in the pathogenesis of depression. Thus, in the recent past, there has been a growing effort in determining the mechanism of this pathogenesis. While attempting to map out, this mechanism researchers and clinicians have searched for clinically relevant biomarkers for use in the diagnosis and for the assessment of those suffering from depression. In this study, we have performed a retrospective analysis of biomarkers with clinically relevant potentials, including peripheral catecholamines, chemokines, cytokines, and neurotransmitters. The retrospective analysis was performed on data collected over a six-year period of time (July 2009 to July 2015), gathered from patients (N=1399; Mage=42, SD=13; 71% female, 29% male) who submitted samples with complaints of feeling hopeless, worthless, isolated, alone, general sadness, overwhelmed, and/or a lack of interest in things they once enjoyed. The data collected consisted of quantitative values of urinary catecholamines and neurotransmitters (peripheral dopamine, epinephrine, histamine, kynurenic acid, norepinephrine, β-PEA, and serotonin), salivary hormones (peripheral cortisol and melatonin), and peripheral blood mononuclear cell secreted cytokines and chemokines (Interleukins 1β, 6, 8, 10, MCP-1, GCSF, and TNFα). Statistical and clinical significance was assessed by comparison with a control group (N=2395; Mage=42, SD=13; 70% female, 30% male), calculating the percent mean difference, p value, and effect size (Cohen's ɗ) for each parameter between groups. The findings of this study suggested that, in a model of general depression, there is a dysregulation in the enzymatic production and degradation of catecholamines, neurotransmitters, hormones, and immunological proteins. A cycle of interaction was found between all of these biomolecules, where an increase or decrease in one marker could result in a stimulatory or inhibitory effect on others. The mechanism of this was proposed to occur through the interaction of psychological stress, inflammation, and oxidative stress pathways. All of these biomolecules were found to be significantly altered in the general depression group and are key components of the interaction between the neurological and immunological systems. This study serves to further elucidate the role of biomolecules in the regulation of affective disorders, such as depression. Resulting in providing a network of clinically relevant biomarkers to objectively assess and monitor general depression. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Reduction of Cross-Reactive Carbohydrate Determinants in Plant Foodstuff: Elucidation of Clinical Relevance and Implications for Allergy Diagnosis

PubMed Central

Brehler, Randolf; von Schaewen, Antje

2011-01-01

Background A longstanding debate in allergy is whether or not specific immunoglobulin-E antibodies (sIgE), recognizing cross-reactive carbohydrate determinants (CCD), are able to elicit clinical symptoms. In pollen and food allergy, ≥20% of patients display in-vitro CCD reactivity based on presence of α1,3-fucose and/or β1,2-xylose residues on N-glycans of plant (xylose/fucose) and insect (fucose) glycoproteins. Because the allergenicity of tomato glycoallergen Lyc e 2 was ascribed to N-glycan chains alone, this study aimed at evaluating clinical relevance of CCD-reduced foodstuff in patients with carbohydrate-specific IgE (CCD-sIgE). Methodology/Principal Findings Tomato and/or potato plants with stable reduction of Lyc e 2 (tomato) or CCD formation in general were obtained via RNA interference, and gene-silencing was confirmed by immunoblot analyses. Two different CCD-positive patient groups were compared: one with tomato and/or potato food allergy and another with hymenoptera-venom allergy (the latter to distinguish between CCD- and peptide-specific reactions in the food-allergic group). Non-allergic and CCD-negative food-allergic patients served as controls for immunoblot, basophil activation, and ImmunoCAP analyses. Basophil activation tests (BAT) revealed that Lyc e 2 is no key player among other tomato (glyco)allergens. CCD-positive patients showed decreased (re)activity with CCD-reduced foodstuff, most obvious in the hymenoptera venom-allergic but less in the food-allergic group, suggesting that in-vivo reactivity is primarily based on peptide- and not CCD-sIgE. Peptide epitopes remained unaffected in CCD-reduced plants, because CCD-negative patient sera showed reactivity similar to wild-type. In-house-made ImmunoCAPs, applied to investigate feasibility in routine diagnosis, confirmed BAT results at the sIgE level. Conclusions/Significance CCD-positive hymenoptera venom-allergic patients (control group) showed basophil activation despite no allergic symptoms towards tomato and potato. Therefore, this proof-of-principle study demonstrates feasibility of CCD-reduced foodstuff to minimize ‘false-positive results’ in routine serum tests. Despite confirming low clinical relevance of CCD antibodies, we identified one patient with ambiguous in-vitro results, indicating need for further component-resolved diagnosis. PMID:21423762

Prevalence of clinically elevated depressive symptoms in college athletes and differences by gender and sport.

PubMed

Wolanin, Andrew; Hong, Eugene; Marks, Donald; Panchoo, Kelly; Gross, Michael

2016-02-01

There are approximately 400,000 National Collegiate Athletic Association (NCAA) student athletes and 5-7 million high school student athletes competing each year. According to the US Department of Health and Human Services, the depression prevalence rate for young adults, which ranges from 10% to 85% across studies, is higher than that of other age groups. Given the relatively high prevalence of depression in individuals of collegiate age in the general population, the prevalence of depression among athletes in this age group warrants further study. This multiyear study examined the prevalence of depressive symptoms in college athletes, as well as demographic factors related to increased or decreased rates of depressive symptoms by gender and sport. To describe the prevalence of depression symptoms among NCAA division I student athletes at a single institution over 3 consecutive years. Participants (n=465) completed a battery of measures during their yearly spring sports medicine physical across 3 consecutive years. The battery included the Center for Epidemiological Studies Depression Scale (CES-D) and a demographic questionnaire, administered during the course of routine sports medicine physical examinations. Differences in depressive symptoms prevalence and relative risk ratios were calculated by gender and sport. The prevalence rate for a clinically relevant level of depressive symptoms, as measured on the CES-D (CES-D ≥16), was 23.7%. A moderate to severe level of depressive symptoms was reported by 6.3%. There was a significant gender difference in prevalence of depressive symptoms, χ(2) (1)=7.459, p=0.006, with female athletes exhibiting 1.844 times the risk of male athletes for endorsing clinically relevant symptoms. The CES-D identified clinically relevant levels of depressive symptoms in nearly one-quarter of college student athletes in this large cross-sectional sample. Female college athletes reported significantly more depressive symptoms than males. Findings suggest that depression prevalence among college athletes is comparable to that found in the general college population. In light of these findings, sports medicine personnel may wish to implement depression screening and assessment of depressive symptoms across sports to identify at-risk athletes. Risk factors related to depression in college athletes warrant additional study. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

The Effects of Organization Design and Patient Perceptions of Care on Switching Behavior and Reliance on a Health Care System Across Time.

PubMed

Labonte, Alan J; Benzer, Justin K; Burgess, James F; Cramer, Irene E; Meterko, Mark; Pogoda, Terri K; Charns, Martin P

2016-04-01

Sustaining ongoing relationships with patients is a strategic, clinically relevant goal of health care systems. This study develops and tests a conceptual model that aims to account for the influence of organization design, perceptions of quality of patient care, and other patient-level factors on the extent to which patients sustain reliance on a health care system. We use a longitudinal survey design and structural equation modeling to predict increases or decreases in patient reliance on the Department of Veterans Affairs health care system across a 4-year period for Veterans with Parkinson's Disease. Our findings show that specialized and integrated clinical practices have a positive association with the quality of patient care. Health care systems may be able to foster long-term relations with patients and improve service quality by allocating resources to form integrated, specialized, disease-specific centers of care designed for patients with chronic illnesses. © The Author(s) 2016.

Reward-Related Brain Function as a Predictor of Treatment Response in Adolescents with Major Depressive Disorder

PubMed Central

Forbes, Erika E.; Olino, Thomas M.; Ryan, Neal D.; Birmaher, Boris; Axelson, David; Moyles, Donna L.; Dahl, Ronald E.

2009-01-01

The current study provides preliminary evidence that pre-treatment reward-related brain function in the striatum and medial prefrontal cortex (PFC) could have relevance for predicting both final level and rate of change of clinical characteristics in adolescents with major depressive disorder. Adolescents with depression underwent a functional MRI scan during a monetary reward task, participated in an 8-week open trial of cognitive behavioral therapy (CBT) or CBT plus selective serotonin reuptake inhibitor, and completed reports of anxiety and depressive symptoms before, during, and after treatment. Clinicians rated adolescents' improvement and severity at the same time points. Growth models were used to examine change in clinical characteristics and its association with brain function. Severity, anxiety symptoms, and depressive symptoms decreased over treatment. Final levels of severity and anxiety symptoms were associated with pre-treatment striatal reactivity, and rate of anxiety symptom reduction was associated with greater striatal reactivity and lower medial PFC reactivity. PMID:20233959

Indications and radiological findings of acute otitis media and its complications.

PubMed

Pont, Elena; Mazón, Miguel

Most cases of acute otitis media resolve with antibiotics and imaging is not required. When treatment fails or a complication is suspected, imaging plays a crucial role. Since the introduction of antibiotic treatment, the complication rate has decreased dramatically. Nevertheless, given the critical clinical relevance of complications, the importance of early diagnosis is vital. Our objective was to review the clinical and radiological features of acute otitis media and its complications. They were classified based on their location, as intratemporal or intracranial. Imaging makes it possible to diagnose the complications of acute otitis media and to institute appropriate treatment. Computed tomography is the initial technique of choice and, in most cases, the ultimate. Magnetic resonance is useful for evaluating the inner ear and when accurate evaluation of disease extent or better characterization of intracranial complications is required. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. All rights reserved.

Clinical relevance of cannabis tolerance and dependence.

PubMed

Jones, R T; Benowitz, N L; Herning, R I

1981-01-01

Psychoactive drugs are often widely used before tolerance and dependence is fully appreciated. Tolerance to cannabis-induced cardiovascular and autonomic changes, decreased intraocular pressure, sleep and sleep EEG, mood and behavioral changes is acquired and, to a great degree, lost rapidly with optimal conditions. Mechanisms appear more functional than metabolic. Acquisition rate depends on dose and dose schedule. Dependence, manifested by withdrawal symptoms after as little as 7 days of THC administration, is characterized by irritability, restlessness, insomnia, anorexia, nausea, sweating, salivation, increased body temperature, altered sleep and waking EEG, tremor, and weight loss. Mild and transient in the 120 subjects studied, the syndrome was similar to sedative drug withdrawal. Tolerance to drug side effects can be useful. Tolerance to therapeutic effects or target symptoms poses problems. Clinical significance of dependence is difficult to assess since drug-seeking behavior has many determinants. Cannabis-induced super sensitivity should be considered wherever chronic drug administration is anticipated in conditions like epilepsy, glaucoma or chronic pain. Cannabis pharmacology suggests ways of minimizing tolerance and dependence problems.

The cobas® 6800/8800 System: a new era of automation in molecular diagnostics.

PubMed

Cobb, Bryan; Simon, Christian O; Stramer, Susan L; Body, Barbara; Mitchell, P Shawn; Reisch, Natasa; Stevens, Wendy; Carmona, Sergio; Katz, Louis; Will, Stephen; Liesenfeld, Oliver

2017-02-01

Molecular diagnostics is a key component of laboratory medicine. Here, the authors review key triggers of ever-increasing automation in nucleic acid amplification testing (NAAT) with a focus on specific automated Polymerase Chain Reaction (PCR) testing and platforms such as the recently launched cobas® 6800 and cobas® 8800 Systems. The benefits of such automation for different stakeholders including patients, clinicians, laboratory personnel, hospital administrators, payers, and manufacturers are described. Areas Covered: The authors describe how molecular diagnostics has achieved total laboratory automation over time, rivaling clinical chemistry to significantly improve testing efficiency. Finally, the authors discuss how advances in automation decrease the development time for new tests enabling clinicians to more readily provide test results. Expert Commentary: The advancements described enable complete diagnostic solutions whereby specific test results can be combined with relevant patient data sets to allow healthcare providers to deliver comprehensive clinical recommendations in multiple fields ranging from infectious disease to outbreak management and blood safety solutions.

Hemojuvelin: a supposed role in iron metabolism one year after its discovery.

PubMed

Celec, Peter

2005-07-01

The discovery of hemojuvelin and its association with juvenile hemochromatosis are important not only for the diagnostics of this rare severe disease but also for the understanding of the complex mechanism of iron metabolism regulation. Currently, the physiological role of hemojuvelin is obscure. Recent experimental and clinical studies indicate that hemojuvelin will probably be a regulator of hepcidin, similar to HFE and transferrin receptor 2. However, in contrast to transferrin receptor 2, which is relevant in the hepcidin response to changes in transferrin saturation, HFE and especially hemojuvelin seem to be involved in the inflammation-induced hepcidin expression. Hepcidin, generally accepted as a hormone targeting enterocytes and macrophages, decreases iron absorption from the intestinal lumen and iron release from phagocytes. This mechanism explains the central role of hepcidin and, indirectly, its regulator, hemojuvelin, in the pathogenesis of hemochromatosis but also in anemia of chronic disease. Further basic and clinical research is needed to uncover the details of hemojuvelin pathophysiology required for potential pharmacological interventions.

Respiratory motion correction in dynamic MRI using robust data decomposition registration - application to DCE-MRI.

PubMed

Hamy, Valentin; Dikaios, Nikolaos; Punwani, Shonit; Melbourne, Andrew; Latifoltojar, Arash; Makanyanga, Jesica; Chouhan, Manil; Helbren, Emma; Menys, Alex; Taylor, Stuart; Atkinson, David

2014-02-01

Motion correction in Dynamic Contrast Enhanced (DCE-) MRI is challenging because rapid intensity changes can compromise common (intensity based) registration algorithms. In this study we introduce a novel registration technique based on robust principal component analysis (RPCA) to decompose a given time-series into a low rank and a sparse component. This allows robust separation of motion components that can be registered, from intensity variations that are left unchanged. This Robust Data Decomposition Registration (RDDR) is demonstrated on both simulated and a wide range of clinical data. Robustness to different types of motion and breathing choices during acquisition is demonstrated for a variety of imaged organs including liver, small bowel and prostate. The analysis of clinically relevant regions of interest showed both a decrease of error (15-62% reduction following registration) in tissue time-intensity curves and improved areas under the curve (AUC60) at early enhancement. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Biomarker-guided antibiotic therapy—strengths and limitations

PubMed Central

Salluh, Jorge; Martin-Loeches, Ignacio; Póvoa, Pedro

2017-01-01

Biomarkers as C-reactive protein (CRP) and procalcitonin (PCT) emerged as tools to help clinicians to diagnose infection and to properly initiate and define the duration of antibiotic therapy. Several randomized controlled trials, including adult critically ill patients, showed that PCT-guided antibiotic stewardship was repeatedly associated with a decrease in the duration of antibiotic therapy with no apparent harm. There are however some relevant limitations in these trials namely the low rate of compliance of PCT-guided algorithms, the high rate of exclusion (without including common clinical situations and pathogens) and the long duration of antibiotic therapy in control groups. Such limitations weakened the real impact of such algorithms in the clinical decision-making process and strengthened the concept that the initiation and the duration of antibiotic therapy cannot depend solely on a biomarker. Future efforts should address these limitations in order to better clarify the role of biomarkers on the complex and multifactorial issue of antibiotic management and to deeply understand its potential effect on mortality. PMID:28603723

Biomarker-guided antibiotic therapy-strengths and limitations.

PubMed

Nora, David; Salluh, Jorge; Martin-Loeches, Ignacio; Póvoa, Pedro

2017-05-01

Biomarkers as C-reactive protein (CRP) and procalcitonin (PCT) emerged as tools to help clinicians to diagnose infection and to properly initiate and define the duration of antibiotic therapy. Several randomized controlled trials, including adult critically ill patients, showed that PCT-guided antibiotic stewardship was repeatedly associated with a decrease in the duration of antibiotic therapy with no apparent harm. There are however some relevant limitations in these trials namely the low rate of compliance of PCT-guided algorithms, the high rate of exclusion (without including common clinical situations and pathogens) and the long duration of antibiotic therapy in control groups. Such limitations weakened the real impact of such algorithms in the clinical decision-making process and strengthened the concept that the initiation and the duration of antibiotic therapy cannot depend solely on a biomarker. Future efforts should address these limitations in order to better clarify the role of biomarkers on the complex and multifactorial issue of antibiotic management and to deeply understand its potential effect on mortality.

Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier

PubMed Central

Divakaruni, Ajit S.; Wiley, Sandra E.; Rogers, George W.; Andreyev, Alexander Y.; Petrosyan, Susanna; Loviscach, Mattias; Wall, Estelle A.; Yadava, Nagendra; Heuck, Alejandro P.; Ferrick, David A.; Henry, Robert R.; McDonald, William G.; Colca, Jerry R.; Simon, Melvin I.; Ciaraldi, Theodore P.; Murphy, Anne N.

2013-01-01

Facilitated pyruvate transport across the mitochondrial inner membrane is a critical step in carbohydrate, amino acid, and lipid metabolism. We report that clinically relevant concentrations of thiazolidinediones (TZDs), a widely used class of insulin sensitizers, acutely and specifically inhibit mitochondrial pyruvate carrier (MPC) activity in a variety of cell types. Respiratory inhibition was overcome with methyl pyruvate, localizing the effect to facilitated pyruvate transport, and knockdown of either paralog, MPC1 or MPC2, decreased the EC50 for respiratory inhibition by TZDs. Acute MPC inhibition significantly enhanced glucose uptake in human skeletal muscle myocytes after 2 h. These data (i) report that clinically used TZDs inhibit the MPC, (ii) validate that MPC1 and MPC2 are obligatory components of facilitated pyruvate transport in mammalian cells, (iii) indicate that the acute effect of TZDs may be related to insulin sensitization, and (iv) establish mitochondrial pyruvate uptake as a potential therapeutic target for diseases rooted in metabolic dysfunction. PMID:23513224

Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor.

PubMed

Kulmatycki, Kenneth; Hanna, Imad; Meyers, Dan; Salunke, Atish; Movva, Aishwarya; Majumdar, Tapan; Natrillo, Adrienne; Vapurcuyan, Arpine; Rebello, Sam; Sunkara, Gangadhar; Chen, Jin

2015-05-01

An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily x 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC(50) value of 5 μM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17β glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC(50) values of 1.66 ± 0.95 μM, 3.34 ± 0.64 μM, and 0.973 ± 0.11 μM, respectively. In the presence of steady state pradigastat concentrations, AUC(τ, ss) of rosuvastatin was unchanged and its Cmax,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC(τ, ss) and C(max, ss) were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin.

The Effects of Early Postnatal Diuretics Treatment on Kidney Development and Long-Term Kidney Function in Wistar Rats.

PubMed

Bueters, Ruud R G; Jeronimus-Klaasen, Annelies; Maicas, Nuria; Florquin, Sandrine; van den Heuvel, Lambertus P; Schreuder, Michiel F

2016-01-01

Diuretics are administered to neonates to control fluid balance. We studied whether clinical doses affected kidney development and function and whether extrauterine growth retardation (EUGR) could be a modulator. Wistar rats were cross-fostered in normal food or food restricted litters at postnatal day (PND) 2 and treated daily with 0.9% NaCl, 5 mg/kg furosemide or 5 mg/kg hydrochlorothiazide (HCTZ) up to PND 8. Kidneys were evaluated on proliferation, apoptosis and a set of mRNA target genes at PND 8, glomerular- and glomerular generation count at PND 35, clinical pathology parameters at 3- and 9 months, neutrophil gelatinase-associated lipocalin at PND 8, 3 and 6 months, monthly blood pressure from 3 months onward and histopathology at study end. Treatment with furosemide or HCTZ did not have relevant effects on measured parameters. EUGR resulted in lower body weight from day 3 onwards (-29% at weaning; p < 0.001, -10% at necropsy; p < 0.001), less glomerular generations (4.4 ± 0.32 vs. 5.0 ± 0.423; p = 0.025, males only), decreased glomerular numbers (27,861 ± 3,468 vs. 30,527 ± 4,096; p = 0.026), higher creatinine clearance (0.84 ± 0.1 vs. 0.77 ± 0.09 ml/min/kg; p = 0.047) at 3 months and lower plasma creatinine (25.7 ± 1.8 vs. 27.5 ± 2.8 µmol/l; p = 0.043) at 9 months. Furosemide and HCTZ did not influence kidney development or function when administered in a clinically relevant dose to rat pups at a stage of ongoing nephrogenesis. EUGR led to impaired kidney development but did not modify furosemide or HCTZ findings. © 2016 S. Karger AG, Basel.

Acceptability and Preliminary Efficacy of a Lesbian, Gay, Bisexual, and Transgender-Affirmative Mental Health Practice Training in a Highly Stigmatizing National Context.

PubMed

Lelutiu-Weinberger, Corina; Pachankis, John E

2017-10-01

Lesbian, gay, bisexual, and transgender (LGBT) individuals in Romania encounter pervasive stigma and discrimination and there is a high need for LGBT-competent mental health professionals (MHPs). We tested the impact of a pilot LGBT-affirmative training for MHPs in Romania on these professionals' LGBT-relevant attitudes, knowledge, and perception of clinical skills. We conducted a 2-day training for MHPs in Bucharest. Fifty-four attended and 33 provided training evaluation data at baseline and follow-up. The majority of trainees were female (90%) and heterosexual (73%) with a mean age of 36.4 (SD = 7.7). From baseline to follow-up, trainees demonstrated a significant increase in perceived LGBT-relevant clinical skills (P < 0.001) and perceived knowledge (P < 0.05). LGBT-affirmative practice attitudes (P < 0.05) and comfort in addressing the mental health of LGBT individuals (P < 0.01) increased significantly, and homonegative and transnegative attitudes decreased significantly (P < 0.01). Negative attitudes toward LGBT individuals were low at both baseline and follow-up. The majority of trainees reported being highly interested in the training (84%), which they reported had prepared them to interact with and care for LGBT individuals (74%). This pilot training appeared to be effective in increasing perceived LGBT competence among participating MHPs. This type of training model needs to be tested further in a randomized controlled trial with longer follow-up periods to assess intervention durability and implementation of clinical skills. Future trainings can be incorporated into existing curricula. National accreditation bodies might consider encouraging such training as part of standard educational requirements.

Randomized Controlled Trial of Pancreaticojejunostomy versus Stapler Closure of the Pancreatic Stump During Distal Pancreatectomy to Reduce Pancreatic Fistula.

PubMed

Kawai, Manabu; Hirono, Seiko; Okada, Ken-Ichi; Sho, Masayuki; Nakajima, Yoshiyuki; Eguchi, Hidetoshi; Nagano, Hiroaki; Ikoma, Hisashi; Morimura, Ryou; Takeda, Yutaka; Nakahira, Shin; Suzumura, Kazuhiro; Fujimoto, Jiro; Yamaue, Hiroki

2016-07-01

The aim of this study was to evaluate in a multicenter randomized controlled trial (RCT) whether pancreaticojejunostomy (PJ) of pancreatic stump decreases the incidence of pancreatic fistula after distal pancreatectomy (DP) compared with stapler closure. Several studies reported that PJ of pancreatic stump reduces the incidence of pancreatic fistula after DP. However, no RCT has confirmed the efficacy of PJ of pancreatic stump. One hundred thirty-six patients scheduled for DP were enrolled in this study between June 2011 and March 2014 at 6 high-volume surgical centers in Japan. Enrolled patients were randomized to either stapler closure or PJ. The primary endpoint was the incidence of pancreatic fistula based on the International Study Group on Pancreatic Fistula criteria. This RCT was registered with ClinicalTrials.gov (NCT01384617). Sixty-one patients randomized to stapler and 62 patients randomized to PJ were analyzed by intention-to-treat. Pancreatic fistula occurred in 23 patients (37.7%) in the stapler closure group and 24 (38.7%) in the PJ group (P = 0.332) in intention-to-treat analysis. The incidence of clinically relevant pancreatic fistula (grade B or C) was 16.4% for stapler closure and 9.7% for PJ (P = 0.201). Mortality was zero in both groups. In a subgroup analysis for thickness of pancreas greater than 12 mm, the incidence of clinically relevant pancreatic fistula occurred in 22.2% of the patients in the stapler closure group and in 6.2% of the PJ group (P = 0.080). PJ of the pancreatic stump during DP does not reduce pancreatic fistula compared with stapler closure.

Randomized Controlled Trial of Pancreaticojejunostomy versus Stapler Closure of the Pancreatic Stump During Distal Pancreatectomy to Reduce Pancreatic Fistula

PubMed Central

Kawai, Manabu; Hirono, Seiko; Okada, Ken-ichi; Sho, Masayuki; Nakajima, Yoshiyuki; Eguchi, Hidetoshi; Nagano, Hiroaki; Ikoma, Hisashi; Morimura, Ryou; Takeda, Yutaka; Nakahira, Shin; Suzumura, Kazuhiro; Fujimoto, Jiro; Yamaue, Hiroki

2016-01-01

Objectives: The aim of this study was to evaluate in a multicenter randomized controlled trial (RCT) whether pancreaticojejunostomy (PJ) of pancreatic stump decreases the incidence of pancreatic fistula after distal pancreatectomy (DP) compared with stapler closure. Background: Several studies reported that PJ of pancreatic stump reduces the incidence of pancreatic fistula after DP. However, no RCT has confirmed the efficacy of PJ of pancreatic stump. Methods: One hundred thirty-six patients scheduled for DP were enrolled in this study between June 2011 and March 2014 at 6 high-volume surgical centers in Japan. Enrolled patients were randomized to either stapler closure or PJ. The primary endpoint was the incidence of pancreatic fistula based on the International Study Group on Pancreatic Fistula criteria. This RCT was registered with ClinicalTrials.gov (NCT01384617). Results: Sixty-one patients randomized to stapler and 62 patients randomized to PJ were analyzed by intention-to-treat. Pancreatic fistula occurred in 23 patients (37.7%) in the stapler closure group and 24 (38.7%) in the PJ group (P = 0.332) in intention-to-treat analysis. The incidence of clinically relevant pancreatic fistula (grade B or C) was 16.4% for stapler closure and 9.7% for PJ (P = 0.201). Mortality was zero in both groups. In a subgroup analysis for thickness of pancreas greater than 12 mm, the incidence of clinically relevant pancreatic fistula occurred in 22.2% of the patients in the stapler closure group and in 6.2% of the PJ group (P = 0.080). Conclusions: PJ of the pancreatic stump during DP does not reduce pancreatic fistula compared with stapler closure. PMID:26473652

Comparable efficacy and safety of 8 weeks treatment with agomelatine 25-50mg or fluoxetine 20-40mg in Asian out-patients with major depressive disorder.

PubMed

Shu, L; Sulaiman, A H; Huang, Y S; Fones Soon Leng, C; Crutel, V Strijckmans; Kim, Y S

2014-04-01

This randomized, double-blind study evaluates the efficacy and tolerability of agomelatine, using fluoxetine as an active comparator, in Asian patients suffering from moderate to severe major depressive disorder (MDD). Patients were randomly assigned to receive either agomelatine (25-50mg/day, n=314) or fluoxetine (20-40mg/day, n=314) during an 8-week treatment period. The main outcome measure was the change in Hamilton Depression Rating Scale 17 items (HAM-D17) scores. Secondary efficacy criteria included scores on Clinical Global Impression Severity of illness (CGI-S) and Improvement of illness (CGI-I), patient sleeping improvement using the self-rating Leeds Sleep Evaluation Questionnaire (LSEQ) and anxiety using the Hamilton Anxiety Rating Scale (HAM-A) scores. Tolerability and safety evaluations were based on emergent adverse events. Agomelatine and fluoxetine exert a comparable antidepressant efficacy in the Asian population. Mean changes over 8 weeks were clinically relevant and similar in both groups (-14.8±7.3 and -15.0±8.1 on HAM-D17 scale in agomelatine and fluoxetine groups, respectively). The between-group difference reached statistical significance on non-inferiority test (p=0.015). Clinically relevant decreases in CGI-S and CGI-I scores were observed over the treatment period in both groups. The two treatments were equally effective on the symptoms of both anxiety and sleep. The good tolerability profile and safety of both doses of agomelatine was confirmed in the Asian population. Agomelatine and fluoxetine are equally effective in the treatment of MDD-associated symptoms in Asian depressed patients. Copyright © 2013 Elsevier B.V. All rights reserved.

[Efficacy of epidural steroid injections for chronic lumbar pain syndromes without neurological deficits. A randomized, double blind study as part of a multimodal treatment concept].

PubMed

Niemier, K; Schindler, M; Volk, T; Baum, K; Wolf, B; Eberitsch, J; Seidel, W

2015-07-01

Chronic lumbar pain syndromes without neurological deficits are generated by a multitude of causes. Functional, morphological and psychosocial factors are discussed. In many cases a diseased intervertebral disc is found on radiological examination but the clinical relevance of these findings is not clear. For this study it was postulated that a diseased disc results in a local inflammatory reaction therefore causing pain and impairing treatability of patients. An epidural injection of steroids can reduce inflammation and therefore improve treatability and ultimately treatment outcome. A double blind randomized prospective trial was carried out. Patients treated in hospital for a chronic lumbar pain syndrome without neurological deficits within a multimodal treatment program were screened for indications for an epidural steroid injection (e.g. diseased lumbar disc and intention to treat). Patients eligible for the study were randomized into two groups. The treatment group received an epidural injection of 80 mg triamcinolone and 8 ml bupivacaine 0.25 %. The control group received only an epidural injection of 8 ml bupivacaine 0.25 %. In both groups pain intensity and treatability showed a statistically significant improvement after the epidural injection. The differences between the control and treatment groups were small and not clinically relevant. A small subgroup might profit from the steroid injection. In addition the treatability was dependent on psychometric values and the long-term outcome from a reduction of muscular skeletal dysfunctions. After the epidural injection the decrease in pain and increase in treatability was statistically significant. The mechanism of the improvement is not clear and should be examined further. The epidural injection of a steroid in this subgroup of patients did not lead to a clinical improvement in the outcome.

Health-Related Quality of Life in University Dance Students.

PubMed

White, Hayley M; Hoch, Johanna M; Hoch, Matthew C

2018-03-01

Injuries are common among dancers and may negatively affect health-related quality of life (HRQL). The modified Disablement in the Physically Active Scale (mDPA) is a generic patient-reported outcome instrument that could be used when providing care to patients participating in performing arts. The objective of this pilot study was to examine the internal consistency of the mDPA and assess overall HRQL using the mDPA in university dance students. Thirty-one female university dance students completed the mDPA during one data collection session. Higher scores on the Physical Summary Component (mDPA-PSC), the Mental Summary Component (mDPAMSC), and mDPA-Total indicated increased disablement. The internal consistency was determined using Cronbachs alpha. The mDPA-Total, mDPA-PSC, and mDPAMSC scores were examined descriptively using mean and standard deviations. Individual item responses were also examined. The proportion of university dance students with clinically relevant levels of disablement on the mDPA-Total was examined using a previously established minimally clinically important difference value. The internal consistency for the mDPA-MSC (a=0.91) and mDPATotal (a=0.90) was excellent and good for the mDPA-PSC (a=0.88). A large proportion (71%) of university dance students demonstrated clinically relevant levels of disablement despite fully participating in dance-related activities. Pain, impaired motion, and stress were the greatest contributors to increased disablement in these individuals. The mDPA scores observed in this pilot study indicate that many dance students experience levels of disablement and decreased HRQL which may warrant physical and mental intervention. Clinicians providing healthcare services to performing artists should consider using the mDPA to provide patient-centered care.

A Flexible-Dose Study of Paliperidone ER in Patients With Nonacute Schizophrenia Previously Treated Unsuccessfully With Oral Olanzapine

PubMed Central

KOTLER, MOSHE; DILBAZ, NESRIN; ROSA, FERNANDA; PATERAKIS, PERIKLIS; MILANOVA, VIHRA; SMULEVICH, ANATOLY B.; LAHAYE, MARJOLEIN

2016-01-01

Objective: The goal of this study was to explore the tolerability, safety, and treatment response of switching from oral olanzapine to paliperidone extended release (ER). Methods: Adult patients with nonacute schizophrenia who had been treated unsuccessfully with oral olanzapine were switched to flexible doses of paliperidone ER (3 to 12 mg/d). The primary efficacy outcome was a ≥20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint for patients who switched medications because of lack of efficacy with olanzapine and noninferiority versus previous olanzapine treatment (mean endpoint change in PANSS total scores vs. baseline of ≤5 points) for patients who switched for reasons other than lack of efficacy. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms, and weight change. Results: Of 396 patients, 65.2% were men, mean age was 40.0±12.0 years, and 75.5% had paranoid schizophrenia. Among the patients whose main reason for switching was lack of efficacy, an improvement in the PANSS total score of ≥20% occurred in 57.4% of patients. Noninferiority was confirmed for each subgroup of patients whose main reason for switching was something other than lack of efficacy. Paliperidone ER was generally well tolerated. Extrapyramidal symptoms as measured by total Extrapyramidal Symptom Rating Scale scores showed statistically significant and clinically relevant improvements at endpoint, the average weight decreased by 0.8±5.2 kg at endpoint, and a clinically relevant weight gain of ≥7% occurred in 8.0% of patients. Conclusion: Paliperidone ER flexibly-dosed over 6 months was well tolerated and associated with a meaningful clinical response in patients with nonacute schizophrenia who had previously been unsuccessfully treated with oral olanzapine. PMID:26813484

A Flexible-Dose Study of Paliperidone ER in Patients With Nonacute Schizophrenia Previously Treated Unsuccessfully With Oral Olanzapine.

PubMed

Kotler, Moshe; Dilbaz, Nesrin; Rosa, Fernanda; Paterakis, Periklis; Milanova, Vihra; Smulevich, Anatoly B; Lahaye, Marjolein; Schreiner, Andreas

2016-01-01

The goal of this study was to explore the tolerability, safety, and treatment response of switching from oral olanzapine to paliperidone extended release (ER). Adult patients with nonacute schizophrenia who had been treated unsuccessfully with oral olanzapine were switched to flexible doses of paliperidone ER (3 to 12 mg/d). The primary efficacy outcome was a ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint for patients who switched medications because of lack of efficacy with olanzapine and noninferiority versus previous olanzapine treatment (mean endpoint change in PANSS total scores vs. baseline of ≤ 5 points) for patients who switched for reasons other than lack of efficacy. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms, and weight change. Of 396 patients, 65.2% were men, mean age was 40.0 ± 12.0 years, and 75.5% had paranoid schizophrenia. Among the patients whose main reason for switching was lack of efficacy, an improvement in the PANSS total score of ≥ 20% occurred in 57.4% of patients. Noninferiority was confirmed for each subgroup of patients whose main reason for switching was something other than lack of efficacy. Paliperidone ER was generally well tolerated. Extrapyramidal symptoms as measured by total Extrapyramidal Symptom Rating Scale scores showed statistically significant and clinically relevant improvements at endpoint, the average weight decreased by 0.8 ± 5.2 kg at endpoint, and a clinically relevant weight gain of ≥ 7% occurred in 8.0% of patients. Paliperidone ER flexibly-dosed over 6 months was well tolerated and associated with a meaningful clinical response in patients with nonacute schizophrenia who had previously been unsuccessfully treated with oral olanzapine.

Acceptability and Preliminary Efficacy of a Lesbian, Gay, Bisexual, and Transgender-Affirmative Mental Health Practice Training in a Highly Stigmatizing National Context

PubMed Central

Pachankis, John E.

2017-01-01

Abstract Purpose: Lesbian, gay, bisexual, and transgender (LGBT) individuals in Romania encounter pervasive stigma and discrimination and there is a high need for LGBT-competent mental health professionals (MHPs). We tested the impact of a pilot LGBT-affirmative training for MHPs in Romania on these professionals' LGBT-relevant attitudes, knowledge, and perception of clinical skills. Methods: We conducted a 2-day training for MHPs in Bucharest. Fifty-four attended and 33 provided training evaluation data at baseline and follow-up. Results: The majority of trainees were female (90%) and heterosexual (73%) with a mean age of 36.4 (SD = 7.7). From baseline to follow-up, trainees demonstrated a significant increase in perceived LGBT-relevant clinical skills (P < 0.001) and perceived knowledge (P < 0.05). LGBT-affirmative practice attitudes (P < 0.05) and comfort in addressing the mental health of LGBT individuals (P < 0.01) increased significantly, and homonegative and transnegative attitudes decreased significantly (P < 0.01). Negative attitudes toward LGBT individuals were low at both baseline and follow-up. The majority of trainees reported being highly interested in the training (84%), which they reported had prepared them to interact with and care for LGBT individuals (74%). Conclusion: This pilot training appeared to be effective in increasing perceived LGBT competence among participating MHPs. This type of training model needs to be tested further in a randomized controlled trial with longer follow-up periods to assess intervention durability and implementation of clinical skills. Future trainings can be incorporated into existing curricula. National accreditation bodies might consider encouraging such training as part of standard educational requirements. PMID:28891750

Antidrug Antibody Formation in Oncology: Clinical Relevance and Challenges.

PubMed

van Brummelen, Emilie M J; Ros, Willeke; Wolbink, Gertjan; Beijnen, Jos H; Schellens, Jan H M

2016-10-01

: In oncology, an increasing number of targeted anticancer agents and immunotherapies are of biological origin. These biological drugs may trigger immune responses that lead to the formation of antidrug antibodies (ADAs). ADAs are directed against immunogenic parts of the drug and may affect efficacy and safety. In other medical fields, such as rheumatology and hematology, the relevance of ADA formation is well established. However, the relevance of ADAs in oncology is just starting to be recognized, and literature on this topic is scarce. In an attempt to fill this gap in the literature, we provide an up-to-date status of ADA formation in oncology. In this focused review, data on ADAs was extracted from 81 clinical trials with biological anticancer agents. We found that most biological anticancer drugs in these trials are immunogenic and induce ADAs (63%). However, it is difficult to establish the clinical relevance of these ADAs. In order to determine this relevance, the possible effects of ADAs on pharmacokinetics, efficacy, and safety parameters need to be investigated. Our data show that this was done in fewer than 50% of the trials. In addition, we describe the incidence and consequences of ADAs for registered agents. We highlight the challenges in ADA detection and argue for the importance of validating, standardizing, and describing well the used assays. Finally, we discuss prevention strategies such as immunosuppression and regimen adaptations. We encourage the launch of clinical trials that explore these strategies in oncology. Because of the increasing use of biologicals in oncology, many patients are at risk of developing antidrug antibodies (ADAs) during therapy. Although clinical consequences are uncertain, ADAs may affect pharmacokinetics, patient safety, and treatment efficacy. ADA detection and reporting is currently highly inconsistent, which makes it difficult to evaluate the clinical consequences. Standardized reporting of ADA investigations in the context of the aforementioned parameters is critical to understanding the relevance of ADA formation for each drug. Furthermore, the development of trials that specifically aim to investigate clinical prevention strategies in oncology is needed. ©AlphaMed Press.

Effect, Feasibility, and Clinical Relevance of Cell Enrichment in Large Volume Fat Grafting: A Systematic Review.

PubMed

Rasmussen, Bo Sonnich; Lykke Sørensen, Celine; Vester-Glowinski, Peter Viktor; Herly, Mikkel; Trojahn Kølle, Stig-Frederik; Fischer-Nielsen, Anne; Drzewiecki, Krzysztof Tadeusz

2017-07-01

Large volume fat grafting is limited by unpredictable volume loss; therefore, methods of improving graft retention have been developed. Fat graft enrichment with either stromal vascular fraction (SVF) cells or adipose tissue-derived stem/stromal cells (ASCs) has been investigated in several animal and human studies, and significantly improved graft retention has been reported. Improvement of graft retention and the feasibility of these techniques are equally important in evaluating the clinical relevance of cell enrichment. We conducted a systematic search of PubMed to identify studies on fat graft enrichment that used either SVF cells or ASCs, and only studies reporting volume assessment were included. A total of 38 articles (15 human and 23 animal) were included to investigate the effects of cell enrichment on graft retention as well as the feasibility and clinical relevance of cell-enriched fat grafting. Improvements in graft retention, the SVF to fat (SVF:fat) ratio, and the ASC concentration used for enrichment were emphasized. We proposed an increased retention rate greater than 1.5-fold relative to nonenriched grafts and a maximum SVF:fat ratio of 1:1 as the thresholds for clinical relevance and feasibility, respectively. Nine studies fulfilled these criteria, whereof 6 used ASCs for enrichment. We found no convincing evidence of a clinically relevant effect of SVF enrichment in humans. ASC enrichment has shown promising results in enhancing graft retention, but additional clinical trials are needed to substantiate this claim and also determine the optimal concentration of SVF cells/ASCs for enrichment. 4. © 2017 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.

Clinical Evidence: a useful tool for promoting evidence-based practice?

PubMed

Formoso, Giulio; Moja, Lorenzo; Nonino, Francesco; Dri, Pietro; Addis, Antonio; Martini, Nello; Liberati, Alessandro

2003-12-23

Research has shown that many healthcare professionals have problems with guidelines as they would prefer to be given all relevant information relevant to decision-making rather than being told what they should do. This study assesses doctors' judgement of the validity, relevance, clarity and usability of the Italian translation of Clinical Evidence (CE) after its free distribution launched by the Italian Ministry of Health. Opinions elicited using a standardised questionnaire delivered either by mail or during educational or professional meetings. Twenty percent (n = 1350) doctors participated the study. Most of them found CE's content valid, useful and relevant for their clinical practice, and said CE can foster communications among clinicians, particularly among GPs and specialists. Hospital doctors (63%) more often than GPs (48%) read the detailed presentation of individual chapters. Twenty-nine percent said CE brought changes in their clinical practice. Doctors appreciated CE's nature of an evidence-based information compendium and would have not preferred a collection of practice guidelines. Overall, the pilot initiative launched by the Italian Ministry of Health seems to have been well received and to support the subsequent decision to make the Italian edition of Clinical Evidence concise available to all doctors practising in the country. Local implementation initiatives should be warranted to favour doctor's use of CE.

Downregulation of TXNIP leads to high proliferative activity and estrogen-dependent cell growth in breast cancer.

PubMed

Park, Jun Won; Lee, Su Hyung; Woo, Gye-Hyung; Kwon, Hyo-Jung; Kim, Dae-Yong

2018-04-06

TXNIP is a potent tumor suppressor with reduced expression in various types of human cancer. The prognostic and predictive power of TXNIP has been recognized in human breast cancer. The aim of this study is to investigate the clinical relevance and functional roles of TXNIP downregulation in breast cancer. We examined TXNIP expression at the protein level in tissue microarray (TMA)-based human breast cancers and its correlation with clinical parameters and molecular markers on immunohistochemistry (IHC). Compared with normal tissues, TXNIP expression was significantly decreased in human breast cancer tissues and animal mammary tumors, along with tumor progression. TXNIP was restored immediately after histone deacetylase inhibitor treatment in breast cancer cells, implying transcriptional regulation of TXNIP by histone modification. Decreased TXNIP protein levels were more common in tumors showing high proliferative activity, such as high Ki-67 labeling indexes and low p27 expression. TXNIP knockdown led to increased in vitro and in vivo breast cancer cell growth accompanied by p27 reduction and GLUT1 induction. Interestingly, estrogen receptor (ER)-positive breast cancer samples showed higher TXNIP expression compared to ER-negative samples. TXNIP expression decreased when ER signaling was activated by estradiol, while its expression increased under ER blockage by anti-estrogen fulvestrant. In addition, TXNIP knockdown in breast cancer cells caused significant reduction in the cell-growth inhibitory effect of anti-estrogen fulvestrant. In conclusion, our data demonstrated that TXNIP functions to suppress high proliferative activity and estrogen-dependent cell growth in breast cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

Pharmacokinetic interactions between lersivirine and zidovudine, tenofovir disoproxil fumarate/emtricitabine and abacavir/lamivudine.

PubMed

Vourvahis, Manoli; Davis, John; Langdon, Grant; Layton, Gary; Fang, Juanzhi; Choo, Heng Wee; Hansson, Arne G; Tawadrous, Margaret

2013-01-01

To investigate pharmacokinetic interactions associated with coadministration of lersivirine with zidovudine, tenofovir disoproxil fumarate (DF)/emtricitabine (Truvada(®)) or abacavir/lamivudine (Epzicom(®)/Kivexa(®)). Three Phase I, open, crossover studies with two (studies 1 and 3) or three (study 2) treatment periods were conducted in healthy individuals. In study 1, individuals received zidovudine and placebo or zidovudine and lersivirine on days 1-14. In study 2, individuals received lersivirine and tenofovir DF/emtricitabine, lersivirine and placebo or tenofovir DF/emtricitabine and placebo on days 1-10. In study 3, individuals received abacavir/lamivudine only in period 1 (5 days) and abacavir/lamivudine and lersivirine in period 2 (10 days). Blood samples were taken on days 1-14 (study 1) or day of final dose (studies 2 and 3) and analysed using high performance liquid chromatography/dual mass spectrometry. Pharmacokinetic parameters were calculated by standard non-compartmental methods. When coadministered with lersivirine, zidovudine exposure increased by 35%, and exposure of its metabolite zidovudine-glucuronide decreased by 19%. Following coadministration of lersivirine and tenofovir DF/emtricitabine, tenofovir exposure increased by 30%, and lersivirine exposure decreased by 12%. Coadministration of lersivirine and abacavir/lamivudine increased abacavir exposure by 27% and decreased lamivudine exposure by 8%. Adverse events were predominantly mild in these Phase I studies. Coadministration of lersivirine with zidovudine, tenofovir DF/emtricitabine or abacavir/lamivudine influenced the systemic exposure of all nucleoside reverse transcriptase inhibitor agents investigated (except for lamivudine; emtricitabine pharmacokinetics were not assessed). Changes were not considered clinically meaningful for zidovudine and abacavir. The clinical relevance of the effect on tenofovir pharmacokinetics is currently unknown.

Systematic review of quantitative clinical gait analysis in patients with dementia.

PubMed

van Iersel, M B; Hoefsloot, W; Munneke, M; Bloem, B R; Olde Rikkert, M G M

2004-02-01

Diminished mobility often accompanies dementia and has a great impact on independence and quality of life. New treatment strategies for dementia are emerging, but the effects on gait remains to be studied objectively. In this review we address the general effects of dementia on gait as revealed by quantitative gait analysis. A systematic literature search with the (MESH) terms: 'dementia' and 'gait disorders' in Medline, CC, Psychlit and CinaHL between 1980-2002. Main inclusion criteria: controlled studies; patients with dementia; quantitative gait data. Seven publications met the inclusion criteria. All compared gait in Alzheimer's Disease (AD) with healthy elderly controls; one also assessed gait in Vascular Dementia (VaD). The methodology used was inconsistent and often had many shortcomings. However, there were several consistent findings: walking velocity decreased in dementia compared to healthy controls and decreased further with progressing severity of dementia. VaD was associated with a significant decrease in walking velocity compared to AD subjects. Dementia was associated with a shortened step length, an increased double support time and step to step variability. Gait in dementia is hardly analyzed in a well-designed manner. Despite this, the literature suggests that quantitative gait analysis can be sufficiently reliable and responsive to measure decline in walking velocity between subjects with and without dementia. More research is required to assess, both on an individual and a group level, how the minimal clinically relevant changes in gait in elderly demented patients should be defined and what would be the most responsive method to measure these changes.

Objective assessment of the compensatory effect of clinical hind limb lameness in horses: 37 cases (2011-2014).

PubMed

Maliye, Sylvia; Marshall, John F

2016-10-15

OBJECTIVE To characterize and describe the compensatory load redistribution that results from unilateral hind limb lameness in horses. DESIGN Retrospective case series. ANIMALS 37 client-owned horses. PROCEDURES Medical records were reviewed to identify horses with unilateral hind limb lameness that responded positively (by objective assessment) to diagnostic local anesthesia during lameness evaluation and that were evaluated before and after diagnostic local anesthesia with an inertial sensor-based lameness diagnosis system. Horses were grouped as having hind limb lameness only, hind limb and ipsilateral forelimb lameness, or hind limb and contralateral forelimb lameness. Measures of head and pelvic movement asymmetry before (baseline) and after diagnostic local anesthesia were compared. The effect of group on baseline pelvic movement asymmetry variables was analyzed statistically. RESULTS Maximum pelvic height significantly decreased from the baseline value after diagnostic local anesthesia in each of the 3 lameness groups and in all horses combined. Minimum pelvic height significantly decreased after the procedure in all groups except the hind limb and contralateral forelimb lameness group. Head movement asymmetry was significantly decreased after diagnostic local anesthesia for horses with hind limb and ipsilateral forelimb lameness and for all horses combined, but not for those with hind limb lameness only or those with hind limb and contralateral forelimb lameness. CONCLUSIONS AND CLINICAL RELEVANCE Results supported that hind limb lameness can cause compensatory load redistribution evidenced as ipsilateral forelimb lameness. In this population of horses, contralateral forelimb lameness was not compensatory and likely reflected true lameness. Further studies are needed to investigate the source of the contralateral forelimb lameness in such horses.

Clinically Relevant Changes in Emotional Expression in Children with ADHD Treated with Lisdexamfetamine Dimesylate

ERIC Educational Resources Information Center

Katic, Alain; Ginsberg, Lawrence; Jain, Rakesh; Adeyi, Ben; Dirks, Bryan; Babcock, Thomas; Scheckner, Brian; Richards, Cynthia; Lasser, Robert; Turgay, Atilla; Findling, Robert L.

2012-01-01

Objective: To describe clinically relevant effects of lisdexamfetamine dimesylate (LDX) on emotional expression (EE) in children with ADHD. Method: Children with ADHD participated in a 7-week, open-label, LDX dose-optimization study. Expression and Emotion Scale for Children (EESC) change scores were analyzed post hoc using two methods to…

Chiral drug analysis using mass spectrometric detection relevant to research and practice in clinical and forensic toxicology.

PubMed

Schwaninger, Andrea E; Meyer, Markus R; Maurer, Hans H

2012-12-21

This paper reviews analytical approaches published in 2002-2012 for chiral drug analysis and their relevance in research and practice in the field of clinical and forensic toxicology. Separation systems such as gas chromatography, high performance liquid chromatography, capillary electromigration, and supercritical fluid chromatography, all coupled to mass spectrometry, are discussed. Typical applications are reviewed for relevant chiral analytes such as amphetamines and amphetamine-derived designer drugs, methadone, tramadol, psychotropic and other CNS acting drugs, anticoagulants, cardiovascular drugs, and some other drugs. Usefulness of chiral drug analysis in the interpretation of analytical results in clinical and forensic toxicology is discussed as well. Copyright © 2012 Elsevier B.V. All rights reserved.

Influence of hyaluronic acid on bacterial and fungal species, including clinically relevant opportunistic pathogens.

PubMed

Ardizzoni, Andrea; Neglia, Rachele G; Baschieri, Maria C; Cermelli, Claudio; Caratozzolo, Manuela; Righi, Elena; Palmieri, Beniamino; Blasi, Elisabetta

2011-10-01

Hyaluronic acid (HA) has several clinical applications (aesthetic surgery, dermatology, orthopaedics and ophtalmology). Following recent evidence, suggesting antimicrobial and antiviral properties for HA, we investigated its effects on 15 ATCC strains, representative of clinically relevant bacterial and fungal species. The in vitro system employed allowed to assess optical density of broth cultures as a measure of microbial load in a time-dependent manner. The results showed that different microbial species and, sometimes, different strains belonging to the same species, are differently affected by HA. In particular, staphylococci, enterococci, Streptococcus mutans, two Escherichia coli strains, Pseudomonas aeruginosa, Candida glabrata and C. parapsilosis displayed a HA dose-dependent growth inhibition; no HA effects were detected in E. coli ATCC 13768 and C. albicans; S. sanguinis was favoured by the highest HA dose. Therefore, the influence of HA on bacteria and fungi warrants further studies aimed at better establishing its relevance in clinical applications.

Quality of life in patients with muscle invasive and non-muscle invasive bladder cancer.

PubMed

Singer, S; Ziegler, C; Schwalenberg, T; Hinz, A; Götze, H; Schulte, T

2013-05-01

Compared to the literature on other malignancies, data on quality of life (QoL) in bladder cancer are sparse. This study sought answers to the following questions: In what QoL domains do patients with bladder cancer differ from the general population? Do patients with radical cystectomy differ in QoL compared to those who received conservative treatment? Do patients with neobladder generally have better QoL compared to patients with other diversion methods? At the beginning of inpatient rehabilitation, N = 823 patients with bladder cancer were assessed. Data of a representative community sample (N = 2037) were used for comparison. The questionnaire EORTC QLQ-C30 was used to measure QoL. Multivariate linear regression models were computed to investigate differences between groups. Patients with both non-muscle invasive and muscle invasive bladder cancer reported significantly more problems and worse functioning than the general population. Radiotherapy is associated with clinically relevant more pain, dyspnoea, constipation, appetite loss and decreased social functioning while chemotherapy is associated more with dyspnoea. Cystectomy patients reported more fatigue, appetite loss and decreased role functioning. Male patients ≥70 years with conduit experienced more sleep and emotional problems. These effects of urinary diversion were not observed in women and younger patients. Patients with bladder cancer experience various QoL concerns at the beginning of inpatient rehabilitation. These problems can partly be explained by the type of treatment the patients receive. Type of urinary diversion is relevant for QoL in subgroups of patients.

Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol in comparison to one containing levonorgestrel and ethinylestradiol on markers of endocrine function.

PubMed

Ågren, Ulla M; Anttila, Marjatta; Mäenpää-Liukko, Kristiina; Rantala, Maija-Liisa; Rautiainen, Hilkka; Sommer, Werner F; Mommers, Ellen

2011-12-01

To compare the effects of two monophasic combined oral contraceptives, containing either nomegestrol acetate/17β-oestradiol (NOMAC/E2) or levonorgestrel/ ethinylestradiol (LNG/EE) on endocrine function, androgens, and sex hormone-binding globulin (SHBG). Randomised, open-label, multi-centre trial involving 121 healthy women, aged 18-50 years old. Participants received NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n=60) or LNG/EE (150 μg/30 μg) in a 21/7-day regimen (n=61) for six cycles. The primary outcome was the change from baseline to cycle 6 in markers of adrenal and thyroid function, androgens, and SHBG. Total cortisol, corticosteroid-binding globulin (CBG), and thyroxine-binding globulin (TBG) increased from baseline in both groups, with significantly greater increases in the LNG/EE group. No relevant changes from baseline or differences between the groups were observed for thyroid-stimulating hormone (TSH) and free thyroxine (T4). Androgens and androgen precursors decreased from baseline in both groups, with significantly greater decreases in the LNG/EE group (except for free testosterone). A greater increase in SHBG was observed with NOMAC/E2 than with LNG/EE. NOMAC/E2 has significantly less influence on markers of adrenal and thyroid function and androgens than LNG/EE. The clinical relevance of these findings requires further study.

Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol in comparison to one containing levonorgestrel and ethinylestradiol on markers of endocrine function

PubMed Central

Ågren, Ulla M; Anttilat, Marjatta; Mäenpää-Liukko, Kristiina; Rantala, Maija-Liisa; Rautiainen, Hilkka; Sommer, Werner F; Mommers, Ellen

2011-01-01

Objectives To compare the effects of two monophasic combined oral contraceptives, containing either nomegestrol acetate/17β-oestradiol (NOMAC/E2) or levonorgestrel/ ethinylestradiol (LNG/EE) on endocrine function, androgens, and sex hormone-binding globulin (SHBG). Methods Randomised, open-label, multi-centre trial involving 121 healthy women, aged 18-50 years old. Participants received NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n = 60) or LNG/EE (150 μg/30 μg) in a 21/7-day regimen (n = 61) for six cycles. The primary outcome was the change from baseline to cycle 6 in markers of adrenal and thyroid function, androgens, and SHBG. Results Total cortisol, corticosteroid-binding globulin (CBG), and thyroxine-binding globulin (TBG) increased from baseline in both groups, with significantly greater increases in the LNG/EE group. No relevant changes from baseline or differences between the groups were observed for thyroid-stimulating hormone (TSH) and free thyroxine (T4). Androgens and androgen precursors decreased from baseline in both groups, with significantly greater decreases in the LNG/EE group (except for free testosterone). A greater increase in SHBG was observed with NOMAC/E2 than with LNG/EE. Conclusions NOMAC/E2 has significantly less influence on markers of adrenal and thyroid function and androgens than LNG/EE. The clinical relevance of these findings requires further study. PMID:21942708

An informatics approach to analyzing the incidentalome.

PubMed

Berg, Jonathan S; Adams, Michael; Nassar, Nassib; Bizon, Chris; Lee, Kristy; Schmitt, Charles P; Wilhelmsen, Kirk C; Evans, James P

2013-01-01

Next-generation sequencing has transformed genetic research and is poised to revolutionize clinical diagnosis. However, the vast amount of data and inevitable discovery of incidental findings require novel analytic approaches. We therefore implemented for the first time a strategy that utilizes an a priori structured framework and a conservative threshold for selecting clinically relevant incidental findings. We categorized 2,016 genes linked with Mendelian diseases into "bins" based on clinical utility and validity, and used a computational algorithm to analyze 80 whole-genome sequences in order to explore the use of such an approach in a simulated real-world setting. The algorithm effectively reduced the number of variants requiring human review and identified incidental variants with likely clinical relevance. Incorporation of the Human Gene Mutation Database improved the yield for missense mutations but also revealed that a substantial proportion of purported disease-causing mutations were misleading. This approach is adaptable to any clinically relevant bin structure, scalable to the demands of a clinical laboratory workflow, and flexible with respect to advances in genomics. We anticipate that application of this strategy will facilitate pretest informed consent, laboratory analysis, and posttest return of results in a clinical context.

Point-of-care diagnostics for niche applications.

PubMed

Cummins, Brian M; Ligler, Frances S; Walker, Glenn M

2016-01-01

Point-of-care or point-of-use diagnostics are analytical devices that provide clinically relevant information without the need for a core clinical laboratory. In this review we define point-of-care diagnostics as portable versions of assays performed in a traditional clinical chemistry laboratory. This review discusses five areas relevant to human and animal health where increased attention could produce significant impact: veterinary medicine, space travel, sports medicine, emergency medicine, and operating room efficiency. For each of these areas, clinical need, available commercial products, and ongoing research into new devices are highlighted. Copyright © 2016 Elsevier Inc. All rights reserved.

What's New in the Medicine Cabinet?: A Panoramic Review of Clinically Relevant Information for the Busy Dermatologist.

PubMed

Del Rosso, James Q; Zeichner, Joshua

2014-01-01

This article is the first in a periodic series of therapeutic topics with short reviews gleaned from major dermatology meetings, especially Scientific Poster Sessions, and is designed to provide information that may assist the readers in adapting information from the literature to their clinical practice. The topics covered in this issue are discussions of the clinical relevance of newer information about acne pathophysiology, acne in adult women, and topical corticosteroid spray formulations for chronic plaque psoriasis.

Consultant paediatric outreach clinics--a practical step in integration.

PubMed

Spencer, N J

1993-04-01

Ten years' experience of paediatric outreach clinics is reviewed and evaluated. The advantages and disadvantages of paediatric outreach and its possible place in the new era of contracting and more developed community paediatric services are discussed. It is concluded that paediatric outreach increases parental and professional choice and access to paediatric consultant services, increases service flexibility, reduces unnecessary hospital visits, and enables more rational and relevant clinical decision making. Outreach is particularly relevant in areas of deprivation where paediatric needs are greatest.

Consultant paediatric outreach clinics--a practical step in integration.

PubMed Central

Spencer, N J

1993-01-01

Ten years' experience of paediatric outreach clinics is reviewed and evaluated. The advantages and disadvantages of paediatric outreach and its possible place in the new era of contracting and more developed community paediatric services are discussed. It is concluded that paediatric outreach increases parental and professional choice and access to paediatric consultant services, increases service flexibility, reduces unnecessary hospital visits, and enables more rational and relevant clinical decision making. Outreach is particularly relevant in areas of deprivation where paediatric needs are greatest. PMID:8503675

T-wave alternans and beat-to-beat variability of repolarization: pathophysiological backgrounds and clinical relevance.

PubMed

Floré, Vincent; Willems, Rik

2012-12-01

In this review, we focus on temporal variability of cardiac repolarization. This phenomenon has been related to a higher risk for ventricular arrhythmia and is therefore interesting as a marker of sudden cardiac death risk. We review two non-invasive clinical techniques quantifying repolarization variability: T-wave alternans (TWA) and beat-to-beat variability of repolarization (BVR). We discuss their pathophysiological link with ventricular arrhythmia and the current clinical relevance of these techniques.

Fluoride rinse effect on retention of CaF2 formed on enamel/dentine by fluoride application.

PubMed

Falcão, Amanda; Masson, Nadia; Leitão, Tarcísio Jorge; Botelho, Juliana Nunes; Ferreira-Nóbilo, Naiara de Paula; Tabchoury, Cínthia Pereira Machado; Tenuta, Livia Maria Andaló; Cury, Jaime Aparecido

2016-01-01

Calcium fluoride-like materials ("CaF2") formed on dental surfaces after professional fluoride application are unstable in the oral environment but can be retained longer with a daily NaF mouthrinse. We tested the effect of twice daily 0.05% NaF rinses on the retention of "CaF2" formed on enamel and dentine after applying acidulated phosphate fluoride (APF). "CaF2" formed on enamel/dentine by APF application significantly decreased after exposure to artificial saliva and the 0.05% NaF rinse was ineffective to avoid this reduction. These findings suggest that the combination of APF and 0.05% NaF is not clinically relevant, either for caries or dental hypersensitivity.

Pharmacogenomics of CYP2C9: Functional and Clinical Considerations†

PubMed Central

Rettie, Allan E.; Fowler, Douglas M.; Miners, John O.

2017-01-01

CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare ‘variants of uncertain significance’, which are increasingly detected as more exome and genome sequencing of diverse populations is conducted. PMID:29283396

Therapeutic Misconception in Psychiatry Research: A Systematic Review.

PubMed

Thong, Ivan Sk; Foo, Meng Yee; Sum, Min Yi; Capps, Benjamin; Lee, Tih-Shih; Ho, Calvin; Sim, Kang

2016-02-29

Therapeutic misconception (TM) denotes the phenomenon in which research subjects conflate research purpose, protocols and procedures with clinical treatment. We examined the prevalence, contributory factors, clinical associations, impact, and collated solutions on TM within psychiatric research, and made suggestions going ahead. Literature search for relevant empirical research papers was conducted until February 2015. Eighty-eight reports were extracted, of which 31 were selected, summarised into different headings for discussion of implications and collated solutions of TM. We found variable and high rates of TM (ranging from 12.5% to 86%) in some psychiatry research populations. Contributory factors to TM included perceived medical roles of researchers, media, research setting and subject factors. Greater TM in affective, neurodevelopmental and psychotic spectrum conditions were associated with demographic variables (such as lower education, increased age), clinical factors (such as poor insight, cognitive deficits, increased symptoms, poorer self-rated quality of health), and social functioning (such as decreased independence). Inattention to TM may lead to frustration, negative impression and abandonment of participation in psychiatry research. Strategies such as the employment of a neutral educator during the informed consent process and education modules may be effective in addressing TM. Further research is warranted to examine the different TM facets, specific clinical correlates and more effective management strategies.

An exploration into study design for biomarker identification: issues and recommendations.

PubMed

Hall, Jacqueline A; Brown, Robert; Paul, Jim

2007-01-01

Genomic profiling produces large amounts of data and a challenge remains in identifying relevant biological processes associated with clinical outcome. Many candidate biomarkers have been identified but few have been successfully validated and make an impact clinically. This review focuses on some of the study design issues encountered in data mining for biomarker identification with illustrations of how study design may influence the final results. This includes issues of clinical endpoint use and selection, power, statistical, biological and clinical significance. We give particular attention to study design for the application of supervised clustering methods for identification of gene networks associated with clinical outcome and provide recommendations for future work to increase the success of identification of clinically relevant biomarkers.

Teplizumab for treatment of type 1 diabetes mellitus.

PubMed

Skelley, Jessica W; Elmore, Lindsey K; Kyle, Jeffrey A

2012-10-01

To review the pharmacology, pharmacokinetics, safety, and efficacy of teplizumab and evaluate relevant clinical trial data. Searches of MEDLINE, International Pharmaceutical Abstracts, ClinicalTrials.gov, American Diabetes Association scientific posters, and Google Scholar (1966-May 2012) were conducted using the key words teplizumab, anti-CD3 monoclonal antibody, MGA031, and hOKT3γ1 (Ala-Ala). Searches were limited to articles published in English. Clinical trials evaluating teplizumab for type 1 diabetes mellitus (T1DM) published in English were selected from the data sources. All published relevant abstracts were included. References cited in identified articles were used for additional citations. T1DM accounts for up to 10% of all cases of diabetes mellitus. T1DM is characterized as a chronic and progressive autoimmune disease leading to the destruction of insulin-producing β-cells of the pancreas. Teplizumab is a humanized Fc-mutated anti-CD3 monoclonal antibody that alters the function of the T-lymphocytes that mediate the destruction of the insulin-producing β-cells. While clinical data are limited, both Phase 2 and Phase 3 studies have demonstrated preserved C-peptide response as a measure of insulin production, decreased exogenous insulin use, and improved glycemic control following a 12- to 14-day teplizumab infusion in patients diagnosed with T1DM within the previous 6 weeks. However, 1 Phase 3 trial failed to find the same benefits in those diagnosed with T1DM within the previous 12 weeks when a lower cumulative teplizumab dose was used. Initial studies indicated that teplizumab is well tolerated, with a self-limiting rash as the most commonly reported adverse effect. Teplizumab is an anti-CD3 human monoclonal antibody with promising activity in treatment of patients with T1DM. Results from Phase 3 trials are needed to further determine safety, efficacy, and dosing frequency.

Differences in ability to perform activities of daily living among women with fibromyalgia: A cross-sectional study.

PubMed

von Bülow, Cecilie; Amris, Kirstine; la Cour, Karen; Danneskiold-Samsøe, Bente; Ejlersen, Eva Wæhrens

2015-11-01

To investigate whether the Assessment of Motor and Process Skills (AMPS), the physical function subscales of the Fibromyalgia Impact Questionnaire (FIQ PF) and the 36-item Short Form (SF-36 PF) can identify subgroups of women with fibromyalgia with clinically relevant differences in ability to perform activities of daily living. Cross-sectional study. A total of 257 women with fibromyalgia. Participants were evaluated with the AMPS (measuring activities of daily living motor and activities of daily living process ability), FIQ and SF-36. AMPS independence cut-offs were used to divide the participants into 4 subgroups. Clinically relevant differences between subgroups were investigated based on the AMPS, FIQ PF and SF-36 PF. Participants in the 4 AMPS-derived subgroups demon-strated clinically relevant differences in observed activities of daily living motor and process ability. Neither the FIQ PF nor the SF-36 PF could differentiate between subgroups with clinically relevant differences in AMPS activities of daily living process ability. Activities of daily living process skills reflect underlying organizational and adaptive capacities of the individual and are relevant targets for interventions aiming at improving activities of daily living ability. Since self-report instruments do not capture differences in activities of daily living process ability, clinicians should include observations-based assessment of activities of daily living ability in order to individualize interventions offered.

A Review of Atomoxetine Effects in Young People with Developmental Disabilities

PubMed Central

Aman, Michael G.; Smith, Tristram; Arnold, L. Eugene; Corbett-Dick, Patricia; Rameshwari.Tumuluru; Hollway, Jill A.; Hyman, Susan L.; Mendoza-Burchamm, Marissa; Pan, Xueliang; Mruzek, Daniel W.; Lecavalier, Luc; Levato, Lynne; Silverman, Laura B.; Handen, Benjamin

2014-01-01

This review summarizes the pharmacokinetic characteristics, pharmacodynamic properties, common side effects, and clinical advantages and disadvantages associated with atomoxetine (ATX) treatment in typically developing children and adults with ADHD. Then the clinical research to date in developmental disabilities (DD), including autism spectrum disorders (ASD), is summarized and reviewed. Of the 11 relevant reports available, only two were placebo-controlled randomized clinical trials, and both focused on a single DD population (ASD). All trials but one indicated clinical improvement in ADHD symptoms with ATX, although it was difficult to judge the magnitude and validity of reported improvement in the absence of placebo controls. Effects of ATX on co-occurring behavioral and cognitive symptoms were much less consistent. Appetite decrease, nausea, and irritability were the most common adverse events reported among children with DD; clinicians should be aware that, as with stimulants, irritability appears to occur much more commonly in persons with DD than in typically developing individuals. Splitting the dose initially, starting below the recommended starting dose, and titrating slowly may prevent or ameliorate side effects. Patience is needed for the slow build-up of benefit. Conclusions: ATX holds promise for managing ADHD symptoms in DD, but properly controlled, randomized clinical trials of atomoxetine in intellectual disability and ASD are sorely needed. Clinicians and researchers should be vigilant for emergence of irritability with ATX treatment. Effects of ATX on cognition in DD are virtually unstudied. PMID:24732041

Daily rhythms of left atrial pressure in beagle dogs with mitral valve regurgitation.

PubMed

Ishikawa, T; Tanaka, R; Suzuki, S; Saida, Y; Soda, A; Fukushima, R; Yamane, Y

2009-01-01

Mitral valve regurgitation (MR) causes increased left atrial pressure (LAP) and is associated with occurrence of clinical signs. It will be useful to understand diurnal variations of LAP for the management of MR. Circulatory parameters and diurnal rhythm are linked to clinical signs in cardiac diseases. LAP also exhibits a diurnal rhythm in dogs with MR. Five healthy Beagle dogs weighing 9.8-12.8 kg (3 males and 2 females; aged 2 years) were used. A radiotelemetry system for continuous measurement of LAP was used in this study. Rupture of the chordae tendineae was experimentally induced via left atriotomy, and a transmitter catheter was inserted into the left atrium. The body of the transmitter was implanted SC. After clinical condition was stabilized, the severity of MR was evaluated by echocardiography, and LAP was recorded for 72 consecutive hours for the analysis of diurnal variation. Abrupt increases in LAP, which averaged 16.7 mmHg, were observed at feeding periods. In contrast, strong diurnal LAP variations were found, with a significant but slight increase in daytime LAP compared with nighttime LAP. Diurnal LAP is characterized by a slight but significant nocturnal decrease and abrupt increases in response to excitation. The latter seemed to be more important considering the relationship with clinical manifestations. The clinical relevance of exercise restriction in the management of MR was acknowledged.

[The assessment of the clinical effectiveness of fenspiride for the treatment of acute obstruction of the Eustachian tube].

PubMed

Fedin, A V

2015-01-01

The objective of the present study was to estimate the clinical effectiveness of fenspiride used to correct the obstruction of the Eustachian tube in 80 patients presenting with acute tubootitis and exudative otitis media. The algorithm of the examination included the evaluation of the severity of subjective clinical symptoms based on the relevant analog-visual scale, results of tonal audiometry, and tympanometry. The control group was comprised of 34 patients treated with antibacterial preparations, topical decongestants, and transtubal administration of glucocorticoids. The study group included 46 patients who received fenspiride at a dose of 80 mg thrice daily in addition to the above pharmacotherapy. The severity of clinical symptoms in the patients treated with fenspiride decreased faster than in the control subjects. The frequency analysis of dynamics of the air-bone gaps on the audiometric curves revealed the significantly more intensive recovery of the hearing function in the patients treated by basal pharmacotherapy in the combination with fenspiride. Type A tympanograms predominated on day 7 after the onset of the conservative treatment with the use of fenspiride whereas type C tympanograms continued to predominate in the patients of the control group. It is concluded that the introduction of fenspiride into combined therapy of acute tubootitis and exudative otitis media promotes the normalization of the ventilation and drainage functions and relieves the severity of subjective clinical symptoms.

Clinical relevance of smartphone apps for diabetes management: A global overview.

PubMed

Huang, Zhilian; Soljak, Michael; Boehm, Bernhard Otto; Car, Josip

2018-05-01

We assessed the number, proportion, and clinical relevance of diabetes self-management apps in major languages spoken by 10 countries with the highest number of people with diabetes. China, India, USA, Brazil, Russian Federation, Mexico, Indonesia, Egypt, Japan, and Pakistan were identified as the 10 countries with the largest number of people with diabetes based on the latest NCD-RisC survey. Android and iOS apps in the 10 national languages were extracted with a search strategy. App titles and descriptions were systematically screened by trained reviewers, including apps specific for diabetes self-management and excluding apps for health care providers, general well-being, health and product promotion, and traditional cure. Eighteen apps in the above languages were then downloaded based on availability and popularity and assessed for clinical relevance to diabetes self-management with reference to current clinical guidelines. The diabetes-related search terms identified 3374 Android and 4477 iOS apps, where 1019 Android and 1303 iOS apps were screened as being relevant for diabetes self-management. Chinese and English language apps constitute above 80% of the diabetes apps, have more downloads, and more comprehensive clinically relevant functions compared with other languages. None of the apps assessed met all criteria for information provision and app functionalities nor provided information cited from accredited sources. Our study showed that apps could play an important role in complementing multifaceted diabetes care, but should preferably be regulated, context specific, and more tailored to users' needs with clear guidance for patients and clinicians about the choices. Copyright © 2018 John Wiley & Sons, Ltd.

Mitomycin-C in corneal surface excimer laser ablation techniques: a report by the American Academy of Ophthalmology.

PubMed

Majmudar, Parag A; Schallhorn, Steven C; Cason, John B; Donaldson, Kendall E; Kymionis, George D; Shtein, Roni M; Verity, Steven M; Farjo, Ayad A

2015-06-01

To review the published literature assessing the efficacy and safety of mitomycin-C (MMC) as an adjunctive treatment in corneal surface excimer laser ablation procedures. Literature searches of the PubMed and Cochrane Library databases were last conducted on August 19, 2014, without language or date limitations. The searches retrieved a total of 239 references. Of these, members of the Ophthalmic Technology Assessment Committee Refractive Management/Intervention Panel selected 26 articles that were considered to be of high or medium clinical relevance, and the panel methodologist rated each article according to the strength of evidence. Ten studies were rated as level I evidence, 5 studies were rated as level II evidence, and the remaining 11 studies were rated as level III evidence. The majority of the articles surveyed in this report support the role of MMC as an adjunctive treatment in surface ablation procedures. When MMC is applied in the appropriate concentration and confined to the central cornea, the incidence of post-surface ablation haze is decreased. Although a minority of studies that evaluated endothelial cell density (ECD) reported an MMC-related decrease in ECD, no clinical adverse outcomes were reported. Over the past 15 years, the use of MMC during surgery in surface ablation has become widespread. There is good evidence of the effectiveness of MMC when used intraoperatively as prophylaxis against haze in higher myopic ablations. Although there are reports of decreased endothelial counts after the administration of MMC during surgery, the clinical significance of this finding remains uncertain, because no adverse outcomes were reported with as much as 5 years of follow-up. Optimal dosage, effectiveness as prophylaxis in lower myopic and hyperopic ablations, and long-term safety, particularly in eyes with reduced corneal endothelial cell counts from prior intraocular surgery, have yet to be established. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Minimally important difference for the Expanded Prostate Cancer Index Composite Short Form.

PubMed

Skolarus, Ted A; Dunn, Rodney L; Sanda, Martin G; Chang, Peter; Greenfield, Thomas K; Litwin, Mark S; Wei, John T

2015-01-01

To establish a score threshold that constitutes a clinically relevant change for each domain of the Expanded Prostate Cancer Index Composite (EPIC) Short Form (EPIC-26). Although its use in clinical practice and clinical trials has increased worldwide, the clinical interpretation of this 26-item disease-specific patient-reported quality of life questionnaire for men with localized prostate cancer would be facilitated by characterization of score thresholds for clinically relevant change (the minimally important differences [MIDs]). We used distribution- and anchor-based approaches to establish the MID range for each EPIC-26 domain (urinary, sexual, bowel, and vitality/hormonal) based on a prospective multi-institutional cohort of 1201 men treated for prostate cancer between 2003 and 2006 and followed up for 3 years after treatment. For the anchor-based approach, we compared within-subject and between-subject score changes for each domain to an external "anchor" measure of overall cancer treatment satisfaction. We found the bowel and vitality/hormonal domains to have the lowest MID range (a 4-6 point change should be considered clinically relevant), whereas the sexual domain had the greatest MID values (10-12). Urinary incontinence appeared to have a greater MID range (6-9) than the urinary irritation/obstruction domain (5-7). Using 2 independent approaches, we established the MIDs for each EPIC-26 domain. A definition of these MID values is essential for the researcher or clinician to understand when changes in symptom burden among prostate cancer survivors are clinically relevant. Copyright © 2015 Elsevier Inc. All rights reserved.

The medical genetics workforce: an analysis of clinical geneticist subgroups.

PubMed

Cooksey, Judith A; Forte, Gaetano; Flanagan, Patricia A; Benkendorf, Judith; Blitzer, Miriam G

2006-10-01

Clinical geneticists with a Doctor of Medicine degree face challenges to meet the growing population demand for genetic services. This study was designed to assist the profession with workforce planning by identifying clinically relevant subgroups of geneticists and describing their professional characteristics and clinical practices. Geneticists' patient care productivity is compared across subgroups and other medical specialists. Part of a comprehensive national study of genetic services and the health workforce, this study uses data from a 2003 survey of geneticists certified by the American Board of Medical Genetics. This study includes 610 clinical geneticists who spend at least 5% of their time in direct patient-care services. An iterative approach was used to identify five subgroups based on the types of new patients seen. We conducted a descriptive analysis of subgroups by demographic, training, professional, and practice characteristics. The subgroups include general (36%), pediatric (28%), reproductive (15%), metabolic (14%), and adult (7%) geneticists. Clinically relevant variations across subgroups were noted in training, professional, and practice parameters. Subgroups vary across patient care hours (median, 15-33 hours/week) and total weekly work hours (52-60 hours). New patient visits (mean, 222-900/year) are higher than follow-up patient visits (mean, 155-405) for all subgroups except metabolic geneticists. Although many geneticists practice as generalist geneticists, this study provides an evidence base for distinguishing clinically relevant subgroups of geneticists. Geneticists provide similar numbers of new patient visits and far fewer follow-up visits than other medical specialists. These findings are relevant to geneticist workforce planning.

Impaction durability of porous polyether-ether-ketone (PEEK) and titanium-coated PEEK interbody fusion devices.

PubMed

Torstrick, F Brennan; Klosterhoff, Brett S; Westerlund, L Erik; Foley, Kevin T; Gochuico, Joanna; Lee, Christopher S D; Gall, Ken; Safranski, David L

2018-05-01

Various surface modifications, often incorporating roughened or porous surfaces, have recently been introduced to enhance osseointegration of interbody fusion devices. However, these topographical features can be vulnerable to damage during clinical impaction. Despite the potential negative impact of surface damage on clinical outcomes, current testing standards do not replicate clinically relevant impaction loading conditions. The purpose of this study was to compare the impaction durability of conventional smooth polyether-ether-ketone (PEEK) cervical interbody fusion devices with two surface-modified PEEK devices that feature either a porous structure or plasma-sprayed titanium coating. A recently developed biomechanical test method was adapted to simulate clinically relevant impaction loading conditions during cervical interbody fusion procedures. Three cervical interbody fusion devices were used in this study: smooth PEEK, plasma-sprayed titanium-coated PEEK, and porous PEEK (n=6). Following Kienle et al., devices were impacted between two polyurethane blocks mimicking vertebral bodies under a constant 200 N preload. The posterior tip of the device was placed at the entrance between the polyurethane blocks, and a guided 1-lb weight was impacted upon the anterior face with a maximum speed of 2.6 m/s to represent the strike force of a surgical mallet. Impacts were repeated until the device was fully impacted. Porous PEEK durability was assessed using micro-computed tomography (µCT) pre- and postimpaction. Titanium-coating coverage pre- and postimpaction was assessed using scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy. Changes to the surface roughness of smooth and titanium-coated devices were also evaluated. Porous PEEK and smooth PEEK devices showed minimal macroscopic signs of surface damage, whereas the titanium-coated devices exhibited substantial visible coating loss. Quantification of the porous PEEK deformation demonstrated that the porous structure maintained a high porosity (>65%) following impaction that would be available for bone ingrowth, and exhibited minimal changes to pore size and depth. SEM and energy dispersive X-ray spectroscopy analysis of titanium-coated devices demonstrated substantial titanium coating loss after impaction that was corroborated with a decrease in surface roughness. Smooth PEEK showed minimal signs of damage using SEM, but demonstrated a decrease in surface roughness. Although recent surface modifications to interbody fusion devices are beneficial for osseointegration, they may be susceptible to damage and wear during impaction. The current study found porous PEEK devices to show minimal damage during simulated cervical impaction, whereas titanium-coated PEEK devices lost substantial titanium coverage. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

A Bridge between Two Cultures: Uncovering the Chemistry Concepts Relevant to the Nursing Clinical Practice

ERIC Educational Resources Information Center

Brown, Corina E.; Henry, Melissa L. M.; Barbera, Jack; Hyslop, Richard M.

2012-01-01

This study focused on the undergraduate course that covers basic topics in general, organic, and biological (GOB) chemistry at a mid-sized state university in the western United States. The central objective of the research was to identify the main topics of GOB chemistry relevant to the clinical practice of nursing. The collection of data was…

Autoantibodies Against the Node of Ranvier in Seropositive Chronic Inflammatory Demyelinating Polyneuropathy: Diagnostic, Pathogenic, and Therapeutic Relevance

PubMed Central

Vural, Atay; Doppler, Kathrin; Meinl, Edgar

2018-01-01

Discovery of disease-associated autoantibodies has transformed the clinical management of a variety of neurological disorders. Detection of autoantibodies aids diagnosis and allows patient stratification resulting in treatment optimization. In the last years, a set of autoantibodies against proteins located at the node of Ranvier has been identified in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies target neurofascin, contactin1, or contactin-associated protein 1, and we propose to name CIDP patients with these antibodies collectively as seropositive. They have unique clinical characteristics that differ from seronegative CIDP. Moreover, there is compelling evidence that autoantibodies are relevant for the pathogenesis. In this article, we review the current knowledge on the characteristics of autoantibodies against the node of Ranvier proteins and their clinical relevance in CIDP. We start with a description of the structure of the node of Ranvier followed by a summary of assays used to identify seropositive patients; and then, we describe clinical features and characteristics linked to seropositivity. We review knowledge on the role of these autoantibodies for the pathogenesis with relevance for the emerging concept of nodopathy/paranodopathy and summarize the treatment implications. PMID:29867996

Autoantibodies Against the Node of Ranvier in Seropositive Chronic Inflammatory Demyelinating Polyneuropathy: Diagnostic, Pathogenic, and Therapeutic Relevance.

PubMed

Vural, Atay; Doppler, Kathrin; Meinl, Edgar

2018-01-01

Discovery of disease-associated autoantibodies has transformed the clinical management of a variety of neurological disorders. Detection of autoantibodies aids diagnosis and allows patient stratification resulting in treatment optimization. In the last years, a set of autoantibodies against proteins located at the node of Ranvier has been identified in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies target neurofascin, contactin1, or contactin-associated protein 1, and we propose to name CIDP patients with these antibodies collectively as seropositive. They have unique clinical characteristics that differ from seronegative CIDP. Moreover, there is compelling evidence that autoantibodies are relevant for the pathogenesis. In this article, we review the current knowledge on the characteristics of autoantibodies against the node of Ranvier proteins and their clinical relevance in CIDP. We start with a description of the structure of the node of Ranvier followed by a summary of assays used to identify seropositive patients; and then, we describe clinical features and characteristics linked to seropositivity. We review knowledge on the role of these autoantibodies for the pathogenesis with relevance for the emerging concept of nodopathy/paranodopathy and summarize the treatment implications.

Clinically relevant diagnostic research in primary care: the example of B-type natriuretic peptides in the detection of heart failure.

PubMed

Kelder, Johannes C; Rutten, Frans H; Hoes, Arno W

2009-02-01

With the emergence of novel diagnostic tests, e.g. point-of-care tests, clinically relevant empirical evidence is needed to assess whether such a test should be used in daily practice. With the example of the value of B-type natriuretic peptides (BNP) in the diagnostic assessment of suspected heart failure, we will discuss the major methodological issues crucial in diagnostic research; most notably the choice of the study population and the data analysis with a multivariable approach. BNP have been studied extensively in the emergency care setting, and also several studies in the primary care are available. The usefulness of this test when applied in combination with other readily available tests is still not adequately addressed in the relevant patient domain, i.e. those who are clinically suspected of heart failure by their GP. Future diagnostic research in primary care should be targeted much more at answering the clinically relevant question 'Is it useful to add this (new) test to the other tests I usually perform, including history taking and physical examination, in patients I suspect of having a certain disease'.

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.

Rates of decline in Alzheimer disease decrease with age.

PubMed

Holland, Dominic; Desikan, Rahul S; Dale, Anders M; McEvoy, Linda K

2012-01-01

Age is the strongest risk factor for sporadic Alzheimer disease (AD), yet the effects of age on rates of clinical decline and brain atrophy in AD have been largely unexplored. Here, we examined longitudinal rates of change as a function of baseline age for measures of clinical decline and structural MRI-based regional brain atrophy, in cohorts of AD, mild cognitive impairment (MCI), and cognitively healthy (HC) individuals aged 65 to 90 years (total n = 723). The effect of age was modeled using mixed effects linear regression. There was pronounced reduction in rates of clinical decline and atrophy with age for AD and MCI individuals, whereas HCs showed increased rates of clinical decline and atrophy with age. This resulted in convergence in rates of change for HCs and patients with advancing age for several measures. Baseline cerebrospinal fluid densities of AD-relevant proteins, Aβ(1-42), tau, and phospho-tau(181p) (ptau), showed a similar pattern of convergence with advanced age across cohorts, particularly for ptau. In contrast, baseline clinical measures did not differ by age, indicating uniformity of clinical severity at baseline. These results imply that the phenotypic expression of AD is relatively mild in individuals older than approximately 85 years, and this may affect the ability to distinguish AD from normal aging in the very old. Our findings show that inclusion of older individuals in clinical trials will substantially reduce the power to detect disease-modifying therapeutic effects, leading to dramatic increases in required clinical trial sample sizes with age of study sample.

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.

Decaying Relevance of Clinical Data Towards Future Decisions in Data-Driven Inpatient Clinical Order Sets

PubMed Central

Chen, Jonathan H; Alagappan, Muthuraman; Goldstein, Mary K; Asch, Steven M; Altman, Russ B

2017-01-01

Objective Determine how varying longitudinal historical training data can impact prediction of future clinical decisions. Estimate the “decay rate” of clinical data source relevance. Materials and Methods We trained a clinical order recommender system, analogous to Netflix or Amazon’s “Customers who bought A also bought B…” product recommenders, based on a tertiary academic hospital’s structured electronic health record data. We used this system to predict future (2013) admission orders based on different subsets of historical training data (2009 through 2012), relative to existing human-authored order sets. Results Predicting future (2013) inpatient orders is more accurate with models trained on just one month of recent (2012) data than with 12 months of older (2009) data (ROC AUC 0.91 vs. 0.88, precision 27% vs. 22%, recall 52% vs. 43%, all P<10−10). Algorithmically learned models from even the older (2009) data was still more effective than existing human-authored order sets (ROC AUC 0.81, precision 16% recall 35%). Training with more longitudinal data (2009–2012) was no better than using only the most recent (2012) data, unless applying a decaying weighting scheme with a “half-life” of data relevance about 4 months. Discussion Clinical practice patterns (automatically) learned from electronic health record data can vary substantially across years. Gold standards for clinical decision support are elusive moving targets, reinforcing the need for automated methods that can adapt to evolving information. Conclusions and Relevance Prioritizing small amounts of recent data is more effective than using larger amounts of older data towards future clinical predictions. PMID:28495350

Next-generation sequencing diagnostics of bacteremia in sepsis (Next GeneSiS-Trial): Study protocol of a prospective, observational, noninterventional, multicenter, clinical trial.

PubMed

Brenner, Thorsten; Decker, Sebastian O; Grumaz, Silke; Stevens, Philip; Bruckner, Thomas; Schmoch, Thomas; Pletz, Mathias W; Bracht, Hendrik; Hofer, Stefan; Marx, Gernot; Weigand, Markus A; Sohn, Kai

2018-02-01

Sepsis remains a major challenge, even in modern intensive care medicine. The identification of the causative pathogen is crucial for an early optimization of the antimicrobial treatment regime. In this context, culture-based diagnostic procedures (e.g., blood cultures) represent the standard of care, although they are associated with relevant limitations. Accordingly, culture-independent molecular diagnostic procedures might be of help for the identification of the causative pathogen in infected patients. The concept of an unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma samples of septic patients by next-generation sequencing (NGS) has recently been identified to be a promising diagnostic platform for critically ill patients suffering from bloodstream infections. Although this new approach might be more sensitive and specific than culture-based state-of-the-art technologies, additional clinical trials are needed to exactly define the performance as well as clinical value of a NGS-based approach. Next GeneSiS is a prospective, observational, noninterventional, multicenter study to assess the diagnostic performance of a NGS-based approach for the detection of relevant infecting organisms in patients with suspected or proven sepsis [according to recent sepsis definitions (sepsis-3)] by the use of the quantitative sepsis indicating quantifier (SIQ) score in comparison to standard (culture-based) microbiological diagnostics. The clinical value of this NGS-based approach will be estimated by a panel of independent clinical specialists, retrospectively identifying potential changes in patients' management based on NGS results. Further subgroup analyses will focus on the clinical value especially for patients suffering from a failure of empiric treatment within the first 3 days after onset [as assessed by death of the patient or lack of improvement of the patient's clinical condition (in terms of an inadequate decrease of SOFA-score) or persistent high procalcitonin levels]. This prospective, observational, noninterventional, multicenter study for the first time investigates the performance as well as the clinical value of a NGS-based approach for the detection of bacteremia in patients with sepsis and may therefore be a pivotal step toward the clinical use of NGS in this indication. DRKS-ID: DRKS00011911 (registered October 9, 2017) https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011911; ClinicalTrials.gov Identifier: NCT03356249 (registered November 29, 2017) https://clinicaltrials.gov/ct2/show/NCT03356249.

[Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption].

PubMed

Silva, Adauto Carvalho; Toffoletto, Odaly; Lucio, Luiz Antonio Galvão; Santos, Paula Ferreira Dos; Afiune, Jorge Barros; Massud Filho, João; Tufik, Sergio

2010-02-01

Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74% when drug intake was associated with alcohol. These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.

Targeting of tumor endothelial cells combining 2 Gy/day of X-ray with Everolimus is the effective modality for overcoming clinically relevant radioresistant tumors

PubMed Central

Kuwahara, Yoshikazu; Mori, Miyuki; Kitahara, Shuji; Fukumoto, Motoi; Ezaki, Taichi; Mori, Shiro; Echigo, Seishi; Ohkubo, Yasuhito; Fukumoto, Manabu

2014-01-01

Radiotherapy is widely used to treat cancer because it has the advantage of physically and functionally conserving the affected organ. To improve radiotherapy and investigate the molecular mechanisms of cellular radioresistance, we established a clinically relevant radioresistant (CRR) cell line, SAS-R, from SAS cells. SAS-R cells continue to proliferate when exposed to fractionated radiation (FR) of 2 Gy/day for more than 30 days in vitro. A xenograft tumor model of SAS-R was also resistant to 2 Gy/day of X-rays for 30 days. The density of blood vessels in SAS-R tumors was higher than in SAS tumors. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, sensitized microvascular endothelial cells to radiation, but failed to radiosensitize SAS and SAS-R cells in vitro. Everolimus with FR markedly reduced SAS and SAS-R tumor volumes. Additionally, the apoptosis of endothelial cells (ECs) increased in SAS-R tumor tissues when both Everolimus and radiation were administered. Both CD34-positive and tomato lectin-positive blood vessel densities in SAS-R tumor tissues decreased remarkably after the Everolimus and radiation treatment. Everolimus-induced apoptosis of vascular ECs in response to radiation was also followed by thrombus formation that leads to tumor necrosis. We conclude that FR combined with Everolimus may be an effective modality to overcome radioresistant tumors via targeting tumor ECs. PMID:24464839

Side effects of beta-blocker treatments as related to the central nervous system.

PubMed

Dahlöf, C; Dimenäs, E

1990-04-01

During the last decade beta-adrenoceptor antagonists have become one of the first-line treatments for hypertension. Generally, they have been shown to be safe with a low frequency of serious side effects. However, minor subjective symptoms, usually considered to be CNS-related, have been reported for all beta-blockers used. Thus, all beta-blockers on the market seem to have a high benefit:risk ratio; independent of their physicochemical properties and pharmacodynamic profile, however, they seem to cause CNS-related side effects to about the same extent. These minor side effects, the mechanisms of which are unclear, consist of subtle effects on general well being, decreased initiative, a depressed frame of mind, and disturbed sleep. Generally, however, beta-blockers in therapeutic dosages do not affect the qualitative functions of the brain. The results so far available have been obtained primarily by using objective methods. Further comparison has now been initiated using documented subjective methods to investigate whether the objectively documented differences are of any clinical relevance to the patient's quality of life. Although it cannot be claimed with certainty, nonselective beta-blockers seem to cause CNS-related side effects to a greater extent than beta 1-selective blockers. Differences in the degree of hydrophilicity of the beta-blocker are apparently of no clinical relevance in this respect. Rather, the plasma concentration of the beta-blocking drug (degree of beta-blockade) seems to be the major determinant of whether or not CNS-related symptoms appear in susceptible patients.

Surgical inpatient satisfaction: what are the real drivers?

PubMed

Danforth, Rachel M; Pitt, Henry A; Flanagan, Mindy E; Brewster, Benjamin D; Brand, Elizabeth W; Frankel, Richard M

2014-08-01

Inpatient satisfaction is a key element of hospital pay-for-performance programs. Communication and pain management are known to influence results, but additional factors may affect satisfaction scores. We tested the hypothesis that patient factors and outcome parameters not considered previously are clinically important drivers of inpatient satisfaction. Medical records were reviewed for 1,340 surgical patients who returned nationally standardized inpatient satisfaction questionnaires. These patients were managed by 41 surgeons in seven specialties at two academic medical centers. Thirty-two parameters based on the patient, surgeon, outcomes, and survey were measured. Univariate and multivariable analyses were performed. Inpatients rated their overall experience favorably 75.7% of the time. Less-satisfied patients were more likely to be female, younger, less ill, taking outpatient narcotics, and admitted via the emergency department (all P < .02). Less-satisfied patients also were more likely to have unresected cancer (P < .001) or a postoperative complication (P < .001). The most relevant independent predictors of dissatisfaction in multivariable analyses were younger age, admission via the emergency department, preoperative narcotic use, lesser severity of illness, unresected cancer, and postoperative morbidity (all P < .01). Several patient factors, expectations of patients with cancer, and postoperative complications are important and clinically relevant drivers of surgical inpatient satisfaction. Programs to manage expectations of cancer patient expectations and decrease postoperative morbidity should improve surgical inpatient satisfaction. Further efforts to risk-adjust patient satisfaction scores should be undertaken. Copyright © 2014 Mosby, Inc. All rights reserved.

Low-level laser therapy on MCF-7 cells: a micro-Fourier transform infrared spectroscopy study.

PubMed

Magrini, Taciana D; dos Santos, Nathalia Villa; Milazzotto, Marcella Pecora; Cerchiaro, Giselle; da Silva Martinho, Herculano

2012-10-01

Low-level laser therapy (LLLT) is an emerging therapeutic approach for several clinical conditions. The clinical effects induced by LLLT presumably scale from photobiostimulation/photobioinhibition at the cellular level to the molecular level. The detailed mechanism underlying this effect remains unknown. This study quantifies some relevant aspects of LLLT related to molecular and cellular variations. Malignant breast cells (MCF-7) were exposed to spatially filtered light from a He-Ne laser (633 nm) with fluences of 5, 28.8, and 1000  mJ/cm². The cell viability was evaluated by optical microscopy using the Trypan Blue viability test. The micro-Fourier transform infrared technique was employed to obtain the vibrational spectra of each experimental group (control and irradiated) and identify the relevant biochemical alterations that occurred due to the process. It was observed that the red light influenced the RNA, phosphate, and serine/threonine/tyrosine bands. We found that light can influence cell metabolism depending on the laser fluence. For 5  mJ/cm², MCF-7 cells suffer bioinhibition with decreased metabolic rates. In contrast, for the 1  J/cm² laser fluence, cells present biostimulation accompanied by a metabolic rate elevation. Surprisingly, at the intermediate fluence, 28.8  mJ/cm², the metabolic rate is increased despite the absence of proliferative results. The data were interpreted within the retrograde signaling pathway mechanism activated with light irradiation.

Immediate effects of hip mobilization with movement in patients with hip osteoarthritis: A randomised controlled trial.

PubMed

Beselga, Carlos; Neto, Francisco; Alburquerque-Sendín, Francisco; Hall, Toby; Oliveira-Campelo, Natália

2016-04-01

Mobilization with movement (MWM) has been shown to reduce pain, increase range of motion (ROM) and physical function in a range of different musculoskeletal disorders. Despite this evidence, there is a lack of studies evaluating the effects of MWM for hip osteoarthritis (OA). To determine the immediate effects of MWM on pain, ROM and functional performance in patients with hip OA. Randomized controlled trial with immediate follow-up. Forty consenting patients (mean age 78 ± 6 years; 54% female) satisfied the eligibility criteria. All participants completed the study. Two forms of MWM techniques (n = 20) or a simulated MWM (sham) (n = 20) were applied. pain recorded by numerical rating scale (NRS). hip flexion and internal rotation ROM, and physical performance (timed up and go, sit to stand, and 40 m self placed walk test) were assessed before and after the intervention. For the MWM group, pain decreased by 2 points on the NRS, hip flexion increased by 12.2°, internal rotation by 4.4°, and functional tests were also improved with clinically relevant effects following the MWM. There were no significant changes in the sham group for any outcome variable. Pain, hip flexion ROM and physical performance immediately improved after the application of MWM in elderly patients suffering hip OA. The observed immediate changes were of clinical relevance. Future studies are required to determine the long-term effects of this intervention. Copyright © 2015 Elsevier Ltd. All rights reserved.

Animal models of transcranial direct current stimulation: Methods and mechanisms.

PubMed

Jackson, Mark P; Rahman, Asif; Lafon, Belen; Kronberg, Gregory; Ling, Doris; Parra, Lucas C; Bikson, Marom

2016-11-01

The objective of this review is to summarize the contribution of animal research using direct current stimulation (DCS) to our understanding of the physiological effects of transcranial direct current stimulation (tDCS). We comprehensively address experimental methodology in animal studies, broadly classified as: (1) transcranial stimulation; (2) direct cortical stimulation in vivo and (3) in vitro models. In each case advantages and disadvantages for translational research are discussed including dose translation and the overarching "quasi-uniform" assumption, which underpins translational relevance in all animal models of tDCS. Terminology such as anode, cathode, inward current, outward current, current density, electric field, and uniform are defined. Though we put key animal experiments spanning decades in perspective, our goal is not simply an exhaustive cataloging of relevant animal studies, but rather to put them in context of ongoing efforts to improve tDCS. Cellular targets, including excitatory neuronal somas, dendrites, axons, interneurons, glial cells, and endothelial cells are considered. We emphasize neurons are always depolarized and hyperpolarized such that effects of DCS on neuronal excitability can only be evaluated within subcellular regions of the neuron. Findings from animal studies on the effects of DCS on plasticity (LTP/LTD) and network oscillations are reviewed extensively. Any endogenous phenomena dependent on membrane potential changes are, in theory, susceptible to modulation by DCS. The relevance of morphological changes (galvanotropy) to tDCS is also considered, as we suggest microscopic migration of axon terminals or dendritic spines may be relevant during tDCS. A majority of clinical studies using tDCS employ a simplistic dose strategy where excitability is singularly increased or decreased under the anode and cathode, respectively. We discuss how this strategy, itself based on classic animal studies, cannot account for the complexity of normal and pathological brain function, and how recent studies have already indicated more sophisticated approaches are necessary. One tDCS theory regarding "functional targeting" suggests the specificity of tDCS effects are possible by modulating ongoing function (plasticity). Use of animal models of disease are summarized including pain, movement disorders, stroke, and epilepsy. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Can the theoretical domains framework account for the implementation of clinical quality interventions?

PubMed

Lipworth, Wendy; Taylor, Natalie; Braithwaite, Jeffrey

2013-12-21

The health care quality improvement movement is a complex enterprise. Implementing clinical quality initiatives requires attitude and behaviour change on the part of clinicians, but this has proven to be difficult. In an attempt to solve this kind of behavioural challenge, the theoretical domains framework (TDF) has been developed. The TDF consists of 14 domains from psychological and organisational theory said to influence behaviour change. No systematic research has been conducted into the ways in which clinical quality initiatives map on to the domains of the framework. We therefore conducted a qualitative mapping experiment to determine to what extent, and in what ways, the TDF is relevant to the implementation of clinical quality interventions. We conducted a thematic synthesis of the qualitative literature exploring clinicians' perceptions of various clinical quality interventions. We analysed and synthesised 50 studies in total, in five domains of clinical quality interventions: clinical quality interventions in general, structural interventions, audit-type interventions, interventions aimed at making practice more evidence-based, and risk management interventions. Data were analysed thematically, followed by synthesis of these themes into categories and concepts, which were then mapped to the domains of the TDF. Our results suggest that the TDF is highly relevant to the implementation of clinical quality interventions. It can be used to map most, if not all, of the attitudinal and behavioural barriers and facilitators of uptake of clinical quality interventions. Each of these 14 domains appeared to be relevant to many different types of clinical quality interventions. One possible additional domain might relate to perceived trustworthiness of those instituting clinical quality interventions. The TDF can be usefully applied to a wide range of clinical quality interventions. Because all 14 of the domains emerged as relevant, and we did not identify any obvious differences between different kinds of clinical quality interventions, our findings support an initially broad approach to identifying barriers and facilitators, followed by a "drilling down" to what is most contextually salient. In future, it may be possible to establish a model of clinical quality policy implementation using the TDF.

Can the theoretical domains framework account for the implementation of clinical quality interventions?

PubMed Central

2013-01-01

Background The health care quality improvement movement is a complex enterprise. Implementing clinical quality initiatives requires attitude and behaviour change on the part of clinicians, but this has proven to be difficult. In an attempt to solve this kind of behavioural challenge, the theoretical domains framework (TDF) has been developed. The TDF consists of 14 domains from psychological and organisational theory said to influence behaviour change. No systematic research has been conducted into the ways in which clinical quality initiatives map on to the domains of the framework. We therefore conducted a qualitative mapping experiment to determine to what extent, and in what ways, the TDF is relevant to the implementation of clinical quality interventions. Methods We conducted a thematic synthesis of the qualitative literature exploring clinicians’ perceptions of various clinical quality interventions. We analysed and synthesised 50 studies in total, in five domains of clinical quality interventions: clinical quality interventions in general, structural interventions, audit-type interventions, interventions aimed at making practice more evidence-based, and risk management interventions. Data were analysed thematically, followed by synthesis of these themes into categories and concepts, which were then mapped to the domains of the TDF. Results Our results suggest that the TDF is highly relevant to the implementation of clinical quality interventions. It can be used to map most, if not all, of the attitudinal and behavioural barriers and facilitators of uptake of clinical quality interventions. Each of these 14 domains appeared to be relevant to many different types of clinical quality interventions. One possible additional domain might relate to perceived trustworthiness of those instituting clinical quality interventions. Conclusions The TDF can be usefully applied to a wide range of clinical quality interventions. Because all 14 of the domains emerged as relevant, and we did not identify any obvious differences between different kinds of clinical quality interventions, our findings support an initially broad approach to identifying barriers and facilitators, followed by a “drilling down” to what is most contextually salient. In future, it may be possible to establish a model of clinical quality policy implementation using the TDF. PMID:24359085

In vitro activity of levofloxacin against planktonic and biofilm Stenotrophomonas maltophilia lifestyles under conditions relevant to pulmonary infection in cystic fibrosis, and relationship with SmeDEF multidrug efflux pump expression.

PubMed

Pompilio, Arianna; Crocetta, Valentina; Verginelli, Fabio; Di Bonaventura, Giovanni

2016-07-01

The activity of levofloxacin against planktonic and biofilm Stenotrophomonas maltophilia cells and the role played by the multidrug efflux pump SmeDEF were evaluated under conditions relevant to the cystic fibrosis (CF) lung. MIC, MBC and MBEC of levofloxacin were assessed, against five CF strains, under 'standard' (CLSI-recommended) and 'CF-like' (pH 6.8, 5% CO2, in a synthetic CF sputum) conditions. Levofloxacin was tested against biofilms at concentrations (10, 50 and 100 μg mL(-1)) corresponding to achievable serum levels and sputum levels by aerosolisation. smeD expression was evaluated, under both conditions, in planktonic and biofilm cells by RT-PCR. The bactericidal effect of levofloxacin was decreased, in three out of five strains tested, under 'CF-like' conditions (MBC: 2-4 vs 8-16 μg mL(-1), under 'standard' and 'CF-like' conditions, respectively). Biofilm was intrinsically resistant to levofloxacin, regardless of conditions tested (MBECs ≥ 100 μg mL(-1) for all strains). Only under 'CF-like' conditions, smeD expression increased during planktonic-to-biofilm transition, and in biofilm cells compared to stationary planktonic cells. Our findings confirmed that S. maltophilia biofilm is intrinsically resistant to therapeutic concentrations of levofloxacin. Under conditions relevant to CF, smeD overexpression could contribute to levofloxacin resistance. Further studies are warranted to define the clinical relevance of our findings. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The relationship between immediate relevant basic science knowledge and clinical knowledge: physiology knowledge and transthoracic echocardiography image interpretation.

PubMed

Nielsen, Dorte Guldbrand; Gotzsche, Ole; Sonne, Ole; Eika, Berit

2012-10-01

Two major views on the relationship between basic science knowledge and clinical knowledge stand out; the Two-world view seeing basic science and clinical science as two separate knowledge bases and the encapsulated knowledge view stating that basic science knowledge plays an overt role being encapsulated in the clinical knowledge. However, resent research has implied that a more complex relationship between the two knowledge bases exists. In this study, we explore the relationship between immediate relevant basic science (physiology) and clinical knowledge within a specific domain of medicine (echocardiography). Twenty eight medical students in their 3rd year and 45 physicians (15 interns, 15 cardiology residents and 15 cardiology consultants) took a multiple-choice test of physiology knowledge. The physicians also viewed images of a transthoracic echocardiography (TTE) examination and completed a checklist of possible pathologies found. A total score for each participant was calculated for the physiology test, and for all physicians also for the TTE checklist. Consultants scored significantly higher on the physiology test than did medical students and interns. A significant correlation between physiology test scores and TTE checklist scores was found for the cardiology residents only. Basic science knowledge of immediate relevance for daily clinical work expands with increased work experience within a specific domain. Consultants showed no relationship between physiology knowledge and TTE interpretation indicating that experts do not use basic science knowledge in routine daily practice, but knowledge of immediate relevance remains ready for use.

Proximal duodenoileal anastomosis for treatment of small intestinal obstruction and volvulus in a green iguana (Iguana iguana).

PubMed

Wills, Sarah; Beaufrère, Hugues; Watrous, Gwyneth; Oblak, Michelle L; Smith, Dale A

2016-11-01

CASE DESCRIPTION A 13-year-old female green iguana (Iguana iguana) was examined because of a 6-day history of vomiting, anorexia, and lethargy and a 4-day history of decreased fecal and urate output. CLINICAL FINDINGS Physical examination revealed a distended abdomen, signs of depression, pallor, tachycardia, harsh lung sounds, and vomiting. Abdominal radiographs revealed gas distention of the stomach and small intestine with fluid lines evident on the lateral view. Plasma biochemical analysis indicated hypochloremic metabolic alkalosis, hyperglycemia, and hyperuricemia. TREATMENT AND OUTCOME Exploratory laparotomy confirmed a diagnosis of small intestinal entrapment and 170° volvulus involving approximately 80% (20 to 30 cm) of the small intestine. The portion of the small intestine extending from the middle portion of the duodenum to the caudal extent of the ileum was resected, and end-to-end anastomosis of the remaining small intestine was performed. The iguana recovered without apparent complications and was reportedly doing well 1 year after surgery. CLINICAL RELEVANCE Findings suggested that iguanas, as hindgut fermenters, may tolerate > 70% resection of the small intestine with a good outcome and no clinical evidence of residual gastrointestinal dysfunction.

Thyroid abnormalities after therapeutic external radiation

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

Hancock, S.L.; McDougall, I.R.; Constine, L.S.

1995-03-30

The thyroid gland is the largest pure endocrine gland in the body and one of the organs most likely to produce clinically significant abnormalities after therapeutic external radiation. Radiation doses to the thyroid that exceed approximately 26 Gy frequently produce hypothyroidism, which may be clinically overt or subclinical, as manifested by increased serum thyrotropin and normal serum-free thyroxine concentrations. Pituitary or hypothalamic hypothyroidism may arise when the pituitary region receives doses exceeding 50 Gy with conventional, 1.8-2 Gy fractionation. Direct irradiation of the thyroid may increase the risk of Graves` disease or euthyroid Graves` ophthalmopathy. Silent thyroiditis, cystic degeneration, benignmore » adenoma, and thyroid cancer have been observed after therapeutically relevant doses of external radiation. Direct or incidental thyroid irradiation increases the risk for well-differentiated, papillary, and follicular thyroid cancer from 15- to 53-fold. Thyroid cancer risk is highest following radiation at a young age, decreases with increasing age at treatment, and increases with follow-up duration. The potentially prolonged latent period between radiation exposure and the development of thyroid dysfunction, thyroid nodularity, and thyroid cancer means that individuals who have received neck or pituitary irradiation require careful, periodic clinical and laboratory evaluation to avoid excess morbidity. 39 refs.« less

Term Relevance Weights in On-Line Information Retrieval

ERIC Educational Resources Information Center

Salton, G.; Waldstein, R. K.

1978-01-01

Term relevance weighting systems in interactive information retrieval are reviewed. An experiment in which information retrieval users ranked query terms in decreasing order of presumed importance prior to actual search and retrieval is described. (Author/KP)

Effect of LED irradiation on the expression of MMP-3 and MMP-13 in SW1353 cells in vitro

NASA Astrophysics Data System (ADS)

Zeng, Chang-chun; Guo, Zhou-yi; Zhang, Feng-xue; Deng, Wen-di; Liu, Song-hao

2007-05-01

Matrix Metalloproteinase (MMP) plays an active role in remodeling cartilage in osteoarthritic cartilage. To find an effective method of prevention of osteoclasia, this in vitro study focuses on the expression of MMP-3 and MMP-13 in the SW1353 cells by LED irradiation. The human chondrosarcoma cell line SW1353 were stimulated with the proinflammatory cytokine IL-1beta or tumor necrosis factor-alpha (TNF-alpha), and were received the irradiation of LED (632nm, 4mW/cm2). The cell count was assessed over a 96-hour period by using Trypan blue dye exclusion assay, and the cell activity was evaluated with a Cell Counting Kit-8 Assays. The subsequent expression of MMP-3 and MMP-13 was quantified. Results of this experiment showed that the cultural cell activity was decreased, and the expression of MMP-3 and MMP-13 was increased by being stimulated with IL-1beta or TNF-alpha. After received LED irradiation, the death rate of cultural cell was increased and the expression of MMP-3 and MMP-13 was decreased significantly. The present study concluded that particular LED irradiation stimulates SW1353 cell proliferation activity and inhibit the MMP-3 and MMP-13 enzymatic activity. These findings might be clinically relevant, indicating that the low power laser irradiation treatment is likely to achieve the repair of articular cartilage in clinic.

Product-evaluation registry of Meriva®, a curcumin-phosphatidylcholine complex, for the complementary management of osteoarthritis.

PubMed

Belcaro, G; Cesarone, M R; Dugall, M; Pellegrini, L; Ledda, A; Grossi, M G; Togni, S; Appendino, G

2010-06-01

A proprietary complex of curcumin with soy phosphatidylcholine (Meriva®, Indena SpA) was evaluated in a registry study to define its efficacy in 50 patients with osteoarthritis (OA) at dosages corresponding to 200 mg curcumin per diem. OA signs/symptoms were evaluated by the WOMAC scores. Mobility was studied by walking performance (treadmill), and inflammatory status was assessed by measurements of C-reactive protein (CRP). After three months of treatment, the global WOMAC score decreased by 58% (P<0.05), walking distance in the treadmill test was prolonged from 76 m to 332 m (P<0.05), and CRP levels decreased from 168 +/- 18 to 11.3 +/-. 4.1 mg/L in the subpopulation with high CRP. In comparison, the control group experienced only a modest improvement in these parameters (2% in the WOMAC score, from 82 m to 129 m in the treadmill test, and from 175 +/- 12.3 to 112 +/- 22.2 mg/L in the CRP plasma concentration), while the treatment costs (use of anti-inflammatory drugs, treatment and hospitalization) were reduced significantly in the treatment group. These results show that Meriva® is clinically effective in the management and treatment of osteoarthritis and suggest that the increased stability and better absorption of curcumin induced by complexation with phospholipids have clinical relevance, setting the stage for larger and more prolonged studies.

Whole body vibration training improves vibration perception threshold in healthy young adults: A randomized clinical trial pilot study

PubMed Central

Hernandez-Mocholi, M.A.; Dominguez-Muñoz, F.J.; Corzo, H.; Silva, S.C.S.; Adsuar, J.C.; Gusi, N.

2016-01-01

Objectives: Loss of foot sensitivity is a relevant parameter to assess and prevent in several diseases. It is crucial to determine the vibro-tactile sensitivity threshold response to acute conditions to explore innovative monitor tools and interventions to prevent and treat this challenge. The aims were: 1) to analyze the acute effects of a single whole body vibration session (4min-18Hz-4mm) on vibro-tactile perception threshold in healthy young adults. 2) to analyze the 48 hours effects of 3 whole body vibration sessions on vibro-tactile perception threshold in healthy young adults. Methods: A randomized controlled clinical trial over 3 sessions of whole body vibration intervention or 3 sessions of placebo intervention. Twenty-eight healthy young adults were included: 11 experimental group and 12 placebo group. The experimental group performed 3 sessions of WBV while the placebo group performed 3 sessions of placebo intervention. Results: The vibro-tactile threshold increased right after a single WBV session in comparison with placebo. Nevertheless, after 3 whole body vibration sessions and 48 hours, the threshold decreased to values lower than the initial. Conclusions: The acute response of the vibro-tactile threshold to one whole body vibration session increased, but the 48 hours short-term response of this threshold decreased in healthy young adults. PMID:26944818

Acquired resistance to tyrosine kinase inhibitors may be linked with the decreased sensitivity to X-ray irradiation

PubMed Central

Sorokin, Maxim; Kholodenko, Roman; Grekhova, Anna; Suntsova, Maria; Pustovalova, Margarita; Vorobyeva, Natalia; Kholodenko, Irina; Malakhova, Galina; Garazha, Andrew; Nedoluzhko, Artem; Vasilov, Raif; Poddubskaya, Elena; Kovalchuk, Olga; Adamyan, Leila; Prassolov, Vladimir; Allina, Daria; Kuzmin, Denis; Ignatev, Kirill; Osipov, Andreyan; Buzdin, Anton

2018-01-01

Acquired resistance to chemotherapy and radiation therapy is one of the major obstacles decreasing efficiency of treatment of the oncologic diseases. In this study, on the two cell lines (ovarian carcinoma SKOV-3 and neuroblastoma NGP-127), we modeled acquired resistance to five target anticancer drugs. The cells were grown on gradually increasing concentrations of the clinically relevant tyrosine kinase inhibitors (TKIs) Sorafenib, Pazopanib and Sunitinib, and rapalogs Everolimus and Temsirolimus, for 20 weeks. After 20 weeks of culturing, the half-inhibitory concentrations (IC50) increased by 25 – 186% for the particular combinations of the drugs and cell types. We next subjected cells to 10 Gy irradiation, a dose frequently used in clinical radiation therapy. For the SKOV-3, but not NGP-127 cells, for the TKIs Sorafenib, Pazopanib and Sunitinib, we noticed statistically significant increase in capacity to repair radiation-induced DNA double strand breaks compared to naïve control cells not previously treated with TKIs. These peculiarities were linked with the increased activation of ATM DNA repair pathway in the TKI-treated SKOV-3, but not NGP-127 cells. Our results provide a new cell culture model for studying anti-cancer therapy efficiency and evidence that there may be a tissue-specific radioresistance emerging as a side effect of treatment with TKIs. PMID:29435166

Long-echo time MR spectroscopy for skeletal muscle acetylcarnitine detection.

PubMed

Lindeboom, Lucas; Nabuurs, Christine I; Hoeks, Joris; Brouwers, Bram; Phielix, Esther; Kooi, M Eline; Hesselink, Matthijs K C; Wildberger, Joachim E; Stevens, Robert D; Koves, Timothy; Muoio, Deborah M; Schrauwen, Patrick; Schrauwen-Hinderling, Vera B

2014-11-01

Animal models suggest that acetylcarnitine production is essential for maintaining metabolic flexibility and insulin sensitivity. Because current methods to detect acetylcarnitine involve biopsy of the tissue of interest, noninvasive alternatives to measure acetylcarnitine concentrations could facilitate our understanding of its physiological relevance in humans. Here, we investigated the use of long-echo time (TE) proton magnetic resonance spectroscopy (1H-MRS) to measure skeletal muscle acetylcarnitine concentrations on a clinical 3T scanner. We applied long-TE 1H-MRS to measure acetylcarnitine in endurance-trained athletes, lean and obese sedentary subjects, and type 2 diabetes mellitus (T2DM) patients to cover a wide spectrum in insulin sensitivity. A long-TE 1H-MRS protocol was implemented for successful detection of skeletal muscle acetylcarnitine in these individuals. There were pronounced differences in insulin sensitivity, as measured by hyperinsulinemic-euglycemic clamp, and skeletal muscle mitochondrial function, as measured by phosphorus-MRS (31P-MRS), across groups. Insulin sensitivity and mitochondrial function were highest in trained athletes and lowest in T2DM patients. Skeletal muscle acetylcarnitine concentration showed a reciprocal distribution, with mean acetylcarnitine concentration correlating with mean insulin sensitivity in each group. These results demonstrate that measuring acetylcarnitine concentrations with 1H-MRS is feasible on clinical MR scanners and support the hypothesis that T2DM patients are characterized by a decreased formation of acetylcarnitine, possibly underlying decreased insulin sensitivity.

Long–echo time MR spectroscopy for skeletal muscle acetylcarnitine detection

PubMed Central

Lindeboom, Lucas; Nabuurs, Christine I.; Hoeks, Joris; Brouwers, Bram; Phielix, Esther; Kooi, M. Eline; Hesselink, Matthijs K.C.; Wildberger, Joachim E.; Stevens, Robert D.; Koves, Timothy; Muoio, Deborah M.; Schrauwen, Patrick; Schrauwen-Hinderling, Vera B.

2014-01-01

Animal models suggest that acetylcarnitine production is essential for maintaining metabolic flexibility and insulin sensitivity. Because current methods to detect acetylcarnitine involve biopsy of the tissue of interest, noninvasive alternatives to measure acetylcarnitine concentrations could facilitate our understanding of its physiological relevance in humans. Here, we investigated the use of long–echo time (TE) proton magnetic resonance spectroscopy (1H-MRS) to measure skeletal muscle acetylcarnitine concentrations on a clinical 3T scanner. We applied long-TE 1H-MRS to measure acetylcarnitine in endurance-trained athletes, lean and obese sedentary subjects, and type 2 diabetes mellitus (T2DM) patients to cover a wide spectrum in insulin sensitivity. A long-TE 1H-MRS protocol was implemented for successful detection of skeletal muscle acetylcarnitine in these individuals. There were pronounced differences in insulin sensitivity, as measured by hyperinsulinemic-euglycemic clamp, and skeletal muscle mitochondrial function, as measured by phosphorus-MRS (31P-MRS), across groups. Insulin sensitivity and mitochondrial function were highest in trained athletes and lowest in T2DM patients. Skeletal muscle acetylcarnitine concentration showed a reciprocal distribution, with mean acetylcarnitine concentration correlating with mean insulin sensitivity in each group. These results demonstrate that measuring acetylcarnitine concentrations with 1H-MRS is feasible on clinical MR scanners and support the hypothesis that T2DM patients are characterized by a decreased formation of acetylcarnitine, possibly underlying decreased insulin sensitivity. PMID:25271624

New directions in type 2 diabetes mellitus: an update of current oral antidiabetic therapy.

PubMed Central

Brown, D. L.; Brillon, D.

1999-01-01

This article reviewed the relevant literature including published clinical trials and reviews on currently available oral hypoglycemic agents. Results showed that the benefits of glycemic control have been established through multiple clinical trials. Long-term control of blood glucose levels in type 1 and type 2 diabetic patients will decrease the incidence and prolong the time until progression of diabetic retinopathy, nephropathy, and neuropathy. Our increased understanding of the pathophysiology behind type 2 diabetes has led to the development of many new agents that are aimed at treating the underlying insulin resistance and relative insulinopenia. The sulfonylureas as a group have been used for many years and act by stimulating insulin secretion. They are useful alone or as combination therapy with insulin or another oral hypoglycemic agent. The biguanides act by decreasing hepatic glucose production and by increasing peripheral insulin sensitivity. The alpha-glucosidase inhibitors act nonsystemically by blocking the metabolism of digested polysaccharides and therefore lowering the amount of carbohydrate absorbed in a meal. Benzoic acid derivatives act in a manner similar to that of sulfonylureas by enhancing pancreatic insulin production. They offer a shorter duration of action, lowering the risk of hypoglycemia. The thiazolidinediones increase peripheral insulin sensitivity and are effective as both monotherapy and combination therapy. Oral hypoglycemic agents, when properly administered, are very effective in controlling type 2 diabetes and preventing long-term complications. PMID:10643211

Intensive Communicative Therapy Reduces Symptoms of Depression in Chronic Nonfluent Aphasia

PubMed Central

Mohr, Bettina; Stahl, Benjamin; Berthier, Marcelo L.; Pulvermüller, Friedemann

2017-01-01

Background. Patients with brain lesions and resultant chronic aphasia frequently suffer from depression. However, no effective interventions are available to target neuropsychiatric symptoms in patients with aphasia who have severe language and communication deficits. Objective. The present study aimed to investigate the efficacy of 2 different methods of speech and language therapy in reducing symptoms of depression in aphasia on the Beck Depression Inventory (BDI) using secondary analysis (BILAT-1 trial). Methods. In a crossover randomized controlled trial, 18 participants with chronic nonfluent aphasia following left-hemispheric brain lesions were assigned to 2 consecutive treatments: (1) intensive language-action therapy (ILAT), emphasizing communicative language use in social interaction, and (2) intensive naming therapy (INT), an utterance-centered standard method. Patients were randomly assigned to 2 groups, receiving both treatments in counterbalanced order. Both interventions were applied for 3.5 hours daily over a period of 6 consecutive working days. Outcome measures included depression scores on the BDI and a clinical language test (Aachen Aphasia Test). Results. Patients showed a significant decrease in symptoms of depression after ILAT but not after INT, which paralleled changes on clinical language tests. Treatment-induced decreases in depression scores persisted when controlling for individual changes in language performance. Conclusions. Intensive training of behaviorally relevant verbal communication in social interaction might help reduce symptoms of depression in patients with chronic nonfluent aphasia. PMID:29192534

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.

Magnetic resonance imaging in the evaluation of clinical treatment of otospongiosis: a pilot study.

PubMed

de Oliveira Vicente, Andy; Chandrasekhar, Sujana S; Yamashita, Helio K; Cruz, Oswaldo Laercio M; Barros, Flavia A; Penido, Norma O

2015-06-01

To evaluate the applicability of magnetic resonance imaging (MRI) as a method for monitoring the activity of otospongiotic lesions before and after clinical treatment. Prospective, randomized, controlled, double-blind study. One single tertiary care institution in a large, cosmopolitan city. Twenty-six patients (n = 42 ears) with clinical, audiometric, and tomographic diagnosis of otosclerosis were enrolled. If computed tomography (CT) demonstrated active lesions, these patients underwent MRI to detect otospongiotic foci, seen as areas of gadolinium enhancement. Patients were divided into 3 groups and received treatment with placebo, sodium alendronate, or sodium fluoride for 6 months. After this period, clinical and audiometric evaluations and a second MRI were performed. Each MRI was evaluated by both a neuroradiologist and an otolaryngologist in a subjective (visual) and objective (using specific eFilm Workstation software) manner. Otospongiosis was most predominantly identified in the region anterior to the oval window, and this site was reliable for comparing pre- and posttreatment scans. The patients in the alendronate and sodium fluoride groups had MRI findings that suggested a decrease in activity of otospongiotic lesions, more relevant in the alendronate group. These findings were statistically significant for both subjective and objective MRI evaluations. MRI shows higher sensitivity than clinical or audiometric assessment for detecting reduction in activity of otospongiosis. The objective MRI evaluation based on software analysis was the most accurate method of monitoring clinical treatment response in otospongiosis. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.

Therapeutic horticulture in clinical depression: a prospective study of active components.

PubMed

Gonzalez, Marianne Thorsen; Hartig, Terry; Patil, Grete Grindal; Martinsen, Egil W; Kirkevold, Marit

2010-09-01

This paper is a report of a study conducted to assess change in depression severity, perceived attentional capacity and rumination (brooding) in individuals with clinical depression during a therapeutic horticulture programme and to investigate if the changes were mediated by experiences of being away and fascination. Individuals with clinical depression suffer from distortion of attention and rumination. Interventions can help to disrupt maladaptive rumination and promote restoration of depleted attentional capacity. A single-group study was conducted with a convenience sample of 28 people with clinical depression in 2009. Data were collected before, twice during, and immediately after a 12-week therapeutic horticulture programme, and at 3-month follow-up. Assessment instruments were the Beck Depression Inventory, Attentional Function Index, Brooding Scale, and Being Away and Fascination subscales from the Perceived Restorativeness Scale. Mean Beck Depression Inventory scores declined by 4.5 points during the intervention (F = 5.49, P = 0.002). The decline was clinically relevant for 50% of participants. Attentional Function Index scores increased (F = 4.14, P = 0.009), while Brooding scores decreased (F = 4.51, P = 0.015). The changes in Beck Depression Inventory and Attentional Function Index scores were mediated by increases in Being Away and Fascination, and decline in Beck Depression Inventory scores was also mediated by decline in Brooding. Participants maintained their improvements in Beck Depression Inventory scores at 3-month follow-up. Being away and fascination appear to work as active components in a therapeutic horticulture intervention for clinical depression.

Safety and efficacy of intravenous infusion of allogeneic cryopreserved mesenchymal stem cells for treatment of chronic kidney disease in cats: results of three sequential pilot studies

PubMed Central

2013-01-01

Introduction Administration of mesenchymal stem cells (MSCs) has been shown to improve renal function in rodent models of chronic kidney disease (CKD), in part by reducing intrarenal inflammation and suppressing fibrosis. CKD in cats is characterized by tubulointerstitial inflammation and fibrosis, and thus treatment with MSCs might improve renal function and urinary markers of inflammation in this disease. Therefore, a series of pilot studies was conducted to assess the safety and efficacy of intravenous administration of allogeneic adipose-derived MSCs (aMSCs) in cats with naturally occurring CKD. Methods Cats enrolled in these studies received an intravenous infusion of allogeneic aMSCs every 2 weeks collected from healthy, young, specific pathogen-free cats. Cats in pilot study 1 (six cats) received 2 × 106 cryopreserved aMSCs per infusion, cats in pilot study 2 (five cats) received 4 × 106 cryopreserved aMSCs per infusion, and cats in pilot study 3 (five cats) received 4 × 106 aMSCs cultured from cryopreserved adipose. Serum biochemistry, complete blood count, urinalysis, urine protein, glomerular filtration rate, and urinary cytokine concentrations were monitored during the treatment period. Changes in clinical parameters were compared statistically by means of repeated measures analysis of variance (ANOVA) followed by Bonferroni’s correction. Results Cats in pilot study 1 had few adverse effects from the aMSC infusions and there was a statistically significant decrease in serum creatinine concentrations during the study period, however the degree of decrease seems unlikely to be clinically relevant. Adverse effects of the aMSC infusion in cats in pilot study 2 included vomiting (2/5 cats) during infusion and increased respiratory rate and effort (4/5 cats). Cats in pilot study 3 did not experience any adverse side effects. Serum creatinine concentrations and glomerular filtration rates did not change significantly in cats in pilot studies 2 and 3. Conclusions Administration of cryopreserved aMSCs was associated with significant adverse effects and no discernible clinically relevant improvement in renal functional parameters. Administration of aMSCs cultured from cryopreserved adipose was not associated with adverse effects, but was also not associated with improvement in renal functional parameters. PMID:23632128

Contact fatigue mechanisms as a function of crystal aspect ratio in baria-silicate glass ceramics

NASA Astrophysics Data System (ADS)

Suputtamongkol, Kallaya

2003-10-01

Ceramic materials are potentially useful for dental applications because of their esthetic potential and biocompatibility. However, the existence of fatigue damage in ceramics raises considerable concern regarding its effect on the life prediction of dental prostheses. During normal mastication, dental restorations are subjected to repeated loading more than a thousand times per day and relatively high clinical failure rates for ceramic prostheses have been reported. To simulate the intraoral loads, Hertzian indentation loading was used in this study to characterize the fatigue failure mechanisms of ceramic materials using clinically relevant parameters. The baria-silicate system was chosen because of the nearly identical composition between the crystal and the glass matrix. Little or no residual stress is expected from the elastic modulus and thermal expansion mismatches between the two phases. Crystallites with different aspect ratios can also be produced by controlled heat treatment schedules. The objective of this study was to characterize the effect of crystal morphology on the fatigue mechanisms of bariasilicate glass-ceramics under clinically relevant conditions. The results show that the failure of materials with a low toughness such as baria-silicate glass (0.7 MPa•m1/2) and glass-ceramic with an aspect ratio of 3/1 (1.3 MPa•m1/2) initiated from a cone crack developed during cyclic loading for 103 to 105 cycles. The mean strength values of baria-silicate glass and glass-ceramic with an aspect ratio of 3/1 decreased significantly as a result of the presence of a cone crack. Failure of baria-silicate glass-ceramics with an aspect ratio of 8/1 (Kc = 2.1 MPa•m1/2) was initiated from surface flaws caused by either polishing or cyclic loading. The gradual decrease of fracture stress was observed in specimens with an aspect ratio of 8/1 after loading in air for 103 to 10 5 cycles. A reduction of approximately 50% in fracture stress levels was found for specimens with an aspect ratio of 8/1 after loading for 10 5 cycles in deionized water. The mechanisms for cyclic fatigue crack propagation in baria-silicate glass-ceramics are similar to those observed under quasi-static loading conditions. An intergranular fracture path was observed in glass-ceramics with an aspect ratio of 3/1. For an aspect ratio of 8/1, a transgranular fracture mode was dominant.

Clinical effectiveness of garlic (Allium sativum).

PubMed

Pittler, Max H; Ernst, Edzard

2007-11-01

The objective of this review is to update and assess the clinical evidence based on rigorous trials of the effectiveness of garlic (A. sativum). Systematic searches were carried out in Medline, Embase, Amed, the Cochrane Database of Systematic Reviews, Natural Standard, and the Natural Medicines Comprehensive Database (search date December 2006). Our own files, the bibliographies of relevant papers and the contents pages of all issues of the review journal FACT were searched for further studies. No language restrictions were imposed. To be included, trials were required to state that they were randomized and double blind. Systematic reviews and meta-analyses of garlic were included if based on the results of randomized, double-blind trials. The literature searches identified six relevant systematic reviews and meta-analysis and double-blind randomized trials (RCT) that were published subsequently. These relate to cancer, common cold, hypercholesterolemia, hypertension, peripheral arterial disease and pre-eclampsia. The evidence based on rigorous clinical trials of garlic is not convincing. For hypercholesterolemia, the reported effects are small and may therefore not be of clinical relevance. For reducing blood pressure, few studies are available and the reported effects are too small to be clinically meaningful. For all other conditions not enough data are available for clinical recommendations.

Education and Training for Clinical Neuropsychologists in Integrated Care Settings.

PubMed

Roper, Brad L; Block, Cady K; Osborn, Katie; Ready, Rebecca E

2018-05-01

The increasing importance of integrated care necessitates that education and training experiences prepare clinical neuropsychologists for competent practice in integrated care settings, which includes (a) general competence related to an integrated/interdisciplinary approach and (b) competence specific to the setting. Formal neuropsychology training prepares neuropsychologists with a wide range of knowledge and skills in assessment, intervention, teaching/supervision, and research that are relevant to such settings. However, less attention has been paid to the knowledge and skills that directly address functioning within integrated teams, such as the ability to develop, maintain, and expand collaboration across disciplines, bidirectional clinical-research translation and implementation in integrated team settings, and how such collaboration contributes to clinical and research activities. Foundational knowledge and skills relevant to interdisciplinary systems have been articulated as part of competencies for entry into clinical neuropsychology, but their emphasis in education and training programs is unclear. Recommendations and resources are provided regarding how competencies relevant to integrated care can be provided across the continuum of education and training (i.e., doctoral, internship, postdoctoral, and post-licensure).

Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

PubMed Central

Papale, Alessandro; Morella, Ilaria Maria; Indrigo, Marzia Tina; Bernardi, Rick Eugene; Marrone, Livia; Marchisella, Francesca; Brancale, Andrea; Spanagel, Rainer; Brambilla, Riccardo; Fasano, Stefania

2016-01-01

Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction. DOI: http://dx.doi.org/10.7554/eLife.17111.001 PMID:27557444

Quantifying App Store Dynamics: Longitudinal Tracking of Mental Health Apps

PubMed Central

Nicholas, Jennifer; Christensen, Helen

2016-01-01

Background For many mental health conditions, mobile health apps offer the ability to deliver information, support, and intervention outside the clinical setting. However, there are difficulties with the use of a commercial app store to distribute health care resources, including turnover of apps, irrelevance of apps, and discordance with evidence-based practice. Objective The primary aim of this study was to quantify the longevity and rate of turnover of mental health apps within the official Android and iOS app stores. The secondary aim was to quantify the proportion of apps that were clinically relevant and assess whether the longevity of these apps differed from clinically nonrelevant apps. The tertiary aim was to establish the proportion of clinically relevant apps that included claims of clinical effectiveness. We performed additional subgroup analyses using additional data from the app stores, including search result ranking, user ratings, and number of downloads. Methods We searched iTunes (iOS) and the Google Play (Android) app stores each day over a 9-month period for apps related to depression, bipolar disorder, and suicide. We performed additional app-specific searches if an app no longer appeared within the main search Results On the Android platform, 50% of the search results changed after 130 days (depression), 195 days (bipolar disorder), and 115 days (suicide). Search results were more stable on the iOS platform, with 50% of the search results remaining at the end of the study period. Approximately 75% of Android and 90% of iOS apps were still available to download at the end of the study. We identified only 35.3% (347/982) of apps as being clinically relevant for depression, of which 9 (2.6%) claimed clinical effectiveness. Only 3 included a full citation to a published study. Conclusions The mental health app environment is volatile, with a clinically relevant app for depression becoming unavailable to download every 2.9 days. This poses challenges for consumers and clinicians seeking relevant and long-term apps, as well as for researchers seeking to evaluate the evidence base for publicly available apps. PMID:27507641

Dyslipdemia induced by chronic low dose co-exposure to lead, cadmium and manganese in rats: the role of oxidative stress.

PubMed

Oladipo, Olusola Olalekan; Ayo, Joseph Olusegun; Ambali, Suleiman Folorunsho; Mohammed, Bisalla; Aluwong, Tanang

2017-07-01

Lead (Pb), cadmium (Cd) and manganese (Mn) have many potential adverse health effects in vitro and in animal models of clinical toxicity. The current study investigated the dyslipidaemic and oxidative stress effects of chronic low-dose oral exposure to Pb, Cd and Mn and the combination (Pb+Cd+Mn) in rats for 15 weeks. Chronic exposure to the metals did not significantly (P>0.05) alter serum lipid profiles. However, the atherogenic index decreased by 32.2% in the Pb+Cd+Mn group, relative to the control. The triglyceride/high-density lipoprotein cholesterol ratio decreased by 39.4% in the Pb+Cd+Mn group, relative to the control, and elevated by 81.8, 94.8 and 20.8%, relative to the Pb, Cd and Mn groups, respectively. While the serum concentrations of malondialdehyde significantly increased in the Mn and Pb+Cd+Mn groups, that of glutathione peroxidase-1 decreased in the Pb+Cd+Mn group, and metallothionein-1 and zinc concentrations markedly decreased in all the metal treatment groups. The results suggest that long-term exposure of rats to Pb+Cd+Mn may result in hypolipidaemia, mediated via oxidative stress and metal interactions. Individuals who are constantly exposed to environmentally relevant levels of the metals may be at risk of hypolipidaemia. Copyright © 2017 Elsevier B.V. All rights reserved.

The Distribution of and Relationship between Autistic Traits and Social Anxiety in a UK Student Population

ERIC Educational Resources Information Center

Freeth, Megan; Bullock, Tom; Milne, Elizabeth

2013-01-01

Traits associated with autism and social anxiety were assessed in a UK student population (n = 1325) using the Autism-spectrum Quotient and the Liebowitz Social Anxiety Scale. Clinically relevant levels of autistic traits were observed in 3.3% of the cohort; 10.1% of the cohort reported clinically relevant levels of social anxiety; 1.8% of the…

Translating orthopaedic basic science into clinical relevance.

PubMed

Madry, Henning

2014-12-01

In orthopaedic and trauma surgery, the rapid evolution of biomedical research has fundamentally changed the perception of the musculoskeletal system. Here, the rigor of basic science and the art of musculoskeletal surgery have come together to create a new discipline -experimental orthopaedics- that holds great promise for the causative cure of many orthopaedic conditions. The Journal of Experimental Orthopaedics intends to bridge the gap between orthopaedic basic science and clinical relevance, to allow for a fruitful clinical translation of excellent and important investigations in the field of the entire musculoskeletal system.

Developing education tailored to clinical roles: genetics education for haemophilia nurses.

PubMed

Burke, Sarah; Barker, Colin; Marshall, Dianne

2012-01-01

Genetics is an important component of the clinical work of haemophilia nurses, but little was known about the genetic education needs of haemophilia nurses. To develop, deliver and evaluate genetic education for haemophilia nurses, based on clinical roles. Perceived relevance of genetics to haemophilia nursing practice was explored using electronic voting (response rate 75%, 58/77). A follow-on questionnaire to a volunteer sample of participants explored educational preferences (response rate 41%, 17/41). Results informed development of a two-hour genetics workshop session, evaluated by questionnaire (response rate 67%, 47/70). Genetic competences were considered relevant to the clinical practice of haemophilia nurses, and learning needs were identified. Preference was expressed for education focused on practical skills. During the subsequent workshop, participant confidence ratings significantly increased in the four areas addressed. Planned changes to clinical care and training were reported. Within new areas of advanced nursing practice, learning needs can be addressed by: identifying relevant clinical activities and associated learning needs; creating a strategy and resources using preferred forms of delivery; implementing the strategy; and evaluating its effect. This will enable development of education that addresses the real needs of practising nurses, grounded in their daily clinical practice. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

Towards clinically translatable in vivo nanodiagnostics

NASA Astrophysics Data System (ADS)

Park, Seung-Min; Aalipour, Amin; Vermesh, Ophir; Yu, Jung Ho; Gambhir, Sanjiv S.

2017-05-01

Nanodiagnostics as a field makes use of fundamental advances in nanobiotechnology to diagnose, characterize and manage disease at the molecular scale. As these strategies move closer to routine clinical use, a proper understanding of different imaging modalities, relevant biological systems and physical properties governing nanoscale interactions is necessary to rationally engineer next-generation bionanomaterials. In this Review, we analyse the background physics of several clinically relevant imaging modalities and their associated sensitivity and specificity, provide an overview of the materials currently used for in vivo nanodiagnostics, and assess the progress made towards clinical translation. This work provides a framework for understanding both the impressive progress made thus far in the nanodiagnostics field as well as presenting challenges that must be overcome to obtain widespread clinical adoption.

Nutritional issues in heart transplant candidates and recipients.

PubMed

Amarelli, Cristiano; Buonocore, Marianna; Romano, Gianpaolo; Maiello, Ciro; De Santo, Luca Salvatore

2012-01-01

Heart transplant is the golden standard in the management of end-stage heart failure. Recent studies have pointed out the role of nutritional issues in patients evaluated for heart transplant listing. In particular, extremes in body habitus, cachexia and obesity, have been characterized and identified as independent prognostic factors and clinically relevant target for therapeutic interventions. Effects of such conditions exert a prognostic implication well beyond waiting time up to early post transplant setting. Changes in posttransplant clinical conditions and nutritional status have been recently described in their pattern of presentation and implications on weight gain, reversal of preoperative cachexia and early and late morbidity and mortality. New onset diabetes mellitus and metabolic syndrome have been disclosed as relevant clinical conditions in this setting. Implications for tailoring of immunosuppressive therapy and dietary prescription emerged as main stem of long term recipient management. All this issues have been reviewed focusing on the clinical relevance of this growing body of knowledge and emphasizing the role of a multidisciplinary approach for selection and management of heart transplant recipients.

Prevalence of Potential and Clinically Relevant Statin-Drug Interactions in Frail and Robust Older Inpatients.

PubMed

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

2015-10-01

A significant proportion of older people are prescribed statins and are also exposed to polypharmacy, placing them at increased risk of statin-drug interactions. To describe the prevalence rates of potential and clinically relevant statin-drug interactions in older inpatients according to frailty status. A cross-sectional study of patients aged ≥65 years who were prescribed a statin and were admitted to a teaching hospital between 30 July and 10 October 2014 in Sydney, Australia, was conducted. Data on socio-demographics, comorbidities and medications were collected using a standardized questionnaire. Potential statin-drug interactions were defined if listed in the Australian Medicines Handbook and three international drug information sources: the British National Formulary, Drug Interaction Facts and Drug-Reax(®). Clinically relevant statin-drug interactions were defined as interactions with the highest severity rating in at least two of the three international drug information sources. Frailty was assessed using the Reported Edmonton Frail Scale. A total of 180 participants were recruited (median age 78 years, interquartile range 14), 35.0% frail and 65.0% robust. Potential statin-drug interactions were identified in 10% of participants, 12.7% of frail participants and 8.5% of robust participants. Clinically relevant statin-drug interactions were identified in 7.8% of participants, 9.5% of frail participants and 6.8% of robust participants. Depending on the drug information source used, the prevalence rates of potential and clinically relevant statin-drug interactions ranged between 14.4 and 35.6% and between 14.4 and 20.6%, respectively. In our study of frail and robust older inpatients taking statins, the overall prevalence of potential statin-drug interactions was low and varied significantly according to the drug information source used.

Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective

PubMed Central

Oza, A.M.; Castonguay, V.; Tsoref, D.; Diaz–Padilla, I.; Karakasis, K.; Mackay, H.; Welch, S.; Weberpals, J.; Hoskins, P.; Plante, M.; Provencher, D.; Tonkin, K.; Covens, A.; Ghatage, P.; Gregoire, J.; Hirte, H.; Miller, D.; Rosen, B.; Maroun, J.; Buyse, M.; Coens, C.; Brady, M.F.; Stuart, G.C.E.

2011-01-01

Ovarian cancer is leading cause of gynecologic cancer mortality in Canada. To date, overall survival (os) has been the most-used endpoint in oncology trials because of its relevance and objectivity. However, as a result of various factors, including the pattern of sequential salvage therapies, measurement of os and collection of os data are becoming particularly challenging. Phase ii and iii trials have therefore adopted progression-free survival (pfs) as a more convenient surrogate endpoint; however, the clinical significance of pfs remains unclear. This position paper presents discussion topics and findings from a pan-Canadian meeting of experts that set out to evaluate the relevance of pfs as a valid endpoint in ovarian cancer;reach a Canadian consensus on the relevance of pfs in ovarian cancer; andtry to address how pfs translates into clinical benefit in ovarian cancer. Overall, the findings and the group consensus posit that future studies should ensure that trials are designed to evaluate pfs, os, and other clinically relevant endpoints such as disease-related symptoms or quality of life;incorporate interim futility analyses intended to stop accrual early when the experimental regimen is not active;stop trials early to declare superiority only when compelling evidence suggests that a new treatment provides benefit for a pre-specified, clinically relevant endpoint such as os or symptom relief; anddiscourage early release of secondary endpoint results when such a release might increase the frequency of crossover to the experimental intervention. PMID:21969808

Research as a standard of care in PICU

PubMed Central

Zimmerman, Jerry J.; Anand, Kanwaljeet J. S.; Meert, Kathleen L.; Willson, Douglas F.; Newth, Christopher J. L.; Harrison, Rick; Carcillo, Joseph A.; Berger, John; Jenkins, Tammara L.; Nicholson, Carol; Dean, J. Michael

2016-01-01

Background Excellence in clinical care coupled with basic and applied research reflects the maturation of a medical subspecialty, advances that field, and provides objective data for identifying best practices. Pediatric intensive care units (PICU) are uniquely suited for conducting translational and clinical research. Moreover, multiple investigations have reported that a majority of parents are interested in their children’s participation in clinical research, even when the research offers no direct benefit to their child. However, such activity may generate ethical conflict with bedside care providers trying to acutely identify the best approach for an individual critically ill child. Ultimately, this conflict may diminish enthusiasm for the generation of scientific evidence that supports application of evidence-based medicine into PICU clinical standard work. Objective Provide an overview of current state PICU clinical research strengths, liabilities, opportunities, and barriers, and contrast this with an established pediatric hematology-oncology iterative research model that constitutes a learning healthcare system. Design Narrative review of medical literature published in English. Conclusions Currently most PICU therapy is not evidence-based. Developing a learning healthcare system in the PICU integrates clinical research into usual practice and fosters a culture of evidence-based learning and continual care improvement. As PICU mortality has significantly decreased, identification and validation of patient-centered, clinically relevant research outcome measures other than mortality is essential for future clinical trial design. Because most pediatric critical illness may be classified as rare diseases, participation in research networks will facilitate iterative, collaborative, multi-institutional investigations that over time identify best practices to improve PICU outcomes. Despite real ethical challenges, critically ill children and their families should have the opportunity to participate in translational/clinical research whenever feasible. PMID:26513203

Efficacy of curcumin for age-associated cognitive decline: a narrative review of preclinical and clinical studies.

PubMed

Sarker, Marjana Rahman; Franks, Susan F

2018-04-21

Processes such as aberrant redox signaling and chronic low-grade systemic inflammation have been reported to modulate age-associated pathologies such as cognitive impairment. Curcumin, the primary therapeutic component of the Indian spice, Turmeric (Curcuma longa), has long been known for its strong anti-inflammatory and antioxidant activity attributable to its unique molecular structure. Recently, an interest in this polyphenol as a cognitive therapeutic for the elderly has emerged. The purpose of this paper is to critically review preclinical and clinical studies that have evaluated the efficacy of curcumin in ameliorating and preventing age-associated cognitive decline and address the translational progress of preclinical to clinical efficacy. PubMed, semantic scholar, and Google scholar searches were used for preclinical studies; and clinicaltrials.gov , the Australian and New Zealand clinical trials registry, and PubMed search were used to select relevant completed clinical studies. Results from preclinical studies consistently demonstrate curcumin and its analogues to be efficacious for various aspects of cognitive impairment and processes that contribute to age-associated cognitive impairment. Results of published clinical studies, while mixed, continue to show promise for curcumin's use as a therapeutic for cognitive decline but overall remain inconclusive at this time. Both in vitro and in vivo studies have found that curcumin can significantly decrease oxidative stress, systemic inflammation, and obstruct pathways that activate transcription factors that augment these processes. Future clinical studies would benefit from including evaluation of peripheral and cerebrospinal fluid biomarkers of dementia and behavioral markers of cognitive decline, as well as targeting the appropriate population.

2015 American College of Rheumatology Workforce Study: Supply and Demand Projections of Adult Rheumatology Workforce, 2015-2030.

PubMed

Battafarano, Daniel F; Ditmyer, Marcia; Bolster, Marcy B; Fitzgerald, John D; Deal, Chad; Bass, Ann R; Molina, Rodolfo; Erickson, Alan R; Hausmann, Jonathan S; Klein-Gitelman, Marisa; Imundo, Lisa F; Smith, Benjamin J; Jones, Karla; Greene, Kamilah; Monrad, Seetha U

2018-04-01

To describe the character and composition of the 2015 US adult rheumatology workforce, evaluate workforce trends, and project supply and demand for clinical rheumatology care for 2015-2030. The 2015 Workforce Study of Rheumatology Specialists in the US used primary and secondary data sources to estimate the baseline adult rheumatology workforce and determine demographic and geographic factors relevant to workforce modeling. Supply and demand was projected through 2030, utilizing data-driven estimations regarding the proportion and clinical full-time equivalent (FTE) of academic versus nonacademic practitioners. The 2015 adult workforce (physicians, nurse practitioners, and physician assistants) was estimated to be 6,013 providers (5,415 clinical FTE). At baseline, the estimated demand exceeded the supply of clinical FTE by 700 (12.9%). By 2030, the supply of rheumatology clinical providers is projected to fall to 4,882 providers, or 4,051 clinical FTE (a 25.2% decrease in supply from 2015 baseline levels). Demand in 2030 is projected to exceed supply by 4,133 clinical FTE (102%). The adult rheumatology workforce projections reflect a major demographic and geographic shift that will significantly impact the supply of the future workforce by 2030. These shifts include baby-boomer retirements, a millennial predominance, and an increase of female and part-time providers, in parallel with an increased demand for adult rheumatology care due to the growing and aging US population. Regional and innovative strategies will be necessary to manage access to care and reduce barriers to care for rheumatology patients. © 2018, American College of Rheumatology.

Biomarkers and surrogate endpoints in glaucoma clinical trials

PubMed Central

Medeiros, Felipe A

2015-01-01

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

Identification of a Heterozygous SPG11 Mutation by Clinical Exome Sequencing in a Patient With Hereditary Spastic Paraplegia: A Case Report.

PubMed

Oh, Ja-Young; Do, Hyun Jung; Lee, Seungok; Jang, Ja-Hyun; Cho, Eun-Hae; Jang, Dae-Hyun

2016-12-01

Next-generation sequencing, such as whole-genome sequencing, whole-exome sequencing, and targeted panel sequencing have been applied for diagnosis of many genetic diseases, and are in the process of replacing the traditional methods of genetic analysis. Clinical exome sequencing (CES), which provides not only sequence variation data but also clinical interpretation, aids in reaching a final conclusion with regards to genetic diagnosis. Sequencing of genes with clinical relevance rather than whole exome sequencing might be more suitable for the diagnosis of known hereditary disease with genetic heterogeneity. Here, we present the clinical usefulness of CES for the diagnosis of hereditary spastic paraplegia (HSP). We report a case of patient who was strongly suspected of having HSP based on her clinical manifestations. HSP is one of the diseases with high genetic heterogeneity, the 72 different loci and 59 discovered genes identified so far. Therefore, traditional approach for diagnosis of HSP with genetic analysis is very challenging and time-consuming. CES with TruSight One Sequencing Panel, which enriches about 4,800 genes with clinical relevance, revealed compound heterozygous mutations in SPG11 . One workflow and one procedure can provide the results of genetic analysis, and CES with enrichment of clinically relevant genes is a cost-effective and time-saving diagnostic tool for diseases with genetic heterogeneity, including HSP.

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

When to trust our learners? Clinical teachers' perceptions of decision variables in the entrustment process.

PubMed

Duijn, Chantal C M A; Welink, Lisanne S; Bok, Harold G J; Ten Cate, Olle T J

2018-06-01

Clinical training programs increasingly use entrustable professional activities (EPAs) as focus of assessment. However, questions remain about which information should ground decisions to trust learners. This qualitative study aimed to identify decision variables in the workplace that clinical teachers find relevant in the elaboration of the entrustment decision processes. The findings can substantiate entrustment decision-making in the clinical workplace. Focus groups were conducted with medical and veterinary clinical teachers, using the structured consensus method of the Nominal Group Technique to generate decision variables. A ranking was made based on a relevance score assigned by the clinical teachers to the different decision variables. Field notes, audio recordings and flip chart lists were analyzed and subsequently translated and, as a form of axial coding, merged into one list, combining the decision variables that were similar in their meaning. A list of 11 and 17 decision variables were acknowledged as relevant by the medical and veterinary teacher groups, respectively. The focus groups yielded 21 unique decision variables that were considered relevant to inform readiness to perform a clinical task on a designated level of supervision. The decision variables consisted of skills, generic qualities, characteristics, previous performance or other information. We were able to group the decision variables into five categories: ability, humility, integrity, reliability and adequate exposure. To entrust a learner to perform a task at a specific level of supervision, a supervisor needs information to support such a judgement. This trust cannot be credited on a single case at a single moment of assessment, but requires different variables and multiple sources of information. This study provides an overview of decision variables giving evidence to justify the multifactorial process of making an entrustment decision.