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Early clinical successes are driving enthusiasm for fecal microbiota transplantation (FMT), the transfer of healthy gut bacteria through whole stool, as emerging research is linking the microbiome to many different diseases. However, preliminary trials have yielded mixed results and suggest that heterogeneity in donor stool may play a role in patient response. Thus, clinical trials may fail because an ineffective donor was chosen rather than because FMT is not appropriate for the indication. Here, we describe a conceptual framework to guide rational donor selection to increase the likelihood that FMT clinical trials will succeed. We argue that the mechanism by which the microbiome is hypothesized to be associated with a given indication should inform how healthy donors are selected for FMT trials, categorizing these mechanisms into four disease models and presenting associated donor selection strategies. We next walk through examples based on previously published FMT trials and ongoing investigations to illustrate how donor selection might occur in practice. Finally, we show that typical FMT trials are not powered to discover individual taxa mediating patient responses, suggesting that clinicians should develop targeted hypotheses for retrospective analyses and design their clinical trials accordingly. Moving forward, developing and applying novel clinical trial design methodologies like rational donor selection will be necessary to ensure that FMT successfully translates into clinical impact. [ABSTRACT FROM AUTHOR]

Fundamental scientific advances can take decades to translate into improvements in human health. Shortening this interval would increase the rate at which scientific discoveries lead to successful treatment of human disease. One way to accomplish this would be to identify which advances in knowledge are most likely to translate into clinical research. Toward that end, we built a machine learning system that detects whether a paper is likely to be cited by a future clinical trial or guideline. Despite the noisiness of citation dynamics, as little as 2 years of postpublication data yield accurate predictions about a paper's eventual citation by a clinical article (accuracy = 84%, F1 score = 0.56; compared to 19% accuracy by chance). We found that distinct knowledge flow trajectories are linked to papers that either succeed or fail to influence clinical research. Translational progress in biomedicine can therefore be assessed and predicted in real time based on information conveyed by the scientific community's early reaction to a paper. [ABSTRACT FROM AUTHOR]

There is strong epidemiological evidence that poor diet is associated with depression. The reverse has also been shown, namely that eating a healthy diet rich in fruit, vegetables, fish and lean meat, is associated with reduced risk of depression. To date, only one randomised controlled trial (RCT) has been conducted with elevated depression symptoms being an inclusion criterion, with results showing that a diet intervention can reduce clinical levels of depression. No such RCTs have been performed in young adults. Young adults with elevated levels of depression symptoms and who habitually consume a poor diet were randomly allocated to a brief 3-week diet intervention (Diet Group) or a habitual diet control group (Control Group). The primary and secondary outcome measures assessed at baseline and after the intervention included symptoms of depression (Centre for Epidemiological Studies Depression Scale; CESD-R; and Depression Anxiety and Stress Scale– 21 depression subscale; DASS-21-D), current mood (Profile of Mood States), self-efficacy (New General Self-Efficacy Scale) and memory (Hopkins Verbal Learning Test). Diet compliance was measured via self-report questionnaires and spectrophotometry. One-hundred-and-one individuals were enrolled in the study and randomly assigned to the Diet Group or the Control Group. Upon completion of the study, there was complete data for 38 individuals in each group. There was good compliance with the diet intervention recommendations assessed using self-report and spectrophotometry. The Diet group had significantly lower self-reported depression symptoms than the Control Group on the CESD-R (p = 0.007, Cohen’s d = 0.65) and DASS-21 depression subscale (p = 0.002, Cohen’s d = 0.75) controlling for baseline scores on these scales. Reduced DASS-21 depression subscale scores were maintained on follow up phone call 3 months later (p = .009). These results are the first to show that young adults with elevated depression symptoms can engage in and adhere to a diet intervention, and that this can reduce symptoms of depression. The findings provide justification for future research into the duration of these benefits, the impacts of varying diet composition, and their biological basis. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) remains a morbid disease with poor prognosis and treatment that typically leaves patients with permanent damage to critical functions such as eating and talking. Currently only three targeted therapies are FDA approved for use in HNSCC, two of which are recently approved immunotherapies. In this work, we identify biological pathways involved with this disease that could potentially be targeted by current FDA approved cancer drugs and thereby expand the pool of potential therapies for use in HNSCC treatment. We analyzed 508 HNSCC patients with sequencing information from the Genomic Data Commons (GDC) database and assessed which biological pathways were significantly enriched for somatic mutations or copy number alterations. We then further classified pathways as either “light” or “dark” to the current reach of FDA-approved cancer drugs using the Cancer Targetome, a compendium of drug-target information. Light pathways are statistically enriched with somatic mutations (or copy number alterations) and contain one or more targets of current FDA-approved cancer drugs, while dark pathways are enriched with somatic mutations (or copy number alterations) but not currently targeted by FDA-approved cancer drugs. Our analyses indicated that approximately 35–38% of disease-specific pathways are in scope for repurposing of current cancer drugs. We further assess light and dark pathways for subgroups of patient tumor samples according to HPV status. The framework of light and dark pathways for HNSCC-enriched biological pathways allows us to better prioritize targeted therapies for further research in HNSCC based on the HNSCC genetic landscape and FDA-approved cancer drug information. We also highlight the importance in the identification of sub-pathways where targeting and cross targeting of other pathways may be most beneficial to predict positive or negative synergy with potential clinical significance. This framework is ideal for precision drug panel development, as well as identification of highly aberrant, untargeted candidates for future drug development. [ABSTRACT FROM AUTHOR]

Introduction: Despite increased treatment availability, HIV-infected individuals continue to start antiretroviral therapy (ART) late in disease progression, increasing early mortality risk. Materials and methods: Nested prospective cohort study within a randomized clinical trial of adult patients initiating ART at clinics in urban Nairobi and rural Maseno, Kenya, between 2013–2014. We estimated mortality incidence rates following ART initiation and used Cox proportional hazards regression to identify predictors of mortality within 12 months of ART initiation. Analyses were stratified by clinic site to examine differences in mortality correlates and risk by location. Results: Among 811 participants initiated on ART, the mortality incidence rate within a year of initiating ART was 7.44 per 100 person-years (95% CI 5.71, 9.69). Among 207 Maseno and 612 Nairobi participants initiated on ART, the mortality incidence rates (per 100 person-years) were 12.78 (95% CI 8.49, 19.23) and 5.72 (95% CI 4.05, 8.09). Maseno had a 2.20-fold greater risk of mortality than Nairobi (95% CI 1.29, 3.76; P = 0.004). This association remained [adjusted hazard ratio (HR) = 2.09 (95% CI 1.17, 3.74); P = 0.013] when adjusting for age, gender, education, pre-treatment drug resistance (PDR), and CD4 count, but not when adjusting for BMI. In unadjusted analyses, other predictors (P<0.05) of mortality included male gender (HR = 1.74), age (HR = 1.04 for 1-year increase), fewer years of education (HR = 0.92 for 1-year increase), unemployment (HR = 1.89), low body mass index (BMI<18.5 m/kg2; HR = 4.99), CD4 count <100 (HR = 11.67) and 100–199 (HR = 3.40) vs. 200–350 cells/μL, and pre-treatment drug resistance (PDR; HR = 2.49). The increased mortality risk associated with older age, males, and greater education remained when adjusted for location, age, education and PDR, but not when adjusted for BMI and CD4 count. PDR remained associated with increased mortality risk when adjusted for location, age, gender, education, and BMI, but not when adjusted for CD4 count. CD4 and BMI associations with increased mortality risk persisted in multivariable analyses. Despite similar baseline CD4 counts across locations, mortality risk associated with low CD4 count, low BMI, and PDR was greater in Maseno than Nairobi in stratified analyses. Conclusions: High short-term post-ART mortality was observed, partially due to low CD4 count and BMI at presentation, especially in the rural setting. Male gender, older age, and markers of lower socioeconomic status were also associated with greater mortality risk. Engaging patients earlier in HIV infection remains critical. PDR may influence short-term mortality and further studies to optimize management will be important in settings with increasing PDR. [ABSTRACT FROM AUTHOR]

Background: Active management of third stage of labor is the most indispensable intervention to avert post-partum hemorrhage which is one of the typical causes of maternal morbidity and mortality. Therefore, the aim of the study was to assess practice and factors associated with active management of third stage of labor among obstetric care providers in referral hospitals. Methods: Institution based cross-sectional study design was conducted from April 1–30, 2018. Simple random sampling technique was used to select a total of 356 obstetric care providers. Data were collected using pretested, structured and self-administered questionnaires. Data were entered to Epi data version 3.1 statistical software and exported to SPSS 23 for analysis. Bivariate and multivariate logistic regression analyses were performed to identify associated factors. P value <0.05 with 95% confidence level were used to declare statistical significance. Result: This study revealed that practice of active management of third stage of labor was 61.2%. Age group of 20–30 years [AOR = 1.95 (95%CI;1.13–3.38)], Being male obstetric care provider [AOR = 1.74 (95%CI;1.03–2.94)], having work experience ≥2 years [AOR = 1.95(95%CI;1.13–3.38)], availability of oxytocin [AOR = 5.46 (95%CI; 2.41–12.3)], having exposure to manage third stage of labor [AOR = 2.91(95%CI; 1.55–5.48)], and having good knowledge [AOR = 2.67 (95%CI; 1.46–4.90)], were the factors associated with practice. Conclusion: This study showed that practice of active management of third stage of labor was high. Age group between 20–30 years, being a male obstetric care provider, having ≥2years work experience, availability of oxytocin, exposure to third stage management and having good knowledge were factors associated with practice. Therefore, all referral hospitals and concerned bodies need efforts to focus on providing training to increase health care provider’s knowledge so as to sustain good practice through appropriate interventions. [ABSTRACT FROM AUTHOR]

Background and objective: Trial registration is widely endorsed as it is considered not only to enhance transparency and quality of reporting but also to help safeguard against outcome reporting bias and probably spin, known as specific reporting that could distort the interpretation of results thus mislead readers. We planned to investigate the current registration status of recently published randomized controlled trials (RCTs) of acupuncture, outcome reporting bias in the prospectively registered trials, and the association between trial registration and presence of spin and methodological factors in acupuncture RCTs. Methods: Acupuncture RCTs published in English in recent 5 years (January 2013 to December 2017) were searched in PubMed, Cochrane Central Register of Controlled Trials, and EMBASE. Trial registration records identified in the publications and trial registries were classified into prospectively registered, retrospectively registered, or unregistered. Primary outcomes were identified and the direction of the results was judged as statistically significant (positive) or statistically nonsignificant (negative). We compared registered and published primary outcomes to assess outcome reporting bias and assessed whether discrepancies favored statistically significant outcomes. Frequency and strategies of spin in published reports with statistically nonsignificant results for primary outcomes were then identified. We also analyzed whether the trial registration status was associated with spin and quality of methodological factors. Results: Of the 322 included RCTs, 41.9% (n = 135) were prospectively registered. Among 64 studies that were prospectively registered and specified primary outcomes, 25 trials had the discrepancies between the registered and published primary outcomes and 60% of them (15 trials) favored the statistically significant findings. Among 169 studies that specified primary outcomes, trial registration status was not associated with the direction of results, i.e., statistically significant or not. Spin was identified in 56.4% out of 78 studies with statistically nonsignificant primary outcomes and claiming efficacy with no consideration of statistically nonsignificant primary outcomes was the most common strategy for spin. Trial registration status was not statistically different between studies with and without spin. Conclusion: While trial registration seemed to have improved over time, primary outcomes in registered records and publications were often inconsistent, tending to favor statistically significant findings and spin was common in studies with statistically nonsignificant primary outcomes. Journal editors and researchers in this field should be alerted to still prevalent reporting bias and spin. [ABSTRACT FROM AUTHOR]

Background: It remains unknown which is the optimal first-line treatment regimen for patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). We performed a network meta-analysis to address this important issue. Methods: PubMed, Embase, Cochrane Library, Web of Science and major international scientific meetings were searched for relevant randomized controlled trials (RCTs). Progression-free survival (PFS) data was the primary outcome of interest, and overall survival (OS) and serious adverse events (SAEs) were the secondary outcomes of interests, reported as hazard ratio (HR) or odds ratio (OR) and 95% confidence intervals (CIs). Results: 25 RCTs with a total of 5005 patients randomized to receive seven treatments were included in the meta-analysis. Third-generation tyrosine kinase inhibitor (TKI) (osimertinib) and first-generation TKIs (F-TKIs) in combination with chemotherapy (F-TKIs+CT) were more effective than F-TKIs alone in terms of PFS (HR = 0.46, 95% CI: 0.22–0.93; P = 0.031 and HR = 0.62, 95% CI: 0.39–0.98; P = 0.041) and OS (HR = 0.63, 95% CI: 0.43–0.91; P = 0.014 and HR = 0.73, 95% CI: 0.57–0.92; P = 0.008). Second-generation TKIs (S-TKIs) showed significant OS advantage over F-TKIs (HR = 0.83, 95% CI: 0.70–0.99; P = 0.04). Based on treatment ranking in terms of PFS and OS, osimertinib had the highest probability of being the most effective treatment (89% and 86%) and with the best tolerability. F-TKIs+CT was ranked the second-most effective regimen, but with relatively high risk of SAEs. Conclusions: Osimertinib seemed to be the most preferable first-line treatment in advanced EGFR-mutated NSCLC. However, limitations of the study including a single RCT investigating osimertinib and immature OS data need to be considered. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii, has been developing resistance to even the last line of drugs. Antimicrobial peptides (AMPs) to which bacteria do not develop resistance easily may be the last hope. A few independent experimental studies have designed and studied the activity of AMPs on A. baumannii, however the number of such studies are still limited. With the goal of developing a rational approach to the screening of AMPs against A. baumannii, we carefully curated the drug activity data from 75 cationic AMPs, all measured with a similar protocol, and on the same ATCC 19606 strain. A quantitative model developed and validated with a part of the data. While the model may be used for predicting the activity of any designed AMPs, in this work, we perform an in silico screening for the entire database of naturally occurring AMPs, to provide a rational guidance in this urgently needed drug development. [ABSTRACT FROM AUTHOR]

Objective: We assessed the impact of intravenous (IV) infusion versus intramuscular (IM) oxytocin on postpartum blood loss and rates of postpartum hemorrhage (PPH) when administered during the third stage of labor. While oxytocin is recommended for prevention of PPH, few double-blind studies have compared outcomes by routes of administration. Methods: A double-blind, placebo-controlled randomized trial was conducted at a hospital in Argentina. Participants were assigned to receive 10 IU oxytocin via IV infusion or IM injection and a matching saline ampoule for the other route after vaginal birth. Blood loss was measured using a calibrated receptacle for a 1-hour minimum. Shock index (SI) was also calculated, based on vital signs measurements, and additional interventions were recorded. Primary outcomes included: the frequency of blood loss ≥500ml and mean blood loss. Results: 239 (IV infusion) and 241 (IM) women were enrolled with comparable baseline characteristics. Mean blood loss was 43ml less in the IV infusion group (p = 0.161). Rates of blood loss ≥500ml were similar (IV infusion = 21%; IM = 24%, p = 0.362). Women in the IV infusion group received significantly fewer additional uterotonics (5%), than women in the IM group (12%, p = 0.007). Women with PPH in the IM group experienced a larger increase in SI after delivery, which may have influenced recourse to additional interventions. Conclusions: The route of oxytocin administration for PPH prevention did not significantly impact measured blood loss after vaginal birth. However, differences were observed in recourse to additional uterotonics, favoring IV infusion over IM. In settings where IV lines are routinely placed, oxytocin infusion may be preferable to IM injection. [ABSTRACT FROM AUTHOR]

Human parasitic nematodes are the causative agents of lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness), diseases that are endemic to more than 80 countries and that consistently rank in the top ten for the highest number of years lived with disability. These filarial nematodes have evolved an obligate mutualistic association with an intracellular bacterium, Wolbachia, a symbiont that is essential for the successful development, reproduction, and survival of adult filarial worms. Elimination of the bacteria causes adult worms to die, making Wolbachia a primary target for developing new interventional tools to combat filariases. To further explore Wolbachia as a promising indirect macrofilaricidal drug target, the essential cellular processes that define the symbiotic Wolbachia-host interactions need to be identified. Genomic analyses revealed that while filarial nematodes encode all the enzymes necessary for glycolysis, Wolbachia does not encode the genes for three glycolytic enzymes: hexokinase, 6-phosphofructokinase, and pyruvate kinase. These enzymes are necessary for converting glucose into pyruvate. Wolbachia, however, has the full complement of genes required for gluconeogenesis starting with pyruvate, and for energy metabolism via the tricarboxylic acid cycle. Therefore, we hypothesized that Wolbachia might depend on host glycolysis to maintain a mutualistic association with their parasitic host. We did conditional experiments in vitro that confirmed that glycolysis and its end-product, pyruvate, sustain this symbiotic relationship. Analysis of alternative sources of pyruvate within the worm indicated that the filarial lactate dehydrogenase could also regulate the local intracellular concentration of pyruvate in proximity to Wolbachia and thus help control bacterial growth via molecular interactions with the bacteria. Lastly, we have shown that the parasite’s pyruvate kinase, the enzyme that performs the last step in glycolysis, could be a potential novel anti-filarial drug target. Establishing that glycolysis is an essential component of symbiosis in filarial worms could have a broader impact on research focused on other intracellular bacteria-host interactions where the role of glycolysis in supporting intracellular survival of bacteria has been reported. [ABSTRACT FROM AUTHOR]

Observational studies have demonstrated that de-escalation of antimicrobial therapy is independently associated with lower mortality. This most probably results from confounding by indication. Reaching clinical stability is associated with the decision to de-escalate and with survival. However, studies rarely adjust for this confounder. We quantified the potential confounding effect of clinical stability on the estimated impact of de-escalation on mortality in patients with community-acquired pneumonia. Data were used from the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA). The primary outcome was 30-day mortality. We performed Cox proportional-hazards regression with de-escalation as time-dependent variable and adjusted for baseline characteristics using propensity scores. The potential impact of unmeasured confounding was quantified through simulating a variable representing clinical stability on day three, using data on prevalence and associations with mortality from the literature. Of 1,536 included patients, 257 (16.7%) were de-escalated, 123 (8.0%) were escalated and in 1156 (75.3%) the antibiotic spectrum remained unchanged. Crude 30-day mortality was 3.5% (9/257) and 10.9% (107/986) in the de-escalation and continuation groups, respectively. The adjusted hazard ratio of de-escalation for 30-day mortality (compared to patients with unchanged coverage), without adjustment for clinical stability, was 0.39 (95%CI: 0.19–0.79). If 90% to 100% of de-escalated patients were clinically stable on day three, the fully adjusted hazard ratio would be 0.56 (95%CI: 0.27–1.12) to 1.04 (95%CI: 0.49–2.23), respectively. The simulated confounder was substantially stronger than any of the baseline confounders in our dataset. Quantification of effects of de-escalation on patient outcomes without proper adjustment for clinical stability results in strong negative bias. This study suggests the effect of de-escalation on mortality needs further well-designed prospective research to determine effect size more accurately. [ABSTRACT FROM AUTHOR]

Background: An earlier open label, prospective, non-randomized, non-comparative, multi-centric study conducted within public health facilities in Bihar, India (CTRI/2012/08/002891) measured the field effectiveness of three new treatment regimens for visceral leishmaniasis (VL): single dose AmBisome (SDA), and combination therapies of AmBisome and miltefosine (AmB+Milt) and miltefosine and paromomycin (Milt+PM) up to 6 months follow-up. The National Vector Borne Disease Control Program (NVBDCP) recommended an extended follow up at 12 months post-treatment of the original study cohort to quantify late relapses. Methods: The 1,761 patients enrolled in the original study with the three new regimens were contacted and traced between 10 and 36 months following completion of treatment to determine their health status and any occurrence of VL relapse. Results: Of 1,761 patients enrolled in the original study, 1,368 were traced at the extended follow-up visit: 711 (80.5%), 295 (83.2%) and 362 (71.5%) patients treated with SDA, AmB+Milt and Milt+PM respectively. Of those traced, a total of 75 patients were reported to have relapsed by the extended follow-up; 45 (6.3%) in the SDA, 25 (8.5%) in the AmB+Milt and 5 (1.4%) in the Milt+PM arms. Of the 75 relapse cases, 55 had already been identified in the 6-months follow-up and 20 were identified as new cases of relapse at extended follow-up; 7 in the SDA, 10 in the AmB+Milt and 3 in the Milt+PM arms. Conclusion: Extending follow-up beyond the standard 6 months identified additional relapses, suggesting that 12-month sentinel follow-up may be useful as a programmatic tool to better identify and quantify relapses. With limited drug options, there remains an urgent need to develop effective new chemical entities (NCEs) for VL. [ABSTRACT FROM AUTHOR]

Background: Commercial or industry funding is associated with outcomes that favour the study funder in published studies, across various areas of research. However, it is currently unclear whether there are differences between trials with and without industry involvement at the stage of trial registration. Objective: To determine whether industry involvement (industry sponsorship, funding, or collaboration) is associated with trial characteristics at the time of trial registration. Methods: We conducted a cross-sectional analysis of all interventional studies registered on the Australian New Zealand Clinical Trials Registry in 2017 and classified them by industry involvement. We analysed whether there were differences in study characteristics (including type of control, sample size, study phase, randomisation, registration timing, and purpose of study) by industry involvement. Results: Industry involvement was reported by 21% of the 1,433 included trials. Only 40% of trials with industry involvement used an active control compared to 58% of non-industry trials (OR = 0.49, 95%CI = 0.38 to 0.63, p < .001), and industry trials reported smaller sample sizes (Median(IQR)industry = 45(24–100), Median(IQR)non-industry = 70(35–160), Mean Difference = -153, 95% CI = -233 to -75, p < .001). Industry trials were more likely to be earlier phase trials (Χ2(df) = 71.46(4), p < .001). There was no difference in use of randomisation between industry (70%) and non-industry trials (73%) (OR = 0.88, 95%CI = 0.67–1.20, p = .38). Eighty-three percent of industry trials compared to 70% of non-industry trials were prospectively registered (OR = 2.02, 95%CI = 1.47–2.82, p < .001). Industry trials were more likely to assess treatment (85%), rather than prevention, education or diagnosis compared to non-industry trials (64%) (OR = 3.02, 95%CI = 2.17–4.32, p < .001). Conclusion: The current study gives insight into differences in trial characteristics by industry involvement at registration stage. There was a reduced use of active controls in trials with industry involvement which has previously been proposed as a mechanism behind more favourable results. Non-industry funders and sponsors are crucial to ensure research addresses not only treatments, but also prevention, diagnosis and education questions. [ABSTRACT FROM AUTHOR]

In pediatric burns the use of systemic antibiotic prophylaxis is a standard procedure in some burn centers, though its beneficial effect on the infectious complications is debated. The present meta-analysis aimed at determining whether systemic antibiotic prophylaxis prevents infectious complications in pediatric patients with burn injuries. We searched the PubMed, EMBASE, and Cochrane Library databases from inception to August 2019. We included 6 studies, in which event rates of infectious complications were reported in children with burn injuries receiving or not receiving systemic antibiotic prophylaxis. We found that the overall odds ratio (OR) of developing an infection (including local and systemic) was not different between the groups (OR = 1.35; 95% CI, 0.44, 4.18). The chances for systemic infectious complications alone were also not different between antibiotic-treated and non-treated patients (OR = 0.74; 95% CI, 0.38, 1.45). Based on the age, affected total body surface area, and country income level, we did not find any subgroup that benefited from the prophylaxis. Our findings provide quantitative evidence for the inefficacy of systemic antibiotic prophylaxis in preventing infections in pediatric burns. To validate our conclusion, multinational, randomized trials in a diverse population of children with burn injuries are warranted. [ABSTRACT FROM AUTHOR]

Novel manipulations of the well-established multivariate calibration models namely; partial least square regression (PLSR) and support vector regression (SVR) are introduced in the presented comparative study. Two preprocessing methods comprising first derivatization and orthogonal projection to latent structures (OPLS) are implemented prior to modeling with PLSR and SVR. Quantitative determination of pyridostigmine bromide (PR) in existence of its two associated substances; impurity a (IMP A) and impurity b (IMP B); was utilized as a case study for achieving comparison. A series consisting of 16 mixtures with numerous percentages of the studied compounds was applied for implementation of a 3 factor 4 level experimental design. Additionally, a series consisting of 9 mixtures was employed in an independent test to verify the predictive power of the suggested models. Significant improvement of predictive abilities of the two studied chemometric models was attained via implementation of OPLS processing method. The root mean square error of prediction RMSEP for the test set mixtures was employed as a key comparison tool. About PLSR model, RMSEP was found 0.5283 without preprocessing method, 1.1750 when first derivative data was used and 0.2890 when OPLS preprocessing method was applied. With regard to SVR model, RMSEP was found 0.2173 without preprocessing method, 0.3516 when first derivative data was used and 0.1819 when OPLS preprocessing method was applied. [ABSTRACT FROM AUTHOR]

Background: Transcatheter aortic valve implantation (TAVI) is an option for treatment for patients with severe aortic stenosis who are at high risk for death with surgical aortic valve replacement (SAVR). It is unknown whether TAVI can be safely introduced to intermediate- and low-risk patients. Objective: To compare the efficacy and safety of TAVI and SAVR in patients with intermediate- and low-surgical risk. Data sources: Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception to April 15, 2019. Study selection: We included randomized controlled trials comparing TAVI with SAVR in patients with intermediate- and low-surgical risk. Data extraction: Meta-analyses were conducted using random-effects models to calculate risk ratios (RR) with corresponding 95% confidence interval (CI). Two independent reviewers completed citation screening, data abstraction, and risk assessment. Primary outcome was a composite of all-cause mortality or disabling stroke at 12 months. Data Synthesis: A total of 5 trials randomizing 6390 patients were included. In patients with low risk, TAVI was associated with a significant reduction in the composite of all-cause mortality or disabling stroke compared with SAVR (RR, 0.56; 95%CI, 0.40–0.79; I2 = 0%). This benefit was not replicated in patients with intermediate risk (RR, 0.96; 95% CI, 0.80–1.15; I2 = 0%). Similar results were seen separately in all-cause mortality and disabling stroke when TAVI was compared with SAVR. Conclusion: For patients with severe aortic stenosis who were at low risk for death from surgery, TAVI achieved superior clinical outcomes compared to SAVR; however, these benefits were not seen in those with intermediate risk. This information may inform discussions about deciding between SAVR and TAVI for patients with low to intermediate risk separately. [ABSTRACT FROM AUTHOR]

Background: The Cochrane risk of bias (CROB) tool and Physiotherapy Evidence Database (PEDro) scale are used to evaluate risk of bias of randomized controlled trials. We assessed the level of agreement between the instruments. Methods: We searched the Cochrane Library to identify trials included in systematic reviews evaluating physical therapy interventions. For trials that met our inclusion criteria (primary reference in Cochrane review, review used CROB (2008 version), indexed in PEDro), CROB items were extracted from the reviews and PEDro items and total score were downloaded from PEDro. Kappa statistics were used to determine the agreement between CROB and PEDro scale items that evaluate similar constructs (e.g., randomization). The total PEDro score was compared to the CROB summary score (% of items met) using an Intraclass Correlation Coefficient. Sensitivity analyses explored the impact of the CROB “unclear” category and variants of CROB blinding items. Kappa statistics were used to determine agreement between different thresholds for “acceptable” risk of bias between CROB and PEDro scale summary scores. Results: We included 1442 trials from 108 Cochrane reviews. Agreement was “moderate” for three of the six CROB and PEDro scale items that evaluate similar constructs (allocation concealment, participant blinding, assessor blinding; Kappa = 0.479–0.582). Agreement between the summary scores was “poor” (Intraclass Correlation Coefficient = 0.285). Agreement was highest when the CROB “unclear” category was collapsed with “high” and when participant, personnel and assessor blinding were evaluated separately in CROB. Agreement for different thresholds for “acceptable” risk of bias between CROB and PEDro summary scores was, at best, “fair”. Conclusion: There was moderate agreement for half of the PEDro and CROB items that evaluate similar constructs. Interpretation of the CROB “unclear” category and variants of the CROB blinding items substantially influenced agreement. Either instrument can be used to quantify risk of bias, but they can’t be used interchangeably. [ABSTRACT FROM AUTHOR]

Stewart Cole and colleagues determined the complete genome sequence of Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), in 1998 []. This was a landmark achievement that heralded a new age in TB drug discovery. With the genome sequence in hand, drug discoverers suddenly had thousands of new potential targets to explore. But the excitement has since faded []. It is unquestioned that genomics has transformed our understanding of the biology of this pathogen. However, the expectation that the Mtb genome sequence would rapidly lead to new therapeutic interventions remains unfulfilled []. One of the (many) reasons for this unrealized potential is that our tools to systematically interrogate the Mtb genome and its drug targets—so-called functional genomics—have been limited. In this Pearl, I argue that the recent development of robust CRISPR-based genetics in Mtb [] overcomes many prior limitations and holds the potential to close the gap between genomics and TB drug discovery. [ABSTRACT FROM AUTHOR]

Objective: To analyze the relationships between insight, medication adherence, addiction, coping and social support—components of Illness Management and Recovery (IMR)—as determinants of clinical, functional and personal recovery in patients with schizophrenia and other severe mental illnesses. Our rationale lay in the interrelations between these concepts suggested in a conceptual framework of IMR. Methods: The cross-sectional design used baseline data of outpatient participants in a randomized clinical trial on IMR (N = 187). We used structural equation modeling (SEM) to describe pathways between degrees of insight, medication adherence, addiction, coping and social support, and degree of clinical, functional and personal recovery. We also explored whether clinical recovery mediated functional and personal recovery. Results: Our final model showed that coping was associated with clinical, functional and personal recovery. Direct associations between coping and functional and personal recovery were stronger than indirect associations via clinical recovery. Although SEM also showed a significant but weak direct pathway between social support and functional recovery, there were no significant pathways either between social support and clinical or personal recovery, or between insight, medication adherence, addiction and any type of recovery. Conclusions: Coping may be a determinant of all three types of recovery, and social support a determinant of functional recovery. Clinical recovery appears not to be a prerequisite for functional or personal recovery. While our results also suggest the relevance of improving coping skills and of enhancing social support, they only partially support the conceptual framework of IMR. [ABSTRACT FROM AUTHOR]

Introduction: Artemisinin-based combination therapy is currently the best option for the treatment of uncomplicated malaria. Quinine is recommended as a rescue treatment. Safety information during repeated treatment with the same drug is scarce. We report safety data from the Quinact randomized clinical trial (RCT) that was designed to assess efficacy and safety of artesunate-amodiaquine (ASAQ), artemether-lumefantrine (AL) and quinine+clindamycin (QnC). Methodology: Males and females aged 12 to 59 months with uncomplicated malaria were treated with ASAQ and followed up during 42 days (preRCT). Clinical failures were randomized to one of the 3 treatments and followed up for 28 days (RCT). Subsequent failures were repeatedly treated with ASAQ several times as needed (postRCT1, postRCT2 and so on) until a 28-days follow up period without parasitaemia. Results: Eight hundred and sixty-five, 242 and 64 patients were recruited respectively in preRCT, RCT and postRCTs. In preRCT, 433 (50.0%) patients experienced at least one drug-related adverse event (AE). The most reported AEs were anorexia (22.9%), asthenia (19.4%), and abnormal behavior (14.6%). Twenty-nine AEs (3.5%) were reported to be severe. In RCT, at least one drug-related AE was reported in 54.7%, 21.5% and 40.0% of patient randomized respectively to ASAQ, AL and QnC (p<0.001). During postRCT1 (n = 64), postRCT 2 (n = 17) and postRCT3 (n = 7), respectively 32.8%, 35.3% and 71.4% of patients experienced at least one drug-related AE. Three serious adverse events occurred but not judged related to study medication. Conclusion: The proportion of AEs did not increase over the treatment courses with ASAQ. However, continuous monitoring is important. [ABSTRACT FROM AUTHOR]

Background: Core outcome sets (COS) have the potential to reduce waste in research by improving the consistency of outcomes measured in trials of the same health condition. However, this reduction in waste will only be realised through the uptake of COS by clinical trialists. Without uptake, the continued development of COS that are not implemented may add to waste in research. Funders of clinical trials have the potential to have an impact on COS uptake by recommending their use to those applying for funding. The aim of our study was to assess the extent to which applicants followed the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme’s recommendation to search for a COS to include in their clinical trial. Methods and findings: We examined the outcomes section and detailed project descriptions of all 95 researcher-led primary research applications submitted to the NIHR HTA between January 2012, when the recommendation to search for a COS was included in the guidance for applicants, and December 2015 for evidence that a search for a COS had taken place and rationale for outcome choice in the absence of COS. A survey of applicants was conducted to further explore their use of COS and choice of outcomes with a response rate of 49%. Nine out of 95 applicants (10%) stated in their application that they had searched the COMET (Core Outcome Measures for Effectiveness Trials) Initiative database for a COS and another nine referred to searching for a COS using another method, e.g. a review of the literature. Of the 77 (81%) applicants that did not mention COMET or COS in their application, eight stated in the survey that they had searched the COMET database and ten carried out a search using another method. Some applicants who did not search for a COS gave reasons for their choice of outcomes including taking advice from patients and the public and choosing outcomes used in previous trials. Conclusion: A funding body can have an impact on COS uptake by encouraging trialists to search for a COS. Funders could take further steps by putting processes in place to prompt applicants to be explicit about searching for COS in their application and notifying the funding board if a search has not taken place. The sources of information used by trialists to make decisions about outcomes in the absence of COS may suggest methods of dissemination for COS. [ABSTRACT FROM AUTHOR]

Background: In situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorisation (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorisation recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorisation remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and postauthorisation measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorised through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies.Methods and Findings: We used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorised through CMA or AA pathways during January 1, 2011 to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomised controlled trials supporting the surrogate-clinical outcome relationship were rated as 'validated'. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorised based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being 'reasonably likely' (n = 30; 61%) or of having 'biological plausibility' (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorisations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalisable to products authorised through the standard assessment pathway.Conclusions: The pivotal trial evidence supporting marketing authorisations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorisations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, postauthorisation measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorisation holders. [ABSTRACT FROM AUTHOR]

Concerns about the extent to which graduate programs adequately prepare students for the workplace have prompted numerous calls for reform. Understanding what employers look for in doctoral graduates can help schools better align graduate training with workplace needs. Twelve pharmaceutical scientists across diverse specialties and career pathways described the skills considered requisite for success in today’s science economy. Depth and breadth of knowledge, communication, collaboration, adaptability, research productivity, experiential training, and motivation and drive were among the themes identified. These results can be used to inform the development of doctoral curricula in the biomedical sciences. [ABSTRACT FROM AUTHOR]

Background: Suicide prevention is a global priority. Despite the focus on primary care in suicide prevention, little is known about the contributory role of community pharmacists and nothing about the role of the wider community pharmacy team in this area. We aimed to explore the current and potential role of community pharmacy teams in self-harm and suicide prevention. Methods: We conducted one-to-one semi-structured qualitative interviews with community pharmacy staff (pharmacists, pre-registration pharmacists, pharmacy technicians, dispensing/pharmacy assistants, delivery drivers) in the North West of England, UK. We identified themes from the interview transcripts through an iterative process of inductive thematic analysis. Results: We conducted twenty-five interviews with community pharmacy staff. Many described examples of helping those who were contemplating suicide or self-harm. No participants had received suicide prevention training. We identified six themes. The first two themes (i) Relationship with Patient and (ii) Pharmacy environment were seen as facilitators, which, if supported by (iii) Training, could underpin the final three themes: (iv) Opportunities for contact, (v) Facilitated referral pathway and (v) Restricting access to means. The distinct lack of training should be overcome with evidence-informed training. Referral pathways should be clear and enable direct and accessible referral by community pharmacy teams. There are opportunities for existing pharmacy services and schemes to be adapted to maximise suicide and self-harm prevention activities. Pharmacy teams did not identify themselves to have a clear role in restricting access to medication. Conclusions: Pharmacy teams already support patients in relation to self-harm and suicide, often relying on their personal experience in the absence of formal training. With the implementation of evidence-informed training and clear referral pathways, this could be done in a more effectively. [ABSTRACT FROM AUTHOR]

Christian Lienhardt and colleagues discuss the importance of communication and coordination between regulators, researchers, and policy makers to ensure tuberculosis trials provide high-quality evidence for policy decisions. [ABSTRACT FROM AUTHOR]

In-silico identification of potential target genes for disease is an essential aspect of drug target discovery. Recent studies suggest that successful targets can be found through by leveraging genetic, genomic and protein interaction information. Here, we systematically tested the ability of 12 varied algorithms, based on network propagation, to identify genes that have been targeted by any drug, on gene-disease data from 22 common non-cancerous diseases in OpenTargets. We considered two biological networks, six performance metrics and compared two types of input gene-disease association scores. The impact of the design factors in performance was quantified through additive explanatory models. Standard cross-validation led to over-optimistic performance estimates due to the presence of protein complexes. In order to obtain realistic estimates, we introduced two novel protein complex-aware cross-validation schemes. When seeding biological networks with known drug targets, machine learning and diffusion-based methods found around 2-4 true targets within the top 20 suggestions. Seeding the networks with genes associated to disease by genetics decreased performance below 1 true hit on average. The use of a larger network, although noisier, improved overall performance. We conclude that diffusion-based prioritisers and machine learning applied to diffusion-based features are suited for drug discovery in practice and improve over simpler neighbour-voting methods. We also demonstrate the large impact of choosing an adequate validation strategy and the definition of seed disease genes. [ABSTRACT FROM AUTHOR]

Pathway analysis is widely used to gain mechanistic insights from high-throughput omics data. However, most existing methods do not consider signal integration represented by pathway topology, resulting in enrichment of convergent pathways when downstream genes are modulated. Incorporation of signal flow and integration in pathway analysis could rank the pathways based on modulation in key regulatory genes. This implementation can be facilitated for large-scale data by discrete state network modeling due to simplicity in parameterization. Here, we model cellular heterogeneity using discrete state dynamics and measure pathway activities in cross-sectional data. We introduce a new algorithm, Boolean Omics Network Invariant-Time Analysis (BONITA), for signal propagation, signal integration, and pathway analysis. Our signal propagation approach models heterogeneity in transcriptomic data as arising from intercellular heterogeneity rather than intracellular stochasticity, and propagates binary signals repeatedly across networks. Logic rules defining signal integration are inferred by genetic algorithm and are refined by local search. The rules determine the impact of each node in a pathway, which is used to score the probability of the pathway’s modulation by chance. We have comprehensively tested BONITA for application to transcriptomics data from translational studies. Comparison with state-of-the-art pathway analysis methods shows that BONITA has higher sensitivity at lower levels source node modulation and similar sensitivity at higher levels of source node modulation. Application of BONITA pathway analysis to previously validated RNA-sequencing studies identifies additional relevant pathways in in-vitro human cell line experiments and in-vivo infant studies. Additionally, BONITA successfully detected modulation of disease specific pathways when comparing relevant RNA-sequencing data with healthy controls. Most interestingly, the two highest impact score nodes identified by BONITA included known drug targets. Thus, BONITA is a powerful approach to prioritize not only pathways but also specific mechanistic role of genes compared to existing methods. BONITA is available at: . [ABSTRACT FROM AUTHOR]

Background: There has been a growing interest in understanding the effects of social networks on health-related behaviour, with a particular backdrop being the emerging prominence of complexity or systems science in public health. Social network interventions specifically use or alter the characteristics of social networks to generate, accelerate, or maintain health behaviours. We conducted a systematic review and meta-analysis to investigate health behaviour outcomes of social network interventions.Methods and Findings: We searched eight databases and two trial registries from 1990 to May 28, 2019, for English-language reports of randomised controlled trials (RCTs) and before-and-after studies investigating social network interventions for health behaviours and outcomes. Trials that did not specifically use social networks or that did not include a comparator group were excluded. We screened studies and extracted data from published reports independently. The primary outcome of health behaviours or outcomes at ≤6 months was assessed by random-effects meta-analysis. Secondary outcomes included those measures at >6-12 months and >12 months. This study is registered with the International Prospective Register of Systematic Reviews, PROSPERO: CRD42015023541. We identified 26,503 reports; after exclusion, 37 studies, conducted between 1996 and 2018 from 11 countries, were eligible for analysis, with a total of 53,891 participants (mean age 32.4 years [SD 12.7]; 45.5% females). A range of study designs were included: 27 used RCT/cluster RCT designs, and 10 used other study designs. Eligible studies addressed a variety of health outcomes, in particular sexual health and substance use. Social network interventions showed a significant intervention effect compared with comparator groups for sexual health outcomes. The pooled odds ratio (OR) was 1.46 (95% confidence interval [CI] 1.01-2.11; I2 = 76%) for sexual health outcomes at ≤6 months and OR 1.51 (95% CI 1.27-1.81; I2 = 40%) for sexual health outcomes at >6-12 months. Intervention effects for drug risk outcomes at each time point were not significant. There were also significant intervention effects for some other health outcomes including alcohol misuse, well-being, change in haemoglobin A1c (HbA1c), and smoking cessation. Because of clinical and measurement heterogeneity, it was not appropriate to pool data on these other behaviours in a meta-analysis. For sexual health outcomes, prespecified subgroup analyses were significant for intervention approach (p < 0.001), mean age of participants (p = 0.002), and intervention length (p = 0.05). Overall, 22 of the 37 studies demonstrated a high risk of bias, as measured by the Cochrane Risk of Bias tool. The main study limitations identified were the inclusion of studies of variable quality; difficulty in isolating the effects of specific social network intervention components on health outcomes, as interventions included other active components; and reliance on self-reported outcomes, which have inherent recall and desirability biases.Conclusions: Our findings suggest that social network interventions can be effective in the short term (<6 months) and longer term (>6 months) for sexual health outcomes. Intervention effects for drug risk outcomes at each time point were not significant. There were also significant intervention effects for some other health outcomes including alcohol misuse, well-being, change in HbA1c, and smoking cessation. [ABSTRACT FROM AUTHOR]

Background: Randomized clinical trials compare participants receiving an experimental intervention to participants receiving standard of care (SOC). If one could predict the outcome for participants receiving SOC, a trial could be designed where all participants received the experimental intervention, with the observed outcome of the experimental group compared to the prediction for those individuals. Methods: We used the CancerMath calculator to predict outcomes for participants in two large clinical trials of adjuvant chemotherapy for breast cancer: NSABPB15 and CALGB9344. NSABPB15 was the training set, and we used the modified algorithm to predict outcomes for two groups from CALGB9344: one which received standard of care (SOC) chemotherapy and one which received paclitaxel in addition. We made a prediction for each individual CALGB9344 participant, assuming each received only SOC. Results: The predicted outcome for the group which received only SOC matched what was observed in the CALGB9344 trial. In contrast, the predicted outcome for the group also receiving paclitaxel was significantly worse than what was observed for this group. This matches the conclusion of CALGB9344 that adding paclitaxel to SOC improves survival. Conclusion: This project proves that a statistical model can predict the outcome of clinical trial participants treated with SOC. In some circumstances, a predictive model could be used instead of a control arm, allowing all participants to receive experimental treatment. Predictive models for cancer and other diseases could be constructed using the vast amount of outcomes data available to the federal government, and made available for public use. [ABSTRACT FROM AUTHOR]

Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and complicates interpretation of clinical studies. We hypothesised that boys with DMD could be clustered into groups sharing similar trajectories of ambulatory function over time, as measured by the North Star Ambulatory Assessment (NSAA) total score. We also explored associations with other variables such as age, functional abilities, and genotype. Using the NorthStar Clinical Network database, 395 patients with >1 NSAA assessment were identified. We utilised latent class trajectory analysis of longitudinal NSAA scores, which produced evidence for at least four clusters of boys sharing similar trajectories versus age in decreasing order of clinical severity: 25% of the boys were in cluster 1 (NSAA falling to ≤ 5 at age ~10y), 35% were in cluster 2 (NSAA ≤ 5 ~12y), 21% in were cluster 3 (NSAA≤ 5 ~14y), and 19% in cluster 4 (NSAA > 5 up to 15y). Mean ages at diagnosis of DMD were similar across clusters (4.2, 3.9, 4.3, and 4.8y, respectively). However, at the first NSAA assessment, a significant (p<0.05) association was observed between earlier declining clusters and younger age, worse NSAA, slower rise from supine, slower 10 metre walk/run times, and younger age of steroid initiation. In order to assess the probability of observing complete loss of function for individual NSAA items, we examined the proportion of patients who shifted from a score of 1 or 2 at baseline to a score of 0. We also assessed the probability of gain of function using the inverse assessment and stratified the probability of deterioration, improvement–or static behavior–by age ranges and using baseline functional status. Using this tool, our study provides a comprehensive assessment of the NSAA in a large population of patients with DMD and, for the first time, describes discrete clusters of disease progression; this will be invaluable for future DMD clinical trial design and interpretation of findings. [ABSTRACT FROM AUTHOR]

Objectives: To analyze health effects of mindfulness- and acceptance-based interventions, including mindfulness-based stress reduction (MBSR), mindfulness-based cognitive therapy (MBCT) and acceptance and commitment therapy (ACT). Additionally, we aimed to explore content and delivery components in terms of procedure, instructors, mode, length, fidelity and adherence in the included interventions. Methods: We performed a systematic literature search in the databases MEDLINE, PsychINFO, CINAHL, EMBASE, Cochrane Central and AMED from 1990 to January 2019. We included randomized and quasi-randomized controlled trials analyzing health effects of mindfulness- and acceptance-based interventions for patients with fibromyalgia compared to no intervention, wait-list control, treatment as usual, or active interventions. MBSR combined with other treatments were included. Predefined outcomes were pain, fatigue, sleep quality, psychological distress, depression, anxiety, mindfulness, health-related quality of life and work ability. The Template for Intervention Description and Replication (TIDieR) checklist and guide was used to explore content and delivery components in the interventions. Meta-analyses were performed, and GRADE was used to assess the certainty in the evidence. Results: The search identified 4430 records, of which nine original trials were included. The vast majority of the participants were women. The analyses showed small to moderate effects in favor of mindfulness- and acceptance-based interventions compared to controls in pain (SMD -0.46 [95% CI -0.75, -0.17]), depression (SMD -0.49 [95% CI -0.85, -0.12]), anxiety (SMD -0.37 [95% CI -0.71, -0.02]), mindfulness (SMD -0.40 [-0.69, -0.11]), sleep quality (SMD -0.33 [-0.70, 0.04]) and health-related quality of life (SMD -0.74 [95% CI -2.02, 0.54]) at end of treatment. The effects are uncertain due to individual study limitations, inconsistent results and imprecision. Conclusion: Health effects of mindfulness- and acceptance-based interventions for patients with fibromyalgia are promising but uncertain. Future trials should consider investigating whether strategies to improve adherence and fidelity of mindfulness- and acceptance-based interventions can improve health outcomes. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma (PC) is a lethal malignancy that is familial or associated with genetic syndromes in 10% of cases. Gene-based surveillance strategies for at-risk individuals may improve clinical outcomes. However, familial PC (FPC) is plagued by genetic heterogeneity and the genetic basis for the majority of FPC remains elusive, hampering the development of gene-based surveillance programs. The study was powered to identify genes with a cumulative pathogenic variant prevalence of at least 3%, which includes the most prevalent PC susceptibility gene, BRCA2. Since the majority of known PC susceptibility genes are involved in DNA repair, we focused on genes implicated in these pathways. We performed a region-based association study using the Mixed-Effects Score Test, followed by leave-one-out characterization of PC-associated gene regions and variants to identify the genes and variants driving risk associations. We evaluated 398 cases from two case series and 987 controls without a personal history of cancer. The first case series consisted of 109 patients with either FPC (n = 101) or PC at ≤50 years of age (n = 8). The second case series was composed of 289 unselected PC cases. We validated this discovery strategy by identifying known pathogenic BRCA2 variants, and also identified SMG1, encoding a serine/threonine protein kinase, to be significantly associated with PC following correction for multiple testing (p = 3.22x10-7). The SMG1 association was validated in a second independent series of 532 FPC cases and 753 controls (p<0.0062, OR = 1.88, 95%CI 1.17–3.03). We showed segregation of the c.4249A>G SMG1 variant in 3 affected relatives in a FPC kindred, and we found c.103G>A to be a recurrent SMG1 variant associating with PC in both the discovery and validation series. These results suggest that SMG1 is a novel PC susceptibility gene, and we identified specific SMG1 gene variants associated with PC risk. [ABSTRACT FROM AUTHOR]

Background and purpose: Few data are available concerning the safety of bevacizumab (B) in combination with locoregional radiation therapy (RT). The objective of this study was to evaluate the 5-year late toxicity of concurrent B and RT in non-metastatic breast cancer. Materials and methods: This multicentre prospective study included non-metastatic breast cancer patients enrolled in phase 3 clinical trials evaluating B with concurrent RT versus RT alone. All patients received neoadjuvant or adjuvant chemotherapy and normofractionated breast or chest wall RT, with or without regional lymph node RT. B was administered at an equivalent dose of 5 mg/kg once a week for 1 year. The safety profile was evaluated 1, 3 and 5 years after completion of radiotherapy. Results: A total of 64 patients were included between November 2007 and April 2010. Median follow-up was 60 months (12–73) and 5-year late toxicity data were available for 46 patients. The majority of tumours were triple-negative (68.8%), tumour size <2cm (41.3%) with negative nodal status (50.8%). Median total dose of B was 15,000mg and median duration was 11.2 months. No grade ≥3 toxicity was observed. Only 8 patients experienced grade 1–2 toxicities: n = 3 (6.5%) grade 1 lymphedema, n = 2 (4.3%) grade 1 pain, n = 1 (2.2%) grade 2 lymphedema, n = 1 (2.2%) grade 1 fibrosis. Five-year overall survival was 93.8%, disease-free survival was 89% and locoregional recurrence-free survival was 93.1%. Conclusion: Concurrent B and locoregional RT are associated with acceptable 5-year toxicity in patients with non-metastatic breast cancer. No grade ≥3 toxicity was observed. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency is associated with decreased cellular immunity, which may predispose patients with iron deficiency anemia (IDA) to increased risk of developing tuberculosis (TB). This study investigated the relationship between newly diagnosed IDA and TB infection in Taiwan. Methods: The study included data on 21,946 patients with incident IDA and 87,555 non-IDA controls from a national database covering the period 2000–2012. IDA and non-IDA subjects were matched 1:4 on age, gender, and index year. The follow-up period was defined as the time from the initial IDA diagnosis to the date of developing TB or 31 December 2013. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals, with the control group as the reference. Results: The adjusted hazard ratio of TB for the IDA group was 1.99 (95% confidence interval, 1.77–2.25) compared with the control group. The subgroup analysis showed that for both genders, all age groups, and patients with diabetes mellitus, hyperlipidemia, hypertension, cancer, chronic obstructive pulmonary disease, and hepatitis B virus infection, the IDA group had significantly higher TB incidence. The association was significantly stronger within the 5 years after new IDA diagnosis for both genders and all age groups. Conclusions: Higher TB incidence was discovered in the IDA group, especially for patients with comorbidities. [ABSTRACT FROM AUTHOR]

Deficits in general emotion regulation skills have been shown to be associated with various mental disorders. Thus, general affect-regulation training has been proposed as promising transdiagnostic approach to the treatment of psychopathology. In the present study, we aimed to evaluate the efficacy of a general affect-regulation as a stand-alone, group-based treatment for depression. For this purpose, we randomly assigned 218 individuals who met criteria for major depressive disorder (MDD) to the Affect Regulation Training (ART), to a waitlist control condition (WLC), or to a condition controlling for common factors (CFC). The primary outcome was the course of depressive symptom severity as assessed with the Hamilton Rating Scale for Depression and the Beck Depression Inventory. Multi-level analyses indicated that participation in ART was associated with a greater reduction of depressive symptom severity than was participation in WLC (d = 0.56), whereas the slight superiority of ART over CFC (d = 0.25) was not statistically significant. Mediation analyses indicated that changes in emotion regulation skills mediated the differences between ART/CFC and WLC. Thus, the findings provide evidence for enhancing emotion regulation skills as a common mechanism of change in psychological treatments for depression. The study was registered with ClinicalTrials.gov (NCT01330485) and was supported by grants from the German Research Association (DFG; BE 4510/3-1; HI 456/6-2). Future research should compare the (cost-) efficacy of ART with that of disorder-specific interventions. [ABSTRACT FROM AUTHOR]

The development of a new drug is an extremely high-risk enterprise. The attrition rates of development projects and the average costs for each launched product are daunting, and the completion of a development program requires a very long time horizon. These facts imply that there are huge potential gains, should one be able to improve efficiency and enhance decision-making capabilities. In this paper, we argue that substantial gains can be achieved by adapting a holistic view of drug development. Historically, too much planning, design and decision-making in the pharmaceutical development has been based on locally optimising separate parts of the development program, and too often important sources of uncertainty are ignored. We propose instead a model-based approach built on two essential pillars; (1) an integrated holistic view of the development program, including post-launch marketing and sales, with all parts evaluated simultaneously; (2) an explicit appreciation of all relevant sources of uncertainty. Computer simulations are utilised to evaluate the properties of the program options at hand, and to provide valuable quantitative decision support. Applications of this modelling approach have proven to add large value to development projects in terms of better program options being generated and more value-adding decisions taken. [ABSTRACT FROM AUTHOR]

Objective: To compare effectiveness and safety of warfarin and the direct oral anticoagulants (DOAC) dabigatran, rivaroxaban and apixaban in non-valvular atrial fibrillation in routine care. Methods: From nationwide registries, we identified treatment-naïve patients initiating warfarin, dabigatran, rivaroxaban or apixaban for non-valvular atrial fibrillation from July 2013 to December 2015 in Norway. We assessed prescription duration using reverse waiting time distribution. Adjusting for confounding in a Cox proportional hazards model, we estimated one-year risks for ischemic stroke, transient ischemic attack (TIA) or systemic embolism, major or clinically relevant non-major bleeding; intracranial; gastrointestinal; and other bleeding. We censored at switch of treatment or 365 days of follow-up. Results: We included 30,820 treatment-naïve patients. Compared to warfarin, the adjusted hazard ratios (HR) for ischemic stroke, TIA or systemic embolism were 0.96 (95% CI 0.71–1.28) for dabigatran, 1.12 (95% CI 0.87–1.45) for rivaroxaban and 0.97 (95% CI 0.75–1.26) for apixaban. Corresponding hazard ratios for major or clinically relevant non-major bleeding were 0.73 (95% CI 0.62–0.86) for dabigatran, 0.97 (95% CI 0.84–1.12) for rivaroxaban and 0.71 (95% CI 0.62–0.82) for apixaban. Statistically significant differences of other safety outcomes compared to warfarin were fewer intracranial bleedings with dabigatran (HR 0.28, 95% CI 0.14–0.56), rivaroxaban (HR 0.40, 95% CI 0.23–0.69) and apixaban (HR 0.56, 95% CI 0.34–0.92); fewer gastrointestinal bleedings with apixaban (HR 0.70, 95% CI 0.52–0.93); and fewer other bleedings with dabigatran (HR 0.67, 95% CI 0.55–0.81) and apixaban (HR 0.70, 95% CI 0.59–0.83). Conclusion: After 1 year follow-up in treatment-naïve patients initiating oral anticoagulation for non-valvular atrial fibrillation, all DOACs were similarly effective as warfarin in prevention of ischemic stroke, TIA or systemic embolism. Safety from bleedings was similar or better, including fewer intracranial bleedings with all direct oral anticoagulants, fewer gastrointestinal bleedings with apixaban and fewer other bleedings with dabigatran and apixaban. [ABSTRACT FROM AUTHOR]

Background: Positive Behaviour Support (PBS) for challenging behaviour is a complex intervention. Process evaluation is pivotal in fully understanding the mechanisms and contextual factors that impact on participant outcomes. Aims: To conduct a process evaluation of a national clinical trial investigating the impact of PBS-based staff training on the level of challenging behaviour in adults with intellectual disability. Method: The Medical Research Council guidance for process evaluation of complex interventions was followed. Semi-structured interviews with 62 stakeholders from the intervention arm (service users, family and paid carers, service managers, staff who delivered the intervention and PBS trainers), quantitative data from the study database and an external evaluation of the quality of the PBS plans were used. Results: Twenty-one health staff volunteered to be trained in delivering PBS. Available log data from 17 therapists revealed that they worked with 63 participants a median of 11.50 hours (IQR 8–32). Only 33 out of 108 reports had included all elements of the intervention. Another 47 reports had some elements of the intervention. All PBS plans were rated weak, indicating insufficient quality to impact challenging behaviour. Stakeholders reported an appreciation of PBS and its potential to impact quality of care and engagement with the participant. However, they also identified important challenges including managing PBS-related caseloads, paid carer turnover and service commitment to the delivery of PBS. Conclusions: PBS-based staff training was well received, but therapists found it difficult to undertake all the elements of the intervention in routine care. Implementing a workforce training strategy is important to better define the active components of PBS, and resource implications if the intervention is no better than usual care. [ABSTRACT FROM AUTHOR]

Introduction: Plasmodium falciparum synthesizes phosphatidylcholine for the membrane development through serine decarboxylase–phosphoethanolamine methyltransferase pathway for growth in human host. Phosphoethanolamine-methyltransferase (PfPMT) is a crucial enzyme for the synthesis of phosphocholine which is a precursor for phosphatidylcholine synthesis and is considered as a pivotal drug target as it is absent in the host. The inhibition of PfPMT may kill malaria parasite and hence is being considered as potential target for rational antimalarial drug designing. Methods: In this study, we have used computer aided drug designing (CADD) approaches to establish potential PfPMT inhibitors from Asinex compound library virtually screened for ADMET and the docking affinity. The selected compounds were tested for in-vitro schizonticidal, gametocidal and cytotoxicity activity. Nontoxic compounds were further studied for PfPMT enzyme specificity and antimalarial efficacy for P. berghei in albino mice model. Results: Our results have identified two nontoxic PfPMT competitive inhibitors ASN.1 and ASN.3 with better schizonticidal and gametocidal activity which were found to inhibit PfPMT at IC50 1.49μM and 2.31μM respectively. The promising reduction in parasitaemia was found both in orally (50 & 10 mg/kg) and intravenous (IV) (5& 1 mg/kg) however, the better growth inhibition was found in intravenous groups. Conclusion: We report that the compounds containing Pyridinyl-Pyrimidine and Phenyl-Furan scaffolds as the potential inhibitors of PfPMT and thus may act as promising antimalarial inhibitor candidates which can be further optimized and used as leads for template based antimalarial drug development. [ABSTRACT FROM AUTHOR]

Background: Amoebiasis, caused by Entamoeba histolytica infection, is a global public health problem. However, available drugs to treat amoebiasis are currently limited, and no effective vaccine exists. Therefore, development of new preventive measures against amoebiasis is urgently needed. Methodology/Principal findings: Here, to develop new drugs against amoebiasis, we focused on E. histolytica adenosine 5′-phosphosulfate kinase (EhAPSK), an essential enzyme in Entamoeba sulfolipid metabolism. Fatty alcohol disulfates and cholesteryl sulfate, sulfolipids synthesized in Entamoeba, play important roles in trophozoite proliferation and cyst formation. These processes are closely associated with clinical manifestation and severe pathogenesis of amoebiasis and with disease transmission, respectively. We validated a combination approach of in silico molecular docking analysis and an in vitro enzyme activity assay for large scale screening. Docking simulation ranked the binding free energy between a homology modeling structure of EhAPSK and 400 compounds. The 400 compounds were also screened by a 96-well plate-based in vitro APSK activity assay. Among fifteen compounds identified as EhAPSK inhibitors by the in vitro system, six were ranked by the in silico analysis as having high affinity toward EhAPSK. Furthermore, 2-(3-fluorophenoxy)-N-[4-(2-pyridyl)thiazol-2-yl]-acetamide, 3-phenyl-N-[4-(2-pyridyl)thiazol-2-yl]-imidazole-4-carboxamide, and auranofin, which were identified as EhAPSK inhibitors by both in silico and in vitro analyses, halted not only Entamoeba trophozoite proliferation but also cyst formation. These three compounds also dose-dependently impaired the synthesis of sulfolipids in E. histolytica. Conclusions/Significance: Hence, the combined approach of in silico and in vitro-based EhAPSK analyses identified compounds that can be evaluated for their effects on Entamoeba. This can provide leads for the development of new anti-amoebic and amoebiasis transmission-blocking drugs. This strategy can also be applied to identify specific APSK inhibitors, which will benefit research into sulfur metabolism and the ubiquitous pathway terminally synthesizing essential sulfur-containing biomolecules. [ABSTRACT FROM AUTHOR]

Recently, a range of organisations, including car and consumer electronics manufacturers, have applied so-called patent pledges. A patent pledge is a publicly announced intervention by patent-owning entities ('pledgers') to out-license active patents to the restricted or unrestricted public free from or bound to certain conditions for a reasonable or no monetary compensation. Despite growing research to better understand this phenomenon, the underlying terminology remains contradictory. We apply an inductive research approach using qualitative coding to analyse 60 patent pledges made by 80 organisations. Based on this analysis, we propose a three-dimensional taxonomy that distinguishes eight types of patent pledges. Extending this taxonomy using case examples, we then propose a generalised patent licensing taxonomy. This second taxonomy can be used to distinguish patent licensing strategies, including other frequently used approaches, such as patent pools and cross-licenses. Finally, we use the patent pledge taxonomy to illustrate how patent owners change their licensing strategies over time and how it can support strategic decision processes within an organisation. We contribute to the field of patent management by building an ontology of patent pledges through proposing a definition and eight types. The patent licensing taxonomy enables organisations to devise and choose licensing strategies, and to illustrate licensing approaches of competitors, for instance. [ABSTRACT FROM AUTHOR]

Although corporate social responsibility (CSR) activities are common in the pharmaceutical industry, there is little empirical evidence on consumer responses to CSR practices. We investigated public awareness, preferences, and expectations regarding social contribution of the pharmaceutical industry's CSR activities, and identified the factors associated with such activities. We conducted an online survey with 1,298 respondents comprising two groups: healthy individuals (546) and patients (752). Most respondents (78%) expressed interest in CSR activities undertaken by pharmaceutical companies. However, they reported a lack of awareness and experience thereof; only 26.9% were aware of and 7.9% had experience with such activities. Among our six CSR activity categories, both survey groups showed the highest preference for the "promoting public health" (healthy group: 6.34/10; patient group: 6.37/10) and "emergency disaster relief support" (6.31 and 6.35) categories. Among sub-categories, activities related to "development of innovative drugs in untreated areas" (6.63 and 6.82) and "support for research on new drug development" (6.59 and 6.84) received the highest scores. The mean expectation score of social contribution of all CSR activities was slightly higher than the mean preference score (6.37 and 6.06, respectively). The patient group exhibited a larger difference between the highest and lowest expectation scores than the healthy group (1.11 and 0.64, respectively). The results of the regression analysis revealed that being a patient, being male, and having positive attitudes toward CSR and its expected effects significantly and positively affected public preferences regarding CSR activities. We can conclude that CSR activities with high public preference might be an effective strategy to improve public awareness of the pharmaceutical industry's CSR activities. Furthermore, the highest preference for CSR activities relates to new drug development, indicating that our society believes the pharmaceutical industry's key CSR activity should be to pursue its intrinsic mission: to fulfill unmet medical needs by developing new drugs. [ABSTRACT FROM AUTHOR]

Leptospirosis is one of the leading zoonotic infections worldwide. As with other infectious diseases, report of antimicrobial resistance to existing therapeutic arsenal poses challenges in the management of disease. Hence, identification of novel drug targets for the pathogen deems essential. Present study used combined approach of comparative and subtractive genomics to identify putative drug targets. Crucial genes of 16 pathogenic Leptospira strains were filtered and subjected to homology search via target identification tool "TiD". Thereafter, comparative analysis was performed for non-homologous, essential genes to accomplish the broad-spectrum drug target. Consequently, 37 essential genes were found to be conserved in at least 10 strains of Leptospira. Further, prioritization of resultant set of genes revealed 18 were hubs in protein–protein interaction network. Sixteen putative targets among the hub genes were conserved in all strains of Leptospira. Out of sixteen, fourteen were enzymes while 8 were novel and 4 were involved in virulence mechanism. In addition, genome scale metabolic network reconstruction and choke point analysis revealed cobA (porphyrin and chlorophyll metabolism) and thiL (thiamine metabolism) as chokepoints in their respective metabolic pathways. The proposed hub genes could act as putative broad-spectrum drug targets for Leptospira species, however, these putative targets should be validated to ensure them as real one prior to utilizing them for target based lead discovery. [ABSTRACT FROM AUTHOR]

Amita Gupta and colleagues discuss priorities in clinical research aimed at improving tuberculosis prevention and treatment in pregnant women, children, and people with HIV. [ABSTRACT FROM AUTHOR]

Physical inactivity has been identified as a leading risk factor for premature mortality globally, and adolescents, in particular, have low physical activity levels. Schools have been identified as a setting to tackle physical inactivity. Economic evidence of school-based physical activity programmes is limited, and the costs of these programmes are not always collected in full. This paper describes a micro-costing and cost-consequence analysis of the ‘Girls Active’ secondary school-based programme as part of a cluster randomised controlled trial (RCT). Micro-costing and cost-consequence analyses were conducted using bespoke cost diaries and questionnaires to collect programme delivery information. Outcomes for the cost-consequence analysis included health-related quality of life measured by the Child Health Utility-9D (CHU-9D), primary care General Practitioner (GP) and school-based (school nurse and school counsellor) service use as part of a cluster RCT of the ‘Girls Active’ programme. Overall, 1,752 secondary pupils were recruited and a complete case sample of 997 participants (Intervention n = 570, Control n = 427) was used for the cost-consequence analysis. The micro-costing analysis demonstrated that, depending upon how the programme was delivered, ‘Girls Active’ costs ranged from £1,054 (£2 per pupil, per school year) to £3,489 (£7 per pupil, per school year). The least costly option was to absorb ‘Girls Active’ strictly within curriculum hours. The analysis demonstrated no effect for the programme for the three main outcomes of interest (health-related quality of life, physical activity and service use).Micro-costing analyses demonstrated the costs of delivering the ‘Girls Active’ programme, addressing a gap in the United Kingdom (UK) literature regarding economic evidence from school-based physical activity programmes. This paper provides recommendations for those gathering cost and service use data in school settings to supplement validated and objective measures, furthering economic research in this field. Trial registration: -ISRCTN, . [ABSTRACT FROM AUTHOR]

Data from clinical trials investigating on-demand medication often consist of an intentionally varying number of measurements per patient. These measurements are often observations of discrete events of when the medication was taken, including for example data on symptom severity. In addition to the varying number of observations between patients, the data have another important feature: they are characterized by a hierarchical structure in which the events are nested within patients. Traditionally, the observed events of patients are aggregated into means and subsequently analyzed using, for example, a repeated measures ANOVA. This procedure has drawbacks. One drawback is that these patient means have different standard errors, first, because the variance of the underlying events differs between patients and second, because the number of events per patient differs. In this paper, we argue that such data should be analyzed by applying a multilevel analysis using the individual observed events as separate nested observations. Such a multilevel approach handles this drawback and it also enables the examination of varying drug effects across patients by estimating random effects. We show how multilevel analyses can be applied to on-demand medication data from a clinical trial investigating the efficacy of a drug for women with low sexual desire. We also explore linear and quadratic time effects that can only be performed when the individual events are considered as separate observations and we discuss several important statistical topics relevant for multilevel modeling. Taken together, the use of a multilevel approach considering events as nested observations in these types of data is advocated as it is more valid and provides more information than other (traditional) methods. [ABSTRACT FROM AUTHOR]

This study aimed to assess patient investigational medication knowledge and to identify factors associated with medication understanding by adult outpatients included in clinical trials. A cross-sectional prospectively designed survey was conducted on consecutive volunteers at 21 university teaching hospitals (in France) from February to December 2014. Investigational medication understanding was assessed at the time of the first dispensing using a structured interviewer-administered questionnaire based on information obtained from the literature that provided an 8-point score. Demographic and other baseline data were collected using structured interviews. Of the 236 participants, 139 (58.9%) of the respondents were male, and the median age was 54.9 years (range: 18–83 years). The mean understanding score was 6.24 and 72.5% of the patients had a score of 6 or higher. In univariate analysis, the medication understanding score was negatively correlated with age (r = -0.15, p = 0.0247) and positively correlated with the level of education (r = 0.25, p = 0.0002). In multivariate analysis, prognostic factors of a higher medication understanding score were: graduation from high school or a higher level of education; HIV infection; phase II/III/IV studies; mention of the drug on the prescription form, and the dispensing of a single investigational medication. Only a quarter of the adult outpatients included in clinical trials had a maximum possible investigational medication understanding score. Being old and having a low level of education were found to be important risk factors for inadequate medication understanding. This and other data suggest that sponsors should encourage initiatives aimed at improving investigational medication understanding in adults enrolled in clinical trials. [ABSTRACT FROM AUTHOR]

Background and objectives: An invasive approach is recommended as the treatment of patients with non-ST elevated acute coronary syndromes (NSTE-ACS). However, it remains unclear that the optimal time of angiography and intervention for patients with NSTE-ACS at present. This study was designed to compare the effect of early and delayed invasive strategies on short-medium term prognosis in patients with those. Methods: Pubmed, Cochrane Library and Embase were searched up to Dec-30-2018. Randomized clinical trials comparing an early versus a delayed invasive strategy in patients with NSTE-ACS were included. The primary endpoint (all-cause death and recurrent myocardial infarction) and secondary endpoint (major bleeding and recurrent revascularization), as well as composite endpoint were assessed by random or fixed effected meta-analysis with software RevMan 5.3 version after short-medium term follow up. Result: A total of six randomized clinical trials involving 4,277 early or delayed invasive strategies patients with NSTE-ACS were included in the meta-analysis. Time to coronary angiography varied from 0.5 to 24 h in the early invasive strategy and from 18.6 to 72 h in the delayed invasive strategy. There was a statistical difference in the primary endpoint of all-cause death among patients with NSTE-ACS between early and delayed invasive strategies (4.6% vs 6%; OR:0.76; 95% CI:0.58 to 1.00; P = 0.05; I2 = 0%), but not for recurrent myocardial infarction (6.0% vs 6.3%; OR: 0.94; 95% CI: 0.55 to 1.61; P = 0.82; I2 = 60%). The major bleeding in patients with NSTE-ACS was similar between both invasive strategies (2.7% vs 3.1%; OR:0.88; 95% CI:0.59 to 1.31; P = 0.54; I2 = 0%). However, the composite endpoint in the early invasive strategy patients with NSTE-ACS was significantly lower than that of the delayed invasive strategy (10.9% vs 13.9%; OR:0.76; 95% CI:0.63 to 0.92; P = 0.006; I2 = 0%), and the recurrent revascularization between both strategies was just the opposite (8.7% vs 5.9%; OR:1.5; 95%CI:1.15 to 1.97; P = 0.003; I2 = 0%). Conclusion: The systematic review and meta-analysis demonstrated that the early invasive strategy had a beneficial trend on all-cause death and significantly reduced the composite endpoint in patients with NSTE-ACS, but increased the rate of revascularization. These data could provide a solution for patients with those. [ABSTRACT FROM AUTHOR]

Objective: Research biopsies are an essential component of cancer clinical trials for studying drug efficacy and identifying biomarkers. Site-level clinical investigators, however, do not have access to results on the adequacy of research biopsies for histological or molecular assays, because samples are sent to central labs and the test results are seldom reported back to site-level investigators unless requested. We evaluated the feasibility, safety, and adequacy of research biopsies performed at an academic medical center. Materials and methods: We retrospectively reviewed the data on 122 research biopsy sessions conducted in 99 patients via percutaneous core needle biopsy for 39 clinical trials from January 2017 to February 2018 at a single institute. We asked the sponsors of each clinical trial for the adequacy of the biopsy samples for histological or molecular assays. Results: The biopsy success rate was 93.4% (113/122), with nine samples categorized as inadequate for obtaining pathologic diagnosis. Post-biopsy complications occurred in 9.8% (12/122) of biopsies, all of which were mild and completely recovered by the day after the biopsy. The sponsors of clinical trials provided feedbacks on the adequacy of 76 biopsy samples, and noted that a total of 8 biopsy samples from 7 patients were inadequate for analysis, resulting in an adequacy rate of 89.5% (68/76): the reasons for inadequacy were insufficient tumor content for immunohistochemistry (n = 3) and low RNA yield for sequencing (n = 5). Conclusion: Research biopsies performed at an experienced, multidisciplinary center had acceptable safety for patients as well as practicality in terms of obtaining adequate tissue samples for molecular studies. [ABSTRACT FROM AUTHOR]