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Key summary points: Aim: This study aimed to investigate changes in vitamin E intake in older adults with low cognitive performance using NHANES. Findings: An increased dietary intake of vitamin E has been associated with decreased cognitive impairment in individuals over 60 years old. The dose–response curve showed an L-shaped association between dietary vitamin E intake and cognitive decline in US adults, with an inflection point of approximately 9.296 mg/day. Message: These findings highlight the importance of including vitamin E-rich foods in the diet, particularly for older adults who may be at a higher risk of cognitive impairment. However, further research is needed to confirm these results and to better understand the mechanisms underlying the relationship between vitamin E and cognitive function. Purpose: Numerous studies have reported that vitamin E plays a key role in nervous system development and neurotransmitter production. This study aimed to investigate changes in vitamin E intake in older adults with low cognitive performance using NHANES. Methods: In this cross-sectional study, we examined a sample of 2255 American adults aged 60 and over between 2011 and 2014. We collected dietary data by averaging two recalls for dietary use to determine vitamin E intake. We assessed cognitive function using five tests and analyzed the association between these variables using a multivariate logistic regression model. Results: A total of 2255 participants aged ≥ 60 years from the National Health and Nutrition Examination Survey (NHANES) for the 2011–2014 cycle were included in the analysis. Vitamin E intake was negatively associated with cognitive function. In the Z test, with each 1 mg/day increase in dietary intake of vitamin E, there was a 6% decrease in the correlation with cognitive impairment (OR = 0.94, 95% CI 0.91–0.97) in the fully fitted model (OR = 0.94, 95% CI 0.91–0.97). These findings remained consistent when analyzing the exposure as a categorical variable. In comparison to Q1, Q4 showed a 53% reduction in the incidence of cognitive impairment in the Z test (OR = 0.47, 95% CI 0.33–0.67).No significant statistical interaction between the variables was found. Conclusion: An increased dietary intake of vitamin E has been associated with decreased cognitive impairment in individuals over 60 years old. The dose–response curve showed an L-shaped association between dietary vitamin E intake and cognitive decline in US adults, with an inflection point of approximately 9.296 mg/day. [ABSTRACT FROM AUTHOR]

Medical journals have adhered to a reporting practice that seriously limits the usefulness of published trial findings. Medical decision makers commonly observe many patient covariates and seek to use this information to personalize treatment choices. Yet standard summaries of trial findings only partition subjects into broad subgroups, typically binary categories. Given this reporting practice, we study the problem of inference on long mean treatment outcomes E[y(t)|x], where t is a treatment, y(t) is a treatment outcome, and the covariate vector x has length K, each component being a binary variable. The available data are estimates of {E[y(t)|xk = 0], E[y(t)|xk = 1], P(xk)}, k = 1,..., K reported in journal articles. We show that reported trial findings partially identify {E[y(t)|x], P(x)}. Illustrative computations demonstrate that the summaries of trial findings in journal articles may imply only wide bounds on long mean outcomes. One can realistically tighten inferences if one can combine reported trial findings with credible assumptions having identifying power, such as bounded-variation assumptions. [ABSTRACT FROM AUTHOR]

The analysis of whole genomes of pan‐cancer data sets provides a challenge for researchers, and we contribute to the literature concerning the identification of robust subgroups with clear biological interpretation. Specifically, we tackle this unsupervised problem via a novel rank‐based Bayesian clustering method. The advantages of our method are the integration and quantification of all uncertainties related to both the input data and the model, the probabilistic interpretation of final results to allow straightforward assessment of the stability of clusters leading to reliable conclusions, and the transparent biological interpretation of the identified clusters since each cluster is characterized by its top‐ranked genomic features. We applied our method to RNA‐seq data from cancer samples from 12 tumor types from the Cancer Genome Atlas. We identified a robust clustering that mostly reflects tissue of origin but also includes pan‐cancer clusters. Importantly, we identified three pan‐squamous clusters composed of a mix of lung squamous cell carcinoma, head and neck squamous carcinoma, and bladder cancer, with different biological functions over‐represented in the top genes that characterize the three clusters. We also found two novel subtypes of kidney cancer that show different prognosis, and we reproduced known subtypes of breast cancer. Taken together, our method allows the identification of robust and biologically meaningful clusters of pan‐cancer samples. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to investigate the impact of acupuncture therapy on relapse of patients with gouty arthritis (GA). Methods: "gout OR gouty arthritis" AND "acupuncture therapy OR acupuncture OR moxibustion OR electroacupuncture OR fire needle OR acupotomology OR blood-letting puncture OR plum blossom needle" were used as search strategies for searching related studies. Twenty-two studies involving 2394 patients were enrolled in this research through the analysis of databases of CNKI, Wanfang, VIP, PubMed, Embase and Cochrane Library. Results: The results of pairwise meta-analysis and network meta-analysis (NMA) indicated that patients with acupuncture therapy had a significantly lower relapse rate (RR) compared with those without acupuncture therapy (OR = 0.21, 95% CI: 0.16-0.26, P < 0.00001); the follow-up time (TFU) and serum urate concentration (SUA) before treatment had no significant effect on the reduction of RR caused by acupuncture therapy (P > 0.05); and patients treated with acupuncture plus Western medicine (WM) had the lowest RR (surface under the cumulative acupuncture therapy (P > 0.05); and patients treated with acupuncture plus Western medicine (WM) had the lowest RR (surface under the cumulative ranking [SUCRA] = 85.0%), followed by acupuncture plus traditional Chinese medicine (TCM, SUCRA = 73.5%), acupuncture only (SUCRA = 72.8%), fourthly acupuncture plus TCM and WM (SUCRA = 33.0%), then TCM (SUCRA = 28.7%), finally WM (SUCRA = 7.0%). Conclusion: Our finding may facilitate the application of acupuncture therapy in patients with GA. Our research also offered some information for the future research. [ABSTRACT FROM AUTHOR]

Objective: To identify multivariable subgroups of patients with differential responses to a nurse-delivered care transition intervention after an emergency department (ED) visit in a randomized controlled trial (RCT) using an emerging data-driven method.Design: Secondary analysis of RCT.Participants: 512 individuals enrolled in an RCT of a nurse-delivered care transition intervention after an ED visit. All 512 participants were included in a pre-specified subgroup analysis, and 451 of these had sufficient complete case data to be included in a model-based recursive (MoB) partitioning analysis.Methods: The primary outcome was having at least one ED visit in 30 days after the index ED visit. Two analytical methods explored heterogeneity of treatment effects: data driven model-based recursive partitioning (MoB) using 37 candidate baseline variables, and a contextual point of comparison with prespecified subgroups defined by ED super-user status (≥ 3 ED visits in previous 6 months or not), sex (male/female), and age, individually examined via treatment arm by subgroup interaction terms in logistic regression models. Internal validation of the MoB analysis via bootstrap resampling with an optimism corrected c-statistic was conducted to provide a bias-corrected estimate.Results: MoB detected treatment effect heterogeneity in a single subgroup, marital status. Unmarried patients randomized to the intervention had a repeat ED use rate of 22% compared to 34% in the usual care group; married patients randomized to the intervention had a 27% ED return rate compared to 12% in the usual care group. Internal validation demonstrated an optimism corrected c-statistic of 0.54. No treatment-by-covariate subgroup interactions were identified among the 3 prespecified subgroups.Conclusion: Although exploratory, the results of the MoB analysis suggest that patient factors related to social relationships such as marital status may be important contributors to differential response to a care transition intervention after an ED visit. These were characteristics that the investigators had not anticipated or planned to examine in the individual prespecified subgroup analysis. Data-driven methods can yield unexpected findings and contribute to a more complete understanding of differential treatment effects in subgroup analysis, which can inform further work on development of effective care transition interventions in the ED setting. [ABSTRACT FROM AUTHOR]

• Several differences in baseline health status exist between males and females undergoing ACDF. • Sex by itself is not an independent risk factor for higher perioperative morbidity or mortality in patients undergoing ACDF. • This finding has implications for patient counseling.. Differences in morbidity and mortality measures between males and females have been demonstrated for a variety of spinal surgeries, however, studies of anterior cervical discectomy and fusion (ACDF) are limited. To investigate the impact of sex on 30-day perioperative outcomes of ACDF. Retrospective 1:1 propensity score-matched cohort study. Patients who underwent ACDF between 2016 and 2018 were reviewed from the ACS-NSQIP database. Propensity score matching and subgroup analysis were used. 21,180 patients met inclusion criteria. 11,194 patients underwent single-level ACDF and 9986 patients underwent multi-level ACDF. In the single-level group, there were 6168 (55.1%) males and 5026 (44.9%) females. In the multi-level group, there were 5033 (50.4%) males and 4953 (49.6%) females. In both single/multi-level groups, females were more likely to be of older age, be functionally dependent, and have higher BMI and lower preoperative hematocrit level. Males were more likely to be Caucasian, smokers, have myelopathy, diabetes mellitus, hypertension and bleeding disorders. In both single/multi-level groups, except for the higher incidence of urinary tract infection (UTI) in females and myocardial infarction (MI) in males, there were no significant differences in morbidity and mortality between males and females. Several differences in demographics and baseline health status exist between males and females undergoing ACDF. When attempting to control for comorbid conditions, we found that sex by itself is not an independent risk factor for higher perioperative morbidity or mortality in patients undergoing ACDF, except for the higher incidence of UTI in females and MI in males. These results are important findings for clinicians and spine surgeons while counseling patients undergoing this type of procedure. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials (RCTs) with continuous outcomes usually only examine mean differences in response between trial arms. If the intervention has heterogeneous effects, then outcome variances will also differ between arms. Power of an individual trial to assess heterogeneity is lower than the power to detect the same size of main effect.Methods: We describe several methods for assessing differences in variance in trial arms and apply them to a single trial with individual patient data and to meta-analyses using summary data. Where individual data are available, we use regression-based methods to examine the effects of covariates on variation. We present an additional method to meta-analyze differences in variances with summary data.Results: In the single trial, there was agreement between methods, and the difference in variance was largely due to differences in prevalence of depression at baseline. In two meta-analyses, most individual trials did not show strong evidence of a difference in variance between arms, with wide confidence intervals. However, both meta-analyses showed evidence of greater variance in the control arm, and in one example, this was perhaps because mean outcome in the control arm was higher.Conclusions: Using meta-analysis, we overcame low power of individual trials to examine differences in variance using meta-analysis. Evidence of differences in variance should be followed up to identify potential effect modifiers and explore other possible causes such as varying compliance. [ABSTRACT FROM AUTHOR]

The relationship between dietary metal intake and mortality risk is controversial, and we investigated the relationship between intake of five metals (iron, copper, selenium, zinc, and magnesium) and all-cause, cardiovascular mortality in the total population, gender subgroups, and age subgroups. 17,207 participants from the National Health and Nutrition Examination Survey (NHANES) database from 2009 to 2016 were included in this study. Kaplan-Meier survival curves, multivariate Cox proportional hazards models, and restrictive cubic spline (RCS) curves were used to explore the association between metal intake and all-cause, cardiovascular mortality. In this study, the average dietary metal intake of men and older people was lower than that of women and younger people. The RCS curves found in the whole population that all-cause mortality was negative linearly associated with copper intakes, L-shaped with zinc and magnesium intakes. Further subgroup analyses of copper, zinc, and magnesium by age and gender revealed that only magnesium showed statistically significant differences in the age subgroups. In the 20–40 population, there was a non-linear increasing trend in magnesium intake and all-cause mortality, whereas there was a non-linear decreasing trend in the > 60 population. The relationship between metal intake and mortality is more than a simple linear correlation, and differences in age can affect this correlation. In metal exposure studies, different populations can be studied to better determine the effect of metal exposure on mortality. The dataset used for statistical analysis in this study is available on the NHANES website: https://www.cdc.gov/nchs/nhanes/index.htm. [Display omitted] [ABSTRACT FROM AUTHOR]

The effect of pre-stroke use of aspirin on small subcortical infarct dimensions or outcomes is not well described. We aimed to bridge this knowledge gap amongst a well-described and heterogeneous patient population. We performed a post-hoc analysis of the Secondary Prevention of Small Subcortical Stroke (SPS3) trial. The primary exposure was aspirin use ≤7 days of index stroke. The primary outcomes were infarct dimensions. Functional outcomes by modified Rankin Scale (mRS) was a secondary outcome. Age restricted (≥55 years) subgroup analyses were performed as a sensitivity analysis. Descriptive statistical and regression modeling were performed for data analysis. We included 1423 participants of which 453(31.8 %) used aspirin. Aspirin use was associated with more cardiovascular risk diagnoses. Maximal infarct diameter did not differ with pre-stroke aspirin use (11.3±4.2 mm versus 11.8±4.1 mm, p =0.057) however infarct area was smaller with exposure (126.4±90.0 mm2 versus 137.4±97.0 mm2, p =0.037) regardless of aspirin strength. Participants ≥55 years had smaller infarct diameters (11.1±4.2 mm versus 11.9±4.4 mm, p =0.019) and area (123.4±87.1 mm2 versus 130.6±93.2 mm2, p =0.037) with aspirin use. mRS did not significantly differ in our analyses. In this post-hoc analysis of the SPS3 trial, pre-stroke aspirin use was associated with a smaller infarct area regardless of aspirin strength and without impact on functional outcomes. These findings were more pronounced in participants ≥55 years. https://clinicaltrials.gov/study/NCT00059306?term= %22sps3 %22&rank=1 [ABSTRACT FROM AUTHOR]

This study analyzes the keywords of health literacy research, network structure and attributes, characteristics of subgroups, and association by research period. The current research conducted a semantic network analysis on 3,971 papers published in PubMed (https://pubmed.ncbi.nlm.nih.gov/) between 1985 and 2020. Seventy-one keywords were selected from 3,284 words. To visualize the network structure of health literacy research, analyze subgroups, and carry out QAP analysis, data matrices of 71*71 was prepared in Ucinet and Netdraw software. Spring-embedded algorithms and degree centrality visualized the network structure. For the sub-group analysis, we employed the modularity using NCD (Newman Community Detection) algorithm. The keywords such as patient (798 times), health (777 times), mental (360 times), adult (323 times), and low (249 times) appeared to be frequent in the health literacy research. Additionally, considering the degree centrality, such keywords as patients, assessments, education, health, low, adult, care, use, improvement, and formation played an important role around health literacy in the overall network structure. We found that the subgroup was best classified as three groups. The first group includes keywords such as develop, health, educate, mental, and formation, and was named 'Development and Evaluation of Health Literacy Measurement Scale.' In the second group, behavior, status, treatment, and adult became the keywords and they named it 'Effects and Outcomes of Health Literacy.' The third group contained keywords including, risk, women, cancer, Chinese, and quality, and was named 'Application and Use of Various Targets of Health Literacy.' [ABSTRACT FROM AUTHOR]

Preterm birth is a substantial public health concern. In 2019, the US preterm birth rate was 10.23%, which is the fifth straight year of increase in this rate. Moreover, preterm birth accounts for approximately 1 in 6 infant deaths, and surviving children often suffer developmental delay or long-term neurologic impairment. Although the burden of preterm birth is clear, identifying strategies to reduce preterm birth has been challenging. On October 29, 2019, a US Food and Drug Administration advisory committee voted 9 vs 7 to withdraw interim accelerated approval of 17-alpha hydroxyprogesterone caproate for preventing recurrent preterm birth because the called for a confirmatory trial, known as the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery trial, was not confirmatory. The Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery trial included subjects enrolled in the United States and Canada to ensure that at least 10% of patients would be from North America; however, this trial took 9 years to complete and did not demonstrate significant treatment effects in the 2 primary outcomes of interest. Delivery before 35 weeks' gestation occurred in 122 of 1130 women (11%) given 17-alpha hydroxyprogesterone caproate compared with 66 of 578 women (11.5%) given placebo (relative risk, 0.95; 95% confidence interval, 0.71-1.26; P=.72). Similarly, the coprimary outcome neonatal composite index occurred in 61 of 1093 women (5.6%) given 17-alpha hydroxyprogesterone caproate compared with 28 of 559 women (5.0%) given placebo (relative risk, 1.12; 95% confidence interval, 0.68-1.61; P=.73). There was also a lack of efficacy for 17-alpha hydroxyprogesterone caproate treatment in the analysis of a variety of secondary outcomes. Like the Maternal-Fetal Medicine Units Network trial, the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery trial was also flawed. Importantly, the Maternal-Fetal Medicine Unit Network trial was the sole justification for treating women in the United States with 17-alpha hydroxyprogesterone caproate for nearly 2 decades. Currently, despite more than half a century, 17-alpha hydroxyprogesterone caproate still has not been found to be clearly effective. In this context, how does the advising physician dependent on scientific evidence advise a patient that 17-alpha hydroxyprogesterone caproate is effective when the evidence to support this advice has repeatedly been found to be inadequate? This clinical opinion is a critical appraisal of the 2 randomized trials examining the efficacy of 17-alpha hydroxyprogesterone caproate to prevent recurrent preterm birth and a chronicle of events in the regulatory process of drug approval to help answer this question. With this examination, these events illustrate the complexity of pharmaceutical regulations in the era of accelerated Food and Drug Administration approval and characterize the financial impact and influence in medicine. In this report, we also emphasize the value of observational studies in contemporary practice and identify other examples in medicine where accelerated Food and Drug Administration approval has been withdrawn. Importantly, the themes of the 17-alpha hydroxyprogesterone caproate story are not limited to obstetrics. It can also serve as a microcosm of issues within the US healthcare system, which ultimately contributes to the high cost of healthcare. In our opinion, the answer to the question is clear-the facts speak for themselves-and we believe 17-alpha hydroxyprogesterone caproate should not be endorsed for use to prevent recurrent preterm birth in the United States. [ABSTRACT FROM AUTHOR]

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated in AMBER (treatment-naïve adults; NCT02431247) and EMERALD (treatment-experienced, virologically-suppressed adults; NCT02269917). To describe a Week 96 pre-planned subgroup analysis of D/C/F/TAF arms by demographic characteristics (age ≤/>50 years, gender, black/non-black race), and baseline clinical characteristics (AMBER: viral load [VL], CD4+ count, WHO clinical stage, HIV-1 subtype and antiretroviral resistance; EMERALD: prior virologic failure [VF], antiretroviral experience, screening boosted protease inhibitor [PI], and boosting agent). Patients in D/C/F/TAF and control arms could continue on/switch to D/C/F/TAF in a single-arm, open-label extension phase after Week 48 until Week 96. Efficacy endpoints were percentage cumulative confirmed VL ≥50 copies/mL (virologic rebound; EMERALD), and VL <50 (virologic response), or ≥50 copies/mL (VF) (FDA snapshot; both trials). D/C/F/TAF demonstrated high Week 96 virologic responses (AMBER: 85% [308/362]; EMERALD: 91% [692/763]) and low VF rates (AMBER: 6% [20/362]; EMERALD: 1% [9/763]). In EMERALD, D/C/F/TAF showed low virologic rebound cumulative through Week 96 (3% [24/763]). Results were consistent across subgroups, including prior antiretroviral experience in EMERALD. No darunavir, primary PI, or tenofovir resistance-associated mutations were observed post-baseline. Study-drug-related serious adverse events (AEs) and AE-related discontinuations were <1% and 2%, respectively (both D/C/F/TAF arms), and similar across subgroups. eGFRcyst and bone mineral density improved or were stable and lipids increased through Week 96 across demographic subgroups, with small changes in total-cholesterol/HDL-cholesterol ratio. D/C/F/TAF was effective with a high barrier to resistance and bone/renal safety benefits, regardless of demographic or clinical characteristics for treatment-naïve and treatment-experienced, virologically-suppressed adults. [ABSTRACT FROM AUTHOR]

Inconsistent results across regions have been reported in a number of recent large trials. In this research, by reviewing results from studies that showed inconsistent treatment effects, and summarizing lessons learned, we provide some recommendations for minimizing the chance of inconsistency and allowing more accurate interpretation when such signs of heterogeneity arise, for example: keep the number of regions for consistency evaluation at a minimum to avoid observing false inconsistency signals; proactively address in the protocol the differences in culture, medical practices, and other factors that are potentially different across regions; closely monitor the blinded data from early-enrolled patients to more effectively identify and address issues such as imbalance of baseline covariates or inconsistency of primary outcome rates across regions. For treatments of life-threatening conditions, the stakes for accurate interpretation of MRCT results are high; the criteria for decisions warrant careful consideration. [ABSTRACT FROM AUTHOR]

• In acute SVO patients, IV-TPA within 4.5 h improved functional outcome. • IV-TPA within 4.5 h showed a low SICH risk in patients due to SVO. • IV-TPA was more effective in patients aged ≥80. Intravenous tissue-plasminogen activator (IV-TPA) treatment in acute ischemic stroke (AIS) patients due to small vessel occlusion (SVO) has been debated because of its small expected benefit and symptomatic intracranial hemorrhage (SICH) risk. Furthermore, data on subgroups of SVO patients are limited. From a prospective multicenter stroke registry database, AIS patients due to SVO within 24 h from onset were selected. Efficacy outcomes were 3-month modified Rankin Scale (mRS) score 0–1 proportion and mRS score distribution. Additionally, subgroup analyses were conducted by age, sex, initial National Institute Health Stroke Scale (NIHSS) score, and presenting limb paresis. This study included 2482 patients: 193 in the IV-TPA group and 2289 in the control group. After adjusting covariates, IV-TPA treatment was associated with an increased mRS 0-1 outcome (adjusted OR [95% CI], 1.56 [1.06–2.29]; P = 0.0249), but was not significantly associated with a favorable mRS shift (1.33 [0.98–1.81]; P = 0.0709). SICH and 3-month death occurred in three (1.6%) and none in the IV-TPA group versus one (0.04%) and 16 (0.7%) in the control group. In subgroup analyses, the IV-TPA effect appeared significantly greater in patients aged ≥80 versus <80 for mRS score distribution (P interaction = 0.012). This study showed that, in SVO patients, IV-TPA within 4.5 h may improve functional outcome with a low SICH risk. The benefit appeared more substantial in patients aged ≥80. [ABSTRACT FROM AUTHOR]

Public health and governmental organizations have acknowledged the importance of obtaining information of various characteristics for small areas, such as counties. Spatial smoothing models have been developed to gain reliable information on the geographical distribution of the outcome of interest. When the geographical analysis is based on survey data, two issues pose challenges: (1) the complex design of the survey and (2) the presence of missing data due to non-response. We investigate the influence of missing data and the adjustment thereof in the context of the 2013 Florida Behavioral Risk Factor Surveillance System (BRFSS) health survey. We focus on the application and comparison of the Hajek ratio estimator and two model-based approaches for estimation of the spatial trend of the prevalence of having no health insurance coverage. The model-based methods are compared using the Deviance Information Criterion which show the benefits of modeling the weights as flexibly as possible. Methods are extended towards subgroup analyses and the estimation of area-specific standardized rates, where household incomes was identified as an important factor to include in the analysis. [ABSTRACT FROM AUTHOR]

A systematic review is a comprehensive search, critical evaluation, and synthesis of all the relevant studies on a specific (clinical) topic that can be applied to the evaluation of diagnostic and screening imaging studies. It can be a qualitative or a quantitative (meta-analysis) review of available literature. A meta-analysis uses statistical methods to combine and summarize the results of several studies. In this review, a 12-step approach to performing a systematic review (and meta-analysis) is outlined under the four domains: (1) Problem Formulation and Data Acquisition, (2) Quality Appraisal of Eligible Studies, (3) Statistical Analysis of Quantitative Data, and (4) Clinical Interpretation of the Evidence. This review is specifically geared toward the performance of a systematic review and meta-analysis of diagnostic test accuracy (imaging) studies. [ABSTRACT FROM AUTHOR]

BACKGROUND: End-stage renal disease (ESRD) imposes significant economic and social burdens on patients and healthcare systems. In the United States alone, more than 600,000 Americans have ESRD, with an estimated annual cost of treatment of more than $30 billion. Peritoneal dialysis and hemodialysis are competing renal replacement therapies in ESRD; however, data comparing quality-of-life outcomes between these 2 modalities are limited. OBJECTIVES: To compare the effectiveness of peritoneal dialysis with the more common treatment modality of hemodialysis on the health-related quality of life (HRQoL) of patients with ESRD in the general, physical, and psychological domains; and to determine whether the time of publication and the origin of each study influenced its findings regarding the effectiveness of the 2 modalities. METHODS: This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta- Analyses guidelines to collect the data. PubMed, MEDLINE, and PsycINFO were the primary databases searched. Only articles published in English were included in this meta-analysis. The measure of effect size was Cohen's standardized mean difference. A random-effects model was used to test the hypothesis of equality in the mean HRQoL. RESULTS: A total of 15 studies with a combined sample size of 4318 patients met the study criteria and were included in the analysis. The pooled effect sizes based on the random-effects model were 0.24 (95% confidence interval [CI], -0.17-0.66) in the general domain; 0.10 (95% CI, -0.09-0.29) in the physical-functioning domain; and 0.29 (95% CI, -0.13-0.71) in the psychological-functioning domain. None of the summary effect sizes was statistically significant. Subgroup analyses favored peritoneal dialysis regarding the time and country of publication. CONCLUSION: The majority of the studies included in this analysis favored peritoneal dialysis over hemodialysis in all 3 domains. However, the pooled effect sizes were not significant, resulting in the inability to conclude that peritoneal dialysis is the more effective of these 2 treatment modalities. [ABSTRACT FROM AUTHOR]

Background: There has been an increased emphasis on the proactive and comprehensive evaluation of safety endpoints to ensure patient well-being throughout the medical product life cycle. In fact, depending on the severity of the underlying disease, it is important to plan for a comprehensive safety evaluation at the start of any development program. Statisticians should be intimately involved in this process and contribute their expertise to study design, safety data collection, analysis, reporting (including data visualization), and interpretation. Methods: In this manuscript, we review the challenges associated with the analysis of safety endpoints and describe the safety data that are available to influence the design and analysis of premarket clinical trials. Results: We share our recommendations for the statistical and graphical methodologies necessary to appropriately analyze, report, and interpret safety outcomes, and we discuss the advantages and disadvantages of safety data obtained from clinical trials compared to other sources. Conclusions: Clinical trials are an important source of safety data that contribute to the totality of safety information available to generate evidence for regulators, sponsors, payers, physicians, and patients. This work is a result of the efforts of the American Statistical Association Biopharmaceutical Section Safety Working Group. [ABSTRACT FROM AUTHOR]

New statisticians entering industry tend to “test statistical interactions” whenever there is a need. However, in many real-world applications, especially in clinical development of new drugs, most interactions need to be estimated, instead of tested. In this manuscript, the distinction between hypothesis testing and estimation will be articulated, and the use of statistical interactions in clinical development programs will be discussed. According to ICH E-9, the treatment by subgroup interaction should not be included in the prespecified primary statistical analysis model. The reasons behind this ICH E-9 recommendation are also clarified in this manuscript. [ABSTRACT FROM AUTHOR]

Background Daclizumab beta is a humanized monoclonal antibody specific for the human interleukin-2 receptor alpha chain (CD25). In two pivotal studies in relapsing multiple sclerosis (MS), patients treated with daclizumab beta exhibited lower annualized relapse rates (ARR) when compared with placebo or with intramuscular (IM) interferon beta-1a. Objectives To determine if the efficacy of daclizumab beta demonstrated in the phase 2 SELECT study and the phase 3 DECIDE study was consistent in patient subgroups. Methods In the SELECT study, patients received daclizumab beta 150 or 300 mg administered subcutaneously every 4 weeks for 52 weeks, and were compared with patients who received placebo. In the DECIDE study, patients received daclizumab beta 150 mg administered subcutaneously every 4 weeks for 96–144 weeks, and were compared with patients who received IM interferon beta-1a 30 µg. Subgroups were defined by sex, age, the number of relapses in the year before the study, disease duration, baseline disability measured by EDSS, presence of Gd-enhancing lesions, T2 hyperintense lesion volume at baseline, and previous interferon beta-1a use. Results Treatment with daclizumab beta was associated with relative lower ARR, with 95% confidence intervals (CIs) below 1 in 13 of 15 subgroups (SELECT study) compared with placebo and in all 17 subgroups compared with interferon beta-1a (DECIDE study). In 2 subgroups in the SELECT study (patients who were older than 35 years of age or who had a disease duration of 10 or more years), the rate ratio point estimate for the ARR was in favor of daclizumab beta but the 95% CI overlapped with 1. The clinical benefits in ARR achieved with daclizumab beta treatment compared with placebo or interferon beta-1a across subgroups were similarly supported by reductions in lesion activity on magnetic resonance images (MRIs). Conclusions These findings suggest that treatment with daclizumab beta is consistently effective among clinically important patient subgroups and support its potential as a viable therapeutic option across the spectrum of relapsing MS. [ABSTRACT FROM AUTHOR]

Patients with peripheral artery disease (PAD) requiring lower extremity revascularization (LER) have a high risk of adverse limb and cardiovascular events. The results from the VOYAGER PAD (efficacy and safety of rivaroxaban in reducing the risk of major thrombotic vascular events in subjects with symptomatic peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities) trial have demonstrated that rivaroxaban significantly reduced this risk with an overall favorable net benefit for patients undergoing surgical revascularization. However, the efficacy and safety for those treated by surgical bypass, including stratification by bypass conduit (venous or prosthetic), has not yet been described. In the VOYAGER PAD trial, patients who had undergone surgical and endovascular infrainguinal LER to treat PAD were randomized to rivaroxaban 2.5 mg twice daily or placebo on top of background antiplatelet therapy (aspirin 100 mg to be used in all and clopidogrel in some at the treating physician's discretion) and followed up for a median of 28 months. The primary end point was a composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, and cardiovascular death. The principal safety outcome was major bleeding using the TIMI (thrombolysis in myocardial infarction) scale. The index procedure details, including conduit type (venous vs prosthetic), were collected at baseline. Among 6564 randomized patients, 2185 (33%) had undergone surgical LER. Of these 2185 patients, surgical bypass had been performed for 1448 (66%), using a prosthetic conduit for 773 patients (53%) and venous conduit for 646 patients (45%). Adjusting for the baseline differences and anatomic factors, the risk of unplanned limb revascularization in the placebo arm was 2.5-fold higher for those receiving a prosthetic conduit vs a venous conduit (adjusted hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.65-3.90; P <.001), and the risk of acute limb ischemia was three times greater (adjusted HR, 3.07; 95% CI, 1.84-5.11; P <.001). The use of rivaroxaban reduced the primary outcome for the patients treated with bypass surgery (HR, 0.78; 95% CI, 0.62-0.98), with consistent benefits for those receiving venous (HR, 0.66; 95% CI, 0.49-0.96) and prosthetic (HR, 0.87; 95% CI, 0.66-1.15) conduits (P interaction =.254). In the overall trial, major bleeding using the TIMI scale was increased with rivaroxaban. However, the numbers for those treated with bypass surgery were low (five with rivaroxaban vs nine with placebo; HR, 0.55; 95% CI, 0.18-1.65) and not powered to show statistical significance. Surgical bypass with a prosthetic conduit was associated with significantly higher rates of major adverse limb events relative to venous conduits even after adjustment for patient and anatomic characteristics. Adding rivaroxaban 2.5 mg twice daily to aspirin or dual antiplatelet therapy significantly reduced this risk, with an increase in the bleeding risk, but had a favorable benefit risk for patients treated with bypass surgery, regardless of conduit type. Rivaroxaban should be considered after lower extremity bypass for symptomatic PAD to reduce ischemic complications of the heart, limb, and brain. [ABSTRACT FROM AUTHOR]

Highlights • Efficacy and safety of teriflunomide in Asian patients with relapsing MS were comparable to the overall TOWER population. • No new or unexpected safety findings were observed. • This analysis provides evidence of the clinical benefits of teriflunomide in a diverse patient population with relapsing MS. Abstract In the phase 3 TOWER (NCT00751881) study, teriflunomide 14 mg significantly reduced annualized relapse rate (ARR) and risk of 12-week confirmed disability worsening (12-w CDW) vs placebo in patients with relapsing forms of MS (RMS). The TOWER population included an appreciable proportion of Asian patients. Reductions in ARR and 12-w CDW associated with teriflunomide 14 mg were comparable between the Asian and overall populations, as were the rates for adverse events and serious adverse events, with no new or unexpected safety findings. These observations provide further evidence to support the clinical benefits and safety profile of teriflunomide in a broad range of patients with RMS. [ABSTRACT FROM AUTHOR]

We develop an unsupervised probabilistic model for heterogeneous Electronic Health Record (EHR) data. Utilizing a mixture model formulation, our approach directly models sequences of arbitrary length, such as medications and laboratory results. This allows for subgrouping and incorporation of the dynamics underlying heterogeneous data types. The model consists of a layered set of latent variables that encode underlying structure in the data. These variables represent subject subgroups at the top layer, and unobserved states for sequences in the second layer. We train this model on episodic data from subjects receiving medical care in the Kaiser Permanente Northern California integrated healthcare delivery system. The resulting properties of the trained model generate novel insight from these complex and multifaceted data. In addition, we show how the model can be used to analyze sequences that contribute to assessment of mortality likelihood. [ABSTRACT FROM AUTHOR]

Randomised controlled trials (RCT s) are gold standard in the evaluation of treatment efficacy in medical investigations, only if well designed and implemented. Till date, distorted views and misapplications of statistical procedures involved in RCTs are still in practice. Hence, clarification of concepts and acceptable practices related to certain statistical issues involved in the design, conduct and reporting of randomised controlled trials is needed. This narrative synthesis aimed at providing succinct but clear information on the concepts and practices of selected statistical issues in RCT s to inform correct applications. The use of tests of significance is no longer acceptable as means to compare baseline similarity between treatment groups and in determining which covariate(s) should be included in the model for adjustment. Distribution of baseline attributes simply presented in tabular form is however, rather preferred. Regarding covariate selection, such approach that makes use of information on the degree of correlation between the covariate(s) and the outcome variable is more in tandem with statistical principle(s) than that based on tests of significance. Stratification and minimisation are not alternatives to covariate adjusted analysis; in fact they establish the need for one. Intention-to-treat is the preferred approach for the evaluation of primary outcome measures and researchers have responsibility to report whether or not the procedure was followed. A major use of results from subgroup analysis is to generate hypothesis for future clinical trials. Since RCT s are gold standard in the comparison of medical interventions, researchers cannot afford the practices of distorted allocation or statistical procedures in this all important experimental design method. [ABSTRACT FROM AUTHOR]

The article addresses the operating characteristics of multipopulation tailoring trials based on the conceptual decision framework of Brian Millen et al and relevant error rate control. Topics discussed include a review of issues and analysis principles of multipopulation tailoring trials, case studies illustrating application of decision principles and associated design considerations and practical implementation of multipopulation trial designs in the regulatory approval of new treatments.

Abstract: Purpose: To present mixture regression analysis as an alternative to more standard regression analysis for predicting adolescent delinquency. We demonstrate how mixture regression analysis allows for the identification of population subgroups defined by the salience of multiple risk factors. Methods: We identified population subgroups (i.e., latent classes) of individuals based on their coefficients in a regression model predicting adolescent delinquency from eight previously established risk indices drawn from the community, school, family, peer, and individual levels. The study included N = 37,763 10th-grade adolescents who participated in the Communities That Care Youth Survey. Standard, zero-inflated, and mixture Poisson and negative binomial regression models were considered. Results: Standard and mixture negative binomial regression models were selected as optimal. The five-class regression model was interpreted based on the class-specific regression coefficients, indicating that risk factors had varying salience across classes of adolescents. Conclusions: Standard regression showed that all risk factors were significantly associated with delinquency. Mixture regression provided more nuanced information, suggesting a unique set of risk factors that were salient for different subgroups of adolescents. Implications for the design of subgroup-specific interventions are discussed. [Copyright &y& Elsevier]

Rationale and Objectives: Multiple diagnostic tests are often available for a disease. Their diagnostic accuracy may depend on the characteristics of testing subjects. The investigators propose a new tree-structured data-mining method that identifies subgroups and their corresponding diagnostic tests to achieve the maximum area under the receiver-operating characteristic curve. Materials and Methods: The Osteoporosis and Ultrasound Study is a prospectively designed, population-based European multicenter observational study to evaluate state-of-the-art diagnostic methods for assessing osteoporosis. A total 2837 women underwent dual x-ray absorptiometry (DXA) and quantitative ultrasound (QUS). Prevalent vertebral fractures were determined by a centralized radiology laboratory on the basis of radiographs. The data-mining algorithm includes three steps: defining the criteria for node splitting and selection of the best diagnostic test on the basis of the area under the curve, using a random forest to estimate the probability of DXA being the preferred diagnostic method for each participant, and building a single regression tree to describe subgroups for which either DXA or QUS is the more accurate test or for which the two tests are equivalent. Results: For participants with weights ≤54.5 kg, QUS had a higher area under the curve in identifying prevalent vertebral fracture. For participants whose weights were >58.5 kg and whose heights were ≤167.5 cm, DXA was better, and for the remaining participants, DXA and QUS had comparable accuracy and could be used interchangeably. Conclusions: The proposed tree-structured subgroup analysis successfully defines subgroups and their best diagnostic tests. The method can be used to develop optimal diagnostic strategies in personalized medicine. [Copyright &y& Elsevier]

This article focuses on statistical analysis of clinical trials pursuing tailored therapy objectives, wherein evaluation of treatment effect occurs in the overall population as well as in a predefined subpopulation(s). The design and analysis principles presented provide a framework for decision making based on these novel multipopulation tailoring trial designs, considering the particular case of confirmatory trials. These principles include traditional multiple testing considerations, as well as 2 new analysis principles. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the correlation of transition from high school graduation to college matriculation with the significant increases in alcohol use and the effects of parent- and peer-based intervention components. The study uses Latent Transition Analysis (LTA) among a sample of high-risk matriculating college students. The study reveals that those participants in parent and peer conditions were least likely to transition to heavy drinkers status.

In many settings, testing has been proposed to assess the effect of an experimental regimen within a biomarker-positive subgroup where it is biologically plausible that benefit is stronger in such patients, and in the overall population that also includes biomarker-negative subjects less likely to benefit from that regimen. A statistically favorable result in the biomarker-positive subgroup would lead to a claim for that subgroup, whereas a statistically favorable result for the overall population would lead to a claim that includes both biomarker subgroups. The latter setting is problematic when biomarker-negative patients truly do not benefit from the experimental regimen. When it is prespecified that biomarker-negative patients should not be included in the primary analysis of treatment effect in biomarker-positive patients because of the likelihood that treatment effects would differ between the 2 subgroups, it is logically inconsistent to include biomarker-positive patients in the primary analysis of treatment effect in biomarker-negative patients. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The efficacy of quantified Crataegus extract in chronic heart failure (CHF) has been assessed in numerous clinical studies. The present pooled analysis evaluates the impact of baseline severity and gender on objective and patient-reported endpoints and associations between both types of outcomes in patients with early CHF. Methods: Available data from 687 individual patients treated with quantified Crataegus extract or placebo in ten studies were pooled. Treatment effects on physiologic outcome parameters and on symptoms were analysed for their association with baseline severity and gender. Changes in symptom scores were investigated with respect to their relation to physiologic outcome parameters. Results were compared with observations in a 3-year cohort study. Results: Physiologic outcome parameters maximal workload (MWL), left ventricular ejection fraction (LVEF) and pressure-heart rate product increase (PHRPI) at 50W ergometric exercise improved more in active treatment than in placebo patients. Magnitude of improvement was independent from baseline for LVEF but increased for MWL and PHRPI with baseline severity. Improvement of typical symptoms like reduced exercise tolerance, exertional dyspnea, weakness, fatigue, and palpitations improved more with active treatment and in patients with more severe symptoms. A weak association between improvements in MWL, PRHP, and symptoms could be demonstrated. Gender differences in treatment effects could be explained by baseline differences. Results of the pooled analysis are in agreement with observations in the cohort study. Conclusions: Crataegus extract treatment effects on physiologic outcomes and typical symptoms were modulated by baseline severity. Taking baseline differences into account, benefits were comparable in male and female patients with impaired exercise-tolerance in early chronic heart-failure. [Copyright &y& Elsevier]

Previous systematic reviews of silver-impregnated dressings have been contradictory regarding the healing of leg wounds/ulcers. Our systematic review was restricted to randomized controlled trials. Cochrane Library, Scopus, and MEDLINE databases were searched using the term “silver” in combination with “wound” or “ulcer” (and plural versions) without date/language restriction. Study quality was assessed and meta-analysis conducted for complete wound healing, wound size reduction, and healing rates. Overall study quality was fair with most studies having some bias. Evidence for wound healing using individual studies was poor. Meta-analyses found strong evidence for wound healing based on wound size reduction but no evidence based on complete wound-healing or healing rates. Although our results provide some evidence that silver-impregnated dressings improve the short-term healing of wounds and ulcers, long-term effects remain unclear. Clinical trial data with longer follow-up times are needed to address these issues. [ABSTRACT FROM AUTHOR]

Using the best evidence synthesis method (Slavin, 1995), we find out an accurate summary on the link between budgetary participation (BP) and managerial performance (MP). The use of selection criteria allowed to decrease the heterogeneity. Our results report the presence of the heterogeneity by cultural and industrial contingencies. American surveys reveal a significant positive link but suffer from heterogeneity of the sample. Under the sample homogeneity principle, Australian surveys reveal a non-significant negative link and only Taiwanese surveys reveal a positive and significant link. This last result has to encourage researchers to continue the study of publicly traded firms in the Taiwan Stock Exchange to study the causal link between the two variables with a Granger test and to study the evolution of this link over time in other countries. [ABSTRACT FROM AUTHOR]

Abstract: The 2005 St. Gallen Consensus Panel provided recommendations for the treatment of early breast cancer which rely on target identification first. The foremost advance since 2005—demonstration of trastuzumab efficacy for patients with HER2-positive disease—was realized because an effective treatment was being evaluated and because the trial patients had the targeted disease as determined by quality-controlled assessment prior to study entry. The BIG 1-98 trial provides a striking reminder of patients’ benefit from reliable pathological tumor assessment so that targeted therapies are effectively utilized. Several statistical methods facilitate use of clinical trial data for individualizing treatment. Subgroup analyses summarized using forest plots are essential for better understanding the disease and its treatment. The HERA trial illustrates the interpretation of relative and absolute treatment effects and estimating hazard rates over time as means to distinguish relevant differences across subgroups. Overview analyses, joint analyses, the STEPP (subpopulation treatment effect pattern plot) method and recursive partitioning are valuable tools. [Copyright &y& Elsevier]