A Word of Caution for Future Studies in Patellofemoral Pain: A Systematic Review With Meta-analysis.

BACKGROUND: Patellar maltracking is widely accepted as an underlying mechanism of patellofemoral pain. However, methodological differences in the literature hinder our ability to generate a universal quantitative definition of pathological patellofemoral kinematics (patellar maltracking) in patellofemoral pain, leaving us unable to determine the cause of patellofemoral pain. PURPOSE: To systematically review the literature to provide evidence regarding the influence of confounding variables on patellofemoral kinematics. STUDY DESIGN: Systematic review and random effects meta-analysis of control-case studies. METHODS: A literature search of case-control studies that evaluated patellofemoral kinematics at or near full extension and were written in English was conducted using Embase, PubMed, Scopus, and Web of Science up to September 2019. Cases were defined as patients with patellofemoral pain. Studies were eliminated if they lacked quantitative findings; had a primary aim to assess therapy efficacy; or included participants with osteoarthritis and/or previous trauma, pathology, or surgery. A quality assessment checklist was employed to evaluate each study. Meta-analyses were conducted to determine the influence of confounding variables on measures of patellofemoral kinematics. RESULTS: Forty studies met the selection criteria, with quality scores ranging from 13% to 81%. Patient characteristics, data acquisition, and measurement methods were the primary sources of methodological variability. Active quadriceps significantly increased lateral shift (standardized mean difference [SMD]shift = 0.33; P = .0102) and lateral tilt (SMDtilt = 0.43; P = .006) maltracking. Individuals with pain secondary to dislocation had greater effect sizes for lateral maltracking than had those with isolated patellofemoral pain (ΔSMDshift = 0.71, P = .0071; ΔSMDtilt = 1.38, P = .0055). CONCLUSION: This review exposed large methodological variability across the literature, which not only hinders the generalization of results, but ultimately mitigates our understanding of the underlying mechanism of patellofemoral pain. Although our meta-analyses support the diagnostic value of maltracking in patellofemoral pain, the numerous distinct methods for measuring maltracking and the limited control for cofounding variables across the literature prohibit defining a single quantitative profile. Compliance with specific standards for anatomic and outcome measures must be addressed by the scientific and clinical community to establish methodological uniformity in this field.

The Effects of Obesity on Outcome in Preclinical Animal Models of Infection and Sepsis: A Systematic Review and Meta-Analysis.

Background: Clinical studies suggest obesity paradoxically increases survival during bacterial infection and sepsis but decreases it with influenza, but these studies are observational. By contrast, animal studies of obesity in infection can prospectively compare obese versus nonobese controls. We performed a systematic review and meta-analysis of animal investigations to further examine obesity's survival effect in infection and sepsis. Methods: Databases were searched for studies comparing survival in obese versus nonobese controls. We performed a systematic review and meta-analysis of animal investigations to further examine obesity's survival effect in infection and sepsis. Methods. Databases were searched for studies comparing survival in obese versus nonobese animals following bacteria, lipopolysaccharide, or influenza virus challenges. Results: Twenty-one studies (761 obese and 603 control animals) met the inclusion criteria. Obesity reduced survival in 19 studies (11 significantly) and the odds ratio (95% CI) of survival (0.21(0.13, 0.35); I 2 = 64%, p < 0.01p < 0.01p < 0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n = 6 studies, 0.21(0.13, 0.34); I 2 = 64%, p < 0.01p < 0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n = 6 studies, 0.21(0.13, 0.34); I 2 = 64%, p < 0.01p < 0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n = 6 studies, 0.21(0.13, 0.34); I 2 = 64%, p < 0.01p < 0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n = 6 studies, 0.21(0.13, 0.34); I 2 = 64%, p < 0.01p < 0.01p < 0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n = 6 studies, 0.21(0.13, 0.34); I 2 = 31%, p=0.20 and n = 5, 0.22(0.13, 0.36); I 2 = 0%, p=0.59, respectively), (2) not significantly with cecal ligation and puncture (n = 4, 0.72(0.08, 6.23); I 2 = 75%, p < 0.01), and (3) significantly with influenza but with high heterogeneity (n = 6, 0.12(0.04, 0.34); I 2 = 73%, p < 0.01). Obesity's survival effects did not differ significantly comparing the four challenge types (p=0.49). Animal models did not include antimicrobials or glycemic control and study quality was low. Conclusions: Preclinical and clinical studies together emphasize the need for prospective studies in patients accurately assessing obesity's impact on survival during severe infection.

Antibiotic- and Fluid-Focused Bundles Potentially Improve Sepsis Management, but High-Quality Evidence Is Lacking for the Specificity Required in the Centers for Medicare and Medicaid Service's Sepsis Bundle (SEP-1).

OBJECTIVE: To address three controversial components in the Centers for Medicare and Medicaid Service's sepsis bundle for performance measure (SEP-1): antibiotics within 3 hours, a 30 mL/kg fluid infusion for all hypotensive patients, and repeat lactate measurements within 6 hours if initially elevated. We hypothesized that antibiotic- and fluid-focused bundles like SEP-1 would probably show benefit, but evidence supporting specific antibiotic timing, fluid dosing, or serial lactate requirements would not be concordant. Therefore, we performed a meta-analysis of studies of sepsis bundles like SEP-1. DATA SOURCES: PubMed, Embase, ClinicalTrials.gov through March 15, 2018. STUDY SELECTION: Studies comparing survival in septic adults receiving versus not receiving antibiotic- and fluid-focused bundles. DATA EXTRACTION: Two investigators (D.J.P., P.Q.E.). DATA SYNTHESIS: Seventeen observational studies (11,303 controls and 4,977 bundle subjects) met inclusion criteria. Bundles were associated with increased odds ratios of survival (odds ratio [95% CI]) in 15 studies with substantial heterogeneity (I = 61%; p < 0.01). Survival benefits were consistent in the five largest (1,697-12,486 patients per study) (1.20 [1.11-1.30]; I = 0%) and six medium-sized studies (167-1,029) (2.03 [1.52-2.71]; I = 8%) but not the six smallest (64-137) (1.25 [0.42-3.66]; I = 57%). Bundles were associated with similarly increased survival benefits whether requiring antibiotics within 1 hour (n = 7 studies) versus 3 hours (n = 8) versus no specified time (n = 2); or 30 mL/kg fluid (n = 7) versus another volume (≥ 2 L, n = 1; ≥ 20 mL/kg, n = 2; 1.5-2 L or 500 mL, n = 1 each; none specified, n = 4) (p = 0.19 for each comparison). In the only study employing serial lactate measurements, survival was not increased versus others. No study had a low risk of bias or assessed potential adverse bundle effects. CONCLUSIONS: Available studies support the notion that antibiotic- and fluid-focused sepsis bundles like SEP-1 improve survival but do not demonstrate the superiority of any specific antibiotic time or fluid volume or of serial lactate measurements. Until strong reproducible evidence demonstrates the safety and benefit of any fixed requirement for these interventions, the present findings support the revision of SEP-1 to allow flexibility in treatment according to physician judgment.

Health Disparities and Sepsis: a Systematic Review and Meta-Analysis on the Influence of Race on Sepsis-Related Mortality.

RATIONALE: Racial disparities in sepsis outcomes have been previously reported. However, recently, there have been inconsistencies in identifying which socioeconomic variables, such as race, account for these disparities. The objective of this study was to perform a systematic review in order to examine the impact of race on sepsis-attributable mortality. METHODS: Systematic searches for English-language articles identified through MEDLINE, EBSCOhost, PubMed, ERIC, and Cochrane Library databases from 1960 to 1 February 2017. Included studies examined sepsis outcomes in the context of sepsis incidence and/or mortality. Two investigators independently extracted data and assessed study quality. The meta-analysis was performed in accordance with the Cochrane Collaboration guidelines. RESULTS: Twenty-one studies adhered to the predefined selection criteria and were included in the review. Of the 21 studies, we pooled data from 6 studies comparing African American/Black race as a risk factor for sepsis-related mortality disparities (reference group being Caucasian/White). From the meta-analysis on these six studies, African American/Black race was found to have no statistical significant relationship with sepsis-related mortality (odds ratio 1.20, 95% CI, 0.81 to 1.77). Similar results were found for other races (Native Americans, Asians) and ethnicities (Hispanic/Latinos). CONCLUSION: On the basis of available evidence from a limited number of observation retrospective studies, race alone cannot fully explain sepsis-related disparities, especially sepsis-attributable mortality.

Procalcitonin-Guided Antibiotic Discontinuation and Mortality in Critically Ill Adults: A Systematic Review and Meta-analysis.

BACKGROUND: Procalcitonin (PCT)-guided antibiotic discontinuation appears to decrease antibiotic use in critically ill patients, but its impact on survival remains less certain. METHODS: We searched PubMed, Embase, Scopus, Web of Science, and CENTRAL for randomized controlled trials (RCTs) of PCT-guided antibiotic discontinuation in critically ill adults reporting survival or antibiotic duration. Searches were conducted without language restrictions from inception to July 23, 2018. Two reviewers independently conducted all review stages; another adjudicated differences. Data were pooled using random-effects meta-analysis. Study quality was assessed with the Cochrane risk of bias tool, and evidence was graded using GRADEpro. RESULTS: Among critically ill adults (5,158 randomized; 5,000 analyzed), PCT-guided antibiotic discontinuation was associated with decreased mortality (16 RCTs; risk ratio [RR], 0.89; 95% CI, 0.83-0.97; I2 = 0%; low certainty). Death was the primary outcome in only one study and a survival benefit was not observed in the subset specified as sepsis (10 RCTs; RR, 0.94; 95% CI, 0.85-1.03; I2 = 0%), those without industry sponsorship (nine RCTs; RR, 0.98; 95% CI, 0.87-1.10; I2 = 0%), high PCT-guided algorithm adherence (five RCTs; RR, 0.93; 95% CI, 0.71-1.22; I2 = 0%), and PCT-guided algorithms without C-reactive protein (eight RCTs; RR, 0.96; 95% CI, 0.87-1.06; I2 = 0%). PCT-guided antibiotic discontinuation decreased antibiotic duration (mean difference, 1.31 days; 95% CI, -2.27 to -0.35; I2 = 93%) (low certainty). CONCLUSIONS: Our findings of increased survival and decreased antibiotic utilization associated with PCT-guided antibiotic discontinuation represent low-certainty evidence with a high risk of bias. This relationship was primarily observed in studies without high protocol adherence and in studies with algorithms combining PCT and C-reactive protein. Properly designed studies with mortality as the primary outcome are needed to address this question. TRIAL REGISTRY: International Prospective Register of Systematic Reviews (PROSPERO); No.: CRD42016049715; URL: http://www.crd.york.ac.uk/PROSPERO_REBRANDING/display_record.asp?ID=CRD42016049715.

Evidence Underpinning the Centers for Medicare & Medicaid Services' Severe Sepsis and Septic Shock Management Bundle (SEP-1): A Systematic Review.

This article has been corrected. To see what has changed, please read the Letter to the Editor and the authors' response. The original version (PDF) is appended to this article as a Supplement. Background: The Severe Sepsis and Septic Shock Early Management Bundle (SEP-1), the sepsis performance measure introduced in 2015 by the Centers for Medicare & Medicaid Services (CMS), requires the reporting of up to 5 hemodynamic interventions, as many as 141 tasks, and 3 hours to document for a single patient. Purpose: To evaluate whether moderate- or high-level evidence shows that use of the 2015 SEP-1 or its hemodynamic interventions improves survival in adults with sepsis. Data Sources: PubMed, Embase, Scopus, Web of Science, and ClinicalTrials.gov from inception to 28 November 2017 with no language restrictions. Study Selection: Randomized and observational studies of death among adults with sepsis who received versus those who did not receive either the entire SEP-1 bundle or 1 or more SEP-1 hemodynamic interventions, including serial lactate measurements; a fluid infusion of 30 mL/kg of body weight; and assessment of volume status and tissue perfusion with a focused examination, bedside cardiovascular ultrasonography, or fluid responsiveness testing. Data Extraction: Two investigators independently extracted study data and assessed each study's risk of bias; 4 authors rated level of evidence by consensus using CMS criteria published in 2013. High- or moderate-level evidence required studies to have no confounders and low risk of bias. Data Synthesis: Of 56 563 references, 20 studies (18 reports) met inclusion criteria. One single-center observational study reported lower in-hospital mortality after implementation of the SEP-1 bundle. Sixteen studies (2 randomized and 14 observational) reported increased survival with serial lactate measurements or 30-mL/kg fluid infusions. None of the 17 studies were free of confounders or at low risk of bias. In 3 randomized trials, fluid responsiveness testing did not alter survival. Limitations: Few trials, poor-quality and confounded studies, and no studies (with survival outcomes) of the focused examination or bedside cardiovascular ultrasonography. Use of the 2015 version of SEP-1 and 2013 version of CMS evidence criteria, both of which were updated in 2017. Conclusion: No high- or moderate-level evidence shows that SEP-1 or its hemodynamic interventions improve survival in adults with sepsis. Primary Funding Source: National Institutes of Health. (PROSPERO: CRD42016052716).

The impact and incidence of altered body image in patients with head and neck tumors: a systematic review.

Body image dissatisfaction is a common issue among patients with cancer and is associated with difficulty coping, anxiety, and depression. Patients with tumors involving the head and neck are at increased risk of body image dissatisfaction due to the visible disfigurement that can occur from their illness and its treatment. Patients with primary central nervous system (CNS) malignancies often face similar tumor-related and treatment-related effects, yet there is limited research conducted in this population. Our aim was to perform a systematic review of the literature on body image in patients with tumors of the head and neck, and identify factors associated with body image alterations during treatment, with the intention of applying these approaches to those with CNS disease. A systematic search of PubMed and EMBASE was performed using predefined criteria. Nine studies met the inclusion criteria and were selected for review. The literature collected showed a relationship between body image and age, depressive symptoms, and tumor grade or stage. In addition, body image disturbance had an impact on patients' daily functioning and psychosocial indices including anxiety, coping, and body reintegration. Evaluation of the impact of body image alterations in patients with CNS tumors is needed to direct clinical care, explore research opportunities, and improve patient quality of life.

Correction: A systematic review and meta-analysis of preclinical trials testing anti-toxin therapies for B. anthracis infection: A need for more robust study designs and results.

[This corrects the article DOI: 10.1371/journal.pone.0182879.].

A Systematic Review of Exercise Systematic Reviews in the Cancer Literature (2005-2017).

BACKGROUND: Evidence supports the benefits of exercise for patients with cancer; however, specific guidance for clinical decision making regarding exercise timing, frequency, duration, and intensity is lacking. Efforts are needed to optimize clinical recommendations for exercise in the cancer population. OBJECTIVES: To aggregate information regarding the benefit of exercise through a systematic review of existing systematic reviews in the cancer exercise literature. DATA SOURCES: PubMed, CINAHL Plus, Scopus, Web of Science, and EMBASE. STUDY ELIGIBILITY CRITERIA: Systematic reviews and meta-analyses of the impact of movement-based exercise on the adult cancer population. METHODS: Two author teams reviewed 302 abstracts for inclusion with 93 selected for full-text review. A total of 53 studies were analyzed. A Measurement Tool to Assess Systematic Reviews (AMSTAR) was used as a quality measure of the reviews. Information was extracted using the PICO format (ie, participants, intervention, comparison, outcomes). Descriptive findings are reported. RESULTS: Mean AMSTAR score = 7.66/11 (±2.04) suggests moderate quality of the systematic reviews. Exercise is beneficial before, during, and after cancer treatment, across all cancer types, and for a variety of cancer-related impairments. Moderate-to-vigorous exercise is the best level of exercise intensity to improve physical function and mitigate cancer-related impairments. Therapeutic exercises are beneficial to manage treatment side effects, may enhance tolerance to cancer treatments, and improve functional outcomes. Supervised exercise yielded superior benefits versus unsupervised. Serious adverse events were not common. LIMITATIONS: Movement-based exercise intervention outcomes are reported. No analysis of pooled effects was calculated across reviews due to significant heterogeneity within the systematic reviews. Findings do not consider exercise in advanced cancers or pediatric populations. CONCLUSIONS: Exercise promotes significant improvements in clinical, functional, and in some populations, survival outcomes and can be recommended regardless of the type of cancer. Although generally safe, patients should be screened and appropriate precautions taken. Efforts to strengthen uniformity in clinical trial reporting, develop clinical practice guidelines, and integrate exercise and rehabilitation services into the cancer delivery system are needed.

A systematic review and meta-analysis of preclinical trials testing anti-toxin therapies for B. anthracis infection: A need for more robust study designs and results.

BACKGROUND: B. anthracis anti-toxin agents are approved and included in the Strategic National Stockpile based primarily on animal infection trials. However, in the only anthrax outbreak an approved anti-toxin agent was administered in, survival did not differ comparing recipients and non-recipients, although recipients appeared sicker. OBJECTIVE: Employ a systematic review and meta-analysis to investigate preclinical studies supporting anthrax anti-toxin agents. DATA SOURCE: PubMed, EMBASE, and Scopus. STUDY ELIGIBILITY: Compared survival with an anti-toxin agent versus control in B. anthracis challenged, antibiotic treated animals. STUDY METHODS: Examine model and study design and the effect of anti-toxin agents on relative risk of death(95%CI) (RR). RESULTS: From 9 studies, 29 experiments were analyzed which included 4 species (748 animals) and 5 agents; LFI, AIG, AVP-21D9, Raxibacumab, and ETI-204. Only five experiments were blinded and no experiment included the cardiopulmonary support sick B. anthracis patients receive. Only one agent in a single un-blinded experiment reduced RR significantly [0.45(0.22,0.940]. However, in six studies testing an agent in more than one experiment in the same species, agents had consistent survival effects across experiments [I2 = 0, p≥0.55 in five and I2 = 42%, p = 0.16 in one]. Within each species, agents had effects on the side of benefit; in one study testing AVP-21D9 in mice [0.11(0.01,1.82)] or guinea pigs [0.70(0.48,1.03)]; across eight rabbit studies testing LFI, Raxibacumab, AIG or ETI-204 [0.62(0.45,0.87); I2 = 17.4%, p = 0.29]; and across three monkey studies testing Raxibacumab, AIG or ETI-204 [0.66(0.34,1.27); I2 = 25.3%, p = 0.26]. Across all agents and species, agents decreased RR [0.64(0.52,0.79); I2 = 5.3%, p = 0.39]. LIMITATIONS: Incidence of selective reporting not identifiable. CONCLUSIONS: Although overall significant, individually anti-toxin agents had weak beneficial effects. Lack of study blinding and relevant clinical therapies further weakened studies. Although difficult, preclinical studies with more robust designs and results are warranted to justify the resources necessary to maintain anti-toxin agents in national stockpiles.

TMPRSS2:ERG Gene Fusions in Prostate Cancer of West African Men and a Meta-Analysis of Racial Differences.

The prevalence of fusions of the transmembrane protease, serine 2, gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2:ERG, in prostate cancer varies by race. However, such somatic aberration and its association with prognostic factors have neither been studied in a West African population nor been systematically reviewed in the context of racial differences. We used immunohistochemistry to assess oncoprotein encoded by the ERG gene as the established surrogate of ERG fusion genes among 262 prostate cancer biopsies from the Ghana Prostate Study (2004-2006). Poisson regression with robust variance estimation provided prevalence ratios and 95% confidence intervals of ERG expression in relation to patient characteristics. We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. We further conducted a systematic review and meta-analysis of TMPRSS2:ERG fusions in relation to race, Gleason score, and tumor stage, combining results from Ghana with 40 additional studies. Meta-analysis showed the prevalence of TMPRSS2:ERG fusions in prostate cancer to be highest in men of European descent (49%), followed by men of Asian (27%) and then African (25%) descent. The lower prevalence of TMPRSS2:ERG fusions in men of African descent implies that alternative genomic mechanisms might explain the disproportionately high prostate cancer burden in such populations.

A Two-Gene Prognostic Classifier for Early-Stage Lung Squamous Cell Carcinoma in Multiple Large-Scale and Geographically Diverse Cohorts.

INTRODUCTION: There are no validated molecular methods that prospectively identify patients with surgically resected lung squamous cell carcinoma (SCC) at high risk for recurrence. By focusing on the expression of genes with known functions in development of lung SCC and prognosis, we sought to develop a robust prognostic classifier of early-stage lung SCC. METHODS: The expression of 253 genes selected by literature search was evaluated in microarrays from 107 stage I/II tumors. Associations with survival were evaluated by Cox regression and Kaplan-Meier survival analyses in two independent cohorts of 121 and 91 patients with SCC, respectively. A classifier score based on multivariable Cox regression was derived and examined in six additional publicly available data sets of stage I/II lung SCC expression profiles (n = 358). The prognostic value of this classifier was evaluated in meta-analysis of patients with stage I/II (n = 479) and stage I (n = 326) lung SCC. RESULTS: Dual specificity phosphatase 6 gene (DUSP6) and actinin alpha 4 gene (ACTN4) were associated with prognostic outcome in two independent patient cohorts. Their expression values were utilized to develop a classifier that identified patients with stage I/II lung SCC at high risk for recurrence (hazard ratio [HR] = 4.7, p = 0.018) or cancer-specific mortality (HR = 3.5, p = 0.016). This classifier also identified patients at high risk for recurrence (HR = 2.7, p = 0.008) or death (HR = 2.2, p = 0.001) in publicly available data sets of stage I/II and in meta-analysis of stage I patients. CONCLUSIONS: We have established and validated a prognostic classifier to inform clinical management of patients with lung SCC after surgical resection.

Increased body mass index and adjusted mortality in ICU patients with sepsis or septic shock: a systematic review and meta-analysis.

BACKGROUND: At least 25 % of adults admitted to intensive care units (ICU) in the United States have an overweight, obese or morbidly obese body mass index (BMI). The effect of BMI on adjusted mortality in adults requiring ICU treatment for sepsis is unclear. We performed a systematic review of adjusted all-cause mortality for underweight, overweight, obese and morbidly obese BMIs relative to normal BMI for adults admitted to the ICU with sepsis, severe sepsis, and septic shock. METHOD: PubMed, the Cochrane Library, and EMBASE electronic databases were searched through November 18, 2015, without language restrictions. We included studies that reported multivariate regression analyses for all-cause mortality using standard BMI categories for adults admitted to the ICU for sepsis, severe sepsis, and septic shock. Articles were selected by consensus among multiple reviewers. Electronic database searches yielded 10,312 articles, of which six were eligible. Data were extracted by one reviewer and then reviewed by three independent reviewers. For the meta-analyses performed, the adjusted odds ratios (aOR) of mortality were combined using a random-effects model. Risk of bias was assessed using the Newcastle-Ottawa quality assessment scale for cohort studies. RESULTS: Four retrospective (n = 6609 patients) and two prospective (n = 556) studies met inclusion criteria. Compared to normal BMI, across five studies each, overweight or obese BMIs reduced the adjusted odds ratio (95 % CI) of mortality [aOR] [0.83 (0.75, 0.91) p < 0.001 and 0.82 (0.67, 0.99) p = 0.04, respectively] with low or moderate heterogeneity (I(2) = 15.7 %, p = 0.31 and I(2) = 53.0 %, p = 0.07, respectively). Across three studies each, morbidly obese BMI and underweight BMI did not alter aOR [0.90 (0.59, 1.39), p = 0.64; I(2) = 43.3 %, p = 0.17; and 1.24 (0.79, 1.95), p = 0.35; I(2) = 15.6 %, p = 0.31 respectively]. Only one study clearly defined how and when height and weight measurements were calculated. Site of underlying infection and illness severity may have favored overweight and obese BMIs. CONCLUSIONS: This is the first meta-analysis to show that overweight or obese BMIs reduce adjusted mortality in adults admitted to the ICU with sepsis, severe sepsis, or septic shock. More rigorous studies that address these limitations are needed to clarify the impact of BMI on sepsis ICU outcomes. TRIAL REGISTRATION: PROSPERO International prospective register of systematic reviews 10.15124/ CRD42014010556 . Registered on July 11, 2014.

Is birthweight associated with total and aggressive/lethal prostate cancer risks? A systematic review and meta-analysis.

BACKGROUND: It has been hypothesised that intrauterine exposures are important for subsequent prostate cancer risk. Prior epidemiological studies have used birthweight as a proxy of cumulative intrauterine exposures to test this hypothesis, but results have been inconsistent partly because of limited statistical power. METHODS: We investigated birthweight in relation to prostate cancer in the Medical Research Council (MRC) National Survey of Health and Development (NSHD) using Cox proportional hazards models. We then conducted a meta-analysis of birthweight in relation to total and aggressive/lethal prostate cancer risks, combining results from the NSHD analysis with 13 additional studies on this relationship identified from a systematic search in four major scientific literature databases through January 2015. RESULTS: Random-effects models found that per kg increase in birthweight was positively associated with total (OR=1.02, 95% confidence interval (95% CI)=1.00, 1.05; I(2)=13%) and aggressive/lethal prostate cancer (OR=1.08, 95% CI=0.99, 1.19; I(2)=40%). Sensitivity analyses restricted to studies with birthweight extracted from medical records demonstrated stronger positive associations with total (OR=1.11, 95% CI=1.03, 1.19; I(2)=0%) and aggressive/lethal (OR=1.37, 95% CI=1.09, 1.74; I(2)=0%) prostate cancer. These studies heavily overlapped with those based in Nordic countries. CONCLUSIONS: This study provides evidence that heavier birthweight may be associated with modest increased risks of total and aggressive/lethal prostate cancer, which supports the hypothesis that intrauterine exposures may be related to subsequent prostate cancer risks.

An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma Based on mRNA, microRNA, and DNA Methylation Biomarkers.

INTRODUCTION: Up to 30% stage I lung cancer patients suffer recurrence within 5 years of curative surgery. We sought to improve existing protein-coding gene and microRNA expression prognostic classifiers by incorporating epigenetic biomarkers. METHODS: Genome-wide screening of DNA methylation and pyrosequencing analysis of HOXA9 promoter methylation were performed in two independently collected cohorts of stage I lung adenocarcinoma. The prognostic value of HOXA9 promoter methylation alone and in combination with mRNA and miRNA biomarkers was assessed by Cox regression and Kaplan-Meier survival analysis in both cohorts. RESULTS: Promoters of genes marked by polycomb in embryonic stem cells were methylated de novo in tumors and identified patients with poor prognosis. The HOXA9 locus was methylated de novo in stage I tumors (p < 0.0005). High HOXA9 promoter methylation was associated with worse cancer-specific survival (hazard ratio [HR], 2.6; p = 0.02) and recurrence-free survival (HR, 3.0; p = 0.01), and identified high-risk patients in stratified analysis of stages IA and IB. Four protein-coding gene (XPO1, BRCA1, HIF1α, and DLC1), miR-21 expression, and HOXA9 promoter methylation were each independently associated with outcome (HR, 2.8; p = 0.002; HR, 2.3; p = 0.01; and HR, 2.4; p = 0.005, respectively), and when combined, identified high-risk, therapy naive, stage I patients (HR, 10.2; p = 3 × 10). All associations were confirmed in two independently collected cohorts. CONCLUSION: A prognostic classifier comprising three types of genomic and epigenomic data may help guide the postoperative management of stage I lung cancer patients at high risk of recurrence.

Biomedical Data Sharing and Reuse: Attitudes and Practices of Clinical and Scientific Research Staff.

BACKGROUND: Significant efforts are underway within the biomedical research community to encourage sharing and reuse of research data in order to enhance research reproducibility and enable scientific discovery. While some technological challenges do exist, many of the barriers to sharing and reuse are social in nature, arising from researchers' concerns about and attitudes toward sharing their data. In addition, clinical and basic science researchers face their own unique sets of challenges to sharing data within their communities. This study investigates these differences in experiences with and perceptions about sharing data, as well as barriers to sharing among clinical and basic science researchers. METHODS: Clinical and basic science researchers in the Intramural Research Program at the National Institutes of Health were surveyed about their attitudes toward and experiences with sharing and reusing research data. Of 190 respondents to the survey, the 135 respondents who identified themselves as clinical or basic science researchers were included in this analysis. Odds ratio and Fisher's exact tests were the primary methods to examine potential relationships between variables. Worst-case scenario sensitivity tests were conducted when necessary. RESULTS AND DISCUSSION: While most respondents considered data sharing and reuse important to their work, they generally rated their expertise as low. Sharing data directly with other researchers was common, but most respondents did not have experience with uploading data to a repository. A number of significant differences exist between the attitudes and practices of clinical and basic science researchers, including their motivations for sharing, their reasons for not sharing, and the amount of work required to prepare their data. CONCLUSIONS: Even within the scope of biomedical research, addressing the unique concerns of diverse research communities is important to encouraging researchers to share and reuse data. Efforts at promoting data sharing and reuse should be aimed at solving not only technological problems, but also addressing researchers' concerns about sharing their data. Given the varied practices of individual researchers and research communities, standardizing data practices like data citation and repository upload could make sharing and reuse easier.

Tidal volume and plateau pressure use for acute lung injury from 2000 to present: a systematic literature review.

OBJECTIVE: Since publication of the Respiratory Management of Acute Lung Injury and Acute Respiratory Distress Syndrome (ARMA) trial in 2000, use of tidal volume (VT) less than or equal to 6 mL/kg predicted body weight with corresponding plateau airway pressures (PPlat) less than or equal to 30 cm H2O has been advocated for acute lung injury. However, compliance with these recommendations is unknown. We therefore investigated VT (mL/kg predicted body weight) and PPlat (cm H2O) practices reported in studies of acute lung injury since ARMA using a systematic literature review (i.e., not a meta-analysis). DATA SOURCES: PubMed, Scopus, and EMBASE. STUDY SELECTION: Randomized controlled trials and nonrandomized studies enrolling patients with acute lung injury from May 2000 to June 2013 and reporting VT. DATA EXTRACTION: Whether the study was a randomized controlled trial or a nonrandomized study and performed or not at an Acute Respiratory Distress Syndrome Network center; in randomized controlled trials, the pre- and postrandomization VT (mL/kg predicted body weight) and PPlat (cm H2O) and whether a VT protocol was used postrandomization; in nonrandomized studies, baseline VT and PPlat. DATA SYNTHESIS: Twenty-two randomized controlled trials and 71 nonrandomized studies were included. Since 2000 at acute respiratory distress syndrome Network centers, routine VT was similar comparing randomized controlled trials and nonrandomized studies (p = 0.25) and unchanged over time (p = 0.75) with a mean value of 6.81 (95% CI, 6.45, 7.18). At non-acute respiratory distress syndrome Network centers, routine VT was also similar when comparing randomized controlled trials and nonrandomized studies (p = 0.71), but decreased (p = 0.001); the most recent estimate for it was 6.77 (6.22, 7.32). All VT estimates were significantly greater than 6 (p ≤ 0.02). In randomized controlled trials employing VT protocols, routine VT was reduced in both acute respiratory distress syndrome Network (n = 4) and non-acute respiratory distress syndrome Network (n = 11) trials (p ≤ 0.01 for both), but even postrandomization was greater than 6 (6.47 [6.29, 6.65] and 6.80 [6.42, 7.17], respectively; p ≤ 0.0001 for both). In 59 studies providing data, routine PPlat, averaged across acute respiratory distress syndrome Network or non-acute respiratory distress syndrome Network centers, was significantly less than 30 (p ≤ 0.02). CONCLUSIONS: For clinicians treating acute lung injury since 2000, achieving VT less than or equal to 6 mL/kg predicted body weight may not have been as attainable or important as PPlat less than or equal to 30 cm H2O. If so, there may be equipoise to test if VT less than or equal to 6 mL/kg predicted body weight are necessary to improve acute lung injury outcome.

Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs.

Bloom syndrome is a rare autosomal recessive disorder characterized by genetic instability and cancer predisposition, and caused by mutations in the gene encoding the Bloom syndrome, RecQ helicase-like (BLM) protein. To determine whether altered gene expression might be responsible for pathological features of Bloom syndrome, we analyzed mRNA and microRNA (miRNA) expression in fibroblasts from individuals with Bloom syndrome and in BLM-depleted control fibroblasts. We identified mRNA and miRNA expression differences in Bloom syndrome patient and BLM-depleted cells. Differentially expressed mRNAs are connected with cell proliferation, survival, and molecular mechanisms of cancer, and differentially expressed miRNAs target genes involved in cancer and in immune function. These and additional altered functions or pathways may contribute to the proportional dwarfism, elevated cancer risk, immune dysfunction, and other features observed in Bloom syndrome individuals. BLM binds to G-quadruplex (G4) DNA, and G4 motifs were enriched at transcription start sites (TSS) and especially within first introns (false discovery rate ≤ 0.001) of differentially expressed mRNAs in Bloom syndrome compared with normal cells, suggesting that G-quadruplex structures formed at these motifs are physiologic targets for BLM. These results identify a network of mRNAs and miRNAs that may drive the pathogenesis of Bloom syndrome.

Antitumor necrosis factor therapy is associated with improved survival in clinical sepsis trials: a meta-analysis.

OBJECTIVES: Sepsis is a lethal syndrome annually affecting approximately 900,000 patients in the United States alone. Despite their benefit in rheumatoid disease, selective antitumor necrosis factor agents failed to improve outcome in early sepsis trials in the 1990s. However, data from additional sepsis trials testing these agents are now available. We therefore sought to determine the effect on survival of selective antitumor necrosis factor agents in randomized clinical sepsis trials.. DATA SOURCES: PubMed, Scopus, Embase, and Web of Science. STUDY SELECTION: Randomized human sepsis trials of selective antitumor necrosis factor agents reporting survival rates. DATA EXTRACTION: Two investigators independently collected relevant data on study characteristics, treatment interventions, and patients from each study. DATA SYNTHESIS: Antitumor necrosis factor agents in 15 sepsis trials (n=8,896 patients) meeting inclusion criteria had similar effects (I=0, p=0.84) and compared with controls (placebo in 14 trials or a lower dose in one trial) overall decreased the relative risk of death (95% CI) (0.93 [0.88-0.98], p=0.01). In subgroup analysis, tumor necrosis factor monoclonal antibodies (10 trials, n=6,818) alone produced a significant survival benefit (0.93 [0.87, 0.99], p=0.02) (I=0, p=0.83). Tumor necrosis factor polyclonal antibodies (two trials, n=151) and low-molecular-weight soluble receptor (two trials, n=1,786) had similar beneficial effects to antitumor necrosis factor agents overall (0.82 [0.49-1.37], p=0.45; 0.93 [0.81-1.08], p=0.33, respectively). The effect of tumor necrosis factor high-molecular-weight soluble receptor (one trial, n=141) was not significantly different from other agents but was on the side of harm (1.50 [0.86-2.61], p=0.16). CONCLUSION: Antitumor necrosis factor agents produced a modest but significant decrease in the risk of dying with sepsis. Prior individual trials failed to demonstrate benefit, likely because they were underpowered. A definitive trial demonstrating the potential benefit of such agents might require 10,000 or more patients with sepsis.

Combination of protein coding and noncoding gene expression as a robust prognostic classifier in stage I lung adenocarcinoma.

Prognostic tests for patients with early-stage lung cancer may provide needed guidance on postoperative surveillance and therapeutic decisions. We used a novel strategy to develop and validate a prognostic classifier for early-stage lung cancer. Specifically, we focused on 42 genes with roles in lung cancer or cancer prognosis. Expression of these biologically relevant genes and their association with relapse-free survival (RFS) were evaluated using microarray data from 148 patients with stage I lung adenocarcinoma. Seven genes associated with RFS were further examined by quantitative reverse transcription PCR in 291 lung adenocarcinoma tissues from Japan, the United States, and Norway. Only BRCA1, HIF1A, DLC1, and XPO1 were each significantly associated with prognosis in the Japan and US/Norway cohorts. A Cox regression-based classifier was developed using these four genes on the Japan cohort and validated in stage I lung adenocarcinoma from the US/Norway cohort and three publicly available lung adenocarcinoma expression profiling datasets. The results suggest that the classifier is robust across ethnically and geographically diverse populations regardless of the technology used to measure gene expression. We evaluated the combination of the four-gene classifier with miRNA miR-21 (MIR21) expression and found that the combination improved associations with prognosis, which were significant in stratified analyses on stage IA and stage IB patients. Thus, the four coding gene classifier, alone or with miR-21 expression, may provide a clinically useful tool to identify high-risk patients and guide recommendations regarding adjuvant therapy and postoperative surveillance of patients with stage I lung adenocarcinoma.