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BACKGROUND: While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome. PATIENTS AND METHODS: We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10(−5)), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas. RESULTS: The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16–1.32, P = 1.9 × 10(−7)). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10(−2)) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10(−8)). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1–1.9, P = 4.6 × 10(−2)). CONCLUSIONS: Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival.

Objective To assess whether lifelong higher circulating 25-hydroxyvitamin D [25(OH)D] levels increase serum calcium levels and kidney stone disease (KSD) risk. Methods Summary data for KSD were obtained from the UK biobank genome-wide association study (6536 cases and 388 508 controls). We acquired summary data for 25(OH)D from 120 618 Europeans and another large-scale analysis (443 734 Europeans) for primary and secondary analysis. Random-effect inverse-variance weighted (IVW) and 7 additional sensitivity analyses were applied. Next, multivariable Mendelian randomization (MVMR) was performed by introducing data for serum calcium levels. Results Genetic predisposition for a 1-SD higher 25(OH)D level was associated with increased serum calcium levels (IVW; beta, 0.014; 95% CI, 0.010-0.018; P = 7.64E-10). Genetically predicted higher circulating 25(OH)D levels were associated with increased the risk of KSD, with per 1-SD odds ratios (ORs) of 1.47 (95% CI, 1.22-1.77; P = 5.49E-05) and 1.36 (95% CI, 1.03-1.80; P = 0.029) using the IVW and MVMR-Egger methods, respectively. In secondary analysis, similar results were found: 25(OH)D was associated with an increased risk of KSD in univariate Mendelian randomization (IVW; OR 1.71; 95% CI, 1.26-2.32; P = 0.001) and MVMR (OR 1.43; 95% CI, 1.16-1.76; P < 0.001) analyses. Most sensitivity analyses were consistent with the primary results, both for the primary and secondary analyses. Conclusions Our study supports that higher genetically predicted lifelong circulating 25(OH)D levels are associated with higher calcium levels and KSD risk. The effects of 25(OH)D on KSD were partially attenuated—but still significant—in MVMR.

Epidemiological evidence is consistent with a protective effect of vitamin D against colorectal cancer (CRC), but the observed strong associations are open to confounders and potential reverse causation. Previous Mendelian randomisation (MR) studies were limited by poor genetic instruments and inadequate statistical power. Moreover, whether genetically higher CRC risk can influence vitamin D level, namely the reverse causation, still remains unknown. Herein, we report the first bidirectional MR study. We employed 110 newly identified genetic variants as proxies for vitamin D to obtain unconfounded effect estimates on CRC risk in 26 397 CRC cases and 41 481 controls of European ancestry. To test for reserve causation, we estimated effects of 115 CRC-risk variants on vitamin D level among 417 580 participants from the UK Biobank. The causal association was estimated using the random-effect inverse-variance weighted (IVW) method. We found no significant causal effect of vitamin D on CRC risk [IVW estimate odds ratio: 0.97, 95% confidence interval (CI) = 0.88-1.07, P =.565]. Similarly, no significant reverse causal association was identified between genetically increased CRC risk and vitamin D levels (IVW estimate β: −0.002, 95% CI = −0.008 to 0.004, P =.543). Stratified analysis by tumour sites did not identify significant causal associations in either direction between vitamin D and colon or rectal cancer. Despite the improved statistical power of this study, we found no evidence of causal association of either direction between circulating vitamin D and CRC risk. Significant associations reported by observational studies may be primarily driven by unidentified confounders.

Previous studies using additive genetic models failed to identify robust evidence of associations between colorectal cancer (CRC) risk variants and survival outcomes. However, additive models can be prone to false negative detection if the underlying inheritance mode is recessive. Here, we tested all currently known CRC-risk variants (n = 129) in a discovery analysis of 5675 patients from a Scottish cohort. Significant associations were then validated in 2474 CRC cases from UK Biobank. We found that the TT genotype of the intron variant rs7495132 in the CRTC3 gene was associated with clinically relevant poorer CRC-specific survival in both the discovery (HR = 1.97, 95% CI = 1.41-2.74, P = 6.1x10-5 ) and validation analysis (HR = 1.69, 95% CI = 1.03-2.79, P = 0.038). In addition, the GG genotype of rs10161980 (intronic variant of AL139383.1 lncRNA) was associated with worse overall survival in the discovery cohort (HR = 1.24, 95% CI = 1.10-1.39, P = 3.4x10-4 ) and CRC-specific survival in the validation cohort (HR = 1.26, 95% CI = 1.01-1.56, P = 0.040). Our findings show that common genetic risk factors can also influence CRC survival outcome. This article is protected by copyright. All rights reserved.

Background There is a clear need for systematic appraisal of models/factors predicting colorectal cancer (CRC) metastasis and recurrence because clinical decisions about adjuvant treatment are taken on the basis of such variables. Methods We conducted an umbrella review of all systematic reviews of observational studies (with/without meta-analysis) that evaluated risk factors of CRC metastasis and recurrence. We also generated an updated synthesis of risk prediction models for CRC metastasis and recurrence. We cross-assessed individual risk factors and risk prediction models. Results Thirty-four risk factors for CRC metastasis and 17 for recurrence were investigated. Twelve of 34 and 4/17 risk factors with p vascular invasion for lymph node metastasis [LNM] in pT1 CRC) presented convincing evidence. We identified 24 CRC risk prediction models. Across 12 metastasis models, six out of 27 unique predictors were assessed in the umbrella review and four of them changed the odds of the outcome at least 3-fold. Across 12 recurrence models, five out of 25 unique predictors were assessed in the umbrella review and only one changed the odds of the outcome at least 3-fold. Conclusions This study provides an in-depth evaluation and cross-assessment of 51 risk factors and 24 prediction models. Our findings suggest that a minority of influential risk factors are employed in prediction models, which indicates the need for a more rigorous and systematic model construction process following evidence-based methods.

A growing body of evidence suggests that vitamin D deficiency has been associated with an increased susceptibility to viral and bacterial respiratory infections. In this study, we aimed to examine the association between vitamin D and COVID-19 risk and outcomes. We used logistic regression to identify associations between vitamin D variables and COVID-19 (risk of infection, hospitalisation and death) in 417,342 participants from UK Biobank. We subsequently performed a Mendelian Randomisation (MR) study to look for evidence of a causal effect. In total, 1746 COVID-19 cases (399 deaths) were registered between March and June 2020. We found no significant associations between COVID-19 infection risk and measured 25-OHD levels after adjusted for covariates, but this finding is limited by the fact that the vitamin D levels were measured on average 11 years before the pandemic. Ambient UVB was strongly and inversely associated with COVID-19 hospitalization and death overall and consistently after stratification by BMI and ethnicity. We also observed an interaction that suggested greater protective effect of genetically-predicted vitamin D levels when ambient UVB radiation is stronger. The main MR analysis did not show that genetically-predicted vitamin D levels are causally associated with COVID-19 risk (OR = 0.77, 95% CI 0.55–1.11, P = 0.160), but MR sensitivity analyses indicated a potential causal effect (weighted mode MR: OR = 0.72, 95% CI 0.55–0.95, P = 0.021; weighted median MR: OR = 0.61, 95% CI 0.42–0.92, P = 0.016). Analysis of MR-PRESSO did not find outliers for any instrumental variables and suggested a potential causal effect (OR = 0.80, 95% CI 0.66–0.98, p-val = 0.030). In conclusion, the effect of vitamin D levels on the risk or severity of COVID-19 remains controversial, further studies are needed to validate vitamin D supplementation as a means of protecting against worsened COVID-19.

Background With local recurrence of rectal cancer continuing to decrease, distant recurrence is becoming a major concern, especially for patients with low- and intermediate-risk stage II/III rectal cancer. Therefore, a new treatment strategy is warranted for these patients. This single-arm phase II trial aimed to assess the effect of neoadjuvant chemotherapy (NCT) in low- and intermediate-risk stage II/III rectal cancer and explore candidate radiological and clinical parameters for early prediction of tumour response after two cycles of CAPOX. Methods Patients with mid–low stage II/III rectal cancer with low and intermediate risk were examined. The primary outcome was defined as a clinicopathological response by integrating tumour longitudinal length reduction (TLLR) on MRI into pathological tumour regression grade (TRG). After completing NCT, patients with TRG0–2 and TRG3 with a TLLR rate greater than 30 per cent were considered to be responders. Secondary outcomes included pathological complete response (pCR), adverse events and local and distant recurrence. Results This study enrolled 61 eligible patients. No patient was converted to neoadjuvant chemoradiotherapy owing to tumour progression. The clinicopathological response and pCR rates were 78.7 and 21.3 per cent respectively. After two cycles of CAPOX, TLLR, TRG on MRI, and mucosal lesion regression grade on endoscopy had potential discriminative ability (area under the curve greater than 0.7) for predicting both clinicopathological and pathological response. Conclusion NCT alone achieves good tumour response rates in patients with low- and intermediate-risk stage II/III rectal cancer, and predicting tumour response to NCT is feasible at an early treatment phase. Registration number NCT03666442 (http://www.clinicaltrials.gov).

Objective:Inflammation has been suggested to play an important role in the development and progression of metabolic syndrome (MetS). Dietary inflammatory index (DII), a measurement of inflammatory potential in diets, was suggested to be associated with MetS. The aim of this systematic review and meta-analysis was to establish the associations of DII with MetS and its components based on available observational studies.Design:Systematic review and meta-analysis.Setting:A comprehensive literature search of studies that assessed the associations between DII and MetS was conducted in PubMed, Medline and Embase, using a combination of search terms relating to DII and MetS.Participants:Eighteen articles were eligible, of which fourteen were cross-sectional and four were cohort in design.Results:Results from the random effects meta-analysis showed significantly positive associations of higher DII (top v. bottom quartiles) with MetS (OR: 1·23 (95 % CI 1·10, 1·37)), abdominal obesity (OR: 1·15 (95 % CI 1·02, 1·29)), high blood pressure (OR: 1·17 (95 % CI 1·07, 1·29)), hyperglycaemia (OR: 1·18 (95 % CI 1·05, 1·33)) and hypertriacylglycerolaemia (OR: 1·17 (95 % CI 1·07, 1·28)). The effects of summary OR became stronger when analyses were restricted to cohorts, studies that adjudged for covariates (including BMI, physical activity and total energy intake).Conclusions:Higher DII, representing pro-inflammatory diet, is associated with higher odds of MetS and its components, except for low HDL-cholesterol. The findings prompt dietary interventions for preventing MetS from the aspect of inflammation.

Background: Pharmacotherapy provides an option for overweight and obese adults to reduce their body weight if lifestyle modification fails. This systematic review summarises latest and likely practice-changing evidence for the benefits and harms of weight-lowering drugs. Methods: The network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) for randomised controlled trials of weight-lowering drugs in overweight and obese adults. We performed a frequentist random-effect network meta-analysis to summarise the evidence and applied GRADE frameworks to rate the certainty of the evidence, calculate the absolute effects, categorise interventions and present the findings. Findings: The 143 eligible trials enrolled 49 810 participants. Except for levocarnitine, all drugs lowered body weight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification alone. High to moderate certainty evidence established phentermine/topiramate (odds ratio [OR] of ≥5% weight reduction: 8·00, 95% confidence interval [CI]: 5·19 to 12·34; mean difference [MD] of percent body weight change: −7·97%, 95%CI: −9·28 to −6·66%) and glucagon-like peptide-1 (GLP-1) receptor agonists (OR: 6·20, 95% CI: 4·88 to 7·89; MD: −5·75%, 95%CI: −6·30 to −5·20%) were among the most effective in lowering weight. Naltrexone/bupropion (OR: 2·68, 95% CI: 2·06 to 3·49), phentermine/topiramate (OR, 2·36, 95% CI: 1·60 to 3·46), GLP-1 receptor agonists (OR: 2·16, 95% CI: 1·68 to 2·78), and orlistat (OR: 1·68, 95% CI: 1·38 to 2·05) increase any adverse event leading to drug discontinuation. In a post hoc analysis, semaglutide, one of the GLP-1 receptor agonists, demonstrated for both likelihood of ≥5% weight loss (OR: 9·81, 95% CI: 7·06 to 13·63) and percent body weight change (MD: −11.41%, 95%CI: −12.54 to −10.27%) and substantially larger than any other drugs with an increased risk of adverse events leading to discontinuation (OR: 1·98; 95% CI: 1·33 to 2·96). Interpretation: In overweight and obese adults, phentermine/topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide may be the most effective. Funding: 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (grant numbers ZYGD18022 and 2020HXF011). Declaration of Interest: We declare no competing interests.

Background It is of paramount importance to understand the transmission of SARS-CoV-2 in schools, which could support the decision-making about educational facilities closure or re-opening with effective prevention and control measures in place. Methods We conducted a systematic review and meta-analysis to investigate the extent of SARS-CoV-2 transmission in schools. We performed risk of bias evaluation of all included studies using the Newcastle-Ottawa Scale (NOS). Results 2178 articles were retrieved and 11 studies were included. Five cohort studies reported a combined 22 student and 21 staff index cases that exposed 3345 contacts with 18 transmissions (overall infection attack rate (IAR): 0.08%, 95% confidence interval (CI) = 0.00%-0.86%). IARs for students and school staff were 0.15% (95% CI = 0.00%-0.93%) and 0.70% (95% CI = 0.00%-3.56%) respectively. Six cross-sectional studies reported 639 SARS-CoV-2 positive cases in 6682 study participants tested [overall SARS-CoV-2 positivity rate: 8.00% (95% CI = 2.17%-16.95%). SARS-CoV-2 positivity rate was estimated to be 8.74% (95% CI = 2.34%-18.53%) among students, compared to 13.68% (95% CI = 1.68%-33.89%) among school staff. Gender differences were not found for secondary infection (OR = 1.44, 95% CI = 0.50-4.14, P = 0.49) and SARS-CoV-2 positivity (OR = 0.90, 95% CI = 0.72-1.13, P = 0.36) in schools. Fever, cough, dyspnea, ageusia, anosmia, rhinitis, sore throat, headache, myalgia, asthenia, and diarrhoea were all associated with the detection of SARS-CoV-2 antibodies (based on two studies). Overall, study quality was judged to be poor with risk of performance and attrition bias, limiting the confidence in the results. Conclusions There is limited high-quality evidence available to quantify the extent of SARS-CoV-2 transmission in schools or to compare it to community transmission. Emerging evidence suggests lower IAR and SARS-CoV-2 positivity rate in students compared to school staff. Future prospective and adequately controlled cohort studies are necessary to confirm this finding.

BackgroundIt is of paramount importance to understand the transmission of SARS-CoV-2 in schools, which could support the decision-making about educational facilities closure or re-opening with effective prevention and control measures in place.MethodsWe conducted a systematic review and meta-analysis to investigate the extent of SARS-CoV-2 transmission in schools. We performed risk of bias evaluation of all included studies using the Newcastle-Ottawa Scale (NOS).Results2,178 articles were retrieved and 11 studies were included. Five cohort studies reported a combined 22 student and 21 staff index cases that exposed 3,345 contacts with 18 transmissions [overall infection attack rate (IAR): 0.08% (95% CI: 0.00%–0.86%)]. IARs for students and school staff were 0.15% (95% CI: 0.00%–0.93%) and 0.70% (95% CI: 0.00%–3.56%) respectively. Six cross-sectional studies reported 639 SARS-CoV-2 positive cases in 6,682 study participants tested [overall SARS-CoV-2 positivity rate: 8.00% (95% CI: 2.17%–16.95%)]. SARS-CoV-2 positivity rate was estimated to be 8.74% (95% CI: 2.34%–18.53%) among students, compared to 13.68% (95% CI: 1.68%–33.89%) among school staff. Gender differences were not found for secondary infection (OR: 1.44, 95% CI: 0.50-4.14, P= 0.49) and SARS-CoV-2 positivity (OR: 0.90, 95% CI: 0.72-1.13, P= 0.36) in schools. Fever, cough, dyspnea, ageusia, anosmia, rhinitis, sore throat, headache, myalgia, asthenia, and diarrhoea were all associated with the detection of SARS-CoV-2 antibodies (based on two studies). Overall, study quality was judged to be poor with risk of performance and attrition bias, limiting the confidence in the results.ConclusionsThere is limited high-quality evidence available to quantify the extent of SARS-CoV-2 transmission in schools or to compare it to community transmission. Emerging evidence suggests lower IAR and SARS-CoV-2 positivity rate in students compared to school staff. Future prospective and adequately controlled cohort studies are necessary to confirm this finding.

Objective To identify potential bias in non-inferiority design of published cancer trials, and to provide suggestions for future practice. Study Design and Setting We systematically searched MEDLINE, Embase and CENTRAL databases (until April 17, 2020) to obtain non-inferiority phase III cancer trials and protocols. Distribution of essential characteristics and study design parameters was compared between trials with and without concluding non-inferiority using multivariable logistic regression. Results A total of 291 eligible trials were included. We observed that increased odds of concluding non-inferiority was significantly associated with more lenient non-inferiority margins (OR = 1•94, 95% CI 1•02–3•69) and higher hypothesized event rate (OR = 1•24, 95% CI 1•06–1•47). Trials that established non-inferiority adopted margins that were more dispersedly distributed (dispersion OR = 2•90, 95% CI 1•88–4.48). Conclusion Although limited by the exploratory nature, our study demonstrated existence of possible distorted non-inferiority design which could incur excess non-inferiority in cancer clinical trials. Pre-registration and transparent reporting of detailed non-inferiority design is imperative for future research.

A growing body of evidence shows that poor vitamin D status has been associated with an increased susceptibility to viral and bacterial respiratory infections. In this study, we aimed to examine the association between vitamin D and COVID-19 risk and outcomes, and to explore potential causal effects. We used logistic regression to identify associations between different vitamin D variables (25-hydroxyvitamin D concentration (25-OHD), ambient UVB and genetically-predicted 25-OHD concentrations) and COVID-19 (risk of infection, hospitalisation and death) in 495,780 participants from UK Biobank. We subsequently performed a Mendelian Randomisation (MR) study to test if there was any causal effect. In total, 1,746 COVID-19 cases and 399 COVID-19 deaths occurred between March and June 2020. We found significant inverse associations between COVID-19 infection and 25-OHD in univariable models, but these associations were non-significant after adjustment for confounders. Ambient UVB was strongly and inversely associated with hospitalization and death. Although the main MR analysis showed that genetically-predicted vitamin D levels were not causally associated with COVID-19 risk, MR sensitivity analysis using weighted mode method indicated a potential causal effect (OR=0.72, 95% CI:0.53-0.98; P=0.041). In conclusion, our study found suggestive evidence of association between vitamin D and the risk or severity of COVID-19 but further studies are needed.

Physical activity (PA) is known to be a protective lifestyle factor against several non-communicable diseases while its impact on infectious diseases, including Coronavirus Disease 2019 (COVID-19) is not as clear. We performed univariate and multivariate logistic regression to identify associations between body mass index (BMI) and both objectively and subjectively measured PA collected prospectively and COVID-19 related outcomes (Overall COVID-19, inpatient COVID-19, outpatient COVID-19, and COVID-19 death) in the UK Biobank (UKBB) cohort. Subsequently, we tested causality by using two-sample Mendelian randomisation (MR) analysis. In the multivariable model, the increased acceleration vector magnitude PA (AMPA) was associated with a decreased probability of overall and outpatient COVID-19. No association was found between self-reported moderate-to-vigorous PA (MVPA) or BMI and COVID-19 related outcomes. Although no causal association was found by MR analyses, this may be due to limited power and we conclude policies to encourage and facilitate exercise at a population level during the pandemic should be considered.

SummaryBackgroundStratifying the risk of colorectal cancer (CRC) based on polygenic risk scores (PRSs) within populations has the potential to optimize screening and develop targeted prevention strategies.MethodsA meta-analysis of eleven genome-wide association studies (GWAS), comprising 16 871 cases and 26 328 controls, was performed to capture CRC susceptibility variants. Genetic models with several candidate PRSs were generated from Scottish CRC case–control studies (6478 cases and 11 043 controls) for prediction of overall and site-specific CRC. Model performance was validated in UK Biobank (4800 cases and 20 287 controls). The 10-year absolute risk of CRC was estimated by modelling PRS with age and sex using the CRC incidence and mortality rates in the UK population.FindingsA weighted PRS including 116 CRC SNPs (wPRS116) showed the strongest performance. Deconstructing the PRS into multiple genetic risk regional scores or inclusion of additional SNPs that did not reach genome-wide significance did not provide any further improvement on predictive performance. The odds ratio (OR) for CRC risk per SD of wPRS116 in Scottish dataset was 1·46 (95%CI: 1·41-1·50, c-statistics: 0·603). Consistent estimates were observed in UK Biobank (OR=1·49, 95%CI: 1·44-1·54, c-statistics: 0·610) and showed no substantial heterogeneity among tumor sites. Compared to the middle quintile, those in the highest 1% of PRSs had 3·25-fold higher risk and those in the lowest 1% had 0·32-fold lower risk of developing CRC. Modelling PRS with age and sex in the general UK population allows the identification of a high-risk group with 10-year absolute risk ≥5%.InterpretationBy optimizing wPRS116, we show that genetic factors increase predictive performance but this increment is equivalent to the extraction of only one-tenth of the genetic susceptibility. When employing genetic risk profiling in population settings it provides a degree of risk discrimination that could, in principle, be integrated into population-based screening programs.

Several associations between non‐genetic biomarkers and colorectal cancer (CRC) risk have been detected, but the strength of evidence and the direction of associations are not confirmed. We aimed to evaluate the evidence of these associations and integrate results from different approaches to assess causal inference. We searched Medline and Embase for meta‐analyses of observational studies, meta‐analyses of randomized clinical trials (RCTs), and Mendelian randomization (MR) studies measuring the associations between non‐genetic biomarkers and CRC risk and meta‐analyses of RCTs on supplementary micronutrients. We repeated the meta‐analyses using random‐effects models and categorized the evidence based on predefined criteria. We described each MR study and evaluated their credibility. Seventy‐two meta‐analyses of observational studies and 18 MR studies on non‐genetic biomarkers and six meta‐analyses of RCTs on micronutrient intake and CRC risk considering 65, 42, and five unique associations, respectively, were identified. No meta‐analyses of RCTs on blood level biomarkers have been found. None of the associations were classified as convincing or highly suggestive, three were classified as suggestive, and 26 were classified as weak. For three biomarkers explored in MR studies, there was evidence of causality and seven were classified as likely noncausal. For the first time, results from both observational and MR studies were integrated by triangulating the evidence for a wide variety of non‐genetic biomarkers and CRC risk. At blood level, lower vitamin D, higher homeostatic model assessment‐insulin resistance, and human papillomavirus infection were associated with higher CRC risk while increased linoleic acid and oleic acid and decreased arachidonic acid were likely causally associated with lower CRC risk. No association was found convincing in both study types., The identification of specific biomarkers related to colorectal cancer (CRC) risk is essential to understand cancer aetiology and mechanisms of progression. This is the first time that evidence of associations between a wide range of non‐genetic biomarkers and CRC risk from a huge number of epidemiological workswere evaluated. Three associations detected from meta‐analyses of observational studies were classified as suggestive, three and seven associations detected from Mendelian randomisation studies were classified as evidence of causality and likely non‐causal respectively.

ObjectiveAccumulating evidence suggests that cancer survivors may have a relatively higher risk of stroke. The aim of this meta-analysis was to determine whether cancer survivors have a relatively higher risk of stroke than cancer-free populations on the basis of published data from population-based cohort studies.MethodsPubMed, Embase, and Cochrane Library were searched from inception to February 8, 2020, for population-based cohort studies. Effect estimates with 95% confidence intervals (CIs) were pooled using the random-effects model. We conducted subgroup analyses and meta-regression to explore sources of heterogeneity and the stability of the results.ResultsTwenty population-based cohort studies involving 10,479,530 participants were identified. Overall, the relative risk (RR) for stroke in cancer survivors was 1.66 (95% CI 1.35–2.04; p < 0.001) compared with that in cancer-free controls; survivors of head and neck, hematologic, lung, pancreas, and stomach cancer (all p < 0.05) showed consistently significant results, whereas no significant increased risk was observed for patients with other cancer types. The effects were more prominent in cancer survivors with female sex (RR 1.38, 95% CI 1.18–1.61; p < 0.001), younger age at cancer diagnosis (p = 0.009), and shorter cancer survival duration (≥1–2 years) (RR 1.69, 95% CI 1.18–2.42; p = 0.004). Moreover, cancer survivors had a significantly increased risk of ischemic stroke (RR 1.53, 95% CI 1.28–1.84; p < 0.001) compared with hemorrhagic stroke.ConclusionsCancer plays a critical role in the etiologic of stroke. Due to the existence of substantial heterogeneity among the included studies, the results should be interpreted with caution. However, early prevention and effective intervention of stroke in cancer survivors require attention from health policy makers.

OBJECTIVE After the failure of the first antiepileptic drug (AED) at doses > 50% defined daily dose (DDD), there are three options for patients with epilepsy: combination therapy, alternative therapy, and increased dosage of the first AED. However, present studies have not provided evidence for which option is best. Therefore, we conducted this retrospective observational cohort study to compare the effects of three treatment schedules. METHODS Patients diagnosed with newly diagnosed epilepsy at the epilepsy clinic of West China Hospital between August 2006 and February 2016 were evaluated for eligibility for this study. Patients who failed to respond to the first AED at doses > 50% DDD were included, and divided into three cohorts: increased dosage, combination therapy, and alternative therapy. Cumulative incidence curves for time to seizure freedom were compared for different cohorts by Gray test. Competing risk regression was conducted to evaluate the association of clinical predictors with seizure freedom. RESULTS Altogether, 502 patients (277 male, 55.2%) were included for further analysis, and the median duration of follow-up was 32 months (range = 8-127). The probability of seizure freedom was significantly higher in patients receiving combination therapy (n = 323) compared to the alternative therapy cohort (n = 76, P

Objective The aim of our study was to compare percutaneous vascular interventions (PVI) versus bypass surgeries (BSX) in patients with critical limb ischemia (CLI). Background Previous relevant reviews with limited numbers of included studies did not strictly confine the inclusion criteria to CLI, also involving patients with severe claudication, which may introduce bias in the decision-making of CLI revascularization. Current treatment strategies for CLI still remain controversial. Methods We performed a meta-analysis of all available randomized controlled trials and observational clinical studies comparing PVI with BSX in CLI patients. Primary endpoints included overall survival, amputation-free survival, 30-day mortality, and major adverse cardiovascular and cerebrovascular events. Results We identified 45 cohorts and 1 RCT in over 20,903 patients. In overall population, PVI reduced the risks of 30-day mortality [odds ratio (OR) 0.69, 95% confidence interval (CI) 0.51-0.95), major adverse cardiovascular and cerebrovascular events (OR 0.42, 95% CI 0.29-0.61), and surgical site infection (OR 0.31, 95% CI 0.19-0.51), but increased the risks of long-term all-cause mortality [hazard ratio (HR) 1.16, 95% CI 1.05-1.27) and primary patency failure (HR 1.31, 95% CI 1.08-1.58). When compared with autogenous BSX, PVI was also associated with additional increased risks of long-term death or amputation (HR 1.41, 95% CI 1.02-1.94) and secondary patency failure (HR 1.51, 95% CI 1.17-1.95). In patients with infrapopliteal lesions, we found PVI had inferior primary patency (HR 1.39, 95% CI 1.10-1.75) compared with BSX. Conclusion For patients in good physical condition with long life-expectancy, BSX may represent a better choice compared with PVI, particularly when autogenous bypass is available. While enhanced perioperative care for cardiovascular events and surgical site should be considered in patients underwent BSX to achieve comparable short-term outcomes provided by PVI.

Background: Germline genetic variants may influence pathways of tumor progression common to multiple cancer types. Here, we investigated the association between survival after colorectal cancer diagnosis and 128 common genetic variants previously associated with prognosis in genome-wide association studies in different cancer types. Methods: We studied survival outcomes in a large well-documented, prospective, population-based cohort (5,675 patients with colorectal cancer) with up to 20 years' follow-up. Results: None of the 128 variants were significantly associated with overall or colorectal cancer–specific survival (P < 5 × 10−4, Bonferroni-corrected threshold). We observed suggestive evidence (P < 0.05) for eight variants (rs17026425, rs17057166, rs6854845, rs1728400, rs17693104, rs202280, rs6797464, and rs823920) in all colorectal cancer and two variants (rs17026425 and rs6854845) in rectal cancer that were concordant with previous reports. Conclusions: Given good statistical power (>0.80 for 75% of variants), this study indicates that most previously reported variants associated with cancer survival have limited influence on colorectal cancer prognosis. Impact: Although small effects cannot be excluded, clinically meaningful germline influences on patients with colorectal cancer as a group are unlikely.

Matrix metalloproteinase (MMP) promoter polymorphisms are considered to play roles in the aetiology of endometriosis and adenomyosis, however, the evidence available are inconsistent. We aimed to systematically review the asscociation between MMP-1 -1607 1G/2G MMP-2 -735 C/T, MMP-3 -1171 5A/6A and MMP-9 -1562 C/T polymorphisms and the risk of endometriosis and adenomyosis. A systemic search was conducted in Ovid, PubMed, Chinese National Knowledge Infrastructure and ChineseWanfang Database.We used the pooled odds ratio (OR) and their corresponding 95% confidence interval (CI) to calculate the statistical power. Besides, we evaluated the quality of individual studies based on Newcastle-Ottawa scale. A total of 13 papers with 18 studies conformed to our inclusion criteria. We observed a significant association between MMP-1 -1607 1G/2G polymorphism and the susceptibility of endometriosis and adenomyosis under recessive model (OR = 1.25, 95%CI = 1.03-1.53, P = 0.03). While no significant association was found in MMP-2 -735 C/T, MMP-3 -1171 5A/6A and MMP-9 -1562 C/T polymorphisms. This systemic review and meta-analysis suggested that theMMP-1 -1607 1G/2G polymorphism might play an important role in the risk of endometriosis and adenomyosis. Further, more well-designed and large-scale studies regarding gene-gene and gene-environment interactions are needed in the future.

Background Many effects of statins on non-cardiovascular disease (non-CVD) outcomes have been reported. Purpose To evaluate the quantity, validity, and credibility of evidence regarding associations between statins and non-CVD outcomes and the effects of statins on these outcomes. Data sources MEDLINE and EMBASE (English terms only, inception to 28 May 2018). Study selection Meta-analyses (published in English) of observational studies and of randomized controlled trials (RCTs) that examined non-CVD outcomes of statin intake. Data extraction Two investigators extracted data from meta-analyses and individual studies. Credibility assessments based on summary effect sizes from a random-effects model, between-study heterogeneity, 95% prediction interval, small-study effect, excess significance, and credibility ceilings were devised to classify evidence. Data synthesis This review explored 278 unique non-CVD outcomes from 112 meta-analyses of observational studies and 144 meta-analyses of RCTs. For observational studies, no convincing (class I) evidence, 2 highly suggestive (class II) associations (decreased cancer mortality in patients with cancer and decreased exacerbation in patients with chronic obstructive pulmonary disease), 21 suggestive (class III) associations, and 42 weak (class IV) associations were identified. One outcome from the RCTs (decreased all-cause mortality in patients with chronic kidney disease) attained a sufficient amount of evidence with no hints of bias. For adverse events, observational studies showed suggestive evidence that statins increase the risk for diabetes and myopathy. Among the RCTs, no statistically significant effects were found on myopathy, myalgia, or rhabdomyolysis. Limitations Studies with relevant data and outcomes not included in the meta-analyses may have been missed. Credibility assessments relied on several assumptions and arbitrary thresholds. Conclusion The absence of convincing evidence of an association between statins and non-CVD outcomes supports leaving the current recommendations unchanged. Primary funding source None.

Objective Spontaneous isolated celiac artery dissection (SICAD) and spontaneous isolated superior mesenteric artery dissection (SISMAD) represent the major types of spontaneous visceral artery dissection. However, no quantitative meta-analysis of SICAD and SISMAD is available. The aim of our study was to pool current evidence concerning basic profiles, treatment strategies, long-term adverse events, and morphologic changes of lesioned vessels in SICAD and SISMAD patients. Methods We searched the MEDLINE, Embase, Scopus, and Cochrane Databases (January 1, 1946-September 21, 2017) for studies of SICAD and SISMAD. Related cohort studies or case series with sample size larger than 10 were included. Two reviewers independently extracted and summarized the data. A random-effects model was used to calculate pooled estimates. Results In total, 43 studies were included. An estimated 8% (95% confidence interval [CI], 0.01-0.21) symptomatic SICAD and 12% (95% CI, 0.06-0.19) symptomatic SISMAD patients with initial conservative management required secondary intervention during follow-up, whereas none of the asymptomatic patients treated conservatively required secondary intervention. As for morphologic changes during follow-up, a higher proportion of SICAD patients (64%; 95% CI, 0.47-0.80) achieved complete remodeling compared with SISMAD patients (25%; 95% CI, 0.19-0.32), and an estimated 6% (95% CI, 0.00-0.16) of SICAD and 12% (95% CI, 0.05-0.20) of SISMAD patients had morphologic progression. Overall, the pooled estimate of long-term all-cause mortality was 0% (95% CI, 0.00-0.03) in SICAD and 1% (95% CI, 0.00-0.02) in SISMAD. When stratified by symptoms, symptomatic patients were associated with a significantly increased probability of accomplishing complete remodeling (odds ratio, 3.95; 95% CI, 1.31-11.85) compared with asymptomatic patients. Conclusions Initial conservative treatment is safe for asymptomatic SICAD or SISMAD patients. Symptomatic patients managed conservatively have relatively high occurrence of late secondary intervention, which may require closer surveillance, especially in SISMAD because of a lower rate of remodeling.

Objective.Several studies have evaluated the association betweenCYP1A1polymorphisms and the susceptibility of chronic obstructive pulmonary disease (COPD) with inconclusive results. We performed the first comprehensive meta-analysis to summarize the association betweenCYP1A1polymorphisms and COPD risk.Method.A systematic literature search was conducted (up to April 2015) in five online databases: PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), WeiPu, and WanFang databases. The strength of association was calculated by odds ratio (OR) and corresponding 95% confidence interval (CI).Results.Seven case-control studies with 1050 cases and 1202 controls were included. Our study suggested a significant association between the MspI polymorphism and COPD risk (CC versus TC + TT: OR = 1.57, CI: 1.09–2.26,P=0.02; CC versus TT: OR = 1.73, CI: 1.18–2.55,P=0.005). For the Ile/Val polymorphism, a significant association with COPD risk was observed (GG versus AG + AA: OR = 2.75, CI: 1.29–5.84,P= 0.009; GG versus AA: OR = 3.23, CI: 1.50–6.93,P=0.003; AG versus AA: OR = 1.39, CI: 1.01–1.90,P=0.04). Subgroup analysis indicated a significant association between the MspI variation and COPD risk among Asians (CC versus TC + TT: OR = 1.70, CI: 1.06–2.71,P=0.03; CC versus TT: OR = 1.84, CI: 1.11–3.06,P=0.02).Conclusion.The MspI and Ile/Val polymorphisms might alter the susceptibility of COPD, and MspI polymorphism might play a role in COPD risk among Asian population.

Introduction The plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism was considered to be associated with risk of venous thromboembolism (VTE), while evidence remains inadequate. To provide a more accurate estimation of this relationship, we performed an updated meta-analysis of all eligible studies. Materials and Methods A systematical search was performed in PubMed, EMBASE, Wanfang, China National Knowledge Infrastructure (CNKI) and Cqvip databases to identify relevant studies published before March 6th 2014. The odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using the fixed/random-effects model using Review Manager 5.1 and STATA 12.0. Results A total of 34 studies with 3561 cases and 5693 controls were analyzed. Overall, significant association between the PAI-1 4G/5G variant and VTE risk in total population (dominant model: OR = 1.32, 95%CI: 1.13-1.54) was observed. And this variant was also related to the deep vein thrombosis risk (dominant model: OR = 1.60, 95%CI: 1.24-2.06, P = 0.0003). In the subgroup analyses on ethnicity, significant results were obtained in both Asians (dominant model: OR = 2.08, 95%CI: 1.29-3.35, P = 0.003) and Caucasians (dominant model: OR = 1.31, 95%CI: 1.10-1.56, P = 0.003). However, no significant association was found in patients with provoked VTE. In terms of subgroup analyses on co-existence of other thrombotic risk factors, the PAI-1 4G/5G polymorphism was significantly associated with VTE risk in patients with factor V Leiden mutation (dominant model: OR = 1.72, 95%CI: 1.17-2.53), but not in patients with cancer or surgery. Conclusion Our findings demonstrate the role of PAI-1 4G/5G polymorphism being a risk candidate locus for VTE susceptibility, especially in patients with other genetic thrombophilic disorders.

Background It remains unclear whether or not preservation of the left colic artery (LCA) for colorectal cancer surgery. The objective of this updated systematic review and meta-analysis is to evaluate the current scientific evidence of LCA non-preservation versus LCA preservation in colorectal cancer surgery. Methods A systematic search was conducted in the Medline, Embase, PubMed, Cochrane Library, ClinicalTrials, Web of Science, China National Knowledge Infrastructure and Chinese BioMedical Literature Database, and reference without limits. Quality of studies was evaluated by using the Newcastle-Ottawa scale and the Cochrane Collaboration's tool for assessing the risk of bias. Effective sizes were pooled under a random- or fixed-effects model. The funnel plot was used to assess the publication bias. The outcomes of interest were oncologic consideration including the number of apical lymph nodes, overall recurrence, 5-years overall survival, and 5-years disease-free survival (DFS); safety consideration including overall 30-day postoperative morbidity and overall 30-day postoperative mortality; anatomic consideration including anastomotic circulation, anastomotic leakage, urogenital, and defaecatory dysfunction. Results Twenty-four studies including 4 randomized controlled trials (RCTs) and 20 cohort studies with a total of 8456 patients (4058 patients underwent LCA non-preservation surgery vs 4398 patients underwent LCA preservation surgery) were enrolled in this meta-analysis. The preservation of LCA was associated with significantly less anastomotic leakage (odds ratio 1.23, 95% confidence interval 1.02-1.48, P = .03). In term of sexual dysfunction, urinary retention, the number of apical lymph nodes, and long-term oncologic outcomes, there were no significant differences between the LCA non-preservation and LCA preservation group. It was hard to draw definitive conclusions on other outcomes including operation time, blood loss, the first postoperative exhaust time, and perioperative morbidity and mortality for insufficient data and highly significant heterogeneity among studies. Conclusions The pooled data provided evidence to support the LCA preservation preferred over LCA non-preservation in anastomotic leakage. Future more large-volume, well-designed RCTs with extensive follow-up are needed to draw a definitive conclusion on this dilemma.

Epidemiological studies have assessed the association between HIF-1α polymorphisms and cancer risk. However, the results remained conflicting rather than conclusive. Therefore, we performed a systematic review to provide a complete picture and conducted a meta-analysis to derive a precise estimation. We searched PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases until July 2013 to identify eligible studies. Data sets (43) from 39 studies with a total of 10,841 cases and 14,682 controls were included. The most commonly investigated polymorphism was C1772T, followed by G1790A, C111A, and rs2057482. Overall, C1772T and G1790A but not rs2057482 were associated with increased risk for cancer. When stratified by cancer type, C1772T was associated with increased risk for cervical cancer (T/T vs. C/T+C/C: OR = 8.80, 95 % CI = 2.30-33.70), prostate cancer (T vs. C: OR = 1.54, 95 % CI = 1.04-2.30), and other cancers (T vs. C: OR = 1.42, 95 % CI = 1.07-1.89), but not oral, breast, colorectal, endometrial, lung, and bladder cancers or renal cell carcinoma. G1790A was associated with marginal but insignificant risk for prostate cancer (A vs. G: OR = 1.46, 95 % CI = 1.00-2.13, P = 0.056) and with increased risk for oral (A vs. G: OR = 9.66, 95 % CI = 1.31-71.15), lung (A vs. G: OR = 2.27, 95 % CI = 1.74-2.96), and other cancers (A vs. G: OR = 2.06, 95 % CI = 1.26-3.37) and renal cell carcinoma (A/A vs. G/A+G/G: OR = 3.05, 95 % CI = 1.36-6.84), but not breast, colorectal, cervical, or bladder cancer. Furthermore, we detected increased cancer risk in haplotypes TA and CA and in those carrying at least one risk allele, and decreased cancer risk in haplotype TG regarding C1772T and G1790A polymorphisms. Further well-designed studies on various cancer types are warranted to verify our findings.

Study results on the association between RAD51 gene -135G/C polymorphism and risk of myelodysplastic syndrome (MDS) or acute leukemia are inconsistent. A meta-analysis was conducted to identify the association. A systematic search was performed in PubMed, Embase, CNKI, VIP, Wanfang databases to collect all relevant studies until January 2013. Meta-analysis was carried out using fixed/random model by Review Manager 5.1 and STATA10.0. A total of 10 eligible studies with 2,656 patients and 3,725 controls were included in meta-analysis. Significant association was detected between -135G/C polymorphism and increased MDS risk (CC + GC vs. GG: OR = 1.46, 95% CI = 1.11-1.92; CC vs. GC + GG: OR = 2.45, 95% CI = 1.23-4.89), while no association was observed for acute leukemia. Subgroup analysis by subtypes of acute leukemia and ethnicity showed no significant results either. Our meta-analysis indicated that the -135G/C polymorphism might be associated with increased susceptibility of MDS. However, lack of evidence supported association of this polymorphism with acute leukemia. Additional well-designed studies with larger samples are required to verify our results.

Objectives To review and synthesize published evidence of pay-for-performance (P4P) effects on management of diabetes. Methods Databases including Ovid MEDLINE, EMbase, PubMed, The Cochrane Library (Issue 3, 2012) were comprehensively searched for the effects of P4P programs in terms of patient outcomes and physician behaviors. Studies covering detailed data were included and synthesized. The quality of the body of evidence for each quality indicator was determined using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Results Among 742 identified articles, 12 interrupted time series studies, 7 controlled before-after studies, and 2 cross-sectional studies were included. Additionally, 12 studies were further included for quantitative analysis. Results of meta-analysis showed that P4P produced generally positive effects in most indicators (eg, patients with records of total cholesterol or blood pressure). However, these results were inconsistent. The percentage of patients with HbA1c ≤ 7% or 53 mmol/mol showed a pooled odds ratio of 0.98 in patients, but a pooled mean difference of 19.71% in the physician groups. The odds ratios of receiving tests/reaching an outcome level were also diverse in patients (odds ratios ranged from 0.98 to 3.32). Besides, process indicators had higher rates of improvement than outcome indicators. Conclusions P4P programs have variable impacts on patient outcomes of diabetes as well as physician behaviors, with various effects from negligible to strongly beneficial. Considering the low quality of the included studies, this conclusion should be cautiously interpreted.

Single-nucleotide polymorphisms located in the microRNA biogenesis pathway could alter the risk for developing prostate cancer. The present study was intended to identify common genetic variants responsible for prostate cancer susceptibility in the GEMIN4 gene. The high-resolution melting method was used to genotype seven polymorphisms (rs7813, rs4968104, rs3744741, rs2740348, rs1062923, rs910925, and rs910924) in the GEMIN4 gene in 300 prostate cancer patients and 244 matched controls. The encouraging discovery in this study was in the rs2740348. Patients carrying the variant heterozygote GC genotype in the rs2740348 were at a 36% decreased risk of prostate cancer (odds ratio [OR] = 0.64; 95% confidence interval [CI] = 0.42, 0.99). Similarly, this variant allele carrier showed significant risk for prostate cancer (OR = 0.64). In addition, subjects carrying the homozygote TT genotype in the rs7813 had a significantly increased risk of prostate cancer (OR = 2.53, 95% CI = 1.07, 6.28). Two common haplotypes were found to be associated with decreased risk of prostate cancer. In the subgroup analysis, higher risk of more severity of prostate cancer (clinical stage III and IV) was observed in individuals with the rs7813 TT genotype (OR = 2.64, 95% CI = 1.02, 7.64), while lower risk of more severity of prostate cancer was observed in individuals with the rs3744741 T allele (OR = 0.69, 95% CI = 0.50, 0.96). Overall, our study provides substantial support for the association between the GEMIN4 gene and the risk of prostate cancer.

Background Over half of the patients were diagnosed with colorectal cancer after 70 years of age. The choice of the most suitable chemotherapy strategy is the major challenge for elderly patients. Previous trials indicated that elderly patients with stage II/III colorectal cancer obtained no significant benefits from oxaliplatin-based adjuvant chemotherapy. Therefore, single-agent oral capecitabine is regarded as an effective alternative with retained efficacy and improved flexibility. However, the optimal dose of capecitabine for elderly patients remains controversial. Recent studies have adopted a low-dose strategy (1,000 mg/m2) for elderly patients, but the long-term efficacy of this strategy has not been identified so far. Thus, we designed this trial to investigate non-inferiority of the lower-dose strategy of capecitabine compared with the approved-dose strategy for adjuvant chemotherapy of elderly patients with stage II/III colorectal cancer. Methods LC-ACEC (Low-dose Capecitabine Adjuvant Chemotherapy for Elderly Patients With Stage II/III Colorectal Cancer) is a prospective, randomized, open-label, non-inferiority phase III clinical trial including 926 eligible patients. Patients will be randomly assigned to receive a capecitabine adjuvant chemotherapy strategy of lower dose (1,000 mg/m2 twice daily on days 1 to 14 of every 21 days) or approved dose (1,250 mg/m2 twice daily on days 1 to 14 of every 21 days). The primary outcome is 3-year disease-free survival. Secondary outcomes include 3-year overall survival, toxic and side effects during treatment, completion rate, and quality of life. Discussion This is the first randomized trial to evaluate the efficacy and safety of a low-dose strategy of capecitabine in adjuvant chemotherapy of elderly patients with stage II/III colorectal cancer, and the results are believed to provide new evidence on the treatment of elderly patients with colorectal cancer. Trial registration ClinicalTrials.gov identifier NCT02316535 (Dec. 12, 2014).

The effect of gender on outcomes after lower extremity revascularization is controversial. The aim of our systemic review and meta-analysis was to evaluate the gender-related outcomes after peripheral vascular interventions.We systematically searched MEDLINE, Embase, Cochrane Database, and Scopus to identify studies comparing outcomes after revascularization according to gender. A random-effects model was used to pool outcomes. Time-to-event data were reported using hazard ratios (HRs) and dichotomous data were presented using odds ratios (ORs).Included were 40 studies. Pooling of short-term outcomes after intervention showed that women had significantly increased risks of 30-day mortality (OR, 1.31; 95% confidence interval [CI], 1.11-1.55; P = .001), amputation (OR, 1.07; 95% CI, 1.02-1.12; P = .002), early graft thrombosis (OR, 1.56; 95% CI, 1.28-1.90; P .0001), embolization (OR, 1.64; 95% CI, 1.24-2.17; P = .0005), incisional site complication (OR, 1.56; 95% CI, 1.34-1.80; P .0001), cardiac events (OR, 1.21; 95% CI, 1.16-1.26; P .0001), stroke (OR, 1.35; 95% CI, 1.19-1.53; P .0001), and pulmonary complication (OR, 1.07; 95% CI, 1.03-1.12; P = .0006). No significant differences were found between women and men for short-term reinterventions (OR, 1.06; 95% CI, 0.73-1.54; P = .74) and renal complications (OR, 1.03; 95% CI, 0.76-1.39; P = .86). No significant differences in long-term outcomes between women and men were found, with similar rates of cumulative survival (HR, 1.10; 95% CI, 0.97-1.24; P = .12), primary patency (HR, 1.14; 95% CI, 1.00-1.30; P = .06), secondary patency (HR, 1.07; 95% CI, 0.86-1.34; P = .54), and limb salvage (HR, 0.93; 95% CI, 0.70-1.24; P = .63). However, in the open surgery subgroup, women had significantly reduced survival compared with men (HR, 1.21; 95% CI, 1.01-1.44; P = .04).Women have inferior short-term outcomes but similar long-term outcomes compared with men after lower limb revascularization. A higher treatment threshold may be warranted when considering intervening on women with symptomatic peripheral arterial disease owing to the increased risks of postprocedural mortality and complications.

We read with great interest the comprehensive study by Mocellin and colleagues1 who developed a quantitative summary of candidate genetic variants for gastric cancer susceptibility. Based on different tumour sites, the authors conducted a subgroup analysis for cardia cancer (CC) and non-cardia cancer (NCC). It is well established that CC has distinctive characteristics compared with NCC, but shares some common risk factors and pathogenesis with oesophageal cancer (OSC). In addition, there are some different genetic factors such as genetic variants between patients with CC and NCC. There is an argument that CC, located at oesophago-gastric junction, belongs to oesophageal more than gastric cancer. According to the results of subgroup analysis, Mocellin and colleagues1 found several variants showing different results with CC and NCC risk. However, only PLCE1 rs2274223 was reported to be significantly associated with CC but not NCC risk with high credibility …