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Abstract Background Although associations have been reported linking pretreatment thrombocytosis to cancer survival outcomes, the validity and strength of existing observational evidence have been contested. This study aimed to conduct an umbrella review to comprehensively appraise the strength, validity and credibility of these reported associations. Methods We searched Medline, Embase and Cochrane Database of Systematic Reviews from inception to 8 April 2023 to retrieve meta-analyses of observational studies. Meta-analyses were re-performed using a random-effect model and the strength of evidence was graded as convincing, highly suggestive, suggestive and weak according to seven pre-defined quantitative criteria reflecting statistical significance, amount of data, heterogeneity, and evidence of bias. The quality of review was appraised using the AMSTAR2 checklist. The umbrella review was reported adhering to the PRISMA guideline and was registered on PROSPERO (CRD42023455391). Results A total of 21 unique meta-analyses investigating ten cancer subtypes were included. All meta-analyses reported inferior survival outcome in cancer patients with pretreatment thrombocytosis, and 18 of them (85.7%) yielded statistically significant results (P 300 or 400 × 109 /L) to define thrombocytosis. Although evidence appraisal did not identify convincing evidence (Class I), the associations of thrombocytosis with inferior overall survival of lung, gastric, colorectal cancer and malignant mesothelioma were classified as highly suggestive evidence (Class II). According to AMSTAR2 ratings, no meta-analysis was identified with high or moderate quality. Conclusions Our findings consolidated the association between pretreatment thrombocytosis and poor survival outcomes in various cancers. Nonetheless, the absence of convincing associations indicates a need for further large-scale, high-quality evidence to confirm whether platelets can serve as a prognostic predictor or a therapeutic target.

Previous studies have reported inconsistent associations between platelet count (PLT) and cancer survival. However, whether there is linear causal effect merits in-depth investigations. We conducted a cohort study using the UK Biobank and a two-sample Mendelian randomization (MR) analysis. PLT levels were measured prior to cancer diagnosis. We adopted overall survival (OS) as the primary outcome. Cox models were utilized to estimate the effects of PLTs on survival outcomes at multiple lag times for cancer diagnosis. We employed 34 genetic variants as PLT proxies for MR analysis. Linear and non-linear effects were modeled. Prognostic effects of gene expression harboring the instrumental variants were also investigated. A total of 65 471 cancer patients were included. We identified a significant association between elevated PLTs (per 100 × 109/L) and inferior OS (HR: 1.07; 95% CI: 1.04–1.10; p

Abstract Few predictive biomarkers exist for identifying patients who may benefit from neoadjuvant therapy (NAT). The intratumoral microbial composition is comprehensively profiled to predict the efficacy and prognosis of patients with esophageal squamous cell carcinoma (ESCC) who underwent NAT and curative esophagectomy. Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis is conducted to screen for the most closely related microbiota and develop a microbiota‐based risk prediction (MRP) model on the genera of TM7x, Sphingobacterium, and Prevotella. The predictive accuracy and prognostic value of the MRP model across multiple centers are validated. The MRP model demonstrates good predictive accuracy for therapeutic responses in the training, validation, and independent validation sets. The MRP model also predicts disease‐free survival (p = 0.00074 in the internal validation set and p = 0.0017 in the independent validation set) and overall survival (p = 0.00023 in the internal validation set and p = 0.11 in the independent validation set) of patients. The MRP‐plus model basing on MRP, tumor stage, and tumor size can also predict the patients who can benefit from NAT. In conclusion, the developed MRP and MRP‐plus models may function as promising biomarkers and prognostic indicators accessible at the time of diagnosis.

Abstract Background: Diverticular disease has been inconsistently associated with colorectal cancer risk. We conducted a bidirectional Mendelian randomization study to assess this association. Methods: Forty-three and seventy single-nucleotide polymorphisms associated with diverticular disease and colorectal cancer at the genome-wide significance level (p

Abstract Background Approximately 10% of stage I colorectal cancer (CRC) patients experience unfavorable clinical outcomes after surgery. However, little is known about the subset of stage I patients who are predisposed to high risk of recurrence or death. Previous evidence was limited by small sample sizes and lack of validation. Methods We aimed to identify early indicators and develop a risk stratification model to inform prognosis of stage I patients by employing two large prospective cohorts. Prognostic factors for stage II tumors, including T stage, number of nodes examined, preoperative carcinoma embryonic antigen (CEA), lymphovascular invasion, perineural invasion (PNI), and tumor grade were investigated in the discovery cohort, and significant findings were further validated in the other cohort. We adopted disease-free survival (DFS) as the primary outcome for maximum statistical power and recurrence rate and overall survival (OS) as secondary outcomes. Hazard ratios (HRs) were estimated from Cox proportional hazard models, which were subsequently utilized to develop a multivariable model to predict DFS. Predictive performance was assessed in relation to discrimination, calibration and net benefit. Results A total of 728 and 413 patients were included for discovery and validation. Overall, 6.7% and 4.1% of the patients developed recurrences during follow-up. We identified consistent significant effects of PNI and higher preoperative CEA on inferior DFS in both the discovery (PNI: HR = 4.26, 95% CI: 1.70–10.67, p = 0.002; CEA: HR = 1.46, 95% CI: 1.13–1.87, p = 0.003) and the validation analysis (PNI: HR = 3.31, 95% CI: 1.01–10.89, p = 0.049; CEA: HR = 1.58, 95% CI: 1.10–2.28, p = 0.014). They were also significantly associated with recurrence rate. Age at diagnosis was a prominent determinant of OS. A prediction model on DFS using Age at diagnosis, CEA, PNI, and number of LYmph nodes examined (ACEPLY) showed significant discriminative performance (C-index: 0.69, 95% CI:0.60–0.77) in the external validation cohort. Decision curve analysis demonstrated added clinical benefit of applying the model for risk stratification. Conclusions PNI and preoperative CEA are useful indicators for inferior survival outcomes of stage I CRC. Identification of stage I patients at high risk of recurrence is feasible using the ACEPLY model, although the predictive performance is yet to be improved.

Epigenetics plays an important role in regulating stem cell signaling, as well as in the oncogenesis of lung cancer and therapeutic resistance. Determining how to employ these regulatory mechanisms to treat cancer is an intriguing medical challenge. Lung cancer is caused by signals that cause aberrant differentiation of stem cells or progenitor cells. The different pathological subtypes of lung cancer are determined by the cells of origin. Additionally, emerging studies have demonstrated that the occurrence of cancer treatment resistance is connected to the hijacking of normal stem cell capability by lung cancer stem cells, especially in the processes of drug transport, DNA damage repair, and niche protection. In this review, we summarize the principles of the epigenetic regulation of stem cell signaling in relation to the emergence of lung cancer and resistance to therapy. Furthermore, several investigations have shown that the tumor immune microenvironment in lung cancer affects these regulatory pathways. And ongoing experiments on epigenetics-related therapeutic strategies provide new insight for the treatment of lung cancer in the future.

The Laser Powder Bed Fusion (LPBF) in-situ alloying is a novel technology for preparing novel alloys efficiently. However, the narrow process window limit its application. A micro-scale integrated simulation model is designed and constructed based on the Discrete Element Method (DEM), the Finite Element Method (FEM), and Calculation of phase diagram (CALPHAD) method in the work. The equation of the methods are introduced. By defining the parameters such as composition inhomogeneity ω, the forming performance of LPBF in-situ alloying FeCoCrNi medium entropy alloys are predicted. The calculation results show that the hysteresis diffusion effect makes the mixing powders more challenging to be in-situ alloyed than conventional main component alloys. For the mixed powder beds consisting of 15–53 μm particles with equal mass ratio, the composition deviation on the micro-scale is within 2.5%, and the composition homogeneity reaches 98.9 %. Under a laser power of 150 W and a scanning speed of 500 mm/s, several laser remelting process are indispensable to eliminate unmelted elements. Experiments are carried out to verify the accuracy of the integrated simulation model, and the high-efficiency preparation experiment of non-equiatomic ratio medium entropy alloy was carried out by using the technology.

Surgery is a crucial treatment option for patients with resectable esophageal cancer. The emergence of minimally invasive esophageal techniques has led to the popularity of video-assisted thoracoscopic esophagectomy, which has proven to be more advantageous than traditional thoracotomy. However, some patients with esophageal cancer may not benefit from this procedure. Individualized treatment plans may be necessary for patients with varying conditions and tolerances to anesthesia, making conventional surgical methods unsuitable. Inflatable video-assisted mediastinoscopic transhiatal esophagectomy (IVMTE) has emerged as a promising treatment option for esophageal cancer because it does not require one-lung ventilation, reduces postoperative complications, and expands surgical indications. This technique also provides surgical opportunities for patients with impaired pulmonary function or thoracic lesions. It is crucial to have a comprehensive understanding of the advancements and limitations of IVMTE to tailor treatment plans and improve outcomes in patients with esophageal cancer. Understanding the advantages and limitations of this surgical method will help specific patients with esophageal cancer. We conducted a thorough review of the relevant literature to examine the importance of IVMTE for individualized treatment of this disease.

N6-methyladenosine (m6A) modification has been demonstrated to exhibit a crucial prognostic effect on colorectal cancer (CRC). Nonetheless, potential mechanism of m6A in survival rate and immunotherapeutic response remains unknown. Here we investigated the genes associated with m6A regulators and developed a risk score for predicting the overall survival (OS) of CRC patients. RNA-seq transcriptomic profiling data of COAD/READ samples were obtained from The Cancer Genome Atlas (TCGA) database. Absolute Shrinkage and Selection Operator (LASSO)- Cox regression analysis was conducted to identify the m6A-related gene expression signatures and the selected genes were inputted into stepwise regression to develop a prognostic risk score in TCGA, and its predictive performance of CRC survival was further validated in Gene Expression Omnibus (GEO) datasets. According to our results, the risk score comprising 18 m6A-related mRNAs was significantly associated with CRC survival in both TCGA and GEO datasets. And the stratified analysis also confirmed that high-risk score acted as a poor factor in different age, sex, T stage, and tumour, node, metastasis (TNM) stages. The m6A-related prognostic score in combination with clinical characteristics yielded time-dependent area under the receiver operating characteristic curve (AUCs) of 0.85 (95%CI: 0.79–0.91), 0.84 (95%CI: 0.79–0.90) and 0.80 (95%CI: 0.71–0.88) for the prediction of the 1-, 3-, 5-year OS of CRC in TCGA cohort. Furthermore, mutation of oncogenes occurred more frequently in the high-risk group and the composition of immune cells in tumour microenvironment (TME) was significantly distinct between the low- and high-risk groups. The low-risk group had a lower microsatellite instability (MSI) score, T-cell exclusion score and dysfunction score, implying that low-risk patients may have a better immunotherapy response than high-risk patients. In summary, a prognostic risk score derived from m6A-related gene expression signatures could serve as a potential prognostic predictor for CRC survival and indicator for predicting immunotherapy response in CRC patients.

Abstract 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.

BackgroundHigh low-density lipoprotein-cholesterol (LDL-C) is a public health issue contributing to ischemic heart disease (IHD) and stroke.MethodIn this ecological study, we collected summary exposure values (SEVs), deaths, disability-adjusted life of years (DALYs), and Social Demographic Index (SDI) of high LDL-C from 1990 to 2019 using the query tool from the Global Burden of Disease (GBD) Collaborative Network. Outcomes include SEVs, deaths, and DALYs attributable to high LDL-C stratified by sex, age, region, SDI, countries, and territories. Estimated annual percentage changes (EAPCs) were applied to estimate annual trends of changes in these outcomes. We applied the weighted segmented regression with break-point estimation to detect the linear piecewise relationship between SDI and high LDL-C disease burden.ResultsGlobally, 3.00 million (95% uncertainty interval [UI], 2.35–3.76 million) people in 1990 and 4.40 million (95% UI, 3.30–5.65 million) people died from high LDL-C in 2019. The absolute annual burden from deaths and DALYs attributed to high LDL-C increased by 46% (95% UI, 35–56%) and 41% (95% UI, 31–50%) from 1990 to 2019. The age-standardized SEV, death, and DALY was decreased by 9% (95% UI, −11 to −8%), 37% (95% UI, −41−33%), and 32% (95% UI, −37 to −28%), respectively, during the study period. There was a negative association between SDI and high LDL-C-related age-standardized death and DALY rates when SDI surpassed 0.71 and 0.71, respectively.ConclusionAlthough the overall age-standardized burden of high LDL-C is controlled in the past 30 years, it remains increasing in moderate SDI countries, and decreasing trends are disappearing in high SDI countries. New challenges require new actions stratified by countries with different SDI levels.

Abstract 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.

Abstract 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

BackgroundMany clinical practice guidelines strongly recommend exercise as an intervention for patients with sarcopenia. However, the significance of exercise on patient-important outcomes in older adults with sarcopenia is inconsistent when considering available minimal important differences. To synthesize current systematic review and meta-analyses evidence on the efficacy of exercise on patient-important outcomes in the treatment of sarcopenia in older adults.MethodsWe searched MEDLINE, EMBASE, Cochrane Library (Cochrane database of systematic review, CDSR) via OvidSP and Web of science until April 2021 and reference lists. Two independent investigators performed abstracted and title screening, assessed the full text and quality of evidence. This umbrella review included systematic reviews and meta-analyses of randomized controlled trials (RCTs). Eligible reviews aim to evaluate the effect of exercise on patient-important sarcopenic outcomes (muscle or physical function, mortality, and quality of life) in treating sarcopenia in older people. We used the minimally important differences (MIDs) of these outcomes to assess if the effects of exercise matter to patients.ResultsThis umbrella review provided a broad overview of the existing evidence and evaluated the systematic reviews' methodological quality and evidence for all these associations. In older patients with sarcopenia, moderate- to high-quality evidence showed that exercise intervention probably increases walking speed and improved physical performance (measured by TUG test); exercise may increase the muscle strength (grip strength, keen extension strength); but the effect size for grip strength probably too small to achieve patients important changes. Evidence for older people with sarcopenic obesity is limited, and we found the consistent effect of exercise interventions on grip strength and usual walking speed.ConclusionExercise has a positive and important effect on physical performance for older adults with sarcopenia, which supports leaving the current recommendations unchanged. New systematic reviews to summarize the effect of exercise on the quality of life are warranted to fill the current evidence gap.

Fe-25Cr-15Co (wt.%) permanent magnets were fabricated via selective laser melting (SLM) and in situ alloying from a blend of Fe, Cr and Co elemental powders. Under the optimal laser scanning process, the as-built Fe-25Cr-15Co alloy has a homogeneous composition distribution without defects such as holes or un-melted particles, and presents a single α phase with the bcc crystal structure. The density of as-built samples was 7.705 g/cm3 (the relative density is 99.32%). The preferred magnetic properties of the sample in the isotropic state were obtained as Hc = 22.84 kA/m, Br = 0.86 T and (BH)max = 7.98 kJ/m3. The hardness and yield strength of Fe-25Cr-15Co permanent magnets are above 331.5 HV and 800 MPa, respectively. The results of this study verified the feasibility of fabricating Fe-Cr-Co permanent magnets by SLM in situ alloying and can be extended to a wide range of applications that require complex shapes with variable magnetic circuit characteristics or gradient structures.

IntroductionA high prevalence of cryptoglandular and Crohn's perianal fistulas has been reported worldwide, and several surgical options are available for the management of anal fistula, with varying clinical efficacy. However, currently, the available evidence for the effectiveness of these surgical approaches are lacking and of concern in terms of the credibility and strength. The purpose of this study is to evaluate the credibility of the published systematic reviews and meta-analyses that assess the efficacy and safety of the surgical options for cryptoglandular and Crohn's perianal fistulas through an umbrella review.Methods and analysisA systematic search in PubMed, Embase and Cochrane library will be performed from inception to December 2020 without any language restriction. We will include systematic reviews and meta-analyses that investigate the efficacy and safety of surgical approaches in the management of cryptoglandular and Crohn's perianal fistulas. Two reviewers will independently screen search results through reading the titles or abstracts. Relevant information will be extracted from each eligible systematic review or meta-analysis. Based on random effects model summary estimates along with their p values, 95% prediction intervals, between-study heterogeneity, small-study effects and excess significance, we will classify the evidence from convincing (class I) to weak (class IV). Findings will be summarized using quantitative synthesis combined with a narrative approach. Cryptoglandular and Crohn's perianal fistulas will be summarized separately. Two authors will independently perform the literature search, data extraction, and quality assessment of each included systematic review and meta-analysis. Any unresolved conflicts or doubts will be resolved by discussion or by consulting a senior author. The risk of bias of the systematic reviews will be assessed using a 16-item Assessment of Multiple Systematic Reviews 2 (AMSTAR2) checklist. The strength of evidence for the included systematic reviews will be classified as "high", "moderate", "low", or "critically low" quality.Ethics and disseminationEthics approval is not required as we will collect data from the published systematic reviews and meta-analyses without using individual patient data. The results of this umbrella review will be published in a peer-reviewed journal and will be presented at an anorectal disease conference.Prospero registration numberCRD42020200754.

Abstract Background Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. Methods We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk. We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. Results The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 × 10− 11), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51–2.07, P = 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69–1.19, P = 0.48). Conclusions Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk. Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven.

BackgroundThe role of urate in cardiovascular diseases (CVDs) has been extensively investigated in observational studies; however, the extent of any causal effect remains unclear, making it difficult to evaluate its clinical relevance.Methods and findingsA phenome-wide association study (PheWAS) together with a Bayesian analysis of tree-structured phenotypic model (TreeWAS) was performed to examine disease outcomes related to genetically determined serum urate levels in 339,256 unrelated White British individuals (54% female) in the UK Biobank who were aged 40-69 years (mean age, 56.87; SD, 7.99) when recruited from 2006 to 2010. Mendelian randomization (MR) analyses were performed to replicate significant findings using various genome-wide association study (GWAS) consortia data. Sensitivity analyses were conducted to examine possible pleiotropic effects on metabolic traits of the genetic variants used as instruments for urate. PheWAS analysis, examining the association with 1,431 disease outcomes, identified 13 distinct phecodes representing 4 disease groups (inflammatory polyarthropathies, hypertensive disease, circulatory disease, and metabolic disorders) and 9 disease outcomes (gout, gouty arthropathy, pyogenic arthritis, essential hypertension, coronary atherosclerosis, ischemic heart disease, chronic ischemic heart disease, myocardial infarction, and hypercholesterolemia) that were associated with genetically determined serum urate levels after multiple testing correction (p < 3.35 × 10-4). TreeWAS analysis, examining 10,750 ICD-10 diagnostic terms, identified more sub-phenotypes of cardiovascular and cerebrovascular diseases (e.g., angina pectoris, heart failure, cerebral infarction). MR analysis successfully replicated the association with gout, hypertension, heart diseases, and blood lipid levels but indicated the existence of genetic pleiotropy. Sensitivity analyses support an inference that pleiotropic effects of genetic variants on urate and metabolic traits contribute to the observational associations with CVDs. The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and possible misclassification of cases for mild disease that did not require hospitalization.ConclusionIn this study, high serum urate levels were found to be associated with increased risk of different types of cardiac events. The finding of genetic pleiotropy indicates the existence of common upstream pathological elements influencing both urate and metabolic traits, and this may suggest new opportunities and challenges for developing drugs targeting a common mediator that would be beneficial for both the treatment of gout and the prevention of cardiovascular comorbidities.

BACKGROUND: To compare short-term and long-term results of colorectal patients undergoing laparoscopic and open hepatectomy. Moreover, outcomes of laparoscopic versus open procedures for simultaneous primary colorectal tumor and liver metastasis resection were compared. METHODS: A systematic search was conducted in the PubMed and EmBase databases (until Oct. 22. 2013) with no limits. Bibliographic citation management software (EndNote X6) was used for extracted literature management. Quality assessment was performed according to a modification of the Newcastle-Ottawa Scale. The data were analyzed using Review Manager (Version 5.1), and sensitivity analysis was performed by sequentially omitting each study. RESULTS: Finally, 14 studies, including a total of 975 CLM (colorectal liver metastasis) patients, compared laparoscopic with open hepatectomy. 3 studies of them, including a total of 107 CLM patients, compared laparoscopic with open procedures for synchronous hepatectomy and colectomy. Laparoscopic hepatectomy was associated with a significantly less blood loss, shorter hospitalization time, and less operative transfusion rate. In addition, lower hospital morbidity rate (OR=0.57, 95%CI:0.42-0.78, P=0.0005) and better R0 resection (OR=2.44, 95%CI:1.21-4.94, P=0.01) were observed in laparoscopic hepatectomy. For long-term outcomes, there were no significant differences between two surgical procedures on recurrence and overall survival. In comparison of synchronous hepatectomy and colectomy, laparoscopic procedure displayed shorter hospitalization (MD = -3.40, 95%CI:-4.37-2.44, P

BACKGROUND: Association between the single nucleotide polymorphism rs3218536 (known as Arg188His) located in the X-ray repair cross complementing group 2 (XRCC2) gene and cancer susceptibility has been widely investigated. However, results thus far have remained controversial. A meta-analysis was performed to identify the impact of this polymorphism on cancer susceptibility. METHODS: PubMed and Embase databases were searched systematically until September 7, 2013 to obtain all the records evaluating the association between the XRCC2 Arg188His polymorphism and the risk of all types of cancers. We used the odds ratio (OR) as measure of effect, and pooled the data in a Mantel-Haenszel weighed random-effects meta-analysis to provide a summary estimate of the impact of this polymorphism on breast cancer, ovarian cancer and other cancers. All the analyses were carried out in STATA 12.0. RESULTS: With 30868 cases and 38656 controls, a total of 45 case-control studies from 26 publications were eventually included in our meta-analysis. No significant association was observed between the XRCC2 Arg188His polymorphism and breast cancer susceptibility (dominant model: OR = 0.94, 95%CI = 0.86-1.04, P = 0.232). However, a significant impact of this polymorphism was detected on decreased ovarian cancer risk (dominant model: OR = 0.83, 95%CI = 0.73-0.95, P = 0.007). In addition, we found this polymorphism was associated with increased upper aerodigestive tract (UADT) cancer susceptibility (dominant model: OR = 1.51, 95%CI = 1.04-2.20, P = 0.032). CONCLUSION: The Arg188His polymorphism might play different roles in carcinogenesis of various cancer types. Current evidence did not suggest that this polymorphism was directly associated with breast cancer susceptibility. However, this polymorphism might contribute to decreased gynecological cancer risk and increased UADT cancer risk. More preclinical and epidemiological studies were still imperative for further evaluation.

Background: The authors aimed to comprehensively evaluate the efficacy and safety of antibiotic prophylaxis through surgical and nonsurgical scenarios and assess the strength of evidence. Materials and methods: The authors performed an umbrella review of meta-analyses of randomized controlled trials (RCTs). An evidence map was created to summarize the absolute benefits of antibiotic prophylaxis in each scenario and certainty of evidence. Results: Seventy-five meta-analyses proved eligible with 725 RCTs and 78 clinical scenarios in surgical and medical prophylaxis. Of 119 health outcomes, 67 (56.3%) showed statistically significant benefits, 34 of which were supported by convincing or highly suggestive evidence from RCTs. For surgeries, antibiotic prophylaxis may minimize infection occurrences in most surgeries except Mohs surgery, simple hand surgery, herniorrhaphy surgery, hepatectomy, thyroid surgery, rhinoplasty, stented distal hypospadias repair, midurethral sling placement, endoscopic sinus surgery, and transurethral resection of bladder tumors with only low to very low certainty evidence. For nonsurgery invasive procedures, only low to very low certainty evidence showed benefits of antibiotic prophylaxis for cystoscopy, postoperative urinary catheterization, and urodynamic study. For medical prophylaxis, antibiotic prophylaxis showed greater benefits in nonemergency scenarios, in which patients were mainly with weakened immune systems, or at risk of recurrent chronic infections. Antibiotics prophylaxis may increase antibiotic resistance or other adverse events in most scenarios and reached significance in cystoscopy, afebrile neutropenia following chemotherapy and hematopoietic stem cell transplantation. Conclusions: Antibiotic prophylaxis in surgical and nonsurgical scenarios is generally effective and seems independent of surgical cleanliness and urgency of diseases. Its safety is not well determined due to lack of available data. Nevertheless, the low quality of current evidence limits the external validity of these findings, necessitating clinicians to judiciously assess indications, balancing low infection rates with antibiotic-related side effects. [ABSTRACT FROM AUTHOR]

Background: Total neoadjuvant therapy is a promising treatment for locally advanced rectal cancer, utilizing either short-course radiotherapy or long-course chemoradiotherapy, but their relative efficacy remains unclear. The aim of this Bayesian network meta-analysis was to investigate clinical outcomes amongst patients receiving total neoadjuvant therapy with short-course radiotherapy or long-course chemoradiotherapy, and those receiving long-course chemoradiotherapy alone. Methods: A systematic literature search was performed. All studies that compared at least two of these three treatments for locally advanced rectal cancer were included. The primary endpoint was the pathological complete response rate, and survival outcomes were adopted as secondary outcomes. Results: Thirty cohorts were included. Compared with long-course chemoradiotherapy, both total neoadjuvant therapy with longcourse chemoradiotherapy (OR 1.78, 95 per cent c.i. 1.43 to 2.26) and total neoadjuvant therapy with short-course radiotherapy (OR 1.75, 95 per cent c.i. 1.23 to 2.50) improved the pathological complete response rate. Similar benefits were observed in the sensitivity and subgroup analyses, except for short-course radiotherapy with one to two cycles of chemotherapy. No significant differences in survival outcomes were found amongst the three treatments. Long-course chemoradiotherapy with consolidation chemotherapy (HR 0.44, 95 per cent c.i. 0.20 to 0.99) exhibited higher disease-free survival than long-course chemoradiotherapy alone. Conclusion: Compared with long-course chemoradiotherapy, both short-course radiotherapy with greater than or equal to three cycles of chemotherapy and total neoadjuvant therapy with long-course chemoradiotherapy can improve the pathological complete response rate, and long-course chemoradiotherapy with consolidation chemotherapy may lead to a marginal benefit in disease-free survival. The pathological complete response rate and survival outcomes are similar for total neoadjuvant therapy with short-course radiotherapy or long-course chemoradiotherapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Better understanding of SARS-CoV-2 transmission risks is needed to support decision-making around mitigation measures for COVID-19 in schools. Methods We updated a living systematic review and meta-analysis to investigate the extent of SARS-CoV-2 transmission in schools. In this update we modified our inclusion criteria to include: 1) cohort studies; 2) cross-sectional studies that investigated and cross-assessed SARS-COV-2 positivity rates in schools and communities; and 3) pre-post studies. We performed risk of bias evaluation for all included studies using the Newcastle-Ottawa Scale (NOS). Results 6270 articles were retrieved and six new studies were added in this update. In total from the two updates and using the new inclusion criteria, we identified 11 cohort studies (1st update: n = 5; 2nd update: n = 6) and one cross-sectional study (1st update: n = 1; 2nd update: n = 0). We performed a meta-analysis on nine of the 11 cohort studies investigating IAR in schools. Nine cohort studies reported a total of 91 student and 52 staff index cases that exposed 5698 contacts with 101 secondary infections (overall infection attack rate (IAR) = 1.45%, 95% CI = 0.31%-3.26%). IARs for students and school staff were 1.66% (95% CI=0.08%-4.78%) and 1.18% (95% CI = 0.00%-4.43%) respectively. The risk of bias was found to be high for most studies identified, limiting the confidence in 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 the overall IAR and SARS-CoV-2 positivity rate in school settings are low. Higher IAR were found in students, compared to staff. Note This article is a living systematic review that will be updated to reflect emerging evidence. This is the second version of the original article published on 23 December 2020 (J Glob Health 2020;11:021104), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity. [ABSTRACT FROM AUTHOR]

Background: Understanding carriage and transmission potential of SARSCoV- 2 in children is of paramount importance to understand the spread of virus in school and community settings. Methods: We performed an updated rapid review to investigate the role of children in the transmission of SARS-CoV-2. We synthesized evidence for five categories and results are reported narratively. Results: A total of 33 new studies were included for this review. We did not identify additional studies that reported documented cases of SARS-CoV-2 transmission by children. We identified 15 new studies that demonstrate children's susceptibility and transmission risk of SARS-CoV-2 with evidence provided on the chance of being index or secondary cases, the potential of faecal-oral transmission, and the possibility of asymptomatic transmission. There is little data on the transmission of SARS-CoV-2 in schools. There were three studies reporting COVID-19 school outbreaks in France (Oise), Australia (New South Wales) and Israel. The remaining four studies found that all reported cases did not infect any other pupils or staff. With data from seven studies and governmental websites, the proportion of children among all confirmed COVID-19 patients was estimated for 29 countries, varying from 0.3% (lowest in Spain) up to 13.8% (highest in Argentina). Lastly, we identified seven studies reporting on PIMS-TS linked to COVID-19 among paediatric patients. Conclusions: There is somewhat limited evidence available for quantifying the extent to which children may contribute to overall transmission, but the balance of evidence so far suggests that children and schools play only a limited role in overall transmission. [ABSTRACT FROM AUTHOR]

Background 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. Methods We performed univariate and multivariate logistic regression to identify associations between 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 cohort. Subsequently, we tested causality by using Mendelian randomisation (MR) analyses. Results In the multivariable model, the increased acceleration vector magnitude PA (AMPA) is associated with a decreased probability of overall and outpatient COVID-19 with an odds ratio (OR) and 95% confidence interval (CI) of 0.80 (0.69, 0.93) and 0.74 (0.58, 0.95), respectively. No association is found between self-reported moderate-to-vigorous PA (MVPA) and COVID-19 related outcomes. No association is found by MR analyses. Conclusions Our results indicate a protective effect of objectively measured PA and COVID-19 outcomes (outpatient COVID-19 and overall COVID-19) independent of age, sex, measures of obesity, and smoking status. Although the MR analyses do not support a causal association, that may be due to limited power. We conclude that policies to encourage and facilitate exercise at a population level during the pandemic should be considered. [ABSTRACT FROM AUTHOR]

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 < 0.001) and increased dosage cohort (n = 103, P = 0.025). Competing risk regression analysis showed that combination therapy significantly increased the probability of seizure freedom (hazard ratio [HR] = 2.423, 95% confidence interval [CI] = 1.529-3.841, P < 0.001). In addition, male sex and generalized seizure were significantly associated with increased probability of seizure freedom (male sex: HR = 1.440, 95% CI = 1.106-1.880, P = 0.007; generalized seizure: HR = 1.543, 95% CI = 1.176-2.020, P = 0.002). Significance: Combination therapy may increase the probability of seizure freedom for patients with first AED failure due to lack of efficacy. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to investigate the role of serum uric acid (SUA) level in a broad spectrum of disease outcomes using data for 120 091 individuals from UK Biobank.Methods: We performed a phenome-wide association study (PheWAS) to identify disease outcomes associated with SUA genetic risk loci. We then implemented conventional Mendelianrandomisation (MR) analysis to investigate the causal relevance between SUA level and disease outcomes identified from PheWAS. We next applied MR Egger analysis to detect and account for potential pleiotropy, which conventional MR analysis might mistake for causality, and used the HEIDI (heterogeneity in dependent instruments) test to remove cross-phenotype associations that were likely due to genetic linkage.Results: Our PheWAS identified 25 disease groups/outcomes associated with SUA genetic risk loci after multiple testing correction (P<8.57e-05). Our conventional MR analysis implicated a causal role of SUA level in three disease groups: inflammatory polyarthropathies (OR=1.22, 95% CI 1.11 to 1.34), hypertensive disease (OR=1.08, 95% CI 1.03 to 1.14) and disorders of metabolism (OR=1.07, 95% CI 1.01 to 1.14); and four disease outcomes: gout (OR=4.88, 95% CI 3.91 to 6.09), essential hypertension (OR=1.08, 95% CI 1.03 to 1.14), myocardial infarction (OR=1.16, 95% CI 1.03 to 1.30) and coeliac disease (OR=1.41, 95% CI 1.05 to 1.89). After balancing pleiotropic effects in MR Egger analysis, only gout and its encompassing disease group of inflammatory polyarthropathies were considered to be causally associated with SUA level. Our analysis highlighted a locus (ATXN2/S2HB3) that may influence SUA level and multiple cardiovascular and autoimmune diseases via pleiotropy.Conclusions: Elevated SUA level is convincing to cause gout and inflammatory polyarthropathies, and might act as a marker for the wider range of diseases with which it associates. Our findings support further investigation on the clinical relevance of SUA level with cardiovascular, metabolic, autoimmune and respiratory diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Genetic Variation and Gastric Cancer Risk: A Field Synopsis and Meta-Analysis," by S. Mocellin et al that was published in a 2015 issue.