Risk factors for prostate cancer: An umbrella review of prospective observational studies and mendelian randomization analyses.

BACKGROUND: The incidence of prostate cancer is increasing in older males globally. Age, ethnicity, and family history are identified as the well-known risk factors for prostate cancer, but few modifiable factors have been firmly established. The objective of this study was to identify and evaluate various factors modifying the risk of prostate cancer reported in meta-analyses of prospective observational studies and mendelian randomization (MR) analyses. METHODS AND FINDINGS: We searched PubMed, Embase, and Web of Science from the inception to January 10, 2022, updated on September 9, 2023, to identify meta-analyses and MR studies on prostate cancer. Eligibility criteria for meta-analyses were (1) meta-analyses including prospective observational studies or studies that declared outcome-free at baseline; (2) evaluating the factors of any category associated with prostate cancer incidence; and (3) providing effect estimates for further data synthesis. Similar criteria were applied to MR studies. Meta-analysis was repeated using the random-effects inverse-variance model with DerSimonian-Laird method. Quality assessment was then conducted for included meta-analyses using AMSTAR-2 tool and for MR studies using STROBE-MR and assumption evaluation. Subsequent evidence grading criteria for significant associations in meta-analyses contained sample size, P values and 95% confidence intervals, 95% prediction intervals, heterogeneity, and publication bias, assigning 4 evidence grades (convincing, highly suggestive, suggestive, or weak). Significant associations in MR studies were graded as robust, probable, suggestive, or insufficient considering P values and concordance of effect directions. Finally, 92 selected from 411 meta-analyses and 64 selected from 118 MR studies were included after excluding the overlapping and outdated studies which were published earlier and contained fewer participants or fewer instrument variables for the same exposure. In total, 123 observational associations (45 significant and 78 null) and 145 causal associations (55 significant and 90 null) were categorized into lifestyle; diet and nutrition; anthropometric indices; biomarkers; clinical variables, diseases, and treatments; and environmental factors. Concerning evidence grading on significant associations, there were 5 highly suggestive, 36 suggestive, and 4 weak associations in meta-analyses, and 10 robust, 24 probable, 4 suggestive, and 17 insufficient causal associations in MR studies. Twenty-six overlapping factors between meta-analyses and MR studies were identified, with consistent significant effects found for physical activity (PA) (occupational PA in meta: OR = 0.87, 95% CI: 0.80, 0.94; accelerator-measured PA in MR: OR = 0.49, 95% CI: 0.33, 0.72), height (meta: OR = 1.09, 95% CI: 1.06, 1.12; MR: OR = 1.07, 95% CI: 1.01, 1.15, for aggressive prostate cancer), and smoking (current smoking in meta: OR = 0.74, 95% CI: 0.68, 0.80; smoking initiation in MR: OR = 0.91, 95% CI: 0.86, 0.97). Methodological limitation is that the evidence grading criteria could be expanded by considering more indices. CONCLUSIONS: In this large-scale study, we summarized the associations of various factors with prostate cancer risk and provided comparisons between observational associations by meta-analysis and genetically estimated causality by MR analyses. In the absence of convincing overlapping evidence based on the existing literature, no robust associations were identified, but some effects were observed for height, physical activity, and smoking.

Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke.

While carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (N = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (N = 45,185) and any stroke (AS, Ncase/Ncontrol=40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMTmax-AS: hazard ratio (HR) = 1.39, 95%CI = 1.09-1.79; cIMTmean-AS: HR = 1.39, 95%CI = 1.09-1.78; cIMTmin-AS: HR = 1.32, 95%CI = 1.04-1.68). A positive global genetic correlation was observed (cIMTmax-AS: [Formula: see text]=0.23, P=9.44 × 10-5; cIMTmean-AS: [Formula: see text]=0.21, P=3.00 × 10-4; cIMTmin-AS: [Formula: see text]=0.16, P=6.30 × 10-3). This was further substantiated by five shared independent loci and 15 shared expression-trait associations. Mendelian randomization analyses suggested no causal effect of cIMT on stroke (cIMTmax-AS: odds ratio (OR)=1.12, 95%CI=0.97-1.28; cIMTmean-AS: OR=1.09, 95%CI=0.93-1.26; cIMTmin-AS: OR=1.03, 95%CI = 0.90-1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMTmax: beta=0.07, 95%CI = 0.01-0.13; AS-cIMTmean: beta=0.08, 95%CI = 0.01-0.15; AS-cIMTmin: beta = 0.08, 95%CI = 0.01-0.16) in the reverse direction MR, which attenuated to non-significant in sensitivity analysis. Our work does not find evidence supporting causal associations between cIMT and stroke. The pronounced cIMT-stroke association is intrinsic, and mostly attributed to shared genetic components. The clinical value of cIMT as a surrogate marker for stroke risk in the general population is likely limited.

Assessment of the causal relationship between inflammatory bowel diseases and chronic kidney diseases: A two-sample bidirectional mendelian randomization study among European population.

BACKGROUND: Kidney function can be impaired in patients with inflammatory bowel diseases (IBD), including Crohn's diseases (CD) and ulcerative colitis (UC). However, the causal relationship between IBD and chronic kidney diseases (CKD) remains unclear. METHODS: We determined the causal association between IBD and CKD by performing two-sample bidirectional mendelian randomization (MR) analyses. Independent genetic variants were selected as instrumental variables (IVs) of the exposure from open-access genome-wide association studies (GWAS) among European ancestry. IVs-outcome estimates were extracted from three separate GWAS for IBD and two for CKD, respectively. Inverse-variance-weighted model was used as the primary MR method. The pleiotropic effect and heterogeneity were evaluated. For either direction, analyses were performed per outcome database and were subsequently meta-analysed. RESULTS: Genetically predicted IBD was associated with higher risk of CKD (OR: 1.045, 95% CI: 1.016-1.073, P = 0.002) by including 42 344 IBD cases and 229 164 controls. Further analyses showed genetic liability to CD increased the risk of CKD (OR: 1.057, 95% CI: 1.027-1.087, p < 0.001) whereas UC did not (OR: 0.999, 95% CI:0.969-1.031, p = 0.970). In contrast, genetically predicted CKD was not associated with IBD (OR: 1.010, 95% CI: 0.965-1.056, p = 0.676), UC (OR: 1.011, 95% CI: 0.948-1.078, p = 0.746) and CD (OR: 1.024; 95% CI: 0.963-1.089, p = 0.447). CONCLUSIONS: We concluded that CD, but not UC, can increase the risk of CKD causally. CD, but not UC, can increase the risk of chronic kidney disease causally. These findings enhance our understanding of the differential impact of IBD subtypes on CKD. It may be necessary to monitor kidney function regularly in patients with CD.

Moderating effect of a sodium-rich diet on the association between long-term exposure to fine particulate matter and blood lipids in children and adolescents.

BACKGROUND: Several studies reported that exposure to higher levels of fine particulate matter (PM2.5) was associated with deteriorated lipid profiles in children and adolescents. However, whether a sodium-rich diet could modify the associations remains unknown. We aimed to examine the associations of long-term exposure to PM2.5 with blood lipids in children and adolescents, and further examine the effect modification by dietary and urinary sodium levels based on a multi-community population in China. METHODS: The 3711 study participants were from a cross-sectional study, which interviewed children and adolescents aged 6 to 17 years across Sichuan Province, China between 2015 and 2017. Blood lipid outcomes including blood total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were assessed. Information on daily dietary sodium consumption was estimated with a semi-quantitative food frequency questionnaire (FFQ), and urinary sodium was used as an internal exposure biomarker. A linear regression model was applied to estimate the associations of prior 2-years' average exposure to ambient PM2.5 with blood lipids. The effect modification by dietary and urinary sodium was examined by stratified analyses. RESULTS: The participants from rural areas had higher levels of daily sodium consumptions. The results of multivariable regression analysis indicated that per 10 µg/m3 incremental change in PM2.5 was associated with a 1.56% (95% confidence interval 0.90%-2.23%) and a 2.26% (1.15%-3.38%) higher blood TC and LDL-C levels, respectively. Among the study participants with higher levels of dietary sodium or urinary sodium, exposure to higher levels of PM2.5 was significantly associated with deteriorated lipid profiles. For example, each 10 µg/m3 incremental change in exposure to PM2.5 was correlated with a 2.83 (-4.65 to -0.97) lower percentage decrease in blood HDL-C levels among the participants who were from the highest quartile of urinary sodium levels. While, these associations changed to be nonsignificant in the participants who were from the lowest quartile of dietary sodium levels. CONCLUSION: Exposure to higher levels of PM2.5 was associated with deteriorated blood lipid levels in children and adolescents. It is noteworthy that these associations might be ameliorated through the adoption of a low-sodium dietary regimen.

Epidemiological and genetic evidence for the relationship between ABO blood group and human cancer.

To comprehensively evaluate the etiological role of ABO blood group in human cancer, we conducted a large-scale meta-analysis of 127 publications totaling 20 million participants including 231 737 patients of 20 cancers, supplemented by genetic evidence. Effects of A, AB and B groups on cancer risk were investigated by respectively comparing with O group and their combined counterparts, and subgroup analysis by ethnicity was conducted for O-referent models. For cancer categories, A group increased risk of cancers of oral cavity and nasopharynx, digestive and female genital organs, while both AB and B groups showed associations with cancers of digestive and female genital organs. For individual cancers, A group significantly increased the risk of nine cancers including oral cavity (OR = 1.17, P = .013), stomach (OR = 1.19, P = 3.90 × 10-15 ), pancreas (OR = 1.33, P = 9.89 × 10-33 ), colorectum (OR = 1.09, P = .001), liver (OR = 1.23, P = .011), ovary (OR = 1.13, P = .001), cervix (OR = 1.17, P = .025), bladder (OR = 1.12, P = .025) and breast (OR = 1.06, P = .043). AB group showed associations with only three cancers: stomach (OR = 1.10, P = .007), pancreas (OR = 1.21, P = .001) and ovary (OR = 1.28, P = .006). B group, except for shared associations with A group on pancreas (OR = 1.20, P = 2.27 × 10-5 ) and cervix cancers (OR = 1.13, P = .011), had two distinct associations with esophagus (OR = 1.17, P = .002) and nonmelanoma skin cancers (OR = 0.96, P = .017). Ethnicity-specific analyses revealed the notable effects of non-O groups on pancreatic cancer both in Caucasians and Asians. In genetic analysis, four SNPs were associated with the risk of pancreatic cancer, with rs505922 corresponding to O group showing the strongest protective effect (P = 1.16 × 10-23 ). Our study provided comprehensive evidence of ABO blood group associated with cancers and highlighted its carcinogenic role.

Migraine, chronic kidney disease and kidney function: observational and genetic analyses.

Epidemiological studies demonstrate an association between migraine and chronic kidney disease (CKD), while the genetic basis underlying the phenotypic association has not been investigated. We aimed to help avoid unnecessary interventions in individuals with migraine through the investigation of phenotypic and genetic relationships underlying migraine, CKD, and kidney function. We first evaluated phenotypic associations using observational data from UK Biobank (N = 255,896). We then investigated genetic relationships leveraging genomic data in European ancestry for migraine (Ncase/Ncontrol = 48,975/540,381), CKD (Ncase/Ncontrol = 41,395/439,303), and two traits of kidney function (estimated glomerular filtration rate [eGFR, N = 567,460] and urinary albumin-to-creatinine ratio [UACR, N = 547,361]). Observational analyses suggested no significant association of migraine with the risk of CKD (HR = 1.13, 95% CI = 0.85-1.50). While we did not find any global genetic correlation in general, we identified four specific genomic regions showing significant for migraine with eGFR. Cross-trait meta-analysis identified one candidate causal variant (rs1047891) underlying migraine, CKD, and kidney function. Transcriptome-wide association study detected 28 shared expression-trait associations between migraine and kidney function. Mendelian randomization analysis suggested no causal effect of migraine on CKD (OR = 1.03, 95% CI = 0.98-1.09; P = 0.28). Despite a putative causal effect of migraine on an increased level of UACR (log-scale-beta = 0.02, 95% CI = 0.01-0.04; P = 1.92 × 10-3), it attenuated to null when accounting for both correlated and uncorrelated pleiotropy. Our work does not find evidence supporting a causal association between migraine and CKD. However, our study highlights significant biological pleiotropy between migraine and kidney function. The value of a migraine prophylactic treatment for reducing future CKD in people with migraine is likely limited.

Filamin A is overexpressed in non-alcoholic steatohepatitis and contributes to the progression of inflammation and fibrosis.

Non-alcoholic steatohepatitis (NASH) is a chronic and progressive liver disease characterized by steatosis, inflammation, and fibrosis. Filamin A (FLNA), an actin-binding protein, is involved in various cell functions, including the regulation of immune cells and fibroblasts. However, its role in the development of NASH through inflammation and fibrogenesis is not fully understood. In this study, we found that FLNA expression was increased in liver tissues of patients with cirrhosis and mice with non-alcoholic fatty liver disease (NAFLD)/NASH and fibrosis. Immunofluorescence analysis showed that FLNA was primarily expressed in macrophages and hepatic stellate cells (HSCs). Knocking down of FLNA by specific shRNA in phorbol-12-myristate-13-acetate (PMA)-derived THP-1 macrophages reduced lipopolysaccharide (LPS)-stimulated inflammatory response. The decreased mRNA levels of inflammatory cytokines and chemokines and suppression of the STAT3 signaling were observed in FLNA-downregulated macrophages. In addition, knockdown of FLNA in immortalized human hepatic stellate cells (LX-2 cells) resulted in decreased mRNA levels of fibrotic cytokines and enzymes involved in collagen synthesis, as well as increased levels of metalloproteinases and pro-apoptotic proteins. Overall, these results suggest that FLNA may contribute to the pathogenesis of NASH through its role in the regulation of inflammatory and fibrotic mediators.

Increases in BMI contribute to worsening inflammatory biomarkers related to breast cancer risk in women: a longitudinal study.

BACKGROUND: Inflammatory adipokines and cytokines play a pivotal role in linking obesity and breast cancer (BC) risk in women. We investigated the longitudinal associations between BMI change and trajectories of inflammatory biomarkers related to BC risk. METHODS: A longitudinal study was conducted among 442 Chinese women with 3-year repeated measures from 2019 to 2021. Plasma circulating inflammatory biomarkers related to BC risk, including adiponectin (ADP), resistin (RETN), soluble leptin receptor (sOB-R), insulin-like growth factor-binding protein-3 (IGFBP-3), and C-reactive protein (CRP), were examined annually. Linear mixed-effect models (LMM) were applied to investigate associations of time-varying BMI with trajectories of biomarkers. We additionally examined the modification effect of baseline BMI groups, menopausal status, and metabolic syndrome. RESULTS: BMI was associated with increased levels of RETN, CRP, sOB-R, and decreased levels of ADP at baseline. An increasing BMI rate was significantly associated with an average 3-year increase in RETN (ß = 0.019, 95% CI 0.004 to 0.034) and sOB-R (ß = 0.022, 95% CI 0.009 to 0.035), as well as a decrease in ADP (ß = - 0.006, 95% CI - 0.012 to 0.001). These associations persisted across different baseline BMI groups. An increasing BMI rate was significantly associated with an average 3-year increase in CRP levels among normal weight (ß = 0.045, 95% CI 0.001 to 0.088) and overweight (ß = 0.060, 95% CI 0.014 to 0.107) women. As BMI increased over time, a more remarkable decrease in ADP was observed among women with metabolic syndrome (ß = - 0.016, 95% CI - 0.029 to - 0.004) than those without metabolic syndrome at baseline. CONCLUSIONS: A higher increase rate of BMI was associated with poorer trajectories of inflammatory biomarkers related to BC risk. Recommendations for BMI reduction may benefit BC prevention in women, particularly for those with metabolic syndrome.

Impact of gallstone disease on the risk of stroke and coronary artery disease: evidence from prospective observational studies and genetic analyses.

BACKGROUND: Despite epidemiological evidence associating gallstone disease (GSD) with cardiovascular disease (CVD), a dilemma remains on the role of cholecystectomy in modifying the risk of CVD. We aimed to characterize the phenotypic and genetic relationships between GSD and two CVD events - stroke and coronary artery disease (CAD). METHODS: We first performed a meta-analysis of cohort studies to quantify an overall phenotypic association between GSD and CVD. We then investigated the genetic relationship leveraging the largest genome-wide genetic summary statistics. We finally examined the phenotypic association using the comprehensive data from UK Biobank (UKB). RESULTS: An overall significant effect of GSD on CVD was found in meta-analysis (relative risk [RR] = 1.26, 95% confidence interval [CI] = 1.19-1.34). Genetically, a positive shared genetic basis was observed for GSD with stroke ([Formula: see text]=0.16, P = 6.00 × 10-4) and CAD ([Formula: see text]=0.27, P = 2.27 × 10-15), corroborated by local signals. The shared genetic architecture was largely explained by the multiple pleiotropic loci identified in cross-phenotype association study and the shared gene-tissue pairs detected by transcriptome-wide association study, but not a causal relationship (GSD to CVD) examined through Mendelian randomization (MR) (GSD-stroke: odds ratio [OR] = 1.00, 95%CI = 0.97-1.03; GSD-CAD: OR = 1.01, 95%CI = 0.98-1.04). After a careful adjustment of confounders or considering lag time using UKB data, no significant phenotypic effect of GSD on CVD was detected (GSD-stroke: hazard ratio [HR] = 0.95, 95%CI = 0.83-1.09; GSD-CAD: HR = 0.98, 95%CI = 0.91-1.06), further supporting MR findings. CONCLUSIONS: Our work demonstrates a phenotypic and genetic relationship between GSD and CVD, highlighting a shared biological mechanism rather than a direct causal effect. These findings may provide insight into clinical and public health applications.

Understanding the relationship between circulating lipids and risk of chronic kidney disease: a prospective cohort study and large-scale genetic analyses.

BACKGROUND: This study aims to comprehensively investigate the phenotypic and genetic relationships between four common lipids (high-density lipoprotein cholesterol, HDL-C; low-density lipoprotein cholesterol, LDL-C; total cholesterol, TC; and triglycerides, TG), chronic kidney disease (CKD), and estimated glomerular filtration rate (eGFR). METHODS: We first investigated the observational association of lipids (exposures) with CKD (primary outcome) and eGFR (secondary outcome) using data from UK Biobank. We then explored the genetic relationship using summary statistics from the largest genome-wide association study of four lipids (N = 1,320,016), CKD (Ncase = 41,395, Ncontrol = 439,303), and eGFR(N = 567,460). RESULTS: There were significant phenotypic associations (HDL-C: hazard ratio (HR) = 0.76, 95%CI = 0.60-0.95; TG: HR = 1.08, 95%CI = 1.02-1.13) and global genetic correlations (HDL-C: [Formula: see text] = - 0.132, P = 1.00 × 10-4; TG: [Formula: see text] = 0.176; P = 2.66 × 10-5) between HDL-C, TG, and CKD risk. Partitioning the whole genome into 2353 LD-independent regions, twelve significant regions were observed for four lipids and CKD. The shared genetic basis was largely explained by 29 pleiotropic loci and 36 shared gene-tissue pairs. Mendelian randomization revealed an independent causal relationship of genetically predicted HDL-C (odds ratio = 0.91, 95%CI = 0.85-0.98), but not for LDL-C, TC, or TG, with the risk of CKD. Regarding eGFR, a similar pattern of correlation and pleiotropy was observed. CONCLUSIONS: Our work demonstrates a putative causal role of HDL-C in CKD and a significant biological pleiotropy underlying lipids and CKD in populations of European ancestry. Management of low HDL-C levels could potentially benefit in reducing the long-term risk of CKD.

Using human genetics to understand the epidemiological association between obesity, serum urate, and gout.

OBJECTIVES: We aimed to clarify the genetic overlaps underlying obesity-related traits, serum urate, and gout. METHODS: We conducted a comprehensive genome-wide cross-trait analysis to identify genetic correlation, pleiotropic loci, and causal relationships between obesity (the exposure variable), gout (the primary outcome) and serum urate (the secondary outcome). Summary statistics were collected from the hitherto largest genome-wide association studies conducted for BMI (N = 806 834), waist-to-hip ratio (WHR; N = 697 734), WHR adjusted for BMI (WHRadjBMI; N = 694 649), serum urate (N = 288 649), and gout (Ncases = 13 179 and Ncontrols = 750 634). RESULTS: Positive overall genetic correlations were observed for BMI (rg = 0.27, P = 6.62 × 10-7), WHR (rg = 0.22, P = 6.26 × 10-7) and WHRadjBMI (rg = 0.07, P = 6.08 × 10-3) with gout. Partitioning the whole genome into 1703 LD (linkage disequilibrium)-independent regions, a significant local signal at 4q22 was identified for BMI and gout. The global and local shared genetic basis was further strengthened by the multiple pleiotropic loci identified in the cross-phenotype association study, multiple shared gene-tissue pairs observed by Transcriptome-wide association studies, as well as causal relationships demonstrated by Mendelian randomization [BMI-gout: OR (odds ratio) = 1.66, 95% CI = 1.45, 1.88; WHR-gout: OR = 1.57, 95% CI = 1.37, 1.81]. Replacing the binary disease status of gout with its latent pathological measure, serum urate, a similar pattern of correlation, pleiotropy and causality was observed with even more pronounced magnitude and significance. CONCLUSION: Our comprehensive genome-wide cross-trait analysis demonstrates a shared genetic basis and pleiotropic loci, as well as a causal relationship between obesity, serum urate, and gout, highlighting an intrinsic link underlying these complex traits.

Using human genetics to understand the phenotypic association between chronotype and breast cancer.

Little is known regarding the shared genetic influences underlying the observed phenotypic association between chronotype and breast cancer in women. Leveraging summary statistics from the hitherto largest genome-wide association study conducted in each trait, we investigated the genetic correlation, pleiotropic loci, and causal relationship of chronotype with overall breast cancer, and with its subtypes defined by the status of oestrogen receptor. We identified a negative genomic correlation between chronotype and overall breast cancer ( r g $$ {r}_g $$ = -0.06, p = 3.00 × 10-4 ), consistent across oestrogen receptor-positive ( r g $$ {r}_g $$ = -0.05, p = 3.30 × 10-3 ) and oestrogen receptor-negative subtypes ( r g $$ {r}_g $$ = -0.05, p = 1.11 × 10-2 ). Five specific genomic regions were further identified as contributing a significant local genetic correlation. Cross-trait meta-analysis identified 78 loci shared between chronotype and breast cancer, of which 23 were novel. Transcriptome-wide association study revealed 13 shared genes, targeting tissues of the nervous, cardiovascular, digestive, and exocrine/endocrine systems. Mendelian randomisation demonstrated a significantly reduced risk of overall breast cancer (odds ratio 0.89, 95% confidence interval 0.83-0.94; p = 1.30 × 10-4 ) for genetically predicted morning chronotype. No reverse causality was found. Our work demonstrates an intrinsic link underlying chronotype and breast cancer, which may provide clues to inform management of sleep habits to improve female health.

Silicone gel sheeting for treating keloid scars.

BACKGROUND: Keloid scarring is one of the most common types of pathological scarring. Keloid scars that fail to heal can affect a person's physical and psychological function by causing pain, pruritus, contractures, and cosmetic disfigurement. Silicone gel sheeting (SGS) is made from medical-grade silicone reinforced with a silicone membrane backing and is one of the most commonly used treatments for keloid scars. However, there is no up-to-date systematic review assessing the effectiveness of SGS for keloid scars. A clear and rigorous review of current evidence is required to guide clinicians, healthcare managers and people with keloid scarring. OBJECTIVES: To assess the effectiveness of silicone gel sheeting for the treatment of keloid scars compared with standard care or other therapies. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was December 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that recruited people with any keloid scars and assessed the effectiveness of SGS. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment, data extraction and GRADE assessment of the certainty of evidence. We resolved initial disagreements by discussion, or by consulting a third review author when necessary. MAIN RESULTS: Two studies met the inclusion criteria. Study sample sizes were 16 and 20 participants. The trials were clinically heterogeneous with differences in causes for scarring (e.g. surgery, infected wounds, and trauma), site (e.g. chest and back), and ages of scars. The duration of follow-up was three and four and a half months. The included studies reported three comparisons; SGS compared with no treatment, SGS compared with non-silicone gel sheeting (a dressing similar to SGS but which does not contain silicone), and SGS compared with intralesional injections of triamcinolone acetonide. One trial had a split-body design and one trial had an unclear design (resulting in a mix of paired and clustered data). The included studies reported limited outcome data for the primary review outcome of scar severity measured by health professionals and no data were reported for severity of scar measured by patients or adverse events. For secondary outcomes some data on pain were reported, but health-related quality of life and cost-effectiveness were not reported. Both trials had suboptimal outcome reporting, thus many domains in the risk of bias were assessed as unclear. All evidence was rated as being very low-certainty, mainly due to risk of bias, indirectness, and imprecision.  SGS compared with no treatment Two studies with 33 participants (76 scars) reported the severity of scar assessed by health professionals, and we are uncertain about the effect of SGS on scar severity compared with no treatment (very low-certainty evidence, downgraded once for risk of bias, once for inconsistency, once for indirectness, and once for imprecision). We are uncertain about the effect of SGS on pain compared with no treatment (21 participants with 40 scars; very low-certainty evidence, downgraded once for risk of bias, once for inconsistency, once for indirectness, and once for imprecision). No data were reported for other outcomes including scar severity assessed by patients, adverse events, adherence to treatment, health-related quality of life and cost-effectiveness. SGS compared with non-SGS One study with 16 participants (25 scars) was included in this comparison. We are uncertain about the effect of SGS on scar severity assessed by health professionals compared with non-SGS (very low-certainty evidence, downgraded once for risk of bias, once for indirectness, and once for imprecision). We are also uncertain about the effect of SGS on pain compared with non-SGS (very low-certainty evidence, downgraded once for risk of bias, once for indirectness, and once for imprecision). No data were reported for other outcomes including scar severity assessed by patients, adverse events, adherence to treatment, health-related quality of life and cost-effectiveness. SGS compared with intralesional injections of triamcinolone acetonide One study with 17 participants (51 scars) reported scar severity assessed by health professionals, and we are uncertain about the effect of SGS on scar severity compared with intralesional injections of triamcinolone acetonide (very low-certainty evidence, downgraded once for risk of bias, once for indirectness, and once for imprecision). This study also reported pain assessed by health professionals among 5 participants (15 scars) and we are uncertain about the effect of SGS on pain compared with intralesional injections of triamcinolone acetonide (very low-certainty evidence, downgraded once for risk of bias, once for indirectness, and twice for imprecision). No data were reported for other outcomes including scar severity assessed by patients, adverse events, adherence to treatment, health-related quality of life and cost-effectiveness. AUTHORS' CONCLUSIONS: There is currently a lack of RCT evidence about the clinical effectiveness of SGS in the treatment of keloid scars. From the two studies identified, there is insufficient evidence to demonstrate whether the use of SGS compared with no treatment, non-SGS, or intralesional injections of triamcinolone acetonide makes any difference in the treatment of keloid scars. Evidence from the included studies is of very low certainty, mainly driven by the risk of bias, indirectness, and imprecision due to small sample size. Further well-designed studies that have good reporting methodologies and address important clinical, quality of life and economic outcomes are required to reduce uncertainty around decision-making in the use of SGS to treat keloid scars.

A cross-sectional study on knowledge and behavior regarding medication usage among guardians of left-behind children: evidence from China.

PURPOSE: The primary objective of this study was to evaluate knowledge and behavior of medication use among guardians of left-behind children (LBC) and non-left-behind children (NLBC). METHODS: A cross-sectional study was conducted in Chengdu, the major city of southwestern China from May 2020 to August 2020. A logistic regression model was conducted to assess medication-related knowledge and behavior of guardians between the LBC group and NLBC group, adjusted for confounders. Stratified analysis was further performed. RESULTS: The overall mean scores for knowledge and for behavior were 20.22 (standard deviation = 4.472) and 15.77 (standard deviation = 3.604), respectively. No significant difference was found in medication-related knowledge and behavior scores between LBC and NLBC guardians (P > 0.05). A significant difference was only observed after adjusting for past medical history and history of present illness (HPI). CONCLUSION: There was no significant difference in the awareness and behavior of medication use between guardians of LBC and NLBC in this study, having more contact with the doctor was an effective method of health education that could possibly improve their health literacy.

Temporal relationship between sleep duration and obesity among Chinese Han people and ethnic minorities.

BACKGROUND: No studies have assessed the association between sleep duration and obesity in Chinese ethnic minorities. Whether the relationship between sleep duration and obesity is different between Chinese Han people and Chinese ethnic minorities remains unclear. The study aimed to explore the relationship between sleep duration and obesity among Chinese Han people and Chinese ethnic minorities. METHODS: We applied data from the Guizhou Population Health Cohort Study (GPHCS), which 9,280 participants were recruited in the baseline survey from 2010 to 2012, and 8,163 completed the follow-up survey from 2016 to 2020. A total of 5,096 participants (3,188 Han Chinese and 1,908 ethnic minorities) were included in the ultimate analysis. Information on sleep duration (total 24-hour sleep time), body mass index (BMI), and waist circumference (WC) was collected at the baseline and follow-up survey, respectively. Cross-lagged panel analyses were conducted to explore the temporal relationship between sleep duration and obesity for Han people and ethnic minorities. RESULTS: For Han people, the results from cross-lagged panel analyses indicated that baseline sleep duration was significantly associated with follow-up BMI (ßBMI = -0.041, 95% CIBMI: -0.072 ~ -0.009) and follow-up WC (ßWC = -0.070, 95%CIWC: -0.103 ~ -0.038), but baseline BMI (ßBMI = -0.016, 95% CIBMI: -0.050 ~ 0.018) and baseline WC (ßWC = -0.019, 95% CIWC: -0.053 ~ 0.016) were not associated with follow-up sleep duration. In addition, the relationship between baseline sleep duration and follow-up BMI was gender-specific and significant only in the Han people female (ßBMI = -0.047, 95% CIBMI: -0.090 ~ -0.003) but not in the Han people male (ßBMI = -0.029, 95% CIBMI: -0.075 ~ 0.016). For ethnic minorities, the results indicated that there was no relationship between sleep duration and obesity at all, either from sleep duration to obesity (ßBMI = 0.028, 95%CIBMI: -0.012 ~ 0.068; ßWC = 0.020, 95%CIWC: -0.022 ~ 0.062), or from obesity to sleep duration (ßBMI = -0.022, 95%CIBMI: -0.067 ~ 0.022; ßWC = -0.042, 95%CIWC: -0.087 ~ 0.003). CONCLUSION: The relationship pattern between sleep duration and obesity across Han people and ethnic minorities is different. Future sleep-aimed overweight and obesity intervention should be conducted according to population characteristics.

Assessing the causal effect of long-term exposure to air pollution on cognitive decline in middle-aged and older adults - Empirical evidence from a nationwide longitudinal cohort.

Air pollution remains a risk factor for the global burden of disease. Middle-aged and older people are more susceptible to air pollution because of their declining physical function and are more likely to develop diseases from long-term air pollution exposure. Studies of the effects of air pollution on cognitive function in middle-aged and older adults have been inconsistent. More representative and definitive evidence is needed. This study analysed data from the Chinese Family Panel Study, an ongoing nationwide prospective cohort study, collected in waves 2014, 2016 and 2018. Rigorously tested instrument was selected for analysis and participants' PM2.5 and instrument exposures were assessed using high-precision satellite data. The causal relationship between long-term exposure to air pollution and poor cognitive function in middle-aged and older adults was investigated using the Correlated Random Effects Control Function (CRE-CF) method within a quasi-experimental framework. This study included a total of 7042 participants aged 45 years or older. A comparison of CRE-CF with other models (OLS model, ordered probit model, and ordered probit-CRE model) demonstrated the necessity of using CRE-CF given the endogeneity of air pollution. The credibility and validity of the instrumental variable were verified. In the CRE-CF model, long-term exposure to PM2.5 was found to accelerate cognitive decline in middle-aged and older adults (coefficients of -0.159, -0.336 and -0.244 for the total cognitive, verbal and mathematical scores, respectively). Taken together, these results suggest that chronic exposure to ambient air pollution is associated with cognitive decline in middle-aged and older adults, which highlights the need for appropriate protective policies.

Associations between changes of smartphone pedometer-assessed step counts and levels of obesity-related breast cancer biomarkers in non-cancer women: A population-based observational study.

While a higher level of physical activity (PA) is inversely associated with a higher breast cancer (BC) risk, the health benefits of daily steps on obesity-related BC biomarkers remain unclear. We aimed to understand the associations of changes in step counts with levels of five obesity-related BC biomarkers during a two-year follow-up. In total, 144 non-cancer women (47.96 ± 5.72) were observed on both 2019 and 2021. A structured questionnaire, daily steps and fasting blood samples were collected before (t0, 2019) and after (t1, 2021). Levels of biomarkers (IGF-binding proteins 3, adiponectin, soluble leptin receptor, C-reactive protein, and resistin) were assayed by ELISA. Participants were divided into persistent low steps, decreasing steps, increasing steps, and persistent high steps. Associations of categories on proposed biomarkers were estimated using linear regression models, with persistent low steps as reference. Associations between time-varying step counts with biomarkers were quantified using mixed linear models. Compared with persistent low steps, increasing steps is associated with a reduction in C-reactive protein level (ß=-0.74, 95%CI=-1.23--0.26, P-value = 2.98 × 10-3). An inverse association between time-varying step counts with C-reactive protein level was identified, consistent across different obesity types and baseline step level categories. No association with daily step counts was observed for other proteins.

Analysis of pre-hospital delay in Chinese patients with diabetic foot ulcers: Based on 46 cases.

To study the causes of pre-hospital delay in Chinese patients with diabetic foot ulcers (DFUs). A retrospective study, investigating a case series of 46 DFUs treated at a single hospital, was conducted to evaluate wound condition, wound treatment, costs, and patients' complete medical records, and analyse the reasons causing the pre-hospital delay. We assessed 46 DFUs aged between 53 and 92 years old. The average pre-hospital delay was 5 months, with nearly 20% being delayed for more than 1 year. The average length of hospital stay in China was 21 days, with an average cost of $8672. Recurrence rate of DFUs was 21%, and three patients were recommended to transfer to upper-level hospital. Besides, the intervention was limited and homogenous and medical records were incomplete. Medical service users' limited understanding of diseases, high costs that patients need to afford, and unsatisfactory treatment by medical service providers are the main reasons for patients' delay in seeking treatment. Recommendations are offered to reduce the pre-hospital delay of Chinese patients with DFUs.

Omega-3 fatty acids impair miR-1-3p-dependent Notch3 down-regulation and alleviate sepsis-induced intestinal injury.

BACKGROUND: Sepsis is a troublesome syndrome that can cause intestinal injury and even high mortality rates. Omega-3 fatty acids (FAs) are known to protect against intestinal damage. Accordingly, the current study set out to explore if omega-3 FAs could affect sepsis-induced intestinal injury with the involvement of the microRNA (miR)-1-3p/Notch3-Smad axis. METHODS: First, cecal ligation and perforation (CLP) was performed to establish septic mouse models in C57BL/6J mice, and mouse intestinal epithelial MODE-K cells were induced by lipopolysaccharide (LPS) to establish sepsis cell models. The CLP-induced septic mice or LPS-exposed cells were subjected to treatment with Omega-3 FAs and activin (Smad signaling activator), miR-1-3p inhibitor and over-expressed/short hairpin RNA (oe-/sh)-Notch3 to explore their roles in inflammation, intestinal oxidative stress and cell apoptosis. A dual-luciferase reporter gene assay was further performed to verify the regulatory relationship between miR-1-3p and Notch3. RESULTS: Omega-3 FAs inhibited CLP-induced intestinal injury and ameliorated LPS-induced intestinal epithelial cell injury by down-regulating miR-1-3p, as evidenced by decreased levels of tumor necrosis factor-α, interleukin-1ß (IL-1ß) and IL-6, in addition to diminished levels of reactive oxygen species, malondialdehyde levels and superoxide dismutase activity. Furthermore, miR-1-3p could down-regulate Notch3, which inactivated the Smad pathway. CONCLUSION: Collectively, our findings indicated that omega-3 FAs elevate the expression of Notch3 by down-regulating miR-1-3p, and then blocking the Smad pathway to alleviate intestinal epithelial inflammation and oxidative stress injury caused by sepsis.

Roles and Applications of Red Blood Cell-Derived Extracellular Vesicles in Health and Diseases.

Red blood cell-derived extracellular vesicles (RBCEVs) are vesicles naturally produced by red blood cells and play multiple roles such as acting as cell-to-cell communication messengers in both normal physiological and diseased states. RBCEVs are highly promising delivery vehicles for therapeutic agents such as biomolecules and nucleic acids as they are easy to source, safe, and versatile. RBCEVs autonomously target the liver and pass the blood-brain barrier into the brain, which is highly valuable for the treatment of liver and brain diseases. RBCEVs can be modified by various functional units, including various functional molecules and nanoparticles, to improve their active targeting capabilities for tumors or other sites. Moreover, the RBCEV level is significantly shifted in many diseased states; hence, they can also serve as important biomarkers for disease diagnoses. It is clear that RBCEVs have considerable potential in multiple medical applications. In this review, we briefly introduce the biological roles of RBCEVs, presented interesting advances in RBCEV applications, and discuss several challenges that need to be addressed for their clinical translation.