Risk factors for nephrolithiasis formation: An Umbrella Review.

OBJECTIVE: Nephrolithiasis is prevalent and burdensome worldwide. At present, evidence on the risk factors for nephrolithiasis is unconsolidated and the associations remain uncertain. We systematically evaluate the robustness of the meta-analytic evidence and aid more reliable interpretations of the epidemiological relationships. METHODS: We conducted a comprehensive review of the meta-analyses, screened the included studies with the aid of the AMSTAR 2 evaluation tool, and then used R (4.1.1) software to perform data analysis to evaluate the association between candidate risk factors and kidney stones, and evaluated the credibility of the evidence of the association between risk factors and kidney stones according to the GRADE classification, and finally obtained the strength and effectiveness of the association. RESULTS: We finally included 17 meta-analyses regarding 46 risk factors, 34 of which (73.9%) showed statistically significant association with nephrolithiasis. Among the significant associations, we found that waist circumference, BMI, dietary intake and fructose intake were positively correlated with the occurrence and development of nephrolithiasis. Caffeine, dietary fiber and DASH-diet showed a tendency to reduce kidney stones. Interestingly, calcium supplementation, dietary calcium, and vitamin D, which are widely believed to be responsible for stone formation, made no difference or even reduced the risk of nephrolithiasis. CONCLUSIONS: Our study demonstrates the suggestive causal (central obesity, T2D, gout, dietary sodium, fructose intake and higher temperatures) risk factors of nephrolithiasis. We also demonstrate the suggestive causal (coffee/alcohol/beer intake, dietary calcium and DASH-diet) protective factors of nephrolithiasis. To provide epidemiological basis for the treatment and prevention of nephrolithiasis.

Risk Factors for Pelvic Organ Prolapse: Wide-Angled Mendelian Randomization Analysis.

INTRODUCTION AND HYPOTHESIS: We hypothesized that some metabolic factors, lifestyle factors, and socioeconomic factors may have a causal effect on pelvic organ prolapse (POP). METHODS: We selected instruments from corresponding genome-wide association studies (GWAS), which identified independent single nucleotide polymorphisms strongly associated with 12 potential risk factors. Summary statistics for POP were derived from two GWAS datasets, serving for discovery and replication stage. The primary analysis involved the use of the inverse-variance weighting mendelian randomization (MR) method, with additional sensitivity MR analyses conducted. RESULTS: The univariable mendelian randomization (UVMR) analysis in both the discovery and replication stage provided evidence for significant causal effects between higher waist-to-hip ratio adjusted for body mass index (WHRadjBMI) levels, lower high-density lipoprotein cholesterol (HDL-C) levels, and lower educational attainment and higher POP risk, as well as a suggestive positive causal effect between triglycerides and POP. The multivariable mendelian randomization (MVMR) analysis showed that only HDL-C among the three blood lipid fractions could reduce the risk of POP. Mediation analysis indicated that HDL-C may partially mediate the effect of WHRadjBMI on POP risk, and the causal effect between educational attainment and POP may be mediated through WHRadjBMI and HDL-C. CONCLUSIONS: Our study's evidence supported a causal relationship between WHRadjBMI, triglycerides, HDL-C, educational attainment, and POP risk. This highlights that clinicians may guide the general female population to control obesity and blood lipid levels to reduce the risk of POP.

Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs. METHODS: This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678. FINDINGS: 14 605 citations were identified by our search, of which 132 eligible trials enrolled 48 209 participants. All drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of ≥5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·98, 95% CI -9·27 to -6·69) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·79, 95% CI -6·34 to -5·25). Naltrexone-bupropion (OR 2·69, 95% CI 2·10 to 3·44), phentermine-topiramate (2·40, 1·68 to 3·44), GLP-1 receptor agonists (2·22, 1·74 to 2·84), and orlistat (1·71, 1·42 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·40, 95% CI -12·51 to -10·29). INTERPRETATION: In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective. FUNDING: 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.

Transperineal anastomotic posterior urethroplasty with bulbocavernosus flap and fibrin sealant in the complicated posterior urethral stricture reconstruction: a retrospective cohort study.

BACKGROUND: Management of complicated posterior urethral stricture is challenging. Modified transperineal anastomotic urethroplasty (TAU) with bulbocavernosus flap interposition and human fibrin sealant provides another treatment option. The authors aimed to evaluate whether this technique could improve the success rate in the complicated posterior urethral stricture reconstruction in this study. MATERIALS AND METHODS: Between 2016 and 2019, 48 patients underwent either conventional or modified TAU. The criteria for success included both the absence of clinical symptoms and no need for further surgical intervention during follow-up. RESULTS: Twelve patients underwent the modified TAU (group A) using bulbocavernosus flap interposition and human fibrin sealant. Thirty-six patients underwent the traditional end-to-end anastomotic urethroplasty (group B). Follow-up was 24.3-57.2 months. The patients in group A had a higher surgery success rate compared to the patients in group B (91.7 vs. 63.9%, P =0.067), with a quasi-significant result. Besides, no postoperative complications were observed in group A, while two individuals in group B had urinary incontinence, but the difference was not significant (0 vs. 5.6%, P =0.404). CONCLUSION: Based on the preliminary results, modified TAU with bulbocavernosus flap interposition and human fibrin sealant is a safe and feasible technique for complicated posterior urethral stricture reconstruction.

Is antibiotic prophylaxis generally safe and effective in surgical and nonsurgical scenarios? Evidence from an umbrella review of randomized controlled trials.

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.

Association between urinary sodium and circulating lipid levels: a Mendelian randomization study.

Background: Urinary sodium was indicated to be associated with dyslipidemia, but inconsistent conclusions for this association exist across the present observational studies. Objectives: This study aimed to evaluate the causal association between urinary sodium and circulating lipid levels [low-density lipoprotein cholesterol (LDL-C), triglycerides, and high-density lipoprotein cholesterol (HDL-C)] through Mendelian randomization. Methods: Univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) with pleiotropy-resistant methods were performed. Data for urinary sodium were obtained from the genome-wide association study (GWAS) from 446,237 European individuals. Data for lipid profiles were extracted from GWAS based on the UK Biobank (for the discovery analysis) and the Global Lipids Genetics Consortium (for the replication analysis). Results: In the discovery analysis, UVMR provided evidence that per 1-unit log-transformed genetically increased urinary sodium was associated with a lower level of HDL-C level (beta = -0.32; 95% CI: -0.43, -0.20; p = 7.25E-08), but not with LDL-C and triglycerides. This effect was still significant in the further MVMR when considering the effect of BMI or the other two lipid contents. In contrast, higher genetically predicted triglycerides could increase urinary sodium in both UVMR (beta = 0.030; 95% CI: 0.020, -0.039; p = 2.12E-10) and MVMR analyses (beta = 0.029; 95% CI: 0.019, 0.037; p = 8.13E-10). Similar results between triglycerides and urinary sodium were found in the replication analysis. Conclusion: Increased urinary sodium may have weak causal effects on decreased circulating HDL-C levels. Furthermore, genetically higher triglyceride levels may have independent causal effects on increased urinary sodium excretion.

Do Obesity-Related Traits Affect Prostate Cancer Risk through Serum Testosterone? A Mendelian Randomization Study.

OBJECTIVE: This study aimed to investigate whether testosterone mediates or confounds the effect of obesity-related traits on prostate cancer (PCa) using Mendelian randomization (MR) analysis. MATERIALS AND METHODS: Data of obesity-related traits (body mass index [BMI], waist-to-hip ratio [WHR], and waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) were obtained from up to 806,834 people of European ancestry; data of testosterone (bioavailable testosterone [BT], total testosterone [TT], and sex hormone-binding globulin [SHBG]) were extracted from up to 194,453 participants in the UK Biobank; and the summary-level data of PCa (79,194 cases and 61,112 controls) were obtained from the PRACTICAL consortium. RESULT: The results supported the causal relationship between higher BMI and a reduced risk of PCa (OR = 0.91, 95% confidence interval [CI]: 0.86-0.96). Furthermore, increased BT levels were associated with an elevated risk of PCa (OR = 1.15, 95% CI: 1.06-1.24). Importantly, our analysis revealed a unidirectional causal effect-higher BMI was linked to lower BT levels (beta = -0.27, 95% CI: -0.3--0.24), but not the other way around. This suggests that BT may mediate the effect of BMI on PCa rather than confound it. Our multivariable MR results further demonstrated that considering BT as a mediator led to the weakening of BMI's effect on PCa risk (OR = 0.97, 95% CI: 0.90-1.05), while the impact of BT on PCa remained unchanged when accounting for BMI. Moreover, we identified a significant indirect effect of BMI on PCa risk (OR = 0.96, 95% CI: 0.94-0.98). CONCLUSION: Our study provided genetic evidence that serum BT can mediate the effect of BMI on the risk of PCa, indicating the possible mechanism by which obesity reduces PCa risk.

Vitamin E and Multiple Health Outcomes: An Umbrella Review of Meta-Analyses.

The relationship between vitamin E intake or circulating α-tocopherol and various health outcomes is still debatable and uncertain. We conducted an umbrella review to identify the relationships between vitamin E intake or circulating tocopherol and health outcomes by merging and recalculating earlier meta-analyses. The connections that were found to be statistically significant were then classified into different evidence levels based on p values, between-study heterogeneity, prediction intervals, and small study effects. We finally included 32 eligible meta-analyses with four vitamin E sources and 64 unique health outcomes. Only the association between circulating α-tocopherol and wheeze or asthma in children was substantiated by consistent evidence. Suggestive evidence was suggested for seven results on endothelial function (supplemental vitamin E): serum C-reactive protein (CRP) concentrations (supplemental vitamin E), cervical cancer (dietary vitamin E), esophageal cancer (dietary vitamin E), cervical intraepithelial neoplasia (CIN, dietary vitamin E), pancreatic cancer (total vitamin E intake), and colorectal cancer (circulating α-tocopherol levels); all of these showed a protective effect consistent with the vitamin E source. In conclusion, our work has indicated that vitamin E is protective for several particular health outcomes. Further prospective studies are required when other factors that may contribute to bias are considered.

The relationship between blood lipid and risk of psoriasis: univariable and multivariable Mendelian randomization analysis.

Background: Psoriasis is a chronic inflammatory skin disease. Dyslipidemia may be a risk factor of psoriasis. But the causal relationship between psoriasis and blood lipid still remains uncertain. Methods: The two data of blood lipid were obtained from UK Biobank (UKBB) and Global Lipid Genetics Consortium Results (GLGC). The primary and secondary database were from large publicly available genome-wide association study (GWAS) with more than 400,000 and 170,000 subjects of European ancestry, respectively. The psoriasis from Finnish biobanks of FinnGen research project for psoriasis, consisting of 6,995 cases and 299,128 controls. The single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) were used to assess the total and direct effects of blood lipid on psoriasis risk. Results: SVMR estimates in primary data of blood lipid showed low-density lipoprotein cholesterol (LDL-C) (odds ratio (OR): 1.11, 95%, confidence interval (CI): 0.99-1.25, p = 0.082 in stage 1; OR: 1.15, 95% CI: 1.05-1.26, p = 0.002 in stage 2; OR: 1.15, 95% CI: 1.04-1.26, p = 0.006 in stage 3) and triglycerides (TG) (OR: 1.22, 95% CI: 1.10-1.35, p = 1.17E-04 in stage 1; OR: 1.15, 95% CI: 1.06-1.24, p = 0.001 in stage 2; OR: 1.14, 95% CI: 1.05-1.24, p = 0.002 in stage 3) had a highly robust causal relationship on the risk of psoriasis. However, there were no robust causal associations between HDL-C and psoriasis. The SVMR results in secondary data of blood lipid were consistent with the primary data. Reverse MR analysis showed a causal association between psoriasis and LDL-C (beta: -0.009, 95% CI: -0.016- -0.002, p = 0.009) and HDL-C (beta: -0.011, 95% CI: -0.021- -0.002, p = 0.016). The reverse causation analyses results between psoriasis and TG did not reach significance. In MVMR of primary data of blood lipid, the LDL-C (OR: 1.05, 95% CI: 0.99-1.25, p = 0.396 in stage 1; OR: 1.07, 95% CI: 1.01-1.14, p = 0.017 in stage 2; OR: 1.08, 95% CI: 1.02-1.15, p = 0.012 in stage 3) and TG (OR: 1.11, 95% CI: 1.01-1.22, p = 0.036 in stage 1; OR: 1.09, 95% CI: 1.03-1.15, p = 0.002 in stage 2; OR: 1.07, 95% CI: 1.01-1.13 p = 0.015 in stage 3) positively correlated with psoriasis, and there had no correlation between HDL-C and psoriasis. The results of the secondary analysis were consistent with the results of primary analysis. Conclusions: Mendelian randomization (MR) findings provide genetic evidence for causal link between psoriasis and blood lipid. It may be meaningful to monitor and control blood lipid level for a management of psoriasis patients in clinic.

Association between urinary phthalate metabolites and nephrolithiasis in adults: A cross-sectional analysis with NHANES 2007-2018.

Nephrolithiasis is highly prevalent and brings health and economic burdens to patients. The augmentation of nephrolithiasis may be associated with exposure to phthalate metabolites. However, few studies investigated the effect of various phthalates exposure on nephrolithiasis. We analyzed data from 7139 participants aged 20 years or above from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. Serum calcium level-stratified univariate and multivariate linear regression analyses were performed to explore the relationship between urinary phthalate metabolites and nephrolithiasis. As a result, the prevalence of nephrolithiasis was approximately 9.96%. After adjusting for confounding factors, associations were found between serum calcium concentration with monoethyl phthalate (P = 0.012) and mono-isobutyl phthalate (P = 0.003) compared with tertile 1 (T1). In adjusted analysis, nephrolithiasis was positively associated with middle and high tertiles of mono benzyl phthalate (P < 0.05) compare with low tertile group. Furthermore, high-level exposure to mono-isobutyl phthalate had a similar positive association with nephrolithiasis (P = 0.028). Our findings provide evidence that exposure to certain phthalate metabolites (i.e. MiBP and MBzP) may be associated with a high risk of nephrolithiasis depending on serum calcium level.

Comparison of the efficacy and safety of holmium laser with the Moses technology and regular mode for stone treatment: a systematic review and meta-analysis.

BACKGROUND: As a new pulse modality of holmium laser in retrograde intrarenal stone surgery, the MOSES technique can reduce the possibility of stone drifting and help to powder kidney stones in vitro and in animal experiments. However, there remains controversy about whether the MOSES mode needs to be used instead of the regular mode in clinical practice. This meta-review was conducted to evaluate the clinical efficacy and safety of MOSES technology for stone disease. METHODS: PubMed, Embase, Web of Science, Cochrane Library, and CNKI were searched for relevant studies until September 2022, with 1 RCT and 6 nonrandomized studies included. We pulled data on adverse events, success rates and operative time to analyze based on the random effect model. RESULTS: We found that using MOSES mode could shorten the operative time (standard mean difference [SMD] - 0.43; 95% confidence interval [CI] - 0.79 to - 0.08; P = 0.016) than regular mode especially in a small sample study or in the Asian area. When the number of women is smaller than the number of men, the reduction of the duration was also significant. Stone-free rates of the two modes had no difference (relative risk [RR] 1.06; 95% CI 0.99-1.12; P = 0.30), and there was no publication bias. In terms of safety, no significant difference in complications was detected between the two approaches (RR 0.85; 95% CI 0.48-1.53; P = 0.81) without significant heterogeneity. CONCLUSION: MOSES mode holmium laser was superior to the regular mode laser in terms of procedure time. There was no large disparity in stone-free rates or complications between the two modes. However, our conclusions should be confirmed in prospective studies with high evidence.

Kidney function may partially mediated the protective effect of urinary uromodulin on kidney stone.

The causal links between urinary uromodulin (uUMOD) and kidney stone disease (KSD) are still not clarified in general population. We assessed their relationships combining 2-sample Mendelian randomization (MR) and multivariable (MVMR) designs among general population of European ancestry. The summary information for uUMOD indexed to creatinine levels (29,315 individuals) and KSD (395,044 individuals) were from 2 independent genome-wide association studies (GWAS). The primary causal effects of exposures on outcomes were evaluated using inverse variance-weighted (IVW) regression model. Multiple sensitivity analyses were also performed. In 2-sample MR, we found that 1-unit higher genetically predicted uUMOD levels were associated with a lower risk of KSD (OR = 0.62; 95% CI 0.55-0.71; P = 2.83E-13). In reverse, we did not find the effect of KSD on uUOMD using IVW (beta = 0.00; 95% CI - 0.06-0.05; P = 0.872) and other sensitivity analyses. In MVMR, uUMOD indexed to creatinine levels were directly associated with the risk of KSD after introducing eGFR, SBP, urinary sodium or all three factors (OR = 0.71; 95% CI 0.64-0.79; P = 1.57E-09). Furthermore, our study supported that the protective effect of uUMOD on KSD may be partially mediated by eGFR (beta = - 0.09; 95% CI - 0.13 to - 0.06; mediation proportion = 20%). Our study supported that the protective effect of genetically predicted higher uUMOD levels on KSD may be partially mediated by eGFR decline, but not via SBP or urinary sodium. uUMOD might be a treatment target in preventing KSD in general population.

Association between antibiotic exposure and adverse outcomes of children and pregnant women: evidence from an umbrella review.

BACKGROUND: Antibiotics are widely prescribed among children and pregnant women, but their safety profile is controversial. This study aimed to summarize and appraise current evidence for the potential impact of antibiotic exposure on pregnancy outcomes and children's health. METHODS: PubMed, Embase, Web of Science and the Cochrane Database of Systematic Reviews were searched from inception to June 2022. Meta-analyses of any study design comparing the impact of antibiotic exposure with nonexposure among children, pregnant women and prepregnant women on adverse health outcomes of children and pregnancy were retrieved. The quality of evidence was assessed by a Measurement Tool to Assess Systematic Reviews 2 (AMSTAR2) and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE). Data were reanalyzed, and the credibility of the evidence was determined. RESULTS: Out of 2956 studies identified, 19 articles with 39 associations were included. Totally 19 of the associations (48.72%) were statistically significant with a P value ≤ 0.05, while only six were supported by highly suggestive evidence. Children with postnatal antibiotic exposure had a higher risk of developing asthma odds ratio (OR): 1.95, 95% confidence interval (CI): 1.76-2.17, wheezing (OR: 1.81, 95% CI 1.65-1.97) and allergic rhinoconjunctivitis (OR: 1.66, 95% CI 1.51-1.83), with prediction intervals excluding the nulls. Quality assessed by both AMSTAR2 and GRADE of included meta-analyses were very low in general. CONCLUSIONS: Antibiotic exposure in early life was associated with children's long-term health, especially in cases of allergic diseases. Prenatal exposure might also influence children's health in some aspects but requires more high-quality evidence. Potential adverse effects of antibiotics on pregnancy outcomes were not observed in our study. Studies with higher quality and better quantification of antibiotic exposure are needed in the future.

YAP-mediated mechanotransduction in urinary bladder remodeling: Based on RNA-seq and CUT&Tag.

Yes-associated protein (YAP) is an important transcriptional coactivator binding to transcriptional factors that engage in many downstream gene transcription. Partial bladder outlet obstruction (pBOO) causes a massive burden to patients and finally leads to bladder fibrosis. Several cell types engage in the pBOO pathological process, including urothelial cells, smooth muscle cells, and fibroblasts. To clarify the function of YAP in bladder fibrosis, we performed the RNA-seq and CUT&Tag of the bladder smooth muscle cell to analyze the YAP ablation of human bladder smooth muscle cells (hBdSMCs) and immunoprecipitation of YAP. 141 differentially expressed genes (DEGs) were identified through RNA-seq between YAP-knockdown and nature control. After matching with the results of CUT&Tag, 36 genes were regulated directly by YAP. Then we identified the hub genes in the DEGs, including CDCA5, CENPA, DTL, NCAPH, and NEIL3, that contribute to cell proliferation. Thus, our study provides a regulatory network of YAP in smooth muscle proliferation. The possible effects of YAP on hBdSMC might be a vital target for pBOO-associated bladder fibrosis.

Vitamin D Levels and Risk of Male Factor Infertility: A Mendelian Randomization Study.

PURPOSE: No consensus exists about the causal relationship between vitamin D (VD) and male factor infertility due to heterogeneity and confounding factors even in randomized controlled trials (RCTs). This study aimed to investigate the causal association between 25 hydroxyvitamin D (25OHD) levels and male factor infertility through Mendelian randomization (MR) and provide complementary information for optimization of future RCTs. MATERIALS AND METHODS: Two-sample MR analyses with four steps were performed. Single-nucleotide polymorphisms (SNPs) for VD were extracted from 417,580 Europeans in the UK Biobank, and the summary-level data of male factor infertility (825 cases and 85,722 controls) were extracted from the FinnGen. RESULTS: Totally 99 SNPs robustly associated with the 25OHD were included, and a 1-unit increase in genetically predicted natural-log transformed 25OHD levels was associated with decreased risk of male factor infertility (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.44-0.89; p=0.010), which was consistent in all three sensitivity analyses (MR-Egger, weighted median, and weighted mode methods). The conclusion still stands after removing SNPs which explained more variation in the male factor infertility than the 25OHD (OR, 0.61; 95% CI, 0.42-0.88; p=0.009; n=62), and which were associated with confounders (body mass index, type 2 diabetes, smoking, and coronary artery diseases) of male factor infertility (OR, 0.58; 95% CI, 0.39-0.85; p=0.005; n=55). CONCLUSIONS: VD supplement to increase serum 25OHD levels may be clinically beneficial for male factor infertility in the general population. The well-designed RCTs should be performed in priority to address this question.

Blood Pressure Mediated the Effects of Urinary Uromodulin Levels on Myocardial Infarction: a Mendelian Randomization Study.

BACKGROUND: The causal links between urinary uromodulin (uUMOD) and cardiovascular disease (CVD) are still not clarified. METHODS: We first assessed the relationship between uUMOD and CVD using bidirectional 2-sample Mendelian randomization. Then, multivariable Mendelian randomization and product of the coefficients methods were used to investigate the role of blood pressure in mediating the effect of uUMOD on CVD. RESULTS: 1-unit higher uUMOD level was associated with a higher risk of myocardial infarction (MI), with an odds ratio of 1.08 ([95% CI, 1.02-1.14]; P=0.009), while MI was not associated with uUMOD levels in reverse. Our study did not support the causal effects of uUMOD on other CVD outcomes, including coronary artery disease, atrial fibrillation, heart failure, and ischemic stroke. In multivariable Mendelian Randomization, the direct effects of uUMOD on MI were attenuated to null after introducing systolic blood pressure or diastolic blood pressure. Mediation analysis showed that the indirect effect of uUMOD on MI mediated by systolic blood pressure or diastolic blood pressure was 1.05 ([95% CI, 1.04-1.06]; mediation proportion=69%) and 1.07 ([95% CI, 1.05-1.08]; mediation proportion=87%), respectively. Similar results were found in sensitivity analysis based on different sets of genetic instruments. CONCLUSIONS: Our findings provide evidence for the effect of higher uUMOD on increasing blood pressure, which mediates a consequent effect on MI risk in the general population. Further studies are necessary to verify the associations between uUMOD and other CVD outcomes.

Development of a novel predictive model for a successful stone removal after flexible ureteroscopic lithotripsy based on ipsilateral renal function: a single-centre, retrospective cohort study in China.

OBJECTIVES: The aims of this study were to investigate the effect of preoperative ipsilateral renal function on the success of kidney stone removal with flexible ureteroscopic lithotripsy and to develop a predictive model based on the results. DESIGN: Retrospective cohort study. SETTING: Data from the 2001-2012 period were collected from the electronic records of West China Hospital, Sichuan University. PARTICIPANTS: 576 patients who underwent flexible ureteroscopic lithotripsy were included in the study. PRIMARY OUTCOME: Stone-free rate (SFR) after the procedures. RESULTS: In patients with suspected impaired kidney function, the overall SFR was 70.1%. Stone volume (OR 1.46; 95% CI 1.18 to 1.80), lower calyx stones (OR 1.80; 95% CI 1.22 to 2.65), age (OR 1.02; 95% CI 1.00 to 1.04), body mass index (OR 1.10; 95% CI 1.04 to 1.17) and estimated glomerular filtration rate of the affected kidney (OR 0.95; 95% CI 0.94 to 0.97) were identified as independent predictors of SFR. Lasso regression selected the same five predictors as those identified by univariate and multivariate logistic regression analyses, thus verifying our model. The mean area under the curve, based on 1000 iterations and 10-fold validation, was 0.715 (95% CI 0.714 to 0.716). The Hodges-Lehmann test and calibration curve analysis revealed no significant mismatch between the prediction model and the retrospective cohort. CONCLUSION: Ipsilateral renal function may be a novel independent risk factor for kidney stone removal with flexible ureteroscopic lithotripsy. A novel nomogram for predicting SFR that uses stone volume, lower calyx stones, age, body mass index and estimated glomerular filtration rate was developed, but remains to be externally validated.

Depression increases the risk of kidney stone: Results from the National Health and Nutrition Examination Survey 2007-2018 and Mendelian randomization analysis.

BACKGROUND: To investigate whether depression increases the kidney stone risk. METHODS: First, we performed an observational study in the National Health and Nutrition Examination Survey (NHANES) 2007-2018. Depression severity was evaluated using the Patient Health Questionnaire-9 (PHQ-9) and classified into no, mild, moderate, and severe depression groups. Multivariable-adjusted logistic regression was used to assess the correlation between depression severity and kidney stone risk. Second, Mendelian randomization (MR) was applied to decrease the bias and avoid the reverse causality in the observational study. Genetic instruments were obtained from a large genome-wide association study (GWAS) meta-analysis of depression involved 246,363 cases and 561,190 controls. We obtained summary data for kidney stone from another large GWAS, which integrates data from 6536 stone formers and 388,508 controls. Inverse variance weighted (IVW) was the primary analytical method. RESULTS: In the observational study, a total of 24,892 individuals were enrolled. Individuals with moderate (OR 1.38, 95 % CI 1.05-1.83, P = 0.022) and severe (OR 1.56, 95 % CI 1.02-2.40, P = 0.040) depression had a higher risk of kidney stone (P for trend = 0.006) compared with the control. For the MR, results also showed that genetically predicted depression was causally associated with a higher risk of kidney stone disease (OR 1.26, 95 % CI 1.04-1.53, P = 0.017) in IVW. CONCLUSIONS: Depression might be associated with kidney stone risk. This finding is needed to be verified in further prospective cohort studies with a large sample size and enough follow-up time.

Genetic Associations of Birthweight, Childhood, and Adult BMI on Testosterone Levels: A Mendelian Randomization.

CONTEXT: Birthweight, childhood, and adult BMI have been indicated associated with the testosterone levels, but the current studies are plagued by significant heterogeneity, and a consensus about the role of these weight traits in testosterone levels is still debated. OBJECTIVE: This work aims to evaluate the genetic associations of birthweight and childhood and adult body mass index (BMI) on the adult testosterone levels (bioavailable testosterone [BT], sex hormone-binding globulin [SHBG], and total testosterone [TT]) in women and men. METHODS: Random-effect inverse-variance weighted (IVW) and 7 sensitivity analyses were performed. Data for weight traits were collected from large-scale genome-wide association studies (GWAS) ranging from 39 620 to 434 794 individuals. Summarized data for testosterone levels were obtained from a GWAS up to 230 454 individuals. RESULTS: Higher adult BMI are significantly associated with lower BT (ß = -0.13; 95% CI, -0.16 to -0.09) and TT in men (ß = -0.25; 95% CI, -0.30 to -0.20). On the contrary, higher adult BMI increased the levels of BT (ß = 0.23; 95% CI, 0.23 to 0.20) and TT (ß = 0.04; 95% CI, 0.01 to 0.07) in women. Similar genetic associations on testosterone levels with sexual differences were observed for childhood BMI. However, higher birthweight led to lower BT levels in adult men (ß = -0.08; 95% CI, -0.12 to -0.03) and women (ß = -0.07; 95% CI, -0.13 to -0.02). CONCLUSION: Our study supports that birthweight, childhood BMI, and adult BMI affect testosterone levels in men and women in adult life. The genetic associations of childhood BMI on testosterone levels are consistent with adult BMI, but not with birthweight.

Higher genetically predicted low-density lipoprotein levels increase the renal cancer risk independent of triglycerides and high-density lipoprotein levels: A Mendelian randomization study.

The causation between lipids and renal cancer remains inconclusive. Our purpose is to explore the causal relationships between the three primary lipid metabolism-related substances, namely triglycerides (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) with the risk of renal cancer using Mendelian randomization (MR) methods. Genetic instruments for lipids were acquired from the UK Biobank. Outcome data were from the FinnGen study (1397 renal cancer cases and 204 070). Single-variable MR (SVMR) and multi-variable MR (MVMR) analyses were conducted with TwoSampleMR package based on R 4.0.3. The random-effect inverse-variance weighted (IVW), MR-Egger, weighted-median method, and weighted mode were the four main computing methods. We found that per 1 SD elevated LDL level was causally associated with renal cancer occurrence based on SVMR (OR, 1.31, 95% CI: 1.05-1.64, P = .016). Similar significant associations were found in other methods. However, the results of SVMR did not support significant associations between TG, and HDL with renal cancer risk in all methods. The association between LDL and renal cancer was still significant in MVMR analysis (OR for IVW method: 1.22 per 1 SD higher trait (SD, 95% CI: 1.11-1.34, P < .001; OR for MR-Egger: 1.22 per 1 SD higher trait, 95% CI: 1.01-1.47, P = .042) when taking TG and HDL into consideration. Our study supported that elevated serum LDL levels is causally associated with an increased risk of renal cancer independent of TG and HDL.