Association of Metformin Use With Risk of Venous Thromboembolism in Adults With Type 2 Diabetes: A General-Population-Based Cohort Study.

Metformin is hypothesized to protect against the risk of venous thromboembolism (VTE); however, there is a paucity of data supporting this hypothesis. Among individuals aged 40-90 years with a diagnosis of type 2 diabetes in the Health Improvement Network database (2000-2019), we compared the risks of incident VTE, pulmonary embolism, and deep vein thrombosis among metformin initiators with those among sulfonylurea initiators. Individuals were followed from their first prescription refill to an incident VTE, drug discontinuation, switching or augmenting, plan disenrollment, or the end of the study, whichever occurred first. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox model, adjusting for confounders using inverse probability of treatment weighting. Among 117,472 initiators of metformin and 13,835 initiators of sulfonylureas, 555 (1.3/1,000 person-years) and 75 (2.1/1,000 person-years) VTE cases occurred in each group, respectively. The multivariable-adjusted HR was 0.65 (95% CI: 0.51, 0.84). The corresponding risks for pulmonary embolism (adjusted HR = 0.71, 95% CI: 0.50, 1.01) and deep vein thrombosis (adjusted HR = 0.64, 95% CI: 0.48, 0.87) were also lower in metformin initiators than in sulfonylurea initiators. Our study provided empirical evidence to support a lower risk of VTE after initiation of metformin as compared with sulfonylureas among patients with type 2 diabetes.

Liver Fibrosis Assessment by Viewing Sinusoidal Capillarization: US Molecular Imaging versus Two-dimensional Shear-Wave Elastography in Rats.

Background US elastography is a first-line assessment of liver fibrosis severity; however, its application is limited by its insufficient sensitivity in early-stage fibrosis detection and its measurements are affected by inflammation. Purpose To assess the sensitivity of US molecular imaging (USMI) in early-stage liver fibrosis detection and to determine whether USMI can specifically distinguish fibrosis regardless of inflammation when compared with two-dimensional (2D) shear-wave elastography (SWE). Materials and methods USMI and 2D SWE were performed prospectively (January to June 2021) in 120 male Sprague-Dawley rats with varying degrees of liver fibrosis and acute hepatitis and control rats. Liver sinusoidal capillarization was viewed at CD34-targeted USMI and quantitatively analyzed by the normalized intensity difference (NID). Data were compared by using a two-sided Student t test or one-way analysis of variance. Linear correlation analyses were used to evaluate the relationships between collagen proportionate area values and NID and liver stiffness measurement (LSM) values. Receiver operating characteristic curves were used to assess the diagnostic performance in detecting liver fibrosis. Results Both NID and LSM values showed good linear correlation with collagen proportionate area values (r = 0.91 and 0.87, respectively). No difference was observed between the areas under the receiver operating characteristic curve in detecting stage F0-F1 between USMI and 2D SWE (0.97 vs 0.91, respectively; P = .20). USMI depicted liver fibrosis at an early stage more accurately than 2D SWE (area under the curve, 0.97 vs 0.82, respectively; P = .01). Rats with hepatitis had higher liver stiffness values than control rats (9.83 kPa ± 0.79 vs 6.55 kPa ± 0.38, respectively; P < .001), with no difference in the NID values between control rats and rats with hepatitis (6.75% ± 1.43 vs 6.74% ± 0.86, respectively; P = .98). Conclusion Sinusoidal capillarization viewed at US molecular imaging helped to detect early-stage liver fibrosis more accurately than two-dimensional shear-wave elastography and helped assess fibrosis regardless of inflammation. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Barr in this issue.

Construction and validation of a revised satisfaction index model for the Chinese urban and rural resident-based basic medical insurance scheme.

BACKGROUND: Quality is the most important factor in satisfaction. However, the existing satisfaction index model of urban and rural resident-based basic medical insurance scheme (SIM_URRBMI) lacks the segmentation of perceived quality elements, it couldn't provide a reference for quality improvement and satisfaction promotion. This study aims to construct a revised SIM_URRBMI that can accurately and detailly measure perceived quality and provide feasible and scientific suggestions for improving the satisfaction of urban and rural residents' basic medical insurance scheme (URRBMI) in China. METHODS: Based on the theoretical framework of the American Customer Satisfaction Index, the elements of perceived quality were refined through literature review and expert consultation, and a pool of alternative measurement variables was formed. A three-stage randomized stratified cluster sampling was adopted. The main decision makers of URRBMI in the families of primary school students in 8 primary schools in Changsha were selected. Both the classic test theory and the item response theory were used for measurement variables selection. The reliability and validity of the model were tested by partial least squares (PLS)-related methods. RESULTS: A total of 1909 respondents who had URRBMI for their children were investigated. The SIM_URRBMI1.0 consists of 11 latent variables and 28 measurement variables with good reliability and validity. Among the three explanatory variables of public satisfaction, perceived quality had the largest total effect (path coefficient) (0.737). The variable with the greatest effect among the five first-order latent variables on perceived quality was the quality of the medical insurance policy (0.472). CONCLUSIONS: The SIM_URRBMI1.0 consists of 28 measurement variables and 11 latent variables. It is a reliable, valid, and standard satisfaction measurement tool for URRBMI with good prediction ability for public satisfaction. In addition, the model provides an accurate evaluation of the perceived quality, which will greatly help with performance improvement diagnosis. The most critical aspects of satisfaction improvement are optimizing the scope and proportion of reimbursement as well as setting appropriate level of deductible and capitation of URRBMI.

Changes in the Intestinal Microbiota in Patients with Stage 5 Chronic Kidney Disease on a Low-Protein Diet and the Effects of Human to Rat Fecal Microbiota Transplantation.

BACKGROUND Dietary protein restriction is recommended for patients with stage 5 chronic kidney disease (CKD), or end-stage renal disease (ESRD). This study aimed to investigate the changes in the intestinal microbiota due to different dietary regimens in patients with stage 5 CKD and the effects of human to rat fecal microbiota transplantation. MATERIAL AND METHODS Second-generation high-throughput sequencing was used to analyze the amplifiers in the 16S rRNA V4 region in the intestinal microbiota of patients with stage 5 CKD and healthy individuals. The intestinal microbiota of patients with stage 5 CKD in the low-protein group and the healthy individual group was transferred by human to rat fecal microbiota transplantation using Sprague-Dawley rats. Data underwent meta-analysis using Meta-Stat. RESULTS Patients with CKD on a very low-protein diet showed an increase in intestinal Escherichia, Shigella, and Klebsiella, a decrease in Blautia, heat map analysis showed that Christensenellaceae R-7 group rs1 were significantly increased, and MetaStat analysis showed that Bacteroides, Prevotella, and Mitsuokella were significantly increased. Following human to rat fecal microbiota transplantation from patients with stage 5 CKD, the profile of the rat intestinal microbiota became similar to the human donors. The weight of the rats fed a very low-protein diet after fecal microbiota transplantation significantly decreased after six weeks compared with normal rats and rats that received normal fecal microbiota transplantation. CONCLUSIONS Patients with stage 5 CKD on a very low-protein diet showed changes in the intestinal microbiota that could be transferred from humans to rats by fecal microbiota transplantation.

A meta-analysis of pregnancy-related outcomes and complications in women with polycystic ovary syndrome undergoing IVF.

This meta-analysis aimed to study whether pregnancy-related outcomes and complications differed between patients with polycystic ovary syndrome (PCOS) and those with other causes of infertility who had undergone IVF. A systematic search of PubMed, Embase, the Cochrane Library and Chinese databases was carried out to identify relevant studies published before July 2018. Outcomes were expressed as odds ratios (OR) and 95% confidence intervals (CI). Subgroup analyses and sensitivity analyses were also conducted. Twenty-nine studies were identified for inclusion. Women with PCOS had higher risks of miscarriage (OR 1.41, 95% CI 1.04-1.91), ovarian hyperstimulation syndrome (OR 4.96, 95% CI 3.73-6.60), gestational diabetes mellitus (OR 2.67, 95% CI 1.43-4.98), pregnancy-induced hypertension (OR 2.06, 95% CI 1.45-2.91), preterm birth (OR 1.60, 95% CI 1.25-2.04) and large-for-gestational-age babies (OR 2.10, 95% CI 1.01-4.37). Women with PCOS showed similar rates of clinical pregnancy, multiple pregnancy, ectopic pregnancy, small for gestational age and congenital malformations, and a higher live birth rate, compared with women without PCOS. This study provides an update on and comprehensive evidence to support the observation that despite the fact that PCOS patients achieve a better live birth rate, physicians should continue to consider them to be at high risk of adverse pregnancy-related outcomes.

A prospective study of maternal postnatal depressive symptoms with infant-feeding practices in a Chinese birth cohort.

BACKGROUND: The first few weeks after childbirth are critical, as women may encounter lactation problems and postpartum depression during this period. However, it is still unclear whether early breastfeeding behaviours are related to the symptoms of postnatal depression (PND) in Chinese populations. Therefore, the current study aimed to investigate the association between symptoms of PND and infant feeding practices based on a large-scale Chinese cohort. METHODS: A prospective study of the community-based cohort was conducted from January 2015 to December 2016. Infant feeding outcomes, including exclusive/partial breastfeeding and formula feeding, were assessed according to the WHO guidelines. Symptoms of PND were assessed by the Edinburgh Postnatal Depression Scale at 4 weeks postpartum. Multivariate generalized estimating equation models were applied to investigate the associations between depressive symptoms and infant feeding behaviours. RESULTS: A total of 956 mother-infant pairs were included. Fifty-six mothers presented screen-positive symptoms of PND with a cut-off ≥10. The percentage of early breastfeeding initiation was 75.8%, while the average duration of exclusive breastfeeding was 3.90 ± 2.33 months. Postnatal depressive symptoms were associated with a shorter breastfeeding duration (8.02 vs. 6.32 months, P < 0.05) and earlier formula introduction (4.98 vs. 3.60 months, P < 0.05). After adjustments were made for covariates, postnatal depressive symptoms were associated with an increased risk of the discontinuation of exclusive and partial breastfeeding (ß = - 0.049, P = 0.047 and ß = - 0.082, P = 0.006, respectively). Compared to mothers without symptoms of PND, mothers with depressive symptoms were more likely to supplement formula for their infants in the first year of life (ß =0.074, P = 0.016). These associations were still significant in the sensitivity analyses, using an EPDS cut-off of ≥13. CONCLUSIONS: Our findings indicate that depressive symptoms at 4 weeks postpartum are associated with the cessation of exclusive and partial breastfeeding duration and the introduction of formula in the 12 months of delivery. Early psychosocial assessment and social support should be offered to mothers in the early postpartum period to indirectly prevent adverse breastfeeding outcomes.

Influence of prenatal and early-life exposures on food allergy and eczema in infancy: a birth cohort study.

BACKGROUND: Few prospective birth cohort studies are available on the effects of prenatal and early-life exposures on food allergy and eczema among Chinese children. The aim of this study was to evaluate the influence of prenatal and early-life exposures on food allergy and eczema during the first year of life in a prospective birth cohort study. METHODS: This study was based on a prospective, observational birth cohort of 976 mother-child pairs in three Streets in Changsha, China from January to December 2015. Data on prenatal, early-life exposures and allergic outcomes were obtained from questionnaires collected at birth, and 1, 3, 6, 8, and 12 months of age. Multivariate logistic regression models were performed to estimate the effects of prenatal and early-life exposures on food allergy and eczema. RESULTS: Common risk factors for food allergy and eczema in infancy were parental history of allergy, while moderate eggs consumption (3-4 times/week) during pregnancy was protective for both of them compared with low consumption (≤ 2 times/week). Factors only associated with food allergy were maternal aquatic products consumption during pregnancy, number of older siblings and age of solid food introduction, whereas factors only associated with eczema were maternal milk or milk products consumption during pregnancy, maternal antibiotic exposure during pregnancy, season of birth and antibiotic exposure through medication during the first year of life. CONCLUSION: Our study suggests that factors associated with food allergy and eczema are multifaceted, which involving hereditary, environmental and nutritional exposures. Furthermore, differential factors influence the development of food allergy and eczema in infants.

[Factors associated with postpartum weight retention based on the generalized estimation equation in Kaifu Districtin Changsha].

OBJECTIVE: To investigate the current status of the postpartum weight retention (PPWR) in Kaifu District of Changsha, and explore the influential factors with PPWR based on the generalized estimating equation model.
 Methods: A cluster sampling method was applied to select women who gave birth at the health service centers of 3 street communities in Kaifu District of Changsha during 2015. According to the inclusion and exclusion criteria, 783 cases were finally included in the study. Data on PPWR were collected prospectively by using the self-made questionnaire at 1, 3, 6 and 8 months after childbirth. Analysis were performed to investigate the associations between PPWR and its potential factors with generalized estimation equation model.
 Results: The mean PPWR of women was gradually decreased with the increase of postpartum time, and 34.6% of them have returned to the pre-pregnancy weight in the 8 months postpartum. Our findings revealed that gestation weight gain (GWG), pre-pregnancy body mass index, feeding patterns, and delivery mode were significantly associated with maternal PPWR (P<0.05). In contrast, maternal age, educational level, per capita income of family, parity and postpartum depression were not contributed to PPWR (P>0.05).
 Conclusion: GWG is one of the most important predictors for PPWR. The key to reducing PPWR is to control GWG systematically. Early targeted interventions and health education should be taken to prevent women from excessive PPWR at the first-year postpartum, in particular to the women who underwent cesarean deliveries and breastfed their infants. It is conducive to reduce the risks of overweight or obesity caused by PPWR.

Associations of childhood socioeconomic status with mid-life and late-life cognition in Chinese middle-aged and older population based on a 5-year period cohort study.

OBJECTIVES: A prospective study was performed to examine the relationship of childhood socioeconomic status (SES) with cognition and the rate of change in a nationally representative sample of community-dwelling middle-aged and older Chinese population. METHODS: This study mainly focused on 3 composite measures of cognitive function, including Telephone Interview of Cognitive Status, word recall, and drawing a figure successfully. Childhood SES was evaluated by parental occupation and education, childhood residence, and self-evaluated financial status. We designed an analysis strategy adding predictors incrementally in different models to examine the changes of effects of childhood SES on cognition by latent growth curve models. RESULTS: Finally, a total of 10 533 respondents were prospectively studied, including 5980 respondents aged 45-59 and 4553 aged 60-90. Cognition in younger cohort showed a curvilinear change, while cognition in older cohort showed a linear decline. After controlling for covariates, middle-aged respondents with higher self-evaluated financial status (ß: -0.22, P < .001), better health status (ß: -0.13, P < .001), higher parental education (ß: 0.17 and 0.10, P < .001), who had lived in city/town before 16 years (ß: 0.69, P < .001), and whose fathers engaged in nonfarming work (ß: 0.43, P < .001) were associated with the better baseline cognition. Similar results were found in older cohort. Additionally, early-life SES was not associated with cognitive decline in both cohorts. CONCLUSIONS: This study indicates that childhood SES is associated with mid-life and late-life baseline cognition, but it is not contributed to cognition decline. Interventions in early-life focused on improving childhood SES might have positive impacts on baseline cognition in later-life.

[Risk factors for delayed breastfeeding initiation based on decision tree model and logistic regression model].

OBJECTIVE: To determine influential factors for delayed breastfeeding initiation.
 Methods: Using questionnaires to collect the data of 950 pregnant women and infants' feeding practices in Changsha, Hunan, logistic regression and decision tree model were used to determine influential factors for delayed breastfeeding initiation.
 Results: Mothers with timely breastfeeding initiation were 594 (62.5%), and those with delayed breastfeeding initiation accounted for 356 (37.5%). Mothers with timely breastfeeding initiation were more likely to use exclusive breastfeeding than those with delayed breastfeeding initiation (P<0.05). Four risk factors were found by logistic regression model and decision tree model, including cesarean delivery, using feeding-bottle before breastfeeding initiation, falling ill, and vomiting during pregnancy. Receiver operating characteristic curve showed no significant difference in the predictive effect of the 2 models (Z=0.142, P=0.889).
 Conclusion: Cesarean delivery, using feeding-bottle before initiation of breastfeeding, and poor physical condition during pregnancy exert negatively effects on breastfeeding initiation. Health workers should help mother to timely initiate breastfeeding and enhance their confidence in exclusive breastfeeding.

Risk factors for postpartum depression among Chinese women: path model analysis.

BACKGROUND: Postpartum depression causes harm to both mothers and infants. The purpose of this study was to find out several potential risk factors, and to identify the intrinsic interrelationships between factors and postpartum depression by constructing a path model. The results of this study may help to control the increasing incidence of maternal postpartum depression. METHODS: The study was based on a sample of mothers from a cross-sectional study which was set up at 4 weeks after a mother had childbirth and was conducted in three streets at Kaifu District of Changsha in Hunan province from January to December 2015. Questionnaires were distributed to subjects who responded to questions concerning factors related to pregnancy, delivery and infants within 4 weeks after childbirth. The Edinburgh Postnatal Depression Scale (EPDS) was used to measure postpartum depression. Chi-square test was used to detect significant differences between non-postpartum depression group and postpartum depression group. A path model was constructed to explore the interrelationships between variables, and to verify the relationships between variables and postpartum depression. RESULTS: The proportion of maternal postpartum depression was 6.7%. Univariate analysis showed that there were significant differences between non-postpartum depression group and postpartum depression group (all P-values <0.05) on the part of maternal age, parity, frequent exposure to mobile phone during pregnancy, gestational hypertensive disorders, fetus number, premature delivery, birth weight, initiation of breastfeeding, mode of feeding, infant illness within 4 weeks after delivery and infant weight at 4 weeks. Path analysis results showed that the final model could be fitted well with sample data (P = 0.687, CMIN/DF = 0.824, NFI = 0.992, RFI = 0.982, IFI = 1.002, TLI =1.004, CFI = 1.000 and RMSEA < 0.001). Frequent exposure to mobile phone during pregnancy, maternal age and gestational hypertensive disorders had both direct and indirect effects on postpartum depression. Mode of feeding and infant weight at 4 weeks, which was the most total effect on postpartum depression, had only a direct impact on postpartum depression. Fetus number, premature delivery, initiation of breastfeeding and birth weight had only an indirect influence on postpartum depression. CONCLUSION: The findings of this study suggest that constructing a path analysis model could identify potential factors and explore the potential interrelations between factors and postpartum depression. It is an effective way to prevent maternal postpartum depression by taking appropriate intervention measures and carrying out health education for pregnant women.

[Influential factors of iron deficient anemia among infants aged 8 months based on a case-control study].

OBJECTIVE: To study the status and influential factors of iron deficient anemia (IDA) among infants aged 8 months in Changsha City.
 Methods: A case-control study was performed in this research. The case group including 105 8-month-old infants definitely diagnosed as IDA based on standardized blood test. Four-times numbers of age- and genger-matched infants without IDA were selected as a control group. Chi-square test and conditional logistic regression was used to analyze the influential factors for IDA.
 Results: The incidence rate of IDA among infants aged 8 months in Changsha City was 14.7%. The risk factors were as follows: mother with anemia in late pregnancy (OR=3.540, 95% CI 1.898 to 6.601), mixed feeding within 6 months old (OR=1.682, 95% CI 1.099 to 2.574), artificial feeding within 6 months old (OR=4.162, 95% CI 1.343 to 12.896), complementary feeding before 6 months old (OR=1.423, 95% CI 1.022 to 1.982), complementary feeding at or after 7 months old (OR=4.415, 95% CI 2.150 to 9.064), recurrent respiratory tract infections within 8 months old (OR=2.878, 95% CI 1.224 to 6.764), and repeated diarrhea within 8 months old (OR=3.710, 95% CI 1.533 to 8.980).
 Conclusion: There is certain incidence rate of IDA among infants aged 8 months in Changsha City. To prevent the IDA among infants, we should treat mothers' anemia during pregnancy, advocate scientific feeding, encourage complete breastfeeding until 6 months old, add complementary food timely and reasonably, treat infants suffering from respiratory or digestive diseases actively.

[Risk factors for nausea and vomiting in pregnant women in Changsha].

OBJECTIVE: To explore the risk factors for nausea and vomiting in pregnant women.
 Methods: Using cluster random sampling method and following the exclusion and inclusion criteria, a total of 713 pregnant women from the health service center of 3 street communities in Changsha city district were enrolled. Statistical analysis was used to analyze the relevant influential factors for nausea and vomiting.
 Results: Vomiting incidence in pregnant women was 59.6%. The risk factors for nausea and vomiting were female fetus (OR=1.404, 95% CI 1.035 to 1.905), vaginal bleeding (OR=1.513, 95%CI 1.062 to 2.156) and life stress (OR=1.031, 95% CI 1.009 to 1.054), and the protective factor for nausea and vomiting was the age (OR=0.798, 95% CI 0.661 to 0.964).
 Conclusion: The pregnant vomiting is a result of a combination of multiple factors. Age, female fetus, vaginal bleeding, negative quality of life are the influential factors for vomiting during pregnancy. Prenatal health education should be strengthened for young pregnant women. Suitable maintenance for pregnant woman life should be performed to reduce the amount of negative stimulus.

[Influential factors for postpartum depression based on the structural equation model in Kaifu District in Changsha].

OBJECTIVE: To investigate the current status of the postpartum depression in Kaifu District in Changsha, and to explore the influential factors for postpartum depression.
 Methods: We selected the mothers, who had a delivery and met the inclusion criteria in Changsha during 2015, as the participants and established a prospective birth cohort study. The social demographic characteristics and health-related information for the mothers and their families were collected by using self-made questionnaire. The mothers' depression symptoms after one month postpartum were assessed by the Edinburgh Postnatal Depression Scale. We used the structural equation model to analyze the influential factors for postpartum depression.
 Results: A total of 961 cases were investigated. 82 of them whose scores of EPDS were≥9 points, and the incidence of PPD was 8.2%. The results of structural equation model revealed the influential factors and their correlations with postpartum depression. It has been shown that maternal age, maternal education level, per capita income of family, intention of pregnancy, pregnancy-related complications, mode of conception, mode of delivery, feeding patterns, birth weight, baby gender, and infant illness could exert effects on postpartum depression.
 Conclusion: The incidence of postpartum depression in Kaifu District is at a low level and the structural equation model can be applied to analyze the influential factors and their relations with postpartum depression.

The Diagnostic Accuracy and Cutoff Value of Phase Angle for Screening Sarcopenia: A Systematic Review and Meta-Analysis.

OBJECTIVES: Phase angle (PhA) declines with age and is a reliable marker for muscle function, making it a potential screening indicator for sarcopenia. However, studies examined the reliability and validity of PhA for detecting sarcopenia, yielding inconsistent results. This meta-analysis aimed to evaluate the accuracy and cutoff value of PhA for screening sarcopenia and examine the potential confounding factors. DESIGN: This is a meta-analysis. SETTING AND PARTICIPANTS: PubMed, Embase, and Cochrane Library were searched up to September 18, 2023. Eighteen studies (6184 participants) were included reporting the diagnostic accuracy of PhA for screening sarcopenia. METHODS: Pooled accuracy [ie, the computed area under the curve value (AUC)] and cutoff value interval for screening sarcopenia were estimated using a random-effects model. Meta-regression analyses were conducted to identify sources of heterogeneity. RESULTS: The AUC value was 0.81. Pooled sensitivity and specificity were 80% and 70%. The calculated 95% CI of the cutoff value of PhA for screening sarcopenia falls between 4.54° and 5.25°. The results of meta-regression analyses showed that ethnicity, body mass index (BMI), health status, and diagnostic criteria were the main factors affecting the diagnostic accuracy for screening sarcopenia (with all P values < 0.01). CONCLUSION AND IMPLICATIONS: PhA may serve as a robust screening tool for sarcopenia, and the recommended cutoff interval falls between 4.54° and 5.25°. Ethnicity, BMI, health status, and diagnostic criteria can affect PhA's efficacy in sarcopenia screening.

Efficacy and Safety of Tramadol for Knee or Hip Osteoarthritis: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To examine efficacy and safety of tramadol for knee or hip osteoarthritis (OA). METHODS: PubMed, Embase, Cochrane Library, and Web of Science were searched up to May 2020 for randomized controlled trials (RCTs) comparing any of the following interventions: tramadol 100 mg/day, 200 mg/day, and 300 mg/day, and placebo for knee or hip OA. Pain and function were measured at or near 12 weeks for efficacy. Gastrointestinal, cardiovascular, and central nervous system (CNS) adverse events (AEs), and withdrawals were measured for safety. Bayesian network meta-analysis was conducted. RESULTS: Six RCTs (3,611 participants) were included. Tramadol 100 mg/day (standardized mean difference [SMD] -0.16 [95% confidence interval (95% CI) -0.34, 0.00]), 200 mg/day (SMD -0.21 [95% CI -0.37, -0.06]), and 300 mg/day (SMD -0.30 [95% CI -0.48, -0.14]) were statistically more effective than placebo in pain relief, but only tramadol 300 mg/day was better than placebo in functional improvement (SMD -0.24 [95% CI -0.47, -0.03]). Tramadol 100 mg/day (relative risk [RR] 2.29 [95% credible interval (CrI) 1.22, 4.25]), 200 mg/day (RR 4.35 [95% CrI 2.31, 8.01]), and 300 mg/day (RR 6.02 [95% CrI 3.22, 11.1]) involved a higher risk of gastrointestinal AEs. Similarly, tramadol 100-300 mg/day showed a higher risk of CNS AEs and withdrawals. However, the risk of cardiovascular AEs remained unclear. CONCLUSION: Only tramadol 300 mg/day showed minimal improvement in pain and function but with increasing AEs compared with placebo. Tramadol may not be sufficiently recommended for knee or hip OA based on the presented evidence, especially in patients with the risk of gastrointestinal and CNS AEs.

Genetically Predicted Levels of Serum Metabolites and Risk of Sarcopenia: A Mendelian Randomization Study.

Metabolites' connection to sarcopenia through inflammation and mitochondrial dysfunction is presumed, but their impact remains unclear due to limitations in conventional observational studies caused by confounding bias and reverse causation. We conducted a Mendelian randomization (MR) analysis to elucidate the association of serum metabolites with sarcopenia and its related traits, i.e., appendicular lean mass and grip strength. Genetic instruments to proxy the serum metabolites were extracted from the most comprehensive genome-wide association study on the topic published so far. The corresponding summary statistics for the associations of genetic instruments with outcomes were calculated from the UK Biobank (n = 324,976 participants). The primary analyses were assessed by an inverse-variance weighted (IVW) method. The weighted median and MR-PRESSO methods were used as sensitive analyses. Fourteen genetically predicted serum metabolites were associated with the risk of sarcopenia (PIVW < 0.05). Two metabolites showed the overlapped association with sarcopenia and its related traits, which were isovalerylcarnitine (sarcopenia: odds ratio [OR] = 4.00, 95% confidence interval [CI] = 1.11~14.52, PIVW = 0.034; appendicular lean mass: ß = -0.45 kg, 95% CI = -0.81~-0.09, PIVW = 0.015; grip strength: ß = -1.51 kg, 95% CI = -2.31~-0.71, PIVW = 2.19 × 10-4) and docosapentaenoate (sarcopenia: OR = 0.16, 95% CI = 0.03~0.83, PIVW = 0.029; appendicular lean mass: ß = -0.45 kg, 95% CI = 0.08~0.81, PIVW = 0.016). Twenty-seven metabolites were suggestive associated with appendicular lean mass or grip strength. This MR study provided evidence for the potential effects of metabolites on sarcopenia.

Genetic Variants, Serum 25-Hydroxyvitamin D Levels, and Sarcopenia: A Mendelian Randomization Analysis.

Importance: Vitamin D deficiency is commonly associated with sarcopenia; however, the latest International Clinical Practice Guidelines for Sarcopenia do not recommend vitamin D supplementation for sarcopenia owing to a lack of an apparent therapeutic effect on the indices of sarcopenia among participants with replete vitamin D concentration (ie, 25-hydroxyvitamin D [25(OH)D] level >20 ng/mL) from randomized clinical trials. While there is consensus in all vitamin D guidelines that serum levels of 25(OH)D less than 10 ng/mL should be corrected, approximately 30% of the world population's 25(OH)D levels range from 10 to 20 ng/mL, and it remains unclear whether such suboptimal levels can maintain optimal health, including sarcopenia risk. Objective: To investigate the association of serum 25(OH)D level, especially suboptimal levels, with sarcopenia risk. Design, Setting, and Participants: This genome-wide genetic association study was performed from August 2022 to February 2023 among the 295 489 unrelated European participants from the UK Biobank (2006-2010). Nonlinear and standard mendelian randomization analyses were used to examine the association of serum 25(OH)D concentration with sarcopenia risk. Exposures: A weighted genetic risk score using 35 unrelated single-nucleotide variants from the UK Biobank and weights from the SUNLIGHT Consortium was selected as an instrumental variable for serum 25(OH)D concentration. Main Outcomes and Measures: The primary outcome was sarcopenia, and the secondary outcomes consisted of grip strength, appendicular lean mass index, and gait speed. Results: The final genetic analyses included 295 489 participants (mean [SD] age, 56.3 [8.1] years; 139 216 female [52.9%]). There was an L-shaped association between genetically predicted serum 25(OH)D concentration and sarcopenia risk. The risk of sarcopenia decreased rapidly as 25(OH)D concentration increased until 20 ng/mL and then leveled off. The odds ratio of sarcopenia for serum 25(OH)D level of 10 vs 20 ng/mL was 1.74 (95% CI, 1.17-2.59). Similar patterns were also observed when the association between serum 25(OH)D concentration and risks of each of the sarcopenia indices were evaluated. Conclusions and Relevance: In this mendelian randomization genetic association study of adults in the UK Biobank, the findings supported a nonlinear association between suboptimal 25(OH)D levels and sarcopenia risk. Randomized clinical trials among participants with suboptimal 25(OH)D levels are required to verify the potential causality.

Combining single-cell RNA sequencing and population-based studies reveals hand osteoarthritis-associated chondrocyte subpopulations and pathways.

Hand osteoarthritis is a common heterogeneous joint disorder with unclear molecular mechanisms and no disease-modifying drugs. In this study, we performed single-cell RNA sequencing analysis to compare the cellular composition and subpopulation-specific gene expression between cartilage with macroscopically confirmed osteoarthritis (n = 5) and cartilage without osteoarthritis (n = 5) from the interphalangeal joints of five donors. Of 105 142 cells, we identified 13 subpopulations, including a novel subpopulation with inflammation-modulating potential annotated as inflammatory chondrocytes. Fibrocartilage chondrocytes exhibited extensive alteration of gene expression patterns in osteoarthritic cartilage compared with nonosteoarthritic cartilage. Both inflammatory chondrocytes and fibrocartilage chondrocytes showed a trend toward increased numbers in osteoarthritic cartilage. In these two subpopulations from osteoarthritic cartilage, the ferroptosis pathway was enriched, and expression of iron overload-related genes, e.g., FTH1, was elevated. To verify these findings, we conducted a Mendelian randomization study using UK Biobank and a population-based cross-sectional study using data collected from Xiangya Osteoarthritis Study. Genetic predisposition toward higher expression of FTH1 mRNA significantly increased the risk of hand osteoarthritis (odds ratio = 1.07, 95% confidence interval: 1.02-1.11) among participants (n = 332 668) in UK Biobank. High levels of serum ferritin (encoded by FTH1), a biomarker of body iron overload, were significantly associated with a high prevalence of hand osteoarthritis among participants (n = 1 241) of Xiangya Osteoarthritis Study (P-for-trend = 0.037). In conclusion, our findings indicate that inflammatory and fibrocartilage chondrocytes are key subpopulations and that ferroptosis may be a key pathway in hand osteoarthritis, providing new insights into the pathophysiology and potential therapeutic targets of hand osteoarthritis.

Causal Relationship of Genetically Predicted Serum Micronutrients Levels With Sarcopenia: A Mendelian Randomization Study.

Objectives: Previous observational studies have suggested associations between concentrations of several circulating micronutrients and sarcopenia. However, the causality inferred from those studies was subjected to residual confounding and reverse causation. Therefore, we aimed to examine the causal effects of the levels of genetically predicted serum micronutrients on sarcopenia. Methods: Single nucleotide polymorphisms (SNPs) were chosen from large-scale genome-wide association studies of participants only with European descent and were used as genetic instruments for the levels of 10 serum micronutrients (calcium, magnesium, selenium, copper, iron, zinc, Vitamin A, Vitamin B12, Vitamin D, and Vitamin E). Sarcopenia was defined by referencing to the 2019 definition given by the European Working Group on Sarcopenia in Older People (EWGSOP). A two-sample Mendelian randomization (MR) analysis was carried out to examine the associations between the levels of genetically predicted serum micronutrients and the risk of sarcopenia. Then, sensitivity analyses (including weighted median, MR-Egger and leave-one-out sensitivity analyses) were performed to evaluate the robustness of study findings. The estimates were presented as odds ratio (OR) with their 95% confidence intervals (CIs) per one standard deviation (SD) increase in the exposures. Results: A total of 378,635 UK Biobank participants, including 572 participants who were identified with sarcopenia, were included in this study. The iron status was shown to have a clear effect on the risk of sarcopenia based on MR analyses. The per one SD increment in the genetically-determined serum iron level corresponded to a 53% increase in the risk of sarcopenia (OR = 1.53, 95% CI: 1.31-1.78, P = 0.001). The exclusion of SNPs of the circulating iron level (i.e., rs1799945 SNP, rs1800562 SNP or rs855791 SNP) did not attenuate the magnitude of the signal in MR analysis. There was little evidence supporting the associations between other remaining micronutrients and sarcopenia. Conclusions: An increased risk of sarcopenia was observed with a genetically higher concentration of iron, suggesting that iron may play a role in the occurrence or development of sarcopenia.