Intermittent fasting and health outcomes: an umbrella review of systematic reviews and meta-analyses of randomised controlled trials.

Background: Benefits of Intermittent fasting (IF) on health-related outcomes have been found in a range of randomised controlled trials (RCTs). Our umbrella review aimed to systematically analyze and synthesize the available causal evidence on IF and its impact on specific health-related outcomes while evaluating its evidence quality. Methods: We comprehensively searched the PubMed, Embase, Web of Science, and Cochrane databases (from inception up to 8 January 2024) to identify related systematic reviews and meta-analyses of RCTs investigating the association between IF and human health outcomes. We recalculated the effect sizes for each meta-analysis as mean difference (MD) or standardized mean difference (SMD) with corresponding 95% confidence intervals (CIs). Subgroup analyses were performed for populations based on three specific status: diabetes, overweight or obesity, and metabolic syndrome. The quality of systematic reviews was evaluated using A Measurement Tool to Assess Systematic Reviews (AMSTAR), and the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system. This study is registered with PROSPERO (CRD42023382004). Findings: A total of 351 associations from 23 meta-analyses with 34 health outcomes were included in the study. A wide range of outcomes were investigated, including anthropometric measures (n = 155), lipid profiles (n = 83), glycemic profiles (n = 57), circulatory system index (n = 41), appetite (n = 9), and others (n = 6). Twenty-one (91%) meta-analyses with 346 associations were rated as high confidence according to the AMSTAR criteria. The summary effects estimates were significant at p < 0.05 in 103 associations, of which 10 (10%) were supported by high certainty of evidence according to GRADE. Specifically, compared with non-intervention diet in adults with overweight or obesity, IF reduced waist circumference (WC) (MD = -1.02 cm; 95% CI: -1.99 to -0.06; p = 0.038), fat mass (MD = -0.72 kg; 95% CI: -1.32 to -0.12; p = 0.019), fasting insulin (SMD = -0.21; 95% CI: -0.40 to -0.02; p = 0.030), low-density lipoprotein cholesterol (LDL-C) (SMD = -0.20; 95% CI: -0.38 to -0.02; p = 0.027), total cholesterol (TC) (SMD = -0.29; 95% CI: -0.48 to -0.10; p = 0.003), and triacylglycerols (TG) (SMD = -0.23; 95% CI: -0.39 to -0.06; p = 0.007), but increased fat free mass (FFM) (MD = 0.98 kg; 95% CI: 0.18-1.78; p = 0.016). Of note, compared with the non-intervention diet, modified alternate-day fasting (MADF) reduced fat mass (MD = -0.70 kg; 95% CI: -1.38 to -0.02; p = 0.044). In people with overweight or obesity, and type 2 diabetes, IF increases high-density lipoprotein cholesterol (HDL-C) levels compared to continuous energy restriction (CER) (MD = 0.03 mmol/L; 95% CI: 0.01-0.05; p = 0.010). However, IF was less effective at reducing systolic blood pressure (SBP) than a CER diet in adults with overweight or obesity (SMD = 0.21; 95% CI: 0.05-0.36; p = 0.008). Interpretation: Our findings suggest that IF may have beneficial effects on a range of health outcomes for adults with overweight or obesity, compared to CER or non-intervention diet. Specifically, IF may decreased WC, fat mass, LDL-C, TG, TC, fasting insulin, and SBP, while increasing HDL-C and FFM. Notably, it is worth noting that the SBP lowering effect of IF appears to be weaker than that of CER. Funding: This work was supported by the National Key Research and Development Program of China (Q-JW), the Natural Science Foundation of China (Q-JW and T-TG), Outstanding Scientific Fund of Shengjing Hospital of China Medical University (Q-JW), and 345 Talent Project of Shengjing Hospital of China Medical University (T-TG).

Bioequivalence and Safety Assessment of 2 Formulations of Low-Dose Metformin Hydrochloride under Fasting Conditions in Healthy Chinese Participants: A Randomized Phase 1 Clinical Trial.

The incidence of type 2 diabetes is high, and the existing metformin hydrochloride (MH) tablets of 250 mg cannot meet the demands of the Chinese drug market. This study aimed to evaluate the bioequivalence and safety of generic formulations of MH tablets (test formulation [T], 250 mg/tablet) and innovative products (reference formulation [R], 250 mg/tablet) under fasting conditions. This was an open-label, single-dose, 2-period, 2-sequence crossover, single-center, randomized phase I clinical trial. T and R were considered bioequivalent if the adjusted geometric mean ratios (GMRs) and 90% confidence intervals of the area under the curve (AUC) and maximum concentration (Cmax ) were within the range of 0.8-1.25. Thirty-five participants completed the trial. The T/R adjusted GMRs (95.7% for Cmax , 98.7% for AUC0→t , 98.8% for AUC0→∞ ) were within the acceptable bioequivalence range of 80%-125%. No serious adverse events or suspected or unexpected serious adverse reactions occurred during this trial. The study findings confirmed that generic MH is a well-tolerated and bioequivalent alternative to innovative products under fasting conditions in healthy Chinese participants. (www.chinadrugtrials.org.cn; registration no. CTR20190356).

SH3RF2 contributes to cisplatin resistance in ovarian cancer cells by promoting RBPMS degradation.

Platinum-based chemotherapy remains one of the major choices for treatment of ovarian cancer (OC). However, primary or acquired drug resistance severely impairs their efficiency, thereby causing chemotherapy failure and poor prognosis. SH3 domain containing ring finger 2 (SH3RF2) has been linked to the development of cancer. Here we find higher levels of SH3RF2 in the tumor tissues from cisplatin-resistant OC patients when compared to those from cisplatin-sensitive patients. Similarly, cisplatin-resistant OC cells also express higher levels of SH3RF2 than normal OC cells. Through in vitro and in vivo loss-of-function experiments, SH3RF2 is identified as a driver of cisplatin resistance, as evidenced by increases in cisplatin-induced cell apoptosis and DNA damage and decreases in cell proliferation induced by SH3RF2 depletion. Mechanistically, SH3RF2 can directly bind to the RNA-binding protein mRNA processing factor (RBPMS). RBPMS has been reported as an inhibitor of cisplatin resistance in OC. As a E3 ligase, SH3RF2 promotes the K48-linked ubiquitination of RBPMS to increase its proteasomal degradation and activator protein 1 (AP-1) transactivation. Impairments in RBPMS function reverse the inhibitory effect of SH3RF2 depletion on cisplatin resistance. Collectively, the SH3RF2-RBPMS-AP-1 axis is an important regulator in cisplatin resistance and inhibition of SH3RF2 may be a potential target in preventing cisplatin resistance.

Development and Validation of a Prediction Model for Venous Thrombus Embolism (VTE) in Patients With Colorectal Cancer.

Cancer patients are at high risk of developing venous thromboembolism (VTE). The risk of VTE could be mitigated with the administration of prophylactic anticoagulants. Therefore, risk assessment models would be a useful tool in order to identify those patients who are at higher risk and will be benefited more by prophylactic anticoagulants. This study retrospectively examined 528 newly diagnosed colorectal cancer patients from January 2019 to January 2021. Specified logistic regression models were employed to screen the factors and establish prediction tools based on nomograms according to the final included variables. Discrimination, calibration, and clinical applicability were used to assess the performance of screening tools. In addition, internal verifications were conducted through 10-fold cross-verification, leave-one-out cross-validation, and Bootstrap verification. Four risk factors, closely related to the occurrence of VTE in colorectal cancer patients, were identified after univariate and multivariate logistic regression, including age, body mass index, activated partial thromboplastin time, and D-Dimer value. Besides, the risk assessment model named ABAD was built on the basis, displaying good discriminations and calibrations. The area under the curve was 0.705 (95% confidence interval [CI], 0.644 to 0.766). According to Hosmer-Lemeshow goodness-of-fit test, a good agreement between the predicted and observed VTE events in patients with newly-diagnosed gastrointestinal cancer was observed for χ2 = 6.864, P = .551. Internal validation was applied with a C-index of 0.669 in the 10-fold cross-verification, 0.658 in the leave-one-out cross verification and 0.684 in the bootstrap verification. We developed a prediction model called ABAD for newly diagnosed colorectal cancer patients, which can be used to predict the risk of VTE. After evaluation and internal verification, we believe that ABAD exhibited high predictive performance and availability and could be recommended.

Congenital thrombophilia in East-Asian venous thromboembolism population: a systematic review and meta-analysis.

Background: Various inherited traits contribute to the overall risk of venous thromboembolism (VTE). In addition, the epidemiology of thrombophilia in the East-Asian VTE population remains unclear; thus, we aimed to assess the proportion of hereditary thrombophilia via a meta-analysis. Methods: Publications from PubMed, EMBASE, web of science, and Cochrane before December 30, 2022, were searched. Studies from Japan, Korea, China, Hong Kong, Taiwan, Singapore, Thailand, Vietnam, Myanmar, and Cambodia were included. Congenital thrombophilia was described as diseases including protein C (PC) deficiency, protein S (PS) deficiency, antithrombin (AT) deficiency, factor (F)V Leiden (FVL), and prothrombin G20210A mutations. Studies were selected by 2 reviewers for methodological quality analysis. A random-effects model was used for the meta-analysis, assuming that estimated effects in the different studies are not identical. Results: Forty-four studies involving 6453 patients from 7 counties/regions were included in the meta-analysis. The prevalence of PC, PS, and AT deficiencies were 7.1%, 8.3%, and 3.8%, respectively. Among 2924 patients from 22 studies, 5 patients were carriers of FVL mutation. Among 2196 patients from 10 studies, 2 patients were carriers of prothrombin G20210A mutation in a Thailand study. Conclusion: The prevalence of PC, PS, and AT deficiencies was relatively high, while a much lower prevalence of FVL and prothrombin G20210A mutations were identified in East-Asian patients with VTE. Our data stress the relative higher prevalence of PC, PS, and AT deficiencies for thrombophilia in the East-Asian VTE population.

Effects of food on pharmacokinetics and safety of metformin hydrochloride tablets: A meta-analysis of pharmacokinetic, bioavailability, or bioequivalence studies.

Background: The effects of food on the pharmacokinetics and safety of metformin hydrochloride (MH) are unclear. Objective: To discover the effects of food on the pharmacokinetics and safety of MH, and its influence factors. Methods: English and Chinese databases, and grey (unpublished) literature were searched for eligible studies (registration No. CRD 42022321067 in PROSPERO network). The summary weighted mean difference for continuous variables, and the risk ratio for dichotomous variables was calculated for the main pharmacokinetic parameters. Heterogeneity among the included studies was analyzed using the I2 test. Subgroup analyses, meta-regression, sensitivity analysis, and publication bias test were conducted. Results: Fourteen clinical trials were included, comprising 408 participants. The pooled AUC0→t, AUC0→∞, and Cmax were decreased by about 30.21% (I2 = 16.7%, p = 0.276), 28.00% (I2 = 73.6%, p < 0.001), and 40.38% (I2 = 92.8%, p < 0.001). Tmax was delayed by about 29.42% (I2 = 45.1%, p = 0.034). Subgroup analysis and meta-regression analysis revealed dosage of MH and gender composition as two significant sources of heterogeneity in AUC0→∞ and Cmax. Sensitivity analysis indicated that most of results were stable. The Egger's regression test and the Begg test (p > 0.05) confirmed that there is no publication bias. Conclusions: Pharmacokinetics parameters of MH were affected by food. High-fat, high-calorie diet lowered the extent and rate of absorption while slowing the absorption of metformin. These findings suggest that it is necessary to increase the dosage of MH in order to maintain the same treatment effect when administration of MH after a high fat, high calorie diet.

Percutaneous transluminal pulmonary angioplasty for Takayasu arteritis-associated pulmonary hypertension: A single-arm meta-analysis.

BACKGROUND: The efficacy and safety of percutaneous transluminal pulmonary angioplasty (PTPA) for Takayasu arteritis-associated pulmonary hypertension (TA-PH) remain unclear. OBJECTIVES: To examine the efficacy and safety of PTPA in TA-PH. METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials Library were searched from inception to August 18, 2022, for articles investigating the efficacy and safety of PTPA for TA-PH. The primary efficacy outcomes were pulmonary vascular resistance (PVR) changes from baseline to re-evaluation and 6-minute walking distance (6MWD). The safety outcome was procedure-related complications. RESULTS: Five articles comprising 104 patients with TA-PH who underwent PTPA were included. The scores of article quality, as assessed using the methodological index for nonrandomized studies tool, were high, ranging from 13 to 15 points. The pooled treatment effects of PVR (weighted mean difference [WMD]: -4.8 WU; 95% confidence interval [CI]: -6.0 to -3.5 WU; I2 = 0.0%), 6MWD (WMD: 101.9 m; 95% CI: 60.3-143.6 m; I2 = 70.4%) significantly improved. Procedure-related complications, which predominantly present as pulmonary artery injury and pulmonary injury, occurred in 32.0% of the included patients. Periprocedural death occurred in one patient (1.0%, 1/100). CONCLUSIONS: Patients with TA-PH could benefit from PTPA in terms of hemodynamics and exercise tolerance, at the expense of procedure-related complications. PTPA should be encouraged to enhance the treatment response in TA-PH. These findings need to be confirmed by further studies, ideally, randomized controlled trials. REGISTRATION: PROSPERO CRD42022354087.

Regulation and therapy, the role of JAK2/STAT3 signaling pathway in OA: a systematic review.

Osteoarthritis (OA) is a multifactorial chronic disease primarily characterized by the degeneration of articular cartilage. Currently, there is a lack of effective treatments for OA other than surgery. The exploration of the mechanisms of occurrence is important in exploring other new and effective treatments for OA. The current evidence shows that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a vital role in cytogenesis and is involved in OA progression. The terms "JAK2", "STAT3", and "Osteoarthritis"were used in a comprehensive literature search in PubMed to further investigate the relationship between the JAK2/STAT3 signaling pathway and OA. This review focuses on the role and mechanism of JAK2/STAT3 signaling in cartilage degradation, subchondral bone dysfunction, and synovial inflammation. In addition, this review summarizes recent evidence of therapeutic approaches to treat OA by targeting the JAK2/STAT3 pathway to accelerate the translation of evidence into the progression of strategies for OA treatment. Video abstract.

The association of macronutrient quality and its interactions with energy intake with survival among patients with ovarian cancer: results from a prospective cohort study.

BACKGROUND: Emerging evidence supports shifting the focus from the quantity of macronutrients to quality to obtain greater benefits for the prognosis of ovarian cancer (OC). Additionally, despite the high relevance between macronutrient quality and quantity, the interaction of these parameters on OC survival remains unknown. OBJECTIVE: A multidimensional macronutrient quality index (MQI) was applied to investigate the association between overall macronutrient quality and the survival of patients with OC. METHODS: A prospective cohort study was conducted with 701 females diagnosed with OC who were enrolled from 2015 to 2020. Dietary intake information was obtained from a validated food frequency questionnaire. The MQI was calculated based on 3 quality indices: carbohydrate quality index (CQI), fat quality index (FQI), and protein quality index (PQI). Cox proportional hazards regression was conducted to calculate HRs and 95% CIs. Furthermore, we evaluated whether energy intake status (total energy intake and energy balance) modified the association between MQI and OC survival. RESULTS: During a median follow-up period of 38 (interquartile: 35-40) mo, 130 deaths occurred. The prediagnosis high MQI scores were associated with substantially improved survival among females with OC (HRtertile 3 vs. tertile 1 = 0.50, 95% CI: 0.33, 0.77). For sub-indices of the MQI, higher CQI (HR = 0.60, 95% CI: 0.36, 0.99), higher FQI (HR = 0.55, 95% CI: 0.34, 0.87), and higher PQI (HR = 0.58, 95% CI: 0.35, 0.94) scores were all associated with better survival. Notably, significant interactions were observed for the MQI score with total energy intake and energy balance as well as the quantity and quality of carbohydrates on survival. CONCLUSIONS: Intake of high-quality macronutrients before diagnosis was associated with improved survival among females with OC, especially for those with energy imbalance.

Association between pre-diagnostic dietary antioxidant vitamin consumption and ovarian cancer survival: a prospective cohort study.

Background: Epidemiological evidence regarding the relationship between dietary antioxidant vitamin intake and ovarian cancer (OC) survival is not clear. Herein, we aimed to first evaluate this topic in a prospective cohort study in China. Methods: The present study included participants from the Ovarian Cancer Follow-Up Study, which was a hospital-based prospective cohort study including OC patients who were aged 18 to 79 years during 2015-2020. The information on the intake of antioxidant vitamins, consisting of vitamin A, retinol, α-carotene, ß-carotene, vitamin C, and vitamin E, and other diet information was obtained through a 111-item food frequency questionnaire. Deaths were recorded until March 31, 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival were evaluated using Cox proportional hazards models. Results: There were 130 (18.49%) deaths among 703 OC patients during a median 37.19 months follow-up. In the multivariable-adjusted model, the highest tertile of dietary vitamin C (HR = 0.43, 95% CI = 0.25-0.75, P for trend <0.05) and ß-carotene intake (HR = 0.52, 95% CI = 0.31-0.87, P for trend <0.05) was inversely associated with the overall survival of OC when compared with the lowest tertile group. Retinol, vitamin A, vitamin E, and α-carotene consumption showed no association with OC survival. Of note is that the multiplicative interaction was identified between vitamin C intake and residual lesions in OC survival (P for interaction <0.05). Conclusion: Our findings indicate that pre-diagnostic higher vitamin C and ß-carotene intake was associated with improved OC survival.

Pre-diagnosis fiber : carbohydrate intake ratio and mortality of ovarian cancer: results from a prospective cohort study.

Background: The association between the ratio of fiber to carbohydrate (F : C-R) and cancer mortality is not currently well-known. We prospectively evaluated for the first time the aforementioned topic among ovarian cancer (OC) patients. Methods: A total of 703 newly diagnosed OC patients aged 18-79 years were included. Pre-diagnosis diet intake details were collected with a validated food frequency questionnaire. Deaths were ascertained until March 31, 2021, based on medical records and the cancer registry. Cox proportional hazard models were used to evaluate hazard ratios (HRs) and 95% confidence intervals (CIs) between pre-diagnostic fiber, carbohydrate, and F : C-R intake and OC mortality. Restricted cubic splines were used to analyze the potential nonlinear relationship between F : C-R and OC mortality. Results: During the follow-up period (median: 37.2 months; interquartile: 24.7-50.2 months), we observed 130 (18.49%) OC patients died. The pre-diagnosis higher fiber intake (comparing the highest with the lowest tertile of intake: HR = 0.56, 95% CI = 0.35-0.92; HR per 1 SD increment: 0.78, 95% CI = 0.64-0.96; P trend < 0.05) and higher F : C-R intake (comparing the highest with the lowest tertile of intake: HR = 0.51, 95% CI = 0.31-0.85; HR per 1-SD increment: 0.73; 95% CI = 0.59-0.91; P trend < 0.05) were significantly associated with lower mortality for OC patients, but no evidence of the association between pre-diagnosis carbohydrate intake and OC mortality was observed. We found no evidence of a nonlinear relationship between F : C-R and OC mortality. Significant inverse associations were also observed for subgroup analyses stratified by age at diagnosis, menopausal status, residual lesions, histological type, FIGO stage, and body mass index, although not all associations showed statistical significance. Conclusion: Pre-diagnosis high fiber intake and high F : C-R diet intake were associated with a decreased risk of OC mortality.

Bioequivalence and safety evaluation of two preparations of metformin hydrochloride sustained-release tablets (Boke® and Glucophage®-XR) in healthy Chinese volunteers: a randomized phase I clinical trial.

BACKGROUND: As per the National Medical Products Administration (NMPA) requirements, the quality and efficacy of generic drugs must be consistent with those of the innovator drug. We aimed to evaluate the bioequivalence and safety of generic metformin hydrochloride sustained-release (MH-SR) tablets (Boke®) developed by Beijing Wanhui Double-crane Pharmaceutical Co. Ltd., China and the innovator product metformin hydrochloride extended-release tablets (Glucophage®-XR) manufactured by Bristol-Myers Squibb Company, New York, NY, in healthy Chinese volunteers. MATERIALS AND METHODS: We performed a bioequivalence and safety assessment of MH-SR (500 mg/tablet) and Glucophage®-XR (500 mg/tablet) tablets in a randomized, open-label, two-period, two-sequence crossover, single-dose oral study in 48 healthy Chinese adult participants under fasting conditions (Chinese Clinical Trial Registration No. CTR20171306). The washout period was seven days. Bioequivalence (80.00-125.00%) was assessed using adjusted geometric mean ratios (GMRs) and two-sided 90% confidence intervals (CIs) of the area under the curve (AUC) and maximum concentration (Cmax) for each component. RESULTS: The 90% CIs of the test/reference preparation for key pharmacokinetic parameters were 97.36-108.30% for AUC0→t, 97.26-108.09% for AUC0→∞ and 96.76-111.37% for Cmax. No severe adverse events (AEs) were observed. However, 38 adverse drug reactions (ADRs) occurred, including metabolic or nutritional conditions (n = 8), infections (n = 2), gastrointestinal conditions (n = 10) and abnormal inspection (n = 18). No significant difference was observed between MH-SR (23 ADRs, 10 participants) and Glucophage®-XR (15 ADRs, 12 participants) (p = .500). Bioequivalence was concluded since the 90% CIs of the main pharmacokinetic parameters were within the equivalence interval (80.00-125.00%). CONCLUSIONS: MH-SR (500 mg/tablet) and Glucophage®-XR (500 mg/tablet) were found to be bioequivalent and safe under fasting conditions in healthy Chinese participants. Thus, the market demand for MH-SR tablets (500 mg/tablet) can be met using the generic alternative.KEY MESSAGESGeneric MH-SR tablets (500 mg, Beijing Wanhui Double-crane Pharmaceutical Co. Ltd., Beijing, China) and innovator MH-SR tablets (Glucophage®-XR, 500 mg, Bristol-Myers Squibb Company, New York, NY, USA) were bioequivalent and safe in healthy Chinese volunteers under single-dose administration and fasting conditions.The main goal of this study is to support an increase in the supply of MH-SR tablets in China by proving the efficacy and safety of a generic alternative.Although no sugar was administered in the BE trial of the MH-SR tablets under fasting conditions, no hypoglycaemic event occurred. The method used in this study is expected to serve as a reference for BE studies of different MH-SR formulations.

Association between dietary acid load and cancer risk and prognosis: An updated systematic review and meta-analysis of observational studies.

Epidemiological studies have suggested that dietary acid load (DAL) might be related to the risk and prognosis of cancer, whereas the evidence is contentious. Several high-quality observational studies have been published following a prior systematic review with only one study included. Consequently, we conducted an updated systematic review and meta-analysis to comprehensively investigate the relationship between DAL and cancer risk and prognosis. A systematic literature search was conducted in the PubMed, Embase, and Web of Science databases from inception to 26 October 2021. Summary relative risks (RRs) with 95% CIs were calculated using a random-effects model. Publication bias, subgroup, meta-regression, and sensitivity analyses were also conducted. Ten observational studies (six cohorts and four case-control studies) with 227,253 participants were included in this systematic review and meta-analysis. The summary RRs revealed a statistically significant associations between DAL and cancer risk (RR = 1.58, 95% CI = 1.23-2.05, I 2 = 71.9%, n = 7) and prognosis (RR = 1.53, 95% CI = 1.10-2.13, I 2 = 77.1%, n = 3). No evidence of publication bias was observed in the current analysis. Positive associations were observed in most subgroup analyses stratified by predefined factors, including region, study design, study quality, study population, participants' gender, age of participants, cancer type, DAL assessment indicator, and adjustment of potential confounding parameters. No evidence of heterogeneity between subgroups was indicated by meta-regression analyses. The high DAL might be associated with an increased risk of cancer, as well as a poor prognosis of cancer. More high-quality prospective studies are warranted to further determine the associations between DAL and risk and prognosis for specific cancers.

Metformin With or Without Clomiphene Citrate Versus Laparoscopic Ovarian Drilling With or Without Clomiphene Citrate to Treat Patients With Clomiphene Citrate-Resistant Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

Introduction: Which is optimal to treat clomiphene citrate-resistant polycystic ovary syndrome (CCR-PCOS) with LOD or metformin remains a problem. There are three inconsistent or even contradictory views. Objectives: The present meta-analysis aimed to evaluate the effectiveness and safety of Metformin with or without CC and to compare them with LOD with or without CC (Met/Met-CC vs. LOD/LOD-CC) in women with CCR-PCOS who also have anovulation. Data source: The PubMed, Cochrane, and Embase databases were searched to identify relevant studies reported between 1 Jan 1966 and 31 Aug 2019; the search was updated on 17 May 2022. Study eligibility criteria: We included randomized controlled trials (RCTs) of CCR-PCOS that had considered Met/Met-CC and LOD/LOD-CC as the exposure variables and fertility as the main outcome variable. Study appraisal and synthesis methods: We assessed study quality using the Cochrane risk-of-bias tool. The primary effectiveness outcome was live birth/ongoing pregnancy rate and the primary safety outcome was miscarriage rate. A fixed-effect meta-analysis was performed. The robustness of the results was assessed using sensitivity analyses. Meta-regression and subgroup analysis were performed to examine the reasons for heterogeneity. Publication bias was examined using the funnel plot, Egger linear regression, and Begg rank correlation tests. The quality of this meta-analysis was estimated according to the GRADE approach. This meta-analysis has been registered in PROSPERO (CRD42021240156). Results: Among 71 potentially relevant studies, we included five RCTs in our meta-analysis. We found no difference in effectiveness between Met-CC and LOD in terms of live birth/ongoing pregnancy (RR = 1.02, 95% CI: 0.87-1.21, z = 0.28; p = 0.780), and miscarriage rates (RR = 0.79, 95% CI: 0.46-1.36, z = 0.86; p = 0.390). I2 tests results revealed moderate or no heterogeneity (I2 = 51.4%, p = 0.083; I2= 0.0%; p = 0.952). Sensitivity analysis confirmed the robustness of the results. Funnel plot, Egger linear regression, and Begg rank correlation tests implied no publication bias (p > 0.05). LOD was more expensive than Met (€1050 vs. €50.16). The evidence quality was moderate. Conclusion: There is no evidence on the difference in the outcomes between the two interventions regarding ovulation, pregnancy, and live birth. As LOD is an invasive procedure and carries inherent risks, the use of Met/Met-CC should be the second-line treatment for women with CCR-PCOS. Systematic Review Registration: identifier CRD42021240156.

Pre-diagnosis meat intake and cooking method and ovarian cancer survival: results from the Ovarian Cancer Follow-Up Study (OOPS).

Objectives: The relationships between pre-diagnosis meat intake and ovarian cancer (OC) survival were limited and controversial. To date, no study has taken account of cooking methods. Thus, we aimed to firstly clarify these associations based on the Ovarian Cancer Follow-Up Study. Methods: This prospective cohort study, including 853 OC patients between 2015 and 2020, was conducted to examine the aforementioned associations. All women completed a food frequency questionnaire. Deaths were ascertained up to March 31, 2021 via medical records and active follow-up. We used the Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During the median follow-up of 37.17 months, 130 women died. Pre-diagnosis fish and seafood intake was associated with better survival (HRT3 vs. T1 = 0.46, 95% CI = 0.26-0.82, p trend <0.05), whereas processed red meat (HR = 1.54, 95% CI = 1.04-2.26) and a high frequency of fried fish intake (HR = 1.49, 95% CI = 1.03-2.16) were associated with worse survival than consuming none. After considering the interaction of cooking methods, we found that compared with the lowest tertile of fish and seafood intake and almost no fried fish cooking, women with the highest tertile of intake and almost no fried fish cooking had better survival (HR = 0.35, 95% CI = 0.13-0.92). Additionally, compared with the lowest tertile of fish and seafood intake and almost no baked fish cooking, women with the lowest tertile of intake and consuming baked fish had worse survival (HR = 3.75, 95% CI = 1.53-9.15). Conclusions: Pre-diagnosis fish and seafood intake was associated with better OC survival, whereas processed red meat intake was associated with worse survival. Cooking methods, especially for fried or baked fish, may play interaction effects with fish intake on OC survival.

The Role of Human Epididymis Protein 4 in the Diagnosis and Prognosis of Diseases: An Umbrella Review of Systematic Reviews and Meta-Analyses of Observational Studies.

Background: The application of human epididymis protein 4 (HE4) in diverse health diseases, especially in cancers, has been extensively studied in recent decades. To summarize the existing evidence of the aforementioned topic, we conducted an umbrella review to systematically evaluate the reliability and strength of evidence regarding the role of HE4 in the diagnostic and prognostic estimate of diverse diseases. Methods: Electronic searches in PubMed, Web of Science, and Embase databases were conducted from inception to September 16, 2021, for meta-analyses, which focus on the role of HE4 in the diagnosis and prognosis of diseases. This study protocol has been registered at PROSPERO (CRD42021284737). We collected the meta-analysis effect size of sensitivity, specificity, positive predictive value, and negative predictive value from diagnostic studies and gathered the hazard ratio (HR) of disease-free survival, overall survival, and progression-free survival from prognostic studies. For each systematic review and meta-analysis, we used a measurable tool for evaluating systematic reviews and meta-analysis (AMSTAR) to evaluate the methodological quality. Additionally, we assessed the quality of evidence on estimating the ability of HE4 in the diagnosis and prognosis of diverse diseases by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guideline. Results: Overall, 20 meta-analyses including a total of 331 primary studies of different diseases were examined, mainly including ovarian cancer (OC) (n = 9), endometrial cancer (EC) (n = 6), and lung cancer (LC) (n = 4). The methodological qualities of all studies were rated as moderate (45%) or high (55%) by the AMSTAR. According to the GRADE, the certainties of 18 diagnostic pieces of evidence (9 for sensitivity and 9 for specificity) were rated as moderate (34%), low (33%), and very low (33%). Moreover, outcomes from prognosis studies showed evidence (1 for disease-free survival) with high certainty in regard to cancers (such as EC, OC, and LC) with the remaining three being moderate. Conclusion: This umbrella review suggested that HE4 was a favored biomarker in the prognosis of cancers, which was supported by high certainty of evidence. Additionally, HE4 could provide a suitable method for the diagnosis of EC, OC, and LC with moderate certainty evidence. Further large prospective cohort studies are needed to better elucidate the diagnostic and prognostic role of HE4 in diseases.

Bioequivalence and Safety Assessment of Two Formulations of Metformin Hydrochloride Sustained-Release Tablets (Yuantang® SR and Glucophage® XR) Under Fed Conditions in Healthy Chinese Adult Subjects: An Open-Label, Two-Way Crossover, Sequence Randomized Phase I Clinical Trial.

OBJECTIVE: The purpose of this single-center, randomized, open, two-period, two-sequence crossover, single-dose administration, bioequivalence research was to evaluate the bioequivalence and safety of the generic formulations of metformin hydrochloride sustained-release (MH-SR) 500 mg tablets (test preparation [T]: Yuantang® SR) and the original formulation (reference preparation [R]: Glucophage® XR) in 36 healthy Chinese volunteers under postprandial conditions. METHODS: Subjects received 500 mg T/R in each period, with a 7-day washout period. Venous blood samples of 4 mL each were collected from each subject 19 times spanning predose (0 h) to 36 h postdose. The metformin concentration in deproteinized plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. Bioequivalence (80.00-125.00%) was assessed by adjusted geometric mean ratios (GMRs) and two-sided 90% confidence intervals (CIs) of the area under the curve (AUC) and maximum concentration (Cmax) for each component. SAS 9.4 software was used for statistical analysis and Phoenix WinNonlin software v7 was used to analyze the pharmacokinetic parameters. RESULTS: Thirty-four volunteers completed the clinical study. The 90% CIs (96.12-105.44% for AUC from time zero to the time of the last measurable concentration [AUCt], 96.22-105.54% for AUC extrapolated from time zero to infinity [AUC∞], and 98.42-105.00% for Cmax) of T/R adjusted GMRs were within the bioequivalence acceptance range of 80.00-125.00%, indicating that they are bioequivalent. No serious adverse events occurred in this study, indicating that the two formulations were effective and well tolerated. CONCLUSIONS: Yuantang® SR was confirmed to be a well tolerated and bioequivalent alternative to Glucophage® XR when taken under postprandial conditions in healthy Chinese volunteers. The Clinical Trials Registry Platform used for this study was http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml . The trial registration numbers (TRNs) and dates of registrations were CTR20180476 (19 April 2018) for this clinical trial and CTR20171595 (11 January 2018) for the pilot trial.

Exercise-Induced Adult Cardiomyocyte Proliferation in Mammals.

Loss of cardiomyocytes is a vital manifestation and predisposing factor of many cardiovascular diseases and will eventually lead to heart failure (HF). On the other hand, adult mammalian cardiomyocytes have a very limited regenerative capacity and cannot achieve self-repair of the myocardium after injury. Therefore, it is necessary to promote regeneration and repair of the myocardium through effective intervention means. Exercise plays an important role in the prevention and rehabilitation of cardiovascular diseases. Exercise can improve ischemia-reperfusion injury, reduce the size of the infarcted area, and improve the quality of life of patients. In addition, exercise has also been shown to be able to elevate the proliferative potential of adult cardiomyocytes and promote myocardial regeneration. Studies have shown that newly formed cardiomyocytes in adult mammalian hearts are mainly derived from pre-existing cardiomyocytes. By regulating various cytokines, transcription factors, and microRNAs (miRNAs), exercise can promote the dedifferentiation and proliferation of pre-existing cardiomyocytes to form new cardiomyocytes. Therefore, this paper focuses on the recent research progress of exercise-induced adult cardiomyocyte proliferation and explores its potential molecular mechanism.

Pharmacokinetic bioequivalence and safety assessment of two metformin hydrochloride tablet formulations using a phase I, randomized, open, two-period, two cross-over, single-dose, fed study in healthy Chinese adult subjects.

OBJECTIVES: To assess the bioequivalence and safety of generic metformin hydrochloride (test preparation) and glucophage (reference preparation) in healthy Chinese subjects. MATERIALS AND METHODS: A bioequivalence and safety assessment of two formulations of metformin (850 mg) using a randomized, open, two-period, two cross-over, single-dose, fed trial in 36 healthy Chinese adult subjects was performed at our center from March 22, 2018, to April 9, 2018. Bioequivalence was determined as two-sided 90% confidence intervals (CI) of the test-to-reference ratio of area under the curve (AUC) and peak concentration (Cmax) for each constituent within 80.00 - 125.00%. SAS 9.4 software was employed for the statistical analysis. RESULTS: One subject was excluded from the trial. The 90% CIs (95.36 - 101.43% for AUC0→t, 95.65 - 101.66% for AUC0→∞; 94.43 - 101.74% for Cmax) of test/reference preparation for these pharmacokinetic parameters were within the range of 80.00 - 125.00%. No severe adverse events were observed during this trial. The two preparations were safe and well-tolerated. CONCLUSION: It was concluded that generic metformin was bioequivalent and as safe as glucophage under fed conditions in healthy Chinese subjects.

Crosstalk Among circRNA/lncRNA, miRNA, and mRNA in Osteoarthritis.

Osteoarthritis (OA) is a joint disease that is pervasive in life, and the incidence and mortality of OA are increasing, causing many adverse effects on people's life. Therefore, it is very vital to identify new biomarkers and therapeutic targets in the clinical diagnosis and treatment of OA. ncRNA is a nonprotein-coding RNA that does not translate into proteins but participates in protein translation. At the RNA level, it can perform biological functions. Many studies have found that miRNA, lncRNA, and circRNA are closely related to the course of OA and play important regulatory roles in transcription, post-transcription, and post-translation, which can be used as biological targets for the prevention, diagnosis, and treatment of OA. In this review, we summarized and described the various roles of different types of miRNA, lncRNA, and circRNA in OA, the roles of different lncRNA/circRNA-miRNA-mRNA axis in OA, and the possible prospects of these ncRNAs in clinical application.