Effects of sustained viral response on lipid in Hepatitis C: a systematic review and meta-analysis.

BACKGROUND: Direct-acting Antiviral Agents (DAAs) influence serum lipids of patients with Hepatitis C virus (HCV). This paper presents an analysis of the relevant literature to investigate the effects of DAAs in treating hepatitis C to achieve a sustained viral response (SVR) on lipid parameters. METHODS: PubMed,Web of science, Embase and Central databases were searched, with a deadline of September 2023. Studies on the effects of sustained viral response on lipid parameters after DAAs treatment for hepatitis C were selected. The required information was extracted from the included studies, and then the Stata 12.0 was used to analyze the data quantitatively. RESULTS: Of 32 studies, the results showed that total cholesterol (TC) levels increased from the end of treatment (WMD = 20.144, 95%CI = 3.404, 36.884,P = 0.018) to one year after treatment (WMD = 24.900, 95%CI = 13.669, 36.131, P < 0.001). From the end of treatment (WMD = 17.728, 95%CI = 4.375, 31.082, P = 0.009) to one year after treatment (WMD = 18.528, 95%CI = 7.622, 29.433, P < 0.001), the levels of low-density lipoprotein (LDL) were also increased. High-density lipoprotein (HDL) levels were elevated from 4 weeks after treatment (WMD = 6.665, 95%CI = 3.906, 9.424, P < 0.001) to 24 weeks after treatment (WMD = 3.159,95% CI = 0.176, 6.142, P = 0.038). Triglyceride (TG) levels showed no significant change after the treatment. CONCLUSIONS: Hepatitis C patients who achieved SVR on DAAs showed the increase of lipid levels and the improvement of hepatic inflammation indicators AST and ALT. This may provide evidence-based medical evidence for the follow-up and monitoring of blood lipids and hyperlipidemia treatment. REGISTRATION: PROSPERO CRD42020180793.

Association between triglyceride glucose index and arterial stiffness and coronary artery calcification: a systematic review and exposure-effect meta-analysis.

BACKGROUND: The triglyceride and glucose (TyG) index has been linked to various cardiovascular diseases. However, it's still unclear whether the TyG index is associated with arterial stiffness and coronary artery calcification (CAC). METHODS: We conducted a systematic review and meta-analysis of relevant studies until September 2022 in the PubMed, Cochrane Library, and Embase databases. We used a random-effects model to calculate the pooled effect estimate and the robust error meta-regression method to summarize the exposure-effect relationship. RESULTS: Twenty-six observational studies involving 87,307 participants were included. In the category analysis, the TyG index was associated with the risk of arterial stiffness (odds ratio [OR]: 1.83; 95% CI 1.55-2.17, I2 = 68%) and CAC (OR: 1.66; 95% CI 1.51-1.82, I2 = 0). The per 1-unit increment in the TyG index was also associated with an increased risk of arterial stiffness (OR: 1.51, 95% CI 1.35-1.69, I2 = 82%) and CAC (OR: 1.73, 95% CI 1.36-2.20, I2 = 51%). Moreover, a higher TyG index was shown to be a risk factor for the progression of CAC (OR = 1.66, 95% CI 1.21-2.27, I2 = 0, in category analysis, OR = 1.47, 95% CI 1.29-1.68, I2 = 41% in continuity analysis). There was a positive nonlinear association between the TyG index and the risk of arterial stiffness (Pnonlinearity < 0.001). CONCLUSION: An elevated TyG index is associated with an increased risk of arterial stiffness and CAC. Prospective studies are needed to assess causality.

Evaluation of blood-based PRO-C3 testing as a diagnostic marker for staging liver fibrosis: A systematic review and meta-analysis.

BACKGROUND AND AIM: With the global increase in chronic liver disease and cirrhosis, there is an increasing need to identify non-invasive biomarkers to measure the severity of disease progression while reducing reliance on pathological biopsies. This study aimed to comprehensively evaluate the diagnostic value of PRO-C3 as a biomarker for staging liver fibrosis in patients with viral hepatitis or fatty liver disease. METHODS: Articles published until January 6, 2023, were searched in the PubMed, Embase, MEDLINE, Web of Science, and Cochrane Library databases. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to evaluate the quality of the included studies. Pooled sensitivity, specificity, diagnostic odds ratio, and likelihood ratios were integrated using a random-effects model, and a summary receiver operating characteristic curve was constructed. Publication bias was also detected. Subgroup and meta-regression analyses, as well as sensitivity analysis, were also performed. RESULTS: Fourteen studies with 4315 patients were included. Summary area under the curve of PRO-C3 for the identification of significant fibrosis (≥ F2) and advanced fibrosis (≥ F3) was 0.80 (95% confidence interval: 0.76-0.83). Subgroup and meta-regression analyses suggested that disease type and sample size may be the primary factors of heterogeneity in PRO-C3 diagnosis of ≥ F2, while study design, study sample type, and enzyme-linked immunosorbent assay kit brand may be the primary sources of heterogeneity in PRO-C3 diagnosis of ≥ F3. CONCLUSIONS: PRO-C3 demonstrated clinically meaningful diagnostic accuracy when used alone as a non-invasive biomarker for diagnosing the liver fibrosis stage in individuals with viral hepatitis or fatty liver disease.

SOX4-mediated repression of specific tRNAs inhibits proliferation of human glioblastoma cells.

Transfer RNAs (tRNAs) are products of RNA polymerase III (Pol III) and essential for mRNA translation and ultimately cell growth and proliferation. Whether and how individual tRNA genes are specifically regulated is not clear. Here, we report that SOX4, a well-known Pol II-dependent transcription factor that is critical for neurogenesis and reprogramming of somatic cells, also directly controls, unexpectedly, the expression of a subset of tRNA genes and therefore protein synthesis and proliferation of human glioblastoma cells. Genome-wide location analysis through chromatin immunoprecipitation-sequencing uncovers specific targeting of SOX4 to a subset of tRNA genes, including those for tRNAiMet Mechanistically, sequence-specific SOX4-binding impedes the recruitment of TATA box binding protein and Pol III to tRNA genes and thereby represses their expression. CRISPR/Cas9-mediated down-regulation of tRNAiMet greatly inhibits growth and proliferation of human glioblastoma cells. Conversely, ectopic tRNAiMet partially rescues SOX4-mediated repression of cell proliferation. Together, these results uncover a regulatory mode of individual tRNA genes to control cell behavior. Such regulation may coordinate codon usage and translation efficiency to meet the demands of diverse tissues and cell types, including cancer cells.

Disease Modeling with Human Neurons Reveals LMNB1 Dysregulation Underlying DYT1 Dystonia.

DYT1 dystonia is a hereditary neurologic movement disorder characterized by uncontrollable muscle contractions. It is caused by a heterozygous mutation in Torsin A (TOR1A), a gene encoding a membrane-embedded ATPase. While animal models provide insights into disease mechanisms, significant species-dependent differences exist since animals with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-specific cholinergic motor neurons (MNs) that are generated through either direct conversion of patients' skin fibroblasts or differentiation of induced pluripotent stem cells (iPSCs). These human MNs with the heterozygous TOR1A mutation show reduced neurite length and branches, markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport (NCT) of mRNAs and proteins, whereas they lack the perinuclear "blebs" that are often observed in animal models. Furthermore, we uncover that the nuclear lamina protein LMNB1 is upregulated in DYT1 cells and exhibits abnormal subcellular distribution in a cholinergic MNs-specific manner. Such dysregulation of LMNB1 can be recapitulated by either ectopic expression of the mutant TOR1A gene or shRNA-mediated downregulation of endogenous TOR1A in healthy control MNs. Interestingly, downregulation of LMNB1 can largely ameliorate all the cellular defects in DYT1 MNs. These results reveal the value of disease modeling with human patient-specific neurons and indicate that dysregulation of LMNB1, a crucial component of the nuclear lamina, may constitute a major molecular mechanism underlying DYT1 pathology.SIGNIFICANCE STATEMENT Inaccessibility to patient neurons greatly impedes our understanding of the pathologic mechanisms for dystonia. In this study, we employ reprogrammed human patient-specific motor neurons (MNs) to model DYT1, the most severe hereditary form of dystonia. Our results reveal disease-dependent deficits in nuclear morphology and nucleocytoplasmic transport (NCT). Most importantly, we further identify LMNB1 dysregulation as a major contributor to these deficits, uncovering a new pathologic mechanism for DYT1 dystonia.

Relationship between the triglyceride-glucose index and risk of cardiovascular diseases and mortality in the general population: a systematic review and meta-analysis.

BACKGROUND: The triglyceride-glucose (TyG) index is a new alternative measure for insulin resistance. This meta-analysis was conducted to assess the associations of the TyG index with the risks of cardiovascular diseases and mortality in the general population. METHODS: The PubMed, Cochrane Library and Embase databases were searched for randomized controlled trials or observational cohort studies reporting associations of the TyG index with cardiovascular diseases and mortality from inception to April 16, 2022. Effect sizes were pooled using random-effects models. Robust error meta-regression methods were applied to fit nonlinear dose-response associations. Evidence quality levels and recommendations were assessed using the Grading of Recommendations Assessment, Development and Evaluation system (GRADE). RESULTS: Twelve cohort studies (6 prospective and 6 retrospective cohorts) involving 6,354,990 participants were included in this meta-analysis. Compared with the lowest TyG index category, the highest TyG index was related to a higher incidence of coronary artery disease (CAD) (3 studies; hazard ratio [HR] = 2.01; 95% confidence interval [CI] 1.68-2.40; I2 = 0%), myocardial infarction (MI) (2 studies; HR = 1.36; 95% CI 1.18-1.56; I2 = 35%), and composite cardiovascular disease (CVD) (5 studies; HR = 1.46; 95% CI 1.23-1.74; I2 = 82%). However, there was no association between the TyG index and mortality (cardiovascular mortality [3 studies; HR = 1.10; 95% CI 0.82-1.47; I2 = 76%] or all-cause mortality [4 studies; HR = 1.08; 95% CI 0.92-1.27; I2 = 87%]). In the dose-response analysis, there was a linear association of the TyG index with the risk of CAD (Pnonlinear = 0.3807) or CVD (Pnonlinear = 0.0612). GRADE assessment indicated very low certainty for CVD, MI, cardiovascular mortality and all-cause mortality, and moderate certainty for CAD. CONCLUSIONS: Based on our current evidence, a higher TyG index may be associated with an increased incidence of CAD (moderate certainty), MI (very low certainty) and CVD (very low certainty) in the general population. There is a potential linear association of the TyG index with CAD and the composite CVD incidence. Further prospective studies (especially in non-Asians) are needed to confirm our findings.

The relationship between vitamin D and risk of atrial fibrillation: a dose-response analysis of observational studies.

BACKGROUND: The relationship between serum vitamin D and atrial fibrillation (AF) or postoperative atrial fibrillation (POAF) in patients undergoing coronary artery bypass graft (CABG) is still debated. It is also unclear whether there is a dose-response relationship between circulating vitamin D and the risk of AF or POAF. METHODS: The Cochrane Library, PubMed, and Embase databases were searched for relevant studies. We used a "one-stage approach" with a restricted cubic spline model to summarize the dose-specific relationships between serum vitamin D and AF. Relative risk (RR) was used to measure the effects in this meta-analysis. RESULTS: In total, 13 studies were included with a total of 6519 cases of AF among 74,885 participants. Vitamin D deficiency (< 20 ng/ml) was associated with increased risks of AF (RR: 1.23, 95% CI: 1.05-1.43). In the dose-response analysis, the summary RR for a 10 ng/ml increased in vitamin D was 0.88 (95% CI: 0.78-0.98) and there was no evidence of a non-linear association, Pnon-linearity = 0.86. In the age subgroup, high vitamin D (per 10 ng/ml increase) reduced the risk of AF in the older group (> 65 years) (RR = 0.68, 95% CI = 0.52-0.89) but not among young individuals (< 65 years) (RR = 0.87, 95% CI = 0.72-1.06). In addition, a strong association was found between a 10 ng/ml increased in vitamin D and POAF incident in the patient after CABG (RR: 0.44, 95% CI: 0.24-0.82). CONCLUSION: Our dose-response meta-analysis suggested serum vitamin D deficiency was associated with an increased risk of AF in the general population and POAF in patients after CABG. Further studies are needed to explore the age difference in the association between serum vitamin D level and the risk of AF and whether vitamin D supplements will prevent AF. TRIAL REGISTRATION: This study has been registered with PROSPERO (International prospective register of systematic reviews)-registration number-CRD42019119258.

Resting Heart Rate and the Risk of Atrial Fibrillation.

In a previous meta-analysis, it was demonstrated that the resting heart rate (RHR) is a potential risk factor for atrial fibrillation (AF). However, the results of that meta-analysis were conflicting, and the relationship between the RHR and AF is still not well established. In the current meta-analysis, our aim is to update evidence with a better statistical model. We searched the Cochrane Library, PubMed, and Embase databases for relevant studies and used a "one-stage approach" with a restricted cubic spline model to summarize the dose-specific relationships between the RHR and AF. Relative risk (RR) was used to measure the effects. In total, 10 studies were included, with a total of 18,630 cases of AF among 431,432 participants. In the dose-response analysis, there was evidence of a nonlinear association between the RHR and the risk of AF (nonlinearity, P < 0.0001), which exhibited a significant J-shaped association between the two factors. An RHR between 68 and 80 bpm had the lowest risk of AF. Among people who had RHR < 70 bpm, the summary RR was 1.09 per 10-RHR decrease (95% confidence interval [CI] = 1.06-1.12; P < 0.001). The results were similar for participants with RHR > 70 bpm (per 10 bpm increase) (RR = 1.06, 95% CI = 1.03-1.08; P < 0.001). Our dose-response meta-analysis revealed a significant J-shaped association between the RHR and AF. Both low RHR and high RHR were associated with an increased risk of AF compared with a modest RHR of 68-80 bpm.

Dysregulation of Kruppel-like factor 4 during brain development leads to hydrocephalus in mice.

Kruppel-like factor 4 (KLF4) is involved in self-renewal of embryonic stem cells and reprogramming of somatic cells to pluripotency. However, its role in lineage-committed stem cells remains largely unknown. Here, we show that KLF4 is expressed in neural stem cells (NSCs) and is down-regulated during neuronal differentiation. Unexpectedly, enhanced expression of KLF4 reduces self-renewal of cultured NSCs and inhibits proliferation of subventricular neural precursors in transgenic mice. Mice with increased KLF4 in NSCs and NSCs-derived ependymal cells developed hydrocephalus-like characteristics, including enlarged ventricles, thinned cortex, agenesis of the corpus callosum, and significantly reduced subcommissural organ. These characteristics were accompanied by elevation of GFAP expression and astrocyte hypertrophy. The ventricular cilia, vital for cerebrospinal fluid flow, are also disrupted in the mutant mice. These results indicate that down-regulation of KLF4 is critical for neural development and its dysregulation may lead to hydrocephalus.

Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease.

Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.

Serum copper and obesity among healthy adults in the National Health and Nutrition Examination Survey.

BACKGROUND: Copper (Cu) homeostasis are important processes in the cause of metabolic diseases, but the association between Cu and obesity remains unclear. METHODS: Participants were drawn from the 2011-2016 National Health and Nutrition Examination Survey (NHANES). Weighted logistic regression assessed the associations of serum Cu concentrations (tertiles) with obesity and central obesity in individuals without comorbidities. Obesity was defined as a BMI ≥30.0 kg/m2, and central obesity was defined as a waist circumference ≥80 cm for women and ≥95 cm for men. RESULTS: This cross-sectional study included 1,665 adults without comorbidities, representing 24,744,034 people (mean age 35.1 years, 48.5% female). High serum Cu levels (tertile 3: ≥19.19 µmol/L) were associated with higher odds of obesity (adjusted odds ratio [OR]: 4.48, 95% CI[confidence interval]: 2.44-8.32) and central obesity (OR: 2.36, 95% CI: 1.19-4.66) compared to low serum Cu levels (tertile 1: ≤15.64 µmol/L). The dose-response curve showed a nonlinear association between Cu levels and obesity (P-nonlinear = 0.02) and a linear association with central obesity (P-nonlinear = 0.21). CONCLUSION: This study suggests that higher serum Cu levels are associated with increased odds of obesity in healthy American adults.

A simple, flexible, and high-efficiency western blot analysis for age-related human induced neurons.

High-throughput western blot (WB) analysis can be used to obtain more consistent, comparable, and informative data from precious samples and materials with extremely limited availability, such as various age-related, subtype-specific human induced neurons (hiNs). In this study, p-toluenesulfonic acid (PTSA), an odorless tissue fixative, was used to inactivate horseradish peroxidase (HRP) and develop a high-throughput WB method. PTSA-treated blots demonstrated rapid and efficient HRP inactivation without detectable protein loss or epitope damage. With a brief PTSA treatment (1 min at room temperature [RT]) before every subsequent probing, 10 dopaminergic hiN proteins could be sequentially, sensitively, and specifically detected in the blot. The resulting WB data confirmed the age-associated and neuron-specific features of hiNs and revealed a significant reduction in two Parkinson's disease-associated proteins, UCHL1 and GAP43, in normal aging dopaminergic neurons. Overall, this study developed a unique and high-efficiency WB analysis method for capturing robust and useful data from limited, precious samples.

Periodontal disease is associated with the risk of cardiovascular disease independent of sex: A meta-analysis.

Objectives: Studies have established a link between periodontal disease and cardiovascular disease (CVD), but it is unclear whether there is a sex difference in their association. Methods: The PubMed, Embase, and Cochrane databases were searched until June, 21 2022. Cardiovascular outcomes included any CVD, myocardial infarction (MI), coronary heart disease (CHD), or stroke. Studies reported the prevalence of CVD in patients with periodontal disease and the relationship between periodontal disease and CVD. The study is registered with PROSPERO (CRD42022333663). The level of evidence and recommendations is assessed by the Grading of Recommendations for Assessment, Development and Evaluation (GRADE). Results: Twenty-six studies were included. In patients with periodontal disease, the prevalence of CVD was 7.2% [9 studies; 95% confidence interval (CI): 2.7-13.6%], and prevalence for CHD, hypertension, stroke, and heart failure was 6.6, 25.3, 1, and 1.1%, respectively. There was a significant association between periodontal disease and CVD in men [odds ratio (OR) = 1.22; 95% CI: 1.12-1.34] and women (OR = 1.11; 95% CI: 1.05-1.17), with no significant sex difference (P > 0.05). Conclusion: Cardiovascular disease is relatively common in patients with periodontal disease, and an increased risk of CVD is associated with periodontal disease independent of sex. Interventions targeting periodontal disease may be beneficial for CVD. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022333663.

Association between weight loss and outcomes in patients undergoing atrial fibrillation ablation: a systematic review and dose-response meta-analysis.

BACKGROUND: Obesity is an strong risk factor for atrial fibrillation (AF), and obesity can affect the prognosis of AF. However, the role of weight loss on outcomes after ablation remains unclear. OBJECTIVES: This study aims to determine the relationship between weight loss and outcomes in patients with AF ablation, as well as the potential dose-response relationship. METHODS: The Cochrane Library, PubMed, and Embase databases were searched to identify studies that reported a relationship between weight loss and ablation up to August 17, 2021. Relative risks (RRs) were pooled using random-effects models. RESULTS: One randomized, open-labeled clinical trial and seven cohort studies involving 1283 patients were included. The mean body mass index of all included studies was over 30 kg/m2. The clinical trial showed a non-significant benefit of weight loss intervention on AF recurrence (Odd risk [OR] = 1.02, 95% confidence interval [CI] 0.70-1.47). Meta-analysis based on observational studies showed that the recurrence rate of AF after ablation was significantly reduced (RR = 0.43, 95% CI 0.22-0.81, I2 = 97%) in relatively obese patients with weight loss compared with the control group. Each 10% reduction in weight was associated with a decreased risk of AF recurrence after ablation (RR = 0.54, 95% CI 0.33-0.88) with high statistical heterogeneity (I2 = 76%). An inverse linear association (Pnon-linearity = 0.27) between AF relapse and increasing weight loss was found. CONCLUSIONS: Our results first suggest an inverse dose-response association between weight loss and risk of recurrent AF after ablation, with moderate certainty.

Efficacy and Safety of Sofosbuvir-based Regimens in Hepatitis C Patients With Decompensated Cirrhosis: A Systematic Review and Meta-analysis.

Background and Aims: Decompensated cirrhotic patients with hepatitis C (HCV) are often under-represented in clinical trials. We aimed to evaluate pooled data on the efficacy and safety of sofosbuvir (SOF)-based regimens in these patients. Methods: We conducted a systemic review and meta-analysis by searching multiple databases for studies published from October 2010 to October 2020. Outcomes of interest were sustained virologic response (SVR) and safety of SOF-based regimens in decompensated HCV patients. Two reviewers independently performed the study selection and data extraction. Results: We included 33 studies that enrolled 5,302 HCV patients. The pooled SVR rate in decompensated patients with SOF-based regimens was 85.1% (95% CI: 82.8-87.3). Patients on SOF/velpatasvir±ribavirin achieved a significantly higher SVR (91.0%, 95% CI: 87.7-93.9) than that of SOF/ledipasvir±ribavirin [(86.3%, 95% CI: 84.6-87.8); p=0.004)], or on SOF/daclatasvir±ribavirin (82.4%, 95% CI: 78.2-86.2%; p<0.001). Adding ribavirin to SOF-based regimens (pooled SVR 84.9%, 95% CI: 81.7-87.9) did not significantly increase the SVR [(83.8% (95% CI: 76.8-89.8%; p=0.76)] in decompensated patients, which was also true in subgroup analyses for each regimen within the same treatment duration. However, adding ribavirin significantly increased the frequency of adverse events from 52.9% (95% CI: 28.0-77.1) to 89.2% (95% CI: 68.1-99.9) and frequency of severe events. The pooled incidence of hepatocellular carcinoma and case-fatality of decompensated patients were 3.1% (95% CI: 1.5-5.0) and 4.6% (95% CI: 3.1-6.3), respectively. The overall heterogeneity was high. There was no publication bias. Conclusions: The analysis found that 12 weeks of SOF/velpatasvir without ribavirin is the preferred therapy, with a significantly higher SVR compared with other SOF-based regimens in decompensated HCV patients.

AcrPred: A hybrid optimization with enumerated machine learning algorithm to predict Anti-CRISPR proteins.

CRISPR-Cas, as a tool for gene editing, has received extensive attention in recent years. Anti-CRISPR (Acr) proteins can inactivate the CRISPR-Cas defense system during interference phase, and can be used as a potential tool for the regulation of gene editing. In-depth study of Anti-CRISPR proteins is of great significance for the implementation of gene editing. In this study, we developed a high-accuracy prediction model based on two-step model fusion strategy, called AcrPred, which could produce an AUC of 0.952 with independent dataset validation. To further validate the proposed model, we compared with published tools and correctly identified 9 of 10 new Acr proteins, indicating the strong generalization ability of our model. Finally, for the convenience of related wet-experimental researchers, a user-friendly web-server AcrPred (Anti-CRISPR proteins Prediction) was established at http://lin-group.cn/server/AcrPred, by which users can easily identify potential Anti-CRISPR proteins.

Chemical screens in aging-relevant human motor neurons identify MAP4Ks as therapeutic targets for amyotrophic lateral sclerosis.

Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.

Atrial fibrillation and breast cancer-Vicious twins? A systematic review and meta-analysis.

Background: Epidemiological studies suggest a bidirectional association between atrial fibrillation and breast cancer. This study aimed to conduct a meta-analysis to elucidate the prevalence of atrial fibrillation among breast cancer patients, and the bidirectional association between atrial fibrillation and breast cancer. Methods: PubMed, the Cochrane Library, and Embase were searched to identify studies reporting the prevalence, incidence, and bidirectional association between atrial fibrillation and breast cancer. The study was registered with PROSPERO (CRD42022313251). Levels of evidence and recommendations were assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: Twenty-three studies (17 retrospective cohort studies, 5 case-control studies and 1 cross-sectional study) involving 8,537,551 participants were included. Among patients with breast cancer, the prevalence of atrial fibrillation was 3% (11 studies; 95% CI: 0.6 to 7.1%) and the incidence was 2.7% (6 studies; 95% CI: 1.1 to 4.9%). Breast cancer was associated with increased risk of atrial fibrillation (5 studies; hazard ratio [HR]: 1.43, 95% CI: 1.12 to 1.82, I2 = 98%). Atrial fibrillation was also significantly associated elevated risk of breast cancer (5 studies HR: 1.18, 95% CI: 1.14 to 1.22, I2 = 0%). Grade assessment shown low certainty of the evidence for the risk of atrial fibrillation and moderate certainty of the evidence for the risk of breast cancer. Conclusion: Atrial fibrillation is not uncommon in patients with breast cancer and vice versa. There is a bidirectional association between atrial fibrillation (low certainty) and breast cancer (moderate certainty).

Is There a Sex Difference in the Prognosis of Hypertrophic Cardiomyopathy? A Systematic Review and Meta-Analysis.

Background It is still unclear whether there is a sex difference in the prognosis of patients with hypertrophic cardiomyopathy (HCM). Therefore, we performed a meta-analysis to elucidate the association between sex and adverse outcomes in patients with HCM. Methods and Results The PubMed, Cochrane Library, and Embase databases were used to search for studies on sex differences in prognosis in patients with HCM up to August 17, 2021. Summary effect sizes were calculated using a random effects model. The protocol was registered in PROSPERO (International prospective register of systematic reviews) (registration number- CRD42021262053). A total of 27 cohorts involving 42 365 patients with HCM were included. Compared with male subjects, female subjects had a higher age at onset (mean difference=5.61 [95% CI, 4.03-7.19]), a higher left ventricular ejection fraction (standard mean difference=0.09 [95% CI, 0.02-0.15]) and a higher left ventricular outflow tract gradient (standard mean difference=0.23 [95% CI, 0.18-0.29]). The results showed that compared with male subjects with HCM, female subjects had higher risks of HCM-related events (risk ratio [RR]=1.61 [95% CI, 1.33-1.94], I2=49%), major cardiovascular events (RR=3.59 [95% CI, 2.26-5.71], I2=0%), HCM-related death (RR=1.57 [95% CI, 1.34-1.82], I2=0%), cardiovascular death (RR=1.55 [95% CI, 1.05-2.28], I2=58%), noncardiovascular death (RR=1.77 [95% CI, 1.46-2.13], I2=0%) and all-cause mortality (RR=1.43 [95% CI, 1.09-1.87], I2=95%), but not atrial fibrillation (RR=1.13 [95% CI, 0.95-1.35], I2=5%), ventricular arrhythmia (RR=0.88 [95% CI, 0.71-1.10], I2=0%), sudden cardiac death (RR=1.04 [95% CI, 0.75-1.42], I2=38%) or composite end point (RR=1.24 [95% CI, 0.96-1.60], I2=85%). Conclusions Based on current evidence, our results show significant sex-specific differences in the prognosis of HCM. Future guidelines may emphasize the use of a sex-specific risk assessment for the diagnosis and management of HCM.

Sex differences in mortality and hospitalization in heart failure with preserved and mid-range ejection fraction: a systematic review and meta-analysis of cohort studies.

Introduction: The influence of sex on the prognosis of heart failure with preserved or intermediate ejection fraction (HFpEF and HFmrEF) remains uncertain. This study aimed to investigate whether sex differences impact the prognosis of patients diagnosed with HFpEF and HFmrEF. Methods: A comprehensive search across three databases (PubMed, the Cochrane Library, and Embase) was conducted to identify sex-related prognostic cohort studies focusing on HFpEF and HFmrEF. Risk estimates were synthesized using the random effects model. The analysis included 14 cohorts comprising 41,508 HFpEF patients (44.65% males) and 10,692 HFmrEF patients (61.79% males). Results: Among HFpEF patients, men exhibited significantly higher rates of all-cause mortality (13 studies; hazard ratio (HR): 1.24, 95% confidence interval (CI): 1.15 to 1.33)) and cardiovascular disease mortality (5 studies; HR: 1.22, 95% CI: 1.14 to 1.31) compared to women. However, no significant difference was observed in HF admissions. For HFmrEF patients, men displayed notably higher all-cause mortality (HR: 1.21, 95% CI: 1.12 to 1.31) but no significant differences in cardiovascular mortality or HF admissions. Discussion: These findings suggest that male patients diagnosed with HFpEF and HFmrEF may face a more unfavorable prognosis in terms of all-cause mortality. Variations were noted in cardiovascular mortality and HF admissions, indicating potential complexities in sex-related prognostic factors within these heart failure categories. In summary, male patients with HFpEF and HFmrEF may have a more unfavorable prognosis.