Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming.

TET proteins oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). 5fC and 5caC are excised by mammalian DNA glycosylase TDG, implicating 5mC oxidation in DNA demethylation. Here, we show that the genomic locations of 5fC can be determined by coupling chemical reduction with biotin tagging. Genome-wide mapping of 5fC in mouse embryonic stem cells (mESCs) reveals that 5fC preferentially occurs at poised enhancers among other gene regulatory elements. Application to Tdg null mESCs further suggests that 5fC production coordinates with p300 in remodeling epigenetic states of enhancers. This process, which is not influenced by 5hmC, appears to be associated with further oxidation of 5hmC and commitment to demethylation through 5fC. Finally, we resolved 5fC at base resolution by hydroxylamine-based protection from bisulfite-mediated deamination, thereby confirming sites of 5fC accumulation. Our results reveal roles of active 5mC/5hmC oxidation and TDG-mediated demethylation in epigenetic tuning at regulatory elements.

Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency.

Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated1. Gestational diabetes has profound and enduring effects on the long-term health of the offspring2,3. However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote4, is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene (Gck), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring.

KRAS mutation-driven angiopoietin 2 bestows anti-VEGF resistance in epithelial carcinomas.

Defining reliable surrogate markers and overcoming drug resistance are the most challenging issues for improving therapeutic outcomes of antiangiogenic drugs (AADs) in cancer patients. At the time of this writing, no biomarkers are clinically available to predict AAD therapeutic benefits and drug resistance. Here, we uncovered a unique mechanism of AAD resistance in epithelial carcinomas with KRAS mutations that targeted angiopoietin 2 (ANG2) to circumvent antivascular endothelial growth factor (anti-VEGF) responses. Mechanistically, KRAS mutations up-regulated the FOXC2 transcription factor that directly elevated ANG2 expression at the transcriptional level. ANG2 bestowed anti-VEGF resistance as an alternative pathway to augment VEGF-independent tumor angiogenesis. Most colorectal and pancreatic cancers with KRAS mutations were intrinsically resistant to monotherapies of anti-VEGF or anti-ANG2 drugs. However, combination therapy with anti-VEGF and anti-ANG2 drugs produced synergistic and potent anticancer effects in KRAS-mutated cancers. Together, these data demonstrate that KRAS mutations in tumors serve as a predictive marker for anti-VEGF resistance and are susceptible to combination therapy with anti-VEGF and anti-ANG2 drugs.

Inhibition of Hmbox1 Promotes Cardiomyocyte Survival and Glucose Metabolism Through Gck Activation in Ischemia/Reperfusion Injury.

BACKGROUND: Exercise-induced physiological cardiac growth regulators may protect the heart from ischemia/reperfusion (I/R) injury. Homeobox-containing 1 (Hmbox1), a homeobox family member, has been identified as a putative transcriptional repressor and is downregulated in the exercised heart. However, its roles in exercise-induced physiological cardiac growth and its potential protective effects against cardiac I/R injury remain largely unexplored. METHODS: We studied the function of Hmbox1 in exercise-induced physiological cardiac growth in mice after 4 weeks of swimming exercise. Hmbox1 expression was then evaluated in human heart samples from deceased patients with myocardial infarction and in the animal cardiac I/R injury model. Its role in cardiac I/R injury was examined in mice with adeno-associated virus 9 (AAV9) vector-mediated Hmbox1 knockdown and in those with cardiac myocyte-specific Hmbox1 ablation. We performed RNA sequencing, promoter prediction, and binding assays and identified glucokinase (Gck) as a downstream effector of Hmbox1. The effects of Hmbox1 together with Gck were examined in cardiomyocytes to evaluate their cell size, proliferation, apoptosis, mitochondrial respiration, and glycolysis. The function of upstream regulator of Hmbox1, ETS1, was investigated through ETS1 overexpression in cardiac I/R mice in vivo. RESULTS: We demonstrated that Hmbox1 downregulation was required for exercise-induced physiological cardiac growth. Inhibition of Hmbox1 increased cardiomyocyte size in isolated neonatal rat cardiomyocytes and human embryonic stem cell-derived cardiomyocytes but did not affect cardiomyocyte proliferation. Under pathological conditions, Hmbox1 was upregulated in both human and animal postinfarct cardiac tissues. Furthermore, both cardiac myocyte-specific Hmbox1 knockout and AAV9-mediated Hmbox1 knockdown protected against cardiac I/R injury and heart failure. Therapeutic effects were observed when sh-Hmbox1 AAV9 was administered after I/R injury. Inhibition of Hmbox1 activated the Akt/mTOR/P70S6K pathway and transcriptionally upregulated Gck, leading to reduced apoptosis and improved mitochondrial respiration and glycolysis in cardiomyocytes. ETS1 functioned as an upstream negative regulator of Hmbox1 transcription, and its overexpression was protective against cardiac I/R injury. CONCLUSIONS: Our studies unravel a new role for the transcriptional repressor Hmbox1 in exercise-induced physiological cardiac growth. They also highlight the therapeutic potential of targeting Hmbox1 to improve myocardial survival and glucose metabolism after I/R injury.

Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development.

Oncogenic imbalance of DNA methylation is well recognized in cancer development. The ten-eleven translocation (TET) family of dioxygenases, which facilitates DNA demethylation, is frequently dysregulated in cancers. How such dysregulation contributes to tumorigenesis remains poorly understood, especially in solid tumors which present infrequent mutational incidence of TET genes. Here, we identify loss-of-function mutations of TET in 7.4% of human lung adenocarcinoma (LUAD), which frequently co-occur with oncogenic KRAS mutations, and this co-occurrence is predictive of poor survival in LUAD patients. Using an autochthonous mouse model of KrasG12D -driven LUAD, we show that individual or combinational loss of Tet genes markedly promotes tumor development. In this Kras-mutant and Tet-deficient model, the premalignant lung epithelium undergoes neoplastic reprogramming of DNA methylation and transcription, with a particular impact on Wnt signaling. Among the Wnt-associated components that undergo reprogramming, multiple canonical Wnt antagonizing genes present impaired expression arising from elevated DNA methylation, triggering aberrant activation of Wnt signaling. These impairments can be largely reversed upon the restoration of TET activity. Correspondingly, genetic depletion of ß-catenin, the transcriptional effector of Wnt signaling, substantially reverts the malignant progression of Tet-deficient LUAD. These findings reveal TET enzymes as critical epigenetic barriers against lung tumorigenesis and highlight the therapeutic vulnerability of TET-mutant lung cancer through targeting Wnt signaling.

Generation of mega brown adipose tissue in adults by controlling brown adipocyte differentiation in vivo.

Brown adipose tissue (BAT) is a highly specialized adipose tissue in its immobile location and size during the entire adulthood. In response to cold exposure and other ß3-adrenoreceptor stimuli, BAT commits energy consumption by nonshivering thermogenesis (NST). However, the molecular machinery in controlling the BAT mass in adults is unknown. Here, we show our surprising findings that the BAT mass and functions can be manipulated in adult animals by controlling BAT adipocyte differentiation in vivo. Platelet-derived growth factor receptor α (PDGFα) expressed in BAT progenitor cells served a signaling function to avert adipose progenitor differentiation. Genetic and pharmacological loss-of-function of PDGFRα eliminated the differentiation barrier and permitted progenitor cell differentiation to mature and functional BAT adipocytes. Consequently, an enlarged BAT mass (megaBAT) was created by PDGFRα inhibition owing to increases of brown adipocyte numbers. Under cold exposure, a microRNA-485 (miR-485) was identified as a master suppressor of the PDGFRα signaling, and delivery of miR-485 also produced megaBAT in adult animals. Noticeably, megaBAT markedly improved global metabolism, insulin sensitivity, high-fat-diet (HFD)-induced obesity, and diabetes by enhancing NST. Together, our findings demonstrate that the adult BAT mass can be increased by blocking the previously unprecedented inhibitory signaling for BAT progenitor cell differentiation. Thus, blocking the PDGFRα for the generation of megaBAT provides an attractive strategy for treating obesity and type 2 diabetes mellitus (T2DM).

Interfacial and Electronic Modulation of W Bridging Heterostructure Between WS2 and Cobalt-Based Compounds for Efficient Overall Water Splitting.

The development of high performance electrocatalysts for effective hydrogen production is urgently needed. Herein, three hybrid catalysts formed by WS2 and Co-based metal-organic frameworks (MOFs) derivatives are constructed, in which the small amount of W in the MOFs derivatives acts as a bridge to provide the charge transfer channel and enhance the stability. In addition, the effects of the surface charge distribution on the catalytic performance are fully investigated. Due to the optimal interfacial electron coupling and rearrangement as well as its unique porous morphology, WS2 @W-CoPx exhibits superior bifunctional performance in alkaline media with low overpotentials in hydrogen evolution reaction (HER) (62 mV at 10 mA cm-2 ) and oxygen evolution reaction (OER) (278 mV at 100 mA cm-2 ). For overall water splitting (OWS), WS2 @W-CoPx only requires a cell voltage of 1.78 V at 50 mA cm-2 and maintains good stability within 72 h. Density functional theory calculations verify that the combination of W-CoPx with WS2 can effectively enhance the activity of OER and HER with weakened OH (or O) adsorption and enhanced H atom adsorption. This work provides a feasible idea for the design and practical application of WS2 or phosphide-based catalysts in OWS.

Coordination Engineering of Carbon Dots and Mn in Co-Based Phosphides for Highly Efficient Seawater Splitting at Ampere-Level Current Density.

Direct electrolysis of seawater to generate hydrogen is an attractive approach for storing renewable energy. However, direct seawater splitting suffers from low current density and limited operating stability, which severely hinders its industrialization. Herein, a promising strategy is reported to obtain a nano needle-like array catalyst-CDs-Mn-CoxP on nickel foam, in which the Mn─O─C bond tightly binds Mn, Carbon dots (CDs), and CoxP together. The coordination engineering of CDs and Mn not only effectively regulates the electronic structure of CoxP, but also endows the as-prepared catalyst with selectivity and marked long-term stability at ampere-level current density. Low overpotentials of 208 and 447 mV are required to achieve 1000 mA cm-2 for hydrogen evolution reaction (HER) and Oxygen evolution reaction (OER) in simulated seawater, respectively. Cell potentials of 1.78 and 1.86 V are needed to reach 500 and 1000 mA cm-2 in alkaline seawater along with excellent durability for 350 h. DFT studies have verified that the introduction of Mn and CDs effectively shifts the d-band center of Co-3d toward higher energy, thereby strengthening the adsorption of intermediates and enhancing the catalytic activity. This study sheds light on the development of highly effective and stable catalysts for large-scale seawater electrolysis.

Charge-transfer-driven ultrasensitive SERS sensing in a two-dimensional titanium carbonitride MXene.

Two-dimensional (2D) MXenes stand out as promising platforms for surface-enhanced Raman scattering (SERS) sensing owing to their metallic feature, various compositions, high surface area, compatibility with functionalization, and ease of fabrication. In this work, we report a high-performance 2D titanium carbonitride (Ti3CN) MXene SERS substrate. We reveal that the abundant electronic density of states near the Fermi level of Ti3CN MXene boosts the efficiency of photo-induced charge transfer at the interface of Ti3CN/molecule, resulting in significant Raman enhancement. The SERS sensitivity of Ti3CN MXene is further promoted through a 2D morphology regulation and molecular enrichment strategies. Moreover, prohibited drugs are detectable on this substrate, presenting the potential of trace-amount analysis on Ti3CN MXene. This work provides a deep insight of the SERS mechanisms of Ti3CN MXene and broadens the practical application of transition metal carbonitride MXene SERS substrates.

Integrating transcriptomics, glycomics and glycoproteomics to characterize hepatitis B virus-associated hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) ranks as the third most common cause of cancer related death globally, representing a substantial challenge to global healthcare systems. In China, the primary risk factor for HCC is the hepatitis B virus (HBV). Aberrant serum glycoconjugate levels have long been linked to the progression of HBV-associated HCC (HBV-HCC). Nevertheless, few study systematically explored the dysregulation of glycoconjugates in the progression of HBV-associated HCC and their potency as the diagnostic and prognostic biomarker. METHODS: An integrated strategy that combined transcriptomics, glycomics, and glycoproteomics was employed to comprehensively investigate the dynamic alterations in glyco-genes, N-glycans, and glycoproteins in the progression of HBV- HCC. RESULTS: Bioinformatic analysis of Gene Expression Omnibus (GEO) datasets uncovered dysregulation of fucosyltransferases (FUTs) in liver tissues from HCC patients compared to adjacent tissues. Glycomic analysis indicated an elevated level of fucosylated N-glycans, especially a progressive increase in fucosylation levels on IgA1 and IgG2 determined by glycoproteomic analysis. CONCLUSIONS: The findings indicate that the abnormal fucosylation plays a pivotal role in the progression of HBV-HCC. Systematic and integrative multi-omic analysis is anticipated to facilitate the discovery of aberrant glycoconjugates in tumor progression.

Biomimetic synthesis of single-crystalline anhydrous xanthine nanoplates in an aqueous solution with high reflectivity.

Biogenic purine crystals can function in vision as light scatters, mirrors, and multilayer reflectors and produce structural colors or depolarization for camouflage. Xanthine crystals form irregular multifocal mirrors in the median ocellus of Archaeognatha. It is important to broaden the study of crystallization strategies to obtain organic crystals with purine rings in the laboratory. In this work, a facile one-step synthesis route to fabricate bio-inspired xanthine crystals is reported for the first time. The obtained rhomboidal xanthine nanoplates have similar morphology and size to biogenic xanthine crystals. Their length and thickness are about 2-4 µm and 50 nm, respectively. Lattice parameters, crystal structure, formation mechanism and optical properties of synthetic single-crystalline xanthine nanoplates were investigated in detail in this work. The obtained xanthine nanoplate crystals are proposed to be anhydrous xanthine with monoclinic symmetry, and the xanthine nanoplates mainly expose the (100) plane. It is proposed that the anhydrous xanthine nanoplates are formed via an amorphous xanthine intermediate precursor. The synthetic anhydrous xanthine nanoplates exhibit excellent optical properties, including high diffuse reflectivity, strong depolarization and pearlescent luster. This work provides a new design to synthesize bio-inspired organic molecular crystals with excellent optical properties.

The association between varicella zoster virus and dementia: a systematic review and meta-analysis of observational studies.

PURPOSE: The relationship between varicella zoster virus (VZV) infection and the risk of dementia has not been previously studied specifically. Therefore, this study sought to determine the relationship between studying VZV infection and dementia occurring in the general population by conducting an extensive meta-analysis of published cases. METHOD: A systematic literature search was conducted in seven online databases by October 31, 2022. Heterogeneity was tested by the I2 index. Pooled HR and 95% CI were used to estimate the effect of VZV infection on dementia. Sensitivity analyses and publication bias were also performed. RESULT: Nine studies involving 3,326,673 subjects were included. VZV infection was associated with an increased risk of dementia (HR = 1.11, 95% CI: 1.02-1.21). The risk of dementia was reduced in those who received antiviral therapy compared to those who did not (HR = 0.84, 95% CI: 0.71-0.99). In addition, VZV infection was found to be associated with an increased risk of developing dementia in the pooled results of the moderate quality study (HR = 1.81,95% CI: 1.27-2.59), and this association persisted when subgroup analyses were performed based on region (Asia: HR = 1.18,95% CI: 1.04-1.33). CONCLUSIONS: Our results suggest that VZV infection might increase the risk of developing dementia, but there is no clear mechanism about the true relationship, and since there is no effective treatment for dementia, and our results suggest that some populations can benefit from antiviral therapy, it is at least arguable that patients who develop VZV infection should be treated with appropriate antiviral medications.

Longitudinal association of nighttime sleep duration with emotional and behavioral problems among rural preschool children.

This study aimed to examine the association between nighttime sleep duration and emotional and behavioral problems (EBPs) among rural preschool children. This longitudinal study including 1595 preschool children aged 3-6 years from 26 kindergartens in four counties was conducted in Anhui Province rural areas. Cross-lagged panel models and multivariable logistic regressions were performed to examine the bidirectional association between nighttime sleep duration and EBPs and further explore the predictive effect of nighttime sleep duration on EBPs. Compared to baseline, preschool children at follow-up had significantly more nighttime sleep duration (10.01 ± 0.68 vs. 10.15 ± 0.69) and lower EBPs (total difficulties: 15.8% vs. 11.2%; prosocial behavior problems: 12.4% vs. 7.0%). Results of cross-lagged panel models indicated that nighttime sleep duration was a predictor for EBPs, but not vice versa. Results of logistic regression analysis showed that each 1-h increase in nighttime sleep duration at T1 was associated with a 0.77-fold reduction in the risk of total difficulties at T2 (the most adjusted OR = 0.774, 95% CI 0.607-0.988, P = 0.040), but not with the prosocial behavior. Interestingly, the predictive effect of nighttime sleep duration at T1 on EBPs at T2 was only found in girls, children aged 3 years and children with lower maternal education. The decreased nighttime sleep duration may predict future EBPs, especially in girls, younger preschool children and children with lower maternal education. Extending sleep duration may improve EBPs in preschool children.

Effect of recombinant human epidermal growth factor on neuropathic pain associated with radiotherapy for head and neck malignancies and nursing strategy.

OBJECTIVE: To evaluate the effect of recombinant human epidermal growth factor (rhEGF) on radiotherapy-related neuropathic pain in patients with head and neck malignancies, and to explore comprehensive nursing strategies. METHODS: In this retrospective study, a total of 80 patients diagnosed with head and neck malignancy and receiving radiotherapy were divided into 2 groups according to treatment. Patients in the control group received conventional radiation therapy and postoperative care, and those in the trial group received rhEGF in addition to conventional radiation therapy and care. Visual analogue scale (VAS) was used to evaluate the pain degree of patients before and after treatment, EORTC QLQ-C30 scale was used to evaluate the quality of life of patients before and after treatment, and the skin and mucosal reactions of patients after radiotherapy were observed. RESULTS: Baseline characteristics were similar between the two groups. VAS scores in the trial group were significantly lower than those in the control group during and after radiotherapy (p < 0.001), and skin and mucosal reactions were less severe (p < 0.05). In addition, compared with the control group, the quality of life and symptom scores of the trial group were significantly improved after treatment (p < 0.05). CONCLUSION: rhEGF can effectively alleviate neuropathic pain during and after radiotherapy in patients with head and neck malignancies, improve skin and mucosal response, and improve quality of life.

Solar-powered detection of organic dyes using nitrogen-doped N-TiO2/Ag2O nanorod arrays.

Organic pollutant detection has caused widespread concern regarding due to their potential environmental and human health risks. In this work, a nitrogen-doped titanium dioxide/silver oxide (N-TiO2/Ag2O) composite has been designed as a sensitive photoelectrochemical (PEC) monitoring platform of organic dyes. Sensitive determination relies on the outstanding PEC performance of N-TiO2/Ag2O. The improved PEC performance stems from the effective separation of photocarriers and the extended light response range provided by the narrowing bandgap and a p-n junction with N-TiO2/Ag2O. The N-TiO2/Ag2O electrode exhibits a photocurrent density of up to 2.2 mA/cm2, demonstrating three times increase compared with the photocurrent density observed with the pure TiO2 film. The linear detection range for rhodamine B (RhB), methylene blue (MB), and methyl orange (MO) is 0.2 ng/mL to 10 µg/mL with an ultrasensitive detection limit of 0.2 ng/mL without bias voltage. Due to the outstanding photocurrent density and sensitive response to organic pollutants, the N-TiO2/Ag2O PEC sensor provided a promising analytical method to detect environmental organic dyes.

Improving X-ray Scintillating Merits of Zero-Dimensional Organic-Manganese(II) Halide Hybrids via Enhancing the Ligand Polarizability for High-Resolution Imaging.

Luminescent metal halides have been exploited as a new class of X-ray scintillators for security checks, nondestructive inspection, and medical imaging. However, the charge traps and hydrolysis vulnerability are always detrimental to the three-dimensional ionic structural scintillators. Here, the two zero-dimensional organic-manganese(II) halide coordination complexes 1-Cl and 2-Br were synthesized for improvements in X-ray scintillation. The introduction of a polarized phosphine oxide can help to increase the stabilities, especially the self-absorption-free merits of these Mn-based hybrids. The X-ray dosage rate detection limits reached up to 3.90 and 0.81 µGyair/s for 1-Cl and 2-Br, respectively, superior to the medical diagnostic standard of 5.50 µGyair/s. The fabricated scintillation films were applied to radioactive imaging with high spatial resolutions of 8.0 and 10.0 lp/mm, respectively, holding promise for use in diagnostic X-ray medical imaging.

Research and application progress of microbial ß-mannanases: a mini-review.

Mannan is a predominant constituent of cork hemicellulose and is widely distributed in various plant tissues. ß-Mannanase is the principal mannan-degrading enzyme, which breaks down the ß-1,4-linked mannosidic bonds in mannans in an endo-acting manner. Microorganisms are a valuable source of ß-mannanase, which exhibits catalytic activity in a wide range of pH and temperature, making it highly versatile and applicable in pharmaceuticals, feed, paper pulping, biorefinery, and other industries. Here, the origin, classification, enzymatic properties, molecular modification, immobilization, and practical applications of microbial ß-mannanases are reviewed, the future research directions for microbial ß-mannanases are also outlined.

Targeting p53 for neuroinflammation: New therapeutic strategies in ischemic stroke.

Ischemic stroke (IS) is characterized by high incidence, high recurrence, and high mortality and places a heavy burden on society and families. The pathological mechanisms of IS are complex, among which secondary neurological impairment mediated by neuroinflammation is considered to be the main factor in cerebral ischemic injury. At present, there is still a lack of specific therapies to treat neuroinflammation. The tumor suppressor protein p53 has long been regarded as a key substance in the regulation of the cell cycle and apoptosis in the past. Recently, studies have found that p53 also plays an important role in neuroinflammatory diseases, such as IS. Therefore, p53 may be a crucial target for the regulation of the neuroinflammatory response. Here, we provide a comprehensive review of the potential of targeting p53 in the treatment of neuroinflammation after IS. We describe the function of p53, the major immune cells involved in neuroinflammation, and the role of p53 in inflammatory responses mediated by these cells. Finally, we summarize the therapeutic strategies of targeting p53 in regulating the neuroinflammatory response after IS to provide new directions and ideas for the treatment of ischemic brain injury.

Effect of physical activity on incidence and mortality in patients with gastric cancer: evidence from real-world studies.

PURPOSE: Physical activity (PA) has been suggested to reduce the risk of cancer. However, previous studies have been inconsistent regarding the relationship between PA and the risk of developing gastric cancer (GC). The purpose of this study was to evaluate the impact of PA on the incidence and mortality risk of GC through a meta-analysis, as well as investigate potential dose-response relationships. METHODS: A systematic literature search was conducted in 10 electronic databases and 4 registries. The combined relative risks (RRs) were calculated using a random-effects model with 95% confidence interval (CIs) to assess the effect of PA on the risk of GC. Relevant subgroup analyses and sensitivity analyses were performed. RESULTS: The results showed that PA correlated with lower incidence of GC (RR: 0.83, 95% CI: 0.77-0.90), decreased risk of GC mortality (RR: 0.76, 95% CI: 0.66-0.89). The results of the subgroup analysis showed that PA was associated with reduced incidence of GC across gender, different regions, study designs, different sites of GC and different types of PA. A linear relationship was found for frequency of PA. CONCLUSIONS: This meta-analysis found that PA was associated with a reduced risk of GC incidence and mortality. The correlation between PA and GC occurrence was in a dose-response relationship.

Efficacy and safety profile of angiotensin receptor neprilysin inhibitors in the management of heart failure: a systematic review and meta-analysis of randomized controlled trials.

Several guidelines have recommended the use of angiotensin receptor neprilysin inhibitors (ARNIs) as replacement for angiotensin-converting enzyme inhibitors in the management of heart failure. Till date, there are no reviews done that comprehensively cover different aspects of efficacy and safety parameters. Hence, we have performed a comprehensive systematic review and meta-analysis on role of ARNIs for the management of heart failure patients. Searches were done in Embase, Scopus, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, PubMed Central, Cochrane Library, MEDLINE, Google Scholar, ScienceDirect and Clinicaltrials.gov until June 2022. Risk of bias assessment was done with Cochrane's risk of bias tool. Meta-analysis was carried out using random-effects model. Pooled standardized mean difference (SMD)/mean difference (MD) and/or risk ratio (RR) with 95% confidence intervals (CIs) was reported. In total, we analysed 34 studies, with almost all of them had a high risk of bias. Pooled RR was 0.88 (95% CI: 0.82-0.95) for all-cause mortality, 0.84 (95% CI: 0.77-0.92) for cardiovascular mortality and 0.78 (95% CI: 0.70-0.87) for hospitalization. Pooled MD was 3.74 (95% CI: 1.93-5.55) for left ventricular ejection fraction, -2.16 (95% CI: -3.58 to -0.74) for left atrial volume index, -3.80 (95% CI: -6.60 to -1.00) for left ventricular end-diastolic dimension and -1.16 (95% CI: -1.98 to -0.35) for E/E' ratio. Regarding adverse events, pooled RR was 1.55 (95% CI: 1.31-1.85) for symptomatic hypotension, 0.93 (95% CI: 0.78-1.11) for worsening renal function, 1.09 (95% CI: 0.94-1.26) for hyperkalaemia and 1.29 (95% CI: 0.67-2.50) for angioedema. ARNIs had beneficial efficacy and safety profile on the management of heart failure especially patients with reduced ejection fraction.