Novel genetic loci in early-onset gout derived from whole genome sequencing of an adolescent gout cohort.

OBJECTIVE: Mechanisms underlying the adolescent-onset and early-onset gout are unclear. This study aimed to discover variants associated with early-onset gout. METHODS: We conducted whole genome sequencing in a discovery adolescent-onset gout cohort of 905 individuals (gout onset 12-19 years) to discover common and low frequency SNVs associated with gout. Candidate common SNVs were genotyped in an early-onset gout cohort of 2834 individuals (gout onset ≤ 30 years old) and meta-analysis was performed with the discovery and replication cohorts to identify loci associated with early-onset gout. Transcriptome and epigenomic analyses, RT-qPCR and RNA-seq in human peripheral blood leukocytes, and knock-down experiments in human THP-1 macrophage cells investigated the regulation and function of candidate gene RCOR1. RESULTS: In addition to ABCG2, a urate transporter previously linked to pediatric-onset and early-onset gout, we identified two novel loci (Pmeta < 5.0 × 10-8): rs12887440 (RCOR1) and rs35213808 (FSTL5-MIR4454). Additionally, we found associations at ABCG2 and SLC22A12 that were driven by low frequency SNVs. SNVs in RCOR1 were linked to elevated blood leukocyte mRNA levels. THP-1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation. CONCLUSION: This is the first comprehensive genetic characterization of adolescent-onset gout. The identified risk loci of early-onset gout mediate inflammatory responsiveness to crystals that could mediate gouty arthritis. This study will contribute to risk prediction and therapeutic interventions to prevent adolescent-onset gout.

PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis.

Epigenetic regulation of metabolism profoundly influences cell fate commitment. During osteoclast differentiation, the activation of RANK signaling is accompanied by metabolic reprogramming, but the epigenetic mechanisms by which RANK signaling induces this reprogramming remain elusive. By transcriptional sequence and ATAC analysis, this study identifies that activation of RANK signaling upregulates PRMT6 by epigenetic modification, triggering a metabolic switching from fatty acids oxidation toward glycolysis. Conversely, Prmt6 deficiency reverses this shift, markedly reducing HIF-1α-mediated glycolysis and enhancing fatty acid oxidation. Consequently, PRMT6 deficiency or inhibitor impedes osteoclast differentiation and alleviates bone loss in ovariectomized (OVX) mice. At the molecular level, Prmt6 deficiency reduces asymmetric dimethylation of H3R2 at the promoters of genes including Ppard, Acox3, and Cpt1a, enhancing genomic accessibility for fatty acid oxidation. PRMT6 thus emerges as a metabolic checkpoint, mediating metabolic switch from fatty acid oxidation to glycolysis, thereby supporting osteoclastogenesis. Unveiling PRMT6's critical role in epigenetically orchestrating metabolic shifts in osteoclastogenesis offers a promising target for anti-resorptive therapy.

Preliminary evidence for the presence of programmed cell death in pressure injuries.

Pressure injuries (PIs) are a common healthcare problem worldwide and are considered to be the most expensive chronic wounds after arterial ulcers. Although the gross factors including ischemia-reperfusion (I/R) have been identified in the etiology of PIs, the precise cellular and molecular mechanisms contributing to PIs development remain unclear. Various forms of programmed cell death including apoptosis, autophagy, pyroptosis, necroptosis and ferroptosis have been identified in PIs. In this paper, we present a detailed overview on various forms of cell death; discuss the recent advances in the roles of cell death in the occurrence and development of PIs and found much of the evidence is novel and based on animal experiments. Herein, we also state critical evaluation of the existing data and future perspective in the field. A better understanding of the programmed cell death mechanism in PIs may have important implications in driving the development of new preventive and therapeutic strategies.

Ferroptosis-related gene signature and clinical prognostic factors as prognostic marker for colon adenocarcinoma.

Aim: To build a ferroptosis-related prognostic model for patients with colon adenocarcinoma (COAD). Methods: COAD expression profiles from The Cancer Genome Atlas were used as the training set and GSE39582 from Gene Expression Omnibus as the validation set. Differentially expressed ferroptosis-related genes between patients with COAD and normal controls were screened, followed by tumor subtype exploration based on ferroptosis-related gene expression levels. A ferroptosis score (FS) model was constructed using least absolute shrinkage and selection operator penalized Cox analysis. Based on FS, patients were subgrouped into high- and low-risk subgroups and overall survival was predicted. The potential prognostic value of the FS model and the clinical characteristics were investigated using receiver operating characteristic curves. Results: Twenty-four differentially expressed ferroptosis-related genes were identified, four of which (CYBB, PRNP, ACSL4, and ACSL6) were included in the prognostic signature. Moreover, age, pathological T stage, and tumor recurrence were independent prognostic factors for COAD. The FS model combined with three independent prognostic factors showed the best prognostic value (The Cancer Genome Atlas: area under the curve = 0.897; GSE39582: area under the curve = 0.858). Conclusion: The novel prognostic model for patients with COAD constructed by pairing the FS model with three important independent prognostic factors showed promising clinical predictive value.

Capsid structure of bacteriophage ΦKZ provides insights into assembly and stabilization of jumbo phages.

Jumbo phages are a group of tailed bacteriophages with large genomes and capsids. As a prototype of jumbo phage, ΦKZ infects Pseudomonas aeruginosa, a multi-drug-resistant (MDR) opportunistic pathogen leading to acute or chronic infection in immunocompromised individuals. It holds potential to be used as an antimicrobial agent and as a model for uncovering basic phage biology. Although previous low-resolution structural studies have indicated that jumbo phages may have more complicated capsid structures than smaller phages such as HK97, the detailed structures and the assembly mechanism of their capsids remain largely unknown. Here, we report a 3.5-Å-resolution cryo-EM structure of the ΦKZ capsid. The structure unveiled ten minor capsid proteins, with some decorating the outer surface of the capsid and the others forming a complex network attached to the capsid's inner surface. This network seems to play roles in driving capsid assembly and capsid stabilization. Similar mechanisms of capsid assembly and stabilization are probably employed by many other jumbo viruses.

Biomimetic Proteoglycans Strengthen the Pericellular Matrix of Normal and Osteoarthritic Human Cartilage.

In osteoarthritis (OA), degradation of cartilage pericellular matrix (PCM), the proteoglycan-rich immediate cell microniche, is a leading event of disease initiation. This study demonstrated that biomimetic proteoglycans (BPGs) can diffuse into human cartilage from both normal and osteoarthritic donors and are preferentially localized within the PCM. Applying immunofluorescence (IF)-guided AFM nanomechanical mapping, we show that this localization of BPGs increases the PCM micromodulus of both normal and OA specimens. These results illustrate the capability of BPGs to integrate with degenerative tissues and support the translational potential of BPGs for treating human OA and other diseases associated with proteoglycan degradation.

A Microfluidic 3D-Tumor-Spheroid Model for the Evaluation of Targeted Therapies from Angiogenesis-Related Cytokines at the Single Spheroid Level.

Angiogenesis is a key player in drug resistance to targeted therapies for breast cancer. The average expression of angiogenesis-related cytokines is widely associated with the treatments of target therapies for a population of cells or spheroids, overlooking the distinct responses for individuals. In this work, a highly integrated microfluidic platform is developed for the generation of monodisperse multicellular tumor spheroids (MTSs), drug treatments, and the measurement of cytokines for individual MTSs in a single chip. The platform allows the correlation evaluation between cytokine secretion and drug treatment at the level of individual spheroids. For validation, quantities of six representative proangiogenic cytokines are tested against treatments with four model drugs at varying times and concentrations. By applying a linear regression model, significant correlations are established between cytokine secretion and the treated drug concentration for individual spheroids. The proposed platform provides a high-throughput method for the investigation of the molecular mechanism of the cytokine response to targeted therapies and paves the way for future drug screening using predictive regression models at the single-spheroid level.

The negative association between the docosapentaenoic acid intake and the incidence of AMD based on NHANES 2005-2008.

Introduction: Age-related macular degeneration (AMD) is an ophthalmic disease that causes visual impairment and is one of the leading causes of blindness in the elderly. Fatty acids are essential nutrients required by the body and play a cornerstone role in the life activities of the body. Many studies have reported that fatty acids are involved in the development of AMD. To confirm this association, we conducted the present study. Methods: We analyzed the association between all fatty acid intake and AMD using National Health and Nutrition Examination Survey (NHANES) data from 2005-2008. Quantile regression was performed to assess the effect of fatty acids on AMD at different intake levels. Results: After adjusting for covariates, only saturated fatty acids showed no significant difference between AMD patients and non-AMD patients (23.64 g vs. 26.03 g, p = 0.052). Total fat (70.88 g vs. 78.86 g, p = 0.024), monounsaturated fatty acids (25.87 g vs. 28.95 g, p = 0.019), polyunsaturated fatty acids (15.10 g vs. 17.07 g, p = 0.017) showed significant differences between the two groups. When AMD was considered as an outcome, the association between AMD and docosaentaenoic acid (DPA) was negative in the multivariate logic model (model 1: OR = <0.001, 95% CI = <0.001 ~ 0.734; model 2: OR = <0.001, 95% CI = <0.001 ~ 0.002; model 3: OR = <0.001, 95% CI = <0.001 ~ 0.002). In the quantile regression, DPA was shown to be negatively associated with the presence of AMD only in the fourth quartile in model 2 and model 3 (model 2: OR = <0.001, 95% CI = <0.001 ~ 0.927; model 3: OR = <0.001, 95% CI = <0.001 ~ 0.775). Discussion: Therefore, based on above results, we concluded that DPA intake could prevent the development of AMD.

Identification and experimental validation of programmed cell death- and mitochondria-associated biomarkers in osteoporosis and immune microenvironment.

Background: Prior research has demonstrated that programmed cell death (PCD) and mitochondria assume pivotal roles in controlling cellular metabolism and maintaining bone cell equilibrium. Nonetheless, the comprehensive elucidation of their mode of operation in osteoporosis (OP) warrants further investigation. Therefore, this study aimed at analyzing the role of genes associated with PCD (PCD-RGs) and mitochondria (mortality factor-related genes; MRGs) in OP. Methods: Differentially expressed genes (DEGs) were identified by subjecting the GSE56815 dataset obtained from the Gene Expression Omnibus database to differential expression analysis and comparing OP patients with healthy individuals. The genes of interest were ascertained through the intersection of DEGs, MRGs, and PCD-RGs; these genes were filtered using machine learning methodologies to discover potential biomarkers. The prospective biomarkers displaying uniform patterns and statistically meaningful variances were identified by evaluating their levels in the GSE56815 dataset and conducting quantitative real-time polymerase chain reaction-based assessments. Moreover, the functional mechanisms of these biomarkers were further delineated by constructing a nomogram, which conducted gene set enrichment analysis, explored immune infiltration, generated regulatory networks, predicted drug responses, and performed molecular docking analyses. Results: Eighteen candidate genes were documented contingent upon the intersection between 2,354 DEGs, 1,136 MRGs, and 1,548 PCD-RGs. The biomarkers DAP3, BIK, and ACAA2 were upregulated in OP and were linked to oxidative phosphorylation. Furthermore, the predictive ability of the nomogram designed based on the OP biomarkers exhibited a certain degree of accuracy. Correlation analysis revealed a strong positive correlation between CD56dim natural killer cells and ACAA2 and a significant negative correlation between central memory CD4+ T cells and DAP3. DAP3, BIK, and ACAA2 were regulated by multiple factors; specifically, SETDB1 and ZNF281 modulated ACAA2 and DAP3, whereas TP63 and TFAP2C governed DAP3 and BIK. Additionally, a stable binding force was observed between the drugs (estradiol, valproic acid, and CGP52608) and the biomarkers. Conclusion: This investigation evidenced that the biomarkers DAP3, BIK, and ACAA2 are associated with PCD and mitochondria in OP, potentially facilitate the diagnosis of OP in clinical settings.

Local photo-crosslinking of native tissue matrix regulates cell function.

Within most tissues, the extracellular microenvironment provides mechanical cues that guide cell fate and function. Changes in the extracellular matrix such as aberrant deposition, densification and increased crosslinking are hallmarks of late-stage fibrotic diseases that often lead to organ dysfunction. Biomaterials have been widely used to mimic the mechanical properties of the fibrotic matrix and study cell function. However, the initiation of fibrosis has largely been overlooked, due to the challenges in recapitulating early fibrotic lesions within the native extracellular microenvironment. Using visible light mediated photochemistry, we induced local crosslinking and stiffening of extracellular matrix proteins within ex vivo murine and human tissue. In ex vivo lung tissue of epithelial cell lineage-traced mice, local matrix crosslinking mimicked early fibrotic lesions that increased alveolar epithelial cell spreading, differentiation and extracellular matrix remodeling. However, inhibition of cytoskeletal tension or integrin engagement reduced epithelial cell spreading and differentiation, resulting in alveolar epithelial cell dedifferentiation and reduced extracellular matrix deposition. Our findings emphasize the role of local extracellular matrix crosslinking and remodeling in early-stage tissue fibrosis and have implications for ex vivo disease modeling and applications to other tissues.

Performance Limits and Advancements in Single 2D Transition Metal Dichalcogenide Transistor.

Two-dimensional (2D) transition metal dichalcogenides (TMDs) allow for atomic-scale manipulation, challenging the conventional limitations of semiconductor materials. This capability may overcome the short-channel effect, sparking significant advancements in electronic devices that utilize 2D TMDs. Exploring the dimension and performance limits of transistors based on 2D TMDs has gained substantial importance. This review provides a comprehensive investigation into these limits of the single 2D-TMD transistor. It delves into the impacts of miniaturization, including the reduction of channel length, gate length, source/drain contact length, and dielectric thickness on transistor operation and performance. In addition, this review provides a detailed analysis of performance parameters such as source/drain contact resistance, subthreshold swing, hysteresis loop, carrier mobility, on/off ratio, and the development of p-type and single logic transistors. This review details the two logical expressions of the single 2D-TMD logic transistor, including current and voltage. It also emphasizes the role of 2D TMD-based transistors as memory devices, focusing on enhancing memory operation speed, endurance, data retention, and extinction ratio, as well as reducing energy consumption in memory devices functioning as artificial synapses. This review demonstrates the two calculating methods for dynamic energy consumption of 2D synaptic devices. This review not only summarizes the current state of the art in this field but also highlights potential future research directions and applications. It underscores the anticipated challenges, opportunities, and potential solutions in navigating the dimension and performance boundaries of 2D transistors.

Left ventricular unloading with gentle chest compressions for patients on veno-arterial extracorporeal membrane oxygenation: two case reports.

Insufficient ventricular unloading is a serious complication during veno-arterial extracorporeal membrane oxygenation (VA-ECMO) that has a crucial impact on patient outcomes. The existing conservative treatment options are limited, while mechanical decompression techniques are challenging and restricted in terms of their adoption and application. Two patients with cardiogenic shock experienced insufficient left ventricular unloading with no pulsatile contraction and aortic valve closure during VA-ECMO support. Gentle chest compression was applied to establish an active left ventricular drainage mechanism, which prevented the formation of intracardiac thrombi. No life-threatening complications or technical problems occurred. Therefore, gentle chest compression was established as an effective and safe method for treating insufficient left ventricular unloading in VA-ECMO patients.

Systematic review and meta-analysis of the diagnostic value of computed tomography angiography for severe internal carotid artery stenosis.

BACKGROUND: Due to the increasing incidence of ischaemic cerebrovascular diseases, the accurate assessment of internal carotid artery (ICA) stenosis is crucial for the development of treatment plans. This systematic review and meta-analysis aimed to evaluate the diagnostic value of computed tomography angiography (CTA) for severe ICAstenosis, thereby providing support for clinical decision-making and promoting diagnostic updates. METHODS: The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database for Chinese Technical Periodicals (VIP), and Chinese Biomedical Literature (CBM) electronic databases were searched from inception to March 21, 2024, to identify publicly available research literature on the use of CTA to diagnose severe ICA stenosis. Literature screening, data extraction, and quality assessment were conducted based on the inclusion and exclusion criteria as well as the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) standards. Data analysis was performed using Stata 17.0 and Meta-Disc 1.4 software. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of the included studies were calculated using Stata 17.0 software, and forest plots and summary receiver operating characteristic (SROC) curves were generated. The area under the curve (AUC) was calculated, and funnel plots were constructed to assess publication bias. RESULTS: A total of 16 studies with 2368 vascular segments were included. The meta-analysis revealed that the combined sensitivity and specificity of CTA for severe ICA stenosis were 0.93 (95% CI: 0.88 ~ 0.96) and 0.99 (95% CI: 0.96 ~ 1.00), respectively. The combined positive likelihood ratio and negative likelihood ratio were 92.0 (95% CI: 24.2 ~ 349.6) and 0.07 (95% CI: 0.04 ~ 0.13), respectively. The diagnostic odds ratio was 1302 (95% CI: 257 ~ 6606), and the AUC of the SROC curve was 0.98. The Deeks funnel plot suggested no publication bias among the included studies. CONCLUSION: CTA demonstrated high sensitivity and specificity for diagnosing severe ICA stenosis. Therefore, this study provided important evidence for the accurate diagnosis and treatment of severe ICA stenosis. However, there was considerable heterogeneity among the included studies, thus indicating the need for additional high-quality prospective studies to confirm the clinical applicability of CTA.

Mild-moderate alcohol consumption and diabetes are associated with liver fibrosis in patients with biopsy-proven MASLD.

Background: It is unclear whether patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are allowed variable low levels of alcohol. This study aimed to evaluate the effect of mild-moderate alcohol consumption on the biochemical and histological characteristics of patients with MASLD. Methods: Alcohol consumption was assessed in 713 patients with steatotic liver disease (SLD) who underwent liver biopsy. Non-drinking, mild-moderate drinking, and excessive drinking were defined as 0 g/day, 1-<20 g/day, and >20 g/day for women and 0 g/day, 1-<30 g/day, and >30 g/day for men, respectively. Liver biopsies were scored according to the NASH CRN system. Results: A total of 713 participants (median age 39.0 years and 77.1% male) with biopsy-proven SLD were enrolled, including 239 nondrinkers, 269 mild-moderate drinkers and 205 excessive drinkers. Excessive drinking was associated with increased risks for lobular inflammation and liver fibrosis compared to nondrinkers and mild-moderate drinkers. Compared with non-drinkers, mild-moderate drinkers had significantly lower odds for steatosis (OR = 0.60, 95% CI = 0.38-0.93, p = 0.025), hepatocellular ballooning (OR = 0.52, 95% CI = 0.29-0.91, p = 0.020) and fibrosis (OR = 0.50, 95% CI = 0.31-0.81, p = 0.005). However, in non-excessive drinkers with type 2 diabetes mellitus (T2DM), there was no association between mild-moderate alcohol consumption and liver fibrosis (OR = 0.562, 95% CI = 0.207-1.530, p = 0.257). Conclusions: Mild-moderate alcohol consumption might be protective against liver fibrosis in MASLD patients, which is modified by the presence of T2DM. However, further longitudinal studies are needed to determine the effect of ongoing alcohol consumption on disease severity.

Benefits of osimertinib treat a lung adenocarcinoma patient with germline EGFR T790M, somatic EGFR 19-Del, TP53 and PIK3CA mutations.

BACKGROUND: Somatic mutations in the EGFR gene occur in about 50% of non-small cell lung cancers, with the T790M mutation significantly contributing to secondary resistance against EGFR-TKI drugs. However, EGFR T790M germline mutations rarely occur. CASE PRESENTATION: In this study, we report a case of a lung adenocarcinoma family lineage linked to a germline EGFR T790M mutation. The main subject was diagnosed with stage IV lung adenocarcinoma and experienced a 19-month period without disease progression while treated with Osimertinib. We collected both clinicopathological and familial data from a patient with lung adenocarcinoma. Next-generation sequencing of 40 key genes was performed on the proband's tumor tissue. To detect EGFR germline mutations, Sanger sequencing was conducted on peripheral blood mononuclear cells from the proband and his two daughters. Mutations such as EGFR T790M, EGFR 19-Del, TP53, and PIK3CA were identified in the proband's lung cancer tissue. Additionally, germline EGFR T790M mutations were confirmed in the proband and his daughters through sequencing of their peripheral blood samples. CT scans revealed multiple pulmonary nodules in both daughters. CONCLUSIONS: These observations suggest that germline mutations in EGFR T790M could be strongly linked to a familial predisposition to lung cancer.

Stevens-Johnson syndrome and toxic epidermal necrolysis associated with immune checkpoint inhibitors: a systematic review.

Introduction: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare yet life-threatening adverse events associated with immune checkpoint inhibitors (ICIs). This systematic review synthesizes the current literature to elucidate the clinical characteristics and outcomes of patients with ICI-related SJS/TEN. Methods: We conducted a thorough search across databases including Embase, Web of Science, Cochrane, MEDLINE, Scopus, and PubMed. Selection criteria focused on reports of SJS/TEN among cancer patients treated with ICIs, analyzing clinical manifestations, therapeutic interventions, and outcomes. Results: Our analysis included 47 articles involving 50 patients with ICI-related SJS/TEN. The cohort had a mean age of 63 years, with a slight male predominance (54%). Most patients had melanoma or non-small cell lung cancer. SJS/TEN typically occurred early, with a median onset of 23 days post-ICI initiation. Treatment primarily involved systemic corticosteroids and intravenous immunoglobulins. The overall mortality rate was 20%, higher for TEN at 32%, with infections and tumor progression as leading causes. Median time from onset to death was 28 days. Survivors experienced a median re-epithelization time of 30 days, positively correlated with the extent of epidermal detachment (rs = 0.639, p = 0.009). Deceased patients exhibited a significantly higher proportion of TEN (90% vs. 48%, p = 0.029) and a larger epidermal detachment area (90% vs. 30% of the body surface area [BSA], p = 0.005) compared to survivors. The combination therapy group showed a higher proportion of TEN compared to corticosteroid monotherapy or non-corticosteroid therapy groups (72% vs. 29% and 50%, p = 0.01), with no significant differences in mortality or re-epithelization time. Dual ICI therapy resulted in a higher TEN rate than single therapy (100% vs. 50%, p = 0.028). Among single ICI therapies, the sintilimab-treated group trended towards a higher TEN rate (75% vs. 40-50%, p = 0.417), a larger detachment area (90% vs. 30-48% of BSA, p = 0.172), and a longer re-epithelization time (44 vs. 14-28 days, p = 0.036) compared to other ICI groups, while mortality rates remained similar. Conclusion: ICI-related SJS/TEN substantially impacts patient outcomes. Prospective clinical trials are critically needed to further clarify the pathogenesis and optimize therapeutic regimens.

NFAT3-FasL axis synchronously regulates apoptosis and necroptosis in murine cochlear outer hair cells after noise trauma.

Existing studies have indicated that noise induces apoptosis and necroptosis in cochlear outer hair cells (OHCs). However, the role of the extrinsic cell death pathway, initiated by death ligands in the cochlea, remains unknown. In this study, we hypothesized that noise could induce the NFAT3/FasL axis-mediated extrinsic death pathway in the cochlea. We found that NFAT3/FasL signaling was silent in normal OHCs. Noise exposure induced apoptosis and necroptosis in OHCs with specifically high FasL expression. Multiplex immunofluorescence staining revealed that NFAT3 nuclear translocation and FasL upregulation were colocalized in the apoptotic and necroptotic OHCs following noise trauma. Administration of FK506 or 11R-vivit (an specific NFAT inhibitor) blocked NFAT3 nuclear translocation, inhibited FasL expression, mitigated apoptosis and necroptosis, and protected against noise-induced hearing loss (NIHL). Finally, FasL knockdown by delivering siRNA intratympanically attenuated apoptosis and necroptosis in OHCs and alleviated NIHL, confirming the role of FasL in OHC death. Collectively, our study demonstrates that the NFAT3/FasL axis mediates noise-induced extrinsic death pathway in OHCs, leading to their apoptosis and necroptosis.

Digital Health Interventions for Chronic Wound Management: A Systematic Review and Meta-Analysis.

BACKGROUND: Digital health interventions (DHIs) have shown promising results for the management of chronic wounds. However, its effectiveness compared to usual care and whether variability in the type of intervention affects wound outcomes are unclear. OBJECTIVE: The main objective was to determine the effectiveness of DHIs on wound healing outcomes in adult patients with chronic wounds. The secondary objectives were to assess if there was any variation in wound healing outcomes across the various types of DHIs. METHODS: In total, 9 databases were searched for the literature up to August 1, 2023. Randomized controlled trials (RCTs), cohort studies, and quasi-experimental studies comparing the efficacy of DHIs with controls in improving wound outcomes in adult patients with chronic wounds were included. Study selection, data extraction, and risk of bias assessment were conducted independently by 2 reviewers. We assessed the quality of each RCT, cohort study, and quasi-experimental study separately using the Cochrane risk of bias tool, ROBINS-I, and the Joanna Briggs Institute Critical Appraisal tools checklists. Relative risks (RRs) and 95% CIs were pooled using the random effects model, and heterogeneity was assessed by the I2 statistic. Subgroup analysis and sensitivity analysis were also performed. RESULTS: A total of 25 studies with 8125 patients were included in this systematic review, while only 20 studies with 6535 patients were included in the meta-analysis. Efficacy outcomes in RCTs showed no significant differences between the DHIs and control groups in terms of wound healing (RR 1.02, 95% CI 0.93-1.12; P=.67) and all-cause mortality around 1 year (RR 1.08, 95% CI 0.55-2.12; P=.83). Compared with the control group, the use of DHIs was associated with significant changes in adverse events (RR 0.44, 95% CI 0.22-0.89; P=.02). Subgroup analysis suggested a positive effect of the digital platforms in improving wound healing (RR 2.19, 95% CI 1.35-3.56; P=.002). Although meta-analysis was not possible in terms of wound size, cost analysis, patient satisfaction, and wound reporting rates, most studies still demonstrated that DHIs were not inferior to usual care in managing chronic wounds. CONCLUSIONS: The findings of our study demonstrate the viability of adopting DHIs to manage chronic wounds. However, more prominent, high-quality RCTs are needed to strengthen the evidence, and more detailed clinical efficacy research is required. TRIAL REGISTRATION: PROSPERO CRD42023392415; https://tinyurl.com/4ybz6bs9.

Resveratrol protects against a high-fat diet-induced neuroinflammation by suppressing mitochondrial fission via targeting SIRT1/PGC-1α.

Various health issues have emerged due to consuming high-fat diets (HFD), particularly the detrimental impact they have on mitochondrial dynamics and subsequet cognition functions. Specially, mitochondrial fission can serve as an upstream signal in the regulation of cortical inflammation and neural pyroptosis. Our study was designed to verify the existence of neuroinflammation in the pathogenesis of HFD-induced cognitive dysfunction and demonstrated that resveratrol (RSV) attenuated neural deficits via regulation of cortical mitochondrial fission. A total of 50 male Sprague Dawley rats were randomly divided into five groups: control (Cont, 26 weeks on normal rodent diet); high-fat diet (HFD); dietary adjustments (HFD + ND); resveratrol intervention (HFD + R); joint intervention (HFD + ND + R) for 26 weeks. The spatial learning and memory function, spine density, NLRP3 inflammasome associated protein, mRNA and protein expression involved in mitochondrial dynamics and SIRT1/PGC-1α signaling pathway in brain were measured. Furthermore, reactive oxygen species (ROS) accumulation and resultant mitochondrial membrane potential (MMP) alteration in PC12 cells exposed to palmitic acid (PA) or Drp1 inhibitor (Mdivi-1) were detected to reflect mitochondrial function. The findings suggested that prolonged treatment of RSV improved cognitive deficits and neuronal damage induced by HFD, potentially attributed to activation of the SIRT1/PGC-1α axis. We further indicated that the activation of the NLRP3 inflammasome in PA (200 µM) treated PC12 cells could be inhibited by Mdivi-1. More importantly, Mdivi-1 (10 µM) reduced intracellular ROS levels and enhanced MMP by reversing Drp1-mediated aberrant mitochondrial fission. To summarize, those results clearly indicated that a HFD inhibited the SIRT1/PGC-1α pathway, which contributed to an imbalance in mitochondrial dynamics and the onset of NLRP3-mediated pyroptosis. This effect was mitigated by the RSV possibly through triggering the SIRT1/PGC-1α axis, prevented aberrant mitochondrial fission and thus inhibited the activation of the NLRP3 inflammatory pathway.