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Commensal-derived acetylcholine enhances mucosal immune education

Cone photoreceptor ablation in microglia-deficient larval zebrafish retina elicits a regenerative response alongside a compensatory immune cell response

Emerging evidence implicates retinal microglia and inflammation as important components impacting the outcome of retinal regeneration, which is spontaneously achieved in zebrafish retina following acute damage but is limited or blocked in mammals. Here we describe the regenerative response in the larval zebrafish retina following ablation of cone photoreceptors. To investigate the role of microglia in the regenerative response, we used irf8 st95 heterozygote (microglia-sufficient) and irf8 st95 homozygous mutant (microglia-deficient) zebrafish. We compared multiple aspects of the regenerative response in irf8  + /- and irf8 -/- larval retinas, including entry of the Müller glia (MG) into the cell cycle, the amplification of MG-derived progenitor cell (MGPC) proliferation, inflammatory and glial reactivity-associated gene expression, and the regeneration of cones. We found only modest impacts to early and late stages of MGPC proliferation and to inflammatory gene expression in irf8 mutants, with no obvious impacts to the regeneration of cones. Notably, we detected a population of immune cells in irf8 mutants that emerged following cone ablation, which expanded in number then were reduced over time, following a trajectory similar to microglia-sufficient siblings but at markedly reduced abundance. The immune cells detected in irf8 mutants included a subset with L-plastin/4C4 antibody staining patterns different than those in microglia-sufficient siblings, suggesting distinct origins and/or phenotype compared to resident microglia in controls. The presence of immune cells in irf8 mutants following cone ablation limited our ability to make strong conclusions about the role of microglia in regeneration of cones. However, our results are consistent with several reports that indicate a role for microglia in regulating MGPC proliferation in the regenerating retina. Collectively considered with other reports, our results further indicate that compensatory responses, which may include different immune cells and/or signaling from other retinal cell types such as Müller glia, may be elicited in microglia-deficient retinas upon neuronal damage.

Evaluation of outcomes in 201 child and youth survivors of Child Sexual Abuse (CSA) who participated in a one-year multimodal treatment program

Background and rationale Child sexual abuse (CSA) is a pervasive and prevalent form of early-life trauma that can increase the risk for PTSD, mood disorders, substance abuse, harmful behaviour, non-suicidal self-harm, suicidal ideation, and death by suicide. Preliminary research has shown positive impacts of multimodal treatment for youth survivors of CSA, but no ‘gold-standard’ currently exists for CSA treatment. The aim of this study was to provide a secondary analysis of data from a longitudinal, episodic, and multimodal treatment program specifically designed to treat child and adolescent survivors of CSA. Methods Child and youth survivors of CSA aged 8–17 completed a one-year multimodal treatment program at a dedicated facility known as the Little Warriors Be Brave Ranch. Participants completed self-report outcome measures for PTSD, depression, anxiety, self-esteem, quality of life, family functioning, and substance use at intake and graduation from the program. Changes in reported outcomes for child and youth participants were analyzed over the course of treatment. Results A total of 201 sequential individuals who completed the one-year treatment program between January 2022-January 2026, from an initial group of 253 participants, were included in this analysis. Most of the completers were biologically female (n = 166, 82.6%) and were adolescents aged 13–17 (n = 116), while the remainder were children aged 8–12 (n = 85). Overall, positive changes in all outcomes were reported in participants from both groups. The largest effect was reported in adolescent PTSD symptoms (d = 0.94, p < 0.001), depression (d = 0.88, p < 0.001), and anxiety (d = 0.86, p < 0.001). Large effect sizes were also reported in levels of PTSD (d = 0.72, p < 0.001), depression (d = 0.82, p < 0.001), and anxiety (d = 0.64, p < 0.001) in child participants. Participants whose PTSD scores remained above the clinical threshold at graduation had higher levels of family dysfunction, more complex histories of trauma, and lower resilience scores. Conclusion The findings of this study support the use of a multimodal treatment program for youth CSA survivors. The results suggest that this program design has the capacity to benefit CSA survivors across several domains of mental health and well-being. However, the findings of this study are limited by the lack of a control group. Future research should investigate the long-term effects of treatment, and include comparisons to a control sample, to further elucidate the sustainability of these positive therapeutic outcomes.

Trends in general practitioner dispensing of thickeners in the NHS England, 2019–24

Introduction Oropharyngeal dysphagia is common and often results in aspiration. Thickeners are widely used to thicken liquids to slow the liquid bolus and prevent aspiration and aspiration pneumonia, despite multiple concerns about their use. To date, there is little data on prescribing/dispensing practices. This study aims to provide the first overview of thickener dispensing practices, serve as foundational material for parties interested in research, practice and policy making, and guide further work in this area. Method We explored English general practitioner thickener dispensing practices for the five-year period 2019–2024 via the NHS Business Services Authority ePACT2 database and using descriptive statistics and linear regression to analyse the data. We hypothesized that with a large data set, it would be possible to detect trends in dispensing. Results Between 2019 and 2024, nearly three million thickening items were dispensed in primary care in England at a cost of nearly 90 million sterling. Thickened liquids is primarily an intervention for older people although there was a significant decreasing trend in dispensed thickener items in adult populations. Thickener dispensing has increased in the youngest age group (0–1-years-old). The cost of thickeners to the NHS has risen in the last year under study despite the significant decline in use observed for most age groups. Of dispensed items over the five-year period, the vast majority were gum-based. Conclusion While the data provided in this study is limited to GP dispensed thickeners in England, it provides researchers, clinicians and policy makers with initial information on dispensing practices. From the available data, a decreasing dispensing trend is seen in the context of rising costs, older people comprise the population who primarily receive thickeners and gum-based products dominate the market. This study raises a number of questions regarding the use of thickeners for people with swallowing problems.

Electric fields probe the symmetry of the ‘heavy hydrogen’ nucleus

Parents’ role as advocates for and against childhood vaccination: Findings from a nationally representative survey

Introduction In 2025, the US recorded the highest number of measles cases in 25 years, signaling an urgent need for renewed attention to increasing childhood vaccination coverage. To identify future intervention partners, we sought to understand parents’ role in advocating for and against childhood vaccines. Methods A nationally representative sample of 1,315 parents of children ages 9–12 years participated in our online survey about vaccine advocacy behaviors in 2025. Separate weighted logistic regression models identified correlates of encouraging or discouraging other parents from getting routine vaccines for their children. Results Over one-third of parents reported encouraging routine vaccines sometimes or more often (36%), while about one-tenth reported discouraging vaccines (12%). These estimates include a small proportion of parents (6%) who reported both behaviors. Parents with higher confidence in the importance of vaccines for their child’s health were more likely to be encouragers and less likely to be discouragers (both p  < .05). Encouragers ( n  = 477) most often advocated for measles (50%) or seasonal flu vaccines (44%). These parents most often engaged family members and close friends, using strategies such as sharing vaccine experiences (47%), information about vaccine effectiveness (38%), and advice or opinions about vaccines (35%). Discouragers ( n  = 151) most often advocated against Covid-19 (53%) or seasonal flu vaccines (41%), with relatively few focusing on measles vaccine (10%). Discouragers engaged similar audiences and strategies as encouragers. Conclusion Findings of our nationally representative study suggest that parents who encourage routine vaccination far outnumber those who discourage it. Given that encouragers often advocate for measles vaccine, future efforts to increase vaccination coverage should consider ways to partner with parent advocates to stem the alarming resurgence of this disease.

Efficacy and limitations of diffusion-weighted imaging with background suppression-based whole-body magnetic resonance imaging in high-risk prostate cancer staging: A retrospective study

Purpose To evaluate the diagnostic performance and limitations of whole-body magnetic resonance imaging (WB-MRI) using diffusion-weighted imaging with background body signal suppression (DWIBS) for staging high-risk prostate cancer (PCa) in comparison with conventional computed tomography (CT) and bone scintigraphy (BS). Materials and methods This retrospective study included 38 patients with newly diagnosed high-risk PCa who underwent CT, bone scintigraphy (BS), and DWIBS, all performed within two months prior to treatment initiation. DWIBS was performed with coverage from the skull base to the proximal femur. Pathological findings from extended pelvic lymph node dissection were available in 14 patients and were used as the reference standard for lymph node metastasis. For all remaining cases and metastatic sites, the reference standard was established by the best valuable comparator consensus of two radiologists and two urologists using imaging and clinical follow-up data. Results For lymph node metastases, both DWIBS and CT demonstrated a sensitivity of 64.3% and a specificity of 100.0%. For bone metastases, DWIBS showed a sensitivity of 88.9% and specificity of 100.0%, whereas BS showed a sensitivity of 100.0% and a specificity of 96.6%. Lung metastases were observed in three patients. Chest CT detected all lesions, whereas DWIBS detected two cases; these were confirmed on coronal T2-weighted images but not visualized on diffusion-weighted imaging alone. Conclusion DWIBS demonstrated acceptable diagnostic performance for staging high-risk PCa, comparable to CT and BS, while offering the advantage of radiation-free WB-MRI and avoidance of radioisotopes. When combined with chest CT, this approach may represent a practical and feasible alternative imaging strategy for initial PCa staging.

Service-oriented cloud manufacturing systems: Balancing profit, customer satisfaction, and resource fairness

The rapid growth of customized demand and geographically distributed manufacturing resources has increased the need for integrated decision-making in cloud manufacturing systems. In such environments, scheduling, logistics, pricing, and quality decisions are highly interrelated and significantly affect both system profitability and customer satisfaction. However, most existing studies address these decisions separately and pay limited attention to customer satisfaction and fairness. To address this gap, this paper proposes a multi-objective mixed-integer programming model that simultaneously integrates scheduling, logistics, pricing, and quality decisions while explicitly considering customer satisfaction and fairness among customers. The model pursues three objectives: maximizing cloud manufacturing system profit, maximizing customer satisfaction as a function of price and product quality, and minimizing unfairness among customers. An LP-metric approach is employed to aggregate the objectives, and the model is solved using CPLEX in GAMS. Computational experiments on small-, medium-, and large-scale instances demonstrate the effectiveness of the proposed framework. The results show that ignoring logistics decisions, customer satisfaction, or earliness/tardiness penalties leads to inferior solutions. Furthermore, a Genetic Algorithm is developed for large-scale instances, where the exact approach becomes computationally demanding. Comparative results indicate that the proposed heuristic provides high-quality solutions with significantly lower computational times for large-scale problems. The findings confirm the effectiveness and scalability of the proposed framework for integrated decision-making in cloud manufacturing systems.

A decade of progress and challenges in Water, Sanitation and Hygiene (WASH) coverage in Bangladesh: Insights from Bangladesh demographic and health survey 2011–2022

Background Access to safe water, sanitation, and hygiene (WASH) remains a critical global public health challenge, with an estimated 2 billion people lacking safe drinking water and basic hygiene services. In Bangladesh, disparities in WASH access persist across regions and socioeconomic groups. This study assesses decade-long changes in WASH coverage, examines its distribution across socio-demographic groups, identifies key associated factors, and highlights underserved regions and population subgroups. Methods Data from four rounds of the Bangladesh Demographic and Health Survey (BDHS) (2011–2022) were analyzed. WASH indicators were classified as improved or unimproved based on WHO–UNICEF Joint Monitoring Programme (JMP) 2017 guidelines and applied consistently across all survey rounds. Spatial mapping was used to assess regional disparities, while regression models identified factors associated with WASH facilities. A classification tree approach was used to explore interactions among predictors. Results Over the decade (2011–2022), access to improved drinking water remained high (above 98%), with improvements in sanitation (22 percentage points), hygiene (30.5 percentage points), and overall WASH facilities (28 percentage points). Classification tree analysis identified wealth index as the most important determinant. Regional disparities were evident, with higher coverage in Dhaka, Rajshahi, and Chattogram, and lower coverage in Barishal and Mymensingh. Wealthier households had higher odds of improved WASH facilities (AOR: 8.72 [6.74, 11.3] in 2011; 9.35 [8.31, 10.5] in 2022) compared to poorer households. Households with more higher educated heads also had higher odds (AOR: 7.10 [5.80, 8.69] in 2011; 3.44 [2.99, 3.96] in 2022) compared to those with no formal education. Other associated factors included family size, region, media access, and mobile ownership. Conclusion Key determinants of WASH access, including wealth, education, and regional disparities, remained largely unchanged over time. Achieving SDG 6 requires targeted subsidies for socioeconomically disadvantaged households, region-specific interventions in underserved areas such as Barishal and Mymensingh, and strengthened awareness programs.

5-Fluorouracil modulates motility and biofilm-associated gene expression in Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic pathogen in which motility, biofilm formation, and stress adaptation contribute to virulence. Drug repurposing represents a practical strategy for identifying compounds that influence these processes. In this study, the effects of 5-fluorouracil (5-FU) on motility, extracellular DNA (eDNA) production, and gene expression were examined in P. aeruginosa PAO1. Swimming, swarming, and twitching motility assays were performed in the presence of increasing concentrations of 5-FU. Transcriptional responses of motility, rhamnolipid, and DNA repair-associated genes were evaluated using quantitative real-time PCR. eDNA levels were quantified using fluorescence-based assays and visualized by confocal laser scanning microscopy. Exposure to 5-FU resulted in concentration-dependent reductions in swimming, swarming, and twitching motility. These changes were associated with downregulation of multiple genes involved in flagellar and type IV pili function, including motA , flhA , fliD , pilA , and pilI , and reduced expression of lasB and rhlAB . At 24 h, eDNA levels were decreased relative to untreated controls, whereas at 48 h, higher concentrations of 5-FU were associated with increased eDNA accumulation and upregulation of several DNA repair genes, including xthA , nth , recJ , sbcB , and eddB . These results indicate the multifaceted effects of 5-FU on important virulence factors of P. aeruginosa.

Counting missing babies in Tanzania: Neonatal mortality data quality from Tanzania’s District Health Information System across 28 Regional and 7 Tertiary hospitals (2015–2024)

Introduction The Sustainable Development Goal 3.2 targets reducing the neonatal mortality rate (NMR) to <12 per 1,000 live births by 2030; however, 65 countries, including Tanzania, remain off track. The 2022/23 Tanzania Demographic and Health Survey (TDHS) reported an NMR of 24 per 1,000 live births, equivalent to 48,000 neonatal deaths annually. Methods Neonatal deaths were extracted from the District Health Information System (DHIS2) for 28 Regional Referral Hospitals (RRHs) and seven tertiary hospitals from 2015 to 2024. Data quality was assessed by: (1) completeness, as the proportion of months each hospital reported neonatal deaths; (2) internal consistency, comparing mean NMR for 2021–2023 with 2024 following WHO guidance; and (3) external plausibility, comparing DHIS2 with DHS and UN estimates. For seven hospitals implementing NEST360 program, NMRs from DHIS2 were compared with the Neonatal Inpatient Dataset (NID) for 2021 and 2024. Results Between 2015 and 2024, DHIS2 recorded an average of >8,500 neonatal deaths annually versus 48,000 expected. RRHs accounted for 30–40% of reported deaths, and tertiary hospitals for 4–11%. Overall monthly reporting completeness was 58.3%, higher in RRHs (median 61.7%, IQR 8.3–95.0%) than in tertiary hospitals (median 50%, IQR 0.8–73.3%), with only 8 RRHs (28.5%) and no tertiary hospital achieving >75% reporting. Only 28.6% of hospitals had internal consistency (NMR within ±33% of the mean) for 2021–2023. The DHIS2 NMR for 2024 was 5.9 per 1,000 (adjusted for ~20% home births), compared to 24 per 1,000 in DHS 2022/23. Compared with NEST360 NID, one tertiary hospital reported lower DHIS2 NMRs, and three RRHs reported higher (ratio >1). Conclusion Neonatal mortality reporting in Tanzania’s DHIS2 remains substantially under-captured, with notable variations across facilities. Although RRHs perform better than tertiary hospitals, overall data quality remains low. Improving reporting in underperforming facilities and leveraging high-performing RRHs can strengthen national neonatal mortality monitoring.

Evaluation of forage oat cultivars for alpine saline-alkaline environments: Trade-offs between yield, quality and stability

Oat cultivation in the alpine saline-alkaline Qaidam Basin requires cultivars that balance yield, quality, and stability. Identifying suitable cultivars is key to sustainable forage production. Three oat cultivars (‘Qinghai 444’, ‘Qingtian No. 1', and ‘Zhengshi No. 1’) were evaluated in a two-year (2024 and 2025) field trial. We measured agronomic traits, yield, photosynthetic parameters, and forage quality. Mixed linear models, correlation analysis, and principal component analysis (PCA) were used to assess genotypic effects, environmental stability, and trait relationships. Cultivars exhibited distinct strategies. ‘Zhengshi No. 1’ achieved the highest fresh yield (3.29 and 1.96 t/ha) linked to greater stem diameter and photosynthetic rates but with high environmental sensitivity. ‘Qingtian No. 1’ provided stable, superior forage quality (highest crude protein: 11.44% and 10.33%). ‘Qinghai 444’ showed the most stable agronomic performance and highest water-use efficiency. Key trade-offs were identified, including a negative correlation between yield-related traits and forage quality (Relative Feed Value). The choice of optimal cultivar depends on primary goals: ‘Zhengshi No. 1’ for maximum biomass, ‘Qingtian No. 1’ for high quality, and ‘Qinghai 444’ for reliable performance under variable conditions. This provides an actionable framework for cultivar selection in saline-alkaline regions.

Video summarization based on multi-scale feature fusion

Video summarization aims to identify the important segments of a video and form a concise representation, enabling users to quickly grasp the core information. Existing graph-based video summarization methods suffer from insufficient modeling of multi-scale feature interactions and difficulties in balancing local and global features. To address this issue, this paper proposes a multi-scale feature fusion video summarization model based on the Message Passing Neural Network (MPNN) framework. First, the model extracts features of representative frames from video shots, and constructs a graph structure where shot features serve as nodes and inter-shot semantic similarity as edges. Second, it decouples the multi-scale features in the graph via the MPNN, and utilizes the Graph Attention Network (GAT) and Graph Neural Network (GNN) to extract local correlation features and global features, respectively. Finally, it fuses the original shot features, local features and global features as the final features to calculate shot importance and generate the video summary. On SumMe (F1 = 50.0) and TVSum (F1 = 61.8) datasets, MSF-MPNN achieves competitive performance against mainstream RNN/GNN-based methods. MSF-MPNN provides a practical solution for efficient video content extraction, with potential in video surveillance and short-video platforms.

Dose-response relationships of sensorimotor-based interventions on balance performance in older adults: A systematic review and meta-regression analysis

Falls are a severe public health challenge for older adults. Although sensorimotor-based interventions can remodel balance, their quantitative dose-response trajectories remain unknown, often leading to blindly accumulated doses. We aimed to identify optimal intervention strategies by deconstructing these non-linear dynamics. A comprehensive search of five databases up to February 2026 identified relevant randomized controlled trials (RCTs). We constructed a random-effects model using the standardized mean difference (Hedges’ g). Restricted cubic spline (RCS) and meta-regression models explored the non-linear dynamics of total intervention dose and the moderating effects of age. We included 24 studies comprising 1,110 participants. Sensorimotor-based interventions significantly improved dynamic balance (Timed Up and Go Test [TUGT]: g = −0.89, Q = 78.19; low-certainty evidence), static balance (Berg Balance Scale [BBS]: g = 0.94, Q = 21.14; high-certainty evidence), and neuromuscular control, including Center of Pressure with eyes open (COP-EO: g = −0.66, Q = 8.19; low-certainty evidence) and Center of Pressure with eyes closed (COP-EC: g = −0.34, Q = 3.54; moderate-certainty evidence). The RCS model suggested significant non-linear dose dependency for dynamic balance (P non-linearity  = 0.004), indicating a potential relative attenuation of effect sizes near a cumulative dose of 1000 minutes. Conversely, static balance showed no significant dose association. Increasing age significantly attenuated dynamic balance benefits (p = 0.047) but did not negatively affect static stability. The adaptive trajectories of dynamic and static balance responding to sensorimotor interventions diverge fundamentally. Based on these non-linear dose-response fluctuations and age-related characteristics, continuous time accumulation may not guarantee proportional linear returns. Optimizing fall prevention requires shifting toward precise interventions that consider dose-efficiency and age stratification rather than a “more is better” approach. Systematic Review Registration: INPLASY202630061.

Cardiorespiratory fitness profile of volunteer firefighters during intermittent incremental exercise: A cross-sectional study

Purpose We aimed to assess the physiological profile of male volunteer firefighters at a broad spectrum of exercise intensities to determine whether their cardiorespiratory fitness level is adequate to meet the physiological demands of their occupational activities. Methods Thirty-one male volunteer firefighters performed an intermittent incremental treadmill running exercise (with 4 min steps, 1 km·h −1 increments and 30 s rest periods). Cardiorespiratory variables were continuously monitored and blood lactate concentrations were obtained at baseline, throughout rest periods and post-exercise. The study followed a cross-sectional laboratory-based assessment, in accordance with the STROBE guidelines for cross-sectional studies. Results The increase in running velocity resulted in progressively higher values from low to severe exercise intensities in oxygen uptake (from 23.6 ± 7.5 to 44.1 ± 7.6 mL·kg −1 ·min −1 ; p  < 0.001; η p 2  = 0.560), heart rate (from 133 ± 24 to 185 ± 14 bpm; p  < 0.001; η p 2  = 0.459) and energy expenditure (from 127 ± 50 to 303 ± 51 kJ; p  < 0.001; η p 2  = 0.654). Aerobic energy contributions progressively declined (94–83%), while anaerobic contributions increased (6–17%) across the incremental intensity domains. Inverse associations were reported between heart rate and body mass index at heavy (r = −0.38; p  = 0.017) and severe (r = −0.34; p  = 0.028) intensities, and with fat mass at heavy intensity (r = −0.32; p  = 0.037). Conclusions Findings evidenced a moderate to strong effect of exercise intensities on most assessed variables, and approximately half of the participants (~52%) did not meet the age-specific oxygen uptake threshold recommended by widely referenced National Fire Protection Association (NFPA-USA) guidelines for performing their professional duties. Given the firefighters’ high physiological demands, they should follow structured training interventions and receive targeted nutritional guidance to improve their cardiorespiratory fitness while ensuring optimal performance in the field.

Identify perceived strategies for promoting happiness among nurses: Protocol for a mixed-methods study

Background Enjoyment at work and overall happiness are essential elements of a thriving workforce, particularly in high-pressure environments like healthcare. Nurses frequently experience occupational burnout and stress due to the demanding nature of their profession, which can adversely affect their performance, job satisfaction, and overall well-being. Understanding the factors that contribute to happiness in nursing is crucial, as fostering a positive work environment can lead to improved patient care, reduced turnover rates, and enhanced mental health among healthcare professionals. Objective This study aims to systematically investigate the current state of happiness among nurses in order to identify perceived strategies for enhancing their well-being. By employing a mixed-methods approach, we will gather quantitative data on happiness levels and qualitative insights into the experiences and perceptions of nurses regarding their work environment. The ultimate goal is to develop evidence-based recommendations that can be implemented within healthcare settings to promote happiness and mitigate the effects of burnout and stress, thereby contributing to a healthier and more productive workforce. Methods Utilizing a mixed-method protocol, the research consists of two distinct phases. The quantitative phase employs a two-stage sampling method to select participants from ten randomly chosen hospitals within a province, ensuring a representative sample. In the qualitative phase, snowball sampling will be utilized to achieve data saturation, allowing for a comprehensive understanding of the factors influencing happiness in nursing. Data collection will involve a range of instruments, including a demographic characteristics and occupational features checklist, the Oxford Happiness Questionnaire, and semi-structured interviews to gather in-depth insights. Data analysis will be conducted using SPSS-24 statistical software for quantitative data and MAXQDA for qualitative data, enabling a robust examination of the findings. Result The study is expected to yield a comprehensive understanding of the levels and determinants of happiness among nurses. Quantitative data will provide statistical insights into the prevalence of happiness and its correlation with demographic and occupational factors. Qualitative findings are anticipated to uncover nuanced perspectives on the challenges and enablers of workplace happiness, offering valuable context to the quantitative results. Together, these findings will inform actionable recommendations for fostering a supportive work environment in healthcare settings. Conclusions The anticipated outcomes of this study highlight the positive impact of workplace happiness on nurses’ health, job satisfaction, and overall quality of patient care. By identifying actionable perceived strategies to promote happiness in the workplace, this research aims to contribute to the development of supportive environments that enhance both staff well-being and patient outcomes. Ultimately, this study represents a vital step toward fostering a healthier, more engaged nursing workforce. Ethics approval IR.MAZUMS.IMAMHOSPITAL.REC.1402.119

Oil and gas drilling is shifting to the deep sea — here’s what is at stake

Lipid-modifying pharmacotherapy in diabetes mellitus: A protocol for a systematic review and network meta-analysis of randomised trials

Introduction The global prevalence of diabetes mellitus (DM) has risen markedly, with patients facing a substantially higher risk of atherosclerotic cardiovascular disease (ASCVD) and related mortality. Although lipid-modifying agents, including statins, fibrates, cholesterol absorption inhibitors, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), bromodomain and extra-terminal motif inhibitors (BETi), and adenosine triphosphate-citrate lyase inhibitors (ACLi) continue to emerge, their comparative efficacy and safety in patients with DM remain uncertain. This study aims to address this gap through a comprehensive network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating cardiovascular outcomes, lipid-modifying efficacy, and safety among these therapies. Methods and analysis A systematic search will be performed in PubMed, Web of Science, Scopus, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase (via Ovid), International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov from inception, without language or regional restrictions. Eligible studies will include parallel-design RCTs comparing monotherapy or combination therapy. The primary outcome will be cardiovascular events (composite and individual), and secondary outcomes will include cardiac biomarkers, ASCVD risk scores, lipid parameters (TC, LDL-C, HDL-C, TG) and safety outcomes. Two reviewers will independently conduct study selection, data extraction, and quality assessment using the Cochrane Risk of Bias 2 (RoB 2.0) tool, with evidence certainty evaluated via the Confidence in Network Meta-Analysis (CINeMA) framework. Data will be standardized where appropriate, and analyses, including assessment of publication bias, will be conducted using Stata 18 and R. The protocol is registered with PROSPERO, and findings will be disseminated through peer-reviewed publication. Registration: PROSPERO CRD420251163974.

Safety profile of camrelizumab: An analysis based on literature and database review

Objective Real-world studies on the safety of camrelizumab are scarce. This study aimed to investigate the adverse drug reactions (ADRs) associated with camrelizumab and evaluate their clinical characteristics and management. Methods We retrieved data on ADRs related to the PD-1 inhibitor camrelizumab from the World Health Organization (WHO) adverse event reporting system database (VigiAccess) for the period from June,2019 to July 2025. Additionally, we conducted a retrospective analysis of case reports and case series on camrelizumab-related ADRs published from 2019 to 2025. Results 601 ADR reports were included in the VigiAccess database. Asian patients accounted for 99% (597/601), and the majority were male (69%). The most common classification of systemic organs (SOC) is hematological disorders (21.8%), skin reactions (14.3%), and systemic symptoms (8.8%). The main adverse reactions were: Hematological system: bone marrow suppression (10.3%), thrombocytopenia (5.1%); Skin: rash (5.7%), pruritus (4.3%), reactive capillary hyperplasia (RCCEP); systemic: fever (2.6%), chest pain (2.1%); serious events: myocarditis (1.2%), toxic epidermal necrolysis (TEN). Literature analysis included 80 patients (from China), with a median age of 60 years (range 20–84), and 72.5% were male. The main indications are non-small cell lung cancer (20%), nasopharyngeal carcinoma (20%) and hepatocellular carcinoma (11.3%). The median occurrence time of adverse reactions was 8 weeks (ranging from 10 minutes to 88 weeks). Typical ADRs include: cutaneous toxicity (45 cases, 56.3%); RCCEP (32 cases), Stevens-Johnson (SJS)/TEN (5 cases); hematological toxicity (38 cases, 47.5%): bone marrow suppression (22 cases), thrombocytopenia (16 cases); cardiotoxicity (13 cases, 16.25%), mainly myocarditis; Others: immune hepatitis (6 cases), thyroid dysfunction (5 cases). Conclusion The ADRs of camrelizumab are primarily hematologic and skin toxicities, with a need to be vigilant for late-onset serious events (e.g., myocarditis, TEN). Early identification and corticosteroid intervention are key management strategies.

Integrated experimental and computational characterization of bioactive metabolites from Streptomyces paradoxus GH53 with antimicrobial, antioxidant, and antitumor activities

Abstract Streptomyces species are widely recognized as valuable sources of secondary metabolites with diverse biological activities. In this study, the isolate GH53 was identified as Streptomyces paradoxus based on morphological characteristics and partial 16 S rRNA gene sequence analysis. Fermentation conditions were optimized to enhance metabolite production, and the crude ethyl acetate extract was chemically characterized using GC-MS, FT-IR, and UV-Vis spectroscopy. The analytical profile suggested the presence of a chemically complex mixture containing fatty acids, fatty acid derivatives, hydrocarbons, and terpenoid-related constituents. The IC₅₀ values of the crude extract were 0.175 ± 0.013 and 0.097 ± 0.006 mg/mL for the DPPH and ABTS radical scavenging assays, respectively. Because the calculated DPPH IC₅₀ value was slightly below the lowest tested concentration, it should be interpreted as a fitted estimate derived from the dose–response curve rather than as a directly measured concentration point. It also showed cytotoxic activity against HePG-2 and MCF-7 cell lines, with IC₅₀ values of 19.50 ± 1.5 and 28.81 ± 2.0 µg/mL, respectively. To provide a preliminary molecular interpretation of these extract-level bioactivities, selected representative metabolites tentatively identified by GC-MS were evaluated individually as defined ligands using molecular docking, molecular dynamics simulation, and ADMET prediction. The modeled compounds showed favorable predicted interactions with selected antimicrobial-, antioxidant-, and anticancer-related protein targets, and the corresponding protein–ligand complexes generally maintained stable interaction profiles during simulation. However, ADMET analysis indicated potential limitations for some high-molecular-weight lipophilic constituents, including poor drug-likeness, limited predicted solubility, and possible toxicity liabilities. Overall, these findings suggest that S. paradoxus GH53 represents a promising source of bioactive metabolites for future fractionation, purification, structural confirmation, and compound-level biological evaluation. The results should be interpreted as preliminary screening evidence and not as confirmation of therapeutic efficacy or direct systemic drug suitability.