Radioresistance is a main reason for treatment failure in patients with small cell lung cancer (SCLC). Consequently, it is important to determine the key mechanism and explore effective strategies to prevent SCLC radioresistance. We use an unbiased CRISPR screen to identify GSDME, a member of the Gasdermin (GSDM) family, as a critical driver of radiosensitivity in SCLC. Furthermore, we identify mTORC2 facilitates SCLC radioresistance by inhibiting GSDME-N-mediated pyroptosis. Mechanistically, mTORC2 phosphorylates GSDME-N at serine 114 (S114), promoting the recruitment of the CUL4B-RBBP4 E3 ubiquitin ligase complex. This complex mediates K48-linked ubiquitination of GSDME-N at lysine 41 (K41), leading to its proteasomal degradation. Clinically, elevated mTORC2 is linked to an unfavorable prognosis in SCLC patients. The study reveals mTORC2 phosphorylates GSDME-N and promotes its Cullin4B-mediated proteasomal degradation to suppress pyroptosis and drive radioresistance in SCLC.

Dietary fiber plays a central role in pediatric gastrointestinal health; however, most children worldwide consume amounts well below recommended levels. Current pediatric guidelines from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (2014) and global nutrition guidance from the World Health Organization recommend adequate dietary fiber intake as part of a balanced diet to support digestive health and prevent noncommunicable diseases. These recommendations generally correspond to daily fiber intake levels of approximately 14-31 g/day, or the practical rule of age (years) + 5 g/day for children, yet more than 80%-90% of children fail to meet these targets. This shortfall is clinically significant, as inadequate fiber intake is associated with increased risk of functional constipation, a condition affecting approximately 3%-29% of children globally. Dietary fiber contributes not only to stool bulk but also to the modulation of gut microbiota, gastrointestinal barrier function, and immune and metabolic pathways during critical developmental stages. Among common pediatric gastrointestinal disorders, the strongest evidence supports fiber use in constipation management, where supplementation or increased intake through whole foods has been shown to improve stool frequency and consistency in approximately 50%-60% of affected children. However, clinical trial outcomes remain inconsistent, varying according to fiber type, dosage, duration of intervention, and diagnostic criteria. Evidence for recurrent or functional abdominal pain remains limited and heterogeneous, with small sample sizes, differing endpoints, and high placebo response rates complicating interpretation. In pediatric inflammatory bowel disease, fermentable fibers have been shown to enhance short-chain fatty acid production. Nevertheless, robust pediatric clinical evidence remains insufficient, and findings from adult ulcerative colitis studies cannot be directly extrapolated to children. Dietary fiber represents an important supportive component of pediatric gastrointestinal management, but standardized dosing recommendations and high-quality pediatric clinical trials are still needed to establish evidence-based guidelines for clinical practice.

Background: Evidence supports the effectiveness and safety of open-source automated insulin delivery (AID) in patients with type 1 diabetes. However, evidence regarding the clinical application of open-source AID in perioperative patients with type 2 diabetes remains limited. Methods: This was an open-label, single-center, exploratory pilot randomized controlled trial (RCT) with parallel groups. Patients with diabetes (excluding type 1 diabetes mellitus) scheduled for elective surgery were randomly assigned to the closed-loop group (open-source hybrid closed-loop AID system) or the control group (conventional insulin pump). The primary outcome was the percentage of time in the target glucose range (TIR, 3.9-10.0 mmol/L). Other efficacy and safety outcomes were also compared between the groups. Results: A total of 49 participants were included and randomized to the closed-loop group (n = 25) or the control group (n = 24). Participants underwent abdominal, orthopedic, thoracic surgery, or neurosurgery during hospitalization. Patients in the closed-loop group had significantly higher TIR than patients in the control group (76.4 ± 14.1% vs. 61.2 ± 20.0%, p = 0.005). Compared with the control group, the closed-loop group also exhibited a 15.6 percentage point reduction in time above range (TAR, >10 mmol/L) without increasing time below range (TBR, <3.9 mmol/L). There were no episodes of severe hypoglycemia (<2.2 mmol/L) or diabetic ketoacidosis in either group. Conclusions: This study demonstrates that in patients with diabetes undergoing elective surgery, the open-source hybrid closed-loop AID system provides better glycemic control than conventional insulin pump therapy.

Asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF) are major non-communicable respiratory diseases (NCD-RDs) with high morbidity and mortality. Despite distinct clinical features, they share overlapping mechanisms including oxidative stress, epithelial injury, and immune dysregulation. Asthma is mainly driven by type 2 inflammation, with IL-4, IL-5, and IL-13 inducing eosinophilia, IgE production, mucus hypersecretion, and airway remodeling. Biologics targeting IgE, IL-5, and IL-4Rα have transformed treatment, and agents directed against TSLP and IL-33 further extend the range of targeted interventions. In contrast, COPD involves chronic inflammation with macrophages, neutrophils, and CD8+ T cells, persisting after smoking cessation. Advances include biologics such as dupilumab and benralizumab in eosinophilic COPD, and novel inhaled therapies such as ensifentrine, the first dual PDE3/4 inhibitor delivered via inhalation. IPF, on the other hand, arises from defective epithelial repair and fibroblast activation, causing progressive fibrosis. Approved antifibrotics (nintedanib, pirfenidone) slow lung function decline, while new strategies target TGF-β, CTGF, and fibroblast-directed pathways. Across these diseases, biomarkers and the treatable traits framework are reshaping precision care. Personalized approaches integrating biomarkers, omics, and targeted therapies represent the most promising path for improved outcomes.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are emerging as promising therapies for cardiovascular-kidney-metabolic (CKM) related diseases in individuals with type 2 diabetes mellitus (T2DM) or obesity. But their effects in non-obese and non-diabetic individuals are unclear. This study triangulates evidence using Mendelian randomization (MR), polygenic scores (PGS) and observational analyses to estimate the associations of GLP-1R expression with chronic kidney disease (CKD), heart failure (HF) and metabolic dysfunction-associated steatotic liver disease (MASLD).

For the MR analysis, instruments mimicking GLP-1R expression were identified using pancreas-specific cis-expression quantitative trait loci from GTEx (N ≤ 305). MR-Robust method was used as the primary MR approach. PGS and observational analyses were performed both in non-diabetic and non-obese individuals separately. A genome-wide association study (GWAS) for MASLD (14,231 cases and 348,091 controls) was performed in the general population using data from UK Biobank.

GLP-1R expression showed robust effects on CKD (odds ratio [OR] 0.96, 95%CI 0.95 to 0.97, q = 1.7 × 10^- 10 ), HF (OR = 0.96, 95%CI 0.94 to 0.97, q = 2.5 × 10^- 8) and MASLD (OR = 0.96, 95%CI 0.93 to 0.98, q = 1.3 × 10^- 3) in the general population. Consistent results were observed in validation analyses. Furthermore, PGS and observational analyses among non-T2DM and non-obese individuals found little evidence to support its association with CKD, HF or MASLD. GWAS analysis identified eight conditionally independent variants associated with MASLD, in which rs563199662 was a new signal located at TFPI region.

This study provides multilayered evidence for GLP-1R expression in mitigating CKD, HF and MASLD risks in the general population, while de-prioritized its effect on CKM-related diseases in non-obese and non-diabetic individuals. Further clinical trials are needed to validate the effects of GLP-1R agonists in relative health population.

Diabetic wounds are among the most common complications in patients with diabetes, often occurring in the lower extremities and manifesting as diabetic foot ulcers. These wounds are often associated with issues such as infection, peripheral artery disease, hyperglycemia, and hypoxia, making them difficult to heal and prone to becoming chronic wounds. MNs enable painless, controlled transdermal drug delivery, overcoming limitations of traditional methods such as poor permeability and short drug duration. Stimuli-responsive microneedles targeting specific triggers have developed rapidly in recent years and are expected to contribute to the realization of precision medicine. Diabetic wounds are often accompanied by microenvironmental imbalance, and this complex wound milieu frequently causes them to progress into refractory wounds. Stimuli-responsive microneedles therefore represent a promising therapeutic strategy. Current studies in this field are still mainly limited to single-stimulus-responsive microneedles, whereas multifunctional microneedles capable of responding to multiple stimuli have not yet been fully developed. This review summarizes the research foundation and current progress of stimuli-responsive microneedles for the treatment of diabetic wounds, and further discusses the future prospects and potential directions of multi-stimuli-responsive microneedles. In addition, this review clarifies the conceptual boundary between truly stimuli-responsive microneedles and microenvironment-associated therapeutic platforms, compares major responsive strategies and microneedle platforms, and discusses key translational barriers including mechanical robustness, manufacturing scalability, cargo stability, model relevance, and regulatory considerations.

Patients with type 2 diabetes mellitus (T2DM) are at an increased risk of masked hypertension (normal office blood pressure with increased out-of-office readings) and its cardiovascular complications. However, data from Africa remain scarce.

To describe the occurrence of masked hypertension and its associated factors among Black patients with T2DM.

Patients with T2DM diagnosed for at least 1 year, with office SBP less than 140 mmHg and DBP less than 90 mmHg and not under antihypertensive treatment were consecutively selected from primary healthcare and outpatient clinics, in Maputo and Matola cities in Mozambique. All participants underwent both office and 24-h ambulatory blood pressure (ABPM) measurements. Aortic stiffness was assessed using pulse wave velocity (PWV).

The prevalence of 24-h masked hypertension (95% confidence interval) was 53% (42.8-63.1), being 50% (39.8-60.2) for daytime and 63% (52.8-72.4) for nighttime masked hypertension. The prevalence reached 73% among those with an office SBP greater than 130 mmHg [age-adjusted odds ratio (OR) vs. <120 mmHg = 3.40, P = 0.041] and 82% among those with PWV > 12 m/s (age-adjusted OR vs. <10 m/s = 6.90, P = 0.003).

Over half of Black patients with T2DM and normal office blood pressure had masked hypertension, which was significantly associated with high office SBP values and increased arterial stiffness. These findings highlight the elevated risk of masked hypertension among Black patients with T2DM and the importance of identifying high-risk individuals for ABPM, particularly in resource-limited settings.

Although observational research shows that physical activity and sedentary behavior are associated with the risk of gestational diabetes mellitus (GDM), lipid, and body mass index (BMI), their causal direction and potential mediating mechanism are still unclear, which limits the development of precise prevention strategies. Based on the genetic data on the European ancestry population, the study aimed to investigate the causal relationship of GDM with physical activity and sedentary behavior using Mendelian randomization (MR), and quantify the mediating roles of BMI and lipids in it. The bidirectional dual sample MR analysis based on whole genome association research data revealed that there was a significant negative causal association between physical activity time and the risk of GDM in females (OR = 0.977, 95% CI: 0.956-0.998, P = 0.030), while leisure screen time had a positive causal association with the risk of developing GDM (OR = 1.125, 95% CI: 1.023-1.238, P = 0.015). Mediation analysis indicated that BMI was the primary causal pathway for reducing the risk of GDM through physical activity time, with a mediation ratio of 53.6%. Multivariate MR analysis showed that after adjusting for BMI, the direct effect was no longer significant, indicating that BMI played a major and almost complete mediating role. In the causal pathway of increased GDM risk in leisure screen time, BMI, high-density lipoprotein cholesterol (HDL-C), and Apolipoprotein A1 (ApoA1) effectively mediated the causal relationship between leisure screen time and GDM risk, with mediation proportions of 81.8%, 11.2% and 10.1%, respectively. Physical activity can indirectly reduce the risk of GDM by lowering BMI, while excessive leisure screen time significantly increases the risk of GDM by affecting BMI, HDL-C, and ApoA1. These findings support the potential value of prioritizing weight control and integrating interventions that increase physical activity and limit sedentary behavior as core measures, in order to fundamentally block the pathway of GDM by synergistically optimizing weight and lipid metabolism.

Introduction: Diabetic ketoacidosis (DKA) is a common complication of diabetes mellitus characterized by metabolic acidosis, ketogenesis, hypovolemia, hyperglycemia, and electrolyte depletion. During treatment of DKA with intravenous fluids and insulin, some electrolyte disturbances can worsen. Hypophosphatemia is one such electrolyte disturbance that has not been well characterized in patients with severe DKA requiring Intensive Care Unit (ICU) admissions. This study sought to evaluate the incidence, severity, associations, and outcomes of hypophosphatemia in DKA. Methods: This retrospective multicenter study was conducted across DKA admissions to Queensland ICUs from 2016 to 2021. Adult patients (>18 years) requiring ICU admission for management of DKA were included in this study. Patients with DKA were stratified by lowest recorded phosphate level as: normal ≥ 0.80 mmol/L, mild 0.50-0.79 mmol/L, moderate 0.30-0.49 mmol/L and severe < 0.3 mmol/L. Patient demographics, comorbidities, ICU-related supports, and medications (including fluid, insulin administration, phosphate, and other electrolyte replacement) were collected. Univariate analysis was performed between hypophosphatemia severity and normophosphatemia subgroups to determine risk factors, outcomes, replacement, and progression of hypophosphatemia in the ICU. Phosphate replacement and administered insulin was compared to nadir serum phosphate level. Multivariate analysis and linear regression were performed to identify risk factors for the development of hypophosphatemia. Results: A total of 842 admissions of 669 unique patients due to DKA were included; 436 of 842 (51.8%) admissions maintained normophosphatemia in the ICU, while 220 (26.1%, n = 220/842) had mild hypophosphatemia, 124 (14.7%, n = 124/842) had moderate hypophosphatemia and 62 (7.4%, n = 62/842) had severe hypophosphatemia. Patients with higher BMI, higher APACHE II/III score, cerebrovascular disease and all blood gas parameters (excluding PaO₂) were found to have more severe hypophosphatemia. Lower serum phosphate was associated with greater replacement and greater insulin administration per kilogram body weight. ICU length of stay, hospital length of stay and mortality were not affected by degree of hypophosphatemia (p > 0.05). Linear regression revealed that standard base excess was strongly associated with the development of hypophosphatemia (β = 0.02, 95% CI 0.01-0.02, p < 0.001). Conclusions: Increasing severity of hypophosphatemia was associated with increasing severity of DKA. Increased ICU length of stay was related to increased severity of hypophosphatemia.

Ischemia-reperfusion injury (IRI) contributes to graft dysfunction in solid organ transplantation, with the pancreas vulnerable due to its fragile vasculature. Endothelial glycocalyx (eGCX) disruption is central to this process. This study prospectively examined perioperative endothelial injury in pancreas transplantation.

Fifty-two recipients were included, of whom 47 underwent simultaneous pancreas-kidney (SPK) transplantation and 5 pancreas retransplantation. Biomarkers of eGCX degradation (syndecan-1, heparan sulfate (HS) and hyaluronan) and endothelial injury (soluble thrombomodulin, VEGF and soluble VEGFR1) were measured in plasma preoperatively, 10 min after pancreas reperfusion, 24 h later, and at discharge. Associations with donor type and early post-transplant outcomes were explored.

A marker endothelial injury was evident within 10 min of pancreas reperfusion, before kidney implantation, characterized by increased syndecan-1, HS, and sVEGFR1, together with decreased VEGF. Hyaluronan peaked at 24 h, consistent with a broader systemic endothelial response. Controlled donation after circulatory death donors showed higher syndecan-1 levels at 10 min PR and higher VEGF at 24 h. Seven recipients developed pancreas graft loss, which was linked to lower VEGF at 10 min post-reperfusion and lower hyaluronan levels both before surgery and at discharge. Kidney acute tubular necrosis was related with higher preoperative HS and elevated 24 h sVEGFR1. Among recipients with functioning grafts, preoperative endothelial biomarkers were linked to postoperative complications.

Pancreas transplantation triggers early endothelial injury and glycocalyx shedding, particularly in a predominant SPK setting. Perioperative endothelial biomarkers may have a value for early risk stratification after transplantation.