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PubMed2026

Efficacy and Safety of Once-Weekly Semaglutide 2.0 mg as an Add-On to Dose-Reduced Insulin Glargine versus Dose-Titrated Insulin Glargine in People With Type 2 Diabetes and Overweight (SUSTAIN OPTIMIZE).

AIMS: Type 2 diabetes (T2D) management with basal insulin can lead to hypoglycaemia and weight gain. SUSTAIN OPTIMIZE compared once-weekly semaglutide 2.0 mg as add-on to dose-reduced insulin glargine (Sema+IGlarreduced) versus dose-titrated IGlar (IGlartitrated) on glycated haemoglobin (HbA1c), body weight (BW), daily insulin dose, and participant satisfaction. MATERIALS AND METHODS: SUSTAIN OPTIMIZE was a 40-week, phase 3b, open-label, randomised study. Adults with T2D, overweight (body mass index ≥ 25 kg/m2), and treatment with basal insulin ≤ 40 units/day were randomised 1:1 into Sema+IGlarreduced or IGlartitrated. The primary endpoint was change in HbA1c using a non-inferiority approach. Secondary endpoints assessed superiority of Sema+IGlarreduced versus IGlartitrated in reducing HbA1c, BW, daily insulin dose, and improving Diabetes Treatment Satisfaction Questionnaire change version (DTSQc) scores. RESULTS: Overall, 573 participants were randomised. Sema+IGlarreduced achieved both non-inferiority and superiority versus IGlartitrated in HbA1c reduction (estimated treatment difference [ETD]: -0.74%; 95% confidence interval [CI95]: -0.90, -0.59) and superiority in BW change (ETD: -8.5 kg; CI95: -9.5, -7.4), relative daily insulin dose change (ETD: -121.9%; CI95: -143.1, -100.6), and DTSQc scores (ETD: 2.6; CI95: 1.6, 3.5) (p < 0.0001 for all endpoints). No new safety concerns were identified. Severe hypoglycaemia was reduced (rate ratio: 0.45; CI95: 0.23, 0.87; p = 0.02), while gastrointestinal events were higher for Sema+IGlarreduced (310 vs. 32 events). CONCLUSIONS: Once-weekly subcutaneous semaglutide 2.0 mg as add-on to dose-reduced IGlar achieved superior reductions in HbA1c, BW, and daily insulin dose in people with T2D and overweight, while reducing their risk for severe hypoglycaemia compared to dose-titrated IGlar alone.

Adult↗

PubMed2026

The Association Between NT-Pro BNP, Nephropathy and Endothelial Dysfunction in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) is an established biomarker of heart failure and has been recommended for cardiovascular risk stratification in type 2 diabetes mellitus (T2DM). However, its relationship with diabetic nephropathy and endothelial dysfunction across varying stages of kidney impairment remains unclear. This study examined the associations of NT-Pro BNP, renal impairment, albuminuria and endothelial dysfunction in patients with T2DM without overt heart failure. METHODS: A comparative cross-sectional study was conducted among 192 adults with T2DM. Participants were stratified by KDIGO eGFR groups (≥ 90, 60-89, 30-59 mL/min/1.73m2). NT-Pro BNP was considered abnormal at a cut-off of ≥ 125 pg/mL. Albuminuria was categorized using the urinary albumin-to-creatinine ratio (uACR). Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD). Logistic regression analysis was performed to identify independent factors of elevated NT-Pro BNP, with p-values < 0.05 considered statistically significant. RESULTS: NT-Pro BNP levels were significantly higher in the lower eGFR groups compared with normal eGFR (204.3 vs. 96.8 vs. 62.2 pg/mL, p < 0001). A weak but significant positive correlation was observed between NT-Pro BNP and uACR (r = 0.31, p < 0.001). However, no significant association was found between NT-Pro BNP and FMD (p = 0.388). Following multivariable adjustments, older age (adjusted OR 1.14, 95% CI: 1.06-1.23, p < 0.001), higher systolic blood pressure (adjusted OR 1.05, 95% CI: 1.02-1.08, p = 0.010), lower eGFR (adjusted OR 0.97, 95% CI: 0.95-0.99, p = 0.003) and beta-blocker use (adjusted OR 4.65, 95% CI: 1.61-13.45, p < 0.001) were independently associated with elevated NT-Pro BNP. CONCLUSION: In patients with T2DM without overt heart failure, elevated NT-Pro BNP showed a statistically significant association with lower eGFR and higher albuminuria. Moderate to severe albuminuria becomes an independent factor for elevated NT-Pro BNP after adjustment excluding eGFR. The lack of association with endothelial dysfunction suggests that NT-Pro BNP may reflect different pathophysiological pathways. NT-Pro BNP may serve as a useful biomarker for early cardiovascular risk stratification and identification of individuals at risk of pre-heart failure in diabetic kidney disease.

NT‐Pro BNP↗

PubMed2026

Single-nucleus transcriptomics reveals cell type-specific remodeling and epilepsy-associated microglia.

Temporal lobe epilepsy (TLE) is the most common acquired epilepsy, causing refractory seizures and cognitive deficits. We performed single-nucleus RNA sequencing on hippocampal tissue from mice 3 and 6 weeks following pilocarpine-induced status epilepticus, a robust model of TLE. Epilepsy samples showed reductions in Cck and Lamp5-Lhx6 interneuron subclusters, alongside increases in Cajal-Retzius cells, dentate granule (DG) cell precursors, and a mature DG cell subcluster. Among glia, an astrocyte subcluster and a markedly expanded microglia sublcuster were increased. We term this microglia population epilepsy-associated microglia (EAM). The transcriptomic profile of EAM overlaps with microglia described in models of Alzheimer's disease and traumatic brain injury, including enrichment of Myo1e and Igf1. EAM display amoeboid morphology, can be found in clumps around pyramidal and granule cell body layers, and exhibit enlarged vesicles and mitochondria. Cell-cell interaction analysis predicts DG cells as their primary interaction partners. This dataset defines transcriptomic programs underlying key cellular alterations in TLE, enabling mechanistic dissection of epileptogenesis.

TLE↗

PubMed2026

Mitomycin C in the Endoscopic Treatment of Airway Stenosis: A Systematic Review and a Meta-Analysis.

OBJECTIVE: To assess the efficacy of adjuvant MMC in the endoscopic treatment of airway stenoses. DATA SOURCES: PubMed/MEDLINE, Cochrane Library, Scopus, Embase, and Google Scholar databases. REVIEW METHODS: A literature search was conducted following PRISMA guidelines. The PICOS tool was used to determine the eligibility criteria for this study. A single arm meta-analysis was performed for stenosis resolution, the rate of patients requiring multiple endoscopic procedures, and the rate of patients requiring other surgical treatments. RESULTS: A total number of 358 patients (median age: 48.0 years; 95% CI 44.8-50.8) were included. The median follow-up was 25.2 months (n = 244/358; 95% CI 15.4-38.3). Overall, the cumulative stenosis resolution rate was 76.37% (n = 187/254; 95% CI 59.72-89.64), the rate of patients requiring multiple endoscopic procedures was 52.33% (n = 131/260; 95% CI 32.03-72.25), and the rate of patients requiring other surgical treatments was 4.08% (n = 26/310; 95% CI 0.37-11.48). The median intervention-free interval was 366 days (n = 155/358; 95% CI 270-696). CONCLUSIONS: Current evidence does not allow definitive conclusions regarding the efficacy of adjuvant MMC in reducing recurrence or prolonging intervention-free intervals in airway stenosis. Further well-designed prospective studies are needed to clarify the role of MMC and to inform evidence-based guidelines for patient selection and treatment use. LEVEL OF EVIDENCE: NA.

Humans↗

PubMed2026

High-Dose Intravenous Vitamin C and Mortality and Organ Dysfunction in Severe Burn Injury: The VICTORY Randomized Clinical Trial.

IMPORTANCE: Severe burn injury triggers systemic inflammation that can lead to multiple organ dysfunctions and death. High-dose intravenous vitamin C has been proposed to mitigate these effects, but strong evidence in patients with burn injury is lacking. OBJECTIVE: To evaluate the efficacy of high-dose intravenous vitamin C in patients with severe burn injury. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled phase 3 trial conducted across 24 burn centers in North, Central, and South America; Europe; and Asia. Adults (≥18 years) with deep second- and/or third-degree burns covering 20% or more of total body surface area and requiring skin grafting were enrolled between August 18, 2020, and September 12, 2025. Final follow-up was completed in March 2026. The trial was stopped early after the first prespecified interim analysis for futility/harm. INTERVENTIONS: Patients were randomly assigned (1:1) to receive intravenous vitamin C (50 mg/kg every 6 hours for 96 hours) or matched placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of 28-day mortality and persistent organ dysfunction (defined as dependence on mechanical ventilation, kidney replacement therapy, or vasopressor/inotrope support at day 28). The main secondary outcome was time to discharge alive from hospital within 90 days. RESULTS: Among 238 patients enrolled (mean age, 48.9 [SD, 19.1] years; 79% male; mean total body surface area, 37.0% [SD, 14.6%]), 120 were assigned to vitamin C and 118 to placebo. The primary composite outcome occurred in 49 patients (40.8%) in the vitamin C group and 35 patients (29.7%) in the placebo group (adjusted risk ratio [RR], 1.28 [95% CI, 0.99-1.65]; P = .06), crossing the prespecified futility/harm threshold and prompting early trial termination. Time to discharge alive from hospital within 90 days was not improved (adjusted subdistribution hazard ratio, 0.85 [95% CI, 0.62-1.16]; P = .31). Twenty-eight-day mortality was higher in the vitamin C group (15.0% vs 7.6%; adjusted RR, 1.96 [95% CI, 1.32-2.90]; P = .001), as was hospital mortality (23.3% vs 16.1%; adjusted RR, 1.44 [95% CI, 1.03-2.00]; P = .03). CONCLUSIONS AND RELEVANCE: Among patients with severe burn injury, high-dose intravenous vitamin C did not reduce 28-day mortality and persistent organ dysfunction and is possibly harmful. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04138394.

Humans↗

PubMed2026

Magrolimab Plus Azacitidine Versus Placebo Plus Azacitidine in Patients With Untreated Higher-Risk Myelodysplastic Syndromes: The Phase III ENHANCE Study.

PURPOSE: To evaluate the efficacy and safety of the cluster of differentiation 47-targeted antibody magrolimab plus azacitidine (Magro/Aza) versus azacitidine alone in treatment-naïve patients with higher-risk myelodysplastic syndromes (MDS) in the phase III ENHANCE study (ClinicalTrials.gov identifier: NCT04313881). METHODS: Based on the Revised International Prognostic Scoring System, patients with intermediate- to very-high-risk MDS were randomly assigned to receive Magro (1 mg/kg on days [D]1 and 4; 15 mg/kg on D8; 30 mg/kg on D11 and D15, and then once per week for five doses, followed by 30 mg/kg maintenance doses once every 2 weeks)/Aza (75 mg/m2 daily on D1-7 or on D1-5 and 8-9 in 28-day cycles) or matched placebo plus azacitidine (Placebo/Aza). Dual primary end points were complete remission (CR) rate (per 2006 International Working Group criteria) and overall survival (OS). RESULTS: At final analysis, 539 patients were randomly assigned to Magro/Aza (n = 268) or Placebo/Aza (n = 271) arms. Baseline characteristics were generally well balanced between treatment arms. In the Magro/Aza versus Placebo/Aza arms, the CR rate was 21.3% versus 23.6% (odds ratio, 0.876 [95% CI, 0.585 to 1.312]; P = .5218), and median OS was 15.9 versus 18.6 months (hazard ratio, 1.203 [95% CI, 0.947 to 1.528]; P = .1299). Magro/Aza had a higher incidence of grade ≥3 adverse events (AEs; 92.8% v 79.2%), AE-associated study drug discontinuations (24.0% v 12.1%), serious AEs (71.9% v 51.5%), and fatal AEs (15.2% v 9.8%) versus Placebo/Aza. CONCLUSION: ENHANCE did not meet the primary end points of CR rate and OS, and showed more frequent severe AEs in patients treated in the Magro/Aza arm.

Humans↗

PubMed2026

Importin-8 silencing reduces Ataxin-3 aggregation and alleviates Machado-Joseph disease/spinocerebellar ataxia type 3.

Machado-Joseph disease (MJD) is a polyglutamine neurodegenerative disorder characterized by the formation of neuronal intranuclear Ataxin-3 inclusions. The nucleocytoplasmic transport is known to be profoundly dysregulated from early stages of neurodegeneration, further aggravating its progressive nature. To understand the contribution of these proteins in MJD, we screened the effect of 34 transport proteins on Ataxin-3 aggregation. Importin-8 (Ipo8 gene) was selected for further neuropathology and behavior analysis to evaluate its modulatory effect in vitro and in vivo. Our results showed that Ipo8 mRNA expression is increased in MJD and that, upon Ipo8 downregulation, Ataxin-3 aggregation and neuronal dysfunction are reduced in vitro and in vivo. Furthermore, Ipo8 silencing was demonstrated to alleviate ataxic traits in vivo. Collectively, our findings indicate that Importin-8 may exert its protective effect by modulating NF-kb/p65 and Argonaute-2 proteins, also previously linked to MJD, standing as a promising therapeutic target to delay disease progression.

Argonaute-2↗

PubMed2026

Vitamin D Deficiency During Pregnancy Is Associated With Greater LDL-C Increase, Elevated β-Hydroxybutyrate and Altered Neonatal Metabolic Markers-A Secondary, Pooled Analysis of the Randomized, Controlled Vitamin D and Lifestyle for Gestational Diabetes Prevention Trial (DALI).

INTRODUCTION: Vitamin D (vitD) plays a role in metabolic regulation, including lipid metabolism and insulin sensitivity. During pregnancy, profound physiological changes in lipid handling and ketogenesis occur to support fetal development. However, the extent to which maternal vitamin D status influences these metabolic adaptations and fetal metabolic markers remains unclear. METHODS: In this secondary analysis, we examined lipid distribution throughout pregnancy-from before 20 weeks' gestation to delivery-in women with overweight or obesity, stratified by vitamin D status (deficiency, insufficiency, or sufficiency), assessing both maternal and cord blood. Main inclusion criteria were: age > =18 years, singleton pregnancy, < 20 weeks' gestation, BMI ≥ 29 kg/m2. Women with GDM < 20 weeks' gestation were excluded. In total, 962 pregnant women were divided into vitD deficient (< 30 nmol/L, n = 102), insufficient (30-50 nmol/L, n = 222) and sufficient (> 50 nmol/L, n = 638) groups. VitD levels and lipid concentrations were assessed at < 20, 24-28 and 35-37 weeks' gestation and in cord blood. RESULTS: Compared with vitD sufficient women, women with vitD deficiency had significantly larger increases in LDL-C throughout pregnancy and ß-OH-butyrate at 24-28 weeks' gestation, in adjusted analysis. VitD in cord blood was highest in offspring of mothers with vitD sufficiency. In cord blood, significantly higher ß-OH-butyrate was observed with vitD deficiency; lipid concentrations were similar between groups. CONCLUSIONS: Early vitamin D deficiency before 20 weeks of gestation was associated with altered metabolic trajectories during pregnancy, including greater increases in LDL cholesterol and ketone body concentrations in women with overweight or obesity, as well as higher cord blood ketone levels in their offspring. These findings suggest that early maternal vitamin D status may influence maternal and fetal metabolic adaptations, although causal relationships and clinical implications require further investigation. TRIAL REGISTRATION: Trial registered at ISRCTN registry (https://doi.org/10.1186/ISRCTN70595832) trial number ISRCTN70595832. Registration date 02/12/2011.

Humans↗

PubMed2026

Glucocorticoid receptor antagonism in major depressive disorder with childhood trauma: a randomized controlled trial.

Childhood trauma (CT) is a key risk factor for major depressive disorder (MDD) onset and persistence. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may underlie this link, and preclinical studies suggest glucocorticoid receptor (GR) antagonism can reverse early life stress effects. This study tested whether the GR antagonist mifepristone reduces depressive symptoms in adults with MDD and CT. The RESET-medication study was a randomized, double-blind, placebo-controlled trial evaluating a 7-day course of mifepristone (1200 mg/day) or placebo in 158 adults with MDD and CT, assessed at baseline, 1 week, 6 weeks (primary endpoint), 3 months, and 6 months. The primary outcome was depressive symptom severity (IDS-SR) at week 6; secondary outcomes included symptom severity at other timepoints, clinical response, remission, anxiety, sleep, stress, disability, and salivary cortisol. At week 6, depressive symptoms declined in both groups, with no significant difference between mifepristone and placebo (b=-0.25, d=-0.03, 95% CI [-0.42, 0.36], pnom=0.887), and no group differences were found for secondary outcomes. Morning and evening cortisol were significantly higher with mifepristone at week 1, consistent with GR antagonism, but not at week 6. Adverse events were more frequent with mifepristone; mild and severe events occurred significantly more often, while the proportion reporting at least one adverse event was numerically higher but not statistically significant (93.6%vs. 82.5%, χ²(1)=3.60, p=0.058). Mifepristone produced the expected endocrine response but did not lead to clinical improvements in individuals with MDD and CT compared to placebo.

Humans↗

PubMed2026

Nutrikinetics and bioavailability of Promunel®, a standardized poplar-type propolis phenolic extract: a double-blinded, placebo-controlled, cross-over, randomized trial.

Brown poplar-type propolis has been recognized and used for centuries to help prevent upper respiratory tract infections (URTIs). However, the scarce, incomplete information in humans on the nutrikinetics and bioavailability of its phenolic constituents, combined with a lack of standardization in its phenolic content and profile pose major challenges to develop bioactive ingredients. Thus, the aim of this study was to establish the nutrikinetics and total bioavailability (NKBA) parameters of brown poplar-type propolis phenolics in humans using the Standardized Propolis Extract (SPE) Promunel®. To achieve this, a 48 h NBKA study was conducted following a double blinded, randomized, placebo-controlled, cross-over design in healthy humans (n = 10) with two doses of SPE (1X = 400 mg or 4X = 1600 mg). Phenolic compounds were detected, identified and quantified in the extract, plasma and urine through different LC-MS/UV technologies. The SPE used is a rich (304.44 ± 15.61 µmol mg-1) and diverse source of phenolic compounds (5 sub-families). A total of 63 and 85 phenolic metabolites were identified and quantified in plasma and urine, mostly in the form of glucuronides and sulfates. In plasma, phenolic metabolites reached Cmax (1.22 ± 0.20 for 1X and 4.80 ± 0.48 µM for 4X) after 1 h of SPE intake, while urinary excretion occurred mostly during the first 3 h after. The total net bioavailability of SPE phenolic compounds at 48 h was 57.16 ± 5.71% for 1X and 43.82 ± 6.77% for 4X. Generally, the data between SPE 1X and 4X were proportional, indicating that a higher dose does not substantially modulate total net bioavailability. Overall, our data shows that brown poplar-type SPE phenolic compounds are highly bioavailable in the form of cinnamic acid and flavonoid conjugates, and that these compounds are rapidly absorbed and eliminated through the urine. Our results suggest that, for a sustained presence in circulation, brown poplar-type propolis supplements should be consumed more than once a day.

Humans↗

PubMed2026

Sodium Glucose Co-Transporter 2 Inhibitors and Ventricular Arrhythmias in Patients with Type 2 Diabetes: A Systematic Review of Observational Studies.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2i) may exert antiarrhythmic effects, but their association with ventricular arrhythmias remains unclear. OBJECTIVE: We conducted a systematic review to evaluate the association between SGLT2i use and the risk of ventricular arrhythmias, cardiac arrest, and sudden cardiac death compared with other antidiabetic medications or no SGLT2i use among patients with type 2 diabetes mellitus. METHODS: MEDLINE, EMBASE, and CENTRAL were searched for observational studies published between March 2013 and March 2026. Quality was assessed using the Risk of Bias In Non-Randomized Studies of Interventions (ROBINS-I) tool, alongside evaluation of pharmacoepidemiology-specific biases. RESULTS: A total of 17 studies (16 cohort and one nested case-control) were included. Based on ROBINS-I, seven studies had moderate, eight serious, and two critical risks of bias. Eleven studies had at least one pharmacoepidemiology-specific bias. For ventricular arrhythmias, estimates ranged from a protective effect (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.04-0.97) to a potential increased risk (odds ratio 1.87, 95% CI 0.89-3.95) with SGLT2i use. For cardiac arrest, estimates consistently reported a lower risk with estimates that ranged from HR 0.63 (95% CI 0.59-0.68) to HR 0.85 (95% CI 0.82-0.88). The only study on sudden cardiac death reported a potential risk reduction (HR 0.62, 95% CI 0.38-1.01). CONCLUSIONS: While the association between SGLT2i and ventricular arrhythmias remains inconsistent, the use of SGLT2i likely reduces cardiac arrest and may reduce sudden cardiac death, suggesting a possible protective effect on ventricular arrhythmias among patients with type 2 diabetes.

Journal Article↗

PubMed2026

Intravesical mitomycin-C administered immediately before transurethral resection of bladder tumor in non-muscle-invasive bladder cancer: Clinical outcomes and molecular predictors from over 3 years of extended follow-up in a phase II trial.

PURPOSE: To evaluate the long-term outcomes and molecular correlates of response after immediate preoperative intravesical chemotherapy (IPeIC) with mitomycin-C (MMC) in patients with non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: In this single-center, open-label, randomized phase II trial, 33 patients received two split doses of IPeIC/MMC (40 mg/20 mL), whereas 38 patients underwent transurethral resection of bladder tumor (TURBT) alone. The primary endpoint was 3-year recurrence-free survival (RFS), and secondary endpoints included progression-free survival (PFS). Exploratory RNA sequencing was performed on IPeIC-treated patients (three with recurrence, 25 without) using a Monte Carlo-based resampling strategy. RESULTS: The median follow-up durations were comparable between the intervention (60.0 months) and control arms (60.4 months). IPeIC/MMC reduced recurrence risk by 76.8% versus TURBT alone (p=0.024), yielding a 3-year RFS rate of 90.7% versus 78.6%. On multivariable analysis, IPeIC/MMC independently improved RFS (hazard ratio [HR] 0.266, p=0.044). IPeIC was associated with superior PFS, with 3-year and 5-year rates of 100% versus 92.1% and 85.8%, respectively, in the controls (HR 0.078, p=0.014). Exploratory transcriptomics identified low Glutathione S-transferase Mu 1 (GSTM1) expression as the factor most strongly associated with recurrence. CONCLUSIONS: IPeIC/MMC is associated with improved long-term oncological outcomes compared with TURBT alone and represents a safe prophylactic option for patients with NMIBC who are unable to receive standard immediate postoperative intravesical chemotherapy because of safety concerns or practical constraints. The GSTM1 findings are hypothesis-generating and support future biomarker-driven validation studies.

Aged↗

PubMed2026

Beyond Glycaemia: Fear of Hypoglycaemia, Cognition and Functional Mobility After Advanced Hybrid Closed-Loop Therapy in Older Adults With Type 1 Diabetes: A Prespecified Secondary Analysis of a Randomised, Single-Centre Study.

BACKGROUND: Evidence on psychological, cognitive and functional outcomes of advanced diabetes technologies in older adults with long-standing type 1 diabetes (T1D) remains limited. We evaluated whether initiation of advanced hybrid closed-loop (AHCL) therapy was associated with changes in fear of hypoglycaemia, diabetes distress, psychological well-being, cognition, frailty-related measures and mobility-related function in adults aged ≥ 65 years with T1D. METHODS: This prespecified, exploratory secondary analysis was conducted within a single-centre, open-label, randomised, controlled, parallel-group trial including adults aged ≥ 65 years with long-standing T1D. Participants were randomly assigned (1:1) to initiate AHCL therapy using the MiniMed 780G system or to continue standard diabetes treatment. The secondary outcomes included WHO-5, the 17-item Diabetes Distress Scale (DDS), Hypoglycemia Fear Survey-II (HFS-II), Montreal Cognitive Assessment, Digit Symbol Substitution Test, Fried frailty phenotype and performance-based functional measures. No formal sample-size calculation was performed for these secondary outcomes. RESULTS: Thirty-one participants were randomised and 29 completed 12 months of follow-up and were included in the treatment-effect analyses. In the baseline-adjusted primary analysis, AHCL therapy was associated with a lower HFS-II score than standard treatment (adjusted mean difference -18.9; 95% CI: -32.4 to -5.4; nominal p = 0.008), although this finding did not remain statistically significant after Holm correction (adjusted p = 0.104) or in an exploratory model additionally adjusted for sex (difference -13.6; 95% CI: -32.2 to 5.0; p = 0.145). Diabetes distress, psychological well-being, global cognition and processing speed did not differ between groups. In sex-adjusted sensitivity analyses, the between-group differences remained statistically significant for 6-min walk distance (92.6 m; 95% CI: 36.8 to 148.3; p = 0.002) and Timed Up and Go performance (-2.27 s; 95% CI: -4.28 to -0.27; p = 0.028), but not for gait speed (0.27 m/s; 95% CI: -0.05 to 0.59; p = 0.099). At 12 months, 12 of 14 AHCL participants were robust and 2 were pre-frail; in the control group, 11 of 15 were robust and 4 were pre-frail. No participant was classified as frail at follow-up. CONCLUSIONS: In this small, selected cohort, AHCL therapy was associated with a nominally lower fear-of-hypoglycaemia score and better performance on selected mobility-related tests over 12 months. The fear-of-hypoglycaemia finding did not remain statistically significant after correction for multiple comparisons or additional adjustment for sex. Six-minute walk distance and Timed Up and Go remained statistically significant in the exploratory sex-adjusted sensitivity analyses, whereas the gait-speed difference did not. No measurable between-group deterioration in global cognition or processing speed was observed. These exploratory findings require confirmation in larger studies with balanced representation by sex and direct measurement of physical activity. These findings also support a person-centred clinical message: older age alone should not be regarded as a barrier to AHCL when treatment is introduced with individualised education and appropriate ongoing support.

Humans↗

PubMed2026

Primary pulmonary salivary gland-type tumors in cytopathology practice: A systematic review and meta-analysis.

BACKGROUND: Primary pulmonary salivary gland-type tumors (PSGTs) are rare but clinically significant tumors that originate from the submucosal glands of the tracheobronchial tree. Cytologic samples taken during bronchoscopy are a key component of preoperative evaluation. However, cytologic diagnosis remains challenging because of the submucosal growth and morphologic overlap of PSGTs. In addition, current knowledge of the cytohistologic correlation of PSGTs is fragmented. The objective of this study was to assess the effectiveness of cytologic diagnoses of PSGTs. METHODS: A comprehensive, systematic literature search of the PubMed database was conducted to identify studies with cytologic and histologic diagnoses of PSGTs. Comprehensive data on diagnostic and clinical factors, when available, were collected for all individual patients. The data were tabulated in Microsoft Excel and analyzed using OpenMeta (Analyst) software. RESULTS: In total, 49 studies comprising 106 patients were identified. Final cytohistologic concordance was demonstrated in 48.1% of cases. Fine-needle aspiration showed the highest sensitivity (75.0%), followed by bronchial/tracheal washing (38.1%), and bronchial brushing (34.2%). Adenoid cystic carcinoma was the most common histologic subtype, accounting for 67 cases, followed by mucoepidermoid carcinoma, which accounted for 27 cases. CONCLUSIONS: The cytologic diagnosis of rare PSGTs remains challenging. Overall, cytohistologic concordance was 48.1%. However, fine-needle aspiration demonstrated greater diagnostic accuracy than exfoliative cytology and may facilitate a more accurate preoperative assessment.

Humans↗

PubMed2026

Vertical distribution of accessory canals in different tooth types: A systematic review and meta-analysis.

OBJECTIVE: To systematically analyze the vertical distribution of accessory canals and propose potential root-end resection levels in different tooth types. DATA: Proportional distribution of accessory canals (PD-AC) in 1 mm intervals, cumulative proportions within 2 mm and 3 mm (CP-AC0-2 and CP-AC0-3), mean distance from accessory foramen to root apex or main foramen (MD-AF), and prevalence of accessory canals in 2D cross-sections (PR-AC-2D). SOURCES: A systematic search of electronic databases was conducted through December 25, 2025. The review was registered in PROSPERO (CRD420251107855). STUDY SELECTION: Two reviewers independently performed study selection, data extraction, and risk of bias assessment using the AQUA tool. Nineteen studies were included for qualitative synthesis, of which eleven provided sufficient data for meta-analysis. A random-effects model was used, and subgroup analyses were stratified by tooth type, accessory canal type, and country. Within 0-1 mm, 1-2 mm, 2-3 mm, and 3-4 mm from the apex, 41.5%, 34.3%, 9.9%, and 4.4% of accessory canals were located, respectively. Molars had significantly higher proportions than anterior teeth both within 2 mm (90.0% vs. 72.4%) and 3 mm (96.9% vs. 87.5%). Of apical ramifications, 86.4% were within 2 mm. The pooled MD-AF was 1.472 mm. PR-AC-2D decreased from 29.3% at 1 mm to 1.3% at 5 mm. All studies presented moderate to high risk of bias. CONCLUSIONS: A 2 mm root-end resection level may be sufficient for molars, whereas anterior teeth may require a higher level. Further randomized controlled trials are needed. CLINICAL SIGNIFICANCE: A 2 mm resection may adequately expose or remove most accessory canals in molars, potentially preserving more root length while maintaining treatment efficacy. In anterior teeth, a traditional 3 mm resection remains advisable until further evidence becomes available.

Humans↗

PubMed2026

Long-term safety of oral orforglipron in Japanese participants with type 2 diabetes (ACHIEVE-J): a multicentre, randomised, open-label, parallel-group phase 3 trial.

BACKGROUND: Orforglipron, an oral GLP-1 receptor agonist, requires further evaluation in east Asian populations with type 2 diabetes, given this group's distinct pathophysiological characteristics. This study aimed to assess orforglipron as add-on treatment to diet and exercise alone or to oral antihyperglycaemic medications in Japanese participants with type 2 diabetes. METHODS: This multicentre, randomised, open-label phase 3 study was conducted in 40 medical research centres and hospitals in Japan. Adults with type 2 diabetes and elevated glucose levels managing their condition with diet and exercise alone or with one or two oral antihyperglycaemic medications were assigned (1:1:1) via computer-generated random sequence to receive once-daily oral orforglipron (3 mg, 12 mg, or 36 mg). Randomisation was stratified by background therapy, baseline HbA1c (≤8·5% or >8·5%), and metformin use (yes vs no; applied only to α-glucosidase inhibitors, thiazolidinedione, and glinides). Investigators, participants, and site staff were not masked to treatment. The primary endpoint was safety for 52 weeks, assessed in all randomly assigned participants who received at least one dose of orforglipron. This study is registered with ClinicalTrials.gov, NCT06010004 (ACHIEVE-J). FINDINGS: Between Sept 28, 2023, and June 5, 2025, 450 participants were screened and 401 were randomly assigned to three groups (3 mg, n=132; 12 mg, n=135; and 36 mg, n=134). 352 (88%) completed study treatment. 339 participants (85%, 95% CI 80·7-87·8) had at least one treatment-emergent adverse event (TEAE), more frequently in the 36-mg group (118 [88%, 95% CI 81·5-92·5]) than in the 3-mg (107 [81%, 73·5-86·8]) and 12-mg (114 [84%, 77·4-89·6]) groups. Most TEAEs were of mild (267 [67%, 61·8-71·0]) or moderate (63 [16%, 12·5-19·6]) severity. Discontinuations due to an adverse event occurred in 19 of 134 participants (14%, 95% CI 9·3-21·1) in the 36-mg group compared with seven of 132 (5%, 2·6-10·5) in the 3-mg group and 11 of 135 (8%, 4·6-14·0) in the 12-mg group. Across treatment groups, gastrointestinal symptoms were the most common TEAEs leading to study treatment discontinuation (3 mg: 5 [3·8%, 1·6-8·6]; 12 mg: 8 [5·9%, 3·0-11·3]; and 36 mg: 11 [8·2%, 4·7-14·1]). Level 2 (blood glucose <54 mg/dL) hypoglycaemia events occurred in three of 135 participants in the 12-mg group (2%, 0·8-6·3) and in three of 134 in the 36-mg group (2%, 0·8-6·4) groups. No level 3 (severe) hypoglycaemia events occurred. Outcomes were generally similar across background therapies. INTERPRETATION: Treatment with orforglipron in combination with diet and exercise alone or one or two oral antihyperglycaemic medications for 52 weeks demonstrated an acceptable safety profile in Japanese adults with type 2 diabetes. FUNDING: Eli Lilly. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Aged↗

PubMed2026

Safety and outcomes of dapagliflozin initiation in critically ill patients with acute kidney injury: A post-hoc analysis of the defender trial.

BACKGROUND: SGLT2 inhibitor use in acute kidney injury (AKI) is controversial due to concerns about hemodynamic instability. We evaluated dapagliflozin initiation in critically ill patients with AKI enrolled in the DEFENDER trial. METHODS: Among 212 patients with AKI at enrollment (100 dapagliflozin, 112 control), we compared 28-day mortality, kidney replacement therapy (KRT), and composite death/KRT. Adjusted risk differences were estimated controlling for age, sepsis, baseline vasopressor use, and creatinine. Physiological trajectories (creatinine, urine output, fluid balance, acid-base parameters) over days 1-5 were analyzed using mixed models. Likelihood ratios quantified compatibility with clinically meaningful harm or benefit. RESULTS: Event rates were similar: 28-day mortality 38% vs 40%, KRT 12% vs 18%, composite 41% vs 42% (dapagliflozin vs control). Adjusted risk differences were - 1.9% (95% CI -14.5 to 10.7) for death, -7.4% (-16.2 to 1.5) for KRT, and - 0.9% (-13.6 to 11.8) for the composite. Physiological trajectories showed no divergence suggestive of hemodynamic or metabolic instability. Likelihood ratios provided limited separation: at 5% absolute effect threshold, LR against harm was 1.47 and against benefit 1.19. CONCLUSIONS: Dapagliflozin initiation in critically ill patients with AKI was not associated with excess mortality, KRT, or physiological derangement. The near-neutral evidential profile indicates neither moderate harm nor benefit can be excluded, supporting feasibility of dedicated trials of SGLT2 inhibitors in AKI.

Humans↗

PubMed2026

The neuroendoscopic factors affecting outcome of endoscopic third ventriculostomy in pediatric patients with post infectious hydrocephalus.

BACKGROUND: The role of endoscopic third ventriculostomy(ETV) in infective hydrocephalus remains uncertain. Infection alters cerebrospinal-fluid composition, flow-dynamics, absorptive capacity, undermining the effectiveness of ETV. AIMS AND OBJECTIVES: This study aims to describe the intraventricular morphological findings and its correlation with ETV outcomes in a cohort of paediatric infective hydrocephalus. METHODOLOGY: Total 98 cases of infective HCP underwent ETV, were studied for intraventricular findings. Thin transparent third ventricular floor were considered as type-1, transluscent as type-2, floor with granuloma as type-3 and unidentifiable anatomy as type-4. Infective deposits were sent for histopathology. RESULT: Overall ETV was successful in 46 patients (46.93%). Success rate of ETV in type 1 (72.7%) was better than type-2 (50%) and type-3 (33.3%). The difference between type-1 and type-3 was statistically significant, p = 0.01. The success rate in presence of pre-pontine adhesions (46 cases) was 34.7%, significantly lower than the 66.6% observed in their absence (p = 0.005). ETV was not successful in all the 7 cases withy type-4 floor. Tissue biopsy confirmed microbiological diagnosis in 13 cases and helped in modifying pharmacological treatment as per culture (two with tuberculosis and three with fungal infection). CONCLUSION: ETV offers a meaningful therapeutic option in post-infectious HCP. Endoscopic appearance of the third ventricular floor and the pre-pontine space may predict its outcome. A thin, transparent floor in the absence of cisternal adhesions is associated with best outcomes, while progressive floor thickening, granuloma formation, and pre pontine fibrosis each correlate with declining success rates. The culture from exudates often helps in achieving organism oriented pharmaco-therapy that improves ETV success rate.

Humans↗