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PubMed2026

Acute mild cold exposure with shivering reduces 24 h glucose levels in individuals with type 2 diabetes but not prediabetes.

AIMS/HYPOTHESIS: Repeated cold exposure with shivering has been proposed as a potential strategy to enhance glucose metabolism by increasing energy expenditure and substrate utilisation. However, acute effects/benefits of cold-induced shivering on glucose homeostasis in metabolically compromised individuals are unknown. Here, we aimed to determine whether cold exposure at two different intensities improves 24 h glucose homeostasis in individuals with prediabetes and type 2 diabetes. METHODS: In a randomised crossover trial conducted in the South Limburg/Maastricht region of the Netherlands, men and postmenopausal women with prediabetes (n=12) and stable type 2 diabetes (n=12), aged 40-75 years, body mass index ≥27 and ≤35 kg/m2, non-smoking and sedentary, underwent two whole-body cold exposure sessions using a water-perfused suit. Session order was randomised using an online randomisation tool (randomizer.org); participants were masked to the cold exposure intensity received, but investigators were not. Sessions were designed to elicit ~1.5-fold (mild, 15°C) and ~2.5-fold (moderate, 4°C) increases in resting metabolic rate (RMR). Continuous glucose monitoring assessed interstitial glucose concentrations over 24 h periods before and after each intervention, with controlled diet and activity. Shivering was confirmed via indirect calorimetry and electromyography. RESULTS: In both study groups and periods, RMR increased significantly vs baseline (p<0.001 for all). In prediabetes, the increase in the final 1 h of cold was 1.53 × RMR in mild and 1.94 × RMR in moderate cold. In type 2 diabetes, the increase was 1.57 × RMR and 2.09 × RMR in the final 1 h of mild and moderate cold, respectively. In prediabetes, neither mild nor moderate cold exposure altered mean 24 h glucose levels. In contrast, after mild cold exposure the type 2 diabetes group exhibited a significant reduction in mean 24 h glucose levels (-0.6 ± 0.5 mmol/l, p=0.003) and fasting glucose (-0.6 ± 0.8 mmol/l, p=0.019), as well as an increase in time in normal range (+8.8 ± 10.3%, p=0.013) and reduced time in hyperglycaemia (-10.9 ± 12.9%, p=0.014). Moderate cold did not significantly affect any of the glucose outcomes in type 2 diabetes. Baseline fasting glucose, age and ALT levels were predictors of the glucose-lowering response, suggesting greater benefits in individuals who have higher baseline glucose levels, are younger and/or have more optimal liver health, i.e. lower ALT. CONCLUSIONS/INTERPRETATION: Acute mild cold exposure with shivering reduced 24 h glucose levels in individuals with type 2 diabetes. No changes were observed in prediabetes. The observed effects appear to depend on baseline metabolic status rather than acute substrate utilisation during cold exposure. These findings support the potential of cold exposure as an adjunct non-pharmacological therapy for type 2 diabetes, although further mechanistic studies and validation in larger cohorts are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT05576025 FUNDING: Dutch Organisation for Knowledge and Innovation in Health, Healthcare and Well-being (ZonMw): 09120012010062.

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PubMed2026

First identification and molecular subtyping of Blastocystis spp. in donkeys in Aksaray province, Türkiye.

Blastocystis is a common intestinal protist worldwide that can infect humans and animals. Although its molecular epidemiology in Türkiye is mostly focused primarily on humans and livestock, equids have received limited attention despite their traditional roles and frequent contact with humans and other animals in rural environments. This study aimed to determine the molecular prevalence and subtype (ST) distribution of Blastocystis spp. in donkeys in Aksaray Province, providing the first molecular data on donkeys in Türkiye. A total of 182 fresh fecal samples were collected from donkeys in nine villages within Aksaray province. Genomic DNA was extracted, and the small subunit ribosomal RNA (SSU rRNA) gene fragment of Blastocystis spp. was amplified via PCR analysis. Positive isolates were sequenced bidirectionally for identification and subsequent phylogenetic analysis of Blastocystis in donkeys. The overall molecular prevalence of Blastocystis spp. in donkeys was 4.4% (8/182). The infection rate was higher in young donkeys (under 3 years old; 8.33%) than in adults (3 years or older; 2.46%). However, this difference was not statistically significant. Sequence analysis of the positive PCR products revealed the presence of one known livestock-specific subtype, ST10. Phylogenetic analysis showed that the ST10 isolates characterized in this study clustered with isolates identified from different hosts. This study provides the first molecular data on Blastocystis presence in donkeys in Türkiye. The exclusive detection of ST10 suggests potential cross-species transmission, likely facilitated by the traditional practice of co-housing donkeys with other animals in confined barns. These findings indicate that donkeys may contribute to Blastocystis transmission, underscoring the importance of a "One Health" approach in future epidemiological surveillance.

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PubMed2026

Prognostic Value of Frailty in Aortic Surgery: A Systematic Review and Meta-Analysis Comparing Frailty Assessment Tools.

BACKGROUND: Frailty is increasingly recognized as an important determinant of outcomes after aortic vascular surgery, but assessment methods vary substantially and the optimal tool for risk stratification remains uncertain. This systematic review and meta-analysis evaluated the prognostic value of preoperative frailty and compared the predictive performance of different frailty instruments in aortic surgery. METHODS: PubMed, Embase, and Cochrane Library were searched from inception to April 27, 2026. Eligible studies included patients undergoing open, endovascular, or hybrid aortic procedures involving abdominal, thoracic, thoracoabdominal, arch, and proximal aortic diseases, including aneurysms and dissections, assessed frailty preoperatively, and reported postoperative outcomes. RESULTS: Thirty studies comprising 419,459 patients were included. Frailty was associated with higher early mortality (odds ratio [OR] 2.20; 95% confidence interval [CI] 1.54-3.14) and late mortality (hazard ratio 2.18; 95% CI 1.64-2.90). Frail patients also had increased risks of major complications (OR 2.52; 95% CI 1.22-5.19), acute kidney injury (OR 1.64; 95% CI 1.34-2.02), and nonhome discharge (OR 5.50; 95% CI 3.05-9.92). Associations were consistent across surgical approaches and aortic segments. Judgment-based or phenotype-like tools yielded higher effect estimates than deficit-accumulation indices, although differences were not statistically significant; among index-based tools, Modified Frailty Index (mFI)-11 outperformed mFI-5. CONCLUSION: Preoperative frailty strongly predicts mortality, morbidity, and loss of functional independence after open, endovascular, and hybrid aortic surgery across different aortic segments and pathologies, including aneurysmal and dissecting aortic disease. Routine frailty assessment may improve risk stratification and perioperative decision-making.

Humans↗

PubMed2026

Risk factors for loss of skeletal muscle mass in patients with chronic kidney disease on a low-protein diet.

OBJECTIVES: A low-protein diet (LPD) is recommended for patients with chronic kidney disease (CKD) to prevent a further decline in renal function. However, its impact on muscle mass in these patients remains unclear. This study investigated the risk factors for loss of muscle mass in patients with CKD on an LPD. METHODS: Eighty-four patients with predialysis CKD (59 men, mean age 61.9 ± 11.5 y) who participated in a multicenter randomized controlled trial initiated in 2014 were retrospectively reviewed. We collected data on baseline blood and urine tests, body composition, and dietary records at the start and end of the observation period. We evaluated muscle mass using the skeletal muscle index (SMI) and analyzed risk factors for a decrease in SMI during the 24-wk observation period, using logistic regression analysis. Variables with an association (P < 0.1) in univariate analysis, as well as age, sex, use of low-protein rice, and changes in protein intake, were subjected to multivariate analysis. RESULTS: SMI decreased in 50 patients (59.5%) during the observation period. Multivariate analysis identified significant associations of the SMI with serum albumin at baseline (odds ratio 0.11, 95% confidence interval 0.02-0.52, P = 0.004) and changes in energy intake while on the LPD (odds ratio 3.39, 95% confidence interval 1.00-11.43, P = 0.049). CONCLUSIONS: Risk factors for reduced SMI in patients with CKD on an LPD were malnutrition when initiating the LPD and reduced energy intake during its implementation. Clinicians should optimize nutritional status before initiation of an LPD and ensure adequate energy intake throughout treatment.

Humans↗

PubMed2026

Comparison of clinical outcomes of robotic versus open pyeloplasty in infants under 6 months.

INTRODUCTION: Robotic pyeloplasties have become the popular approach for surgical repair of ureteropelvic junction obstruction (UPJO) in the pediatric population. In infants less than 6 months old, there is concern for lack of intra-abdominal working space and lack of benefit compared to an open approach. Our aim was to compare the peri-operative and post-operative outcomes of patients undergoing open versus robotic pyeloplasty under six months of age. METHODS: A retrospective review was performed of patients less than six months of age undergoing robotic or open pyeloplasty between 2020 and 2024 at a single institution. Patient demographics and clinical outcomes were collected and compared. Surgical success was defined as a >50% reduction in the antero-pelvic diameter (APD) of the affected kidney at one year post pyeloplasty. RESULTS: A total of 32 patients were identified (16 robotic and 16 open), median age at surgery was 4 months old. There was no significant difference in length of hospital stay or narcotic usage between the two groups. The robotic cohort had a significantly longer operative time (209.5 min vs 142.5 min, p < 0.001) compared to the open cohort. There was no significant difference between post-operative complication or surgical success rates between the two groups. CONCLUSION: In this small series, robotic and open pyeloplasty both remain viable options for infants less than 6 months of age with equivalent surgical outcomes and lengths of hospital stay.

Humans↗

PubMed2026

Outcomes of patients with myelofibrosis treated with ruxolitinib and anemia-supporting medications.

OBJECTIVE: This post hoc analysis of the phase 3b JUMP trial evaluated addition of anemia-supporting medications to ruxolitinib in patients with myelofibrosis and anemia. METHODS: 101 patients with baseline hemoglobin <12.0 g/dL initiated an erythropoiesis-stimulating agent (ESA) or danazol <3 months post-enrollment and maintained ESA/danazol ≥3 months; 97% initiated ESAs. Patients enrolled in JUMP who had hemoglobin <12.0 g/dL but did not initiate ESAs/danazol within 3 months were evaluated as an unmatched comparator. Total JUMP population data were also analyzed for spleen length (≥50% reduction from baseline) and symptom response (≥6.5-point improvement in FACT-Lym score). RESULTS: Baseline characteristics were similar to comparator JUMP patients (no ESAs/danazol within 3 months, n = 1242). Mean total daily ruxolitinib dose remained >25 mg. Week 24 spleen length response was achieved by 37% of patients; 26% achieved symptom response, similar to the comparator population (28% and 26%, respectively) and comparable to the total JUMP population (N = 2233). Outcomes were similar between the hemoglobin <12.0 g/dL analysis population and patients with baseline hemoglobin <10.0 g/dL (n = 52). In all groups, hemoglobin levels increased after Week 4 following an expected initial decrease. DISCUSSION: This analysis suggests that patients treated with ruxolitinib and anemia-supporting care continued to receive optimal ruxolitinib dosing; spleen-length and symptom response rates in these patients were comparable to the overall JUMP population, the majority of whom did not have anemia. CONCLUSION: Results support use of anemia-supporting medications with ruxolitinib and may allow maintenance of ruxolitinib dose intensity in patients with myelofibrosis and anemia.

Humans↗

PubMed2026

Donor Human Milk Utilization in a Level 1 Newborn Unit of a High-Volume Delivery Hospital: A Cautionary Tale.

INTRODUCTION: Donor human milk (DHM) is an alternative to formula for supplementation of breastfed newborns and has been associated with higher in-hospital exclusive breast milk feeding rates. Its use has increased substantially, most recently among term newborns, yet there is scarce data to describe patient characteristics and volumes administered. We aimed to characterize DHM utilization in our level 1 nursery. METHODS: We conducted a retrospective cross-sectional study of newborns discharged in 2022 from the level 1 nursery. Variables included sex, gestational age, birth weight, delivery type, hypoglycemia diagnosis, DHM volume, and length of stay. DHM use was compared across preferred language, race, ethnicity, and payer type using chi-square testing. RESULTS: A total of 10,432 discharges were reviewed-those transferred to Neonatal Intensive Care Unit (NICU) or another unit were excluded. Of 9,074 newborns receiving level 1 care, 1,094 (12.1%) received DHM. Newborns born between 35 and 37 weeks gestation, delivered by cesarean section, or diagnosed with hypoglycemia or small for gestational age were more likely to receive DHM (p < 0.05). DHM was also more common among newborns whose birth parent preferred the English language, identified as White or non-Hispanic, or had non-Medicaid insurance (p < 0.05). 6,552.6 ounces were consumed, with a total median of 3.9 ounces per newborn (dose range 2-50 mL). CONCLUSIONS: DHM use in the level 1 nursery varied by clinical and sociodemographic factors, revealing inequities. In addition, some doses exceeded recommended supplemental volumes. Future efforts should focus on ensuring equitable access to DHM, standardized dosing and discontinuation guidelines, and evaluation of impacts on exclusive breastfeeding rates.

Humans↗

PubMed2026

Effects of erector spinae plane block on postoperative pain in patients undergoing implant-based breast reconstruction for breast cancer: a randomized controlled trial.

BACKGROUND: Implant-based breast reconstruction after mastectomy causes acute pain. OBJECTIVE: To determine whether a single-shot T5 erector spinae plane block (ESPB) reduces postoperative pain. DESIGN: Single-center, RCT with allocation concealment; blinded assessors and statisticians. SETTING: Tertiary cancer center in China. PATIENTS: 100 adults scheduled for radical mastectomy with implant reconstruction were randomized (1:1); follow-up complete. INTERVENTION: Before induction, ESPB was given under ultrasound guidance at T5 with 30 mL of 0.375% ropivacaine plus dexmedetomidine 1 μg/kg; controls received no block. Standardized general anesthesia and postoperative PCA for both groups. MAIN OUTCOME MEASURES: Resting NRS at 6 h (MCID=1). Secondary outcomes were opioid consumption, quality of recovery, and PONV. RESULTS: ESPB did not significantly reduce resting pain at 6 h at the median (τ =0.50; adjusted difference -0.9; p = 0.08). At the upper tail, pain intensity was lower (τ = 0.75; -1.8; p <0.01). Repeated measures provided additional time-point information, improving estimation precision and test sensitivity. ESPB get lower pain scores at 6, 12, and 24 hours (all p <0.01). But, the 95% CI includes the MCID, the clinical benefit remains uncertain. Opioid use decreased at 24 h (-13.5 mg; p <0.01) and 48 h (-6.6 mg; p <0.01). Quality of recovery improved at 24 h (difference 5 points; p <0.01), but not later. No differences were observed in intraoperative hemodynamics or PONV. CONCLUSIONS: Single-shot T5 ESPB with perineural dexmedetomidine may reduce postoperative pain and opioid requirements and improve early recovery. Further large trials are warranted. Clinical relevance remains to be confirmed. TRIAL REGISTRATION: ClinicalTrials.gov NCT06143020.

Humans↗

PubMed2026

Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: The clinical potential of orexin 2 receptor (OX2R) agonism for improving measures of wakefulness and cataplexy in patients with narcolepsy type 1 has been described in a phase 2 study. Here, we aimed to evaluate the safety, tolerability, and efficacy of alixorexton, another oral OX2R agonist, in narcolepsy type 1. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, adult participants (aged 18-70 years) with narcolepsy type 1 were recruited from 46 hospitals and private research centres across the USA, Europe, and Australia. Participants were centrally randomly assigned (1:1:1:1) in blocks of four via an interactive response technology system stratified by region and baseline weekly cataplexy rate (WCR) to receive 4 mg, 6 mg, or 8 mg tablets of alixorexton or placebo once daily for 6 weeks, followed by an optional 7-week open-label extension. Participants had narcolepsy type 1, diagnosed per the International Classification of Sleep Disorders, Third Edition, and confirmed by overnight polysomnography and the Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations. The sponsor, assessors, investigators, and participants were masked during the randomised double-blind treatment period. Efficacy and safety assessments were conducted in participants who received at least one dose of study drug. The primary endpoint was change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Safety endpoints included treatment-emergent adverse events. This trial was registered with ClinicalTrials.gov (NCT06358950) and is completed. FINDINGS: Between May 24, 2024, and May 5, 2025, 153 individuals were screened and 92 participants were randomly assigned to receive alixorexton 4 mg (n=23), 6 mg (n=22), 8 mg (n=24), or placebo (n=23). Mean age was 33·5 years (SD 12·1), 57 (62%) were women, and 35 (38%) were men. At week 6, the observed MSL on the MWT was 2·3 min (SD 2·7) for placebo, 24·0 min (8·7) for alixorexton 4 mg, 25·9 min (9·4) for 6 mg, and 28·2 min (11·4) for 8 mg. Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22·2 min (95% CI 17·2-27·2) for alixorexton 4 mg, 24·1 min (19·0-29·1) for 6 mg, and 26·0 min (21·0-31·0) for 8 mg (adjusted p=0·0099 for 4 mg, adjusted p<0·0001 for 6 mg and 8 mg). Treatment-emergent adverse events occurring in at least 5% of participants given alixorexton and more frequently than those given placebo up to week 6 were pollakiuria (38 [55%]), insomnia (19 [28%]), salivary hypersecretion (17 [25%]), micturition urgency (ten [14%]), blurred vision (ten [14%]), and hyperhidrosis (five [7%]). INTERPRETATION: In this phase 2 trial, once-daily oral alixorexton provided clinically meaningful improvements at 6 weeks for participants with narcolepsy type 1, including in wakefulness, excessive daytime sleepiness, and cataplexy. The treatment was generally well tolerated, with adverse events consistent with the known on-target effects of OX2R agonists. Together, these findings support the further phase 3 evaluation of alixorexton as a potential therapeutic option for people with narcolepsy type 1. FUNDING: Alkermes.

Humans↗

PubMed2026

Comparative analysis of gut microbiota in yaks under different feeding management strategies during cold seasons.

Yaks (Bos grunniens) are crucial for the livelihoods of pastoral communities in cold regions, where feed scarcity during the cold season poses challenges to their health and productivity, underscoring the necessity of understanding how dietary management influences the gut microbiota. In this study, 24 yak steers matched for body weight and health status were randomly allocated to four groups: natural grazing or indoor feeding with roughage-to-concentrate ratios of 50:50, 70:30, or 90:10. Fecal samples were collected for 16S rDNA sequencing and subsequent functional prediction of the microbiota. The results showed that Firmicutes and Bacteroidetes were the dominant phyla across all groups, and UCG-005 and Rikenellaceae_RC9_gut_group were the predominant genera. Concentrate supplementation during the cold season significantly enhanced microbial richness and diversity, with the 70:30 ratio exerting the most pronounced beneficial effects on microbiota structure and key taxa enrichment. These findings highlight the critical role of dietary management in shaping the yak gut microbiota during cold seasons and suggest that the 70:30 ratio optimally improves microbial community structure, thereby promoting yak health and productivity under harsh climatic conditions. Future research should explore the long-term implications of such dietary strategies.

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PubMed2026

Effects of Progressive Inspiratory Muscle Training on Lung Volume and Respiratory Strength in Patients With Pre-Dialysis Chronic Kidney Disease.

INTRODUCTION: Chronic kidney disease can present changes in thoracic cavity volume and respiratory muscle weakness, even in the pre-dialysis stage. However, there is little evidence on the effects of inspiratory muscle training in these patients. METHODS: This was a randomized clinical trial which comprised patients with Chronic Kidney Disease in stages 3, 4, and 5 undergoing conservative treatment, allocated experimental group (EG) with progressive loading (up to 50% of maximal inspiratory pressure [MIP]) and control group (CG) with a fixed load (5 cmH2O) and no load progression performed daily for 8 weeks. The outcomes assessed were thoracic cavity volumes, as measured by optoelectronic plethysmography, and inspiratory and expiratory respiratory muscle strength. RESULTS: A total of 30 patients completed the study. All volumes significantly increased at the end of the protocol with a large effect size, but only the pulmonary thoracic cavity volume showed a significant interaction (F = 3.698; p = 0.042). There was an increase in inspiratory muscle strength in the EG (73.88-90.35 cmH2O; p < 0.001) and in the CG (70.85-86.92 cmH2O; p = 0.001), as well as in expiratory muscle strength in the EG (97.71-108.53 cmH2O; p = 0.001) and in the CG (80.69-94.77 cmH2O; p = 0.004). CONCLUSION: Daily IMT increased thoracoabdominal volumes, particularly pulmonary rib cage volume in the progressive-load group, as well as respiratory muscle strength in patients with pre-dialysis CKD. However, progressive-load IMT was not superior to minimal-load training.

Humans↗

PubMed2026

Comparative evaluation of oxidative stress biomarkers F2-isoprostanes and 8-OHdG in Parkinson's disease and Type 2 Diabetes Mellitus: a systematic review and meta-analysis of human studies.

BACKGROUND: Oxidative stress is central to type 2 diabetes mellitus (T2DM) and Parkinson's disease (PD). However, the utility of biomarkers for lipid peroxidation (F2-isoprostanes) and DNA damage (8-OHdG) in the comorbidity of PD and T2DM remains unclear. METHODS: We conducted a systematic review and meta-analysis of 54 unique studies of human subjects aged ≥ 50 years (n = 7,521: 3,522 with T2DM, 722 with PD, and 3,277 controls), measuring biomarkers in serum, plasma, or leukocytes. Mixed-effects models quantified standardized differences (Hedges' g) across subgroups. RESULTS: In T2DM, F2-isoprostanes (g = 1.60, 95% CI: 0.95-2.25) and 8-OHdG (g = 2.64, 95% CI: 2.13-3.14) were markedly elevated (p < 0.001). Stronger effects were observed in younger cohorts and serum/plasma samples, with complications like nephropathy exhibiting extreme oxidative stress (g = 5.24). In PD, 8-OHdG was moderately elevated (g = 0.78, 95% CI: 0.18-1.39; p = 0.011), particularly in randomized controlled trials and plasma samples, whereas F2-isoprostanes were not significantly elevated (g = 0.47, 95% CI: -0.43-1.38). High heterogeneity in T2DM (I2 > 90%) reflected methodological variability. CONCLUSION: Distinct profiles - both markers elevated in T2DM but only 8-OHdG in PD - underscore 8-OHdG's potential in PD-T2DM comorbidity. Future research should focus on standardized assays, multi-compartmental or multi-modal sampling, and longitudinal studies to clarify mechanisms and therapeutic targets.

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PubMed2026

The global prevalence of horizontal strabismus: A systematic review and meta-analysis with a focus on ethnic variation.

The prevalence of the 2 types of horizontal strabismus, esotropia and exotropia, varies considerably between studies. This variability has been attributed to factors such as geography/environment, research methodology, age of study subjects, and/or ethnicity. Comprehensive estimates of regional and global prevalences of esotropia and exotropia are lacking, making it difficult to recognize true patterns, trends, and etiologies. We compile prevalences and ratios of esotropia to exotropia from 315 population-based studies and 374 clinic-based studies. We analyze data to assess effects of ethnicity, geography, age, and we identify generational changes of horizontal strabismus. Major ethnicities differ in patterns and ratios of esotropia and exotropia prevalence, not only in Caucasians and East Asians, but also Latinos/Hispanics, South Asians, Africans, and Native Americans. Compared to population-based studies, clinic-based studies underestimate exotropia frequency. By weighing prevalences according to the population size of ethnicities, we estimate the worldwide prevalence of horizontal strabismus in the current generation at 1.81% (138.5 million people), comprising 60.0 million people with esotropia (0.67%) and 87.5 million with exotropia (1.14%). In the previous generation, the worldwide prevalence of horizontal strabismus was 1.64% (86.5 million people), comprising 50.5 million with esotropia (0.96%) and 36.0 million with exotropia (0.68%). Esotropia and exotropia prevalences differ between generations within the same ethnicity, indicating that extrinsic factors can modify the underlying intrinsic (genetic) disposition.

Humans↗

PubMed2026

A New Highly Concentrated Insulin Aspart AT278 (500 U/mL) Demonstrates Ultra-Rapid Pharmacokinetic and Pharmacodynamic Properties in Type 2 Diabetes Regardless of BMI.

AIMS: To evaluate the pharmacokinetics, pharmacodynamics, and safety of a novel U500 insulin aspart formulation (AT278 [500 U/mL]; AT278-U500) compared with standard concentration insulin aspart (InsAsp [100 U/mL]; InsAsp-U100) and U500 human regular insulin (HumIns [500 IU/mL]; HumIns-U500). MATERIALS AND METHODS: This single-centre, randomised, double-blind crossover 12-h euglycaemic clamp study was conducted in 41 overweight and obese people with type 2 diabetes (BMI 25.0-38.7 kg/m2) receiving a single subcutaneous dose (0.5 U/kg) of AT278-U500 and InsAsp-U100. HumIns-U500 was consecutively studied open label in a 24-h clamp. RESULTS: AT278-U500 exhibited a significantly faster insulin absorption than InsAsp-U100 and HumIns-U500 (t Early50%Cmax: 9 min vs. 35 min vs. 55 min), leading to a significantly higher glucose-lowering effect within the first hour (AUCGIR,0-60min) compared with both InsAsp-U100 (treatment ratio 2.02 [95% CI 1.64; 2.50]) and HumIns-U500 (3.91 [2.89; 5.27]). When divided by median BMI (29.7 kg/m2), AUCGIR,0-60min was significantly higher with AT278-U500 in both the low-BMI and high-BMI subgroup compared to InsAsp-U100. Linear regression showed a significant inverse relationship between BMI and AUCGIR,0-60min for InsAsp-U100 (slope -0.142, p < 0.0001), whereas AT278-U500 showed no such relationship. Overall insulin exposure was similar for AT278-U500 and InsAsp-U100, while overall glucose-lowering effect was comparable across all three treatments. CONCLUSIONS: AT278-U500 maintains its ultra-rapid onset characteristics independent of BMI, representing the first ultra-rapid U500 option for prandial dosing in insulin-resistant people with type 2 diabetes requiring high-dose therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05754424.

Humans↗

PubMed2026

Novelty seeking and rapid symptom improvement across active and sham accelerated iTBS conditions: A pooled individual-patient data analysis.

INTRODUCTION: Major depressive disorder (MDD) is highly prevalent and often treatment-resistant. Accelerated intermittent theta burst stimulation (aiTBS) is a promising intervention for treatment-resistant depression (TRD), though outcomes vary. Personality traits have been examined in relation to rTMS outcomes, yet their role in aiTBS remains underexplored. This pooled individual-patient-data analysis of two randomized, sham-controlled trials examined associations between baseline Temperament and Character Inventory (TCI) traits and one-week symptom change, and whether they differed by condition. METHODS: The left dorsolateral prefrontal cortex was targeted for 20 sessions over 4 days. Personality was assessed with the TCI, depression severity with the 17-item Hamilton Depression Rating Scale (HDRS-17). TCI-symptom-change associations were examined with a robust linear mixed-effects model, adjusting for age, gender, repeated measurements, and study membership. RESULTS: 104 participants were included (M/F 45/59; mean age 40.9 ± 12.7; active/sham 50/54). The model yielded a Time × Novelty Seeking interaction (β = -1.70, p = 0.021): higher baseline Novelty Seeking was associated with faster symptom reduction, without a between-arm difference. However, the interaction did not survive Holm correction across 14 trait-interaction tests (adjusted p = 0.294) and is therefore exploratory. No other interaction reached the uncorrected threshold. CONCLUSIONS: Higher baseline Novelty Seeking showed a nominal association with faster symptom reduction, without a difference between active and sham conditions. Because it did not survive multiplicity correction and was not reproduced in within-arm analyses, it is preliminary and may reflect contextual or nonspecific processes. Independent replication is required before temperament assessment can be clinically informative.

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PubMed2026

Exploring sex differences in endocannabinoid system biomarkers and their relationship with antidepressant treatment outcomes in major depressive disorder: a CAN-BIND 1 secondary analysis.

BACKGROUND: Sex differences in major depressive disorder (MDD) are well documented, but it remains unclear whether sex-related variation in peripheral endocannabinoid system (ECS)-related biomarkers is detectable in MDD. OBJECTIVES: To examine baseline sex differences in ECS-related mRNA expression, DNA methylation, and single nucleotide polymorphisms (SNPs) in MDD, and associations between baseline ECS markers and antidepressant outcomes in sex-stratified analyses. METHODS: Among 178 participants with MDD from CAN-BIND-1, all received escitalopram for 8 weeks; non-responders then received adjunctive aripiprazole from Weeks 8-16.Response was defined as ≥ 50% reduction in MADRS score, and remission as MADRS ≤ 10. ANCOVAs examined baseline sex differences and sex-stratified biomarker associations with percent MADRS reduction at Weeks 8 and 16, as well as categorical response and remission outcomes. Covariates included site, baseline MADRS, age, and ethnicity. False discovery rate correction was applied. RESULTS: Baseline sex differences in methylation were observed for CACNA1H, GABRB2, MAGL, and GABRR2, though none survived correction. No baseline sex differences in mRNA expression or SNPs were detected after correction. Lower baseline DAGLA mRNA in males was associated with greater Week 8 symptom improvement (FDR corrected). This association was not observed in females. No associations with response or remission at Weeks 8 or 16 survived correction. IMPLICATIONS: Baseline sex differences in peripheral ECS-related markers were not detected in this sample. Larger studies are needed to verify whether ECS-related biomarkers, particularly DAGLA, contribute to antidepressant outcomes in a sex-specific manner.

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PubMed2026

Efficacy and safety of ferric citrate tablets in Chinese patients with hyperphosphatemia undergoing maintenance hemodialysis: a multicenter, randomized, open-label, active-controlled, phase III trial.

BACKGROUND: This study aimed to evaluate the efficacy and safety of ferric citrate tablets in Chinese patients with hyperphosphatemia undergoing maintenance hemodialysis (MHD). METHODS: In this phase III, multicenter, randomized, open-label, non-inferiority trial, patients with hyperphosphatemia on maintenance hemodialysis were randomly assigned to receive either ferric citrate or sevelamer carbonate tablets for 12 weeks. The primary endpoint was the change in serum phosphorus levels from baseline to week 12, with a non-inferiority margin of 0.32 mmol/L. Secondary endpoints included changes in serum calcium, intact parathyroid hormone, and safety assessments. RESULTS: A total of 239 patients were randomized to the ferric citrate group (n = 119) or the sevelamer carbonate group (n = 120). The mean change in serum phosphorus levels was -0.70 ± 0.50 mmol/L in the ferric citrate group and -0.61 ± 0.59 mmol/L in the sevelamer carbonate group (least squares mean difference, -0.09 mmol/L; 95% CI, -0.24 to 0.05 mmol/L; non-inferiority margin, 0.32 mmol/L). No significant inter-group differences were found in the percentage of patients achieving target phosphorus levels (49.09% vs. 48.28%, p = 0.902). Ferric citrate significantly improved iron-related parameters and hemoglobin levels. Most treatment-emergent adverse events were mild, with gastrointestinal disorders being the most common. CONCLUSIONS: Ferric citrate tablets were non-inferior to sevelamer carbonate in reducing serum phosphorus levels in hyperphosphatemia patients on maintenance hemodialysis, with the added benefit of improving iron-related anemia and a favorable safety profile.

Adult↗

PubMed2026

10-year outcome of fractional flow reserve-guided complete revascularization in patients with ST-segment elevation myocardial infarction - A DANAMI-3 PRIMULTI substudy.

BACKGROUND: Complete revascularization is recommended in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease. However, whether the non-culprit lesions should be evaluated using angiography or fractional flow reserve (FFR) remains uncertain. The aim of this study was to evaluate the long-term outcome of patients with STEMI and multivessel disease who had non-culprit FFR-values >0.80 and thus deferred PCI. METHODS: Of the 627 patients included in the DANAMI-3-PRIMULTI trial, 314 patients were randomized to FFR-guided complete revascularization and 280 were included in this substudy. Patients were divided into a PCI-deferral group who had no PCI of non-culprit lesions (FFR > 0.80) (n = 106) and a PCI group encompassing patients treated with PCI of at least one non-culprit lesion (FFR ≤ 0.80 or an angiographical diameter stenosis of ≥90%) (n = 174). The combined endpoint included all-cause mortality, myocardial infarction, or urgent revascularization. RESULTS: During a median follow-up of 10.5 years (IQR 9.8-11.4), the composite outcome occurred in 62 (36%) patients in the PCI group and in 50 (47%) patients in the PCI-deferral group (adjusted HR 0.64, 95% CI: 0.44-0.95, p = 0.025). PCI-deferral was associated with a significantly higher risk of cardiovascular mortality (adjusted HR 0.48, CI 95% 0.24-0.97, p = 0.040) compared to the PCI group. CONCLUSION: In patients with STEMI and multivessel disease, deferring PCI of non-culprit lesions based on FFR > 0.80 was associated with an increased risk of the combination of all-cause mortality, myocardial infarction, or urgent revascularization as well as cardiovascular mortality compared to patients treated with PCI of FFR-positive non-culprit lesions.

Humans↗