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PubMed2026

Vaccine preferences and their role for vaccine confidence and uptake: a meta-ethnography.

Vaccine confidence and uptake are influenced by individuals' preferences regarding vaccine composition, quality, or administration pathways. However, literature synthesizing available qualitative insights into individuals' vaccine preferences remains limited. We therefore conducted a meta-ethnographic systematic review of the qualitative literature on vaccine preferences to identify opportunities for enhancing vaccine confidence and uptake. We implemented a comprehensive search strategy and screened 5,528 studies across seven research databases published between 2001 and 2023. We identified and synthesized 97 qualitative articles to delineate factors influencing consumers' vaccine preferences. Our findings revealed four primary domains shaping individuals' vaccine preferences: Product, Place, Price, and Promotion. First, individuals' preferences for vaccines often hinge on perceived quality and safety of the product itself, which can, for example, be associated with vaccine brand or origin, especially in the case of novel vaccines. Second, people prioritize convenience in terms of vaccination sites and delivery methods (wanting vaccinations offered at their doorstep or in local peripheral clinics); evidence regarding preferred groups to administer the vaccines was mixed. Third, the price of vaccines and the secondary costs associated with vaccination played a role in uptake considerations. Finally, both the sources of information (such as healthcare workers, community volunteers, and religious authorities) and the methods of promoting vaccine information (including face-to-face consultations during clinic visits and the distribution of leaflets or banners), emerged as crucial factors shaping decision-making processes. Overall findings highlight the importance of addressing multifaceted preferences to enhance vaccine confidence and uptake. By understanding individuals' vaccine preferences, strategic recommendations can be developed to optimize vaccination programs and ensure acceptability and utilization.

Humans↗

PubMed2026

Closed-loop vasopressor systems for hemodynamic control in perioperative and critical care settings: a systematic review and meta-analysis.

Maintaining mean arterial pressure (MAP) within a predefined target is central to haemodynamic management in surgical and critically ill adults receiving vasopressors. Closed-loop vasopressor (CLV) systems automate titration to optimise blood pressure control, but their clinical effectiveness remains uncertain. We performed a systematic review and meta-analysis comparing CLV with manual titration. This PRISMA 2020-compliant review was prospectively registered in PROSPERO (CRD420250655697). MEDLINE, Embase, Scopus, Web of Science, CENTRAL, and the Cochrane Library were searched (January 2000-June 2025). Randomised controlled trials enrolling adults receiving vasopressors in perioperative or intensive care settings were included. Primary outcomes were time within the MAP target range and time spent in hypotension or hypertension. Risk of bias was assessed using RoB 2.0 and certainty of evidence using GRADE. Random- or fixed-effects models were selected according to heterogeneity. Six randomized controlled trials (215 patients) were included in the systematic review, whereas five perioperative trials contributed to the meta-analysis of haemodynamic control outcomes, and one ICU-based study was summarized narratively because it did not report comparable MAP control endpoints. CLV increased time within the MAP target range (mean difference [MD] 33.94%, 95% CI 20.41-47.46; I2 = 77%) and reduced time in hypotension (MD - 18.24%, 95% CI - 28.95 to - 7.53; I2 = 73%). There was no significant difference in time in hypertension, cumulative norepinephrine dose, or major/minor adverse events. ICU length of stay was not pooled because of clinical and methodological heterogeneity. Certainty of evidence ranged from low to high (moderate for haemodynamic control outcomes). CLV systems improved haemodynamic control, primarily in perioperative settings, but heterogeneity and small samples limit confidence in effect size and generalisability. Evidence in critically ill populations remains limited, and larger trials are needed to determine whether improvements in these physiological surrogate endpoints translate into meaningful patient-centred outcomes.

Humans↗

PubMed2026

Duration and characteristics of hypoglycemia with once-weekly insulin efsitora alfa versus once-daily basal insulins in adults with type 2 diabetes: Exploratory safety analysis of QWINT 2-4.

AIMS: Efsitora is a novel once-weekly basal insulin. Efsitora demonstrated similar efficacy and safety compared with once-daily basal insulin comparators across four phase 3 clinical trials for type 2 diabetes. This exploratory safety analysis further characterizes hypoglycemia events in the efsitora and once-daily treatment groups in three of these trials (QWINT-2, -3, and -4). METHODS: Median duration of hypoglycemia events was assessed with masked continuous glucose monitoring. Incidence of persistent-recurrent (PR) hypoglycemia was assessed by investigators and by a pre-specified algorithm using SMBG e-diary data. Factors contributing to hypoglycemia, characteristics of hypoglycemia, and treatment methods were reported by participants and assessed across groups. RESULTS: Across the three trials, durations of hypoglycemic events for efsitora vs once-daily basal insulin comparators were: Level 1 and 2 [<70 mg/dL]: 40-42.5 vs 40 min; Level 2 [<54 mg/dL]: 35-39.9 vs 35 min. Few incidences of PR hypoglycemia were reported for efsitora or once-daily comparators. No major descriptive differences were observed between hypoglycemia contributing factors, characteristics, or treatment methods in efsitora and once-daily treatment groups. CONCLUSIONS: No clinically relevant differences were observed between the duration or characteristics of hypoglycemic events in efsitora and once-daily treatment groups in the QWINT-2, -3, and -4 trials.

Adult↗

PubMed2026

Glycemic and safety outcomes of the insulin-only bionic pancreas in older adults and individuals with impaired awareness of Hypoglycemia: a post hoc analysis of a randomized pivotal trial.

AIMS: Evaluate the efficacy and safety of iLet Bionic Pancreas (BP) in older adults and individuals with impaired awareness of hypoglycemia (IAH). METHODS: This post hoc analysis used individual participant-level data from the Insulin-Only Bionic Pancreas Pivotal Trial (n = 440; NCT04200313). Eligible participants (n = 96) with type 1 diabetes, aged ≥ 60 years and/or had IAH (Clarke score ≥ 4), were randomized to BP with aspart/lispro (BP-Asp/Lis; n = 45), BP with fast-acting aspart configuration (BP-Fiasp; n = 31), or standard care (SC; n = 20) for 13 weeks. RESULTS: Compared with SC, time-in-range (70-180 mg/dL) significantly increased by 7.49 % (95 % CI: 2.61 to 12.38; ∼1.8 h/day) with BP-Asp/Lis and by 8.28 % (95 % CI: 3.15 to 13.41; ∼2.0 h/day) with BP-Fiasp, driven by reduced hyperglycemia. No significant differences were observed in hypoglycemia exposure. Severe hypoglycemia occurred in four participants (four events) on BP-Asp/Lis and one participant (two events) on SC. One diabetic ketoacidosis event occurred on BP-Fiasp due to an infusion set failure. CONCLUSIONS: In high-risk, clinically vulnerable populations, the BP system significantly improved glycemic control while maintaining safety parity with respect to hypoglycemia risk, providing a resilient therapeutic alternative for vulnerable cohorts.

Humans↗

PubMed2026

Transient acoustic stimulation induces time-dependent synaptic remodeling and enhancement of auditory nerve output after threshold recovery.

BACKGROUND: Acoustic stress can alter cochlear function even in the absence of permanent threshold elevation; however, synaptic consequences of transient acoustic stimulation remain incompletely understood. OBJECTIVE: This study aimed to investigate whether transient acoustic stimulation induces changes in the auditory nerve output and cochlear ribbon synapse morphology following hearing threshold recovery. METHODS: Young adult CBA/CaJ mice were exposed to band-limited acoustic stimulation (45-2,000 Hz, 95 dB SPL, 2 h). Auditory brainstem responses (ABRs), hair cell and spiral ganglion neuron survival, and synaptic morphology were evaluated before exposure and up to 2 weeks post-exposure. RESULTS: ABR thresholds were transiently elevated immediately after exposure but largely recovered by 1 day post-exposure. In contrast, ABR wave I amplitudes significantly increased after threshold recovery across multiple test frequencies. Ribbon-associated puncta in both inner and outer hair cell regions exhibited biphasic temporal changes, with an initial decrease immediately after exposure followed by an increase at 1 day post-exposure. The ribbon-associated punctal area also increased after exposure and remained elevated at later post-exposure time points. No significant loss of hair cells or spiral ganglion neurons was observed. Exploratory genomic analysis suggested enrichment of pathways related to metabolic defense and cellular stress responses. CONCLUSIONS: Transient acoustic stimulation induces time-dependent synaptic remodeling and enhancement of peripheral auditory nerve output without overt cellular degeneration. These findings support a model in which early cochlear responses to acoustic perturbation include adaptive synaptic plasticity and gain regulation, extending current concepts of noise-induced cochlear change beyond irreversible synaptic loss.

Animals↗

PubMed2026

Lipid metabolism is a key central, systemic and gut microbial feature of the decline in rat hippocampal function during middle age.

Middle age is emerging as a turning point in brain ageing, prognostic of future cognitive health and amenable to intervention. Metabolic and proteomic differences during this period are not yet fully understood and may potentially influence functions of the hippocampus, a brain area that regulates memory and anxiety. While the gut microbiota is implicated in brain ageing, the relationship between the gut microbiota, the metabolic state, and hippocampal proteome in middle age has not been investigated. We hypothesise that peripheral metabolic or protein features are associated with hippocampal vulnerability in middle age. Therefore, young adult and middle-aged rats were assessed for behavioural, proteomic, metabolic, and gut microbiota differences. Proteomic profiling of the hippocampus revealed differential expression of proteins indicative of altered synaptic signalling. Concurrently, adult hippocampal neurogenesis was decreased in middle age. Hippocampal microglia exhibited a lipid rich, inflammatory phenotype in middle age which correlated with poorer memory performance. CSF and serum proteomic and metabolomic analyses identified dysregulated lipid-related pathways potentially contributing to hippocampal vulnerability in middle age. Furthermore, 16S rRNA sequencing revealed reduced abundance of bacteria involved in lipid metabolism regulation. However, faecal microbiota transfer from young to middle aged rats was not sufficient to robustly improve hippocampus-dependent spatial memory. Together, these findings highlight dysfunctional lipid metabolism as a key feature of middle age that may contribute to decline in hippocampal function. Given that the scope for intervention is limited during older age, targeting biomarkers involved in metabolic and lipid homeostasis may be pivotal for the development of pharmacological or lifestyle-based interventions during middle age which could ultimately delay future cognitive ageing.

Animals↗

PubMed2026

Measurement of low-density lipoprotein cholesterol and other circulating lipids in Brazil: a systematic literature review.

Accurate laboratory assessment of circulating lipids underpins cardiovascular risk stratification, yet clinical interpretation depends not only on the assays but on the formula chosen to estimate low-density lipoprotein cholesterol (LDL-C). This review integrates the 2019-2025 evidence on laboratory methods for triglycerides (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDLC), and on the formulas estimating LDL-C, VLDL-C, and non-HDL cholesterol, to determine how these should be measured, reported, and harmonized in Brazil, where lipid thresholds are adapted from international consensus. A PRISMA 2020 systematic search (PROSPERO CRD420251241064) of PubMed/MEDLINE, Scopus, SciELO, LILACS, Web of Science, and Embase retrieved 57,915 records; after removing 38,210 duplicates, 19,705 titles/abstracts were screened, 312 full texts assessed, and 25 sources included. Enzymatic colorimetric assays remain standard for TG, TC, and HDLC. For LDL-C, Martin/Hopkins classifies more accurately than Friedewald (89.6% vs 83.2% correct categorization in 5,051,467 patients), particularly at high TG and low LDL-C, while Sampson/NIH and modified Sampson/NIH extend reliable estimation into hypertriglyceridemia and very low LDL-C; direct measurement is reserved for TG beyond the validated range. Although the review centers on the Friedewald, Martin/Hopkins, and Sampson/NIH families that dominate guideline practice, other published equations exist and are addressed in context. In Brazil, atherogenic-lipid thresholds are risk-based decision limits rather than reference intervals; national surveys describe lipid distributions but were not designed to establish them. Analytical standardization through traceability programs, multicenter validation of formulas, and-where the distribution-based construct applies (HDLC, pediatrics)-nationally derived reference intervals are priorities for equitable cardiovascular risk assessment in Brazil.

Humans↗

PubMed2026

Fatty acids and breast cancer: Epidemiology, subtype-specific metabolism, immune regulation, and clinical translation.

Fatty acids (FAs) are bioactive dietary and metabolic molecules that participate in membrane architecture, energy homeostasis, inflammatory signaling, gene regulation and immune function, all of which intersect with breast cancer (BC) risk, progression and treatment response. In this narrative review we integrate epidemiological, clinical, translational and mechanistic evidence on the role of FAs in BC. Saturated, monounsaturated, trans- and polyunsaturated FAs (PUFAs) are treated as distinct biological exposures rather than interchangeable measures of total fat intake. Similarly, evidence from dietary assessment, circulating biomarkers, erythrocyte membrane composition, adipose tissue stores and tumor lipid signatures is interpreted separately, because each captures exposure and biology at a different level. BC subtypes differ in FA synthesis, uptake, oxidation, storage and remodeling: luminal tumors are frequently linked to hormone-regulated lipogenesis, human epidermal growth factor receptor 2 (HER2)-positive tumors to growth-factor-driven lipid metabolism, and triple-negative tumors to exogenous FA uptake, inflammatory lipid mediators and ferroptosis-related vulnerabilities. FA-derived mediators also shape immune-cell polarization, cytokine signaling and the tumor microenvironment, and dietary FAs may reshape the gut microbiota; the fiber-derived short-chain FAs it produces, distinct from dietary FAs, likewise help regulate immune and inflammatory tone. Clinical data suggest possible roles for fat-quality modification and selected n-3 PUFA interventions, but findings are heterogeneous and not yet sufficient to support routine biomarker-guided precision onco-nutrition. Candidate biomarkers, such as erythrocyte n-6:n-3 composition, require prospective validation before clinical implementation. FA biology thus represents a modifiable but complex axis in BC prevention, tumor biology and supportive care.

Humans↗

PubMed2026

Factors Impacting Overall Survival Post-Relapse in High-Risk Neuroblastoma: Children's Oncology Group Outcomes From 2000 to 2019.

PURPOSE: Prior studies of features impacting post-relapse survival in high-risk neuroblastoma (HRNB) evaluated patient cohorts that did not receive contemporary high-risk or relapse therapies. We describe overall survival (OS) after first progression or first relapse of HRNB in a modern cohort. METHODS: Patients with HRNB enrolled on COG ANBL00B1(NCT00904241) between 2000 and 2019, who had relapsed or progressive disease were eligible. Clinical and molecular risk factors at diagnosis, therapy era, clinical trial enrollment, and clinical features at relapse, including site of and time to relapse, were evaluated. OS post-relapse was compared between groups using log-rank tests and Cox models. RESULTS: Among 4253 eligible HRNB patients, 1616 had relapse or progression as a first event. Five-year OS post-relapse was 19.1 ± 1.1%. The risk group with the lowest post-relapse survival was observed in patients with INSS Stage 4 or 4S disease < 18 months of age at diagnosis with MYCN amplified (MYCN-A) tumors. The other significant most unfavorable factors at diagnosis included diagnosis 2000-2004, tumor MYCN-A, 1p loss of heterozygosity (LOH), and elevated LDH or ferritin. Unfavorable factors at relapse included the time to relapse < 36 months from diagnosis, and combined local and metastatic disease at relapse. Multivariable analysis indicated that those with tumors harboring 1p LOH, age ≤ 5 years at diagnosis, or earlier treatment therapy era (2000-2004) had a higher risk of post-relapse death. CONCLUSIONS: While the 5-year OS rate was low in this cohort, there are subsets of patients with relapsed HRNB who demonstrate long-term survival. TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT00904241.

Humans↗

PubMed2026

Opposite metabolic and gut responses to oral glutamine in male and female mice with diet-induced obesity.

Obesity is often associated with sex-dependent metabolic complications, to which altered intestinal barrier function and gut microbiota contribute. Glutamine supplementation has previously shown beneficial effects on gut barrier function and glycemic control. We thus aimed to characterize, in male and female mice, the effects of oral glutamine supplementation during high-fat-diet-induced obesity. Male and female C57BL/6 mice received a standard (SD) or high-fat diet (HFD; 60 % kcal from fat) for 14 weeks (W14). From W12 onward, mice received glutamine in drinking water (2 g/kg/day) or no supplementation. Body composition, glucose tolerance, insulin sensitivity, intestinal permeability, colonic inflammatory response, cecal microbiota and inflammatory/endocrine adipose response were assessed. In both male and female mice, glutamine supplementation failed to improve body weight and body composition. However, glutamine reduced glucose intolerance in HFD-fed males (AUC reduced by 14.57 %) that was associated with a partial restoration of plasma resistin and insulin and a trend toward limiting adipose inflammatory response. In males, glutamine did not affect gut microbiota composition and colonic response. Conversely, in HFD-fed females, glutamine supplementation led to gut microbiota changes (increase in Bacteroidota and Pseudomonadota phyla; increase in Muribaculaceae and Tannerellaceae families), increased colonic inflammatory markers (Il1b, Tlr4, Myd88, Irf3), increased inflammatory response in subcutaneous adipose tissue and increased HOMA-IR. Finally, HFD-fed mice exhibited sex-specific responses to glutamine supplementation with protective effects in males and harmful effects in females that need to be further deeply explored.

Animals↗

PubMed2026

The utility of 18F-fluorodeoxyglucose PET/computed tomography in relapsing polychondritis: a systematic review and meta-analysis.

Relapsing polychondritis is a rare chronic autoimmune inflammation of the cartilage associated with life-threatening respiratory complications. Currently, no clear role of imaging modalities such as 18F-fluorodeoxyglucose (FDG) PET/computed tomography (CT) is defined in the literature. This systematic review and meta-analysis provide current evidence on the PET-positivity rate and utility in relapsing polychondritis. Prospective or retrospective studies with more than five patients of suspected relapsing polychondritis who underwent 18F-FDG PET/CT during their management and reported a PET-positivity rate were included. Low-sample-size studies describing chondritis due to other aetiologies or utilizing PET-based radiopharmaceuticals other than FDG were excluded. A systematic search using relevant keywords was conducted across four databases (PubMed, Embase, Scopus and Web of Science) to include studies up to 25 April 2025. The Joanna Briggs Institute critical appraisal tools were used for risk-of-bias analysis. Data were analysed using the R software package (v4.3.1; 2023). Out of 962 articles, three with a total of 97 patients were included. With a pooled PET-positivity rate of 94% [95% confidence interval (CI): 73-99%, I2 = 0%, P = 0.76] and a pooled baseline SUVmax of 4.0 (95% CI: 3.5-4.6, I2 = 32%, P = 0.23), 18F-FDG PET identified asymptomatic cartilage involvement in more than 25% patients and PET parameters correlated well with inflammatory markers. It had a higher positivity rate for inaccessible sites, such as peripheral airways, and was crucial in treatment monitoring. The pooled PET-positivity rate of 18F-FDG PET in relapsing polychondritis is high but requires prospective large-sample-size studies to explore the diagnostic accuracy and prognostic implications of 18F-FDG PET in relapsing polychondritis.

Polychondritis, Relapsing↗

PubMed2026

Effect of SGLT2 inhibitor drugs on triglyceride-glucose (TyG) index in adults: A systematic review and meta-analysis.

BACKGROUND: Insulin resistance is a serious public health concern. The triglyceride-glucose (TyG) index is a simple, cheap, and reproducible surrogate of insulin resistance, and sodium-glucose cotransporter-2 (SGLT2) inhibitors have reshaped cardio-metabolic care beyond glycemic control. METHODS: We followed PRISMA and registered the protocol in PROSPERO (CRD420251056341). We searched PubMed, Scopus, Web of Science, EMBASE, and Cochrane from inception to May 31st, 2026, including observational studies and clinical trials reporting baseline and follow-up TyG in adults. Two reviewers screened records, a third resolved disagreements, data were extracted with a standardized form, and quality was assessed with Cochrane RoB 2.0, the Newcastle-Ottawa Scale, and the JBI checklists. The primary outcome was within-group change in TyG pooled with random-effects (Hartung-Knapp); tests were two-sided with a significance threshold of 0.05. RESULTS: Twelve studies comprising thirteen study arms were included, with a total of 1845 participants. Follow-up ranged from 12 weeks to 5 years. Across studies, SGLT2 inhibitor therapy was associated with a significant reduction in TyG index (mean difference = -0.28, 95% confidence interval [-0.41; -0.14], I2 = 99.5%). Egger's test suggested possible small-study effects, whereas Begg's test and trim-and-fill analysis did not show clear evidence of publication bias; leave-one-out analyses showed that no single study materially influenced the pooled estimate. CONCLUSION: Despite heterogeneity in populations, drug choice, and follow-up duration, SGLT2 inhibitors were associated with a significant decrease in TyG, although small-study effects cannot be excluded.

Humans↗

PubMed2026

Risk of adverse events in elotuzumab-treated patients with multiple myeloma: a systematic review and meta-analysis.

BACKGROUND: Elotuzumab, an anti-SLAMF7 monoclonal antibody for multiple myeloma (MM), lacks a comprehensive safety profile from meta-analysis. METHODS: We systematically searched PubMed, Web of Science, EMBASE and CENTRAL through February 13, 2025 for randomized controlled trials (RCTs) evaluating elotuzumab in MM. Pooled relative risks(RRs) of adverse events observed in elotuzumab-containing regimens versus control therapies. RESULTS: 6 RCTs (N=1,736) were included. Elotuzumabsignificantly reduced incidence of neutropenia (RR = 0.86, 95% CI: 0.76-0.98), but increased risks of cough (RR = 1.41, 95% CI: 0.96-2.09), pneumonia (RR = 1.30, 95% CI: 1.07-1.59), diarrhea (RR = 1.16, 95% CI: 1.05-1.30), pyrexia (RR = 1.47, 95% CI: 1.10-1.96) and infections (RR = 1.09, 95% CI: 1.03-1.15). No significant differences were observed for anemia, thrombocytopenia, respiratory infections, nausea, appetite loss, back pain, muscle spasms, peripheral edema, insomnia, rash, pruritus, fatigue, or hypokalemia. For grade 3-4 events, elotuzumab was associated with higher risks of lymphopenia (RR = 1.86, 95% CI: 1.31-2.64, p = 0.0005, I2 = 9%), diarrhea (RR = 1.47, 95% CI: 1.00-2.17), pneumonia (RR = 1.57, 95% CI: 1.11-2.23), cataracts (RR = 2.87, 95% CI: 1.15-7.21) and infections (RR = 1.30, 95% CI: 1.04-1.62). CONCLUSION: Elotuzumab in MM appears safe but with a specific adverse events pattern : lower neutropenia, but higher respiratory, gastrointestinal, metabolic, and infectious events. Differences may be influenced by longer treatment and corticosteroid use; therefore, interpretation of outcomes such as hyperglycemia and cataracts requires particular caution.

Humans↗

PubMed2026

Effects of short-bout accumulated exercise on postprandial metabolism in adults: A systematic review and meta-analysis.

OBJECTIVE: To systematically evaluate the acute effects of short-bout accumulated exercise (SBAE) interrupting prolonged sedentary behaviour on postprandial glucose, insulin, and triglycerides in adults. METHODS: Systematic searches in PubMed, Web of Science, Embase, Cochrane Library, CINAHL, SPORTDiscus, and CNKI (inception to 10 December 2025) identified randomised crossover trials comparing SBAE (≤10 min/bout, inter-bout interval ≥30 min or adequate recovery) with continuous sedentary behaviour. Outcomes included postprandial glucose, insulin, and triglyceride AUCs. Standardised mean differences (SMD) were pooled using random-effects models. RESULTS: Thirty-one publications reporting data from 29 independent cohorts involving 573 unique participants (mean age 47.8 ± 20.3 years; 47.5% female; mean BMI 29.0 ± 5.1 kg/m²) were included. Compared with continuous sedentary behaviour, SBAE significantly reduced glucose AUC (SMD = -0.53, 95% CI: -0.71 to -0.34, P < 0.001) and insulin AUC (SMD = -0.58, 95% CI: -0.85 to -0.31, P < 0.001), but not triglyceride AUC (SMD = -0.17, 95% CI: -0.48 to 0.15, P = 0.306).Exploratory subgroup analyses showed statistically significant reductions in glucose and insulin for walking and for inter-bout intervals < 60 min, but not for standing alone or intervals ≥ 60 min. A statistically significant insulin-lowering effect was observed in obese individuals. CONCLUSION: SBAE acutely improves postprandial glucose and insulin control. Exploratory subgroup analyses showed statistically significant effects for walking and for inter-bout intervals < 60 min, but these comparisons are observational and no formal interaction test was conducted. These findings provide preliminary evidence for acute SBAE in sedentary populations, though long-term health effects and real-world generalisability require further investigation.

Adult↗

PubMed2026

Once-weekly IcoSema versus once-daily insulin glargine U100 in type 2 diabetes management (COMBINE 4): an open-label, multicentre, treat-to-target, randomised, phase 3b trial.

BACKGROUND: Stepwise treatment intensification is recommended for managing type 2 diabetes, including insulin initiation when non-insulin glucose-lowering medications are insufficient. Guidelines recommend combining a GLP-1 receptor agonist with basal insulin to improve glycaemic efficacy while reducing weight gain and hypoglycaemia risk. COMBINE 4 evaluated the efficacy and safety of IcoSema, a once-weekly combination therapy of basal insulin icodec and semaglutide (a GLP-1-receptor agonist) versus insulin glargine U100 (glargine U100) in people with type 2 diabetes on oral glucose-lowering medications. METHODS: COMBINE 4 was a 40-week, randomised, open-label, treat-to-target, phase 3b trial conducted across 97 sites in nine countries. Adults (aged ≥18 years) with type 2 diabetes (HbA1c ≥8·0%) receiving oral glucose-lowering medications were randomly allocated in a 1:1 ratio without stratification to IcoSema or once-daily glargine U100. The titration target was 3·9-5·0 mmol/L (70-90 mg/dL). The primary endpoint was change in HbA1c and the secondary confirmatory endpoint was change in bodyweight, both from baseline to week 40, evaluated in all randomly allocated participants. Adverse events were recorded during weeks 0-45. This trial is registered with ClinicalTrials.gov (NCT06269107) and is complete. FINDINGS: Of 653 individuals screened between Feb 15 and Aug 6, 2024, 151 did not meet screening criteria and 17 withdrew before initiating treatment; 243 were randomised to IcoSema and 242 to glargine U100. Of the 485 randomly allocated participants, 286 (59%) were male and 199 (41%) were female, and median age was 58 years (range 26-82). For HbA1c, from baseline (9·57% for IcoSema and 9·50% for glargine U100), mean change to week 40 was greater with IcoSema versus glargine U100 (-3·32 vs -2·44 percentage points; estimated treatment difference [ETD] -0·88 percentage points [95% CI -1·12 to -0·63]), confirming superiority of IcoSema (p<0·001). From baseline to week 40, mean bodyweight decreased with IcoSema and increased with glargine U100 (-0·79 vs 3·81 kg; ETD -4·61 kg [95% CI -5·46 to -3·75]), confirming superiority of IcoSema (p<0·001). Rate of combined clinically significant (blood glucose <3·0 mmol/L [<54 mg/dL], confirmed with a blood glucose meter) or severe hypoglycaemia (severe cognitive impairment requiring external assistance for recovery) was statistically significantly lower with IcoSema versus glargine U100 (0·29 vs 0·59 episodes per person-year of exposure; estimated rate ratio 0·56 [95% CI 0·32 to 0·97]; p=0·04). Gastrointestinal disorders were the most frequently reported adverse events with IcoSema. INTERPRETATION: Once-weekly IcoSema demonstrated superior HbA1c reduction and bodyweight change, with lower rates of clinically significant or severe hypoglycaemia, versus glargine U100, suggesting that IcoSema might be an effective once-weekly treatment option for insulin-naive individuals with type 2 diabetes inadequately controlled on oral glucose-lowering medications. FUNDING: Novo Nordisk.

Humans↗

PubMed2026

Aortoesophageal Fistula: Mending the Lethal Connection-A Systematic Review and Meta-Analysis.

BACKGROUND: Aortoesophageal fistula (AEF) is a rare, life-threatening condition with limited high-quality evidence to guide management. METHODS: We conducted a systematic review and meta-analysis of PubMed and Scopus through December 2025, evaluating survival and complication outcomes according to treatment strategy and morphological severity. Patients were categorized into 5 groups: TEVAR alone, staged TEVAR followed by surgery, primary open or hybrid surgery, TEVAR with esophageal stenting, and supportive/palliative care. Outcomes were pooled as proportions with 95% confidence intervals (CIs). RESULTS: A total of 167 reports representing 528 patients were included. Overall 30-day mortality was 31.2% (95% CI 27.0% to 35.7%) and 1-year mortality 41.2% (95% CI 36.2% to 46.4%). Infection occurred in 32.6%, reintervention in 20.2%, and recurrence in 13.2%. Staged TEVAR followed by surgery showed favorable survival (30-day 12.7%, 1-year 26.1%) but high infection (66.7%) and reintervention (43.2%) rates. TEVAR with esophageal stenting had the lowest early mortality (5.0%) but frequent reintervention (54.5%) and 1-year mortality of 33.3%. TEVAR alone demonstrated the lowest 1-year mortality among definitive strategies (25.5%) but notable recurrence (26.9%). Primary open or hybrid surgery carried higher early and late mortality, while supportive/palliative care had the worst outcomes. Morphological severity correlated strongly with mortality, infection, reintervention, and recurrence, with type IV lesions showing particularly poor prognosis. CONCLUSION: Despite contemporary management, AEF carries high early and late mortality. Definitive strategies, particularly staged TEVAR followed by surgery, offer improved survival but increased complications. Morphology-guided, individualized management is recommended.

Adult↗

PubMed2026

Dietary approaches for glycemic management in type 1 diabetes: A systematic review of Mediterranean and low-carbohydrate diets.

BACKGROUND/OBJECTIVES: Specific dietary approaches for better management of type 1 diabetes (T1D) have not been thoroughly investigated. We conducted a systematic review to evaluate the Mediterranean and low-carbohydrate diets for glycemic management in people with T1D. METHODS: We examined longitudinal studies (cohort studies and clinical trials) including individuals with T1D who followed low-carbohydrate diets (<26% calories from carbohydrates and/or <130 g of carbohydrates per day) and/or a Mediterranean diet, while hemoglobin A1c (HbA1c) and/or time in range (TIR) were measured. Additional eligibility criteria included publication in English and availability of a full-text primary research article. Non-longitudinal studies, abstracts, and studies published in languages other than English were excluded. Results were synthesized narratively, and the GRADEpro Guideline Development Tool was used to assess article quality. RESULTS: A total of 565 studies were identified from PubMed, the Web of Science, and citation chasing. After removal of duplicates and further evaluation, 22 studies (6 cohort studies and 16 clinical trials; total n = 3284) were included in this review. The search was initially completed in May 2024, and updated February 2026. Low-carbohydrate diets were associated with better glycemic management when compared to usual diets or baseline glycemic parameters. Studies using CGM were overall underpowered. The impact of Mediterranean diets was less clear, but generally appeared to be less effective at improving glycemic management than low-carbohydrate diets. DISCUSSION: Although structured dietary interventions for T1D hold promise for improving glycemic outcomes, further research is needed to determine exactly which dietary intervention is most beneficial for this population. The evidence provided by included studies is limited by small sample sizes and short durations; better powered, longer-term studies are required to inform clinical recommendations.

Humans↗

PubMed2026

Durability and Safety of Imeglimin as an Add-On to DPP-4 Inhibitors in Japanese Type 2 Diabetes: The 104-Week FAMILIAR Trial.

AIMS: To evaluate the long-term efficacy and safety of imeglimin added to dipeptidyl peptidase-4 (DPP-4) inhibitors in Japanese patients with type 2 diabetes, focusing on glycemic durability and safety in elderly patients over 104 weeks. MATERIALS AND METHODS: This multicenter, randomized, placebo-controlled trial comprised a 24-week double-blind phase (imeglimin 1000 mg or placebo twice daily) followed by an 80-week open-label extension in which all patients received imeglimin. Eligible patients had inadequate glycemic control despite DPP-4 inhibitor monotherapy. The main assessment measured HbA1c changes from baseline to week 104. Secondary assessments included meal tolerance tests (MTT) for evaluating physiological changes in β-cell function and insulin resistance and safety monitoring. RESULTS: Of 117 randomized patients, 81 completed 104 weeks. In the early-start group that received imeglimin from week 0, the significant HbA1c reduction observed at week 24 (-0.65%) was maintained through week 104 (-0.55%; p < 0.001 vs. baseline). The delayed-start group that switched to imeglimin at week 24 achieved similar glycemic control thereafter. Elderly patients (≥ 65 years) in the early-start group maintained stable HbA1c reduction (-0.58%) without hypoglycemic events over 2 years. MTT analysis in the early-start group showed sustained improvements in glucose AUC and insulin sensitivity without unnecessary insulin secretion over time. CONCLUSIONS: Imeglimin added to DPP-4 inhibitors appeared to improve glycemic control for 104 weeks, without clear attenuation. The combination was well-tolerated with a low risk of hypoglycemia even in elderly patients. The long-term effect may be associated with improvements in insulin sensitivity. TRIAL REGISTRATION: jRCTs061210082.

Humans↗