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PubMed2025

MammaPrint predicts chemotherapy benefit in HR+HER2- early breast cancer: FLEX Registry real-world data.

BACKGROUND: Gene expression assays help personalize adjuvant chemotherapy decisions for hormone receptor-positive, HER2-negative (HR+HER2-) early breast cancer (EBC). The 70-gene risk of distant-recurrence signature, MammaPrint, demonstrated clinical utility in guiding chemotherapy de-escalation in genomically low risk patients in the MINDACT trial. This study evaluates MammaPrint as a continuous predictor of chemotherapy benefit in HR+HER2- EBC using real-world data (RWD) from the FLEX Registry. METHODS: The study evaluated 1002 patients treated with endocrine therapy (ET) only or ET with chemotherapy (ET+CT) enrolled in FLEX (NCT03053193) with 5-year median follow-up. Propensity-score matching balanced treatment groups by menopausal status, T-stage, and nodal status. The primary endpoint was distant recurrence-free interval (DRFI). Regression and Cox proportional hazards models assessed chemotherapy benefit across MammaPrint Index (MPI) risk. RESULTS: Most patients were postmenopausal (70.1%), node-negative (70.0%), and had grade 2 tumors (51.2%). The regression models showed that MPI strongly predicted 5-year DRFI in ET only (R2 = 0.99, P < .001) and ET + CT (R2 = 0.90, P < .001) groups, corresponding to an average absolute chemotherapy benefit of 5.6% in High 1 and 10.9% in High 2. Minimal improvement in DRFI with chemotherapy was observed for Low (1.7%) and UltraLow (<1.0%) risk groups. A multivariate Cox model with an MPI-by-treatment interaction term demonstrated that increasing MPI risk was associated with greater chemotherapy benefit on DRFI (HR = 0.15, P = .047). Chemotherapy benefit was significantly associated with premenopausal status, but not age, T-stage, nodal status, or grade. CONCLUSIONS: These RWD from the FLEX Registry demonstrate that MPI is predictive of both DRFI prognosis and chemotherapy benefit in HR+HER2- EBC. (NCT03053193).

Adult↗

PubMed2026

Association of cancer antigen 15-3 with distant recurrence in immunohistochemically defined breast cancer subtypes in Canadian Cancer Trials Group MA.32.

BACKGROUND: Circulating levels of cancer antigen (CA) 15-3 have been associated with distant breast cancer recurrence; data on breast cancer subtypes are sparse. We examined associations of CA 15-3 with outcomes across immunohistochemically defined breast cancer subtypes in MA.32. METHODS: A total of 3649 participants with T1-3, N0-1, M0 breast cancer were randomly assigned; 2740 (75.1%) provided blood at entry (mean = 278 days postdiagnosis) and 6 months later. Prognostic associations of baseline and 6-month change in CA 15-3 with distant recurrence-free survival (RFS) were examined in luminal (estrogen receptor-positive and/or progesterone receptor-positive, HER2-negative), triple-negative (estrogen receptor, progesterone receptor, HER2 negative) and HER2-positive (any estrogen receptor, progesterone receptor) breast cancer using Cox proportional hazards models. RESULTS: Mean age was 52 years. Breast cancer was luminal in 1589 (58.7%), triple negative in 655 (24.2%), and HER2 positive in 464 (17.1%) participants. Median follow-up was 96 months. CA 15-3 at study entry was not associated with outcome in any subtype. Rising CA 15-3 at 6 months was associated with poor distant RFS in luminal and triple-negative breast cancer (hazard ratio [HR] per 25% increase = 1.41, P < .0001, and HR = 1.35, P < .0001, respectively). New elevations in CA 15-3 at 6 months were adversely associated with distant RFS in those with luminal or triple-negative breast cancer (HR = 4.14, 95% CI = 2.69 to 6.38; P < .001; and HR = 3.57, 95% CI = 1.59 to 7.99; P = .002, respectively). In HER2-positive breast cancer, CA15-3 was not associated with distant RFS. CONCLUSION: Rising CA 15-3 was associated with reduced distant RFS in luminal and triple-negative breast cancer but not in HER2-positive breast cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01101438.

Humans↗

PubMed2025

MUC5B promoter variant and survival in rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVE: The objective of this study was to investigate the association between the MUC5B rs35705950 promoter variant and survival in RA-associated interstitial lung disease (RA-ILD). METHODS: We studied participants in the Veteran Affairs Rheumatoid Arthritis (VARA) registry with validated ILD diagnoses. Participants were followed until death or till the end of the study period. The MUC5B rs35705950 promoter variant was measured using an Infinium genotyping array, assuming autosomal dominant inheritance. Survival and cause of death were determined from VA death records and the National Death Index. Associations of the MUC5B promoter variant with survival were tested in Cox regression models, adjusting for potential confounders. RESULTS: Among 263 participants with RA-ILD (mean age 69 years, 95% male, 73% White, 85% smoking history), the MUC5B promoter variant was present in 33.5%. The mortality rate was similar between those with [12.2/100 PY (95% CI: 9.4, 15.8)] and without [11.1/100 PY (95% CI: 9.1, 13.5)] the variant. MUC5B status was not significantly associated with survival overall [aHR 0.97 (95% CI: 0.68, 1.37)] or when stratified by ILD pattern [clinical usual interstitial pneumonia (UIP) aHR 0.86 (95% CI: 0.55, 1.35); clinical non-UIP aHR 1.15 (95% CI: 0.63, 2.09)]. Further, MUC5B status was not significantly associated with respiratory-related [aHR 0.83 (95% CI: 0.42, 1.66)] or non-respiratory causes of death [aHR 1.08 (95% CI: 0.72, 1.62)]. CONCLUSION: While associated with RA-ILD risk, the MUC5B promoter variant was not predictive of survival among RA-ILD patients in this multicentre cohort. Further studies are needed to identify other genetic and non-genetic prognostic factors in RA-ILD to inform disease management.

Humans↗

PubMed2025

Sex differences in cerebrospinal fluid proteomics of patients with restless legs syndrome.

STUDY OBJECTIVES: The pathobiology of restless legs syndrome (RLS) remains poorly understood, complicating effective treatment. This observational cross-sectional study aimed to identify a cerebrospinal fluid proteomic signature of RLS and to explore sex-specific differences in cerebrospinal fluid proteomics. METHODS: Cerebrospinal fluid samples were collected from 22 untreated RLS patients and 18 controls, matched for age, body mass index, and sex. Proteomic analysis was conducted using the SOMAscan platform, assessing over 7000 peptides. RESULTS: Eight proteins were differentially abundant between patients and controls, with CRP and JAML increased, and TAPBPL and IL1RL1 decreased. Pathway analysis highlighted significant involvement in immune response, coagulation, and cytoskeletal regulation. Analyses were then carried out using sex stratification, comparing men and women separately. Sex-specific analyses revealed more pronounced proteomic alterations in males (68 differentially abundant proteins vs. control males) than in females (17 proteins). Gene enrichment analysis revealed that men with RLS had more involvement in gene regulation and epigenetic factors than control males and women with restless legs syndrome had greater involvement in systemic inflammatory and vascular processes than control females. CONCLUSIONS: This study identified a cerebrospinal fluid proteomic signature in RLS, implicating immune and inflammatory pathways in the disease's pathophysiology. Significant sex differences in protein level suggest potential sex-specific mechanisms in RLS, warranting further investigation. These findings contribute to the current understanding of RLS and could inform future therapeutic strategies.

Humans↗

PubMed2026

A randomized trial of viral vector and adjuvanted protein HBV therapeutic vaccine in people with chronic hepatitis B on nucleos(t)ide analogs.

BACKGROUND: This study assessed the safety, efficacy, and immunogenicity of a therapeutic immunization strategy aimed at reaching a functional cure for chronic hepatitis B (CHB), relying on a heterologous prime-boost with viral vectors ChAd155-hIi-HBV and MVA-HBV, combined with sequential or concomitant administration of adjuvanted recombinant HBV proteins (HBc-HBs/AS01B). METHODS: This single-blind, randomized, controlled, first-in-human, phase 1/2 trial enrolled adults aged 18-65 years with HBeAg-negative CHB, virally suppressed on nucleos(t)ide analogs (NAs), with HBsAg >50 IU/mL. Participants received NAs and the following regimens of 4 doses (8-week intervals): sequential administration of ChAd155-hIi-HBV, MVA-HBV, and 2 HBc-HBs/AS01B doses; co-administration of ChAd155-hIi-HBV+HBc-HBs/AS01B, followed by 3 co-administered MVA-HBV+HBc-HBs/AS01B doses; 4 HBc-HBs/AS01B doses; 2 placebo doses followed by ChAd155-hIi-HBV and MVA-HBV administered alone or with HBc-HBs/AS01B; or 4 placebo doses. Safety, efficacy (≥1-log decrease in quantitative (q)HBsAg or HBsAg loss 24 weeks post-dose 4 [day (D)337]), antibody, and T-cell responses were evaluated. RESULTS: In all, 134 participants were vaccinated. Grade 3 solicited adverse events (AEs) (median duration: 2-3 days) were more frequent after co-administration (systemic: 59.3%; administration-site: 33.3%) than sequential administration (systemic: 10.3%; administration-site: 12.8%) of high-dose viral vectors and proteins. No vaccine-related or fatal serious AEs were reported. After 4 doses, no participant had HBsAg loss or ≥1-log decrease in qHBsAg (D337 vs. D1). Co-administration induced the strongest anti-HBs response (73.7% achieved anti-HBs ≥10 mIU/mL 2 weeks post-dose 4 vs. 40.0% after sequential administration). Both sequential and co-administration induced HBc-specific CD4+ and CD8+ T-cell responses, with a prime-boost effect of the viral vectors. CONCLUSIONS: Heterologous prime-boost with ChAd155-hIi-HBV and MVA-HBV, combined with sequential or co-administration of HBc-HBs/AS01B, had an acceptable safety profile, were moderately immunogenic, but no participants showed the expected efficacy outcome.

Humans↗

PubMed2026

HLA and non-HLA genetic analyses reveal suggestive variants associated with statin-induced liver injury.

BACKGROUND: Statins are widely prescribed for cardiovascular risk reduction and are generally well tolerated. However, they can cause drug-induced liver injury (DILI), and the genetic factors contributing to statin-DILI remain poorly understood. METHODS: HLA association and genome-wide association (GWAS) studies were conducted to identify genetic variants associated with statin-DILI. High-confidence cases (n=71) were identified from the Drug-Induced Liver Injury Network (DILIN) and compared with statin-exposed controls without liver injury (n=551) from the Indiana Biobank. Association testing was performed across ancestries and within ancestry, adjusting for age, sex, and three principal components of genotypes. Top variants were further evaluated in non-statin DILI cases and unexposed controls. In addition, we investigated the frequency of candidate variants among a comprehensive list of pharmacogenetic variants related to statins. RESULTS: HLA-DQA1*03:01 was significantly associated with increased risk of statin-DILI (OR=3.49, 95% CI 2.21-5.51, p-value=1.27×10-7), with enrichment observed across multiple ancestry groups, particularly non-Hispanic Black and Hispanic individuals. From the GWAS, three loci showed suggestive associations (p-value <5×10-06) with statin-DILI, including rs35197737 in RGS1 (OR=5.03, 95% CI 1.11-3.66, p=1.14×10-7), rs75629598 in FRMD4A (OR=4.4, 95% CI=2.33-8.12, p=3.97×10-6), and rs7658630 in the intergenic region on chromosome 4 (OR=4.86, 95% CI 2.66-8.85, p=2.68×10-7). No pharmacogenetic variants revealed statistical significance. CONCLUSION: We identified HLA and non-HLA genetic variants associated with statin DILI. Future studies with larger sample sizes should confirm these observations.

Humans↗

PubMed2024

Multiple urinary peptides are associated with hypertension: a link to molecular pathophysiology.

OBJECTIVES: Hypertension is a common condition worldwide; however, its underlying mechanisms remain largely unknown. This study aimed to identify urinary peptides associated with hypertension to further explore the relevant molecular pathophysiology. METHODS: Peptidome data from 2876 individuals without end-organ damage were retrieved from the Human Urinary Proteome Database, belonging to general population (discovery) or type 2 diabetic (validation) cohorts. Participants were divided based on systolic blood pressure (SBP) and diastolic BP (DBP) into hypertensive (SBP ≥140 mmHg and/or DBP ≥90 mmHg) and normotensive (SBP <120 mmHg and DBP <80 mmHg, without antihypertensive treatment) groups. Differences in peptide abundance between the two groups were confirmed using an external cohort ( n  = 420) of participants without end-organ damage, matched for age, BMI, eGFR, sex, and the presence of diabetes. Furthermore, the association of the peptides with BP as a continuous variable was investigated. The findings were compared with peptide biomarkers of chronic diseases and bioinformatic analyses were conducted to highlight the underlying molecular mechanisms. RESULTS: Between hypertensive and normotensive individuals, 96 (mostly COL1A1 and COL3A1) peptides were found to be significantly different in both the discovery (adjusted) and validation (nominal significance) cohorts, with consistent regulation. Of these, 83 were consistently regulated in the matched cohort. A weak, yet significant, association between their abundance and standardized BP was also observed. CONCLUSION: Hypertension is associated with an altered urinary peptide profile with evident differential regulation of collagen-derived peptides. Peptides related to vascular calcification and sodium regulation were also affected. Whether these modifications reflect the pathophysiology of hypertension and/or early subclinical organ damage requires further investigation.

Humans↗

PubMed2024

Mediating effects of BMI on the association between DNA methylation regions and 24-h blood pressure in African Americans.

BACKGROUND: DNA methylation is an important epigenetic mechanism that may influence blood pressure (BP) regulation and hypertension risk. Obesity, a major lifestyle factor associated with hypertension, may interact with DNA methylation to affect BP. However, the indirect effect of DNA methylation on 24-h BP measurements mediated by obesity-related phenotypes such as BMI has not been investigated. METHODS: Causal mediation analysis was applied to examine the mediating role of BMI in the relation between DNA methylation and 24-h BP phenotypes, including SBP, DBP and mean arterial blood pressure (MAP), in 281 African American participants. RESULTS: Analysis of 38 215 DNA methylation regions, derived from 1 549 368 CpG sites across the genome, identified up to 138 methylation regions that were significantly associated with 24-h BP measurements through BMI mediation. Among them, 38 (19.2%) methylation regions were concurrently associated with SBP, DBP and MAP. Genes associated with BMI-mediated methylation regions are potentially involved in various chronic diseases such as coronary artery disease and renal disease, which are often caused or exacerbated by hypertension. Notably, three genes ( CDH4 , NOTCH1 and COLGALT1 ) showed both direct associations with 24-h BP measurements and indirect associations through BMI after adjusting for age and sex covariates. CONCLUSION: Our findings suggest that DNA methylation may contribute to the regulation of 24-h BP in African Americans both directly and indirectly through BMI mediation.

Humans↗

PubMed2026

Association between orthostatic blood pressure change and masked and white coat hypertension: the Nagahama study.

BACKGROUND: Exaggerated blood pressure (BP) response to orthostatic stimuli is indicative of cardiovascular frailty and may be associated with masked and white coat hypertension, which are BP abnormalities associated with cardiovascular outcomes. We aimed to clarify this possible association in a cross-sectional analysis of a large general population. METHODS: We enrolled 7618 community residents (mean age: 57.7 years). Orthostatic BP change was calculated as the difference between systolic BP measured in a seated position and at 3 min after standing. Orthostatic hypertension and hypotension were defined as >20 mmHg increase or decrease in systolic BP, respectively. Masked and white coat hypertension were defined based on office and home morning BP measurements. RESULTS: The frequency of orthostatic hypotension and hypertension was 1.8% and 1.6%, respectively. A significant association was observed between orthostatic BP change and office-to-home BP differences, that is, the greater the increase in orthostatic BP, the higher the home BP than the office BP. The association between orthostatic hypertension and masked hypertension (crude odds ratio: 3.15; P  < 0.001) remained significant even after adjusting for potential covariates, including office seated BP. In addition, orthostatic hypotension was independently associated with white coat hypertension (crude odds ratio: 2.14; P  = 0.002). Orthostatic BP change measured at 3 min showed a clearer association with masked and white coat hypertension than that measured at 1 min. CONCLUSION: We identified a physiological association between exaggerated postural BP variability and office-to-home BP differences, which were previously considered unrelated.

Humans↗

PubMed2026

Home blood pressure telemonitoring reveals race-specific patterns of target organ damage.

BACKGROUND: Racial differences in cardiac and renal target organ damage (TOD) may persist at comparable blood pressure levels. This study compared TOD in high-risk, non-African-American Black and White patients in relation to the home blood pressure (HBP). METHODS: UPRIGHT-HTM (NCT04299529) is an ongoing international trial comparing risk stratification strategies in asymptomatic patients, aged 55-75  years, with ≥5 risk factors. Patients engage in HBP telemonitoring (OMRON HEM 9210-T). After 34.7 months (median), 287 Black and 154 White patients underwent echocardiography. At baseline, their chronic kidney disease (CKD) grade was assessed by cross-classification of the race-free estimated glomerular filtration rate and albuminuria (2024 KDIGO guideline). HBP was stratified by the 2024 ESC thresholds. Linear and logistic regression models, including a race-by-HBP interaction term, were applied to assess associations with the home systolic HBP. RESULTS: The number of HBP readings was 252 215. Median systolic/diastolic HBP was 127/77 mmHg with 142 patients (32.2%) having home hypertension. Fewer Black patients received statins or combination therapy for hypertension or diabetes. Among nonhypertensive White compared to Black patients, left atrial dimensions, mitral annular s', and stroke volume had a steeper slope in relation to systolic HBP. All patients had concentric left ventricular remodeling, but only 4 Black and 13 White patients had an ejection fraction < 50%. CKD grade was worse in Black than White patients without association with HBP. CONCLUSIONS: TOD primarily affects the kidney in Black and the heart in White patients. Intensifying pharmacological treatment in sub-Saharan Africa, including antihypertensives, lipid-lowering agents, antidiabetic medications, and aspirin, should create an opportunity for improved overall cardiovascular and metabolic prevention.

Aged↗

PubMed2026

Phentermine/Topiramate in Obese, Diabetic Uric Acid Stone Formers: An Open-Label Randomized Feasibility Trial.

PURPOSE: The purpose of this study was to determine whether medical treatment of obesity, diabetes, and low urine pH with combination phentermine/topiramate affects uric acid (UA) kidney stone burden. MATERIALS AND METHODS: Participants with obesity, diabetes mellitus, normal renal function, urine pH < 5.8, and stone analysis ≥ 80% UA were block randomized (2:1 ratio) to phentermine 18.75 mg/topiramate 100 mg vs pragmatic controls for an 18-month, prospective, open-label feasibility study with dose escalation. The primary outcome was change in CT stone volume. Secondary outcomes included medication adherence; patient safety; and change in anthropometrics, laboratory studies, and body composition. RESULTS: Nineteen participants (age 62.1 ± 9.8 years; 68% male; mean BMI = 36.3 ± 2.9 kg/m2) were randomized, and 15 completed the study with 73% pill adherence and no serious adverse events. Stone volume by intention-to-treat analysis fell by 52% in the intervention group and rose by 8.6% in the control group (P = .10), with per-protocol analysis demonstrating statistically significant stone volume reduction (P = .02). At study end and compared with means of controls, the intervention group had greater weight loss (-10.2 vs +2.9 kg), reduction in hemoglobin A1c levels (-0.2 vs +0.5), lower 24-hour urine citrate (309 ± 81 vs 951 ± 782 mg), and lower UA supersaturation (0.7 ± 1.1 vs 1.8 ± 1.0), along with higher 24-hour urine pH (6.2 ± 0.5 vs 5.5 ± 0.4) and calcium phosphate supersaturation (0.9 ± 0.8 vs 0.2 ± 0.1; all P < .05). CONCLUSIONS: Among obese participants with diabetes mellitus and UA nephrolithiasis, phentermine/topiramate was well tolerated and demonstrated significant stone burden reductions by per-protocol analysis. The intervention group also had greater weight loss, higher urinary pH, and lower hemoglobin A1c and urinary citrate levels. These data provide a framework to study the impact of this novel alternative UA therapy on a wider range of patients with obesity and diabetes.

Aged↗

PubMed2026

Epidemiology, diagnosis, and surgical management of urolithiasis in older adults: overview from EAU endourology.

PURPOSE OF REVIEW: Population ageing is changing everyday urological practice. The number of older adults is increasing, and urology already treats a patient population that is, on average, older than the general population. Consequently, older adults with urolithiasis represent a core part of contemporary endourological practice. Given this, a focused review of the available evidence is valuable to inform clinical practice. RECENT FINDINGS: A peak in stone disease can occur in older adults who may also be less likely to present with the classical features of renal colic. As such, delayed or missed diagnosis may carry greater clinical consequences. Although the literature remains relatively limited, ureteroscopy, shock wave lithotripsy, and percutaneous nephrolithotomy remain feasible options in appropriately selected older adults. In this group in particular, broader health associations merit consideration, as the presence of urolithiasis in older adults may reflect overall health status in later life. SUMMARY: The burden of urolithiasis in older adults is increasing and now represents a routine component of everyday clinical practice. Clinical presentation may differ from that seen in younger "index" patients, and complications may have a greater impact on recovery and function. Management should therefore be individualized, taking into account comorbidity, frailty, functional status, and the patient's own priorities.

Humans↗

PubMed2026

Vaginal Hysterectomy Versus Vaginal Assisted Natural Orifice Transluminal Endoscopic Surgery Hysterectomy; Results of a Randomised Controlled Trial.

OBJECTIVE: To compare Vaginal Hysterectomy (VH) with Vaginal Assisted Natural Orifice Transluminal Endoscopic Surgery (NOTES) hysterectomy (VANH) as a day-care procedure. DESIGN: Single-blind, multicentre randomised controlled trial. SETTING: Two Dutch non-academic teaching hospitals. POPULATION: Women aged ≥ 18 years undergoing hysterectomy for benign indications. METHODS: Women were randomised 1:2 (VH or VANH). Primary outcome was SDD. Secondary outcomes included operative time, rate of elective salpingectomies, intraoperative blood loss, complications (Clavien-Dindo), pain scores (NRS) and analgesic use, post-operative recovery (RI-10), and quality of life (EQ-5D-5L). Analyses were performed on an intention-to-treat basis. RESULTS: A total of 113 patients were included in the analyses (n = 42 VH, and n = 71 VANH). SDD occurred significantly more frequently in the VANH group (87.3%) than VH group (71.4%; OR 2.76, 95% CI 1.04-7.25; p = 0.04). VANH was associated with a significantly shorter operative time (median 55 min versus 65 min; p = 0.005), less blood loss (median 50 mL vs. 150 mL; p < 0.001) and more often elective opportunistic salpingectomy compared to VH (100% vs. 77.4%; p = 0.008). NRS were significantly lower in the VANH group the first hour post-operative (3 vs. 1, p < 0.001). Post-operative complications (VH 9.5% vs. VANH 15.5%; p = 0.34), readmission (VH 4.8% vs. VANH 8.5%; p = 0.47), analgesic use, recovery, and quality of life were not statistically significant. CONCLUSIONS: VANH is a safe and effective alternative to VH, offering a higher likelihood of SDD, shorter operative time, reduced blood loss, and more often an elective salpingectomy, without increased complications or differences in pain, recovery, or quality of life.

Humans↗

PubMed2026

Empirical Meropenem Versus Piperacillin/Tazobactam for Critically Ill Adults With Sepsis: Feasibility of a Randomised Trial.

BACKGROUND: Meropenem and piperacillin/tazobactam are commonly used empirical antibiotics in critically ill adults with sepsis, but whether one is superior to the other is uncertain. METHODS: The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an ongoing investigator-initiated, randomised, open-label, adaptive clinical trial with an integrated feasibility phase comparing empirical treatment with meropenem versus piperacillin/tazobactam in critically ill adults with sepsis. The integrated feasibility phase enrolled 200 participants across 10 intensive care units (ICUs) in Denmark between 28 June and 12 December 2025. Five pre-specified feasibility criteria were evaluated; if all feasibility criteria were met, the trial would proceed unaltered, whereas failure to meet one or more criteria would require intervention and re-evaluation. RESULTS: We randomised 200 of 284 screened patients (70.4%). The median age was 70 years (interquartile range (IQR): 60-77), 65.5% were males. At randomisation, 80.0% received vasopressors or inotropes, and 43.5% were on invasive mechanical ventilation. Four of five pre-specified feasibility criteria were met: time to completion of the feasibility phase (5.5 months vs. threshold < 12.0 months), recruitment proportion (70.4% vs. threshold ≥ 50.0%), proportion of participants without consent to the continued collection of data (2.5% vs. threshold < 5.0%) and protocol adherence (81.0% vs. threshold ≥ 75.0%). The proportion of participants with timely primary outcome data availability (30-day mortality) within 45 days was 85.5% and below the pre-specified threshold of ≥ 95.0%. The proportions were low in the first 3 months (33.3%, 22.2% and 30.8%, respectively), increasing to 95.8% in the last month of the feasibility phase. All-cause mortality at 30 days was 30.5%, and specific serious adverse reactions occurred in 4.0% of participants. CONCLUSIONS: In this integrated feasibility evaluation of the EMPRESS trial comparing empirical meropenem versus piperacillin/tazobactam in critically ill adults with sepsis, four of five pre-specified feasibility criteria were met. The unmet criterion, timely primary outcome data availability, improved substantially during the feasibility phase. We consider the trial feasible and will proceed without modifications. EDITORIAL COMMENT: This feasibility study assessed recruitment, randomised allocation and data collection for the multicentre EMPRESS trial. For adaptive trials on trial platforms, careful interim checking of trial design functions is an important and necessary process. TRIAL REGISTRATION: Clinical Trials Information System EUCT number: 2023-509703-33-00; ClinicalTrials.gov identifier: NCT06184659; Universal Trial Number: U1111-1301-6379.

Humans↗

PubMed2025

Integrative proteomic analysis provides novel therapeutic insights for etiological subtypes of diabetes.

AIMS: Type 2 diabetes (T2D) is a highly heterogeneous disease characterised by subtypes with variations in aetiology, disease progression, and risk of complications. However, potential drug targets for these subtypes have not been explored. This study aims to investigate potential drug targets by integrating proteomics. MATERIALS AND METHODS: Summary-level data of circulating proteins were extracted from the UK Biobank and the deCODE Health Study. Genetic associations with five diabetes subtypes were obtained from Swedish All New Diabetics in Scania and Malmö Diet and Cancer cohort, including severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). The associations between circulating proteins and diabetes subtypes were assessed through Mendelian randomisation, followed by multiple sensitivity and colocalization analyses. Additionally, tissue-specific, pathway and functional enrichment analysis, assessment of protein druggability, and the protein-protein interaction (PPI) networks were used to further explore biological mechanisms and therapeutic potential. RESULTS: Genetically predicted levels of 2, 2, 9, 3, and 5 circulating proteins were associated with SIRD, SIDD, MARD, MOD, and SAID, respectively. Colocalization analyses further revealed links between GRN with MARD/SIRD, LILRB5 with SIDD/MARD, CR1 with MARD, TNFSF12 with MOD, and DAPK2 with SAID. Enrichment analysis suggested that these proteins were mainly enriched in blood and adipose tissues and involved in immune and inflammatory related pathways. PPI analysis revealed GRN, TNFSF12, and DAPK2 are associated with known T2D targets. CONCLUSIONS: Our study identified several potential drug targets for different subtypes of diabetes using an integrated genetic approach, yielding new insights for precision medicine of diabetes.

Humans↗

PubMed2026

Gold and Clarke Questionnaires Identify Different People With Insulin-Treated Diabetes and Impaired Awareness of Hypoglycaemia in Almost 60% of Cases: A Post Hoc Analysis From the Hypo-METRICS Study.

AIMS: Gold and Clarke questionnaires are used to identify impaired awareness of hypoglycaemia (IAH) and severe hypoglycaemic event (SHE) risk in people with diabetes (pwD). We explored their overlap, including Clarke's Hypoglycaemia Awareness Status (Clarke-HAS) subfactor, and subsection differences in SHE incidence (Gold, Clarke, overlap). MATERIALS AND METHODS: This post hoc analysis of the Hypo-METRICS study recruited pwD on insulin (type 1: T1D; type 2: T2D) with ≥ 1 hypoglycaemic event in the previous 3 months. IAH was defined as Gold ≥ 4, Clarke ≥ 4, Clarke-HAS ≥ 2. RESULTS: Gold and Clarke were completed by 232 pwT1D and 285 pwT2D (age: 47 vs. 62 years, p < 0.001; HbA1c: 56 mmol/mol (7.3%) vs. 57 mmol/mol (7.4%), p = 0.03). IAH prevalence in T1D vs. T2D was 21% vs. 26% (p = 0.1), 14% vs. 18% (p = 0.2), and 41% vs. 48% (p = 0.2) according to Gold, Clarke and Clarke-HAS. The overlap between Gold ≥ 4, Clarke ≥ 4 was 40% (T1D: 45%; T2D: 37%); between Gold ≥ 4, Clarke-HAS ≥ 2 it was 45% (T1D: 43%; T2D: 47%). The overlap between Gold ≥ 4, Clarke ≥ 4 was 41% vs. 39% in CGM vs. non-CGM users (T1D: 50% vs. 35%; T2D: 32% vs. 40%); between Gold ≥ 4, Clarke-HAS ≥ 2 it was 39% vs. 53% (T1D: 38% vs. 54%; T2D: 40% vs. 53%). In the IAH sample, SHE rate was lower in people found with IAH by Gold vs. Clarke, 9% vs. 53%, and in those assessed by Gold-Clarke overlap vs. Clarke, 20% vs. 53% (all p < 0.001). CONCLUSIONS: Gold and Clarke show moderate consistency (37%-54%) in identifying IAH in insulin-treated diabetes, with/without CGM use, each associated with different SHE rates, indicating the two questionnaires measure different, independent aspects of IAH.

Humans↗

PubMed2026

Large-Scale Plasma Proteomics Identifies Early Molecular Deviations and Improves Risk Prediction for Heart Failure Among Individuals With Obesity.

AIMS: Heart failure (HF) is a major global public health challenge, with obesity being one of its key risk factors. Although several HF risk prediction models have been developed in the general population, few are specifically tailored to individuals with obesity. This underscores the urgent need for precise biomarkers to improve individual risk stratification and enable personalized prevention strategies. We aimed to develop and validate a plasma proteomics-based protein risk score (PRS) to predict incident HF among individuals with obesity. MATERIALS AND METHODS: We analysed 9831 participants with obesity (BMI ≥ 30 kg/m2) from the UK Biobank with baseline measurements of 2911 circulating proteins and up to 16 years of follow-up. Multivariable Cox regression identified proteins associated with incident HF after comprehensive covariate adjustment. A PRS was constructed using LASSO regression and evaluated in a held-out test set. Protein trajectories before HF onset were reconstructed using LOESS modelling. To enhance clinical feasibility, a minimal protein panel was identified using LightGBM with forward feature selection. RESULTS: A total of 727 participants developed HF during follow-up. Multivariable cox analyses identified 578 proteins significantly associated with HF. LASSO regression further selected 81 proteins to build the PRS, which showed a strong association with HF risk in both training (HR 3.57; 95% CI 3.19-4.00) and test cohorts (HR 2.45; 95% CI 2.20-2.74). Adding the PRS improved prediction beyond age and sex (ΔC = 0.091) and beyond the Pooled Cohort Equations to Prevent Heart Failure (PCP-HF) model (ΔC = 0.052), with consistent gains in NRI and IDI. Proteomic deviations were detectable up to 16 years before diagnosis. A four-protein panel (GDF15, NT-proBNP, TNFRSF10B, CTHRC1) achieved robust discrimination (AUC 0.789), outperforming NT-proBNP alone (AUC 0.695) and complementing the PCP-HF model (combined AUC 0.803). DISCUSSION: Large-scale plasma proteomics substantially improves HF risk prediction in individuals with obesity and reveals long-standing molecular alterations preceding clinical onset. A simplified four-protein panel maintains robust predictive accuracy and provides a practical approach for the early detection and targeted prevention of obesity-related HF.

Humans↗

PubMed2026

Baseline Computed Tomography Coronary Angiography and Polygenic Risk Profiles in Adults With Type 2 Diabetes: A Cross-Sectional Analysis From the VOLTAIRE Study.

AIMS: To characterise baseline clinical, anatomical, and genetic cardiovascular risk profiles in participants enrolled in the VOLTAIRE (Evaluation of Polygenic Scores and CT Imaging in Risk Factor Modification in Patients with Type 2 Diabetes) study and examine concordance across these domains. METHODS: This analysis included adults with T2D who completed baseline computed tomography coronary angiography (CTCA) and polygenic risk score (PRS) assessment prior to randomisation in the VOLTAIRE study. Coronary atherosclerosis was evaluated using coronary artery calcium (CAC) score and CTCA-derived stenosis severity. Clinical risk was assessed using the New Zealand Society for the Study of Diabetes 5-year cardiovascular risk calculator. Polygenic risk for coronary artery disease was assessed using a genome-wide PRS and categorised into tertiles. RESULTS: Among 126 participants with T2D (mean age 57.5 ± 8.7 years; 62.7% male), coronary atherosclerotic burden was highly heterogeneous: 34.9% had CAC = 0, whereas 19.8% had CAC ≥ 400. Moderate-to-severe coronary stenosis (≥ 50%) was present in 40.5% of participants overall, including 20.4% of those classified as low clinical risk. PRS distribution was variable (low 37.3%, intermediate 35.7%, high 27.0%). Overlap between anatomical, genetic, and clinical domains was limited, with only 8.7% of participants classified as high risk across all three. CONCLUSIONS: Substantial heterogeneity and limited overlap exist between anatomical, genetic, and clinical cardiovascular risk measures in T2D. These findings support a multimodal approach to risk assessment integrating imaging and genetic profiling. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov; ID: NCT07091162.

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