MicroRNA-132 (miR-132) is a central regulator of adverse cardiac remodeling. Here we evaluated CDR132L, a synthetic antisense oligonucleotide miR-132 inhibitor, in a multinational, randomized, double-blind, placebo-contr...MicroRNA-132 (miR-132) is a central regulator of adverse cardiac remodeling. Here we evaluated CDR132L, a synthetic antisense oligonucleotide miR-132 inhibitor, in a multinational, randomized, double-blind, placebo-controlled phase 2 trial (HF-REVERT) in patients with recent myocardial infarction (MI) and left ventricular (LV) systolic dysfunction. Within 3-14 days after MI, 294 patients were randomized to receive CDR132L 5 mg kg, CDR132L 10 mg kg or placebo as three intravenous doses at 4-week intervals plus guideline-directed therapy. In total, 280 patients (245 men and 35 women) who received at least one dose of the study drug were included in the modified intention-to-treat population. CDR132L was well tolerated, with no hepatic, renal, hematologic or cardiac toxicity signals. The primary endpoint-the percentage change in LV end-systolic volume index at 6 months-improved in all groups but did not differ significantly between the CDR132L groups (5 mg kg and 10 mg kg) and the placebo group. Secondary endpoints, including LV ejection fraction, global longitudinal strain and N-terminal pro B-type natriuretic peptide, were also not significantly different between the CDR132L and placebo groups. Prespecified exploratory analyses suggested potential benefits of CDR132L treatment in patients with advanced adverse remodeling at baseline, supporting further evaluation of CDR132L, including in chronic heart failure conditions. ClinicalTrials.gov: NCT05350969 .
van Veldhuisen DJ, Rienstra M, Mosterd A
… +35 more, Alings M, Voors AA, Damman K, van Asselt ADI, Bouvy ML, Schaap J, van der Wall EE, Crijns HJGM, Touw DJ, Hoogslag PAM, van de Swaluw JEC, Schuurman RJ, van der Sluis A, Bondarenko O, Römer TJ, Oosterhof T, Bartels GL, Koudstaal S, Dijkmans PA, Linssen GCM, Aksoy I, Dorman HGR, Schut A, Hemels MEW, Tieleman RG, Lok DJA, Westendorp ICD, Vijver MAT, Voordes GHD, de Vos AH, Maas-Soer EL, Postmus D, Lunter G, Tijssen JGP, van der Meer P
Digoxin is the oldest drug in cardiovascular medicine, but its value in the current management of heart failure is unclear. Earlier studies have suggested that low-dose digoxin might be beneficial, but evidence from rigo...Digoxin is the oldest drug in cardiovascular medicine, but its value in the current management of heart failure is unclear. Earlier studies have suggested that low-dose digoxin might be beneficial, but evidence from rigorous randomized clinical trials is lacking. In this double-blind, placebo-controlled trial (the DECISION trial), 1,001 patients with symptomatic chronic heart failure and a left ventricular ejection fraction of 50% or less were randomized to low-dose digoxin or placebo, with a target serum digoxin concentration of 0.5-0.9 ng ml. The mean age of the participants was 72 ± 9 years, 28% were women and 29% had atrial fibrillation. The primary outcome was a composite of total worsening heart failure events, defined as total hospitalizations or total urgent hospital visits for worsening heart failure and cardiovascular mortality. Over a median follow-up of 36.5 months, 238 primary-outcome events occurred in 131 of 500 patients in the digoxin group, and 291 primary-outcome events in 152 of 501 patients occurred in the placebo group (rate ratio 0.81; 95% confidence interval (CI) 0.61-1.07, P = 0.133). The total number of worsening heart failure events was 155 and 203 in the digoxin and placebo groups, respectively (rate ratio 0.76, 95% CI 0.54-1.05) and cardiovascular mortality occurred in 83 patients (17%) and 88 (18%) in the digoxin and placebo groups, respectively (hazard ratio 0.93, 95% CI 0.69-1.26). Low-dose digoxin was generally well tolerated and safe, and results were similar between men and women. The results of this trial indicate that in patients with heart failure and reduced or mildly reduced ejection fraction, low-dose digoxin did not significantly reduce the composite endpoint of total worsening heart failure events or cardiovascular mortality. ClinicalTrials.gov registration: NCT03783429 .
Ogbogu PU, Roufosse F, Akuthota P
… +20 more, Kuna P, Groh M, Reiter A, Yokota A, Siddiqui SH, Mutsaers PGNJ, Li B, Khoury P, Bahadori LM, Bednarczyk A, Bouma G, Brooks LG, Ferreira J, Grindebacke H, Ho CN, Jain P, Palmer RL, Jison ML, Klion AD, NATRON study group
The American Heart Association's PREVENT equations estimate risk of total cardiovascular disease (CVD), atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) to guide lipid-lowering and blood pressure-low...The American Heart Association's PREVENT equations estimate risk of total cardiovascular disease (CVD), atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) to guide lipid-lowering and blood pressure-lowering therapy in people ages 30-79 years in the United States. The SCORE2 risk algorithm is used to estimate CVD risk for similar purposes in people ages 40 and older in Europe. Neither set of equations has been comprehensively validated in global observational cohorts and randomized trials. In this study, in 44 observational cohorts and 18 randomized trials, we assessed discrimination and calibration of the two risk algorithms across geographical regions (North America, Europe and Asia/Other or multiregional trials). We also created scaling factors for risk prediction over 1-9 years using the PREVENT equations, enabling shorter-term risk prediction for research purposes or to facilitate clinical trial enrollment. Over 5.1 years of mean follow-up, 293,737 PREVENT total CVD events (fatal and non-fatal ASCVD or HF) and 258,086 SCORE2 CVD events (myocardial infarction, stroke or cardiovascular death) were observed among 6,422,714 and 5,437,384 individuals, respectively. Despite differences in CVD outcome definitions, target populations and predictor variables, overall discrimination and calibration were similar for both equations, with generally good performance across regions, including in multiregional randomized trials. These findings lend support for adoption of PREVENT or SCORE2 for cardiovascular risk stratification across diverse settings.
Demircan K, Carrasco-Zanini J, Williamson A
… +13 more, Beuchel C, Jackson L, Römisch-Margl W, Hansen AL, Finer S, van Heel DA, Genes & Health Research Team, Kastenmüller G, Coghlan M, Moeller I, Wareham NJ, Pietzner M, Langenberg C
New obesity medications have demonstrated efficacy in trials, but their real-world deployment is partly limited by the absence of approaches that identify individuals for treatment based on risks for obesity-related comp...New obesity medications have demonstrated efficacy in trials, but their real-world deployment is partly limited by the absence of approaches that identify individuals for treatment based on risks for obesity-related complications. Here we present a risk prediction model to guide prioritization of high-risk individuals. In a population-based sample of ~200,000 individuals with a body mass index (BMI) exceeding 27 kg m, our machine learning framework identified the 20 most informative features, from among thousands tested, that predict future onset of 18 complications of obesity, providing information beyond BMI. An integrated model (OBSCORE) successfully stratified individuals into risk groups based on incidence over 10 years: for example, 5.7%, 1.8%, 0.9%, 0.4% and 0.1% for cardiovascular mortality. We demonstrate generalizability of the model in independent populations of European and non-European ancestry and, in SURMOUNT-1 trial participants, show that weight loss was similar across baseline OBSCORE risk groups and that predicted risks decreased following treatment with tirzepatide. In summary, OBSCORE provides a framework for prioritizing high-risk individuals with overweight or obesity based on their risk of obesity-related complications, complementing BMI-based frameworks.
Autoimmunity remains challenging to treat without broad immunosuppression. We previously showed that anti-CD38 antibody can rapidly elevate platelet counts in refractory immune thrombocytopenia (ITP), but the underlying...Autoimmunity remains challenging to treat without broad immunosuppression. We previously showed that anti-CD38 antibody can rapidly elevate platelet counts in refractory immune thrombocytopenia (ITP), but the underlying mechanism was unclear. Here we report that anti-CD38 antibody induces platelet recovery within 3 days, including after retreatment in relapsed cases. Mechanistically, CD38-mediated nicotinamide adenine dinucleotide (NAD) depletion drives M1-like macrophage polarization with increased Fc gamma receptor I (FcγRI) expression, thereby promoting macrophage phagocytosis of opsonized platelets. In mice, CD38 inhibition or nicotinamide mononucleotide (NMN) supplementation restores NAD, reprograms macrophages, downregulates FcγRI and prevents thrombocytopenia. In an ovalbumin immunization model, NMN treatment does not impair antigen-specific antibody production, supporting preservation of humoral responses. Based on these findings, we conducted a single-arm, open-label phase 1/2 trial of low-dose oral NMN (450 mg twice daily for 2 weeks) in adults with steroid-refractory or steroid-dependent ITP. Primary endpoints were safety/tolerability and platelet response (≥50 × 10 per liter within 2 weeks, confirmed by two consecutive measurements one or more days apart, without rescue therapy or dose escalation of thrombopoietin receptor agonists or corticosteroids). Among 25 enrolled patients, no dose-limiting toxicities or treatment-related serious adverse events occurred; NMN was well tolerated, with only mild treatment-related adverse events in 12% and non-severe infections (grade 1) in 8% of patients while immunoglobulin levels remained stable, consistent with preserved humoral immunity. Five patients (20.0%) met the primary platelet-response endpoint. In exploratory analyses, overall, 60% of patients achieved platelet counts more than 1.5× baseline during treatment, and 52% maintained responses through week 8. Together, these data identify the CD38-NAD axis as an immunometabolic checkpoint in ITP and support further exploration of NMN as a non-antibody-depleting metabolic strategy for antibody-mediated disease. ClinicalTrials.gov identifier: NCT06776510 .
Trost F, Zhang B, Aring I
… +23 more, Bauer M, Glamann L, Wessolly M, Johnson K, Göbel H, Lerbs T, Sangenne T, Herrmann P, Mairinger F, Kopp C, Michels S, Rasokat A, Heldwein M, Wagner S, Schömig-Markiefka B, Wolf J, Hartmann S, Wickenhauser C, Bychkov A, Klussmann JP, Quaas A, Buettner R, Tolkach Y
Artificial intelligence has advanced cancer pathology, but many systems still depend on hand-crafted features, are hard to explain and rely on fragmented workflows. We introduce SPARK (System of Pathology Agents for Rese...Artificial intelligence has advanced cancer pathology, but many systems still depend on hand-crafted features, are hard to explain and rely on fragmented workflows. We introduce SPARK (System of Pathology Agents for Research and Knowledge), a foundational agentic artificial intelligence approach that uses language as a universal interface to autonomously generate biologically driven concepts for tumor analysis. SPARK turns biological ideas into analytical tools and works directly with complex pathology data without extra model training. We evaluated SPARK across 18 patient cohorts spanning five cancer types (lung adenocarcinoma, lung squamous cell carcinoma, colorectal cancer, breast cancer and oropharyngeal squamous cell carcinoma) and more than 5,400 patients with available histopathology images and clinical/follow-up information, in both prognostic and predictive settings and on a well characterized spatial biology breast cancer dataset (patient n = 625). We found that SPARK produced clinically and biologically relevant concepts correlated with prognosis, known pathological variables and predictive biomarkers, including patterns of tumor progression and temporal change inferred from static images. A dedicated module allows for human interaction with SPARK. Further prospective validation is needed to evaluate the clinical utility of the tools created by SPARK. All code, parameters and results are openly released to help researchers and clinicians improve diagnostic precision and deepen tumor biology insights.
In resource-constrained community settings, identifying which febrile children require referral remains a major unmet need. Current World Health Organization (WHO) danger signs have limited accuracy, resulting in missed...In resource-constrained community settings, identifying which febrile children require referral remains a major unmet need. Current World Health Organization (WHO) danger signs have limited accuracy, resulting in missed severe illness and unnecessary referrals. Here we developed and validated clinical prediction models to support referral decisions using data from 3,405 children aged 1-59 months presenting with community-acquired acute febrile illnesses to seven hospitals across Bangladesh, Cambodia, Indonesia, Laos and Vietnam. Cambodian data were held out for external validation. The model using simple clinical parameters (sensitivity 74.7% (95% confidence interval (CI): 59.4-88.1); specificity 99.1% (95% CI: 97.7-99.7)) outperformed WHO criteria (sensitivity 55.5% (95% CI: 39.4-72.7); specificity 82.6% (95% CI: 77.1-87.6)) for identification of children at risk of severe disease (death or organ support within 2 days). Including either pulse oximetry or the host biomarker soluble TREM1 (sTREM1) increased sensitivity to 88.9% (95% CI: 76.7-97.8; pulse oximetry) and 89.2% (95% CI: 76.9-97.5; sTREM1), respectively. The pulse oximetry-based model achieved these gains with a threefold reduction in referral rates. These approaches appear cost-effective (pulse oximetry incremental cost effectiveness ratio (ICER) = $26.28; sTREM1 ICER = $196.46) and could improve triage for febrile illness in low-resource settings by enabling more accurate referral decisions. They warrant evaluation in community-based trials.
Zhang X, Li Q, Liang Y
… +24 more, Lai C, Cao J, Feng Y, Hu W, Jiang H, Liu C, Zhang F, Wang S, Fang Y, Duojie C, Hu L, Xu F, Chi K, Lin M, Li L, Tham YC, Zhou Y, Cheung CY, Yang X, Sheng B, Zhu Z, Cheng CY, Ng WWY, Yu H
The rising burden of endocrine and metabolic diseases demands scalable and accessible screening tools. Here we developed Reti-Pioneer, a multitask retinal imaging framework that integrates quality-aware modules with pre-...The rising burden of endocrine and metabolic diseases demands scalable and accessible screening tools. Here we developed Reti-Pioneer, a multitask retinal imaging framework that integrates quality-aware modules with pre-trained foundation models for efficient, multidisease detection. In general, the framework was developed using 107,730 color fundus photographs from both community-based and hospital-based cohorts and achieved area under the receiver operating characteristic curve values on internal test data of 0.833 (95% confidence interval 0.810-0.856) for type 2 diabetes mellitus, 0.832 (0.799-0.866) for gout, 0.787 (0.742-0.833) for osteoporosis, 0.740 (0.726-0.755) for hypertension, 0.736 (0.721-0.751) for hyperlipidemia and 0.699 (0.667-0.730) for thyroid disease. The framework generalized well to six external cohorts from both resource-limited and high-resource settings, and showed biological interpretability via plasma proteomic correlations. In a primary care silent trial, it completed screening in 30.6 ± 6.0 s per case, notably faster than standard laboratory workflows. A subsequent clinical pilot for type 2 diabetes mellitus yielded an area under the receiver operating characteristic curve of 0.776 (0.710-0.842) and negative predictive value of 0.966 (0.946-0.983), surpassing the Finnish Diabetes Risk Score, with high acceptance from clinicians and patients. Overall, Reti-Pioneer could provide a translatable, low-cost pathway from oculomics to actionable clinical screening.
van Amsterdam WAC, Oberst M, Feng J
… +13 more, Wiens J, Tang S, Joshi S, Ranganath R, Sendak M, Shalit U, Vogt JE, Beaulieu-Jones B, Mamdani M, Kent D, Heagerty PJ, Fleming TR, Goldenberg A
As artificial intelligence becomes embedded in clinical workflows, trials must accommodate ongoing monitoring and updates.As artificial intelligence becomes embedded in clinical workflows, trials must accommodate ongoing monitoring and updates.