Oligonucleotide-siRNA conjugate for SOD1 amyotrophic lateral sclerosis: a phase 1 trial

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease partly caused by gain-of-function mutations in superoxide dismutase 1 (SOD1). Here we developed RAG-17, an siRNA-targeting SOD1, using an accessory oligonucleotide conjugate platform for enhanced central nervous system (CNS) delivery. Preclinically, RAG-17 rescued motor neuron degeneration, delayed disease progression, preserved motor function and extended survival in SOD1G93A ALS rodents, even with advanced-stage treatment. In cynomolgus monkeys, intrathecal RAG-17 led to dose-dependent, durable reductions in SOD1 mRNA (CNS) and protein (cerebrospinal fluid (CSF)). In a first-in-human trial in patients with SOD1-ALS (n = 6), participants were assigned to two cohorts-cohort 1 (n = 3) received an initial 60 mg dose (seven doses total) and cohort 2 (n = 3) received an initial 90 mg dose (six doses total). The dose was escalated in 30 mg steps to maintenance doses of 150 mg (n = 5) or 180 mg (n = 1). Thus, the primary safety endpoint was met, showing acceptable safety and tolerability. Treatment-emergent adverse events (TEAEs) occurred in 33% of participants (two of six). All TEAEs were mild to moderate, including muscle tremor (two patients) and elevated alanine aminotransferase (one patient), all of which resolved. No serious adverse events were reported. Furthermore, no other clinically meaningful changes were observed in laboratory parameters, vital signs, the ALS Functional Rating Scale-Revised score, physical or neurological examinations or ECG. The key secondary endpoints showed CSF SOD1 reductions of 69% (cohort 1, day 240) and 56% (cohort 2, day 210), and plasma neurofilament light chain reductions of 62% (cohort 1) and 52% (cohort 2), from baseline; no patient required invasive mechanical ventilation or died by the end of the study. These results demonstrate a favorable safety outcome, supporting the continued clinical evaluation of RAG-17 for SOD1-ALS. ClinicalTrials.gov registration: NCT05903690 .

Chen W
Jiang L
Duan C
Kang M
Ye J
Wang L
Pan Y
Qu H
Liao X
Zhou X
Li Y
Gan Z
Chen J
Schacht I
Place RF
Li LC
Wang Y

Amyotrophic Lateral Sclerosis
Humans
Animals
Superoxide Dismutase-1
Female
Male
RNA, Small Interfering
Oligonucleotides
Macaca fascicularis
Middle Aged
Aged
Adult
Motor Neurons


Author Correction: The STARD-AI reporting guideline for diagnostic accuracy studies using artificial intelligence

Sounderajah V
Guni A
Liu X
Collins GS
Karthikesalingam A
Markar SR
Golub RM
Denniston AK
Shetty S
Moher D
Bossuyt PM
Darzi A
Ashrafian H
STARD-AI Steering Committee


An anti-PMEL antibody-drug conjugate with a G(q/1)(1) inhibitor payload in GNAQ/GNA11-mutant melanomas: a phase 1 trial

Abstract: Metastatic uveal melanoma (mUM) is an aggressive cancer with limited treatment options; 85-90% of tumors harbor activating GNAQ and GNA11 mutations. Uveal melanoma cells also express PMEL (also known as PMEL17 or gp100), a melanocyte lineage antigen. DYP688, a novel biology-matched antibody-drug conjugate, binds surface PMEL and delivers the potent Gαq/Gα11 (Gq/11) inhibitor SDZ475 as payload by internalization. This dose-escalating first-in-human phase 1 study of DYP688 in patients with metastatic uveal melanoma and other GNAQ/GNA11-mutant melanomas assessed safety as the primary endpoint and pharmacokinetics and preliminary antitumor activity as secondary endpoints. Sixty-six patients received varying DYP688 doses and schedules. Grade 3 treatment-related adverse events occurred in five patients (7.6%), including one dose-limiting toxicity of grade 3 hypotension. Objective responses were seen in 13 out of 66 patients (19.7%) and tumor reduction in 47 out of 66 patients (71.2%). Median progression-free survival was 7.2 (95% CI: 5.3-7.8) months. In summary, DYP688 was well tolerated and showed preliminary efficacy, supporting this novel therapeutic approach. ClinicalTrials.gov identifier: NCT05415072 .

Carlino MS
Kapiteijn E
Piperno-Neumann S
Sullivan RJ
Carvajal R
Dummer R
Gromke T
Hassel JC
Kee D
Ramelyte E
Shoushtari AN
Wei AZ
Enk A
Handel EE
Montazeri K
Ramon-Patino J
Richly H
Rodrigues M
Sandhu S
Smithy J
Speetjens FM
Milanez-Almeida P
Chaudhury A
Hoffmaster K
Ising M
Otero JA
RamKumar T
Reynolds A
Sharaby S
Werner L
Yerramilli-Rao P
Calvo E


Anti-LAG-3 with or without anti-PD-1 in recurrent glioblastoma: a phase 1 trial

Abstract: Lymphocyte activation gene 3 (LAG-3) is an immune checkpoint implicated in T cell exhaustion and a potential therapeutic target in glioblastoma (GBM). We conducted a multicenter, open-label, phase 1 study with sequential allocation to evaluate the safety and preliminary activity of the anti-LAG-3 antibody relatlimab, administered alone or with the anti-programmed cell death protein 1 (PD-1) antibody nivolumab, in patients with recurrent GBM. Forty-six patients were treated (23 per cohort). The primary endpoint of safety was met, with maximum tolerated doses of 800 mg relatlimab for monotherapy and 160 mg relatlimab/240 mg nivolumab for combination therapy. Treatment-related grade 3-4 adverse events occurred in 6 of 23 patients receiving combination therapy and were not observed with monotherapy. Neoadjuvant administration was associated with increased intratumoral CD8+ T cell infiltration for both monotherapy and combination therapy. Exploratory analyses suggested that tumors with elevated baseline interferon signaling and increased T cell clonality were enriched among patients with durable responses to combination therapy. Twelve-month overall survival was 34.8% with relatlimab alone and 52.2% with combination therapy; however, this study was not designed to assess efficacy. These findings demonstrate an acceptable safety profile and provide preliminary immunologic and clinical signals supporting further evaluation of LAG-3 blockade in GBM. ClinicalTrials.gov identifier: NCT02658981 .

Lim M
Ye X
Piotrowski AF
Desai A
Ahluwalia MS
Walbert T
Lesser G
Ellingson BM
Peereboom DM
Fisher JD
Desideri S
Jackson C
Pant A
Jain A
Verma R
Oberlton B
Piyadasa H
Bettegowda C
Engle L
Taube J
Bendall SC
Choi J
Drappatz J
Lieberman FS
Kleinberg LR
Pardoll DM
Nabors LB
Wen PY
Grossman SA

Antineoplastic Combined Chemotherapy Protocols

Journal Article
Clinical Trial, Phase I
Multicenter Study


Health system learning enables generalist neuroimaging models

Abstract: Frontier artificial intelligence (AI) models have advanced rapidly through training on internet-scale public data, yet such systems lack access to private clinical data. Neuroimaging is underrepresented in the public domain due to identifiable facial features within magnetic resonance imaging (MRI) and computed tomography (CT) scans, restricting model performance in clinical medicine. Here we show that frontier models underperform on neuroimaging tasks and that learning directly from uncurated data generated during routine clinical care at health systems, a paradigm we call 'health system learning', yields high-performance, generalist neuroimaging models. We introduce NeuroVFM, a visual foundation model trained on 5.24 million clinical MRI and CT volumes using a scalable volumetric predictive architecture. NeuroVFM learns comprehensive representations of brain anatomy and pathology, achieving state-of-the-art performance across multiple clinical tasks, including radiologic diagnosis and report generation. The model embeds MRI and CT scans into a shared neuroanatomic latent space and grounds diagnostic findings. When paired with open-source language models, NeuroVFM generates radiology reports that surpass frontier models in accuracy, clinical triage and expert preference. NeuroVFM reduces hallucinated findings and critical errors, offering safer clinical decision support. These results establish health system learning as a paradigm for building generalist medical AI and provide a scalable framework for clinical foundation models.

Kondepudi A
Rao A
Zhao C
Lyu Y
Harake S
Banerjee S
Ogle J
Joshi R
Meissner AK
Hou X
Jiang C
Chowdury A
Srinivasan A
Athey B
Gulani V
Pandey A
Lee H
Hollon T


KRAS-G12D inhibitor HRS-4642 plus chemotherapy in advanced KRAS(G12D)-mutant pancreatic cancer: a phase 1b/2 trial

Abstract: KRASG12D is the predominant oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). While most investigational KRAS-G12D inhibitors are oral small molecules limited by gastrointestinal toxicities and suboptimal tumor exposure, HRS-4642 is a new, high‑affinity, noncovalent KRAS-G12D inhibitor. Formulated as a liposomal nanoparticle for intravenous administration, it is designed to enhance tumor accumulation and prolong the duration of target inhibition. This phase 1b/2 study evaluated HRS-4642 in combination with nab-paclitaxel and gemcitabine (AG) in patients with advanced KRASG12D-mutant PDAC. As of 5 December 2025, 68 patients were screened and 31 (1 previously treated patient and 30 treatment-naive patients) were enrolled and treated. In the phase 1b portion, no dose-limiting toxicities were observed, and the starting dose (500 mg on day 1 and 1,200 mg on day 8, every 3 weeks) was selected as the recommended phase 2 dose. In the phase 2 portion, with a median follow-up of 12.3 months (95% confidence interval (CI) = 12.2-13.0), the primary endpoint was met-the confirmed objective response rate in 30 treatment-naive patients was 63.3% (95% CI = 43.9-80.1). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 90.3% patients, primarily hematologic toxicities consistent with AG chemotherapy. No TRAEs led to treatment discontinuation or death. In conclusion, HRS-4642 combined with AG demonstrates promising antitumor activity and a manageable safety profile in advanced KRASG12D-mutant PDAC, supporting further investigation. Clinicaltrials.gov registration: NCT06520488 .

Cui J
Jiang K
Li W
Ni S
Zong H
Du J
He Y
Liu Z
Kong G
Zhang Y
Li X
Han H
Yao F
Chen Y
Zhou M
Wang L


Human embryonic stem cell-derived dopaminergic cells for Parkinson's disease: a phase 1/2 open-label trial

Abstract: Parkinson's disease (PD) is characterized by progressive loss of nigral dopaminergic neurons, resulting in disabling motor symptoms. Intracerebral transplantation of stem cell-derived dopaminergic progenitors to replace lost endogenous dopaminergic neurons offers a new potentially restorative therapeutic approach for PD. Here we report the 12-month primary safety end point and interim efficacy outcomes from a phase 1/2, open-label, multicenter trial evaluating STEM-PD, a cryopreserved, off-the-shelf dopaminergic progenitor product derived from human pluripotent stem cells. Eight individuals with moderate PD underwent bilateral intraputaminal transplantation at two escalating doses (n = 4 per cohort), followed by 12 months of immunosuppression. Seven participants completed 12-month follow-up; one participant died from a pulmonary infection. No serious adverse events were attributed to the cell product, no graft-induced dyskinesias were observed and serial magnetic resonance imaging showed no evidence of tumor formation. These findings support the feasibility and favorable safety profile of human pluripotent stem cell-derived dopaminergic progenitor transplantation in this early-phase study, with risks primarily associated with the immunosuppression regimen. Ongoing follow-up to 36 months will further evaluate durability, clinical outcomes and graft function. ClinicalTrials.gov identifier: NCT05635409 .

Paul G
Bjartmarz H
Kirkeby A
Nelander J
Smith R
Kayhanian S
Evans A
Harry B
Cutting E
Fazal S
Lao-Kaim NP
van Vliet T
Ullén S
Grubor I
Hansson O
Piccini P
Lindvall O
Björklund A
Widner H
Parmar M
Barker RA


Challenges and future directions for multiple sclerosis after the 2024 McDonald diagnostic criteria

Oh J
Barkhof F
Bar-Or A
Ciccarrelli O
Coetzee T
Filippi M
Granziera C
Hacohen Y
Hemmer B
Kantarci OH
Kim HJ
Lebrun-Frenay C
Montalban X
Mowry E
Ontaneda D
Prat A
Reich DS
Rovira À
Sati P
Siva A
Solomon AJ
Sormani MP
Stankoff B
Thompson A
Tintore M
Traboulsee A
van der Walt A
Wiendl H
Calabresi PA


When the real world becomes the trial


A second chance for gene therapy to restore natural hearing


Biological aging clocks in health and disease

Abstract: There are extensive ongoing efforts to slow or even reverse human aging, such as with epigenetic cellular reprogramming, thymus rejuvenation or senolytics. In parallel, new and diverse metrics-known as biological clocks-have been discovered and shown to track the pace of aging in an individual and their organs, tissues and cells. These clocks have multiple potential use cases, including identifying people at high risk of disease, serving as a foundation for prevention or early detection, and determining whether lifestyle factors or an intervention can modulate the aging process. This review provides a critical appraisal of the progress that is being made with biological clocks and how they might ultimately help understand pathobiology, reduce the burden of disease and extend healthspan.

Humans
Aging
Biological Clocks
Animals
Epigenesis, Genetic


Global breast cancer survival estimates in 2017-2021 to advance the WHO Global Breast Cancer Initiative

Abstract: The World Health Organization (WHO) Global Breast Cancer Initiative aims to attain meaningful global breast cancer mortality reductions by 2040-a target that hinges on improvements in patient outcomes and survival. So far, however, data on cancer survival remain limited in low- and middle-income countries. The WHO estimated population-based age-standardized 5-year net survival for women diagnosed with breast cancer between 2017 and 2021 across all 194 Member States, providing a global benchmark for monitoring breast cancer outcomes. Here we found that median 5-year net survival varied widely across WHO regions during 2017-2021: 39.1% (95% uncertainty interval 34.1-44.7%) in the African Region, 61.0% (51.4-69.8%) in the Eastern Mediterranean Region, 66.3% (57.7-73.7%) in the South-East Asia Region, 81.1% (78.6-83.5%) in the Western Pacific Region, 84.0% (82.8-85.1%) in the European Region and 88.5% (86.7-90.1%) in the Region of the Americas. Persisting disparities in survival reflect profound global inequities; sustained initiatives to narrow gaps in access to diagnosis and treatment for breast cancer are crucial to strengthening health systems. This will enable all countries to ensure optimal outcomes for their patients with breast cancer and achieve Global Breast Cancer Initiative and Sustainable Development Goals targets.

Girardi F
Nyangasi M
Callender C
Ng M
Narita S
Torode J
AlSawahli H
Ong SK
Gnangnon F
McCormack V
Shelpai W
Rizu
Mahmoud L
Wang H
Ilbawi AM


Oncology must confront hidden side effects


Longitudinal multiomics profiling of extracorporeal cross-circulation with pig liver xenografts in human decedents

Abstract: Extracorporeal liver cross-circulation (ELC) using gene-edited porcine liver xenografts offers a potential bridge therapy for liver failure. We previously performed five ELC procedures in four brain-dead human decedents, during which the recipients developed severe thrombocytopenia. The porcine liver xenografts maintained their parenchymal structure, with immune cell infiltration and detectable IgM deposition on endothelial cells. Here, to investigate the underlying host-xenograft interactions, we performed longitudinal proteomic, lipidomic and metabolomic profiling of 64 blood samples, alongside spatial transcriptomics and histology of 25 porcine liver xenograft and 3 native human liver biopsies. Spatial transcriptomic analysis revealed progressive infiltration of human immune cells (predominantly inflammatory macrophages and neutrophils) in the xenografts, concurrent with the loss of porcine Kupffer-like macrophages and T cells. Distinct human and porcine complement dynamics were observed, with suppressed human but elevated porcine complement levels, accompanied by increased levels of porcine acute-phase proteins and coagulation factors. Moreover, multiomics analyses identified candidate cellular and molecular factors associated with thrombocytopenia. Human platelets colocalized with activated porcine endothelial cells, which showed increasing porcine vWF expression over time, as well as with immune cells (primarily macrophages and neutrophils) and hepatocytes in the xenografts. Integrative analyses indicated that ELC procedures provided hepatic support for apolipoprotein synthesis, bilirubin clearance, energy metabolism and detoxification, although circulating lipid levels remained low under anhepatic conditions. Collectively, these findings yield insights into the complex interplay between human and xenograft systems during ELC and inform strategies to improve liver xenograft biocompatibility for clinical translation.

Guo Q
Wang C
Mauduit V
Stukalov A
Mohebnasab M
Sagar A
Vikman S
Williams SH
Maden B
Eitan T
Barone K
Motter JD
Dowdell AK
Robinson FL
Guillot-Tantay C
Zayas Z
Little JP
Verrou KM
Gálvez-Merchán Á
Guo P
Moi K
Stimson E
Gao H
Argibay D
Wu L
Holmes AG
Bartlett AQ
Xin D
Futeran H
Batzoglou S
Joshi S
Rophina M
Zanoni F
Elzawahry MA
Fallon JI
Abbas SH
Olthoff KM
Abrams CS
Chhangawala S
Griesemer A
Friend P
Siddiqui A
Schmauch E
Piening BD
Shaked A
Keating BJ


Spatiotemporal diffusion of the 2024 Oropouche outbreak in Cuba

Abstract: Oropouche virus (OROV) was reported in Cuba in May 2024 and rapidly spread throughout the country. Here, among 147 reverse-transcription polymerase chain reaction-positive cases identified from May to July 2024, we sequenced 39 whole genomes of OROV. Phylogenetic analysis revealed that all sequences formed a monophyletic cluster nested within the reassortant lineage, named OROVBR-2015-2025, which has been circulating extensively in Brazil since 2023. Additional phylogeographic analyses demonstrated that the Cuban subclade probably originated from a single viral introduction from the Brazilian state of Acre in early February 2024, followed by cryptic circulation until its identification in May. The introduction probably occurred in the central region of the country, from which the virus spread and established secondary transmission hubs in the western and eastern regions. These findings underscore the capacity of OROV to spread well beyond South America, which was considered its endemic area of circulation.

Gravier R
Perez MM
Álvarez M
Pérez L
Benítez AJ
Hernández D
Serrano S
de Armas JR
Peña C
Rivera M
Franco L
Leite J
Gresh L
Méndez J
Souza V
Mejía M
Bello G
Arantes I
Resik S
Kouri V
Naveca FG
Guzman MG

Cuba
Phylogeny
Humans
Disease Outbreaks
Orthobunyavirus
Bunyaviridae Infections
Genome, Viral
Phylogeography
Brazil


Multivessel coronary artery bypass grafting via small thoracotomy versus sternotomy (MIST): an investigator-initiated, international, open-label, randomised controlled trial

Abstract: Coronary artery bypass grafting (CABG) is a common but invasive operation traditionally performed through a median sternotomy. Minimally invasive cardiac surgery (MICS) CABG via small thoracotomy might improve postoperative recovery, but randomised evidence has been scarce. We aimed to compare patient-reported recovery after MICS CABG versus sternotomy CABG in patients with multivessel coronary artery disease and to describe clinical and safety outcomes. MIST was an investigator-initiated, international, open-label, randomised controlled trial done at seven centres (four academic hospitals and three community hospitals) in Canada, India, China, Germany, the USA, and Japan. Patients referred to participating surgeons for CABG were eligible if they were aged 18 years or older; had angiographically confirmed multivessel coronary artery disease, defined as lesions of at least 70% stenosis in at least two major epicardial vessels and at least two separate coronary artery territories (left anterior descending artery, left circumflex artery, or right coronary artery) or left main coronary stenosis of 50% or more; and were suitable for coronary surgery both with sternotomy CABG and MICS CABG. Patients who were haemodynamically compromised, had contraindications to either approach, had had previous cardiac surgery, or required concomitant procedures were excluded. Eligible patients were randomly assigned (1:1) to MICS CABG or sternotomy CABG by a central, web-based system, stratified by centre, with block sizes of four and six. The primary endpoint was patient-reported physical recovery at 1 month, assessed by the 36-item Short Form Health Survey Physical Component Summary (SF-36 PCS) score. The primary analysis was by intention to treat; safety analyses were done according to treatment received. Missing 1-month questionnaire data were handled by multiple imputation. The trial was registered with ClinicalTrials.gov (NCT03447938), and is closed to recruitment. Between Aug 24, 2018, and Nov 26, 2024, 176 patients were enrolled, 170 of whom were randomly assigned to MICS CABG (n=86) or sternotomy CABG (n=84). The median age of patients was 67·0 years (IQR 61·0-72·0), 154 (91%) patients were male, and 16 (9%) were female. At 1 month after surgery, SF-36 PCS scores were significantly higher in the MICS CABG group than in the sternotomy CABG group (mean 45·1 [SD 8·0] vs 42·2 [9·1]; mean difference 2·9 [95% CI 0·3-5·5]; p=0·031). Clinical and safety follow-up at 1 month was complete in all patients; 12-month clinical and safety follow-up was complete in all except three patients in the sternotomy CABG group. Up to 12 months after surgery, there were no deaths or strokes in either group; one major adverse cardiac or cerebrovascular event occurred in the MICS CABG group before 1 month and none in the sternotomy CABG group. For selected patients with multivessel coronary artery disease, MICS CABG performed by experienced teams improved patient-reported physical recovery at 1 month compared with sternotomy CABG, with no apparent safety penalty through to 12 months. These findings support consideration of MICS CABG in appropriately selected patients treated by experienced teams, and further studies of implementation, recovery pathways, and long-term outcomes. Medtronic.

Ruel M
Nambala S
Guo MH
Verevkin A
Rabindranauth P
Kikuchi K
Davierwala PM
Lemma M
Ponnambalam M
Sheikh A
Black A
Borger MA
Whitlock RP
Zhang Y
Wells GA


Oncology and emergency care collapse in the West Bank


July 2026 floods in Chattogram, Bangladesh: an escalating emergency


A novel unimolecular GLP1 and amylin receptor agonist for glucose and weight control


Efficacy and safety of once-weekly subcutaneous zenagamtide, a novel unimolecular GLP-1 and amylin receptor agonist, in type 2 diabetes: a multicentre, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial

Abstract: Zenagamtide (formerly amycretin) is a unimolecular agonist of GLP-1, amylin, and calcitonin receptors. We aimed to investigate the dose-response relationship with respect to the efficacy and safety of once-weekly subcutaneous zenagamtide compared with placebo in adults with type 2 diabetes. This 36-week, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial was conducted at 83 hospital and clinic sites across 11 countries. The trial consisted of a 3-week screening period, a 36-week intervention period, and a 4-week follow-up period. Adults (aged 18-75 years) with type 2 diabetes (glycated haemoglobin [HbA1c] 7·0-10·0% [53-86 mmol/mol]), treated with stable doses of metformin with or without a SGLT2 inhibitor, and with a BMI of 23·0 to <50·0 kg/m2 were randomly assigned (6:1) to once-weekly subcutaneous zenagamtide or placebo using a randomisation and trial supplies management system, before being further randomly assigned to one of six dose groups (1:1:1:1:1:1; 0·4, 1·5, 5, 10, 20, or 40 mg). Participants assigned to placebo were similarly allocated to matched placebo regimens corresponding to each dosing schedule. Randomisation was stratified by HbA1c (<8·5% or ≥8·5%) at screening and country of residence (Japan or other countries). The starting dose of subcutaneous zenagamtide was 0·2 mg, with dose escalations every 4 weeks until the maintenance dose was reached (0·4-40 mg). Participants and staff were masked within each dose level to placebo or zenagamtide. The primary outcome was change in HbA1c from baseline to week 36. The primary outcome was assessed in all randomly assigned participants using the efficacy estimand based on on-treatment data without rescue medication. Safety outcomes were assessed in all randomly assigned participants exposed to treatment. The trial is registered with ClinicalTrials.gov, NCT06542874, and is completed. Between Aug 7 and Dec 27, 2024, 262 (29%) of 915 screened individuals were randomly assigned to subcutaneous zenagamtide (n=225) or placebo (n=37). Participants were further randomly assigned (1:1:1:1:1:1) to one of six doses (38 participants to 0·4 mg, 36 participants to 1·5 mg, 37 participants to 5 mg, 38 participants to 10 mg, 38 participants to 20 mg, and 38 participants to 40 mg) or placebo (37 participants). 261 participants were exposed to treatment. At week 36, estimated change in HbA1c (mean across all groups at baseline 7·8% [SD 0·8]) ranged from -0·9% with zenagamtide 0·4 mg (estimated treatment difference vs placebo: -0·77% [95% CI -1·26 to -0·28]; p=0·0021) to -1·7% with zenagamtide 40 mg (-1·56% [-2·05 to -1·07]; p<0·0001). Most adverse events were gastrointestinal and mild to moderate in severity. 21 (8%) of 261 participants reported serious adverse events (four with zenagamtide 0·4 mg, three with 1·5 mg, two with 5 mg, five with 10 mg, three with 20 mg, one with 40 mg, and three with placebo). No deaths occurred. In people with type 2 diabetes, once-weekly subcutaneous zenagamtide 0·4-40 mg demonstrated clinically meaningful and significant improvements in change in HbA1c from baseline to week 36 compared with placebo, with a safety and tolerability profile consistent with that of other GLP-1-based and amylin-based therapies. Novo Nordisk.

Mora P
Aroda VR
Asong M
Blüher M
Heftdal LD
Carlander AF
Vilsen LN
Rosenstock J


Efficacy and safety of once-daily oral zenagamtide, a novel unimolecular GLP-1 and amylin receptor agonist, in adults with type 2 diabetes: a multicentre, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial

Abstract: Zenagamtide (formerly amycretin) is a unimolecular peptide agonist of GLP-1, amylin, and calcitonin receptors. We aimed to investigate the dose-response relationship with respect to the efficacy and safety of once-daily oral zenagamtide compared with placebo in adults with type 2 diabetes. This 36-week, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial was conducted at 83 hospital and clinic sites across 11 countries. The trial consisted of a 3-week screening period, a 36-week intervention period, and a 4-week follow-up period. Adults (aged 18-75 years) with type 2 diabetes (glycated haemoglobin [HbA1c] 7·0-10·0% [53-86 mmol/mol]), treated with stable doses of metformin with or without a SGLT2 inhibitor, and with a BMI of 23·0 to <50·0 kg/m2 were randomly assigned (5:1) to oral zenagamtide or placebo using a randomisation and trial supplies management system, then further randomly assigned (1:1:1) to one of three dose groups (6, 25, or 50 mg). Participants assigned to placebo were similarly assigned to matched placebo regimens corresponding to each dosing schedule. Randomisation was stratified by HbA1c (<8·5% or ≥8·5%) at screening and country of residence (Japan or other countries). The starting dose of oral zenagamtide was 1·5 mg, with dose escalations every 4 weeks until the maintenance dose was reached (6, 25, or 50 mg). Participants and staff were masked within each dose level to placebo or zenagamtide. The primary outcome was change in HbA1c from baseline to week 36. The primary outcome was assessed in all randomly assigned participants using the efficacy estimand based on on-treatment data without rescue medication. Safety outcomes were assessed in all randomly assigned participants exposed to treatment. This trial is registered with ClinicalTrials.gov, NCT06542874, and is completed. Between Aug 7 and Dec 27, 2024, 186 (20%) of 915 screened participants were randomly assigned to oral zenagamtide (54 participants to 6 mg, 51 participants to 25 mg, and 51 participants to 50 mg) or placebo (30 participants) and were included in the full analysis set. At week 36, from baseline (mean range 7·9-8·1%), estimated mean change in HbA1c was -0·9% with zenagamtide 6 mg (estimated treatment difference [ETD] vs placebo -0·5% [95% CI -1·04 to -0·04]; p=0·033), -1·3% with zenagamtide 25 mg (-0·99% [-1·49 to -0·49]; p=0·0001), and -1·4% with zenagamtide 50 mg (-1·09% [-1·59 to -0·59]; p<0·0001). The most common adverse events were gastrointestinal, occurring in 14 (26%) of 54 participants in the zenagamtide 6 mg group, 21 (41%) of 51 participants in the zenagamtide 25 mg group, 24 (47%) of 51 participants in the zenagamtide 50 mg group, and seven (23%) of 30 participants in the placebo group. Serious adverse events were reported in seven (4%) of 186 participants receiving zenagamtide: two in the 6 mg group, two in the 25 mg group, and three in 50 mg group. No serious adverse events were reported in the placebo group. No deaths occurred during the trial. In people with type 2 diabetes, once-daily oral zenagamtide showed clinically meaningful and significant improvements in HbA1c from baseline to week 36 compared with placebo at all three dose levels (6, 25, and 50 mg). The safety and tolerability of oral zenagamtide was consistent with other GLP-1 and amylin receptor agonists. Novo Nordisk.

Mora P
Aroda VR
Asong M
Blüher M
Carlander AF
Kaltoft M
Vilsen LN
Rosenstock J


How definitions shape obesity-attributable death estimates - Authors' reply


How definitions shape obesity-attributable death estimates


PUSH trial limits: why fluids still matter


PUSH trial limits: why fluids still matter - Authors' reply

Scales CD Jr
Desai AC
Reese PP
Lieske JC
Tasian GE


Perspective on proton beam therapy for oropharyngeal cancer - Authors' reply


Representativeness of the Cancer Survival Index in Colombia - Authors' reply

Allemani C
Di Carlo V
Ssenyonga N
Arias-Ortiz NE
Coleman MP


Perspective on proton beam therapy for oropharyngeal cancer


Representativeness of the Cancer Survival Index in Colombia

Ramirez O
Quijano-Lievano ML
Lauzardo M
Bravo LE
Aristizabal P
VIGICANCER Working Group


Global tobacco control in 2026: progress yet deepening inequity


An eleventh lesson: escaping the scarcity equilibrium


Pandora's box: why context is key in inequalities research


Learning from a decade of progress in amyloidosis


Psoriasis

Abstract: Psoriasis is a common, chronic, immune-mediated skin disease affecting more than 40 million individuals worldwide. Psoriasis, along with psoriatic arthritis, are part of a broader psoriatic disease spectrum, and present with inflammatory skin and musculoskeletal manifestations driven by shared genetic, environmental, and immunological mechanisms. Skin psoriasis presents with diverse clinical phenotypes, including chronic plaque psoriasis, guttate, palmoplantar, erythrodermic, and pustular forms. Beyond cutaneous manifestations, psoriasis is associated with a substantial psychosocial burden and a wide range of comorbidities, including mental health disorders and cardio-metabolic diseases. Key psoriasis risk factors include genetic polymorphisms (most notably HLA-C*06:02), obesity, and environmental factors such as trauma, infections, and specific medications. Advances in understanding the key role of the IL-23-IL-17 inflammatory axis and related immunogenetic pathways have redefined psoriasis as a complex immune disorder, leading to the development of highly effective targeted biologic and small-molecule therapies that modulate cytokine signalling and intracellular pathways, offering improved disease control across cutaneous and musculoskeletal domains.


Deramiocel heart-derived cellular therapy in advanced Duchenne muscular dystrophy (HOPE-3): a phase 3, randomised, double-blind, placebo-controlled trial

Abstract: Duchenne muscular dystrophy (DMD) is an X-linked genetic disease of skeletal and cardiac muscle that leads to loss of ambulation and premature death due to progressive myopathy and cardiomyopathy. Deramiocel, a heart-derived cellular therapy consisting of human allogeneic cardiosphere-derived cells, improved cardiac and skeletal muscle function in phase 1-2 studies of DMD. Our aim was to assess the efficacy and safety of deramiocel in advanced DMD and support the findings of HOPE-2. HOPE-3, a phase 3, multicentre, randomised (1:1), double-blind, placebo-controlled study, included participants aged 10 years or older with DMD. Investigational product was infused intravenously every 3 months in outpatient settings. Skeletal and cardiac function was evaluated at 12 months. The primary endpoint was total Performance of the Upper Limb 2.0 (PUL2.0) percentage change from baseline. The trial is registered with ClinicalTrials.gov (NCT05126758). Between June 22, 2022, and May 28, 2024, 139 participants were screened, of whom 106 were randomly assigned to deramiocel (n=54) or placebo (n=52), and included in the intention-to-treat population. The primary endpoint showed significant improvements in the deramiocel group versus placebo. For total PUL2.0, least-squares mean percentage change at 12 months favoured deramiocel by 4·55% (95% CI 0·47-8·63; p=0·029). The safety profile of deramiocel was similar to that of placebo. Deramiocel safely slows disease progression in advanced DMD, preserving skeletal muscle function. Administered quarterly in a simple outpatient regimen, deramiocel is a promising treatment for DMD, agnostic to the precise underlying genetic lesion. Capricor Therapeutics.

McDonald CM
Villa C
Soslow JH
Maharry K
Hogan N
Binks M
Berth KC
Elliott KA
Taylor M
Hor KN
Signorovich J
Henricson EK
Phan HC
Apkon S
Ghosh PS
Tian C
Veerapandiyan A
Ramos-Platt L
Gambetta K
Bernes SM
Varadhachary AS
Iannaccone ST
Laverty CG
Perlman SJ
Bass NE
Mosher K
Butterfield RJ
Mathews KD
Scharf RJ
Smith EC
Emerson JA
Mercuri E
Awadalla MS
Marbán L
Marbán E
HOPE-3 Investigators


Ralinepag for the treatment of pulmonary arterial hypertension (ADVANCE OUTCOMES): a randomised, double-blind, placebo-controlled phase 3 study

Abstract: Pulmonary arterial hypertension (PAH) is a rare, progressive disease characterised by elevated pulmonary vascular resistance that can lead to right ventricular failure and premature death. Ralinepag is an oral, once-daily, selective prostacyclin IP receptor agonist developed to treat PAH. We aimed to evaluate the efficacy and safety of ralinepag in patients with PAH. ADVANCE OUTCOMES was a randomised, double-blind, placebo-controlled, event-driven, phase 3 trial of ralinepag in patients with PAH. Eligible patients were aged 18 years or older and PAH was diagnosed on the basis of the 2022 European Society of Cardiology and European Respiratory Society guidelines (mean pulmonary artery pressure >20 mm Hg, pulmonary artery wedge pressure ≤15 mm Hg, and pulmonary vascular resistance of >2 Wood units). Patients were randomly assigned (1:1) to ralinepag or placebo, initiated at a dose of 50 μg once daily and titrated weekly until the highest tolerated individualised dose was reached. Randomisation was stratified by baseline 6-minute walk distance (6MWD), PAH aetiology, and oral background therapy. A block size of four was used within each combination of stratification factors. The sponsor, patients, and all personnel directly involved with the conduct of the study were masked to study drug identity and randomisation assignments. The primary outcome was time to first clinical worsening event, a composite of death from any cause, admission to hospital due to worsening PAH or right heart failure, initiation of parenteral or inhaled prostacyclin-pathway therapy, disease progression, or unsatisfactory long-term clinical response. Efficacy analyses were done in the full analysis set and safety analyses in the safety set; both sets comprised 687 patients after exclusion of 41 randomly assigned and treated patients from sites in China (exclusions due to regulatory challenges and data integrity concerns). This study is registered with ClinicalTrials.gov (NCT03626688) and euclinicaltrials.eu (2023-509304-16-00) and is complete. Patients were enrolled between Jan 24, 2019, and June 20, 2025. Of 1037 patients screened for eligibility, 728 were randomly assigned and received at least one dose of ralinepag or placebo; 687 were included in the full analysis and safety sets, of whom 350 received ralinepag and 337 received placebo. Median follow-up from randomisation to clinical worsening event, censoring, or study closure was 85·0 weeks (IQR 27·6-160·9) in the ralinepag group and 78·4 weeks (34·6-137) in the placebo group. At baseline, patients had a mean 6MWD of 438·9 m (SD 104·8) and 548 (80%) of 687 patients were receiving dual background PAH therapy. Overall, 64 (18%) of 350 patients in the ralinepag group and 121 (36%) of 337 patients in the placebo group had a first clinical worsening event (hazard ratio 0·45 [95% CI 0·33-0·62]; p<0·0001). The largest numerical between-group differences in components of the composite outcome were observed for disease progression, initiation of parenteral or inhaled prostacyclin-pathway therapy, and unsatisfactory long-term clinical response. Adverse event was the primary reason for treatment discontinuation in 65 (19%) of 350 patients in the ralinepag group and ten (3%) of 337 patients in the placebo group. Serious adverse events occurred in 98 (28%) patients in the ralinepag group and 104 (31%) patients in the placebo group. Adverse events leading to death occurred in 15 (4%) and 14 (4%) patients, respectively. In patients with PAH receiving contemporary background therapy, ralinepag significantly reduced the risk of first clinical worsening compared with placebo, but was associated with more adverse-event-related treatment discontinuations. These results support the use of ralinepag as an oral, once-daily prostacyclin-pathway treatment option for PAH. United Therapeutics Corporation.

McLaughlin VV
Solum D
Lachant D
Ataya A
Barberà JA
Meyer GB
Chang SA
Channick R
Church C
Feenstra J
Gaine S
Giannakoulas G
Jerjes-Sanchez C
Khanna D
Kim NH
Oudiz R
Preston IR
Sood N
Torres F
Vachiery JL
Pulido T
Cella D
Deng C
Escudero M
Lacasse V
Peterson L
Benza R
Humbert M
ADVANCE OUTCOMES Investigators


Medical emergency: urgent medical care for Dr Hussam Abu Safiya

Khan M
Mahroof-Shaffi S
Wiley E
Mohiud-Din S


Intersectionality in climate and health equity research


Oral step-down, optimal drug, and total duration of antibiotic treatment in African children hospitalised with severe community-acquired pneumonia (PediCAP): a factorial randomised controlled trial

Abstract: WHO recommends 5 days of intravenous antibiotics for children hospitalised with severe community-acquired pneumonia (CAP). We aimed to investigate the safety of a step-down to different oral antibiotics and the shortest effective duration. PediCAP was an open-label, parallel group, 2 × 5 factorial randomised controlled trial of children aged 2 months to 6 years hospitalised with severe CAP without complicating factors in 13 hospitals across five sub-Saharan African countries. Children weighing 3-30 kg and with point-of-care C-reactive protein of more than 10 mg/L were randomly assigned (5:5:1) to either a step-down from intravenous antibiotics to oral amoxicillin (250 mg) or amoxicillin-clavulanate (co-amoxiclav; 200 mg amoxicillin to 28·5 mg clavulanate) via dispersible tablets twice daily (superiority comparison) for five total (intravenous plus oral) durations (4-8 days; non-inferiority comparison), or a 5-day, fixed-duration, intravenous-only treatment (non-inferiority comparison). Children were stepped down when clinically improved and able to take oral antibiotics. Clinicians could change antibiotics if clinically indicated. The primary outcome was the proportion of readmission or death at day 28 (non-inferiority margin vs intravenous only: +10%). The study was registered with the ISRCTN registry (ISRCTN63115131) and is complete. Between Dec 7, 2020, and Aug 14, 2023, 2248 children were screened for eligibility and 1101 were randomly allocated (480 [43·6%] girls and 621 [56·4%] boys). The primary outcome was available in 1055 (95·8%) children. For children in the step-down groups, the mean total antibiotic exposure was 6·0 days (SD 3·5) in the 4-day group, 6·8 days (4·2) in the 5-day group, 7·4 (3·6) in the 6-day group, 8·3 days (3·4) in the 7-day group, and 9·2 days (2·9) in the 8-day group (p<0·0001), with 140 (68·6%) of 204, 151 (76·3%) of 198, 167 (85·2%) of 196, 179 (89·5%) of 200, and 186 (91·6%) of 203, respectively, stepping down within their randomised duration (p<0·0001). Primary outcomes occurred in 33 (6·9%) of 475 in the co-amoxiclav group, 27 (5·6%) of 484 in the amoxicillin group, and six (6·3%) of 96 in the intravenous-only group, with both oral step-down strategies non-inferior to the intravenous-only strategy (upper 95% CIs of 6·0 for co-amoxiclav and 5·7 for amoxicillin) and no evidence of superiority for co-amoxiclav over amoxicillin (adjusted risk difference 1·3% [95% CI -1·8 to 4·4]; p=0·40). Primary outcomes occurred in eight (4·1%) of 194 in the 4-day group, ten (5·3%) of 190 in the 5-day group, 16 (8·5%) of 188 in the 6-day group, 16 (8·3%) of 193 in the 7-day group, and ten (5·2%) of 194 in the 8-day group; all durations were non-inferior to the 8-day group (all upper 95% CIs ≤6·0%). There was no evidence of consistent differences in adverse events for oral antibiotic or duration comparisons. For antibiotic-related or serious adverse events, there was one (1·0%) in the intravenous-only group and 12 (2·5%) in the amoxicillin group (adjusted risk difference -2·3% [95% CI -4·2 to -0·3]; p=0·025), and 16 (3·4%) in the co-amoxiclav group (+0·8% [-1·2 to 2·8]; p=0·42); rates increased with randomised duration (slope estimate +0·9% [0·1 to 1·7]; p=0·032). For sub-Saharan African children hospitalised with severe CAP without complicating factors, a strategy of stepping down upon clinical improvement to oral amoxicillin after initial intravenous antibiotics, with a total treatment duration of 4-5 days, is non-inferior to WHO-recommended 5-day intravenous treatment. The Second European and Developing Countries Clinical Trials Partnership (EDCTP2).

Bielicki JA
Clements M
Musiime V
Moore DP
Sidat M
Mulenga V
Mutata C
Nalwanga D
Waggie Z
Chilundo J
Chabala C
Bwakura-Dangarembizi M
Archary M
Kiggwe A
Dangor Z
Spittle B
Kapasa M
Tagoola A
Jeki C
Sacarlal J
Buck WC
Chanda S
Mujuru HA
Giaquinto C
Madhi SA
Walker AS
Sharland M
PediCAP trial team


How long must we treat? A question as old as penicillin


Department of Error


Firearm violence exposure as an adverse childhood experience - Authors' reply

Azzopardi P
Baird S
Biermann O
Ezeh A
Kennedy E
Viner R
Sawyer S


Firearm violence exposure as an adverse childhood experience


Ecological integration for a legitimate and authentic One Health: a Hendra virus case study

Degeling C
Johnson J
Shanahan EA
Peel AJ


Newborn screening for birth defects in LMICs cannot wait


Bernard Roizman


Wintering in Davos


Tamzin Cuming: supporting inclusivity in surgery


Who owns cardiometabolic disease?


High-dose chemotherapy followed by autologous stem-cell transplantation versus non-myeloablative consolidation in primary CNS lymphoma (MATRix/IELSG43): a randomised phase 3 trial

Abstract: Consolidation therapy for primary CNS lymphoma (PCNSL) includes high-dose chemotherapy with autologous stem-cell transplantation (HCT-ASCT), yet its efficacy compared with non-myeloablative chemoimmunotherapy remains uncertain. This study aimed to provide randomised comparative evidence on the efficacy and safety of thiotepa-based HCT-ASCT versus non-myeloablative R-DeVIC consolidation after uniform MATRix induction in newly diagnosed PCNSL. This open-label, randomised, phase 3 trial was conducted across 56 university and academic non-university hospitals with established transplantation facilities in five European countries. Eligible for inclusion were untreated, immunocompetent patients with B-cell PCNSL, aged 18-65 years regardless of Eastern Cooperative Oncology Group (ECOG) performance status, or 66-70 years with ECOG performance status 0-2. Pretreatment corticosteroids were permitted. Exclusion criteria included lymphoma manifestation outside the CNS, and congenital or acquired immunodeficiency. Patients received four cycles of MATRix induction (comprising rituximab, high-dose cytarabine, and thiotepa, in addition to high-dose methotrexate). Patients reaching at least partial response were randomly assigned (1:1) to two cycles of R-DeVIC (rituximab plus dexamethasone, etoposide, ifosfamide, and carboplatin) or HCT-ASCT with carmustine and thiotepa. The primary endpoint was progression-free survival, assessed in the full analysis set (excluding patients with major violations of entry criteria). The safety analysis set contained all randomised patients who initiated therapy. This study is registered with ClinicalTrials.gov (NCT02531841) and the EU Clinical Trials Register (EudraCT number 2012-000620-17). The study is completed. Between July 16, 2014, and Aug 31, 2019, 368 patients were enrolled. 346 (94%) patients started induction treatment, and 230 were randomly assigned; 229 patients were analysed (R-DeVIC group, n=115; HCT-ASCT group, n=114). After a median follow-up of 45·3 months, 3-year progression-free survival was significantly superior in the HCT-ASCT group (hazard ratio 0·43 [95% CI 0·27-0·68]; p=0·0003). The 3-year progression-free survival was 78% (95% CI 69-85) in the HCT-ASCT group compared with 51% (41-60) in the R-DeVIC group. The mean number of adverse events per patient was 9·3 (SD 4·4) in the R-DeVIC group and 14·6 (5·8) in the HCT-ASCT group. Fatal serious adverse events following consolidation treatment occurred in two patients in the R-DeVIC group (both acute myeloid leukaemia) and in five patients in the HCT-ASCT group (infections and infestations [n=4], pulmonary embolism [n=1]); all of these events apart from the pulmonary embolism were judged to be possibly related to treatment. In the largest randomised trial in untreated PCNSL to date, HCT-ASCT significantly improved progression-free and overall survival compared with non-myeloablative consolidation in patients who had completed induction treatment, establishing it as the preferred consolidation strategy in fit patients. German Federal Ministry of Research, Technology and Space; Swiss Cancer Research Foundation; and Riemser Pharma.

Illerhaus G
Ferreri AJM
Wendler J
Binder M
Borchmann P
Hasenkamp J
Stilgenbauer S
Röth A
Egerer G
Ernst T
Weber T
Hertenstein B
Lenz G
Dreyling M
Möhle R
Kobbe G
Schmidt CA
Brunnberg U
Panse J
Kneba M
Heinicke T
Schroll S
Larsen TS
Thurner L
Pukrop T
Salwender H
Naumann R
Hess G
Kroschinsky FP
Blystad AK
Keller U
Pulczynski EJ
Pedersen MB
Re F
Orsucci L
Pospiech L
La Rosée P
Deckert M
Ponzoni M
Gmehlin D
Backenstrass M
Jensch A
Valk E
Calimeri T
Kasenda B
Trepel M
Fricker H
Semenova I
Scherer F
von Gottberg P
Burger E
Grishina O
Hader C
Ihorst G
Finke J
Zucca E
Schorb E


Redefining consolidation in primary CNS lymphoma: autologous stem-cell transplantation as the standard


Pregnancy as exclusion criterion in Ebola research: not again

Schwartz L
Ahmed E
Palmero A
Ho CWL
Ravinetto R


Empirical treatment with valganciclovir in infants living with HIV and hospitalised with severe pneumonia in Africa: a multicentre, open-label, factorial, randomised, controlled, superiority trial

Abstract: Mortality among infants with severe HIV-associated pneumonia remains high. This trial (EMPIRICAL) tested whether empirical valganciclovir treatment for cytomegalovirus improves survival in infants in Africa. This multicentre, open-label, group-sequential designed, 2 × 2 factorial, randomised, controlled, superiority trial was conducted in 19 hospitals across Côte d'Ivoire, Malawi, Mozambique, Uganda, Zambia, and Zimbabwe. Infants aged 28-365 days admitted with severe HIV-associated pneumonia were centrally and individually randomly assigned (1:1:1:1) using a secure web-based system stratified by site and severity to receive standard of care (SOC) comprising treatment for bacterial (WHO-recommended antibiotics) and Pneumocystis jirovecii (cotrimoxazole and steroids) pneumonia, SOC plus 15 days of oral valganciclovir (16 mg/kg per 12 h), or SOC plus 6 months of tuberculosis treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol for 2 months, plus isoniazid and rifampicin for 4 subsequent months), or both interventions combined. The primary endpoint was all-cause mortality, assessed at day 15 and over 1-year follow-up in the intention-to-treat population. In this Article, we report results for the valganciclovir comparison groups. The trial is registered with ClinicalTrials.gov, NCT03915366 and is complete. From March 15, 2020, to Jan 31, 2024, 563 participants were enrolled; 558 were included in the analyses, with 276 allocated to valganciclovir groups (140 valganciclovir; 136 valganciclovir plus tuberculosis treatment) and 282 to groups without valganciclovir (142 SOC; 140 tuberculosis treatment). The median patient age was 4·4 months (IQR 3·2-7·4), and 274 (49%) were female. There was no evidence of interaction between valganciclovir and tuberculosis treatment (adjusted hazard ratio 1·19 [95% CI 0·73-1·95], heterogeneity p=0·48). At day 15, 64 (23%) of 276 participants in the valganciclovir group and 76 (27%) of 282 in groups without valganciclovir died (rate ratio 0·81 [95% CI 0·61-1·08], p=0·15). 24 (9%) of 276 participants and 13 (5%) of 282, respectively, were lost to follow-up. After 12 months, 119 (43%) of 276 participants in the valganciclovir groups and 134 (48%) of 282 in the groups without valganciclovir died (0·88 [95% CI 0·74-1·05] p=0·15). In a time-varying effects model, at day 15, the adjusted hazard ratio of death was 0·60 (95% CI 0·41-0·87, p=0·0063), and their hazard of death over 1 year was 0·79 (0·62-1·01; p=0·068), or 0·76 (0·58-1·00; p=0·0500) when excluding deaths within 48 h of treatment. Severe adverse events during follow-up were not more common in the valganciclovir treatment groups (odds ratio 0·64 [95% CI 0·35-1·16]). Empirical valganciclovir treatment appeared to be associated with a lower hazard of death in infants with severe HIV-associated pneumonia than SOC alone or SOC plus empirical tuberculosis treatment, and there was little evidence of associated harms. European and Developing Countries Clinical Trials Partnership.

Moraleda C
Tagarro A
Domínguez-Rodríguez S
Musiime V
Mujuru H
Chabala C
Mvalo T
Iroh-Tam PY
Bramugy J
Madrid L
Sacarlal J
Passanduca A
Sidat M
Cassia U
Aanyu HT
Tagoola A
Mutata C
Nduna B
Chawinga C
Ghambi L
Bates M
Fernández-Luis S
Seni A
Gafur M
Nalwanga D
Nansera D
Bwakura-Dangarembizi M
Namuziya N
Egbe FN
Tembo J
Ballesteros Á
Moh R
Manukyan L
Lora D
Marcy O
Jacobs TG
Burger D
Bassat Q
Leroy V
Nardone A
Buck WC
Rojo P
Empirical Clinical Trial Group


Physiology-guided coronary artery bypass grafting in valve surgery - Authors' reply


Physiology-guided coronary artery bypass grafting in valve surgery


From targets to minutes: making movement advice actionable


From targets to minutes: making movement advice actionable - Authors' reply

Ekelund U
Tarp J
Ding D
Dalene KE
Fagerland MW


Facility-based blood pressure measurement and treatment


The false promise of nuclear power


Protecting early-career researchers through fair authorship governance


Doctor's Dirty Little Secret - The Cost of Silence


The Inequality-Pandemic Cycle - Rethinking Preparedness

Global Council on Inequality, AIDS, and Pandemics


iEvac-Z, an Inactivated Ebola Vaccine - Phase 1 Study in Japan

Watanabe T
Koga M
Nojima M
Kono M
Tomita Y
Maemura T
Anzai I
Furusawa Y
Duong C
Kino Y
Halfmann PJ
Nagamura F
Yotsuyanagi H
Kawaoka Y


Pregnancies in Patients with Autoimmune Disease Receiving CAR T-Cell Therapy

Schett G
Wirsching A
Rothe T
Visconti V
Kramer N
Metzler M
Krickau T
Kirschen GW
Landau D
Elgarten C
Majithia V
De Langhe E
Vandenberghe P
Maurer B
Amoura Z
Simon D
Krönke G
Gergely P
Fernandes M
Shisha T
Law BM
Koegel A
Chang DJ
Mackensen A
Müller F
Hagen M


Sex Hormone Influences on Cardiovascular Risk. Reply


Sex Hormone Influences on Cardiovascular Risk


Transdermal Estradiol Patches in Prostate Cancer. Reply


Transdermal Estradiol Patches in Prostate Cancer


LDL Cholesterol Targeting in Cardiovascular Disease. Reply


LDL Cholesterol Targeting in Cardiovascular Disease


T-Cell Engager-Mediated HLA Antibody Depletion before Kidney Transplantation

Schatzl M
Mayer KA
Agis H
Haindl S
Kriks D
Fischer G
Exner M
Hönger G
Veljancic N
Allmer DM
Graf I
Diebold M
Halloran PF
Halpin A
Li C
West L
Kozakowski N
Böhmig GA


Cross-Correction in HSC Gene Therapy for Metachromatic Leukodystrophy

Meneghini V
Calbi V
Casalini F
Mangiameli E
Morena F
Piccoli M
Laface I
Rossomanno I
Ornaghi F
Ghiroldi A
Rancoita PMV
Fumagalli F
Martino S
Anastasia L
Naldini L
Aiuti A
Gritti A


Case 22-2026: A 37-Year-Old Woman with Persistent Nasal Ulceration


Milwaukee Shoulder Syndrome


Phase 2b Trial of a Na(V)1.8 Inhibitor for Acute Pain

Abstract: Nav1.8, a voltage-gated sodium channel expressed in the peripheral nervous system, has a critical role in pain signaling. Previous trials of NaV1.8 inhibitors have shown effectiveness in reducing postoperative pain. We conducted a phase 2b, double-blind, randomized, placebo-controlled trial to evaluate LTG-001, a selective Nav1.8 inhibitor, in patients with moderate-to-severe pain after abdominoplasty. Patients were randomly assigned in a 1:1:1:1 ratio to receive a 300-mg loading dose of LTG-001, followed by 150 mg every 12 hours (low-dose group); a 450-mg loading dose of LTG-001, followed by 300 mg every 12 hours (high-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen) every 6 hours; or placebo every 6 hours. All doses were administered orally over a 48-hour period. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour treatment period (SPID48), based on scores on the Numeric Pain Rating Scale (range, 0 to 10, with higher values indicating more severe pain; higher SPID48 values indicate greater pain reduction). Secondary end points included the amount of opioid rescue medication consumed in morphine milligram equivalents (MME) and no receipt of opioid rescue medication. A total of 343 patients underwent randomization. The least-squares mean SPID48 was 161.05 (95% confidence interval [CI], 142.93 to 179.16) in the low-dose group, 185.30 (95% CI, 167.26 to 203.34) in the high-dose group, 164.08 (95% CI, 146.02 to 182.14) in the hydrocodone bitartrate-acetaminophen group, and 123.22 (95% CI, 105.23 to 141.21) in the placebo group. The least-squares mean difference in the SPID48 between LTG-001 and placebo was significant for each dose (low dose: 37.82 [P = 0.003]; high dose: 62.08 [P<0.001]), and that between hydrocodone bitartrate-acetaminophen and placebo was 40.86. High-dose LTG-001, but not low-dose LTG-001, was associated with significantly lower opioid use than placebo (11.00 MME vs. 18.35 MME, P = 0.01), as well as a significantly higher percentage of patients who received no opioid rescue medication (52% vs. 22%, P<0.001). High-dose LTG-001 was associated with a higher incidence of pyrexia than placebo (7% vs. 2%) and a higher incidence of presyncope (6% vs. 1%). LTG-001 led to significantly greater reductions in pain scores than placebo over the course of 48 hours after abdominoplasty. (Funded by Latigo Biotherapeutics; LTG-001-010 ClinicalTrials.gov number, NCT07102459.).

Singla N
Katz NP
Vaughn B
Rogier T
Bertoch T
Minkowitz H
Loflin M

Adult
Female
Humans
Male
Middle Aged
Acetaminophen
Acute Pain
Analgesics, Opioid
Double-Blind Method
Drug Combinations
Hydrocodone
NAV1.8 Voltage-Gated Sodium Channel
Pain Measurement
Postoperative Pain
Voltage-Gated Sodium Channel Blockers
Abdominoplasty
Anti-Inflammatory Agents, Non-Steroidal
Incidence
Dose-Response Relationship, Drug
Fever
Syncope
Young Adult
Treatment Outcome

Journal Article
Randomized Controlled Trial
Clinical Trial, Phase II
Multicenter Study


Phase 3 Trial of Weekly Oral Islatravir-Lenacapavir for HIV-1 Treatment

Abstract: Once-daily, single-tablet regimens have transformed care for persons living with human immunodeficiency virus type 1 (HIV-1); however, challenges to adherence continue to limit effective treatment. Long-acting oral-drug combinations could offer new options with less frequent dose administration. We conducted a phase 3, double-blind, randomized, active-controlled, noninferiority trial in 12 countries to evaluate the efficacy and safety of a switch to once-weekly oral islatravir-lenacapavir (ISL/LEN) from once-daily oral bictegravir-emtricitabine-tenofovir alafenamide (B/F/TAF) in adults in whom HIV-1 had been virologically suppressed for at least 6 months while they were receiving B/F/TAF. Participants were assigned in a 1:1 ratio to receive once-weekly ISL/LEN (2 mg/300 mg) or to continue once-daily B/F/TAF for 96 weeks; all received matched placebo for the alternative regimen. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48, as determined by the Food and Drug Administration-defined snapshot algorithm. Noninferiority was determined at a margin of 4 percentage points. A total of 607 participants underwent randomization; 304 were assigned to the ISL/LEN group and 303 to the B/F/TAF group. A total of 21% of the participants were women, 31% were Black, 26% were Hispanic or Latine, and 15% were 65 years of age or older. At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was reported in no participants in the ISL/LEN group and 1 (0.3%) in the B/F/TAF group (difference, -0.3 percentage points; 95.002% confidence interval [CI], -1.4 to 0.8); an HIV-1 RNA level of less than 50 copies per milliliter was reported in 284 (93.4%) and 280 (92.4%), respectively (difference, 1.0 percentage point, 95% CI, -3.2 to 5.2). The mean change in the CD4+ T-cell count at week 48 was -10 cells per microliter with ISL/LEN and -18 cells per microliter with B/F/TAF (least-squares mean difference, 12 cells per microliter; 95% CI, -16 to 39). The trial regimen was discontinued owing to adverse events in 6 participants (2.0%) in the ISL/LEN group and 5 (1.7%) in the B/F/TAF group; serious adverse events occurred in 16 (5.3%) and 14 (4.6%), respectively. Among persons with virologically suppressed HIV-1, once-weekly oral ISL/LEN was noninferior to once-daily B/F/TAF in maintaining HIV viral load suppression. (Funded by Gilead Sciences and Merck Sharp and Dohme; ISLEND-1 ClinicalTrials.gov number, NCT06630286.).

Rockstroh JK
Ramgopal MN
Curran Fàbregas A
Hedgcock M
Workowski KA
Ronot-Bregigeon S
Cassetti I
Brinson C
Gupta SK
Hung CC
O'Reilly M
Slim J
Gatanaga H
Shalit P
Liu SY
Klopfer SO
Shihadeh F
Patel N
Mercier RC
Shaughnessy M
Dvory-Sobol H
SenGupta D
Llamoso C
Rhee MS
Orkin C
ISLEND-1 Study Team


Braking Bad News


The Paradox of Medical Aid in Dying


Medical Standards by Federal Fiat


Pulsatile Liver in Severe Tricuspid Regurgitation


Cross-Reactive Bundibugyo Antibody Responses after Receipt of Licensed Ebola Vaccines

Lhomme E
Wiedemann A
Ayouba A
Ben-Farhat S
Thaurignac G
Roy C
Beavogui AH
Doumbia S
Kieh M
Leigh B
Sow S
Migueles SA
Watson-Jones D
Yazdanpanah Y
Thiébaut R
Peeters M
Richert L
Levy Y
PREVAC Study Team


Crew Resource Management - Navigating AI's Automation Paradox

Abdulnour RE
Akbarialiabad H
Haghighi A
Leachman SA


Cardiotoxic Effects and Microdystrophin Expression after Gene Therapy for DMD

Samelson-Jones BJ
Martos-Rus C
Yrigollen CM
Tecedor L
Small JC
Matesanz SE
Watson CT
Vanden Heuvel AR
Carrig S
Yum SW
Brandsema JF
Lin K
Wittlieb-Weber C
Viaene AN
Russo PP
Partington S
Huynh K
Seneviratne T
Juarez Rojas S
Doshi BS
Shieh P
Flanigan KM
Frair E
Nicolau S
Lawlor MW
Crudele JM
Davidson BL
George LA


More on Digital Twin-Guided Ablation for Ventricular Tachycardia. Reply


More on Digital Twin-Guided Ablation for Ventricular Tachycardia

Bhagirath P
Porta-Sanchez A
Roca-Luque I


Daraxonrasib in Advanced RAS-Mutated Pancreatic Cancer. Reply


Daraxonrasib in Advanced RAS-Mutated Pancreatic Cancer


Left Atrial Appendage Closure in Atrial Fibrillation. Reply


Left Atrial Appendage Closure in Atrial Fibrillation


Klebsiella Brain Abscess and Evolution of Heterovirulence in the Urinary Tract

Ernst CM
Fischer LKS
Manson AL
Li L
Ma P
Anahtar MN
Bhattacharyya RP
Earl AM
Clatworthy AE
Hung DT


A New Standard in Muscle-Invasive Bladder Cancer - The End of the Cisplatin Era?


Breaking the RAS Barrier in Pancreatic Cancer


Case 21-2026: A 28-Year-Old Man with Headache and Vision Loss in the Right Eye


Koebner Phenomenon from Wet Cupping


Antiretroviral Therapy

Abstract: The development of effective treatment strategies for human immunodeficiency virus (HIV) infection is a major achievement. Antiretroviral drugs inhibit key steps in the viral replication cycle and consist of six mechanistic classes: HIV entry inhibitors, reverse-transcriptase inhibitors (both nucleosides and nonnucleosides), capsid inhibitors, integrase inhibitors, and protease inhibitors. Antiretroviral therapy (ART) suppresses viral replication, thereby enhancing immune function, decreasing morbidity and mortality, and preventing viral transmission. Consequently, ART is recommended for all persons with HIV infection. On the basis of randomized clinical trials, the Food and Drug Administration has approved 36 antiretroviral drugs for the treatment of HIV infection since 1987; of these, 28 are currently available in the United States, and combination ART regimens are used. Initial preferred ART regimens are potent, convenient, and unlikely to cause side effects and consist of an HIV integrase inhibitor with a high barrier to resistance combined with one or two nucleoside reverse-transcriptase inhibitors. In the majority of patients using current ART regimens, viral replication is durably suppressed below detectable levels. Patients receiving ART are monitored for virologic response over time, and if virologic failure occurs, the next regimen is selected on the basis of treatment history and the results of drug-resistance testing; often, antiretroviral drugs from new classes are administered. Today, the life expectancy of someone with HIV infection who consistently takes ART approaches that of the general population.

United States Food and Drug Administration


Enfortumab Vedotin and Pembrolizumab in Cisplatin-Eligible Bladder Cancer

Abstract: Neoadjuvant cisplatin-based chemotherapy is a standard therapy for muscle-invasive bladder cancer. The efficacy and safety of neoadjuvant and adjuvant (perioperative) enfortumab vedotin-pembrolizumab as compared with neoadjuvant cisplatin-based chemotherapy in persons with this cancer are unclear. We conducted a phase 3, open-label, randomized trial involving adults with muscle-invasive bladder cancer eligible for cisplatin-based chemotherapy and radical cystectomy with pelvic lymph-node dissection (cystectomy). Participants were assigned to receive neoadjuvant enfortumab vedotin-pembrolizumab (4 cycles; enfortumab vedotin [1.25 mg per kilogram of body weight on days 1 and 8] and pembrolizumab [200 mg on day 1] every 3 weeks), cystectomy, and 5 cycles of enfortumab vedotin and 13 cycles of pembrolizumab as adjuvant therapy or to receive neoadjuvant cisplatin-gemcitabine (4 cycles; cisplatin [70 mg per square meter of body-surface area on day 1] plus gemcitabine [1000 mg per square meter on days 1 and 8] every 3 weeks) and cystectomy. The primary end point was event-free survival; key secondary end points were overall survival and pathological complete response. Safety was assessed. A total of 405 participants were assigned to receive enfortumab vedotin-pembrolizumab and 403 to receive cisplatin-gemcitabine. The median time from randomization to the data-cutoff date was 33.6 months (range, 22.5 to 53.6). A total of 86.7% of the participants in the enfortumab vedotin-pembrolizumab group and 89.6% of those in the cisplatin-gemcitabine group underwent cystectomy. At 2 years, estimated event-free survival was 79.4% with enfortumab vedotin-pembrolizumab and 66.2% with cisplatin-gemcitabine (hazard ratio for an event or death, 0.53; 95% confidence interval [CI], 0.41 to 0.70; P<0.001); estimated overall survival was 86.9% and 81.3%, respectively (hazard ratio for death, 0.65; 95% CI, 0.48 to 0.89; two-sided P = 0.006). A pathological complete response occurred in 55.8% and 32.5% of the participants (P<0.001). The incidence of grade 3 or higher adverse events of any cause was 75.7% with enfortumab vedotin-pembrolizumab and 67.2% with cisplatin-gemcitabine. Among participants with muscle-invasive bladder cancer eligible for cisplatin-based chemotherapy, perioperative enfortumab vedotin-pembrolizumab led to significantly better event-free and overall survival outcomes and a significantly higher incidence of pathological complete response than neoadjuvant cisplatin-gemcitabine, but with more adverse events of grade 3 or higher. (Funded by Merck Sharp and Dohme and others; KEYNOTE-B15/EV-304 ClinicalTrials.gov number, NCT04700124.).

Galsky MD
Valderrama BP
Maruzzo M
Font A
Ciuleanu T
Chatzkel J
Koie T
Hoimes CJ
Puente J
Zakharia Y
Rosenbaum E
Boehm K
Loriot Y
Bedke J
Powles TB
Necchi A
Wiechno P
Álvarez-Fernández C
Kim TH
Oliveira N
Flaig TW
Wirtz HS
Mihm M
Huang Q
Rogiers A
Homet Moreno B
Gómez de Liaño A
KEYNOTE-B15/EV-304 Investigators

Clinical Trial, Phase III
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Video-Audio Media


National Elimination of Hepatitis C - The Case for Starting in Prisons and Jails


When Celebrities Prescribe - Regulating Drug Promotion on the Internet

Krüger N
Kong Y
Bachinger M
Kesselheim AS


Love and Death


Neurocysticercosis


Discontinuation of Levothyroxine-Reply


Regulation of General Wellness Devices


One-Year Outcomes After Endovascular Treatment for Large Acute Ischemic Stroke: The TESLA Randomized Clinical Trial

Zaidat OO
Al Kasab S
Sheth SA
Rai AT
Ortega-Gutierrez S
Given CA 2nd
Zaidi SF
Grandhi R
Cuellar-Saenz H
Mokin M
Katz JM
Alshekhlee A
Taqi MA
Ansari SA
Siddiqui AH
Barazangi N
Maud A
Kirmani J
Gupta R
Yavagal DR
Tarpley J
Pandya DJ
Cress MC
Dharmadhikari S
Asif KS
Kass-Hout T
Puri AS
Janjua N
Majjhoo AQ
Badruddin A
Spiotta AM
Bhuva P
Salazar-Marioni S
Lin E
Samaniego EA
Kolikonda MK
Jumaa MA
Majoie CBLM
Elijovich L
Jadhav A
Olvany JM
Tariq Z
Brown S
Nguyen TN
Gress D
Dippel DWJ
Smith WS
Yoo AJ
TESLA Investigators


Discontinuation of Levothyroxine


Addition of High-Dose Vitamin D3 to Standard Treatment in Patients With Metastatic Colorectal Cancer: Research Summary


Sorting Results of Unknown Significance-A Framework for Clinicians Navigating Wearable Data in the AI Era


The Need to Avoid a Regulatory Gray Zone in Digital Wellness


Addition of High-Dose Vitamin D3 to Standard Treatment in Patients With Metastatic Colorectal Cancer: The SOLARIS Randomized Clinical Trial (Alliance A021703)

Abstract: In a phase 2 randomized clinical trial, high-dose vitamin D3 added to standard treatment improved progression-free survival (PFS) compared with standard-dose vitamin D3 in patients with metastatic colorectal cancer (mCRC). To determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients with previously untreated mCRC. Double-blind phase 3 randomized clinical trial enrolling 455 patients with previously untreated mCRC, conducted in the US through the National Clinical Trials Network from October 2019 to December 2022 (database freeze: July 15, 2024). mFOLFOX6 (modified FOLFOX6 [5-fluorouracil, leucovorin, oxaliplatin]) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab every 2 weeks with either high-dose vitamin D3 (8000 IU daily × 14 days as loading dose followed by 4000 IU daily) or standard-dose vitamin D3 (400 IU daily) until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was PFS assessed by the unstratified log-rank test. Secondary end points included objective response rate, overall survival, and toxicity. Prespecified subgroup analyses of PFS were performed according to known prognostic factors. Among 455 randomized patients (median age, 59 years; 181 [40%] female) with median follow-up 20 months, the median PFS for high-dose vitamin D3 (n = 228) was 11.8 months (95% CI, 10.3-13.3) vs 10.3 months (95% CI, 9.4-12.2) for standard-dose vitamin D3 (n = 227) (1-sided log-rank P = .25). There were no significant differences in objective response rate between high-dose and standard-dose vitamin D3 (51% [95% CI, 44%-58%] vs 44% [95% CI, 37%-50%], respectively; P = .12), or in overall survival (median, 25.6 vs 27.0 months; 1-sided log-rank P = .66). There were no clinically meaningful differences in the most common grade 3 or greater adverse events between the high- and standard-dose groups, including neutropenia (n = 67 [32%] vs n = 62 [30%]) and hypertension (n = 42 [20%] vs n = 49 [23%]) or in incidence of vitamin D-associated toxicities. Among patients with previously untreated mCRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy plus bevacizumab did not improve PFS. ClinicalTrials.gov Identifier: NCT04094688.

Ng K
Ou FS
Zemla T
Jackson NA
Kalyan A
Devoe C
Shusterman M
Vijayvergia N
Wu CS
Cohen SA
Pulsipher S
Shergill A
Watson Y
Kleiber B
Lee M
Kohn CG
Thalappillil JS
Schwartz LH
Zuckerman D
Hollis BW
O'Reilly EM
Meyerhardt JA


Incorrect Author Affiliations


Ischemic Heart Disease Deaths Increasingly Tied to BMI, Hyperglycemia


FDA Approves First Oral PCSK9 Inhibitor to Lower LDL Cholesterol


FDA Approves At-Home Starting Dose for Anti-Amyloid Therapy


Soccer Players' Brains, P-Tau217 Blood Tests, Lifestyle and Dementia Risk, and More From AAIC 2026


ACOG Releases New HIV Screening and Prevention Guidelines


HHS Launches Voluntary Pledge for More Nutritious Hospital Food


Infections Linked to Increased Risk of Psychiatric and Neurological Disorders


Initial HIV Therapy for Adults and Treatment-Associated Weight Gain: Research Summary


Initial HIV Therapy for Adults and Treatment-Associated Weight Gain: The Opti-DOR Randomized Clinical Trial

Abstract: Antiretroviral therapy (ART), particularly regimens containing tenofovir alafenamide with dolutegravir or bictegravir, is associated with substantial weight gain, potentially exacerbating cardiometabolic risk in people with HIV. To determine whether a regimen with doravirine, lamivudine, and tenofovir disoproxil fumarate results in less weight gain than a regimen with dolutegravir, emtricitabine, and tenofovir alafenamide while maintaining noninferior viral suppression. Open-label, noninferiority randomized clinical trial including ART-naive adults (≥18 years of age) with an HIV RNA level greater than 500 copies/mL and no detectable baseline, high-level doravirine resistance. The study was conducted at 2 South African sites and individuals were recruited between October 2023 and March 2025. The final participant visit occurred in February 2026. A once-daily regimen with 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate (n = 299) or 50 mg of dolutegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide (n = 301). The primary outcome was viral suppression (HIV RNA level <50 copies/mL) at week 48 (prespecified noninferiority margin of -10 percentage points). The key secondary outcomes included changes in body weight, treatment-associated effects on body composition, and safety and adverse events. Among 600 participants, 597 (99.5%) were Black African, 413 (68.8%) were assigned female at birth, and the median age was 34 years (IQR, 28-41). At week 48, 266 participants (89.0%) in the doravirine, lamivudine, and tenofovir disoproxil fumarate group achieved viral suppression (HIV RNA level <50 copies/mL) vs 273 participants (90.7%) in the dolutegravir, emtricitabine, and tenofovir alafenamide group (between-group difference, -1.7 percentage points [95% CI, -6.6 to 3.1], meeting the prespecified noninferiority margin of -10 percentage points). The median weight gain was 3.0 kg in the doravirine, lamivudine, and tenofovir disoproxil fumarate group vs 5.0 kg in the dolutegravir, emtricitabine, and tenofovir alafenamide group (between-group difference, -2.0 kg [95% CI, -3.0 to -1.0 kg]; P < .001). Among participants in the doravirine, lamivudine, and tenofovir disoproxil fumarate group, the median change in hip bone mineral density (BMD) was -2.1% (IQR, -4.1% to -0.5%) and was -3.2% (IQR, -5.4% to -0.8%) for spine BMD vs -0.5% (IQR, -1.9% to 1.2%) for hip BMD and -1.3% (IQR, -3.2% to 0.8%) for spine BMD with dolutegravir, emtricitabine, and tenofovir alafenamide (P < .001 for each between-group comparison). Resistance to doravirine emerged among 7 of 9 participants experiencing virologic failure in the doravirine, lamivudine, and tenofovir disoproxil fumarate group. Of these 7 participants, 5 of 6 achieved viral suppression after switching to dolutegravir-based therapy and 1 was lost to follow-up. Serious adverse events and deaths (n = 2) were infrequent and not considered treatment-related. Among predominantly Black African adults initiating ART, a regimen with doravirine, lamivudine, and tenofovir disoproxil fumarate was noninferior to a regimen with dolutegravir, emtricitabine, and tenofovir alafenamide for 48-week viral suppression and was associated with less weight gain. ClinicalTrials.gov Identifier: NCT05924438.

Woods J
Lebina L
Möller K
Venter WDF
Akpomiemie G
Manentsa N
Taukobong I
Macholo P
Behuhuma NO
Lalla-Edward ST
Manne-Goehler J
Siedner MJ
Collings T
Mashabane N
Hill A
Sokhela SM


Dapagliflozin to Reduce the Risk of Perioperative Acute Kidney Injury in Elective Cardiac Surgery


What Are Nicotine Pouches?


Changes in Clinician Time Expenditure and Visit Quantity With Artificial Intelligence-Powered Scribes


Dapagliflozin and Acute Kidney Injury Following Cardiac Surgery: Research Summary


Physician Advice on E-Cigarettes for Smoking Cessation: Differentiating Evidence From Values


Dapagliflozin and Acute Kidney Injury Following Cardiac Surgery: A Randomized Clinical Trial

Abstract: Two percent to 50% of patients undergoing elective cardiac surgery experience acute kidney injury (AKI) postoperatively. Medications to prevent AKI after elective cardiac surgery have not been identified. In patients undergoing elective cardiac surgery, to evaluate whether initiating dapagliflozin 1 day prior to surgery reduces the incidence of AKI at 7 days after cardiac surgery, compared with placebo. Multicenter, double-blind, placebo-controlled randomized clinical trial conducted at 2 academic medical centers and 5 nonacademic hospitals in the Netherlands. Eligible participants were adults undergoing elective cardiac surgery. Enrollment occurred between June 8, 2023, and January 27, 2025. Final follow-up occurred May 16, 2025. Patients were randomized 1:1 to receive either dapagliflozin (10 mg orally; n = 392) or placebo once daily (n = 392), beginning on the day before surgery and continuing through the second postoperative day (total of 4 doses). The primary outcome was the between-group difference in AKI (defined as an increase in serum creatinine level by at least 0.3 mg/dL [26.5 µmol/L] within 48 hours after surgery, a 1.5-fold creatinine increase within 7 days of surgery, or urine output less than 0.5 mL/kg/h for 6 to 12 hours according to Kidney Disease: Improving Global Outcomes criteria) during the first 7 postoperative days. Of 784 participants enrolled, 778 (99%) completed follow-up testing (median age, 68 [61-74] years; 76% male; 97% White; median body mass index, 27 [IQR, 25-30]; and median estimated glomerular filtration rate, 80 [IQR, 67-89] mL/min/1.73 m2). Compared with placebo, dapagliflozin reduced the incidence of AKI (28% vs 52%; relative risk, 0.54 [95% CI, 0.45-0.65]; P < .001) over 7-day follow-up after surgery. Atrial fibrillation and reoperation were the most frequent adverse events. The incidence of atrial fibrillation was 45% (176/392) in the dapagliflozin group vs 45% (176/392) in the placebo group, and the incidence of reoperation was 11% (43/392) vs 10% (39/392), respectively. In patients undergoing elective cardiac surgery, 4 doses of dapagliflozin, beginning the day before surgery, reduced the incidence of AKI during the 7-day postoperative period. ClinicalTrials.gov Identifier: NCT05590143.

Oosterom-Eijmael MJP
Hulst AH
de Oliveira NPM
Niesten ED
Wietsma NE
Gerritse BM
Scohy TV
Rettig TCD
Snellen FTF
Voogd MF
Godfried MB
de Boer RN
Wink J
van der Werff LMM
Cobbaert CM
Ruhaak LR
Eberl S
Preckel B
Hollmann MW
Schenk J
Hermanides J
van Raalte DH
MERCURI-2 Study Group


Cancer Medicine Approvals in the US

Shkabari B
Vorko NI
Geerlinks WM
Purh E
Diana-Gonsalves CM
Sutaria S
Gyawali B


Nicotine Pouches


Nicotine E-Cigarettes for Cigarette Smoking Cessation: Recommendations to US-Based Clinicians

Abstract: Cigarette smoking, maintained predominantly by nicotine dependence, is a long-term and relapsing behavior that continues to be a leading cause of preventable death and disease worldwide. E-cigarettes with nicotine are less harmful than cigarettes and have been shown to be more effective for smoking cessation than US Food and Drug Administration-approved nicotine replacement therapies. However, misperceptions of the harms of e-cigarettes are common, even among clinicians. This Special Communication is a position manuscript developed by a working group within the Treatment Research Network of the international Society for Research on Nicotine and Tobacco. The aims of the manuscript were to summarize the evidence on the use of e-cigarettes for smoking cessation and to provide recommendations for clinicians on how to engage in conversations with adult patients who currently smoke cigarettes. Specifically, advice is provided on (1) integration of e-cigarettes into patient-centered shared decision-making conversations on the risks and benefits of various pharmacologic smoking cessation treatments; and (2) practical guidance on the use of e-cigarettes for smoking cessation. This Special Communication includes one overarching recommendation: integrate e-cigarettes into conversations on the risks and benefits of all evidence-based pharmacologic treatments for smoking cessation. In support of this recommendation, specific guidance is provided regarding how to discuss potential misperceptions and suggests questions to guide patient conversations. Finally, evidence-based best practices are provided for using e-cigarettes to quit smoking, which can be shared with patients. The significant burden of cigarette smoking, coupled with scientific evidence supporting e-cigarettes for smoking cessation, clearly indicates that it is appropriate to include e-cigarettes in discussions of evidence-based pharmacologic treatment for smoking cessation to reduce the harms of cigarette smoking. These recommendations are intended to provide evidence-informed guidance to clinicians regarding use of e-cigarettes for smoking cessation.

Members of the Society for Research on Nicotine and Tobacco, Treatment Research Network, Harm Reduction Workgroup


Changes in Clinician Time Expenditure and Visit Quantity With Artificial Intelligence-Powered Scribes-Reply


Immigration and Customs Enforcement Detention-Reply


Immigration and Customs Enforcement Detention


Global Low-Density Lipoprotein Cholesterol-Leveraging Estimation for Action


Global Burden of Elevated LDL-C: Findings From the Global Burden of Disease Study 2023

Abstract: Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C-related burden is critical for guiding prevention and treatment strategies. To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Population-level LDL-C concentrations. Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C-attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C-attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

GBD 2023 LDL Cholesterol Collaborators
Razo C
DeCleene NK
Johnson CO
Stark BA
LeGrand K
Aalruz H
Abaraogu UO
Abd ElHafeez S
Abdelmasseh M
Abdelnabi M
Abd-Elsalam S
Abdelsalam Elshenawy R
Abdelwahab SI
Abdolizadeh A
Abdollahi A
Abdoun M
Abdrabou MM
Abdulah DM
Abdullahi A
Abdul-Rahman T
Abebe MS
Abebe Getahun H
Abiodun OO
Abiodun O
Abohashem S
Abonie US
Abourashed NM
Abramov D
Abrar MM
Abtahi D
Abu Farha RK
Abubakar B
Abuhelwa AY
Abukhadijah HJ
Aburuz S
Abushanab D
Adams LC
Adamu NLL
Adane MM
Addo IY
Adedokun KA
Adegbile OE
Adegoke NA
Adekola SA
Adeleke OT
Adesina MA
Adisu MA
Adnan M
Afoakwah C
Afolabi AA
Afrashteh F
Afrifa-Yamoah E
Afzal S
Agordoh PD
Agyemang-Duah W
Ahmad A
Ahmad K
Ahmad S
Ahmad S
Ahmed A
Ahmed GS
Ahmed LA
Ahmed MS
Ahmed MS
Ahmed MSA
Ahmed M
Ahmed N
Ahmed SA
Ahmed Z
Aiyer A
Ajami M
Akalanka KHM
Akhtar MN
Akindele MO
Akkaif MA
Akrami AE
Akyea RK
Al Hasan SM
Al Zoubi MAM
Alahdab F
Al-Ahmad MM
Alajajian S
Alajlani MM
Alalwan TA
Al-Aly Z
Al-Amri IS
Alanzi TM
Alarifi A
Al-Ashwal FY
Al-Azayzih A
Al-Azzam S
Al-Bashaireh AM
Albashtawy M
Al-Dewik N
Aleidi SM
Algahtani FD
Algammal AM
Alhabib KF
Alhalaiqa FN
Ali A
Ali A
Ali BR
Ali MD
Ali MU
Ali R
Ali SS
Al-Iede M
Alif SM
Alipour M
Al-Jabi SW
Aljunid SM
Alkhatib MH
Alkubati SA
Allawi RH
Allemailem KS
Allouh MZ
Almagharbeh WT
Almahmeed W
Al-Marwani S
Almazan JU
Alnaeem MM
Alniss HY
Alomari MA
Alotaibi HFF
Alqahtani SA
AlQudah M
Alqudimat MR
Al-Qudimat AR
Al-Raddadi RM
Alrimawi I
Alrousan SM
Alsbou M
Alshahrani NZ
Al-Shami AS
Altaany Z
Altaf A
Althobiani MA
Altwalbeh D
Alwafi H
Al-Worafi YM
Aly H
Al-Zalabani AH
Alzoubi A
Alzoubi KH
Al-Zubairi AS
Amafah J
Mohammadi MA
Amin A
Amini S
Amini-Salehi E
Amusa GA
Ananda RA
Ancuceanu R
Ang SP
Anieto EM
Anil A
Anjana P
Anuoluwa BS
Anvari S
Anwar SL
Anyasodor AE
Appati W
Arabloo J
Arafa EA
Arafat M
Aravkin AY
Areda D
Arefnezhad R
Aregawi BB
Arias de la Torre J
Aripov T
Arockiaraj J
de Arruda GA
Asdaq SMB
Asghari-Jafarabadi M
Ashraf S
Ashraf SA
Ashraf T
Asiamah-Asare BKY
Atac O
Athar M
Athari SS
Atorkey P
Aurangzeb K
Awan SJ
Awan UA
Awol KLL
Awotidebe AW
Ayala CO
Ayli BI
Azad AKM
Azarboo A
Aziz SA
Azzam AY
Azzolino D
Babiker R
Babu AS
Babu GR
Badar M
Badiye AD
Badran AA
Baghlaf KK
Baig AA
Bakhshali MA
Balabekova M
Balakrishnan S
Baltatu OC
Banach M
Banik PC
Barqawi HJ
Barrow A
Barua L
Bashir MI
Bashir S
Bashiri A
Bastan MM
Bayat M
Bayih MT
Beeraka NM
Begum T
Behera P
Behera SM
Behnam B
Bejarano Ramirez DF
Belayneh M
Bello AB
Belo L
Berihun AA
Bhaskar S
Bhattacharjee P
Bhatti GK
Bhatti JS
Biswas A
Biswas B
Bizzozero-Peroni B
Bodur M
Bogale SK
Bohn L
Boloor A
Bolourinejad P
Bonny A
Botero Carvajal A
Bouaoud S
Boudalia S
Britton G
Bugiardini R
Busch F
Bustanji Y
Butt ZA
Campos LA
Cao Y
Catapano AL
Cegolon L
Cembranel F
Cenko E
Cerin E
Chadwick J
Chakraborty C
Chandika RM
Chandrasekar EK
Chandrasekaran B
Chattu VK
Chau LD
Chaudhary AA
Chaudhuri S
Cheema AAA
Chen AT
Chen H
Chen H
Cheng H
Cheung KC
Chew NWS
Chi G
Chichagi F
Ching PR
Cho WCS
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Multidomain Intervention for Growth in Term Small-for-Gestational-Age Infants: A Randomized Clinical Trial

Abstract: Small-for-gestational-age (SGA) infants face elevated risk of undernutrition and developmental delays. Multidomain interventions may be needed to promote growth and neurodevelopment. To evaluate the effect of an integrated intervention package on growth and neurodevelopment in term SGA infants. Individually randomized clinical trial conducted in low-resource neighborhoods of South Delhi, India. Term SGA infants were enrolled within 14 days of birth; 1300 infants were randomized and followed up to 12 months of age. Recruitment occurred from January 14, 2023, until July 31, 2024, with follow-up completed on August 6, 2025. Outcome assessors were blinded to participant allocation. Infants were randomized in a 1:1 ratio to receive either an integrated intervention package including health, nutrition, early child stimulation, and psychosocial support (n = 647) or usual care through government programs (n = 653). The primary outcomes were weight and weight-for-age z score at 12 months. Secondary outcomes included linear growth, neurodevelopment (assessed using the Bayley Scales of Infant and Toddler Development, Third Edition), anemia, and mortality. At 12 months, 1261 infants (97%) (mean age, 6 days; 48.1% male) had completed follow-up. The mean weight was 8.0 kg (SD, 0.9 kg) in the intervention group vs 7.8 kg (SD, 0.9 kg) in the usual care group (mean difference, 0.22 kg [95% CI, 0.11-0.32 kg]). The mean weight-for-age z score was -1.3 (SD, 0.9) vs -1.6 (SD, 1.0), respectively (mean difference, 0.24 [95% CI, 0.14-0.35]). The intervention group had a lower prevalence of underweight (23.9% vs 32.6%; risk difference, -8.75 [95% CI, -13.70 to -3.80] percentage points), stunting (20.1% vs 27.2%; risk difference, -7.17 [95% CI, -11.85 to -2.49] percentage points), wasting (13.9% vs 19.4%; risk difference, -5.52 [95% CI, -9.63 to -1.41] percentage points), and anemia (34.0% vs 72.5%; risk difference, -38.49 [95% CI, -44.36 to -32.61] percentage points) and higher cognitive scores (mean difference, 1.73 [95% CI, 0.32-3.14]), language scores (mean difference, 2.74 [95% CI, 1.51-3.98]), and motor composite scores (mean difference, 2.32 [95% CI, 1.25-3.38]). Nine children in the usual care group and 5 in the intervention group died. Among term SGA infants, an integrated intervention improved weight and weight-for-age z scores at 12 months. Clinical Trials Registry-India Identifier: CTRI/2021/11/037881.

Chowdhury R
Manapurath R
Upadhyay RP
Sandøy IF
Shaikh S
Chellani H
Jain A
Dhabhai N
Sapra S
Khan A
Choudhary TS
Bhatia K
Martines J
Bhandari N
Strand TA
Taneja S
Small Babies Trial Study Group


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