Castlebrook Clinical Trials Digest — Week 17, 2026

Butler CC et al. · N Engl J Med. 2026 · PMID 42019019

Why it matters: In two open-label trials (PANORAMIC/CanTreatCOVID), nirmatrelvir-ritonavir did not reduce hospitalization or death among vaccinated higher-risk outpatients with SARS-CoV-2 infection — a significant finding challenging the therapeutic role of Paxlovid in the post-vaccination era

Anderson CS et al. · N Engl J Med. 2026 · PMID 42019018

Why it matters: The multinational TRIDENT double-blind RCT demonstrated that a single pill combining three low-dose antihypertensives (telmisartan, amlodipine, indapamide) reduced recurrent stroke by 39% (4.6% vs 7.4%; HR 0.61) and major cardiovascular events in patients with prior intracerebral haemorrhage.

Three Low-Dose Antihypertensive Agents in a Single Pill after Intracerebral Hemorrhage · N Engl J Med, 2026 · PMID 42019018

Invasive vs Conservative Strategy for Frail Older Patients With Myocardial Infarction: A Secondary Analysis of the SENIOR-RITA Randomized Clinical Trial · JAMA Netw Open, 2026 · PMID 42012832

Cognitive Decline Preceding Incident Cardiovascular Events in Older Adults · JAMA Netw Open, 2026 · PMID 42008268

Zodasiran for cholesterol and triglyceride lowering in patients with hyperlipidemia: final report of phase 1 basket trial · Nat Med, 2026 · PMID 41946917

The Risk for Bleeding in Patients With Atrial Fibrillation From Concomitant Use of Apixaban or Rivaroxaban With Diltiazem Compared With Metoprolol · Ann Intern Med, 2026 · PMID 41730211

Pulsed field ablation versus conventional thermal ablation for paroxysmal atrial fibrillation: 4-year outcomes in the ADVENT-LTO study · Nat Med, 2026 · PMID 41652117

Spinal Epidural Abscess · N Engl J Med, 2026 · PMID 42019020

Digital Reminiscence for Predeath Grief Among Family Caregivers of Patients With Dementia: A Pilot Randomized Clinical Trial · JAMA Netw Open, 2026 · PMID 42018322

Advances in the drug treatment of Alzheimer's disease: pathophysiology and mechanisms of action · BMJ, 2026 · PMID 42011967

An international mega-analysis of psychedelic drug effects on brain circuit function · Nat Med, 2026 · PMID 41942645

In adults with ADHD, atomoxetine, methylphenidate, and CBT reduce symptom severity and the drugs are less tolerable vs. control at 12 wk · Ann Intern Med, 2026 · PMID 41941734

Target product profiles for treatments to delay or prevent symptomatic Alzheimer's disease · Nat Med, 2026 · PMID 41933174

LRRK2-targeting antisense oligonucleotide in Parkinson's disease: a phase 1 randomized controlled trial · Nat Med, 2026 · PMID 41876647

Factors shaping the priority of cancer in global health: a qualitative policy analysis · Lancet Glob Health, 2026 · PMID 42030971

Behaviorally Informed Text Messaging to Promote Colon Cancer Screening: A Quality Improvement Randomized Clinical Trial · JAMA Netw Open, 2026 · PMID 42024386

Extended versus standard lymph node dissection for urothelial carcinoma of the bladder in people undergoing radical cystectomy · Cochrane Database Syst Rev, 2026 · PMID 42023708

Non-coding RNAs as biomarkers and therapeutic targets in pancreatic cancer: Clinical implications and translational perspectives · Biomed Pharmacother, 2026 · PMID 42013684

Bright IDEAS-YA Skills Training and Psychosocial Outcomes of Young Adults With Cancer: A Randomized Clinical Trial · JAMA Netw Open, 2026 · PMID 42012831

Targeting MEK in cancer and beyond: mechanistic insights and therapeutic opportunities · Lancet, 2026 · PMID 42001896

Pembrolizumab plus weekly paclitaxel in platinum-resistant recurrent ovarian cancer (ENGOT-ov65/KEYNOTE-B96) · Lancet, 2026 · PMID 41974150

Overall survival with relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): a phase 3 randomised controlled trial · Lancet, 2026 · PMID 41974149

Quemliclustat and chemotherapy with or without zimberelimab in metastatic pancreatic adenocarcinoma: a randomized phase 1 trial · Nat Med, 2026 · PMID 41912809

In vivo generation of anti-BCMA CAR-T cells in relapsed or refractory multiple myeloma: a phase 1 study · Nat Med, 2026 · PMID 41882404

Transdermal Estradiol Patches in Locally Advanced Prostate Cancer · N Engl J Med, 2026 · PMID 41880608

Tumor Debulking in Combination With Chemotherapy in Multiorgan Metastatic Colorectal Cancer: The ORCHESTRA Randomized Clinical Trial · JAMA, 2026 · PMID 41837962

Obesity and Cancer: A Translational Science Review · JAMA, 2026 · PMID 41801209

A small-molecule inverse agonist of PPARgamma for advanced solid tumors: a phase 1 trial · Nat Med, 2026 · PMID 41760953

Ipilimumab and nivolumab followed by chemoradiotherapy as bladder-sparing treatment in muscle-invasive bladder cancer: a phase 2 trial · Nat Med, 2026 · PMID 41760951

Colonoscopy and fecal immunochemical testing versus usual care in diagnostic colorectal cancer screening: the SCREESCO randomized controlled trial · Nat Med, 2026 · PMID 41721101

Time-of-day immunochemotherapy in non-small cell lung cancer: a randomized phase 3 trial · Nat Med, 2026 · PMID 41629425

Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial · Nat Med, 2026 · PMID 41606121

Fecal microbiota transplantation plus immunotherapy in metastatic renal cell carcinoma: the phase 1 PERFORM trial · Nat Med, 2026 · PMID 41606120

Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial · Nat Med, 2026 · PMID 41606119

Hepatitis A prevention in the USA depends on routine universal childhood vaccination · Lancet, 2026 · PMID 42034117

The impact of clinical metagenomic testing on patient management: facts versus fantasy · Lancet Infect Dis, 2026 · PMID 42030968

Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients · N Engl J Med, 2026 · PMID 42019019

Lung transplant in people with cystic fibrosis and nontuberculous mycobacteria infection · Cochrane Database Syst Rev, 2026 · PMID 42011794

Leptospirosis-clinical review and updates on therapeutics · Lancet Infect Dis, 2026 · PMID 42009020

Untangling the complex relationship between HIV-exposure and tuberculosis in children: a narrative review · Lancet Glob Health, 2026 · PMID 41999718

Pharmacokinetics of Dalbavancin in Complicated Staphylococcus aureus Bacteremia: A Secondary Analysis of the DOTS Randomized Clinical Trial · JAMA Netw Open, 2026 · PMID 41999282

A structure-based mRNA vaccine for Nipah virus in healthy adults: a phase 1 trial · Nat Med, 2026 · PMID 41820674

Long-term efficacy and safety of the single-dose tetravalent Butantan dengue vaccine · Nat Med, 2026 · PMID 41781546

Neither Metformin nor Ursodeoxycholic Acid Effectively Treats Postacute Sequelae of COVID-19: A Randomized Clinical Trial · Ann Intern Med, 2026 · PMID 41771135

Outpatient Treatment of Confirmed COVID-19 in Symptomatic Adults: Living, Rapid Practice Points From the American College of Physicians (Version 3) · Ann Intern Med, 2026 · PMID 41662713

Outpatient Treatment of Confirmed COVID-19: A Living, Rapid Review for the American College of Physicians (Version 3) · Ann Intern Med, 2026 · PMID 41662710

Safety and efficacy of CRS3123 in adults with a primary episode or first recurrence of Clostridioides difficile infection · Lancet Infect Dis, 2026 · PMID 41581516

Impact of universal nirsevimab prophylaxis in infants on hospital and primary care outcomes across two respiratory syncytial virus seasons in Galicia, Spain (NIRSE-GAL) · Lancet Infect Dis, 2026 · PMID 41539320

The effectiveness of long-lasting spatial repellent emanators against malaria in humanitarian crisis settings in northern Nigeria · Lancet Infect Dis, 2026 · PMID 41520670

Lassa fever symptomatology, viral dynamics, and host immune response (PREPARE): a prospective, observational cohort study in Liberia · Lancet Infect Dis, 2026 · PMID 41519139

Safety and immunogenicity of PanChol, a single-dose live-attenuated oral cholera vaccine: results from a phase 1a, double-blind, randomised, placebo-controlled trial · Lancet Infect Dis, 2026 · PMID 41519137

Efficacy of ProC6C-AlOH/Matrix-M against Plasmodium falciparum infection and mosquito transmission: a phase 2, randomised, controlled human malaria infection study · Lancet Infect Dis, 2026 · PMID 41418800

Immunogenicity and safety of a group B Streptococcus vaccine (GBS-AlpN) in pregnant women and their infants: a phase 2, multicentre, observer-blind, randomised, placebo-controlled study · Lancet Infect Dis, 2026 · PMID 41386262

Integrase versus protease inhibitor therapy in advanced HIV disease (LAPTOP): a multicountry, randomised, open-label, non-inferiority trial · Lancet Infect Dis, 2026 · PMID 41344354

Kyasanur Forest disease: an emerging arboviral threat · Lancet Infect Dis, 2026 · PMID 41202828

Safe delivery of intensive care for Marburg virus disease in Rwanda · Lancet Infect Dis, 2026 · PMID 41175885

The Emerging Resistance Index: tracking early resistance to new antibiotics · Lancet Infect Dis, 2026 · PMID 41067238

Reconsidering the clinical assessment of resistance to slowly eliminated antimalarial drugs in high-transmission settings · Lancet Infect Dis, 2026 · PMID 41043443

Vitamin D Receptor Polymorphisms and the Effect of Vitamin D Supplementation on Diabetes Risk Among Adults With Prediabetes · JAMA Netw Open, 2026 · PMID 42024385

Adaptive Mobile Health Intervention to Reduce Excess Gestational Weight Gain: A Cluster-Randomized Clinical Trial · JAMA Netw Open, 2026 · PMID 42008264

A Synopsis of the 2025 VA/DoD Clinical Practice Guideline for the Primary Care Management of Asthma · Ann Intern Med, 2026 · PMID 41698207

Buffered solutions versus 0.9% saline for resuscitation in critically ill adults and children · Cochrane Database Syst Rev, 2026 · PMID 42011817

Inpatient Management of Patients With Cirrhosis · Ann Intern Med, 2026 · PMID 41974013

National Estimates of Pediatric Sepsis in US Hospitals Using Clinical Data · JAMA, 2026 · PMID 41865411

Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults · N Engl J Med, 2026 · PMID 41369227

Surgery for women with anterior compartment prolapse · Cochrane Database Syst Rev, 2026 · PMID 42029168

Delivery arrangements for rehabilitation services in health systems: an overview of systematic reviews · Cochrane Database Syst Rev, 2026 · PMID 42011808

Non-surgical casting versus surgical reduction for children with severely displaced distal radial fractures (the CRAFFT Study): a multicentre, randomised, controlled non-inferiority trial and economic evaluation · Lancet, 2026 · PMID 41965242

Stable Supportive Footwear for Self-managing Hip Osteoarthritis Pain: A Randomized Clinical Trial · Ann Intern Med, 2026 · PMID 41730219

Primary sclerosing cholangitis · Lancet, 2026 · PMID 41871593

The future of diagnostics in Africa · Nat Med, 2026 · PMID 42020602

Doula Care and Health Outcomes: A Systematic Review · JAMA Netw Open, 2026 · PMID 42012826

Psychosocial interventions for supporting women to stop smoking in pregnancy · Cochrane Database Syst Rev, 2026 · PMID 42011820

Positive Affect Treatment for Depression, Anxiety, and Low Positive Affect: A Randomized Clinical Trial · JAMA Netw Open, 2026 · PMID 42030048

In-Vehicle Feedback With or Without Parent Communication Training and Teenage Driving Behaviors: A Randomized Clinical Trial · JAMA Netw Open, 2026 · PMID 42030047

Home environment conditions during childhood and psychosocial outcomes across three generations in Sweden: population based adoption-discordant sibling comparison study · BMJ, 2026 · PMID 42019989

Care of Bereaved Persons: A Systematic Review · Ann Intern Med, 2026 · PMID 41628451

Therapeutic potential of plant-derived exosome-like nanovesicles as a phytomedicine in age-related diseases · Biomed Pharmacother, 2026 · PMID 42034933

Evolving role of biomarkers in spinal cord injury: From research to clinical translation · Biomed Pharmacother, 2026 · PMID 42013685

Inflammatory and immune-mediated toxicity of lipid nanoparticles · Biomed Pharmacother, 2026 · PMID 42008951

Diverse structures and shapes of lipid-based nanoparticles: Toward clinical translation · Biomed Pharmacother, 2026 · PMID 41999674

Therapeutic potential of hybridized nanoparticles embedded with hydrophobic and hydrophilic metallic elements: An optical thermometry approach · Biomed Pharmacother, 2026 · PMID 41999673

Cognitive behavioural therapeutics for insomnia symptoms in the perimenopause through to the early postmenopausal period · Cochrane Database Syst Rev, 2026 · PMID 42029175

Effect Modification Analyses in Individual Participant Data Meta-Analyses: A Systematic Review · JAMA Netw Open, 2026 · PMID 42024381

Five tenets for advancing evidence-based precision medicine · Nat Med, 2026 · PMID 41872601

Castlebrook Clinical Intelligence · · 2026-04-26