Fratricide-resistant CD7-CAR T cells in T-ALLOh, Bernice L. Z.; Shimasaki, Noriko; Coustan-Smith, Elaine; Chan, Esther; Poon, Limei; Lee, Shawn H. R.; Yeap, Frances; Tan, Lip Kun; Chai, Louis Y. A.; Le Bert, Nina; Tan, Nicole; Bertoletti, Antonio; Chen, Siew Peng; Del Bufalo, Francesca; Becilli, Marco; Locatelli, Franco; Yeoh, Allen E. J.; Campana, Dario
2024 Nature Medicine
doi: 10.1038/s41591-024-03228-8pmid: 39227445
T cell acute lymphoblastic leukemia (T-ALL) is difficult to treat when it relapses after therapy or is chemoresistant; the prognosis of patients with relapsed or refractory T-ALL is generally poor. We report a case series of 17 such patients who received autologous chimeric antigen receptor (CAR) T cells expressing an anti-CD7 CAR and an anti-CD7 protein expression blocker (PEBL), which prevented CAR T cell fratricide. Despite high leukemic burden and low CAR T cell dosing, 16 of the 17 patients attained minimal residual disease-negative complete remission within 1 month. The remaining patient had CD7− T-ALL cells before infusion, which persisted after infusion. Toxicities were mild: cytokine release syndrome grade 1 in ten patients and grade 2 in three patients; immune effector cell-associated neurotoxicity syndrome grade 1 in two patients. Eleven patients remained relapse-free (median follow-up, 15 months), including all nine patients who received an allotransplant. The first patient is in remission 55 months after infusion without further chemotherapy or transplantation; circulating CAR T cells were detectable for 2 years. T cells regenerating after lymphodepletion lacked CD7 expression, were polyclonal and responded to SARS-CoV-2 vaccination; CD7+ immune cells reemerged concomitantly with CAR T cell disappearance. In conclusion, autologous anti-CD7 PEBL-CAR T cells have powerful antileukemic activity and are potentially an effective option for the treatment of T-ALL.
A time-stratified, case–crossover study of heat exposure and perinatal mortality from 16 hospitals in sub-Saharan AfricaHanson, Claudia; de Bont, Jeroen; Annerstedt, Kristi Sidney; Alsina, Maria del Rosario; Nobile, Federica; Roos, Nathalie; Waiswa, Peter; Pembe, Andrea; Dossou, Jean-Paul; Chipeta, Effie; Benova, Lenka; Kidanto, Hussein; Part, Cherie; Stafoggia, Massimo; Filippi, Veronique; Ljungman, Petter
2024 Nature Medicine
doi: 10.1038/s41591-024-03245-7pmid: 39227446
Growing evidence suggests that extreme heat events affect both pregnant women and their infants, but few studies are available from sub-Saharan Africa. Using data from 138,015 singleton births in 16 hospitals in Benin, Malawi, Tanzania and Uganda, we investigated the association between extreme heat and early perinatal deaths, including antepartum and intrapartum stillbirths, and deaths within 24 h after birth using a time-stratified case–crossover design. We observed an association between an increase from the 75th to the 99th percentile in mean temperature 1 week (lag 0–6 d) before childbirth and perinatal mortality (odds ratio (OR) = 1.34 (95% confidence interval (CI) 1.01–1.78)). The estimates for stillbirths were similarly positive, but CIs included unity: OR = 1.29 (95% CI 0.95–1.77) for all stillbirths, OR = 1.18 (95% CI 0.71–1.95) for antepartum stillbirths and OR = 1.64 (95% CI 0.74–3.63) for intrapartum stillbirths. The cumulative exposure–response curve suggested that the steepest slopes for heat for intrapartum stillbirths and associations were stronger during the hottest seasons. We conclude that short-term heat exposure may increase mortality risks, particularly for intrapartum stillbirths, raising the importance of improved intrapartum care.
Artificial intelligence guided screening for cardiomyopathies in an obstetric population: a pragmatic randomized clinical trialAdedinsewo, Demilade A.; Morales-Lara, Andrea Carolina; Afolabi, Bosede B.; Kushimo, Oyewole A.; Mbakwem, Amam C.; Ibiyemi, Kehinde F.; Ogunmodede, James Ayodele; Raji, Hadijat Olaide; Ringim, Sadiq H.; Habib, Abdullahi A.; Hamza, Sabiu M.; Ogah, Okechukwu S.; Obajimi, Gbolahan; Saanu, Olugbenga Oluseun; Jagun, Olusoji E.; Inofomoh, Francisca O.; Adeolu, Temitope; Karaye, Kamilu M.; Gaya, Sule A.; Alfa, Isiaka; Yohanna, Cynthia; Venkatachalam, K. L.; Dugan, Jennifer; Yao, Xiaoxi; Sledge, Hanna J.; Johnson, Patrick W.; Wieczorek, Mikolaj A.; Attia, Zachi I.; Phillips, Sabrina D.; Yamani, Mohamad H.; Tobah, Yvonne Butler; Rose, Carl H.; Sharpe, Emily E.; Lopez-Jimenez, Francisco; Friedman, Paul A.; Noseworthy, Peter A.; Carter, Rickey E.; ,
2024 Nature Medicine
doi: 10.1038/s41591-024-03243-9pmid: 39223284
Nigeria has the highest reported incidence of peripartum cardiomyopathy worldwide. This open-label, pragmatic clinical trial randomized pregnant and postpartum women to usual care or artificial intelligence (AI)-guided screening to assess its impact on the diagnosis left ventricular systolic dysfunction (LVSD) in the perinatal period. The study intervention included digital stethoscope recordings with point of-care AI predictions and a 12-lead electrocardiogram with asynchronous AI predictions for LVSD. The primary end point was identification of LVSD during the study period. In the intervention arm, the primary end point was defined as the number of identified participants with LVSD as determined by a positive AI screen, confirmed by echocardiography. In the control arm, this was the number of participants with clinical recognition and documentation of LVSD on echocardiography in keeping with current standard of care. Participants in the intervention arm had a confirmatory echocardiogram at baseline for AI model validation. A total of 1,232 (616 in each arm) participants were randomized and 1,195 participants (587 intervention arm and 608 control arm) completed the baseline visit at 6 hospitals in Nigeria between August 2022 and September 2023 with follow-up through May 2024. Using the AI-enabled digital stethoscope, the primary study end point was met with detection of 24 out of 587 (4.1%) versus 12 out of 608 (2.0%) patients with LVSD (intervention versus control odds ratio 2.12, 95% CI 1.05–4.27; P = 0.032). With the 12-lead AI-electrocardiogram model, the primary end point was detected in 20 out of 587 (3.4%) versus 12 out of 608 (2.0%) patients (odds ratio 1.75, 95% CI 0.85–3.62; P = 0.125). A similar direction of effect was observed in prespecified subgroup analysis. There were no serious adverse events related to study participation. In pregnant and postpartum women, AI-guided screening using a digital stethoscope improved the diagnosis of pregnancy-related cardiomyopathy. ClinicalTrials.gov registration: NCT05438576
Integrating liver endpoints in clinical trials of cardiovascular and kidney diseaseZannad, Faiez; Sanyal, Arun J.; Butler, Javed; Miller, Veronica; Harrison, Stephen A.
2024 Nature Medicine
doi: 10.1038/s41591-024-03223-zpmid: 39227442
The intersection of cardiovascular disease, metabolic disorders and chronic kidney disease represents a complex clinical picture challenging healthcare systems worldwide. Metabolic-dysfunction-associated steatotic liver disease (MASLD) often manifests sequentially or concomitantly with these diseases, and may share underlying mechanisms and risk factors. Growing evidence suggests that new therapies could have benefits across these diseases, but trial sponsors and investigators tend to be reluctant to include patients with comorbidities—particularly liver diseases—in clinical trials. In this Perspective, we call for inclusion of patients with MASLD and measurement of liver outcomes in cardio–kidney–metabolic trials, when data suggest mechanistically plausible benefits and liver and cardiovascular safety. We discuss the implications of this new paradigm for clinical trial design and considerations for regulatory approval. Finally, we outline the challenges to implementing such an approach and provide recommendations for future clinical trial conduct.
Advancing global antibiotic research, development and accessPiddock, Laura J. V.; Alimi, Yewande; Anderson, James; de Felice, Damiano; Moore, Catrin E.; Røttingen, John-Arne; Skinner, Henry; Beyer, Peter
2024 Nature Medicine
doi: 10.1038/s41591-024-03218-wpmid: 39227444
The pipeline of new antibiotics is insufficient to keep pace with the growing global burden of drug-resistant infections. Substantial economic challenges discourage private investment in antibiotic research and development (R&D), with a decline in the number of companies and researchers working in the field. Compounding these issues, many countries (from low income to high income) face a growing crisis of antibiotic shortages and inequitable access to existing and emerging treatments. This has led to an increasing role for public and philanthropic funding in supporting antibiotic R&D via the creation of nonprofit public–private partnerships, including Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) and the Global Antibiotic Research and Development Partnership (GARDP), industry support for the AMR Action Fund, and pilot schemes to evaluate and reimburse antibiotics in innovative ways. Now is the time to raise the urgency, ambition and commitments of the world’s leaders to fully support the antibiotic R&D ecosystem, incentivizing all sectors to conduct public health-driven antibiotic R&D and make effective antibiotics accessible to all who need them.