tbuckley/cabot-search huggingface dataset:
Self-regulating gene therapy ameliorates phenotypes and overcomes gene dosage sensitivity in a mouse model of Rett syndrome
Authors: Paul D. Ross, Kamal K. E. Gadalla, Sophie R. Thomson, Jim Selfridge, Noha G. Bahey, Juliana Benito, Suzanne R. Burstein, Rachel McMinn, Brad Bolon, Ralph D. Hector, Stuart R. Cobb
Journal: Science Translational Medicine (2025)

Conventional methods of gene transfer lead to inconsistent transgene expression within cells. This variability can be problematic, particularly in conditions like Rett syndrome (RTT), a neurological disorder caused by mutations in the MECP2 (methyl-CpG binding protein 2) gene, because overexpression of MECP2 can also cause adverse effects. To address these challenges, we devised a gene regulation system called Expression Attenuation via Construct Tuning (EXACT), which uses a self-contained, microRNA-based feed-forward loop that not only ensures more consistent transgene expression but also protects against excessive expression. Through cell-based screening assays, we demonstrated the ability of the EXACT circuit to modulate the expression of full-length human MeCP2. Compared with a conventional construct, an EXACT- MECP2 construct exhibited a narrower range of cellular protein abundance. Furthermore, the degree of regulation by the EXACT circuit increased with higher transgene doses in vitro and in wild-type mice and mice modeling RTT. On the basis of cellular and in vivo testing, we identified an optimal configuration for the adeno-associated virus serotype 9 (AAV9) construct for self-regulated MECP2 gene therapy, designated NGN-401. Delivery of NGN-401 to neonatal male Mecp2 −/y hemizygous mice via intracerebroventricular injection resulted in prolonged survival and amelioration of RTT-like phenotypes compared with vehicle-treated animals. NGN-401 was also well tolerated by female Mecp2 +/− mice and healthy juvenile nonhuman primates, in contrast with a conventional construct, which caused toxicity. The results from these studies underpin a first-in-human pediatric trial of NGN-401 in RTT ( ClinicalTrials.gov , NCT05898620).
Mavoglurant reduces cocaine use in patients with cocaine use disorder in a phase 2 clinical trial
Authors: Baltazar Gomez-Mancilla, Kenneth M. Dürsteler, Marc Vogel, Marcus Herdener, Marta Torrens, Bartolomé P. Gálvez, Antoni Gual, Ricardo M. Corral, Enrique I. Kuper, Daniel L. Mosca, Swati Dumitras, Nicole Pezous, Maria Berkheimer, Ela Walker, Fabrizio Gasparini, Jang-Ho Cha, Ricardo Dolmetsch
Journal: Science Translational Medicine (2025)

Metabotropic glutamate receptor 5 (mGluR5) is involved in cocaine reward processing and addiction. Preclinical studies suggest that blocking this receptor inhibits cocaine self-administration and seeking behavior in rodents. We assessed a selective noncompetitive antagonist of mGluR5 called mavoglurant in a phase 2 randomized, placebo-controlled clinical trial of 68 adults with cocaine use disorder. Study participants were randomly assigned in a 1:1 ratio to an up-titrating schedule of oral mavoglurant twice daily up to 200 mg for 98 days or placebo. The primary end point was the proportion of cocaine use days over the treatment period assessed by a retrospective self-report using Timeline Followback. Secondary end points were urine analysis of the cocaine metabolite benzoylecgonine and alcohol use measured by Timeline Followback assessment. Exploratory end points included testing for cocaine and alcohol metabolites in hair samples. The posterior probability of mavoglurant reducing cocaine use at the end of treatment was ≥99.0% for a treatment difference &lt;0 and ≥36.6% for a treatment difference &lt;−10%. The difference between mavoglurant and placebo was also assessed using analysis of covariance ( P = 0.021). Urine benzoylecgonine concentration was lower in the mavoglurant-treated group versus placebo ( P = 0.025); there was reduced alcohol consumption in the treatment group ( P = 0.072). Seventy-six percent (randomized set) and 79% (safety analysis set) of patients completed the final treatment visit. Adverse events in the treatment group were headache, dizziness, and nausea. In this small and short trial, mavoglurant reduced cocaine and alcohol use in patients with chronic cocaine use disorder.
Genomic divergence shaped the genetic regulation of meiotic homologous recombination in <i>Brassica</i> allopolyploids
Authors: Alexandre Pelé, Matthieu Falque, Maryse Lodé-Taburel, Virginie Huteau, Jérôme Morice, Olivier Coriton, Olivier C Martin, Anne-Marie Chèvre, Mathieu Rousseau-Gueutin
Journal: Molecular Biology and Evolution (2025)

Abstract The tight regulation of meiotic recombination between homologs is disrupted in Brassica AAC allotriploids, a genomic configuration that may have facilitated the formation of rapeseed (Brassica napus L.) ∼7,500 years ago. Indeed, the presence of the haploid C genome induces supernumerary crossovers between homologous A chromosomes with dramatically reshaped distribution. However, the genetic mechanisms driving this phenomenon and their divergence between nascent and established lineages remain unclear. To address these concerns, we generated hybrids carrying additional C chromosomes derived either from an established lineage of the allotetraploid B. napus or from its diploid progenitor B. oleracea. We then assessed recombination variation across twelve populations by mapping male meiotic crossovers using Single Nucleotide Polymorphism markers evenly distributed across the sequenced A genome. Our findings reveal that the C09 chromosome of B. oleracea is responsible for the formation of additional crossovers near pericentromeric regions. Interestingly, its counterpart from an established lineage of B. napus shows no significant effect on its own, despite having a similar content of meiotic genes. However, we showed that the B. napus C09 chromosome influences crossover formation through inter-chromosomal epistatic interactions with other specific C chromosomes. These results provide new insights into the genetic regulation of homologous recombination in Brassica and emphasize the role of genomic divergence since the formation of the allopolyploid B. napus.
Oligodendroglial precursor cells modulate immune response and early demyelination in a murine model of multiple sclerosis
Authors: Qi Wang, Taida Huang, Zihan Zheng, Yixun Su, Zhonghao Wu, Cong Zeng, Guangdan Yu, Yang Liu, Xiaorui Wang, Hui Li, Xiaoying Chen, Zhuoxu Jiang, Jinyu Zhang, Yuan Zhuang, Yi Tian, Qingwu Yang, Alexei Verkhratsky, Ying Wan, Chenju Yi, Jianqin Niu
Journal: Science Translational Medicine (2025)

Reproducing the pathophysiology of human multiple sclerosis (MS) in animal models is critical to identifying mechanisms triggering demyelination and to developing early intervention strategies. Here, we aimed to model overactivated Wnt (wingless-related integration site) signaling previously shown in postmortem brain tissues of patients with MS by inducing experimental autoimmune encephalomyelitis (EAE) in Pdgfra CreER ;Apc fl/fl and Olig2 Cre ;Apc fl/fl mice. These mice have overactivated Wnt signaling in oligodendrocyte precursor cells (OPCs) because of a conditional knockout of the pathway repressor adenomatous polyposis coli (APC). Pdgfra CreER ;Apc fl/fl EAE mice exhibited increased expression of markers for Wnt activation such as Axis inhibition protein 2 (AXIN2) and Wnt inhibitory factor 1 (WIF1) in OPCs and showed exacerbated EAE progression in both the spinal cord and the brain. Genetic or antibody-mediated ablation of CC-chemokine ligand 4 (CCL4) prevented infiltration of CD4 + T cells and arrested disease progression in these mice. A characterization of CNS (central nervous system) immune cell clusters identified an augmented subpopulation of NK1.1 + CD11b + Gr-1 + cytotoxic macrophages in Pdgfra CreER ;Apc fl/fl EAE mice. Microinjection of this subpopulation of macrophages into the brains of wild-type C57/B6J mice was sufficient to induce demyelination. Ablation of CD4 + T cells prevented the effects of Wnt overactivation on demyelination and immune cell infiltration. Antagonizing chemokine receptor 5 (CCR5) using a European Medicines Agency–approved drug, maraviroc, reduced immune cell infiltration, alleviated demyelination, and attenuated EAE progression. We found an OPC-orchestrated immune cellular network that instigates early demyelination, provides insight into MS pathophysiology, and suggests avenues for early interventions.
Risk of Urogenital Infections in People With Type 2 Diabetes Initiating SGLT2i Versus GLP-1RA in Routine Clinical Care: A Danish Cohort Study
Authors: Christine Ljungberg, Frederik Pagh Bredahl Kristensen, Michael Dalager-Pedersen, Christina Vandenbroucke-Grauls, Henrik Toft Sørensen, Mette Nørgaard, Reimar Wernich Thomsen
Journal: Diabetes Care (2025)

OBJECTIVE Anticipated risks of urinary tract infections (UTI) and genital tract infections (GTI) associated with sodium–glucose cotransporter 2 inhibitors (SGLT2i) may prevent their use in clinical practice. We investigated whether initiation of SGLT2i, compared with glucagon-like peptide 1 receptor agonists (GLP-1RAs), was associated with an elevated risk of UTI and GTI in people with type 2 diabetes. RESEARCH DESIGN AND METHODS In this cohort study emulating a target trial, we included all adult metformin users initiating SGLT2i or GLP-1RAs in Denmark in 2016–2021 and used inverse-probability of treatment (IPT) weighting to balance potential confounders. We estimated IPT-weighted risk and risk ratios of community- or hospital-treated UTI and GTI, performing both intention-to-treat and on-treatment analyses. RESULTS This study included 52,414 SGLT2i initiators and 27,023 GLP-1RA initiators with a median follow-up of 2.9 to 3.9 years. The estimated risks of UTI within the first year were nearly identical: 10.0% in SGLT2i and 10.2% in GLP-1RAs in intention-to-treat analyses corresponding to a risk ratio of 0.98 (95% CI 0.94, 1.03). For GTI, the 1-year risks were elevated under SGLT2i therapy at 2.0% vs. 0.7% (risk ratio 2.95 [95% CI 2.52, 3.44]). During the 5-year follow-up, the relative UTI risk remained almost constant (0.96 [95% CI 0.94, 0.99]) whereas the GTI risk ratio with SGLT2is decreased to 1.64 (95% CI 1.49, 1.80). CONCLUSIONS In routine clinical care, SGLT2i initiation is not associated with increased risk of UTI compared with GLP-1RA initiation. However, early GTI risk is up to threefold larger in SGLT2i users.
Lack of Validity of the Glucose Management Indicator in Type 1 Diabetes in Pregnancy
Authors: Claire L. Meek, Denice S. Feig, Eleanor M. Scott, Rosa Corcoy, Helen R. Murphy
Journal: Diabetes Care (2025)

OBJECTIVE The glucose management indicator (GMI) is widely used as a replacement for HbA1c, but information in pregnancy is very limited. We assessed the accuracy of GMI and associations with pregnancy outcomes in type 1 diabetes. RESEARCH DESIGN AND METHODS We compared HbA1c, continuous glucose monitoring (CGM) metrics, GMI at 12, 24, and 34 weeks’ gestation and outcomes in 220 women from the CGM in pregnant women with type 1 diabetes (CONCEPTT) trial using logistic/linear regression and Bland-Altman plots. RESULTS GMI equations performed less accurately in pregnancy, with higher bias, especially in first and third trimesters. GMI and mean CGM glucose had equivalent predictive capability over pregnancy outcomes. GMI did not offer additional predictive capability over time-in-range (63–140 mg/dL; 3.5–7.8 mmol/L), time-above-range (&amp;gt;140 mg/dL; &amp;gt;7.8 mmol/L), and average CGM glucose concentrations. CONCLUSIONS GMI is not an accurate replacement for HbA1c in pregnancy in women with type 1 diabetes.
A Phase 3 Trial of Upadacitinib for Giant-Cell Arteritis
Authors: Daniel Blockmans, Sara K. Penn, Arathi R. Setty, Wolfgang A. Schmidt, Andrea Rubbert-Roth, Ellen M. Hauge, Helen I. Keen, Tomonori Ishii, Nader Khalidi, Christian Dejaco, Maria C. Cid, Bernhard Hellmich, Meng Liu, Weihan Zhao, Ivan Lagunes, Ana B. Romero, Peter K. Wung, Peter A. Merkel
Journal: New England Journal of Medicine (2025)

Giant-cell arteritis is a systemic vasculitis with limited treatment options. The efficacy and safety of upadacitinib - a selective Janus kinase (JAK) inhibitor that blocks the signaling of several cytokines, including interleukin-6 and interferon-γ - are unknown in patients with giant-cell arteritis. We randomly assigned patients with new-onset or relapsing giant-cell arteritis, in a 2:1:1 ratio, to receive upadacitinib at a dose of 15 mg or 7.5 mg orally once daily plus a 26-week glucocorticoid taper or placebo plus a 52-week glucocorticoid taper. The primary end point was sustained remission at week 52, defined by the absence of signs or symptoms of giant-cell arteritis from week 12 through week 52 and adherence to the protocol-specified glucocorticoid taper. A total of 209 patients received upadacitinib at a dose of 15 mg, 107 received upadacitinib at a dose of 7.5 mg, and 112 received placebo; 70% of the patients had new-onset giant-cell arteritis. Upadacitinib at a dose of 15 mg showed superiority over placebo with respect to the primary end point (46.4% [95% confidence interval {CI}, 39.6 to 53.2] vs. 29.0% [95% CI, 20.6 to 37.5]; P = 0.002). Upadacitinib at a dose of 15 mg was superior to placebo in the analysis of the hierarchically prespecified and multiplicity-controlled key secondary end points of sustained complete remission, time to a disease flare, cumulative glucocorticoid exposure, and patient-reported outcomes. Upadacitinib at a dose of 7.5 mg was not superior to placebo with respect to the primary end point (41.1% [95% CI, 31.8 to 50.4]). Safety outcomes during the treatment period of 52 weeks were similar in the upadacitinib and placebo groups. Although cardiovascular risk is a potential concern with a JAK inhibitor, no major adverse cardiovascular events occurred in the upadacitinib groups. In patients with giant-cell arteritis, upadacitinib at a dose of 15 mg - but not 7.5 mg - with a 26-week glucocorticoid taper showed efficacy superior to that of placebo with a 52-week glucocorticoid taper. (Funded by AbbVie; SELECT-GCA ClinicalTrials.gov number, NCT03725202.).
Patient-reported outcomes from the MIRASOL trial evaluating mirvetuximab soravtansine versus chemotherapy in patients with folate receptor α-positive, platinum-resistant ovarian cancer: a randomised, open-label, phase 3 trial
Authors: Toon Van Gorp, Kathleen N Moore, Gottfried E Konecny, Alexandra Leary, Yolanda García-García, Susana Banerjee, Domenica Lorusso, Jung-Yun Lee, John W Moroney, Giuseppe Caruso, Dagmara Klasa-Mazurkiewicz, Jacqueline Tromp, Lainie P Martin, Shani Breuer, Charles A Leath, David Cibula, S John Weroha, Purificación Estévez-García, David M O'Malley, Rowan E Miller, Lan Coffman, Giuseppa Scandurra, Dominique Berton, Lingling Li, Erin Zagadailov, Elisabeth J Diver, Olivier Trédan, Felix Hilpert
Journal: The Lancet Oncology (2025)
First-line talazoparib plus enzalutamide versus placebo plus enzalutamide in men with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: patient-reported outcomes from the randomised, double-blind, placebo-controlled, phase 3 TALAPRO-2 trial
Authors: Andre P Fay, Karim Fizazi, Nobuaki Matsubara, Arun A Azad, Fred Saad, Ugo De Giorgi, Jae Young Joung, Peter C C Fong, Robert J Jones, Stefanie Zschäbitz, Jan Oldenburg, Neal D Shore, Curtis Dunshee, Joan Carles, Paul Cislo, Jane Chang, Cynthia G Healy, Alexander Niyazov, Neeraj Agarwal
Journal: The Lancet Oncology (2025)
Rates, causes, and risk factors for death among justice-involved young people in Australia: a retrospective, population-based data linkage study
Authors: Stuart A Kinner, Lucas Calais-Ferreira, Jesse T Young, Rohan Borschmann, Alan Clough, Ed Heffernan, Scott Harden, Matthew J Spittal, Susan M Sawyer
Journal: The Lancet Public Health (2025)

Children and adolescents exposed to the youth justice system have poor health profiles, but little is known about their subsequent mortality. We aimed to examine mortality outcomes in a large, state-wide cohort of young people in Australia who had contact with the youth justice system. We linked youth justice records in the state of Queensland, Australia from July 1, 1993, to June 30, 2014, with adult correctional records and the National Death Index, for records up to Jan 31, 2017. We calculated all-cause and cause-specific crude mortality rates per 100 000 person-years, and age-standardised and sex-standardised mortality ratios with 95% CIs. Calculations were performed for the whole cohort and in subgroups defined by sex, Indigenous status, and youth justice history. We used survival analysis to identify demographic and criminal justice factors associated with all-cause mortality. Of 49 011 individuals in the study sample, 321 were excluded due to data linkage or data quality issues and 20 were excluded as they did not have an age or date of birth recorded, which resulted in 48 670 (99·3%) participants. 11 897 (24·4%) participants were female, 36 773 (75·6%) were male, and 13 250 (27·2%) were Indigenous. During a median of 13·5 years (IQR 8·4-18·4) of follow-up, we observed 1431 (2·9%) deaths among the 48 670 participants. Median age at end of follow-up was 28·6 years (IQR 23·6-33·6). The most common causes of death were suicide (495 [34·6%]), transport accidents (244 [17·1%]), and accidental drug poisoning (209 [14·6%]). The all-cause crude mortality rate was 218·9 deaths (95% CI 207·9-230·6) and the all-cause standard mortality ratio was 4·2 (3·9-4·4). In multivariable analyses, mortality rates were higher for males (adjusted hazard ratio [aHR] 1·5 [95% CI 1·3-1·7]); those who had been subject to community supervision (aHR 1·3 [1·1-1·5]), or detention (aHR 2·1 [1·8-2·4]) versus charge only; and those under adult correctional supervision in the community (aHR 1·9 [1·5-2·4]) versus unsupervised. More than half of the observed deaths occurred before 25 years of age, and very few (1·6%) occurred in custody. Justice-involved young people are at markedly increased risk of premature death from largely preventable causes. Reducing the burden of preventable death among these young people will require coordinated, multi-sectoral responses that extend beyond the criminal justice system. National Health and Medical Research Council, Australia.
Immunogenicity and safety of a measles and rubella-containing vaccine at age 6 and 9 months in Bangladesh: an open-label, randomised trial
Authors: Takudzwa S Sayi, Umid M Sharapov, Zachary Matson, Melissa M Coughlin, Stephen N Crooke, Qian An, Jennifer K Knapp, Asma Binte Aziz, Mohammad Yunus, Warda Haque, Sohel Rana, Md Al Fazal Khan, James P Alexander, Katrina Kretsinger, Paul A Rota, Khalequ Zaman, Abhijeet Anand
Journal: The Lancet Child & Adolescent Health (2025)
Changes in incarceration and tuberculosis notifications from prisons during the COVID-19 pandemic in Europe and the Americas: a time-series analysis of national surveillance data
Authors: Amy Zheng, Lena Faust, Anthony D Harries, Pedro Avedillo, Michael Akodu, Miranda Galvan, Beatriz Barreto-Duarte, Bruno B Andrade, César Ugarte-Gil, Alberto L Garcia-Basteiro, Marcos Espinal, Joshua L Warren, Leonardo Martinez
Journal: The Lancet Public Health (2025)

The COVID-19 pandemic disrupted tuberculosis control programmes globally; whether or not this disproportionately affected people who were incarcerated is unknown. We aimed to evaluate changes in incarceration and tuberculosis notifications in prisons in Europe and the Americas during the COVID-19 pandemic. Data from WHO Pan American Health Organization (PAHO) and WHO Europe were used to conduct a joint hierarchical Bayesian negative binomial time-series. This approach accounted for world region, country-specific temporal trends, and country-specific autocorrelated random effects to simultaneously model and predict both annual prison population (ie, the offset) and prison tuberculosis cases (ie, the primary outcome). Results were used to calculate percentage differences between predicted and observed annual tuberculosis notifications and prison populations during the COVID-19 pandemic years (2020-22). In total, 22 of 39 countries from PAHO and 25 of 53 countries from WHO Europe were included (representing 4·9 million people incarcerated annually), contributing 520 country-years of follow-up. Observed tuberculosis notifications in prisons were lower than predicted in 2020 (-26·2% [95% credible interval -66·3 to 7·8), 2021 (-46·4% [-108·8 to 3·9]), and 2022 (-48·9 [-124·4 to 10·3]). These decreasing trends were consistent across Europe and the Americas, but larger decreases were seen in low-burden settings in 2020 (-54·8% [-112·4 to -4·8]) and 2021 (-68·4% [-156·6 to -2·9]), high-burden settings in 2021 (-89·4% [-190·3 to -10·4]), and Central and North America in 2021 (-100·3% [-239·0 to -6·3]). Observed incarceration levels were similar to predicted levels (<10% difference overall) during all COVID-19 pandemic years. Tuberculosis notifications in prisons from 47 countries in Europe and the Americas were lower than expected (at times >50% lower) during COVID-19 pandemic years, despite consistent incarceration levels. Reasons for this change in tuberculosis notifications might be multifactorial and include missed diagnoses and implementation of COVID-19 pandemic measures, reducing transmission. Greater prioritisation of people who are incarcerated is needed to ensure appropriate access to care in the face of future pandemics. Canadian Institutes of Health Research, National Institutes of Health, and Oswaldo Cruz Foundation, Brazil.
A 3-week pause versus continued Bruton tyrosine kinase inhibitor use during COVID-19 vaccination in individuals with chronic lymphocytic leukaemia (IMPROVE trial): a randomised, open-label, superiority trial
Authors: Jonathan A Cook, Piers E M Patten, Nicholas Peckham, Paul Moss, Neil Phillips, Abhishek Abhishek, Thomas Roberts, Marie Hodges, Georgina Talbot, Vicki Barber, Anne Francis, Adrian M Shields, Lelia Duley, Robbert Hoogeboom, Brian J Willett, Sam Scott, Nilima Parry-Jones, Toby A Eyre, Gareth Plested, Gratian Vandici, Farooq Ahmad Wandroo, Claire Hutchinson, Shankara Paneesha, Duncan J Murray, Nicolas Martinez-Calle, Stephen Jenkins, Earnest Heartin, Helen M Parry
Journal: The Lancet Haematology (2025)
Rising to the challenge: an international Delphi consensus study on fetal and neonatal alloimmune thrombocytopenia
Authors: Romy Pothof, Elske M van den Akker-van Marle, Thijs W de Vos, Heidi Tiller, James B Bussel, Maria Therese Ahlén, Brian R Curtis, Enrico Lopriore, E J T Joanne Verweij, Masja de Haas
Journal: The Lancet Haematology (2025)
INTEGRATE: international guidelines for the algorithmic treatment of schizophrenia
Authors: Robert A McCutcheon, Toby Pillinger, Ioana Varvari, Sean Halstead, Olatunde O Ayinde, Nicolás A Crossley, Christoph U Correll, Margaret Hahn, Oliver D Howes, John M Kane, Thomas Kabir, Åsa Konradsson-Geuken, Belinda Lennox, Christy Lai Ming Hui, Susan L Rossell, Marco Solmi, Iris E Sommer, Heidi Taipale, Hiroyuki Uchida, Ganesan Venkatasubramanian, Nicola Warren, Dan Siskind
Journal: The Lancet Psychiatry (2025)
Serum type I interferon score as a disease activity biomarker in patients with diffuse cutaneous systemic sclerosis: a retrospective cohort study
Authors: Monique Hinchcliff, Dinesh Khanna, Enrico De Lorenzis, Stefano Di Donato, Antonio Carriero, Rebecca L Ross, Suiyuan Huang, Kathleen A Aren, Elana J Bernstein, Mary Carns, Flavia V Castelino, Robyn T Domsic, Tracy M Frech, Jessica K Gordon, Faye N Hant, Ami A Shah, Victoria K Shanmugam, Virginia D Steen, Shervin Assassi, Francesco Del Galdo
Journal: The Lancet Rheumatology (2025)