tbuckley/cabot-search huggingface dataset:
Diabetes and Driving: A Statement of the American Diabetes Association
Authors: Daniel J. Cox, Brian M. Frier, Brittany Bruggeman, Timur Durrani, Nuha A. ElSayed, Raveendhara R. Bannuru, Aaron Fischer, John Griffin, Daniel B. Kohrman, Anthony May, Jennifer Sherman
Journal: Diabetes Care (2024)

Many people with diabetes in the U.S. will seek or currently hold a license to drive. For many, a driver’s license is essential for everyday life. Considerable discussion has focused on whether, and the extent to which, diabetes may be a relevant factor in determining driver ability and eligibility for a license. This statement addresses such issues in relation to current scientific and medical evidence. A diagnosis of diabetes on its own is not sufficient to make judgments about an individual driver’s ability or safety. This statement provides an overview of existing licensing rules for people with diabetes in the U.S., addresses the factors that affect driving ability, identifies general guidelines for assessing driver fitness and determining appropriately tailored licensing restrictions, and provides practical guidance for health care professionals regarding clinical interventions and education for people with diabetes.
DKN-01 in Combination With Tislelizumab and Chemotherapy as First-Line Therapy in Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: DisTinGuish
Authors: Samuel J. Klempner, Mohamad Bassam Sonbol, Zev A. Wainberg, Hope Elizabeth Uronis, Vi K. Chiu, Aaron James Scott, Syma Iqbal, Mohamedtaki Abdulaziz Tejani, Vincent Chung, Melissa C. Stilian, Mathis Thoma, Ying Zhang, Michael H. Kagey, Jason Baum, Cynthia A. Sirard, Rachel A. Altura, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2024)

PURPOSE The outcomes of anti–PD-1 agents plus fluoropyrimidine/platinum in frontline advanced gastroesophageal adenocarcinomas (aGEAs) remain poor. We investigated the safety, tolerability, and activity of fluoropyrimidine/oxaliplatin and tislelizumab with the DKK1-neutralizing antibody DKN-01 in aGEAs in a phase IIa open-label study. PATIENTS AND METHODS Patients had untreated human epidermal growth factor receptor 2–negative aGEAs, RECIST v1.1 measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and adequate organ function. Patients received intravenous DKN-01 300 mg once every 2 weeks, tislelizumab 200 mg once every 3 weeks, oxaliplatin 130 mg/m 2 once every 3 weeks, and capecitabine 1,000 mg/m 2 twice daily on days 1-15 of each 21-day cycle. The primary end point was safety and tolerability. Key secondary end points included objective response rate (ORR) by RECISTv1.1, progression-free survival (PFS), and overall survival (OS). RESULTS Between September 18, 2020, and April 8, 2021, 25 patients were enrolled. All patients who received at least one dose of DKN-01 were included in the safety analysis. Most patients had gastroesophageal junction tumors, median age was 61 years, 76% were male, and 55% were ECOG of 0. All patients reported at least one treatment-emergent adverse event. The ORR was 73% (95% CI, 49.8 to 89.3), with a disease control rate of 95%. The ORR was 90% (95% CI, 55.5 to 99.7) in the DKK1-high tumor patients and 67% (95% CI, 29.9 to 92.5) in the DKK1-low tumor patients. The median PFS was 11.3 months (95% CI, 5.8 to 12.0) and the 12-month PFS rate was 33%. The median OS was 19.5 months (95% CI, 15.2 to 24.4) with a 12-month OS rate of 76% and an 18-month OS rate of 55%. CONCLUSION DKN-01 can be safely combined with frontline fluoropyrimidine/oxaliplatin and tislelizumab and demonstrates encouraging activity independent of PD-L1 expression levels. A randomized phase II trial is ongoing (ClinicalTrials.gov identifier: NCT04363801 ).
Phenotypic approaches for CNS drugs
Authors: Raahul Sharma, Caitlin R M Oyagawa, Hamid Abbasi, Michael Dragunow, Daniel Conole
Journal: Trends in Pharmacological Sciences (2024)

Central nervous system (CNS) drug development is plagued by high clinical failure rate. Phenotypic assays promote clinical translation of drugs by reducing complex brain diseases to measurable, clinically valid phenotypes. We critique recent platforms integrating patient-derived brain cells, which most accurately recapitulate CNS disease phenotypes, with higher throughput models, including immortalized cells, to balance validity and scalability. These platforms were screened with conventional commercial chemogenomic compound libraries. We explore emerging library curation strategies to improve hit rate and quality, and screening novel fragment libraries as alternatives, for more tractable drug target deconvolution. The clinically relevant models used in these platforms could harbor important, unidentified drug targets, so we review evolving agnostic target deconvolution approaches, including chemical proteomics and artificial intelligence (AI), which aid in phenotypic screening hit mechanism elucidation, thereby facilitating rational hit-to-drug optimization.
Genome-wide CRISPR screen identifies MAD2L1BP and ANAPC15 as targets for brentuximab vedotin sensitivity in CD30+ peripheral T-cell lymphoma
Authors: Keito Suto, Norio Takei, Keito Yokoyama, Masahiro Chiba, Takashi Ishio, Michiyuki Maeda, Hideki Goto, Tomoyuki Endo, Takanori Teshima, Yibin Yang, Masao Nakagawa
Journal: Leukemia (2024)
Development of an implantable sensor system for in vivo strain, temperature, and pH monitoring: comparative evaluation of titanium and resorbable magnesium plates
Authors: A M Rich, W Rubin, S Rickli, T Akhmetshina, J Cossu, L Berger, M Magno, K M Nuss, B Schaller, J F Löffler
Journal: Bioactive Materials (2024)
Asthma symptoms, severity, and control with and without a clinical diagnosis of asthma in early adolescence in sub-Saharan Africa: a multi-country, school-based, cross-sectional study
Authors: Victoria O Oyenuga, Gioia Mosler, Emmanuel Addo-Yobo, Olayinka O Adeyeye, Bernard Arhin, Farida Fortune, Christopher J Griffiths, Marian Kasekete, Elizabeth Mkutumula, Reratilwe Mphahlele, Hilda A Mujuru, Sofia Muyemayema, Rebecca Nantanda, Lovemore M Nkhalamba, Oluwafemi T Ojo, Sandra Kwarteng Owusu, Ismail Ticklay, Peter O Ubuane, Rafiuk C Yakubu, Lindsay Zurba, Refiloe Masekela, Jonathan Grigg
Journal: The Lancet Child & Adolescent Health (2024)
Uncovering the genetic basis of Parkinson's disease globally: from discoveries to the clinic
Authors: Shen-Yang Lim, Ai Huey Tan, Azlina Ahmad-Annuar, Njideka Ulunma Okubadejo, Katja Lohmann, Huw R Morris, Tzi Shin Toh, Yi Wen Tay, Lara M Lange, Sara Bandres-Ciga, Ignacio Mata, Jia Nee Foo, Esther Sammler, Joshua Chin Ern Ooi, Alastair J Noyce, Natascha Bahr, Wei Luo, Rajeev Ojha, Andrew B Singleton, Cornelis Blauwendraat, Christine Klein
Journal: The Lancet Neurology (2024)
The Effect of the “Safety in Dementia” Online Tool to Assist Decision Making for Caregivers of Persons With Dementia and Access to Firearms
Authors: Marian E. Betz, Jennifer Portz, Christopher Knoepke, Megan L. Ranney, Stacy M. Fischer, Ryan A. Peterson, Rachel L. Johnson, Faris Omeragic, Mirella Castaneda, Emily Greenway, Daniel Matlock
Journal: Annals of Internal Medicine (2024)

Caregivers face challenges (including competing desires to prevent injury, respect autonomy, and avoid conflict) when addressing firearm access by community-dwelling persons with Alzheimer disease and related dementias (ADRD).
Colorectal Cancer Screening Completion and Yield in Patients Aged 45 to 50 Years
Authors: Theodore R. Levin, Christopher D. Jensen, Natalia Udaltsova, Andrea A. Burnett-Hartman, Aruna Kamineni, Chun R. Chao, Joanne E. Schottinger, Nirupa R. Ghai, Gaia Pocobelli, Larissa L. White, Malia Oliver, Hina Chowdhry, Brian P. Hixon, Jessica M. Badalov, Shauna R. Goldberg, Susan C. Bradford, Charles P. Quesenberry, Jeffrey K. Lee
Journal: Annals of Internal Medicine (2024)

Guidelines now recommend initiating colorectal cancer (CRC) screening at age 45 years rather than 50 years, but little is known about screening completion and yield among people aged 45 to 49 years.
Artificial Intelligence–Assisted Colonoscopy for Polyp Detection
Authors: Saeed Soleymanjahi, Jack Huebner, Lina Elmansy, Niroop Rajashekar, Nando Lüdtke, Rumzah Paracha, Rachel Thompson, Alyssa A. Grimshaw, Farid Foroutan, Shahnaz Sultan, Dennis L. Shung
Journal: Annals of Internal Medicine (2024)

Randomized clinical trials (RCTs) of computer-aided detection (CADe) system-enhanced colonoscopy compared with conventional colonoscopy suggest increased adenoma detection rate (ADR) and decreased adenoma miss rate (AMR), but the effect on detection of advanced colorectal neoplasia (ACN) is unclear.
A Sr@Ag-based spatiotemporal and step-release scaffold against chronic osteomyelitis, fabricated by coaxial 3D-printing
Authors: Jingyun Wang, Qin Zhang, Hetong Wang, Chunlin Liu, Le Jiang, Wanting Liu, Yixian Wu, Yifan Wang, None Vivian, Hao Yan, Jun Lin, Xiaodan Sun
Journal: Biomaterials (2024)
Finding NEMO in the thymus
Authors: Juan Moises Ocampo-Godinez, Alexandra Y. Kreins
Journal: The Journal of Experimental Medicine (2024)

Rosain et al. (https://doi.org/10.1084/jem.20231152) describe the association between anti-type I interferon autoantibodies and severe viral infections in patients with incontinentia pigmenti and heterozygous loss-of-function NEMO variants, suggesting a role for canonical NF-κB signaling in immune tolerance. The mechanisms behind this selective autoimmunity remain unclear.
Sex differences in clinically diagnosed psychiatric disorders over the lifespan: a nationwide register-based study in Sweden
Authors: Yihui Yang, Fang Fang, Filip K Arnberg, Ralf Kuja-Halkola, Brian M D'Onofrio, Henrik Larsson, Isabell Brikell, Zheng Chang, Ole A Andreassen, Paul Lichtenstein, Unnur A Valdimarsdóttir, Donghao Lu
Journal: The Lancet Regional Health - Europe (2024)
Pharmacological therapies for male infertility
Authors: Amarnath Rambhatla, Rupin Shah, Germar-Michael Pinggera, Taymour Mostafa, Widi Atmoko, Ramadan Saleh, Eric Chung, Taha Hamoda, Selahittin Cayan, Hyun Jun Park, Ates Kadioglu, Logan Hubbard, Ashok Agarwal
Journal: Pharmacological Reviews (2024)

Male factor infertility is a multifaceted problem that affects approximately 50% of couples suffering from infertility. Causes of male infertility include endocrine disturbances, gonadotoxins, genetic abnormalities, varicocele, malignancies, infections, congenital or acquired urogenital abnormalities, iatrogenic factors, immunological factors, and idiopathic reasons. There are a variety of treatment options for male infertility, depending on the underlying cause(s). These can include surgical treatments, medical/hormonal therapies, and assisted reproductive techniques (ART), which can be combined with surgical sperm retrieval (SSR) if necessary. In this review article, the pharmacological therapies for male infertility are grouped by their underlying causes. Some of these therapies are targeted and specific, while others are used empirically to treat idiopathic male infertility. This will include treatments to optimize infertility in patients who have hypogonadism, ejaculatory dysfunction, infections, or idiopathic male infertility. Finally, we will provide an overview of the future directions of pharmacological therapies for male infertility. <b>Significance Statement</b> Male infertility is a significant worldwide problem. Detailed knowledge of the pharmacological therapies available will ensure the prescription of appropriate therapy and avoid the use of unnecessary or harmful treatments.
How to drug a cloud? Targeting intrinsically disordered proteins
Authors: Vladimir N. Uversky
Journal: Pharmacological Reviews (2024)

Biologically active proteins/regions without stable structure (i.e., intrinsically disordered proteins and regions (IDPs and IDRs)) are commonly found in all proteomes. They have a unique functional repertoire that complements the functionalities of ordered proteins and domains. IDPs/IDRs are multifunctional promiscuous binders capable of folding at interaction with specific binding partners on a template- or context-dependent manner, many of which undergo liquid-liquid phase separation, leading to the formation of membrane-less organelles and biomolecular condensates. Many of them are frequently related to the pathogenesis of various human diseases. All this defines IDPs/IDRs as attractive targets for the development of novel drugs. However, their lack of unique structures, multifunctionality, binding promiscuity, and involvement in unusual modes of action preclude direct use of traditional structure-based drug design approaches for targeting IDPs/IDRs, and make disorder-based drug discovery for these "protein clouds" challenging. Despite all these complexities there is continuing progress in the design of small molecules affecting IDPs/IDRs. This article describes the major structural features of IDPs/IDRs and the peculiarities of the disorder-based functionality. It also discusses the roles of IDPs/IDRs in various pathologies, and shows why the approaches elaborated for finding drugs targeting ordered proteins cannot be directly used for the intrinsic disorder-based drug design, and introduces some novel methodologies suitable for these purposes. Finally, it emphasizes that regardless of their multifunctionality, binding promiscuity, lack of unique structures, and highly dynamic nature, "protein clouds" are principally druggable. <b>Significance Statement</b><b>Intrinsically disordered proteins and regions are highly abundant in nature, have multiple important biological functions, are commonly involved in the pathogenesis of a multitude of human diseases, and are therefore considered as very attractive drug targets. Although dealing with these unstructured multifunctional protein/regions is a challenging task, multiple innovative approaches have been designed to target them by small molecules.</b>
Is seborrhoeic dermatitis of infancy and childhood related to maternal history of seborrhoeic dermatitis? A large population-based cohort study from the UK
Authors: Zelma C Chiesa Fuxench, Nandita Mitra, Elizabeth Grice, Ole Hoffstad, David J Margolis
Journal: British Journal of Dermatology (2024)

Abstract Background The pathophysiology of seborrhoeic dermatitis (SebD) is complex and is likely to be related to an interplay of the microbial colonization of the skin and local immunity. There are also genetic components to the illness. At least two forms of SebD exist, infantile (ISebD), which has onset early in life, and SebD with later onset. Objectives We aimed to improve our understanding of SebD by evaluating whether maternal history of SebD is associated with increased risk of ISebD or childhood-onset SebD (CSebD, with onset after 5 years of life). Methods We performed a prospective cohort study of mother–child pairs using data from a large UK primary care electronic medical records database. Results We analysed 1 023 140 children with linked maternal data. The mean (SD) time of follow-up for the children was 10.2 (7.9) years for a total follow-up of more than 10 million person-years. Proportional hazards models [HRs (95% confidence intervals)] were used to examine the association between presence of SebD in mothers and SebD in the child. Maternal history of SebD was associated with development of SebD [1.99 (1.91–2.09)], ISebD [1.86 (1.74–1.99)] and CSebD [2.12 (1.97–2.29)] in their children. However, ISebD in a child was not associated with that child later developing CSebD [0.91 (0.82–1.01)]. Conclusions Maternal history of SebD is a risk factor for the development of SebD in children. While we cannot fully differentiate SebD risk due to mother’s genetics (inheritance) from a newborn’s environment, our results lend credence to the possible role of genetics in SebD. A child with ISebD does not appear to be at risk for developing CSebD.
British Association of Dermatologists living guideline for managing people with alopecia areata 2024
Authors: Matthew J Harries, Anna Ascott, Leila Asfour, Paul Farrant, Gordon Hale, Susan Holmes, Amy Johnson, Victoria M L Jolliffe, Ahmed Kazmi, Abby E Macbeth, Andrew G Messenger, Ali Noor, Anita Takwale, Andrew R Thompson, Maria Hashme, Lina Manounah, M Firouz Mohd Mustapa, Alina M Constantin, S L Chua, W Gorav, R Ramessur, M Hashme, S Tawfik, L S Exton, A M Constantin, M F Mohd Mustapa
Journal: British Journal of Dermatology (2024)

The overall objective of the current iteration of this living guideline is to provide up-to-date, evidence-based recommendations for the management of alopecia areata (AA) in adults (≥18 years of age), children (0-12 years of age) and young people (13-17 years of age).
Efficacy and safety of the oral JAK3/TEC family kinase inhibitor ritlecitinib over 24 months: integrated analysis of the ALLEGRO phase 2b/3 and long-term phase 3 clinical studies in alopecia areata
Authors: Melissa Piliang, Jennifer Soung, Brett King, Jerry Shapiro, Lidia Rudnicka, Paul Farrant, Nina Magnolo, Bianca Maria Piraccini, Xin Luo, Robert Wolk, Deborah Woodworth, Gregor Schaefer, Alexandre Lejeune
Journal: British Journal of Dermatology (2024)

Abstract Background The ALLEGRO phase IIa and IIb/III (NCT02974868 and NCT03732807) studies have demonstrated that ritlecitinib is effective and well tolerated in adults and adolescents with alopecia areata (AA) up to 48 weeks. Objectives To assess the efficacy of ritlecitinib through month 24 and safety through data cutoff in the ALLEGRO phase IIb/III study and the ongoing long-term open-label phase III ALLEGRO-LT study (NCT04006457). Methods Patients aged ≥ 12 years with AA and ≥ 50% scalp hair loss from ALLEGRO IIb/III who rolled over to ALLEGRO-LT after up to 48 weeks were included. Proportions of patients with responses based on clinician-reported Severity of Alopecia Tool (SALT) scores of ≤ 20 and ≤ 10, eyebrow assessment (EBA) and eyelash assessment (ELA), patient global impression of change (PGI-C) and patient satisfaction with hair growth were reported through month 24 for patients who received ritlecitinib 50 mg daily with or without a 200-mg 4-week daily loading dose. Observed and imputed data [last observation carried forward (LOCF)] were reported up to 9 December 2022. Safety was assessed throughout. Results At month 12, a SALT score ≤ 20 was achieved by 45.1% and 45.9% (observed) and 40.3% and 41.8% (LOCF) of the 191 and 194 patients who received ritlecitinib 50 mg and ritlecitinib 200 mg/50 mg, respectively. At month 24, these proportions increased to 60.8% and 63.1% (observed) and 46.1% and 50.8% (LOCF), respectively. Patients with abnormal EBA or ELA scores at baseline achieved responses at month 24 [EBA observed: 57.6% (50 mg), 61.0% (200/50 mg); EBA LOCF: 46.8% (50 mg), 50.9% (200/50 mg); ELA observed: 51.2% (50 mg), 62.7% (200/50 mg); ELA LOCF: 43.2% (50 mg), 51.7% (200/50 mg)]. PGI-C response was achieved by patients at month 24 [observed: 70.0% (50 mg), 76.4% (200/50 mg); LOCF: 56.6% (50 mg), 65.5% (200/50 mg)]. Safety profiles for both treatment groups were consistent with the known safety profile of ritlecitinib. Conclusions Ritlecitinib has clinically meaningful and sustained efficacy beyond 1 year with a favourable safety and tolerability profile, supporting its long-term use in patients aged ≥ 12 years with AA.
Microenvironmental alkalization promotes the therapeutic effects of MSLN-CAR-T cells
Authors: Min Wu, Ling Mao, Xuejia Zhai, Jie Liu, Junhan Wang, Langhong Li, Jiangjie Duan, Jun Wang, Shuang Lin, Jianjun Li, Shicang Yu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Triple-negative breast cancer (TNBC) is characterized by high invasion, prone metastasis, frequent recurrence and poor prognosis. Unfortunately, the curative effects of current clinical therapies, including surgery, radiotherapy, chemotherapy and immunotherapy, are still limited in patients with TNBC. In this study, we showed that the heterogeneous expression at the protein level and subcellular location of mesothelin (MSLN), a potential target for chimeric antigen receptor-T (CAR-T) cell therapy in TNBC, which is caused by acidification of the tumor microenvironment, may be the main obstacle to therapeutic efficacy. Alkalization culture or sodium bicarbonate administration significantly promoted the membrane expression of MSLN and enhanced the killing efficiency of MSLN-CAR-T cells both
Against Odds of Prolonged Warm Ischemia: Early Experience With DCD Heart Transplantation After 20-Minute No-Touch Period
Authors: Gino Gerosa, Giovanni Battista Luciani, Nicola Pradegan, Vincenzo Tarzia, Tea Lena, Paolo Zanatta, Demetrio Pittarello, Francesco Onorati, Antonella Galeone, Leonardo Gottin, Massimo Boffini, Marinella Zanierato, Matteo Marro, Sofia Martin Suarez, Luca Botta, Paola Lilla della Monica, Mariano Feccia, Guido Maria Olivieri, Amedeo Terzi, Alessandra Oliveti, Giuseppe Feltrin, Massimo Cardillo, Claudio Francesco Russo, Davide Pacini, Mauro Rinaldi
Journal: Circulation (2024)
Delayed reinforcement of costimulation improves the efficacy of mRNA vaccines in mice
Authors: Sarah Sanchez, Tanushree Dangi, Bakare Awakoaiye, Min Han Lew, Nahid Irani, Slim Fourati, Pablo Penaloza-MacMaster
Journal: Journal of Clinical Investigation (2024)

mRNA vaccines have demonstrated efficacy during the COVID-19 pandemic and are now being investigated for multiple diseases. However, concerns linger about the durability of immune responses, and the high incidence of breakthrough infections among vaccinated individuals highlights the need for improved mRNA vaccines. In this study, we investigated the effects of reinforcing costimulation via 4-1BB, a member of the TNF receptor superfamily, on immune responses elicited by mRNA vaccines. We first immunized mice with mRNA vaccines, followed by treatment with 4-1BB costimulatory antibodies to reinforce the 4-1BB pathway at different timepoints post-vaccination. Consistent with prior studies, reinforcing 4-1BB costimulation on the day of vaccination did not result in a substantial improvement of vaccine responses. However, reinforcing 4-1BB costimulation at day 4 post-vaccination, when 4-1BB expression levels were highest, resulted in a profound improvement of CD8 T cell responses associated with enhanced protection against pathogen challenges. A similar clinical benefit was observed in a therapeutic cancer vaccine model. We also report time-dependent effects with OX40, another costimulatory molecule of the TNF receptor superfamily. These findings demonstrate that delayed reinforcement of costimulation may exert an immunologic benefit, providing insights for the development of more effective mRNA vaccines for infectious diseases and cancer.