tbuckley/cabot-search huggingface dataset:
Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade
Authors: Justin C. Jagodinsky, Jessica M. Vera, Won Jong Jin, Amanda G. Shea, Paul A. Clark, Raghava N. Sriramaneni, Thomas C. Havighurst, Ishan Chakravarthy, Raad H. Allawi, KyungMann Kim, Paul M. Harari, Paul M. Sondel, Michael A. Newton, Marka R. Crittenden, Michael J. Gough, Jessica R. Miller, Irene M. Ong, Zachary S. Morris
Journal: Science Translational Medicine (2024)

Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors.
ARGX-119 is an agonist antibody for human MuSK that reverses disease relapse in a mouse model of congenital myasthenic syndrome
Authors: Roeland Vanhauwaert, Julien Oury, Bernhardt Vankerckhoven, Christophe Steyaert, Stine Marie Jensen, Dana L. E. Vergoossen, Christa Kneip, Leah Santana, Jamie L. Lim, Jaap J. Plomp, Roy Augustinus, Shohei Koide, Christophe Blanchetot, Peter Ulrichts, Maartje G. Huijbers, Karen Silence, Steven J. Burden
Journal: Science Translational Medicine (2024)

Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of
Development of a High-Resolution Indoor Radon Map Using a New Machine Learning-Based Probabilistic Model and German Radon Survey Data
Authors: Eric Petermann, Peter Bossew, Joachim Kemski, Valeria Gruber, Nils Suhr, Bernd Hoffmann
Journal: Environmental Health Perspectives (2024)

Radon is a carcinogenic, radioactive gas that can accumulate indoors and is undetected by human senses. Therefore, accurate knowledge of indoor radon concentration is crucial for assessing radon-related health effects or identifying radon-prone areas.
PFAS Levels, Early Life Factors, and Mammographic Breast Density in Premenopausal Women
Authors: Yitao S. Ning, Kayla R. Getz, Joy K. Kyeyune, Myung Sik Jeon, Chongliang Luo, Jingqin Luo, Adetunji T. Toriola
Journal: Environmental Health Perspectives (2024)

Mammographic breast density (MBD) is a strong risk factor and an intermediate phenotype for breast cancer, yet there are limited studies on how environmental pollutants are associated with MBD.
Molecular serotyping of diarrheagenic <i>Escherichia coli</i> with a MeltArray assay reveals distinct correlation between serotype and pathotype
Authors: Chen Du, Yiqun Liao, Congcong Ding, Jiayu Huang, Shujuan Zhou, Yiyan Xu, Zhaohui Yang, Xiaolu Shi, Yinghui Li, Min Jiang, Le Zuo, Minxu Li, Shengzhe Bian, Na Xiao, Liqiang Li, Ye Xu, Qinghua Hu, Qingge Li
Journal: Gut Microbes (2024)

Diarrheagenic
Gut microbiota-derived butyrate selectively interferes with growth of carbapenem-resistant <i>Escherichia coli</i> based on their resistance mechanism
Authors: Eva Happ, Kora Schulze, Zinia Afrin, Sabrina Woltemate, Pia Görner, Stefan Ziesing, Dirk Schlüter, Robert Geffers, Volker Winstel, Marius Vital
Journal: Gut Microbes (2024)

We investigated consequences of resistance acquisition in
End-to-end donor screening and manufacturing controls: complementary quality-based strategies to minimize patient risk for donor-derived microbiome therapeutics
Authors: Jason Goldsmith, Sarah Tomkovich, John G. Auniņš, Barbara H. McGovern, Jennifer C. Mahoney, Brooke R. Hasson, Christopher W J McChalicher, David S. Ege
Journal: Gut Microbes (2024)

Advances in microbiome therapeutics have been motivated by a deeper understanding of the role that the gastrointestinal microbiome plays in human health and disease. The FDA approval of two stool-derived live biotherapeutic products (LBPs), REBYOTA® 150 mL enema (fecal microbiota, live-jslm; formerly RBX2660) and VOWST® oral capsules (fecal microbiota spores, live-brpk; formerly SER-109), for the prevention of recurrent CDI in adults following antibiotic treatment for recurrent CDI provides promise and insights for the development of LBPs for other diseases associated with microbiome dysfunction. Donor-derived products carry risk of disease transmission that must be mitigated through a robust donor screening program and downstream manufacturing controls. Most published recommendations for donor screening practices are prescriptive and do not include a systematic, risk-based approach for donor stool-derived products. A general framework for an end-to-end donor screening program is needed using risk management strategies for donor-derived microbiome therapeutic using a matrixed approach, combining the elements of donor screening with manufacturing controls that are designed to minimize risk to patients. A donor screening paradigm that incorporates medical history, physical examination, laboratory testing, and donor sample inspection are only the first steps in reducing risk of transmission of infectious agents. Manufacturing controls are the cornerstone of risk mitigation when screening unwittingly fails. Failure Mode and Effects Analysis (FMEA) can be used as a tool to assess for residual risk that requires further donor or manufacturing controls. Together, a well-reasoned donor program and manufacturing controls are complementary strategies that must be revisited and reexamined frequently with constant vigilance to mitigate risk to patients. In the spirit of full disclosure and informed consent, physicians should discuss any limitations in the donor screening and manufacturing processes with their patients prior to treatment with microbiome-based therapeutics.
ASN Kidney Health Guidance on the Management of Obesity in Persons Living with Kidney Diseases
Authors: T. Alp Ikizler, Holly J. Kramer, Srinivasan Beddhu, Alex R. Chang, Allon N. Friedman, Meera N. Harhay, Elizabeth Yakes Jimenez, Brandon Kistler, Aleksandra Kukla, Kristin Larson, LindaMarie U. Lavenburg, Sankar Dass Navaneethan, John Ortiz, Rocio I. Pereira, David B. Sarwer, Philip R. Schauer, Evan M. Zeitler
Journal: Journal of the American Society of Nephrology (2024)
Intestinal immunity in C. elegans is activated by pathogen effector-triggered aggregation of the guard protein TIR-1 on lysosome-related organelles
Authors: Samantha Y Tse-Kang, Khursheed A Wani, Nicholas D Peterson, Amanda Page, Fiachra Humphries, Read Pukkila-Worley
Journal: Immunity (2024)

Toll/interleukin-1/resistance (TIR)-domain proteins with enzymatic activity are essential for immunity in plants, animals, and bacteria. However, it is not known how these proteins function in pathogen sensing in animals. We discovered that the lone enzymatic TIR-domain protein in the nematode C. elegans (TIR-1, homolog of mammalian sterile alpha and TIR motif-containing 1 [SARM1]) was strategically expressed on the membranes of a specific intracellular compartment called lysosome-related organelles. The positioning of TIR-1 on lysosome-related organelles enables intestinal epithelial cells in the nematode C. elegans to survey for pathogen effector-triggered host damage. A virulence effector secreted by the bacterial pathogen Pseudomonas aeruginosa alkalinized and condensed lysosome-related organelles. This pathogen-induced morphological change in lysosome-related organelles triggered TIR-1 multimerization, which engaged its intrinsic NAD
Urinary Metal Levels and Coronary Artery Calcification
Authors: Katlyn E McGraw, Kathrin Schilling, Ronald A Glabonjat, Marta Galvez-Fernandez, Arce Domingo-Relloso, Irene Martinez-Morata, Miranda R Jones, Anne Nigra, Wendy S Post, Joel Kaufman, Maria Tellez-Plaza, Linda Valeri, Elizabeth R Brown, Richard A Kronmal, R Graham Barr, Steven Shea, Ana Navas-Acien, Tiffany R Sanchez
Journal: Journal of the American College of Cardiology (2024)

Exposure to metals, a newly recognized risk factor for cardiovascular disease (CVD), could be related to atherosclerosis progression.
Patient Self-Guided Interventions to Reduce Sedative Use and Improve Sleep
Authors: David M. Gardner, Justin P. Turner, Sandra Magalhaes, Malgorzata Rajda, Andrea L. Murphy
Journal: JAMA Psychiatry (2024)

Importance Direct-to-patient interventions enabling transitions from long-term benzodiazepine receptor agonist (BZRA) use to cognitive behavioral therapy for insomnia (CBTI) by older adults has the potential to reduce BZRA use and related harms while improving sleep outcomes without requiring prearranged clinician involvement. Objective To compare 2 direct-to-patient behavior change interventions with treatment as usual (TAU) on BZRA use, sleep, and other health outcomes, and uptake of CBTI techniques. Design, Setting, and Participants The Your Answers When Needing Sleep in New Brunswick (YAWNS NB) study was a 3-arm, pragmatic, open-label, minimum-contact, randomized clinical trial. The study began November 2020 and ended June 2022. Participants were randomly allocated to 1 of 3 groups, including 2 different mailed behavior change interventions or no intervention (TAU). Participants were from communities across the province of New Brunswick, Canada, and included adults 65 years and older living independently with long-term use of BZRAs and current or past insomnia. Interventions The Sleepwell package (YAWNS-1) consisted of a cover letter and 2 booklets (“How to Stop Sleeping Pills” and “How to Get Your Sleep Back”). The other package (YAWNS-2) included updated versions of the 2 booklets (“You May Be at Risk” and “How to Get a Good Night’s Sleep Without Medication”) used in the Eliminating Medications Through Patient Ownership of End Results (EMPOWER) study. Main Outcomes and Measures BZRA use at 6 months was the primary measure. Secondary measures included CBTI use, sleep, insomnia, daytime sleepiness, safety, anxiety, frailty, and quality of life. Results A total of 1295 individuals expressed interest in the study, and 565 (43.6%) completed a baseline assessment. Participants had a mean (SD) age of 72.1 (5.7) years, a mean (SD) BZRA use duration of 11.4 (9.1) years, and 362 (64.1%) were female. Discontinuations and dose reductions of 25% or greater were highest with YAWNS-1 (50 of 191 [26.2%]; 39 of 191 [20.4%]; total, 46.6%) compared with YAWNS-2 (38 of 187 [20.3%]; 27 of 187 [14.4%]; total, 34.8%, P = .02) and TAU (14 of 187 [7.5%]; 24 of 187 [12.8%]; total, 20.3%, P &amp;amp;lt; .001). YAWNS-1 also demonstrated better uptake of CBTI techniques and sleep outcomes compared with YAWNS-2 (new CBTI techniques: 3.1 vs 2.4; P =.03; sleep efficiency change: 4.1% vs −1.7%; P =.001) and reduced insomnia severity and daytime sleepiness compared with TAU (insomnia severity index change: −2.0 vs 0.3; P &amp;amp;lt;.001; Epworth Sleepiness Scale change: −0.8 vs 0.3; P =.001). Conclusions and Relevance Results of the YAWNS NB randomized clinical trial show that, as a simple, scalable, direct-to-patient intervention, YAWNS-1 substantially reduced BZRA use and improved sleep outcomes. It could be implemented to transform insomnia care for older adults at the population level. Trial Registration ClinicalTrials.gov Identifier: NCT04406103
Segregation by Payer in Obstetrics and Gynecology Residency Ambulatory Care Sites
Authors: Kavita Vinekar, Neena Qasba, Hannah Reiser, Erika Banks, Kavita S. Arora, Brownsyne Tucker Edmonds, Karen George
Journal: JAMA Network Open (2024)

Many teaching hospitals in the US segregate patients by insurance status, with resident clinics primarily composed of publicly insured or uninsured patients and faculty practices seeing privately insured patients. The prevalence of this model in obstetrics and gynecology residencies is unknown.
Teletrauma Use in US Emergency Departments
Authors: Zain G. Hashmi, Omar Rokayak, Krislyn M. Boggs, Kori S. Zachrison, Janice A. Espinola, Molly P. Jarman, Jan O. Jansen, Jayme E. Locke, Jeffrey D. Kerby, Carlos A. Camargo
Journal: JAMA Surgery (2024)

Importance Nearly 30 million predominantly rural US residents lack timely access to trauma care expertise available at level I or II trauma centers. Telehealth is an established approach to improve access to health care expertise using remote consultation; however, the prevalence of use of telehealth in trauma (teletrauma) across the US is not known. Objective To examine the prevalence of, trends in, and factors associated with teletrauma use and adoption among US emergency departments (EDs). Design, Setting, and Participants This survey study included data from the National Emergency Department Inventory (NEDI)–USA survey from January 1, 2016, to December 31, 2020. Each year, a 1-page survey was sent to the directors of nonfederal, nonspecialty EDs by mail and email up to 3 times; nonresponders were further contacted via telephone to complete the survey. Data were analyzed from January to March 2023. Main Outcomes and Measures The primary outcome was self-reported ED use of teletrauma for each year studied. Additional measures included data regarding self-reported use of any other telehealth service and ED characteristics. Multivariable logistic regression analyses were performed to assess ED characteristics associated with teletrauma use in 2020 and teletrauma adoption between 2017 and 2020. Results Of 5586 EDs in the US in 2020, 4512 had available teletrauma survey data (80.8% response rate); 379 (8.4%) of these EDs reported teletrauma use. In contrast, 2726 (60.4%) reported use of any other telehealth service. Teletrauma use (among EDs with any telehealth use) ranged between 0% in Alabama; Connecticut; Washington, DC; Indiana; New Jersey; Nevada; Oklahoma; Oregon; Rhode Island; and South Carolina to more than 60% in Arkansas (39 of 64 [60.9%]), South Dakota (31 of 41 [75.6%]), and North Dakota (30 of 35 [85.7%]). Factors associated with teletrauma use included rural location (odds ratio [OR], 2.44; 95% CI, 1.77-3.36), critical access hospital (OR, 2.67; 95% CI, 1.83-3.88), and basic stroke hospital vs nonstroke hospital (OR, 1.74; 95% CI, 1.32-2.30) designations. Factors associated with adoption of teletrauma by 2020 included critical access hospital (OR, 1.98; 95% CI, 1.35-2.90) and basic stroke hospital vs nonstroke hospital (OR, 1.42; 95% CI, 1.04-1.94) designation. Conclusion and Relevance This survey study found that teletrauma use lagged significantly behind use of other telehealth services in US EDs in 2020. While most EDs using teletrauma were located in rural areas, there was significant state-level variation in teletrauma use. Future research is needed on how teletrauma is being used and to identify barriers to its wider implementation.
The Science of Biosimilars—Updating Interchangeability
Authors: Patrizia Cavazzoni, Sarah Yim
Journal: JAMA (2024)

This Viewpoint from the US Food and Drug Administration (FDA) summarizes a recent update to an FDA draft interchangeability guidance regarding the need for clinical switching studies to illustrate the FDA’s ongoing efforts to streamline the development of biosimilar medications that are in line with the latest science.
A Patient-Centered Perspective on Changes in Personal Characteristics After Deep Brain Stimulation
Authors: Amanda R. Merner, Thomas W. Frazier, Paul J. Ford, Brittany Lapin, Joshua Wilt, Eric Racine, Natalie Gase, Essence Leslie, Andre Machado, Jerrold L. Vitek, Cynthia S. Kubu
Journal: JAMA Network Open (2024)

Importance Deep brain stimulation (DBS) results in improvements in motor function and quality of life in patients with Parkinson disease (PD), which might impact a patient’s perception of valued personal characteristics. Prior studies investigating whether DBS causes unwanted changes to oneself or one’s personality have methodological limitations that should be addressed. Objective To determine whether DBS is associated with changes in characteristics that patients with PD identify as personally meaningful. Design, Setting, and Participants This cohort study assessed changes in visual analog scale (VAS) ratings reflecting the extent to which patients with PD manifested individually identified personal characteristics before and 6 and 12 months after DBS at a large academic medical center from February 21, 2018, to December 9, 2021. The VAS findings were tailored to reflect the top 3 individually identified personal characteristics the patient most feared losing. The VASs were scored from 0 to 10, with 0 representing the least and 10 the most extreme manifestation of the trait. Change scores were examined at the individual level. Content analysis was used to code the qualitative data. Qualitative and quantitative analyses were performed from January 12, 2019 (initial qualitative coding), to December 15, 2023. Exposure Deep brain stimulation. Main Outcomes and Measures The primary outcome variable was the mean VAS score for the top 3 personal characteristics. The secondary outcome was the incidence of meaningful changes on the patients’ top 3 characteristics at the individual level. Results Fifty-two of 54 dyads of patients with PD and their care partners (96.3%) were recruited from a consecutive series approved for DBS (36 patients [69.2%] were male and 45 care partners [86.5%] were female; mean [SD] age of patients, 61.98 [8.55] years). Two patients and 1 care partner were lost to follow-up. Increases in the mean VAS score (indicative of greater manifestation of [ie, positive changes in] specific characteristics) were apparent following DBS for ratings of both the patients (Wald χ 2 = 16.104; P &amp;amp;lt; .001) and care partners (Wald χ 2 = 6.746; P &amp;amp;lt; .001) over time. The slopes of the changes for both the patient and care partners were correlated, indicating agreement in observed changes over time. The individual level analyses indicated that scores for most patients and care partners remained the same or increased. Conclusions and Relevance In this cohort study, participants reported greater (more positive) manifestations of individually identified, valued characteristics after DBS. These findings may be relevant to informing decision-making for patients with advanced PD who are considering DBS.
Suicidality Calls to a National Helpline After a Terror Attack and War
Authors: Joy Benatov, Liat Itzhaky, Shiri Daniels, Gil Zalsman
Journal: JAMA Psychiatry (2024)

Importance Changes in suicide rates after a nationwide trauma may be different from changes in psychiatric symptoms or general distress after such events. However, very few studies have examined short-term suicide-related reactions after such an event. Objective To evaluate the short-term outcome of the events in Israel on October 7, 2023, a large-scale terror attack and unfolding war, on changes in suicidality as reflected in percentages of suicide-related calls in relation to all calls to a national mental health first aid helpline, the Israeli Association for Emotional First Aid (ERAN). Design, Setting and Participants The data included all interactions via the various ERAN helpline services between January 1, 2022, and December 31, 2023. Exposures The October 7, 2023, terror attack on Israel. Mean Outcomes and Measures Changes in the numbers of overall calls and suicide-related calls to the ERAN helpline using an interrupted time-series analysis. Results A total of 602 323 calls were received by the ERAN helpline. The number of calls reflecting psychological distress in the 3 months before October 7, 2023, was 67 555 compared with 89 445 calls in the 3 months after. Analysis indicated that overall calls increased significantly on October 7 (β = 2089.16; 95% CI, 1918.97-2259.35). In addition, the daily trajectory of all calls changed significantly after October 7 (β = −22.77; 95% CI, −33.37 to −12.16), such that there was a decrease in the number of calls per day (β = −11.34; SE = 1.213; t = −9.35; P &amp;amp;lt; .001). The number of suicide-related calls in the 3 months before October 7 was 1887, whereas 1663 suicide-related calls were registered in the 3 months after. Analysis showed that there were no changes in the daily number of suicide-related calls from before October 7 (β = −0.001; 95% CI, −0.005 to 0.03) or on October 7 (β = −0.22; 95% CI, −3.69 to 3.25). Therefore, the percentage of suicide-related calls decreased significantly on October 7 (β = −1.42; 95% CI, −1.92 to −0.92) and gradually increased in the following period (β = 0.016; 95% CI, 0.006-0.026). Conclusions and Relevance The findings of this cohort study suggest that although short-term emotional distress increased after national trauma, the percentage of suicide-related calls decreased. These results support previous studies suggesting that suicidality is not one of the immediate reactions to such traumas.