tbuckley/cabot-search huggingface dataset:
Advances in the design and delivery of RNA vaccines for infectious diseases
Authors: Abhijeet Girish Lokras, Thomas Rønnemoes Bobak, Saahil Sandeep Baghel, Federica Sebastiani, Camilla Foged
Journal: Advanced Drug Delivery Reviews (2024)

RNA medicines represent a paradigm shift in treatment and prevention of critical diseases of global significance, e.g., infectious diseases. The highly successful messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were developed at record speed during the coronavirus disease 2019 pandemic. A consequence of this is exceptionally shortened vaccine development times, which in combination with adaptability makes the RNA vaccine technology highly attractive against infectious diseases and for pandemic preparedness. Here, we review state of the art in the design and delivery of RNA vaccines for infectious diseases based on different RNA modalities, including linear mRNA, self-amplifying RNA, trans-amplifying RNA, and circular RNA. We provide an overview of the clinical pipeline of RNA vaccines for infectious diseases, and present analytical procedures, which are paramount for characterizing quality attributes and guaranteeing their quality, and we discuss future perspectives for using RNA vaccines to combat pathogens beyond SARS-CoV-2.
Modernizing the Data Infrastructure for Clinical Research to Meet Evolving Demands for Evidence
Authors: Joseph B. Franklin, Caroline Marra, Kaleab Z. Abebe, Atul J. Butte, Deborah J. Cook, Laura Esserman, Lee A. Fleisher, Cynthia I. Grossman, Nancy E. Kass, Harlan M. Krumholz, Kathy Rowan, Amy P. Abernethy, Ali B Abbasi, Kaleab Z Abebe, Amy P Abernethy, Stacey J. Adam, Derek C Angus, Jamy Ard, Rachel A Bender Ignacio, Michael Berkwits, Scott M Berry, Deepak L. Bhatt, Kirsten Bibbins-Domingo, Robert O. Bonow, Marc Bonten, Sharon A. Brangman, John Brownstein, Melinda J. B. Buntin, Atul J Butte, Robert M. Califf, Marion K Campbell, Anne R. Cappola, Anne C Chiang, Deborah Cook, Steven R Cummings, Gregory Curfman, Laura J Esserman, Lee A Fleisher, Joseph B Franklin, Ralph Gonzalez, Cynthia I Grossman, Tufia C. Haddad, Roy S. Herbst, Adrian F. Hernandez, Diane P Holder, Leora Horn, Grant D. Huang, Alison Huang, Nancy Kass, Rohan Khera, Walter J. Koroshetz, Harlan M. Krumholz, Martin Landray, Roger J. Lewis, Tracy A Lieu, Preeti N. Malani, Christa Lese Martin, Mark McClellan, Mary M. McDermott, Stephanie R. Morain, Susan A Murphy, Stuart G Nicholls, Stephen J Nicholls, Peter J. O'Dwyer, Bhakti K Patel, Eric Peterson, Sheila A. Prindiville, Joseph S. Ross, Kathryn M Rowan, Gordon Rubenfeld, Christopher W. Seymour, Rod S Taylor, Joanne Waldstreicher, Tracy Y. Wang
Journal: JAMA (2024)

The ways in which we access, acquire, and use data in clinical trials have evolved very little over time, resulting in a fragmented and inefficient system that limits the amount and quality of evidence that can be generated.
Tissue-specific activation of insulin signaling as a potential target for obesity-related metabolic disorders
Authors: Hideyuki Okuma, Kyoichiro Tsuchiya
Journal: Pharmacology & Therapeutics (2024)

The incidence of obesity is rapidly increasing worldwide. Obesity-associated insulin resistance has long been established as a significant risk factor for obesity-related disorders such as type 2 diabetes and atherosclerosis. Insulin plays a key role in systemic glucose metabolism, with the liver, skeletal muscle, and adipose tissue as the major acting tissues. Insulin receptors and the downstream insulin signaling-related molecules are expressed in various tissues, including vascular endothelial cells, vascular smooth muscle cells, and monocytes/macrophages. In obesity, decreased insulin action is considered a driver for associated disorders. However, whether insulin action has a positive or negative effect on obesity-related disorders depends on the tissue in which it acts. While an enhancement of insulin signaling in the liver increases hepatic fat accumulation and exacerbates dyslipidemia, enhancement of insulin signaling in adipose tissue protects against obesity-related dysfunction of various organs by increasing the capacity for fat accumulation in the adipose tissue and inhibiting ectopic fat accumulation. Thus, this "healthy adipose tissue expansion" by enhancing insulin sensitivity in adipose tissue, but not in the liver, may be an effective therapeutic strategy for obesity-related disorders. To effectively address obesity-related metabolic disorders, the mechanisms of insulin resistance in various tissues of obese patients must be understood and drugs that enhance insulin action must be developed. In this article, we review the potential of interventions that enhance insulin signaling as a therapeutic strategy for obesity-related disorders, focusing on the molecular mechanisms of insulin action in each tissue.
Health, Access to Care, and Financial Barriers to Care Among People Incarcerated in US Prisons
Authors: Emily Lupton Lupez, Steffie Woolhandler, David U. Himmelstein, Laura Hawks, Samuel Dickman, Adam Gaffney, David Bor, Elizabeth Schrier, Chris Cai, Lenore S. Azaroff, Danny McCormick
Journal: JAMA Internal Medicine (2024)

Importance Decades-old data indicate that people imprisoned in the US have poor access to health care despite their constitutional right to care. Most prisons impose co-payments for at least some medical visits. No recent national studies have assessed access to care or whether co-pays are associated with worse access. Objective To determine the proportion of people who are incarcerated with health problems or pregnancy who used health services, changes in the prevalence of those conditions since 2004, and the association between their state’s standard prison co-payment and care receipt in 2016. Design, Setting, and Participants This cross-sectional analysis was conducted in October 2023 and used data from the Bureau of Justice Statistics’ 2016 Survey of Prison Inmates, a nationally representative sample of adults in state or federal prisons, with some comparisons to the 2004 version of that survey. Exposures The state’s standard, per-visit co-payment amount in 2016 compared with weekly earnings at the prison’s minimum wage. Main Outcomes and Measures Self-reported prevalence of 13 chronic physical conditions, 6 mental health conditions, and current severe psychological distress assessed using the Kessler Psychological Distress Scale; proportion of respondents with such problems who did not receive any clinician visit or treatment; and adjusted odds ratios (aORs) comparing the likelihood of no clinician visit according to co-payment level. Results Of 1 421 700 (unweighted: n = 24 848; mean [SD] age, 35.3 [0.3] years; 93.2% male individuals) prison residents in 2016, 61.7% (up from 55.9% in 2004) reported 1 or more chronic physical conditions; among them, 13.8% had received no medical visit since incarceration. A total of 40.1% of respondents reported ever having a mental health condition (up from 24.5% in 2004), of whom 33.0% had received no mental health treatment. A total of 13.3% of respondents met criteria for severe psychological distress, of whom 41.7% had not received mental health treatment in prison. Of state prison residents, 90.4% were in facilities requiring co-payments, including 63.3% in facilities with co-payments exceeding 1 week’s prison wage. Co-payments, particularly when high, were associated with not receiving a needed health care visit (co-pay ≤1 week’s wage: aOR, 1.43; 95% CI, 1.10-1.86; co-pay &amp;amp;gt;1 week’s wage: aOR, 2.17; 95% CI, 1.61-2.93). Conclusions and Relevance This cross-sectional study found that many people who are incarcerated with health problems received no care, particularly in facilities charging co-payments for medical visits.
The subgroup analysis by age and geriatric assessment in a phase III study comparison of trastuzumab emtansine with trastuzumab, pertuzumab, and docetaxel in older patients with advanced stage HER2-positive breast cancer (JCOG1607 HERB TEA study).
Authors: Akihiko Shimomura, Kenji Tamura, Keita Sasaki, Ryo Sadachi, Akihiko Suto, Masataka Sawaki, Yasuaki Sagara, Naohito Yamamoto, Tomoyuki Yoshiyama, Takako Hayashi, Eriko Tokunaga, Takashi Yamanaka, Chikako Shimizu, Tadahiko Shien, Hiroji Iwata
Journal: Journal of Clinical Oncology (2024)

1031 Background: The JCOG1607, HERB TEA Study, is a phase III trial that compared trastuzumab emtansine (T-DM1) with the HPD regimen (trastuzumab, pertuzumab, docetaxel) in older patients with advanced HER2-positive breast cancer. The primary objective was to confirm the non-inferiority of T-DM1 to HPD in overall survival (OS), with a margin of 1.35 for hazard ratio (HR). The trial was terminated early due to futility at the planned first interim analysis. T-DM1 didn't show non-inferiority to HPD in OS (HR 1.263; 95% confidence interval [CI], 0.677-2.357). Median progression-free survival (PFS) was 11.3 months for T-DM1 and 15.6 months for HPD (HR 1.373; 95% CI, 0.917-2.056). However, the condition of older patients varies widely, and we conducted a subgroup analysis to investigate the subgroup that could benefit from T-DM1 with fewer side effects as a first-line treatment. Methods: Subgroup analysis for OS and PFS involved 148 patients enrolled in JCOG1607, considering age and PS (&lt;75 years old and PS 0,1 or &lt;75 years old and PS 2 or ≥75 years old), Geriatric 8 (G8) score (≥15 or &lt;15), Instrumental Activity of Daily Living (IADL) score (8 or &lt;8), visceral/brain metastasis presence (with or without), and other factors. Results: Subgroup of &lt;75 and PS 2 was not evaluable. For OS, HR of T-DM1 arm to HPD arm was 0.749 (95% CI: 0.310-1.808) in the group aged &lt;75 years, while 2.867 (95%CI: 1.018-8.069) in the group aged ≥75 years (Table). G8 score and the IADL score did not show significant differences in HR for OS, although low G8 score group and low IADL score group tended to have higher OS in HPD arm than T-DM1 arm: HR of T-DM1 arm to HPD arm of 1.541 (95% CI: 0.755-3.142) in low G8 score group and 2.147 (95% CI: 0.656-7.025) in low IADL score group. For PFS, patients with visceral/brain metastasis had HR of T-DM1 arm to HPD arm of 1.794 (95% CI: 1.092-2.948). No other subgroup showed a significant difference in HR for PFS. Conclusions: No subgroups benefiting from T-DM1 as first-line treatment were identified. HPD remains the standard for advanced HER2-positive breast cancer, regardless of age (even in ≥75 years) G8 score, or IADL. Clinical trial information: UMIN000030783. [Table: see text]
Surrogate End Points in Trials—SPIRIT and CONSORT Extensions
Authors: Rod S. Taylor, Anthony Muchai Manyara, Joseph S. Ross, Oriana Ciani
Journal: JAMA (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Comparison of Pressure vs Volume Overload Ventricular Wall Stress in Patients With Valvular Heart Disease
Authors: Stavroula Papapostolou, John Kearns, Benedict T. Costello, Jessica O’Brien, Sarah J. Gutman, Shane Nanayakarra, David Kaye, Antony Walton, James Hare, Dion Stub, Andrew J. Taylor
Journal: Journal of the American College of Cardiology (2024)
Myocardial Strain Measured by Cardiac Magnetic Resonance Predicts Cardiovascular Morbidity and Death
Authors: Sucharitha Chadalavada, Kenneth Fung, Elisa Rauseo, Aaron M. Lee, Mohammed Y. Khanji, Alborz Amir-Khalili, Jose Paiva, Hafiz Naderi, Shantanu Banik, Mihaela Chirvasa, Magnus T. Jensen, Nay Aung, Steffen E. Petersen
Journal: Journal of the American College of Cardiology (2024)

Myocardial strain using cardiac magnetic resonance (CMR) is a sensitive marker for predicting adverse outcomes in many cardiac disease states, but the prognostic value in the general population has not been studied conclusively. The goal of this study was to assess the independent prognostic value of CMR feature tracking (FT)—derived LV global longitudinal (GLS), circumferential (GCS), and radial strain (GRS) metrics in predicting adverse outcomes (heart failure, myocardial infarction, stroke, and death). Participants from the UK Biobank population imaging study were included. Univariable and multivariable Cox models were used for each outcome and each strain marker (GLS, GCS, GRS) separately. The multivariable models were tested with adjustment for prognostically important clinical features and conventional global LV imaging markers relevant for each outcome. Overall, 45,700 participants were included in the study (average age 65 ± 8 years), with a median follow-up period of 3 years. All univariable and multivariable models demonstrated that lower absolute GLS, GCS, and GRS were associated with increased incidence of heart failure, myocardial infarction, stroke, and death. All strain markers were independent predictors (incrementally above some respective conventional LV imaging markers) for the morbidity outcomes, but only GLS predicted death independently: (HR: 1.18; 95% CI: 1.07-1.30). In the general population, LV strain metrics derived using CMR-FT in radial, circumferential, and longitudinal directions are strongly and independently predictive of heart failure, myocardial infarction, and stroke, but only GLS is independently predictive of death in an adult population cohort.
Ferritin Cutoffs and Diagnosis of Iron Deficiency in Primary Care
Authors: Levy Jäger, Yael Rachamin, Oliver Senn, Jakob M. Burgstaller, Thomas Rosemann, Stefan Markun
Journal: JAMA Network Open (2024)

Importance Ferritin is often measured by general practitioners, but the association of different cutoffs with the rates of iron deficiency diagnoses, particularly nonanemic iron deficiency, is unknown. Objective To investigate the association of the ferritin cutoff choice with the incidence of nonanemic and anemic iron deficiency diagnoses in primary care. Design, Setting, and Participants In this retrospective cohort study, patients 18 years or older with at least 1 consultation with a general practitioner participating in the Family Medicine Research Using Electronic Medical Records (FIRE) project, an electronic medical records database of Swiss primary care, from January 1, 2021, to November 30, 2023, were evaluated. Exposures Sex, age, clinical patient characteristics, and professional general practitioner characteristics. Main Outcomes and Measures Incidence of iron deficiency diagnoses (nonanemic and anemic) at ferritin cutoffs of 15, 30, and 45 ng/mL and ferritin testing itself. Time-dependent Cox proportional hazards regression was used to examine associations of patient and general practitioner characteristics with ferritin testing as adjusted hazard ratios (AHRs). Results The study included 255 351 patients (median [IQR] age, 52 [36-66] years; 52.1% female). Per 1000 patient-years and at ferritin cutoffs of 15, 30, and 45 ng/mL, iron deficiency diagnoses had incidences of 10.9 (95% CI, 10.6-11.2), 29.9 (95% CI, 29.4-30.4), and 48.3 (95% CI, 47.7-48.9) cases, respectively; nonanemic iron deficiency diagnoses had incidences of 4.1 (95% CI, 3.9-4.2), 14.6 (95% CI, 14.3-15.0), and 25.8 (95% CI, 25.3-26.2) cases, respectively; and anemic iron deficiency diagnoses had incidences of 3.5 (95% CI, 3.3-3.7), 6.0 (95% CI, 5.8-6.2), and 7.5 (95% CI, 7.3-7.7) cases, respectively. Ferritin testing showed notable associations with fatigue (AHR, 2.03; 95% CI, 1.95-2.12), anemia (AHR, 1.75; 95% CI, 1.70-1.79), and iron therapy (AHR, 1.50; 95% CI, 1.46-1.54). Ferritin testing was associated with female sex in all age groups, including postmenopausal. Of the patients who received ferritin testing, 72.1% received concomitant hemoglobin testing, and 49.6% received concomitant C-reactive protein testing. Conclusions and Relevance In this retrospective cohort study of primary care patients, ferritin cutoffs of 30 and 45 ng/mL were associated with a substantially higher incidence of iron deficiency compared with 15 ng/mL. These results provide a basis for health system-level evaluation and benchmarking of ferritin testing in high-resource settings and call for a harmonization of diagnostic criteria for iron deficiency in primary care.
Efficacy and safety of neoadjuvant trastuzumab, pyrotinib, and dalpiciclib without chemotherapy in early-stage HR-negative/HER2-positive breast cancer: An open-label, single-arm phase II trial.
Authors: Xiao Zhi, Feiyu Chen, Liqiu Liao, Shayang Luo, Xuan Liu, Xiangyan Liu, Tao Xu, Yu Hu, Na Luo, Kuansong Wang, Shouman Wang
Journal: Journal of Clinical Oncology (2024)

e12613 Background: The chemotherapy-free neoadjuvant regimens of dual HER2 blockade has showed encouraging rates of pathological complete response (pCR) in patients with HER2-positive breast cancer. Additionally, combining cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors with anti-HER2 therapy has shown synergistic effects in hormone receptor (HR)-positive and HER2-positive breast cancer. However, there is limited data regarding this combination strategy in HR-negative/HER2-positive settings. The objective of this study was to evaluate the efficacy and safety of a chemotherapy-free regimen consisting of the CDK4/6 inhibitor dalpiciclib, and dual anti-HER2 components of pyrotinib and trastuzumab in patients with HR-negative/HER2-positive early breast cancer (EBC). Methods: This open-label, single-arm, phase II study was designed using the Simon two-stage method (Registration number: Chi-CTR-2200060748). Patients with HR-negative/HER2-positive operable EBC (tumor stage T1-3 and nodal stage N0-2) were enrolled. Eligible patients received trastuzumab (HLX02, 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks intravenously) for 15 weeks, plus pyrotinib (240 mg daily orally) and dalpiciclib (125 mg daily orally for 3 weeks, followed by 1 week off) for 16 weeks. Surgery was performed 3-6 weeks after the completion of the last cycle of study treatment. The primary endpoint was pCR (ypT0/Tis ypN0) at surgery, and secondary endpoints included objective response rate (ORR), change of Ki-67 labeling index, biomarker analysis, survival and safety. Results: Between Jun 24, 2022, and Sept 14, 2023, a total of 30 patients with a median age of 54.5 years (range: 35-66) were enrolled and treated in this ongoing trial. As of the data cutoff date on Jan 20, 2024, 26 patients underwent surgery, and pCR was achieved in 18 (69.2%) cases. Out of the 29 patients with evaluable response, 26 achieved partial response and 3 achieved stable disease, resulting in an ORR of 89.7%. The most common grade 3 or more treatment-related adverse events (AEs) were diarrhea (66.7%), decreased neutrophil count (33.3%), and decreased white blood cell count (20.8%). Most AEs were tolerable, and no treatment-related deaths occur. Conclusions: In patients with HR-negative/HER2-positive EBC, a dual HER2-targeted combination of pyrotinib and trastuzumab, along with dalpiciclib in the absence of chemotherapy showed promising efficacy with encouraging pCR and ORR rates, as well as a favorable safety profile in the neoadjuvant setting. Clinical trial information: Chi-CTR-2200060748.
Laertes Loses His Memory
Authors: Rebekka DePew
Journal: JAMA (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Accuracy of <i>ICD-10</i> Diagnostic Codes for Identifying Housing Instability
Authors: Matthew J. O’Brien, Andrew Owen, Sharon Langshur, Bruce Doblin, Keiki Hinami, William Trick, David T. Liss
Journal: JAMA Network Open (2024)

This cohort study assesses the performance of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) Z59 codes for identifying housing instability during health care encounters.
Early Circulating Biomarkers of Language Development in Single Ventricle Heart Disease
Authors: Kelly R. Wolfe, Lindsay M. Thomson, Sierra Niemiec, Christopher A. Mancuso, Ludmila Khailova, Benjamin S. Frank, Jesse A. Davidson
Journal: JAMA Pediatrics (2024)

This cohort study assesses proteins measured in infancy and neurodevelopmental outcomes in single ventricle heart disease.
Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome
Authors: Vaishnavi Dandavate, Nityanand Bolshette, Rachel Van Drunen, Gal Manella, Hanna Bueno-Levy, Mirie Zerbib, Ippei Kawano, Marina Golik, Yaarit Adamovich, Gad Asher
Journal: Cell Metabolism (2024)
Tirzepatide-Induced Rapid Weight Loss–Related Thyrotoxicosis
Authors: Kagan E. Karakus, Viral N. Shah, Halis K. Akturk
Journal: JAMA Internal Medicine (2024)

This Teachable Moment describes a 62-year-old man with thyrotoxicosis due to excess levothyroxine exposure during tirzepatide treatment that induced rapid weight loss.