tbuckley/cabot-search huggingface dataset:
Weak neuronal glycolysis sustains cognition and organismal fitness
Authors: Daniel Jimenez-Blasco, Jesús Agulla, Rebeca Lapresa, Marina Garcia-Macia, Veronica Bobo-Jimenez, Dario Garcia-Rodriguez, Israel Manjarres-Raza, Emilio Fernandez, Yannick Jeanson, Spiro Khoury, Jean-Charles Portais, Daniel Padro, Pedro Ramos-Cabrer, Peter Carmeliet, Angeles Almeida, Juan P. Bolaños
Journal: Nature Metabolism (2024)

The energy cost of neuronal activity is mainly sustained by glucose
Balcinrenone plus dapagliflozin in patients with heart failure and chronic kidney disease: Results from the phase 2b <scp>MIRACLE</scp> trial
Authors: Carolyn S.P. Lam, Lars Køber, Koichiro Kuwahara, Lars H. Lund, Patrick B. Mark, Linda G. Mellbin, Morten Schou, Patricia Ely Pizzato, Anders Gabrielsen, Samvel B. Gasparyan, Alessandro Ghiretti, Judith Hartleib‐Geschwindner, Greggory J. Housler, Paolo Fanti, Maria Leonsson‐Zachrisson, John J.V. McMurray, Scott D. Solomon
Journal: European Journal of Heart Failure (2024)

Aims Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study. Methods and results From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction &lt;60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m 2 and urinary albumin‐to‐creatinine ratio (UACR) ≥30 to &lt;3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose–response relationship. There were possible dose‐dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non‐significant trends towards reduced N‐terminal pro‐B‐type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo. Conclusion While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo.
Therapeutic targeting of white adipose tissue metabolic dysfunction in obesity: mechanisms and opportunities
Authors: Zi‐Han Yang, Fang‐Zhou Chen, Yi‐Xiang Zhang, Min‐Yi Ou, Poh‐Ching Tan, Xue‐Wen Xu, Qing‐Feng Li, Shuang‐Bai Zhou
Journal: MedComm (2024)

Abstract White adipose tissue is not only a highly heterogeneous organ containing various cells, such as adipocytes, adipose stem and progenitor cells, and immune cells, but also an endocrine organ that is highly important for regulating metabolic and immune homeostasis. In individuals with obesity, dynamic cellular changes in adipose tissue result in phenotypic switching and adipose tissue dysfunction, including pathological expansion, WAT fibrosis, immune cell infiltration, endoplasmic reticulum stress, and ectopic lipid accumulation, ultimately leading to chronic low‐grade inflammation and insulin resistance. Recently, many distinct subpopulations of adipose tissue have been identified, providing new insights into the potential mechanisms of adipose dysfunction in individuals with obesity. Therefore, targeting white adipose tissue as a therapeutic agent for treating obesity and obesity‐related metabolic diseases is of great scientific interest. Here, we provide an overview of white adipose tissue remodeling in individuals with obesity including cellular changes and discuss the underlying regulatory mechanisms of white adipose tissue metabolic dysfunction. Currently, various studies have uncovered promising targets and strategies for obesity treatment. We also outline the potential therapeutic signaling pathways of targeting adipose tissue and summarize existing therapeutic strategies for antiobesity treatment including pharmacological approaches, lifestyle interventions, and novel therapies.
Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes
Authors: Vlado Perkovic, Katherine R Tuttle, Peter Rossing, Kenneth W Mahaffey, Johannes F E Mann, George Bakris, Florian M M Baeres, Thomas Idorn, Heidrun Bosch-Traberg, Nanna Leonora Lausvig, Richard Pratley
Journal: New England Journal of Medicine (2024)

Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death. Whether treatment with semaglutide would mitigate these risks is unknown.
Progress in Heart Failure Deaths Reversed Over Past Decade
Authors: Emily Harris
Journal: JAMA (2024)

Ahmed Sayed, MBBS; Dmitry Abramov, MD; Gregg C. Fonarow, MD; Mamas A. Mamas, MD, PhD; Ofer Kobo, MD; Javed Butler, MD, MPH, MBA; Marat Fudim, MD, MHS
Blood Pressure Drugs Linked to More Fractures, Falls in VA Nursing Homes
Authors: Emily Harris
Journal: JAMA (2024)

Chintan V. Dave, PharmD, PhD; Yongmei Li, PhD; Michael A. Steinman, MD; Sei J. Lee, MD, MAS; Xiaojuan Liu, MS; Bocheng Jing, MS; Laura A. Graham, PhD; Zachary A. Marcum, PharmD, PhD; Kathy Z. Fung, MS; Michelle C. Odden, PhD
Preterm and Early-Term Birth, Heat Waves, and Our Changing Climate
Authors: Caleb Dresser, Shruthi Mahalingaiah, Kari C. Nadeau
Journal: JAMA Network Open (2024)

Lyndsey A. Darrow, PhD; Mengjiao Huang, PhD; Joshua L. Warren, PhD; Matthew J. Strickland, PhD; Heather A. Holmes, PhD; Andrew J. Newman, PhD; Howard H. Chang, PhD
Virtual Scribes and Physician Time Spent on Electronic Health Records
Authors: Lisa Rotenstein, Edward R. Melnick, Christine Iannaccone, Jianyi Zhang, Aqsa Mugal, Stuart R. Lipsitz, Michael J. Healey, Christopher Holland, Richard Snyder, Christine A. Sinsky, David Ting, David W. Bates
Journal: JAMA Network Open (2024)

Importance Time on the electronic health record (EHR) is associated with burnout among physicians. Newer virtual scribe models, which enable support from either a real-time or asynchronous scribe, have the potential to reduce the burden of the EHR and EHR-related documentation. Objective To characterize the association of use of virtual scribes with changes in physicians’ EHR time and note and order composition and to identify the physician, scribe, and scribe response factors associated with changes in EHR time upon virtual scribe use. Design, Setting, and Participants Retrospective, pre-post quality improvement study of 144 physicians across specialties who had used a scribe for at least 3 months from January 2020 to September 2022, were affiliated with Brigham and Women’s Hospital and Massachusetts General Hospital, and cared for patients in the outpatient setting. Data were analyzed from November 2022 to January 2024. Exposure Use of either a real-time or asynchronous virtual scribe. Main Outcomes Total EHR time, time on notes, and pajama time (5:30 pm to 7:00 am on weekdays and nonscheduled weekends and holidays), all per appointment; proportion of the note written by the physician and team contribution to orders. Results The main study sample included 144 unique physicians who had used a virtual scribe for at least 3 months in 152 unique scribe participation episodes (134 [88.2%] had used an asynchronous scribe service). Nearly two-thirds of the physicians (91 physicians [63.2%]) were female and more than half (86 physicians [59.7%]) were in primary care specialties. Use of a virtual scribe was associated with significant decreases in total EHR time per appointment (mean [SD] of 5.6 [16.4] minutes; P &amp;amp;lt; .001) in the 3 months after vs the 3 months prior to scribe use. Scribe use was also associated with significant decreases in note time per appointment and pajama time per appointment (mean [SD] of 1.3 [3.3] minutes; P &amp;amp;lt; .001 and 1.1 [4.0] minutes; P = .004). In a multivariable linear regression model, the following factors were associated with significant decreases in total EHR time per appointment with a scribe use at 3 months: practicing in a medical specialty (−7.8; 95% CI, −13.4 to −2.2 minutes), greater baseline EHR time per appointment (−0.3; 95% CI, −0.4 to −0.2 minutes per additional minute of baseline EHR time), and decrease in the percentage of the note contributed by the physician (−9.1; 95% CI, −17.3 to −0.8 minutes for every percentage point decrease). Conclusions and Relevance In 2 academic medical centers, use of virtual scribes was associated with significant decreases in total EHR time, time spent on notes, and pajama time, all per appointment. Virtual scribes may be particularly effective among medical specialists and those physicians with greater baseline EHR time.
VCP activator reverses nuclear proteostasis defects and enhances TDP-43 aggregate clearance in multisystem proteinopathy models
Authors: Jessica M. Phan, Benjamin C. Creekmore, Aivi T. Nguyen, Darya D. Bershadskaya, Nabil F. Darwich, Carolyn N. Mann, Edward B. Lee
Journal: Journal of Clinical Investigation (2024)

Pathogenic variants in VCP cause multisystem proteinopathy (MSP), a disease characterized by multiple clinical phenotypes including inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (FTD). How such diverse phenotypes are driven by pathogenic VCP variants is not known. We found that these diseases exhibit a common pathologic feature, ubiquitinated intranuclear inclusions affecting myocytes, osteoclasts and neurons. Moreover, knock-in cell lines harboring MSP variants show a reduction in nuclear VCP. Given that MSP is associated with neuronal intranuclear inclusions comprised of TDP-43 protein, we developed a cellular model whereby proteostatic stress results in the formation of insoluble intranuclear TDP-43 aggregates. Consistent with a loss of nuclear VCP function, cells harboring MSP variants or cells treated with VCP inhibitor exhibited decreased clearance of insoluble intranuclear TDP-43 aggregates. Moreover, we identified four compounds that activate VCP primarily by increasing D2 ATPase activity whereby pharmacologic VCP activation appears to enhance clearance of insoluble intranuclear TDP-43 aggregate. Our findings suggest that VCP function is important for nuclear protein homeostasis, that impaired nuclear proteostasis may contribute to MSP, and that VCP activation may be potential therapeutic by virtue of enhancing the clearance of intranuclear protein aggregates.
A systematic review and meta‐analysis of nutritional and dietary interventions in randomized controlled trials for skin symptoms in children with atopic dermatitis and without food allergy: An EAACI task force report
Authors: Emilia Vassilopoulou, Anna Comotti, Nikolaos Douladiris, George Ν. Konstantinou, Torsten Zuberbier, Ilaria Alberti, Carlo Agostoni, Roberto Berni Canani, Ioana Corina Bocsan, Antonio Corsello, Valentina De Cosmi, Gavriela Feketea, Kirsi Laitinen, Alessandra Mazzocchi, Nicola A. Monzani, Nikolaos G. Papadopoulos, Diego G. Peroni, Constantinos Pitsios, Franziska Roth‐Walter, Isabel Skypala, Sophia Tsabouri, Abdoulie K. Baldeh, Liam O'Mahony, Carina Venter, Gregorio Paolo Milani
Journal: Allergy (2024)

Abstract This systematic review and meta‐analysis aimed to consolidate evidence on dietary interventions for atopic eczema/dermatitis (AD) skin symptoms in children without food allergies, following PRISMA 2020 guidelines. Systematic review updates were conducted in May 2022 and June 2023, focusing on randomized placebo‐controlled trials (RCTs) involving children with AD but without food allergies. Specific diets or supplements, such as vitamins, minerals, probiotics, prebiotics, symbiotics, or postbiotics, were explored in these trials. Exclusions comprised descriptive studies, systematic reviews, meta‐analyses, letters, case reports, studies involving elimination diets, and those reporting on food allergens in children and adolescents. Additionally, studies assessing exacerbation of AD due to food allergy/sensitization and those evaluating elimination diets' effects on AD were excluded. Nutritional supplementation studies were eligible regardless of sensitization profile. Evaluation of their impact on AD clinical expression was performed using SCORAD scores, and a meta‐analysis of SCORAD outcomes was conducted using random‐effect models (CRD42022328702). The review encompassed 27 RCTs examining prebiotics, Vitamin D, evening primrose oil, and substituting cow's milk formula with partially hydrolyzed whey milk formula. A meta‐analysis of 20 RCTs assessing probiotics, alone or combined with prebiotics, revealed a significant reduction in SCORAD scores, suggesting a consistent trend in alleviating AD symptoms in children without food allergies. Nonetheless, evidence for other dietary interventions remains limited, underscoring the necessity for well‐designed intervention studies targeting multiple factors to understand etiological interactions and propose reliable manipulation strategies.
Incremental increases in physiological fluid shear progressively alter pathogenic phenotypes and gene expression in multidrug resistant <i>Salmonella</i>
Authors: Jiseon Yang, Jennifer Barrila, Eric A. Nauman, Seth D. Nydam, Shanshan Yang, Jin Park, Ami D. Gutierrez-Jensen, Christian L. Castro, C. Mark Ott, Kristina Buss, Jason Steel, Anne D. Zakrajsek, Mary M. Schuff, Cheryl A. Nickerson
Journal: Gut Microbes (2024)

The ability of bacteria to sense and respond to mechanical forces has important implications for pathogens during infection, as they experience wide fluid shear fluctuations in the host. However, little is known about how mechanical forces encountered in the infected host drive microbial pathogenesis. Herein, we combined mathematical modeling with hydrodynamic bacterial culture to profile transcriptomic and pathogenesis-related phenotypes of multidrug resistant S. Typhimurium (ST313 D23580) under different fluid shear conditions relevant to its transition from the intestinal tract to the bloodstream. We report that D23580 exhibited incremental changes in transcriptomic profiles that correlated with its pathogenic phenotypes in response to these progressive increases in fluid shear. This is the first demonstration that incremental changes in fluid shear forces alter stress responses and gene expression in any ST313 strain and offers mechanistic insight into how forces encountered by bacteria during infection might impact their disease-causing ability in unexpected ways.
Differences in presentation, diagnosis and management of heart failure in women. A scientific statement of the Heart Failure Association of the ESC
Authors: Giuseppe M.C. Rosano, Davide Stolfo, Lisa Anderson, Magdy Abdelhamid, Marianna Adamo, Johann Bauersachs, Antoni Bayes‐Genis, Michael Böhm, Ovidiu Chioncel, Gerasimos Filippatos, Loreena Hill, Mitja Lainscak, Ekaterini Lambrinou, Angela H.E.M. Maas, Angela R. Massouh, Brenda Moura, Mark C. Petrie, Amina Rakisheva, Robin Ray, Gianluigi Savarese, Hadi Skouri, Sophie Van Linthout, Cristiana Vitale, Maurizio Volterrani, Marco Metra, Andrew J.S. Coats
Journal: European Journal of Heart Failure (2024)

Despite the progress in the care of individuals with heart failure (HF), important sex disparities in knowledge and management remain, covering all the aspects of the syndrome, from aetiology and pathophysiology to treatment. Important distinctions in phenotypic presentation are widely known, but the mechanisms behind these differences are only partially defined. The impact of sex-specific conditions in the predisposition to HF has gained progressive interest in the HF community. Under-recruitment of women in large randomized clinical trials has continued in the more recent studies despite epidemiological data no longer reporting any substantial difference in the lifetime risk and prognosis between sexes. Target dose of medications and criteria for device eligibility are derived from studies with a large predominance of men, whereas specific information in women is lacking. The present scientific statement encompasses the whole scenario of available evidence on sex-disparities in HF and aims to define the most challenging and urgent residual gaps in the evidence for the scientific and clinical HF communities.
GLP-1 Receptor Agonist Discontinuation Among Patients With Obesity and/or Type 2 Diabetes
Authors: Duy Do, Tiffany Lee, Samuel K. Peasah, Chester B. Good, Angela Inneh, Urvashi Patel
Journal: JAMA Network Open (2024)

This cohort study examines the prevalence of and factors associated with glucagon-like peptide 1 agonist discontinuation among new users.
Evaluating Immune Checkpoint Blockade in Metastatic Castration-Resistant Prostate Cancers with Deleterious <i>CDK12</i> Alterations in the Phase 2 IMPACT Trial
Authors: Charles B. Nguyen, Melissa A. Reimers, Chamila Perera, Wassim Abida, Jonathan Chou, Felix Y. Feng, Emmanuel S. Antonarakis, Rana R. McKay, Russell K. Pachynski, Jingsong Zhang, Zachery R. Reichert, Phillip L. Palmbos, Megan E.V. Caram, Ulka N. Vaishampayan, Elisabeth I. Heath, Alexander C. Hopkins, Marcin P. Cieslik, Yi-Mi Wu, Dan R. Robinson, Veerabhadran Baladandayuthapani, Arul M. Chinnaiyan, Ajjai S. Alva
Journal: Clinical Cancer Research (2024)

Abstract Purpose: CDK12 inactivation in metastatic castration-resistant prostate cancer (mCRPC) may predict immunotherapy responses. This phase 2 trial evaluated the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with CDK12-altered mCRPC. Patients and Methods: Eligible patients had mCRPC with deleterious CDK12 alterations and any prior therapies except ICI. Cohort A received ipilimumab (1 mg/kg) with nivolumab (3 mg/kg) every 3 weeks for up to four cycles, followed by nivolumab 480 mg every 4 weeks. Cohort C received nivolumab alone 480 mg every 4 weeks. Patients with CDK12-altered nonprostate tumors were enrolled in cohort B and not reported. The primary endpoint was a 50% reduction in PSA (PSA50). Key secondary endpoints included PSA progression-free survival, overall survival, objective response rate, and safety. Results: PSA was evaluable in 23 patients in cohort A and 14 in cohort C. Median lines of prior therapy were two in cohorts A and C, including any prior novel hormonal agent (74% and 79%) and chemotherapy (57% and 36%). The PSA50 rate was 9% [95% confidence interval (CI), 1%–28%] in cohort A with two responders; neither had microsatellite instability or a tumor mutational burden &amp;gt;10 mutations/megabase. No PSA50 responses occurred in cohort C. Median PSA progression-free survival was 7.0 months (95% CI, 3.6–11.4) in cohort A and 4.5 months (95% CI, 3.4–13.8) in cohort C. Median overall survival was 9.0 months (95% CI, 6.2–12.3) in cohort A and 13.8 months (95% CI, 3.6–not reached) in cohort C. Conclusions: There was minimal activity with ICI therapy in patients with CDK12-altered mCRPC.
Cow’s Milk Containing Avian Influenza A(H5N1) Virus — Heat Inactivation and Infectivity in Mice
Authors: Lizheng Guan, Amie J Eisfeld, David Pattinson, Chunyang Gu, Asim Biswas, Tadashi Maemura, Sanja Trifkovic, Lavanya Babujee, Robert Presler, Randall Dahn, Peter J Halfmann, Tera Barnhardt, Gabriele Neumann, Alexis Thompson, Amy K Swinford, Kiril M Dimitrov, Keith Poulsen, Yoshihiro Kawaoka
Journal: New England Journal of Medicine (2024)
Dietary potassium loads call on intercalated cell PIEZO1 to go with the flow
Authors: Seth L. Alper, Fouad T. Chebib
Journal: Kidney International (2024)

Adult humans in steady-state excrete ∼90% of dietary K+ via the kidney's connecting segment and cortical collecting duct. Baseline renal K+ secretion is mediated by the principal cell (PC) ROMK K+ channel in a manner sustained by active ENaC-mediated, amiloride-sensitive Na+ reabsorption (Figure 1). 1 Carrisoza-Gaytan R. Mutchler S.M. Carattino F. et al. PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K+ secretion. J Clin Invest. Mar 1 2024; : 134https://doi.org/10.1172/JCI174806 Crossref Scopus (2) Google Scholar ,2 Carrisoza-Gaytan R. Carattino M.D. Kleyman T.R. Satlin L.M. An unexpected journey: conceptual evolution of mechanoregulated potassium transport in the distal nephron. Am J Physiol Cell Physiol. Feb 15 2016; 310: C243-C259https://doi.org/10.1152/ajpcell.00328.2015 Crossref PubMed Scopus (41) Google Scholar The transition to a high K+ (HiK) diet increases renal tubular flow rates, leading to an amiloride-insensitive increase in renal K+ secretion within less than a day. In rabbit kidney, amiloride-insensitive renal K+ excretion develops only after weaning. Similar adaptation is reflected in human ROMK-deficient Type II Bartter syndrome, characterized by post-natal severe hyperkalemia that can transition in later infancy to mild, manageable hypokalemia. This developmentally regulated amiloride-insensitive component of renal K+ secretion is mediated by the large conductance SLO1/BK K+ channel of collecting duct. In adult mice, HiK upregulates both ROMK and BK channels, but only the former is aldosterone-dependent. 2 Carrisoza-Gaytan R. Carattino M.D. Kleyman T.R. Satlin L.M. An unexpected journey: conceptual evolution of mechanoregulated potassium transport in the distal nephron. Am J Physiol Cell Physiol. Feb 15 2016; 310: C243-C259https://doi.org/10.1152/ajpcell.00328.2015 Crossref PubMed Scopus (41) Google Scholar
ZFYVE21 promotes endothelial nitric oxide signaling and vascular barrier function in the kidney during aging
Authors: Quan Jiang, Guiyu Song, Liying He, Xue Li, Bo Jiang, Qianxun Wang, Shaoxun Wang, Catherine Kim, Mahsa Nouri Barkestani, Roberto Lopez, Matthew Fan, Kujani Wanniarachchi, Maya Quaranta, Xuefei Tian, Arya Mani, Anjelica Gonzalez, Julie E. Goodwin, William C. Sessa, Shuta Ishibe, Dan Jane-wit
Journal: Kidney International (2024)

ZFYVE21 is an ancient, endosome-associated protein that is highly expressed in endothelial cells (ECs) but whose function(s) in vivo are undefined. Here, we identified ZFYVE21 as an essential regulator of vascular barrier function in the aging kidney. ZFYVE21 levels significantly decline in ECs in aged human and mouse kidneys. To investigate attendant effects, we generated EC-specific Zfyve21
Long-term efficacy and immunogenicity of Ad26.RSV.preF–RSV preF protein vaccine (CYPRESS): a randomised, double-blind, placebo-controlled, phase 2b study
Authors: Ann R Falsey, Tessa Hosman, Arangassery Rosemary Bastian, Sjouke Vandenberghe, Eric K H Chan, Macaya Douoguih, Esther Heijnen, Christy A Comeaux, Benoit Callendret, Mohammed Allaw, Toby Briskin, Daniel Brune, Richard Egelhof, John Ervin, Ann Falsey, Carolos Fierro, David Fried, Peta-Gay Jackson-Booth, Murray Kimmel, Lorrie McGill, Paul Nugent, Suchet Patel, Barbara Rizzardi, James Ruhlmann, Cynthia Strout, Leslie Tharenos, Timothy Vachris, Tyler Wadsworth
Journal: The Lancet Infectious Diseases (2024)