tbuckley/cabot-search huggingface dataset:
Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial
Authors: Petra Langerbeins, Sandra Robrecht, Pascal Nieper, Paula Cramer, Moritz Fürstenau, Othman Al-Sawaf, Florian Simon, Anna-Maria Fink, Karl-Anton Kreuzer, Ursula Vehling-Kaiser, Eugen Tausch, Christof Schneider, Lothar Müller, Michael Josef Eckart, Rudolf Schlag, Werner Freier, Tobias Gaska, Christina Balser, Marcel Reiser, Martina Stauch, Mark-Oliver Zahn, Steffen Dörfel, Peter Staib, Timo Behlendorf, Manfred Hensel, Holger Hebart, Holger Klaproth, Andreas Block, Rüdiger Liersch, Ulrich Hauch, Bernhard Heinrich, Clemens-Martin Wendtner, Kirsten Fischer, Stephan Stilgenbauer, Barbara Eichhorst, Michael Hallek
Journal: Journal of Clinical Oncology (2024)

PURPOSE The CLL12 trial reassesses the watch-and-wait consensus for early-stage chronic lymphocytic leukemia (CLL) in the context of targeted therapies. METHODS The German CLL Study Group conducted a randomized, double-blind, placebo-controlled phase III trial with 363 patients with asymptomatic, treatment-naïve Binet stage A CLL at increased risk of progression to receive ibrutinib (n = 182) at a daily dose of 420 mg or placebo (n = 181). Additionally, 152 low-risk patients were allocated to the watch-and-wait group. The final analysis included event-free survival, progression-free survival, time to next treatment, overall survival, and safety assessments. RESULTS Ibrutinib significantly delayed progression to symptomatic disease ( P &lt; .001; hazard ratio, 0.276 [95% CI, 0.188 to 0.407]), but no survival benefit was observed with 26 death cases ( P = .562) at a median observation time of 69.3 months. Five-year survival rates were excellent: 93.3% (95% CI, 89.3 to 97.3) in the ibrutinib group, 93.6% (95% CI, 89.5 to 97.7) in the placebo group, and 97.9% (95% CI, 95.6 to 100) in the watch-and-wait cohort. Estimated 10-year survival rates from diagnosis were 86.5% (95% CI, 78.7 to 94.3, placebo), 89.8% (95% CI, 83.3 to 96.3, ibrutinib), and 95.3% (95% CI, 91.1 to 99.4, watch and wait). In the ibrutinib group, one of 12 deaths was CLL-associated, compared with four of 14 fatal cases of CLL progression or Richter transformation in the placebo group. Adverse and serious adverse events occurred in 99.4% and 60% of both treatment groups, respectively. The safety profile indicated increased cardiovascular toxicity in the ibrutinib group. CONCLUSION Ibrutinib treatment in early-stage CLL delayed disease progression compared with placebo. However, with the given observation time and few deaths, no survival benefit was demonstrated. In the era of targeted therapies, watch and wait remains the standard of care irrespective of risk factors.
The path forward for large language models in medicine is open
Authors: Lars Riedemann, Maxime Labonne, Stephen Gilbert
Journal: npj Digital Medicine (2024)

Large language models (LLMs) are increasingly applied in medical documentation and have been proposed for clinical decision support. We argue that the future for LLMs in medicine must be based on transparent and controllable open-source models. Openness enables medical tool developers to control the safety and quality of underlying AI models, while also allowing healthcare professionals to hold these models accountable. For these reasons, the future is open.
Effects of Integrated Care Approaches to Address Co-occurring Depression and Diabetes: A Systematic Review and Meta-analysis
Authors: Zach W. Cooper, Jay O’Shields, Mohammed K. Ali, Lydia Chwastiak, Leslie C.M. Johnson
Journal: Diabetes Care (2024)

BACKGROUND Depressive symptoms frequently co-occur with diabetes and, when unaddressed, can function to worsen diabetes control and increase the risk of diabetes-related morbidity. Integrated care (IC) approaches aim to improve outcomes among people with diabetes and depression, but there are no current meta-analyses examining their effects. PURPOSE In our study we summarize the effects of IC approaches to address depression and diabetes and examine moderating effects of IC approaches (e.g., behavioral intervention used; type of IC approach). DATA SOURCES A systematic search was conducted of PubMed, PsycInfo, CINAHL, and ProQuest. STUDY SELECTION Two reviewers triaged abstracts and full-text articles to identify relevant articles. Randomized controlled trials with enrollment of participants with diabetes and depressive symptoms and with provision of sufficient data on depression scores and hemoglobin A1c were included. DATA EXTRACTION Two reviewers extracted demographic information, depression scores, diabetes outcomes, intervention details, and the risk of bias for each study. DATA SYNTHESIS From 517 abstracts, 75 full-text reports were reviewed and 31 studies with 8,843 participants were analyzed. Among 26 studies with reporting of HbA1c, IC approaches were associated with a significant between-group difference regarding the percent decrease of HbA1c (d = −0.36, 95% CI −0.52 to −0.21). Studies that included a combination of behavioral interventions (behavioral activation with cognitive behavioral therapy) showed greater reductions in HbA1c. Among 23 studies with reporting of depressive symptoms, the pooled effect of IC approaches lowered depressive scores by 0.72 points (95% CI −1.15 to −0.28). LIMITATIONS The inclusion of a wide range of IC approaches increased study heterogeneity. A random effects model and sensitivity analyses mitigated this limitation. CONCLUSIONS IC approaches are associated with improved glycemia and depressive symptoms in comparison with treatment as usual.
A Systematic Review and Meta-analysis on the Safety and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitor Use in Hospitalized Patients
Authors: Frank M. Gao, Aleena S. Ali, Rinaldo Bellomo, Michele Gaca, Ashani Lecamwasam, Leonid Churilov, Elif I. Ekinci
Journal: Diabetes Care (2024)

BACKGROUND The safety and efficacy of sodium–glucose cotransporter 2 (SGLT2) inhibitors in hospitalized patients are unclear. PURPOSE To evaluate outcomes of inpatient SGLT2 inhibitor use. DATA SOURCES MEDLINE, Embase, Emcare, and Cochrane databases were searched through 29 May 2024. STUDY SELECTION Randomized controlled trials (RCTs) and observational cohort studies with assessment of SGLT2 inhibitor use in patients hospitalized for any reason were included. DATA EXTRACTION Study characteristics and clinical outcomes were extracted. DATA SYNTHESIS We performed a random-effects meta-analysis analyzing RCTs and cohort studies separately. Heterogeneity was quantified with the I2 statistic. Twenty-three RCTs comprising 19,846 participants (29.5% with type 2 diabetes) with comparison of SGLT2 inhibitors with placebo or active comparator were included. Ketoacidosis rates were 0.210 per 100 person-years (95% CI 0.119, 0.370) for SGLT2 inhibitors and 0.140 per 100 person-years (95% CI 0.070, 0.280) for control (rate ratio 1.50 [95 CI 0.56, 4.23], P = 0.38). SGLT2 inhibitor use was associated with fewer readmissions and urgent visits (odds ratio [OR] 0.64 [95 CI 0.47, 0.86], P &amp;lt; 0.01) and lower mortality rates (OR 0.74 [95% CI 0.56, 0.98], P = 0.03) in heart failure trials and lower incidence of acute kidney injury (OR 0.76 [95% CI 0.60, 0.97], P = 0.03) among all RCTs. Twenty observational studies were included and did not show increased adverse events. LIMITATIONS Ketoacidosis rates were low, likely leading to lack of power to detect significant differences. CONCLUSIONS SGLT2 inhibitor use among hospitalized patients was associated with numerically higher rates of ketoacidosis, although further studies are required.
3D bioprinting of engineered exosomes secreted from M2-polarized macrophages through immunomodulatory biomaterial promotes in vivo wound healing and angiogenesis
Authors: Sayan Deb Dutta, Jeong Man An, Jin Hexiu, Aayushi Randhawa, Keya Ganguly, Tejal V Patil, Thavasyappan Thambi, Jangho Kim, Yong-Kyu Lee, Ki-Taek Lim
Journal: Bioactive Materials (2024)
Contribution of infection to mortality in people with type 2 diabetes: a population-based cohort study using electronic records
Authors: Iain M Carey, Julia A Critchley, Umar A R Chaudhry, Stephen DeWilde, Elizabeth S Limb, Liza Bowen, Selma Audi, Derek G Cook, Peter H Whincup, Naveed Sattar, Arshia Panahloo, Tess Harris
Journal: The Lancet Regional Health - Europe (2024)
GLP1RA and SGLT2i Prescriptions in Type 2 Diabetes by Kidney and Cardiovascular Disease
Authors: Sneha S. Mehta, Aditya L. Surapaneni, Krutika Pandit, Yunwen Xu, Leora Horwitz, Saul Blecker, Matthew F. Blum, Alexander R. Chang, Jung-Im Shin, Morgan E. Grams
Journal: Journal of the American Society of Nephrology (2024)

Mehta, Sneha S.; Surapaneni, Aditya L.; Pandit, Krutika; Xu, Yunwen; Horwitz, Leora; Blecker, Saul; Blum, Matthew F.; Chang, Alexander R.; Shin, Jung-Im; Grams, Morgan E. Author Information
Seeding-competent TDP-43 persists in human patient and mouse muscle
Authors: Eileen M. Lynch, Sara Pittman, Jil Daw, Chiseko Ikenaga, Sheng Chen, Dhruva D. Dhavale, Meredith E. Jackrel, Yuna M. Ayala, Paul Kotzbauer, Cindy V. Ly, Alan Pestronk, Thomas E. Lloyd, Conrad C. Weihl
Journal: Science Translational Medicine (2024)

TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43–related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.
Metabolic Breakdown
Authors: Pinelopi P. Kapitsinou
Journal: Journal of the American Society of Nephrology (2024)

Feinberg Cardiovascular & Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois Correspondence: Dr. Pinelopi P. Kapitsinou, email: [email protected] See related article, "Glycolysis in Peritubular Endothelial Cells and Microvascular Rarefaction in CKD," on pages XXX–XXX.
Childhood-onset lupus nephritis is characterized by complex interactions between kidney stroma and infiltrating immune cells
Authors: Patrick Danaher, Nicholas Hasle, Elizabeth D. Nguyen, Jordan E. Roberts, Natalie Rosenwasser, Christian Rickert, Elena W. Y. Hsieh, Kristen Hayward, Daryl M. Okamura, Charles E. Alpers, Robyn C. Reed, Sarah K. Baxter, Shaun W. Jackson
Journal: Science Translational Medicine (2024)

Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single-cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, but loss of spatial resolution prevents interrogation of in situ cellular interactions. Using a technical advance in spatial transcriptomics, we generated a spatially resolved, single-cell resolution atlas of kidney tissue from eight patients with cLN and four control individuals. Annotated cells were assigned to 30 reference cell types, including major kidney subsets and infiltrating immune cells. Analysis of spatial distribution demonstrated that individual immune lineages localized to specific regions in cLN kidneys, including myeloid cells that trafficked to inflamed glomeruli and B cells that clustered within tubulointerstitial immune hotspots. Gene expression varied as a function of tissue location, demonstrating how incorporation of spatial data can provide new insights into the immunopathogenesis of SLE. Alterations in immune phenotypes were accompanied by parallel changes in gene expression by resident kidney stromal cells. However, there was little correlation between histologic scoring of cLN disease activity and glomerular cell transcriptional signatures at the level of individual glomeruli. Last, we identified modules of spatially correlated gene expression with predicted roles in induction of inflammation and the development of tubulointerstitial fibrosis. Single-cell spatial transcriptomics allowed insights into the molecular heterogeneity of cLN, paving the way toward more targeted and personalized treatment approaches.
Prevalence and Impact of APOL1 Kidney Risk Variants in West Africa
Authors: Elena Martinelli, Rik Westland, Opeyemi A. Olabisi, Simone Sanna-Cherchi
Journal: Journal of the American Society of Nephrology (2024)

Martinelli, Elena; Westland, Rik; A. Olabisi, Opeyemi; Sanna-Cherchi, Simone Author Information
Targeting the PDE3B-cAMP-autophagy axis prevents liver injury in long-term supercooling liver preservation
Authors: Xingyuan Jiao, Yihu Li, Zhihang Chen, Qi Zhang, Rui He, Yinbing Huang, Zhixiang Zuo
Journal: Science Translational Medicine (2024)

In liver transplantation, donor livers are typically stored in a preservation solution at 4°C for up to 12 hours. However, this short preservation duration can lead to various issues, such as suboptimal donor-recipient matching and limited opportunities for organ sharing. Previous studies have developed a long-term preservation method called supercooling liver preservation (SLP) to address these issues. However, in this study using a rat model, we observed that long-term SLP led to more severe liver damage compared with clinically prevalent traditional static cold storage (SCS) for durations less than 8 hours. To understand the potential mechanism of SLP-induced liver injury, we conducted an integrative metabolomic, transcriptomic, and proteomic analysis. We identified the PDE3B-cAMP-autophagy pathway as a key determinant of SLP-induced liver injury. Specifically, we found that PDE3B was elevated during SLP, which promoted a reduction of cAMP metabolites, triggering an AMPK-dependent autophagy process that led to liver injury in rats. We found that blocking the reduction in cAMP using the PDE3B inhibitor cilostamide inhibited autophagy and substantially ameliorated liver injury during 48-hour SLP in rat livers. Furthermore, we validated the effectiveness of cilostamide treatment in preventing liver injury in pig and human liver 48-hour SLP models. In summary, our results reveal that metabolic reprogramming involving the PDE3B-cAMP-autophagy axis is the key determinant of liver injury in long-term SLP and provide an early therapeutic strategy to prevent liver injury in this setting.
A wearable osmotic microneedle patch provides high-capacity sustained drug delivery in animal models
Authors: Sheng Zhao, Ziyi Lu, Ruisi Cai, Hui Wang, Shukun Gao, Changwei Yang, Ying Zhang, Bowen Luo, Wentao Zhang, Yinxian Yang, Shenqiang Wang, Tao Sheng, Shiqi Wang, Jiahuan You, Ruyi Zhou, Huimin Ji, Haoning Gong, Xiao Ye, Jicheng Yu, Hong-Hu Zhu, Yuqi Zhang, Zhen Gu
Journal: Science Translational Medicine (2024)

The maintenance of stable plasma drug concentrations within a therapeutic window can be critical for drug efficacy. Here, we developed a wearable osmotic microneedle (OMN) patch to support sustained drug dosing for at least 24 hours without the use of electronic components. The OMN patch uses an osmotic pressure driving force to deliver drug solution into the skin through three hollow microneedles with diameters of less than 200 micrometers. The rate of drug release was related to the composition and concentration of the osmogen and drug and to the physical properties of the semipermeable membrane separating the low- and high-solute compartments. The OMN patch released the peptide drug exenatide in rats and mice for 24 hours, whereas subcutaneous injection resulted in a burst release and rapid decline in the plasma drug concentration. OMN release of exenatide improved glycemic control in a diabetic mouse model consistent with a sustained effective plasma concentration of the drug. Continuous release of the small-molecule chemotherapeutic drug cytarabine reduced the progression of acute myeloid leukemia in mice more effectively than subcutaneous injection. Further evaluation of the OMN patch in canines demonstrated continuous dosing of cytarabine up to 225 milligrams for 24 hours, satisfying clinical requirements (150 to 300 milligrams daily). OMN patches were well tolerated in human participants with minimal pain or irritation of the skin and a stated preference over other administration routes. This wearable drug delivery system could provide a platform for stable high-dose drug release with convenience and safety.
Sexually dimorphic differences in angiogenesis markers are associated with brain aging trajectories in humans
Authors: Abel Torres-Espin, Hannah L. Radabaugh, Scott Treiman, Stephen S. Fitzsimons, Danielle Harvey, Austin Chou, Cutter A. Lindbergh, Kaitlin B. Casaletto, Lauren Goldberger, Adam M. Staffaroni, Pauline Maillard, Bruce L. Miller, Charles DeCarli, Jason D. Hinman, Adam R. Ferguson, Joel H. Kramer, Fanny M. Elahi
Journal: Science Translational Medicine (2024)

Aberrant angiogenesis could contribute to the development of cognitive impairment and represent a therapeutic target for preventing dementia. However, most studies addressing angiogenesis and cognitive impairment focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in a pooled two-center sample from deeply phenotyped longitudinal human cohorts ( n = 435; female = 207, age = 74 ± 9) using cognitive assessments, biospecimens, structural brain imaging, and clinical data. Blood markers included ligands involved in angiogenesis and vascular function such as basic fibroblast growth factor (bFGF), members of the vascular endothelial growth factor family (VEGFA, VEGFB, and VEGFC), and placental growth factor (PlGF), in addition to their receptors VEGF receptor 1 (VEGFR1) and tyrosine kinase with immunoglobulin and EGF homology domain 2 (Tie2). Machine learning and traditional statistics revealed sexually dimorphic associations of plasma angiogenic growth factors with brain aging outcomes, including executive function and gray matter atrophy. Specifically, markers of angiogenesis were associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reversed around age 75. Higher concentrations of bFGF, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories in both women and men. An independent sample from a multicenter dataset (MarkVCID; n = 80; female = 30, age = 73 ± 9) was used to externally validate these findings. In conclusion, this analysis demonstrates the association of angiogenesis to human brain aging, with potential therapeutic implications for vascular cognitive impairment and dementia.
Decongestion and Outcomes in Patients Hospitalized for Acute Heart Failure
Authors: Matteo Pagnesi, Laura Staal, Jozine M Ter Maaten, Iris E Beldhuis, Gad Cotter, Beth A Davison, Niels Jongs, G Michael Felker, Gerasimos Filippatos, Barry H Greenberg, Peter S Pang, Piotr Ponikowski, Carlo Mario Lombardi, Marianna Adamo, Thomas Severin, Claudio Gimpelewicz, Adriaan A Voors, John R Teerlink, Marco Metra
Journal: JACC Heart Failure (2024)
An mRNA-encoded dominant-negative inhibitor of transcription factor RUNX1 suppresses vitreoretinal disease in experimental models
Authors: Michael O’Hare, William P. Miller, Said Arevalo-Alquichire, Dhanesh Amarnani, Evhy Apryani, Paula Perez-Corredor, Claudia Marino, Daisy Y. Shu, Timothy E. Vanderleest, Andres Muriel-Torres, Harper B. Gordon, Audrey L. Gunawan, Bryan A. Kaplan, Karim W. Barake, Romy P. Bejjani, Tri H. Doan, Rose Lin, Santiago Delgado-Tirado, Lucia Gonzalez-Buendia, Elizabeth J. Rossin, Guannan Zhao, Dean Eliott, Christine Weinl-Tenbruck, Frédéric Chevessier-Tünnesen, Joanna Rejman, Fabio Montrasio, Leo A. Kim, Joseph F. Arboleda-Velasquez
Journal: Science Translational Medicine (2024)

Messenger RNA (mRNA)–based therapies are a promising approach to medical treatment. Except for infectious diseases, no other disease has mRNA-based therapies available. The eye is an ideal model for mRNA therapeutic development because it requires limited dosing. Proliferative vitreoretinopathy (PVR) is a blinding condition caused by retinal detachment that now lacks available medical treatment, with surgery as the only treatment option. We previously implicated runt-related transcription factor-1 (RUNX1) as a driver of epithelial-to-mesenchymal transition (EMT) in PVR and as a critical mediator of aberrant ocular angiogenesis when up-regulated. On the basis of these findings, an mRNA was designed to express a dominant-negative inhibitor of RUNX1 (RUNX1-Trap). We show that RUNX1-Trap delivered in polymer-lipidoid complexes or lipid nanoparticles sequestered RUNX1 in the cytosol and strongly reduced proliferation in primary cell cultures established from fibrotic membranes derived from patients with PVR. We assessed the preclinical efficacy of intraocular delivery of mRNA-encoded RUNX1-Trap in a rabbit model of PVR and in a laser-induced mouse model of aberrant angiogenesis often used to study wet age-related macular degeneration. mRNA-encoded RUNX1-Trap suppressed ocular pathology, measured as pathological scores in the rabbit PVR model and leakage and lesion size in the laser-induced choroidal neovascularization mouse model. mRNA-encoded RUNX1-Trap also strongly reduced proliferation in a human ex vivo explant model of PVR. These data demonstrate the therapeutic potential of mRNA-encoded therapeutic molecules with dominant-negative properties, highlighting the potential of mRNA-based therapies beyond standard gene supplementation approaches.
Understanding Better the Genetic Causes of Hematuria
Authors: Judy Savige
Journal: Journal of the American Society of Nephrology (2024)

Department of Medicine (Melbourne Health and Northern Health), Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia Correspondence: Dr. Judy Savige, email: [email protected] See related article, "Association of Genetically Predicted Skipping of COL4A4 Exon 27 with Hematuria and Albuminuria," on pages XXX–XXX.
Ultra-low Dose Coronary Computed Tomography Angiography Using Photon-counting Detector Computed Tomography
Authors: Suguru Araki, Satoshi Nakamura, Masafumi Takafuji, Yasutaka Ichikawa, Hajime Sakuma, Kakuya Kitagawa
Journal:  (2024)

Photon-counting detector computed tomography (PCD-CT), which allows the exclusion of electronic noise, shows promise for significant dose reduction in coronary CT angiography (CCTA). This study aimed to assess the radiation dose and image quality of CCTA using PCD-CT, combined with high-pitch helical scanning and an ultra-low tube potential of 70 kVp, and investigate the effect of a sharp kernel on image quality and stenosis assessment in such an ultra-low-dose CCTA setting.