tbuckley/cabot-search huggingface dataset:
AI-based differential diagnosis of dementia etiologies on multimodal data
Authors: Chonghua Xue, Sahana S Kowshik, Diala Lteif, Shreyas Puducheri, Varuna H Jasodanand, Olivia T Zhou, Anika S Walia, Osman B Guney, J Diana Zhang, Serena T Pham, Artem Kaliaev, V Carlota Andreu-Arasa, Brigid C Dwyer, Chad W Farris, Honglin Hao, Sachin Kedar, Asim Z Mian, Daniel L Murman, Sarah A O'Shea, Aaron B Paul, Saurabh Rohatgi, Marie-Helene Saint-Hilaire, Emmett A Sartor, Bindu N Setty, Juan E Small, Arun Swaminathan, Olga Taraschenko, Jing Yuan, Yan Zhou, Shuhan Zhu, Cody Karjadi, Ting Fang Alvin Ang, Sarah A Bargal, Bryan A Plummer, Kathleen L Poston, Meysam Ahangaran, Rhoda Au, Vijaya B Kolachalama
Journal: Nature Medicine (2024)

Abstract Differential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an artificial intelligence (AI) model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51,269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a microaveraged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the microaveraged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two co-occurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in clinical settings and drug trials. Further prospective studies are needed to confirm its ability to improve patient care.
Extension of efficacy range for targeted malaria-elimination interventions due to spillover effects
Authors: Jade Benjamin-Chung, Haodong Li, Anna Nguyen, Gabriella Barratt Heitmann, Adam Bennett, Henry Ntuku, Lisa M. Prach, Munyaradzi Tambo, Lindsey Wu, Chris Drakeley, Roly Gosling, Davis Mumbengegwi, Immo Kleinschmidt, Jennifer L. Smith, Alan Hubbard, Mark van der Laan, Michelle S. Hsiang
Journal: Nature Medicine (2024)

Malaria-elimination interventions aim to extinguish hotspots and prevent transmission to nearby areas. Here, we re-analyzed a cluster-randomized trial of reactive, focal interventions (chemoprevention using artemether-lumefantrine and/or indoor residual spraying with pirimiphos-methyl) delivered within 500 m of confirmed malaria index cases in Namibia to measure direct effects (among intervention recipients within 500 m) and spillover effects (among non-intervention recipients within 3 km) on incidence, prevalence and seroprevalence. There was no or weak evidence of direct effects, but the sample size of intervention recipients was small, limiting statistical power. There was the strongest evidence of spillover effects of combined chemoprevention and indoor residual spraying. Among non-recipients within 1 km of index cases, the combined intervention reduced malaria incidence by 43% (95% confidence interval, 20-59%). In analyses among non-recipients within 3 km of interventions, the combined intervention reduced infection prevalence by 79% (6-95%) and seroprevalence, which captures recent infections and has higher statistical power, by 34% (20-45%). Accounting for spillover effects increased the cost-effectiveness of the combined intervention by 42%. Targeting hotspots with combined chemoprevention and vector-control interventions can indirectly benefit non-recipients up to 3 km away.
Principled distillation of UK Biobank phenotype data reveals underlying structure in human variation
Authors: Caitlin E. Carey, Rebecca Shafee, Robbee Wedow, Amanda Elliott, Duncan S. Palmer, John Compitello, Masahiro Kanai, Liam Abbott, Patrick Schultz, Konrad J. Karczewski, Samuel C. Bryant, Caroline M. Cusick, Claire Churchhouse, Daniel P. Howrigan, Daniel King, George Davey Smith, Benjamin M. Neale, Raymond K. Walters, Elise B. Robinson
Journal: Nature Human Behaviour (2024)

Data within biobanks capture broad yet detailed indices of human variation, but biobank-wide insights can be difficult to extract due to complexity and scale. Here, using large-scale factor analysis, we distill hundreds of variables (diagnoses, assessments and survey items) into 35 latent constructs, using data from unrelated individuals with predominantly estimated European genetic ancestry in UK Biobank. These factors recapitulate known disease classifications, disentangle elements of socioeconomic status, highlight the relevance of psychiatric constructs to health and improve measurement of pro-health behaviours. We go on to demonstrate the power of this approach to clarify genetic signal, enhance discovery and identify associations between underlying phenotypic structure and health outcomes. In building a deeper understanding of ways in which constructs such as socioeconomic status, trauma, or physical activity are structured in the dataset, we emphasize the importance of considering the interwoven nature of the human phenome when evaluating public health patterns.
Striatal projection neurons coexpressing dopamine D1 and D2 receptors modulate the motor function of D1- and D2-SPNs
Authors: Patricia Bonnavion, Christophe Varin, Ghazal Fakhfouri, Pilar Martinez Olondo, Aurélie De Groote, Amandine Cornil, Ramiro Lorenzo Lopez, Elisa Pozuelo Fernandez, Elsa Isingrini, Quentin Rainer, Kathleen Xu, Eleni Tzavara, Erika Vigneault, Sylvie Dumas, Alban de Kerchove d’Exaerde, Bruno Giros
Journal: Nature Neuroscience (2024)
Evaluation and mitigation of the limitations of large language models in clinical decision-making
Authors: Paul Hager, Friederike Jungmann, Robbie Holland, Kunal Bhagat, Inga Hubrecht, Manuel Knauer, Jakob Vielhauer, Marcus Makowski, Rickmer Braren, Georgios Kaissis, Daniel Rueckert
Journal: Nature Medicine (2024)

Clinical decision-making is one of the most impactful parts of a physician's responsibilities and stands to benefit greatly from artificial intelligence solutions and large language models (LLMs) in particular. However, while LLMs have achieved excellent performance on medical licensing exams, these tests fail to assess many skills necessary for deployment in a realistic clinical decision-making environment, including gathering information, adhering to guidelines, and integrating into clinical workflows. Here we have created a curated dataset based on the Medical Information Mart for Intensive Care database spanning 2,400 real patient cases and four common abdominal pathologies as well as a framework to simulate a realistic clinical setting. We show that current state-of-the-art LLMs do not accurately diagnose patients across all pathologies (performing significantly worse than physicians), follow neither diagnostic nor treatment guidelines, and cannot interpret laboratory results, thus posing a serious risk to the health of patients. Furthermore, we move beyond diagnostic accuracy and demonstrate that they cannot be easily integrated into existing workflows because they often fail to follow instructions and are sensitive to both the quantity and order of information. Overall, our analysis reveals that LLMs are currently not ready for autonomous clinical decision-making while providing a dataset and framework to guide future studies.
The transcriptional regulation of the horizontally acquired iron uptake system, yersiniabactin and its contribution to oxidative stress tolerance and pathogenicity of globally emerging <i>salmonella</i> strains
Authors: Imbar Diamant, Boaz Adani, Meir Sylman, Galia Rahav, Ohad Gal-Mor
Journal: Gut Microbes (2024)

The bacterial species
Cannabidiol and Neurodegeneration: From Molecular Mechanisms to Clinical Benefits
Authors: Saurabh Kumar Jha, Vinod Kumar Nelson, Punna Rao Suryadevara, Siva Prasad Panda, Chitikela P. Pullaiah, Mohana Vamsi Nuli, Mehnaz Kamal, Mohd Imran, Saijyothi Ausali, Mosleh Mohammad Abomughaid, Rashi Srivastava, Rahul Deka, Pingal Pritam, Neha Gupta, Harishankar Shyam, Indrakant K. Singh, Bindhy Wasini Pandey, Saikat Dewanjee, Niraj Kumar Jha, Seid Mahdi Jafari
Journal: Ageing Research Reviews (2024)
Association of Autoantibody Concentrations and Trajectories With Lupus Nephritis Histologic Features and Treatment Response
Authors: Andrea Fava, Catriona A. Wagner, Carla J. Guthridge, Joseph Kheir, Susan Macwana, Wade DeJager, Tim Gross, Peter Izmirly, H. Michael Belmont, Betty Diamond, Anne Davidson, Paul J. Utz, Michael H Weisman, Laurence S. Magder, Joel M. Guthridge, Michelle Petri, Jill Buyon, Judith A. James
Journal: Arthritis & Rheumatology (2024)

Autoantibodies are a hallmark of lupus nephritis (LN), but their association with LN classes and treatment response are not adequately known. In this study, we quantified circulating autoantibodies in the Accelerating Medicines Partnership LN longitudinal cohort to identify serological biomarkers of LN histologic classification and treatment response and how these biomarkers change over time based on treatment response.
Imaging of Existing and Newly Translated Proteins Elucidates Mechanisms of Sarcomere Turnover
Authors: Guy Douvdevany, Itai Erlich, Lilac Haimovich-Caspi, Tomer Mashiah, Maksymilian Prondzynski, Maria Rosaria Pricolo, Jorge Alegre-Cebollada, Wolfgang A. Linke, Lucie Carrier, Izhak Kehat
Journal: Circulation Research (2024)

BACKGROUND: How the sarcomeric complex is continuously turned over in long-living cardiomyocytes is unclear. According to the prevailing model of sarcomere maintenance, sarcomeres are maintained by cytoplasmic soluble protein pools with free recycling between pools and sarcomeres. METHODS: We imaged and quantified the turnover of expressed and endogenous sarcomeric proteins, including the giant protein titin, in cardiomyocytes in culture and in vivo, at the single cell and at the single sarcomere level using pulse-chase labeling of Halo-tagged proteins with covalent ligands. RESULTS: We disprove the prevailing protein pool model and instead show an ordered mechanism in which only newly translated proteins enter the sarcomeric complex while older ones are removed and degraded. We also show that degradation is independent of protein age and that proteolytic extraction is a rate-limiting step in the turnover. We show that replacement of sarcomeric proteins occurs at a similar rate within cells and across the heart and is slower in adult cells. CONCLUSIONS: Our findings establish a unidirectional replacement model for cardiac sarcomeres subunit replacement and identify their turnover principles.
Hypoalbuminaemia and heart failure: A practical review of current evidence
Authors: Marta Biancucci, Riccardo Barbiero, Benedetta Pennella, Antonio Cannatà, Walter Ageno, Flavio Tangianu, Andrea Maria Maresca, Francesco Dentali, Aldo Bonaventura
Journal: European Journal of Heart Failure (2024)

Abstract Hypoalbuminaemia (serum albumin levels ≤3.5 g/dl) is associated with poor outcomes among patients with heart failure (HF). This narrative review includes original articles and reviews published over the past 20 years and retrieved from PubMed using the following search terms (or their combination): ‘heart failure’, ‘hypoalbuminaemia’, ‘heart failure with reduced ejection fraction’, ‘heart failure with preserved ejection fraction’, ‘all‐cause mortality’, ‘in‐hospital mortality’, ‘hospitalization’, ‘prognosis’. The aims of this review are to provide an overview on the prevalence of hypoalbuminaemia in HF, its impact on clinical outcomes, and potential mechanisms that may suggest future therapeutic strategies. Hypoalbuminaemia is frequent in HF patients, especially among the elderly. However, data about the exact epidemiology of hypoalbuminaemia are scant due to different definitions, and prevalence is estimated between 5% and 70% across the whole spectrum of ejection fraction. Current evidence points to hypoalbuminaemia as a marker of poor outcomes in HF, irrespective of the ejection fraction, and in other cardiovascular diseases. Among patients who suffered from acute coronary syndrome, those with hypoalbuminaemia had an increased risk of new‐onset HF and in‐hospital mortality. Albumin, however, might also play a role in the natural history of such diseases due to its antioxidant, anti‐inflammatory, and antithrombotic properties. Whether albumin supplementation or nutritional support in general would be beneficial in improving clinical outcomes in HF is not completely clear and should be evaluated in adequately designed studies.
Iron deficiency and supplementation in patients with heart failure: Results from the <scp>IRON</scp>‐<scp>HF</scp> international survey
Authors: Massimiliano Camilli, Federico Ballacci, Valentina Alice Rossi, Antonio Cannatà, Luca Monzo, Nathan Mewton, Nicolas Girerd, Piero Gentile, Marco Marini, Massimo Mapelli, Andreas J Flammer, Nadia Aspromonte, Rocco Antonio Montone, Antonella Lombardo, Gaetano Antonio Lanza, Gianluigi Savarese, Frank Ruschitzka, Filippo Crea
Journal: European Journal of Heart Failure (2024)
Cardiovascular disease risk after a SARS-CoV-2 infection: A systematic review and meta-analysis
Authors: Karla Romero Starke, Pauline Kaboth, Natalie Rath, David Reissig, Daniel Kaempf, Albert Nienhaus, Andreas Seidler
Journal: Journal of Infection (2024)

To our knowledge, there is no systematic review examining CVD risks after a SARS-CoV-2 infection over time, while also taking into account disease severity. All evidence on the risk for pulmonary embolism (PE), myocardial infarction (MI), ischaemic stroke (IS), haemorrhagic stroke (HS), and arterial thrombosis following infection was evaluated.
Another Notch in the Belt of Rheumatoid Arthritis
Authors: Stephanie R. Zack, Osama Alzoubi, Neha Satoeya, Kunwar P. Singh, Sania Deen, Wes Nijim, Myles J. Lewis, Costantino Pitzalis, Nadera Sweiss, Lionel B. Ivashkiv, Shiva Shahrara
Journal: Arthritis & Rheumatology (2024)

Notch ligands and receptors, including JAG1/2, DLL1/4, and Notch1/3, are enriched on macrophages (MΦs), fibroblast‐like synoviocytes (FLS), and/or endothelial cells in rheumatoid arthritis (RA) compared with normal synovial tissues (ST). Power Doppler ultrasound‐guided ST studies reveal that the Notch family is highly involved in early active RA, especially during neovascularization. In contrast, the Notch family is not implicated during the erosive stage, evidenced by their lack of correlation with radiographic damage in RA ST. Toll‐like receptors and tumor necrosis factor (TNF) are the common inducers of Notch expression in RA MΦs, FLS, and endothelial cells. Among Notch ligands, JAG1 and/or DLL4 are most inducible by inflammatory responses in RA MΦs or endothelial cells and transactivate their receptors on RA FLS. TNF plays a central role on Notch ligands, as anti‐TNF good responders display JAG1/2 and DLL1/4 transcriptional downregulation in RA ST myeloid cells. In in vitro studies, TNF increases Notch3 expression in MΦs, which is further amplified by RA FLS addition. Specific disease‐modifying antirheumatic drugs reduced JAG1 and Notch3 expression in MΦ and RA FLS cocultures. Organoids containing FLS and endothelial cells have increased expression of JAG1 and Notch3. Nonetheless, Methotrexate, interleukin‐6 receptor (IL‐6R) antibodies, and B cell blockers are mostly ineffective at decreasing Notch family expression. NF‐κB, MAPK, and AKT pathways are involved in Notch signaling, whereas JAK/STATs are not. Although Notch blockade has been effective in RA preclinical studies, its small molecule inhibitors have failed in phase I and II studies, suggesting that alternative strategies may be required to intercept their function. image
Oral histidine affects gut microbiota and MAIT cells improving glycemic control in type 2 diabetes patients
Authors: Moritz V. Warmbrunn, Ilias Attaye, Judith Aron-Wisnewsky, Elena Rampanelli, Eduard W.J. van der Vossen, Youling Hao, Annefleur Koopen, Per-Olof Bergh, Daniela Stols-Gonçalves, Nadia Mohamed, Marleen Kemper, Xanthe Verdoes, Koen Wortelboer, Mark Davids, Eugeni Belda, Sébastien André, Stanley Hazen, Karine Clement, Bert Groen, Daniel H. van Raalte, Hilde Herrema, Fredrik Backhed, Max Nieuwdorp
Journal: Gut Microbes (2024)

Amino acids, metabolized by host cells as well as commensal gut bacteria, have signaling effects on host metabolism. Oral supplementation of the essential amino acid histidine has been shown to exert metabolic benefits. To investigate whether dietary histidine aids glycemic control, we performed a case-controlled parallel clinical intervention study in participants with type 2 diabetes (T2D) and healthy controls. Participants received oral histidine for seven weeks. After 2 weeks of histidine supplementation, the microbiome was depleted by antibiotics to determine the microbial contribution to histidine metabolism. We assessed glycemic control, immunophenotyping of peripheral blood mononucelar cells (PBMC), DNA methylation of PBMCs and fecal gut microbiota composition. Histidine improves several markers of glycemic control, including postprandial glucose levels with a concordant increase in the proportion of MAIT cells after two weeks of histidine supplementation. The increase in MAIT cells was associated with changes in gut microbial pathways such as riboflavin biosynthesis and epigenetic changes in the amino acid transporter SLC7A5. Associations between the microbiome and MAIT cells were replicated in the MetaCardis cohort. We propose a conceptual framework for how oral histidine may affect MAIT cells via altered gut microbiota composition and SLC7A5 expression in MAIT cells directly and thereby influencing glycemic control. Future studies should focus on the role of flavin biosynthesis intermediates and SLC7A5 modulation in MAIT cells to modulate glycemic control.
Polyamine and EIF5A hypusination downstream of c-Myc confers targeted therapy resistance in BRAF mutant melanoma
Authors: Byung-Sun Park, Heeju Jeon, Yeonseo Kim, Haejin Kwon, Ga-Eun Choi, Sung-Gil Chi, Hyun-Mee Park, Hyunbeom Lee, Tackhoon Kim
Journal: Molecular Cancer (2024)

Abstract Background BRAF inhibitors are widely employed in the treatment of melanoma with the BRAF V600E mutation. However, the development of resistance compromises their therapeutic efficacy. Diverse genomic and transcriptomic alterations are found in BRAF inhibitor resistant melanoma, posing a pressing need for convergent, druggable target that reverse therapy resistant tumor with different resistance mechanisms. Methods CRISPR-Cas9 screens were performed to identify novel target gene whose inhibition selectively targets A375VR, a BRAF V600E mutant cell line with acquired resistance to vemurafenib. Various in vitro and in vivo assays, including cell competition assay, water soluble tetrazolium (WST) assay, live-dead assay and xenograft assay were performed to confirm synergistic cell death. Liquid Chromatography-Mass Spectrometry analyses quantified polyamine biosynthesis and changes in proteome in vemurafenib resistant melanoma. EIF5A hypusination dependent protein translation and subsequent changes in mitochondrial biogenesis and activity were assayed by O-propargyl-puromycin labeling assay, mitotracker, mitoSOX labeling and seahorse assay. Bioinformatics analyses were used to identify the association of polyamine biosynthesis with BRAF inhibitor resistance and poor prognosis in melanoma patient cohorts. Results We elucidate the role of polyamine biosynthesis and its regulatory mechanisms in promoting BRAF inhibitor resistance. Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reduces vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro cell line models and in vivo in a xenograft model. Polyamine biosynthesis signature is associated with poor prognosis and shorter progression free survival after BRAF/MAPK inhibitor treatment in melanoma cohorts, highlighting the clinical relevance of our findings. Conclusions Our findings delineate the molecular mechanisms involving polyamine-EIF5A hypusination-mitochondrial respiration pathway conferring BRAF inhibitor resistance in melanoma. These targets will serve as effective therapeutic targets that can maximize the therapeutic efficacy of existing BRAF inhibitors.
Determinants of achieving serum urate goal with treat‐to‐target urate‐lowering therapy in gout: comment on the article by Helget et al
Authors: Daniel Small
Journal: Arthritis & Rheumatology (2024)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Proteomic Stratification of Prognosis and Treatment Options for Small Cell Lung Cancer
Authors: Zitian Huo, Yaqi Duan, Dongdong Zhan, Xizhen Xu, Nairen Zheng, Jing Cai, Ruifang Sun, Jianping Wang, Fang Cheng, Zhan Gao, Caixia Xu, Wanlin Liu, Yuting Dong, Sailong Ma, Qian Zhang, Yiyun Zheng, Liping Lou, Dong Kuang, Qian Chu, Jun Qin, Guoping Wang, Yi Wang
Journal: Genomics Proteomics & Bioinformatics (2024)

Small cell lung cancer (SCLC) is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models. Here, we analyzed formalin-fixed, paraffin-embedded (FFPE) samples of surgical resections by proteomic profiling, and stratified SCLC into three proteomic subtypes (S-I, S-II, and S-III) with distinct clinical outcomes and chemotherapy responses. The proteomic subtyping was an independent prognostic factor and performed better than current tumor-node-metastasis or Veterans Administration Lung Study Group staging methods. The subtyping results could be further validated using FFPE biopsy samples from an independent cohort, extending the analysis to both surgical and biopsy samples. The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy. Differentially overexpressed proteins in S-III, the worst prognostic subtype, allowed us to nominate potential therapeutic targets, indicating that patient selection may bring new hope for previously failed clinical trials. Finally, analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy. Collectively, our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.