tbuckley/cabot-search huggingface dataset:
Development and validation of a new algorithm for improved cardiovascular risk prediction
Authors: Julia Hippisley-Cox, Carol A. C. Coupland, Mona Bafadhel, Richard E. K. Russell, Aziz Sheikh, Peter Brindle, Keith M. Channon
Journal: Nature Medicine (2024)

Abstract QRISK algorithms use data from millions of people to help clinicians identify individuals at high risk of cardiovascular disease (CVD). Here, we derive and externally validate a new algorithm, which we have named QR4, that incorporates novel risk factors to estimate 10-year CVD risk separately for men and women. Health data from 9.98 million and 6.79 million adults from the United Kingdom were used for derivation and validation of the algorithm, respectively. Cause-specific Cox models were used to develop models to predict CVD risk, and the performance of QR4 was compared with version 3 of QRISK, Systematic Coronary Risk Evaluation 2 (SCORE2) and atherosclerotic cardiovascular disease (ASCVD) risk scores. We identified seven novel risk factors in models for both men and women (brain cancer, lung cancer, Down syndrome, blood cancer, chronic obstructive pulmonary disease, oral cancer and learning disability) and two additional novel risk factors in women (pre-eclampsia and postnatal depression). On external validation, QR4 had a higher C statistic than QRISK3 in both women (0.835 (95% confidence interval (CI), 0.833–0.837) and 0.831 (95% CI, 0.829–0.832) for QR4 and QRISK3, respectively) and men (0.814 (95% CI, 0.812–0.816) and 0.812 (95% CI, 0.810–0.814) for QR4 and QRISK3, respectively). QR4 was also more accurate than the ASCVD and SCORE2 risk scores in both men and women. The QR4 risk score identifies new risk groups and provides superior CVD risk prediction in the United Kingdom compared with other international scoring systems for CVD risk.
The emergence of highly resistant and hypervirulent Klebsiella pneumoniae CC14 clone in a tertiary hospital over 8 years
Authors: Sharif Hala, Mohammed Malaikah, Jiayi Huang, Wesam Bahitham, Omniya Fallatah, Samer Zakri, Chakkiath Paul Antony, Mohammed Alshehri, Raeece Naeem Ghazzali, Fathia Ben-Rached, Abdullah Alsahafi, Asim Alsaedi, Ghadeer AlAhmadi, Mai Kaaki, Meshari Alazmi, Baraa AlhajHussein, Muhammad Yaseen, Hosam M. Zowawi, Majed F. Alghoribi, Abdulhakeem O. Althaqafi, Abdulfattah Al-Amri, Danesh Moradigaravand, Arnab Pain
Journal: Genome Medicine (2024)

Klebsiella pneumoniae is a major bacterial and opportunistic human pathogen, increasingly recognized as a healthcare burden globally. The convergence of resistance and virulence in K. pneumoniae strains has led to the formation of hypervirulent and multidrug-resistant strains with dual risk, limiting treatment options. K. pneumoniae clones are known to emerge locally and spread globally. Therefore, an understanding of the dynamics and evolution of the emerging strains in hospitals is warranted to prevent future outbreaks. In this study, we conducted an in-depth genomic analysis on a large-scale collection of 328 multidrug-resistant (MDR) K. pneumoniae strains recovered from 239 patients from a single major hospital in the western coastal city of Jeddah in Saudi Arabia from 2014 through 2022. We employed a broad range of phylogenetic and phylodynamic methods to understand the evolution of the predominant clones on epidemiological time scales, virulence and resistance determinants, and their dynamics. We also integrated the genomic data with detailed electronic health record (EHR) data for the patients to understand the clinical implications of the resistance and virulence of different strains. We discovered a diverse population underlying the infections, with most strains belonging to Clonal Complex 14 (CC14) exhibiting dominance. Specifically, we observed the emergence and continuous expansion of strains belonging to the dominant ST2096 in the CC14 clade across hospital wards in recent years. These strains acquired resistance mutations against colistin and extended spectrum β-lactamase (ESBL) and carbapenemase genes, namely blaOXA-48 and blaOXA-232, located on three distinct plasmids, on epidemiological time scales. Strains of ST2096 exhibited a high virulence level with the presence of the siderophore aerobactin (iuc) locus situated on the same mosaic plasmid as the ESBL gene. Integration of ST2096 with EHR data confirmed the significant link between colonization by ST2096 and the diagnosis of sepsis and elevated in-hospital mortality (p-value < 0.05). Overall, these results demonstrate the clinical significance of ST2096 clones and illustrate the rapid evolution of an emerging hypervirulent and MDR K. pneumoniae in a clinical setting.
Establishing and Defining an Approach to Climate Conscious Clinical Medical Ethics
Authors: Andrew Hantel, Jonathan M. Marron, Gregory A. Abel
Journal: The American Journal of Bioethics (2024)

An anthropocentric scope for clinical medical ethics (CME) has largely separated this area of bioethics from environmental concerns. In this article, we first identify and reconcile the ethical issues imposed on CME by climate change including the dispersion of related causes and effects, the transdisciplinary and transhuman nature of climate change, and the historic divorce of CME from the environment. We then establish how several moral theories undergirding modern CME, such as virtue ethics, feminist ethics, and several theories of justice, promote both a flourishing of human medical practice and the environment. We conclude by defining an expanded the scope of CME as inclusive of not only patients, families, physicians, and other health professionals but other humans, non-humans, and their shared environment. We then apply this scope and theory to a widely used framework for applying CME, the Four Topics model, to construct a climate conscious approach to CME.
Human Herpesvirus-6 Reactivation and Disease Are Infrequent in Chimeric Antigen Receptor T-cell Therapy Recipients
Authors: Eleftheria Kampouri, Elizabeth M. Krantz, Hu Xie, Sarah S. Ibrahimi, Erika S. Kiem, Mandeep K. Sekhon, Emily C. Liang, Andrew J. Cowan, Andrew Portuguese, Damian J. Green, Aya Albittar, Jennifer J. Huang, Jordan Gauthier, Ailyn C. Pérez-Osorio, Keith R. Jerome, Danielle M. Zerr, Michael J. Boeckh, Joshua A. Hill
Journal: Blood (2024)

Human herpesvirus 6B (HHV-6B) reactivation and disease are increasingly reported after chimeric antigen receptor (CAR) T-cell therapy (CARTx). HHV-6 reactivation in the CAR T-cell product was recently reported, raising questions about product and patient management. Because of overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide 2 lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks after infusion, HHV-6B reactivation occurred in 8 of 89 participants; 3 had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval [CI], 2.2-12.5). HHV-6B detection was low level (median peak, 435 copies per mL; interquartile range, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in the blood and/or cerebrospinal fluid (CSF) within 12 weeks after infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing, with detection in 1. Among 34 patients with CSF HHV-6 testing, 1 patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted.
Standardized indolent systemic mastocytosis evaluations across a healthcare system: implications for screening accuracy
Authors: Jeremy C McMurray, Curtis S Pacheco, Brandon J Schornack, Xiaoping Sun, Janet A. Brunader, Alexis Erica Scott, Juan S. Ariza, Chung-ting J. Kou, Ryan C. Costantino, Luke M. Pittman, Karla E. Adams, Aubri M. Waters, Eric M Pryor, Jonathan J Lyons, Dean Metcalfe, Irina Maric, Nathan A Boggs
Journal: Blood (2024)
Mitochondrial tRNA pseudouridylation governs erythropoiesis
Authors: Bichen Wang, Deyang Shi, Shuang Yang, Yu lian, Haoyuan Li, Mutian Cao, Yifei He, Lele Zhang, Chen Qiu, Tong Liu, Wei Wen, Yuanwu Ma, Lei Shi, Tao Cheng, Lihong Shi, Weiping Yuan, Yajing Chu, Jun Shi
Journal: Blood (2024)

Abstract Pseudouridine is the most prevalent RNA modification, and its aberrant function is implicated in various human diseases. However, the specific impact of pseudouridylation on hematopoiesis remains poorly understood. Here, we investigated the role of transfer RNA (tRNA) pseudouridylation in erythropoiesis and its association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia syndrome (MLASA) pathogenesis. By using patient-specific induced pluripotent stem cells (iPSCs) carrying a genetic pseudouridine synthase 1 (PUS1) mutation and a corresponding mutant mouse model, we demonstrated impaired erythropoiesis in MLASA-iPSCs and anemia in the MLASA mouse model. Both MLASA-iPSCs and mouse erythroblasts exhibited compromised mitochondrial function and impaired protein synthesis. Mechanistically, we revealed that PUS1 deficiency resulted in reduced mitochondrial tRNA levels because of pseudouridylation loss, leading to aberrant mitochondrial translation. Screening of mitochondrial supplements aimed at enhancing respiration or heme synthesis showed limited effect in promoting erythroid differentiation. Interestingly, the mammalian target of rapamycin (mTOR) inhibitor rapamycin facilitated erythroid differentiation in MLASA-iPSCs by suppressing mTOR signaling and protein synthesis, and consistent results were observed in the MLASA mouse model. Importantly, rapamycin treatment partially ameliorated anemia phenotypes in a patient with MLASA. Our findings provide novel insights into the crucial role of mitochondrial tRNA pseudouridylation in governing erythropoiesis and present potential therapeutic strategies for patients with anemia facing challenges related to protein translation.
PARP-ish: Gaps in Molecular Understanding and Clinical Trials Targeting PARP Exacerbate Racial Disparities in Prostate Cancer
Authors: Moriah L. Cunningham, Matthew J. Schiewer
Journal: Cancer Research (2024)

PARP is a nuclear enzyme with a major function in the DNA damage response. PARP inhibitors (PARPi) have been developed for treating tumors harboring homologous recombination repair defects that lead to a dependency on PARP. There are currently three PARPi approved for use in advanced prostate cancer, and several others are in clinical trials for this disease. Recent clinical trial results have reported differential efficacy based on the specific PARPi utilized as well as patient race. There is a racial disparity in prostate cancer, in which African American males are twice as likely to develop and die from the disease compared with European American males. Despite the disparity, there continues to be a lack of diversity in clinical trial cohorts for prostate cancer. In this review, PARP nuclear functions, inhibition, and clinical relevance are explored through the lens of racial differences. This review will touch on the biological variations that have been explored thus far between African American and European American males with prostate cancer to offer a rationale for investigating PARPi response in the context of race at both basic science and clinical development levels.
Filling the prescription gap: the value of community support in psoriasis management
Authors: Melissa C Leeolou, Kavita Y Sarin, David F Fiorentino
Journal: British Journal of Dermatology (2024)

This perspectives article is co-authored with Melissa Leeolou, patient advocate, whose personal experiences with severe psoriasis have provided invaluable insights into the emotional and social dimensions of living with this condition. We offer a unique perspective on dermatological care by highlighting the importance of community support networks and hope to contribute to a more holistic understanding of patient needs.
Fc-silent anti-TIGIT antibodies potentiate anti-tumor immunity without depleting regulatory T cells
Authors: Dana Piovesan, Amber E. de Groot, Soonweng Cho, Amy E. Anderson, Rebecca D. Ray, Amita Patnaik, Paul G. Foster, Casey G. Mitchell, Alejandra Y. Lopez Espinoza, Wandi S. Zhu, Carlo E. Stagnaro, Hema Singh, Xiaoning Zhao, Lisa Seitz, Nigel P. Walker, Matthew J. Walters, Kelsey E. Sivick
Journal: Cancer Research (2024)

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor on immune cells that outcompetes an activating receptor, CD226, for shared ligands. Tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg) and on CD8+ T cells with tumor-reactive or exhausted phenotypes, supporting the potential of therapeutically targeting TIGIT to enhance antitumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand IgG Fc (Fcγ) receptor binding for therapeutic benefit. In this study, we showed that combining Fc-enabled (Fce) or Fc-silent (Fcs) anti-TIGIT with antiprogrammed cell death protein 1 in mice resulted in enhanced control of tumors by differential mechanisms: Fce anti-TIGIT promoted the depletion of intratumoral Treg, whereas Fcs anti-TIGIT did not. Despite leaving Treg numbers intact, Fcs anti-TIGIT potentiated the activation of tumor-specific exhausted CD8+ populations in a lymph node-dependent manner. Fce anti-TIGIT induced antibody-dependent cell-mediated cytotoxicity against human Treg in vitro, and significant decreases in Treg were measured in the peripheral blood of patients with phase I solid tumor cancer treated with Fce anti-TIGIT. In contrast, Fcs anti-TIGIT did not deplete human Treg in vitro and was associated with anecdotal objective clinical responses in two patients with phase I solid tumor cancer whose peripheral Treg frequencies remained stable on treatment. Collectively, these data provide evidence for pharmacologic activity and antitumor efficacy of anti-TIGIT antibodies lacking the ability to engage Fcγ receptor.
The circMYBL2-Encoded p185 Protein Suppresses Colorectal Cancer Progression by Inhibiting Serine Biosynthesis
Authors: Ning Zhao, Yinghao Cao, Ruikang Tao, Xiuxian Zhu, Runze Li, Yajun Chen, Kaixiong Tao, Lei Li, Hengyu Chen, Xianxiong Ma
Journal: Cancer Research (2024)

Circular RNAs are a class of covalently closed single-stranded loop RNAs that have been implicated to play a functional role in almost all types of cancers. Previous studies have revealed that circMYBL2 acts as a tumor-promoting circular RNA. In this study, we found that circMYBL2 in colorectal cancer encodes a 185-amino acid protein, p185. Functionally, circMYBL2-encoded p185 suppressed the growth and aggressiveness of colorectal cancer cells in vitro and in vivo. Mechanistically, p185 counteracted ubiquitin C-terminal hydrolase L3 (UCHL3)-mediated deubiquitination of phosphoglycerate dehydrogenase (PHGDH) by competitively binding to the C1 domain of UCHL3, resulting in PHGDH degradation and a subsequent reduction in serine and glycine biosynthesis. These data revealed that the circMYBL2-encoded p185 isoform serves as a tumor suppressor to inhibit the progression of colorectal cancer by reducing serine biosynthesis. Significance: A p185 protein encoded by circMYBL2 functions as a tumor suppressor that inhibits the progression of colorectal cancer by increasing the degradation of PHGDH to reduce serine biosynthesis.
New insight into air pollution-related cardiovascular disease: an adverse outcome pathway framework of PM2.5-associated vascular calcification
Authors: Ruiyang Ding, Linyuan Huang, Kanglin Yan, Zhiwei Sun, Junchao Duan
Journal: Cardiovascular Research (2024)

Abstract Despite the air quality has been generally improved in recent years, ambient fine particulate matter (PM2.5), a major contributor to air pollution, remains one of the major threats to public health. Vascular calcification is a systematic pathology associated with an increased risk of cardiovascular disease. Although the epidemiological evidence has uncovered the association between PM2.5 exposure and vascular calcification, little is known about the underlying mechanisms. The adverse outcome pathway (AOP) concept offers a comprehensive interpretation of all of the findings obtained by toxicological and epidemiological studies. In this review, reactive oxygen species generation was identified as the molecular initiating event (MIE), which targeted subsequent key events (KEs) such as oxidative stress, inflammation, endoplasmic reticulum stress, and autophagy, from the cellular to the tissue/organ level. These KEs eventually led to the adverse outcome, namely increased incidence of vascular calcification and atherosclerosis morbidity. To the best of our knowledge, this is the first AOP framework devoted to PM2.5-associated vascular calcification, which benefits future investigations by identifying current limitations and latent biomarkers.
Computationally Efficient Demographic History Inference from Allele Frequencies with Supervised Machine Learning
Authors: Linh N Tran, Connie K Sun, Travis J Struck, Mathews Sajan, Ryan N Gutenkunst
Journal: Molecular Biology and Evolution (2024)

Abstract Inferring past demographic history of natural populations from genomic data is of central concern in many studies across research fields. Previously, our group had developed dadi, a widely used demographic history inference method based on the allele frequency spectrum (AFS) and maximum composite-likelihood optimization. However, dadi’s optimization procedure can be computationally expensive. Here, we present donni (demography optimization via neural network inference), a new inference method based on dadi that is more efficient while maintaining comparable inference accuracy. For each dadi-supported demographic model, donni simulates the expected AFS for a range of model parameters then trains a set of Mean Variance Estimation neural networks using the simulated AFS. Trained networks can then be used to instantaneously infer the model parameters from future genomic data summarized by an AFS. We demonstrate that for many demographic models, donni can infer some parameters, such as population size changes, very well and other parameters, such as migration rates and times of demographic events, fairly well. Importantly, donni provides both parameter and confidence interval estimates from input AFS with accuracy comparable to parameters inferred by dadi’s likelihood optimization while bypassing its long and computationally intensive evaluation process. donni’s performance demonstrates that supervised machine learning algorithms may be a promising avenue for developing more sustainable and computationally efficient demographic history inference methods.
The running suture with clip and string technique after colonic endoscopic submucosal dissection
Authors: Mai Ego Makiguchi, Yutaka Saito
Journal: Endoscopy (2024)

A closure technique to prevent bleeding after colorectal endoscopic submucosal dissection (ESD) has previously been reported; Nishizawa et al. reported a string and clip closure technique using the following method [1]. The clip and string can be passed through the instrument channel of a single-channel endoscope and is placed at the distal edge of a large mucosal defect. A second clip is hooked onto the string and placed on the opposite side. Both clips are gathered by pulling the free end of the string, and additional clips are placed to achieve complete closure. This technique has limitations however on the size of the defect that can be completely closed. Therefore, we adapted this method and developed a new closure technique for colorectal ESD ([Video 1]).
Uptake and 4-week quit rates from an opt-out co-located smoking cessation service delivered alongside community-based low-dose computed tomography screening within the Yorkshire Lung Screening Trial
Authors: Rachael L. Murray, Panos Alexandris, David Baldwin, Kate Brain, John Britton, Philip A.J. Crosbie, Rhian Gabe, Sarah Lewis, Steve Parrott, Samantha L. Quaife, Hui Zhen Tam, Qi Wu, Rebecca Beeken, Harriet Copeland, Claire Eckert, Neil Hancock, Jason Lindop, Grace McCutchan, Catriona Marshall, Richard D. Neal, Suzanne Rogerson, Harriet D. Quinn Scoggins, Irene Simmonds, Rebecca Thorley, Matthew E. Callister
Journal: European Respiratory Journal (2024)

Background Up to 50% of those attending for low-dose computed tomography screening for lung cancer continue to smoke and co-delivery of smoking cessation services alongside screening may maximise clinical benefit. Here we present data from an opt-out co-located smoking cessation service delivered alongside the Yorkshire Lung Screening Trial (YLST). Methods Eligible YLST participants were offered an immediate consultation with a smoking cessation practitioner (SCP) at their screening visit with ongoing smoking cessation support over subsequent weeks. Results Of 2150 eligible participants, 1905 (89%) accepted the offer of an SCP consultation during their initial visit, with 1609 (75%) receiving ongoing smoking cessation support over subsequent weeks. Uptake of ongoing support was not associated with age, ethnicity, deprivation or educational level in multivariable analyses, although men were less likely to engage (adjusted OR (OR adj ) 0.71, 95% CI 0.56–0.89). Uptake was higher in those with higher nicotine dependency, motivation to stop smoking and self-efficacy for quitting. Overall, 323 participants self-reported quitting at 4 weeks (15.0% of the eligible population); 266 were validated by exhaled carbon monoxide (12.4%). Multivariable analyses of eligible smokers suggested 4-week quitting was more likely in men (OR adj 1.43, 95% CI 1.11–1.84), those with higher motivation to quit and previous quit attempts, while those with a stronger smoking habit in terms of cigarettes per day were less likely to quit. Conclusions There was high uptake for co-located opt-out smoking cessation support across a wide range of participant demographics. Protected funding for integrated smoking cessation services should be considered to maximise programme equity and benefit.
Smoking cessation at lung cancer screening: joining (life-saving) dots
Authors: Keir E. Lewis
Journal: European Respiratory Journal (2024)

We now know that lung cancer screening with low-dose computed tomography saves lives. We have known for more than 60 years that smoking cessation (SC) saves lives. Can we save even more lives by combining these two effective interventions? The work by Murray et al. [1], in this issue of the European Respiratory Journal , is a big stride to show that we can. Smoking cessation at lung cancer screening is viable and an excellent opportunity <https://bit.ly/3TC0HAf>
“Therapeutic improvement of CFTR function and reversibility of bronchiectasis in cystic fibrosis.” M.O. Wielpütz and M.A. Mall.<i>Eur Respir J</i>2024; 63: 2400234.
Journal: European Respiratory Journal (2024)

In this article, the PRAGMA-CF scoring system was incorrectly referred to as the "PRAGA-CF scoring system" in the sixth paragraph.The corrected sentence is as follows:"Of note, another recent imaging study employing the PRAGMA-CF scoring system based on CT, which is also a visual reader-based technique, did not detect improvements in bronchiectasis in patients with CF aged 12 years and older treated with ETI [29].