tbuckley/cabot-search huggingface dataset:
Economic, cultural, and social inequalities in potentially inappropriate medication: A nationwide survey- and register-based study in Denmark
Authors: Amanda Paust, Claus Vestergaard, Susan M. Smith, Karina Friis, Stine Schramm, Flemming Bro, Anna Mygind, Nynne Bech Utoft, James Larkin, Anders Prior
Journal: PLoS Medicine (2024)

Background Potentially inappropriate medication (PIM) is associated with negative health outcomes and can serve as an indicator of treatment quality. Previous studies have identified social inequality in treatment but often relied on narrow understandings of social position or failed to account for mediation by differential disease risk among social groups. Understanding how social position influences PIM exposure is crucial for improving the targeting of treatment quality and addressing health disparities. This study investigates the association between social position and PIM, considering the mediation effect of long-term conditions. Methods and findings This cross-sectional study utilized data from the 2017 Danish National Health Survey, including 177,495 individuals aged 18 or older. Data were linked to national registers on individual-level. PIM was defined from the STOPP/START criteria and social position was assessed through indicators of economic, cultural, and social capital (from Bourdieu’s Capital Theory). We analyzed odds ratios (ORs) and prevalence proportion differences (PPDs) for PIM using logistic regression, negative binomial regression, and generalized structural equation modeling. The models were adjusted for age and sex and analyzed separately for indicators of under- (START) and overtreatment (STOPP). The mediation analysis was conducted to separate direct and indirect effects via long-term conditions. Overall, 14.7% of participants were exposed to one or more PIMs, with START PIMs being more prevalent (12.5%) than STOPP PIMs (3.1%). All variables for social position except health education were associated with PIM in a dose-response pattern. Individuals with lower wealth (OR: 1.85 [95% CI 1.77, 1.94]), lower income (OR: 1.78 [95% CI 1.69, 1.87]), and lower education level (OR: 1.66 [95% CI 1.56, 1.76]) exhibited the strongest associations with PIM. Similar associations were observed for immigrants, people with low social support, and people with limited social networks. The association with PIM remained significant for most variables after accounting for mediation by long-term conditions. The disparities were predominantly related to overtreatment and did not relate to the number of PIMs. The study’s main limitation is the risk of reverse causation due to the complex nature of social position and medical treatment. Conclusions The findings highlight significant social inequalities in PIM exposure, driven by both economic, cultural, and social capital despite a universal healthcare system. Understanding the social determinants of PIM can inform policies to reduce inappropriate medication use and improve healthcare quality and equity.
Integrated modeling of biomarkers, survival and safety in clinical oncology drug development
Authors: Han Liu, Eman I K Ibrahim, Maddalena Centanni, Céline Sarr, Karthik Venkatakrishnan, Lena E Friberg
Journal: Advanced Drug Delivery Reviews (2024)

Model-based approaches, including population pharmacokinetic-pharmacodynamic modeling, have become an essential component in the clinical phases of oncology drug development. Over the past two decades, models have evolved to describe the temporal dynamics of biomarkers and tumor size, treatment-related adverse events, and their links to survival. Integrated models, defined here as models that incorporate at least two pharmacodynamic/ outcome variables, are applied to answer drug development questions through simulations, e.g. to support the exploration of alternative dosing strategies and study designs in subgroups of patients or other tumor indications. It is expected that these pharmacometric approaches will be expanded as regulatory authorities place further emphasis on early and individualized dosage optimization and inclusive patient-focused development strategies. This review provides an overview of integrated models in the literature, examples of the considerations that need to be made when applying these advanced pharmacometric approaches, and an outlook on the expected further expansion of model-informed drug development of anticancer drugs.
Nevus-associated acral melanoma has lower risk of recurrence and mortality than de novo acral melanoma: A multicenter, retrospective analysis of 482 patients
Authors: Yiqun Zhang, Jin Wu, Xin Cai, Kui Jiang, Weizhen Zhang, Hongfeng Zhou, Zhongwu Li, Shijie Lan, Jiwei Liu, Fang Liu, Yan Wang, Hongxue Meng, Zhen Guo, Liang Guo, Xiang Ji, Mei Xiang, Xinxin Yang, Yongqi Li, Lu Feng, Yuhuan Mao, Di Wu
Journal: Journal of the American Academy of Dermatology (2024)

It is unknown whether acral melanomas (AMs) associated with pre-existing nevi have similar risk to other AMs. To compare risk of recurrence and death between AMs associated with pre-existing nevi and de novo AMs. We conducted a multicenter retrospective cohort study involving patients diagnosed with AMs between February 2011 and November 2022. About 164 patients (34.0%) had nevus-associated acral melanoma (NAAM). NAAM has lower risk of recurrence (hazard ratio: 0.69; 95% CI: 0.52-0.91; P = .008) and mortality (hazard ratio: 0.53; 95% CI: 0.37-0.76; P < .001) than de novo acral melanoma (DNAM). The 5-year recurrence-free survival (RFS) was 55.1% for NAAM compared to 42.3% for DNAM. The 5-year overall survival (OS) was 75.1% for NAAM and 63.2% for DNAM. Multivariate analyses identified Breslow thickness, nevus association, and sentinel node status as independent predictors of RFS. Age, Breslow thickness, nevus association, lymphovascular invasion, ulceration, and sentinel node status were independent predictors of OS. The study's limitations included its retrospective design and missing data. Patients with nevus-associated AMs had significantly better RFS and OS compared to those with de novo AMs. Nevus association was an independent prognostic factor for both RFS and OS.
Real-world clinical data-driven modelling on the initiation time of antiviral prophylaxis among pregnant women with chronic hepatitis B infection
Authors: Mingwang Shen, Shihao He, Naijuan Yao, Rui Li, Jing Wang, Wenting Zhong, Jinyan Wang, Huihui Wang, Li Xie, Guihua Zhuang, Lei Zhang, Tianyan Chen
Journal: Journal of Hepatology (2024)
Histological severity, clinical outcomes and impact of antiviral treatment in indeterminate phase of chronic hepatitis B: a systematic review and meta-analysis
Authors: Jimmy Che-To Lai, Grace Lai-Hung Wong, Yee-Kit Tse, Vicki Wing-Ki Hui, Mandy Sze-Man Lai, Henry Lik-Yuen Chan, Vincent Wai-Sun Wong, Terry Cheuk-Fung Yip
Journal: Journal of Hepatology (2024)
An organotypic atlas of human vascular cells
Authors: Sam N. Barnett, Ana-Maria Cujba, Lu Yang, Ana Raquel Maceiras, Shuang Li, Veronika Kedlian, J. Patrick Pett, Krzysztof Polanski, Antonio M. A. Miranda, Chuan Xu, James Cranley, Kazumasa Kanemaru, Michael Lee, Lukas Mach, Shani Perera, Catherine Tudor, Philomeena D. Joseph, Sophie Pritchard, Rebecca Toscano-Rivalta, Kelvin Tuong, Liam Bolt, Robert Petryszak, Martin Prete, Batuhan Cakir, Alik Huseynov, Ioannis Sarropoulos, Rasheda A. Chowdhury, Rasa Elmentaite, Elo Madissoon, Amanda Oliver, Lia Campos, Agnieska Brazovskaja, Tomás Gomes, Barbara Treutlein, Chang N. Kim, Tomasz J. Nowakowski, Kerstin B. Meyer, Anna M. Randi, Michela Noseda, Sarah A. Teichmann
Journal: Nature Medicine (2024)
Luminal breast epithelial cells of BRCA1 or BRCA2 mutation carriers and noncarriers harbor common breast cancer copy number alterations
Authors: Marc J. Williams, Michael U. J. Oliphant, Vinci Au, Cathy Liu, Caroline Baril, Ciara O’Flanagan, Daniel Lai, Sean Beatty, Michael Van Vliet, Jacky CH Yiu, Lauren O’Connor, Walter L. Goh, Alicia Pollaci, Adam C. Weiner, Diljot Grewal, Andrew McPherson, Klarisa Norton, McKenna Moore, Vikas Prabhakar, Shailesh Agarwal, Judy E. Garber, Deborah A. Dillon, Sohrab P. Shah, Joan S. Brugge, Samuel Aparicio
Journal: Nature Genetics (2024)

The prevalence and nature of somatic copy number alterations (CNAs) in breast epithelium and their role in tumor initiation and evolution remain poorly understood. Using single-cell DNA sequencing (49,238 cells) of epithelium from BRCA1 and BRCA2 carriers or wild-type individuals, we identified recurrent CNAs (for example, 1q-gain and 7q, 10q, 16q and 22q-loss) that are present in a rare population of cells across almost all samples (n = 28). In BRCA1/BRCA2 carriers, these occur before loss of heterozygosity (LOH) of wild-type alleles. These CNAs, common in malignant tumors, are enriched in luminal cells but absent in basal myoepithelial cells. Allele-specific analysis of prevalent CNAs reveals that they arose by independent mutational events, consistent with convergent evolution. BRCA1/BRCA2 carriers contained a small percentage of cells with extreme aneuploidy, featuring loss of TP53, BRCA1/BRCA2 LOH and multiple breast cancer-associated CNAs. Our findings suggest that CNAs arising in normal luminal breast epithelium are precursors to clonally expanded tumor genomes. Single-cell DNA sequencing identifies recurrent copy number changes in healthy breast tissue from women with wild-type or germline BRCA1 or BRCA2 mutations.
Consensus prediction of cell type labels in single-cell data with popV
Authors: Can Ergen, Galen Xing, Chenling Xu, Martin Kim, Michael Jayasuriya, Erin McGeever, Angela Oliveira Pisco, Aaron Streets, Nir Yosef
Journal: Nature Genetics (2024)

Cell-type classification is a crucial step in single-cell sequencing analysis. Various methods have been proposed for transferring a cell-type label from an annotated reference atlas to unannotated query datasets. Existing methods for transferring cell-type labels lack proper uncertainty estimation for the resulting annotations, limiting interpretability and usefulness. To address this, we propose popular Vote (popV), an ensemble of prediction models with an ontology-based voting scheme. PopV achieves accurate cell-type labeling and provides uncertainty scores. In multiple case studies, popV confidently annotates the majority of cells while highlighting cell populations that are challenging to annotate by label transfer. This additional step helps to reduce the load of manual inspection, which is often a necessary component of the annotation process, and enables one to focus on the most problematic parts of the annotation, streamlining the overall annotation process. Popular Vote (popV) is a simple, ensemble popular vote approach for cell type annotation in single-cell omic data, flexibly incorporating various methods in an open-source Python framework. Across various challenging input datasets, popV offers consistent, accurate performance.
Spatial multiomic landscape of the human placenta at molecular resolution
Authors: Johain R. Ounadjela, Ke Zhang, Koseki J. Kobayashi-Kirschvink, Kang Jin, Andrew J. C. Russell, Andreas I. Lackner, Claire Callahan, Francesca Viggiani, Kushal K. Dey, Karthik Jagadeesh, Theresa Maxian, Anna-Maria Prandstetter, Naeem Nadaf, Qiyu Gong, Ruth Raichur, Morgan L. Zvezdov, Mingyang Hui, Mattew Simpson, Xinwen Liu, Wei Min, Martin Knöfler, Fei Chen, Sandra Haider, Jian Shu
Journal: Nature Medicine (2024)
A temporal cortex cell atlas highlights gene expression dynamics during human brain maturation
Authors: Christina Steyn, Ruvimbo Mishi, Stephanie Fillmore, Matthijs B. Verhoog, Jessica More, Ursula K. Rohlwink, Roger Melvill, James Butler, Johannes M. N. Enslin, Muazzam Jacobs, Tatjana Sauka-Spengler, Maria Greco, Sadi Quiñones, Chris G. Dulla, Joseph V. Raimondo, Anthony Figaji, Dorit Hockman
Journal: Nature Genetics (2024)

The human brain undergoes protracted postnatal maturation, guided by dynamic changes in gene expression. Most studies exploring these processes have used bulk tissue analyses, which mask cell-type-specific gene expression dynamics. Here, using single-nucleus RNA sequencing on temporal lobe tissue, including samples of African ancestry, we build a joint pediatric and adult atlas of 75 cell subtypes, which we verify with spatial transcriptomics. We explore the differences between pediatric and adult cell subtypes, revealing the genes and pathways that change during brain maturation. Our results highlight excitatory neuron subtypes, including the LTK and FREM subtypes, that show elevated expression of genes associated with cognition and synaptic plasticity in pediatric tissue. The resources we present here improve our understanding of the brain during its development and contribute to global efforts to build an inclusive brain cell map. This Pediatric Cell Atlas study analyzes temporal cortex single-nucleus RNA sequencing datasets from eight diverse donors from 4 to 50 years of age, describing gene expression dynamics over the course of brain maturation.
Spatially resolved single-cell atlas unveils a distinct cellular signature of fatal lung COVID-19 in a Malawian population
Authors: James Nyirenda, Olympia M. Hardy, João Da Silva Filho, Vanessa Herder, Charalampos Attipa, Charles Ndovi, Memory Siwombo, Takondwa Rex Namalima, Leticia Suwedi, Georgios Ilia, Watipenge Nyasulu, Thokozile Ngulube, Deborah Nyirenda, Leonard Mvaya, Joseph Phiri, Dennis Chasweka, Chisomo Eneya, Chikondi Makwinja, Chisomo Phiri, Frank Ziwoya, Abel Tembo, Kingsley Makwangwala, Stanley Khoswe, Peter Banda, Ben Morton, Orla Hilton, Sarah Lawrence, Monique Freire dos Reis, Gisely Cardoso Melo, Marcus Vinicius Guimaraes de Lacerda, Fabio Trindade Maranhão Costa, Wuelton Marcelo Monteiro, Luiz Carlos de Lima Ferreira, Carla Johnson, Dagmara McGuinness, Kondwani Jambo, Michael Haley, Benjamin Kumwenda, Massimo Palmarini, Donna M. Denno, Wieger Voskuijl, Steve Bvuobvuo Kamiza, Kayla G. Barnes, Kevin Couper, Matthias Marti, Thomas D. Otto, Christopher A. Moxon
Journal: Nature Medicine (2024)

Abstract Postmortem single-cell studies have transformed understanding of lower respiratory tract diseases (LRTDs), including coronavirus disease 2019 (COVID-19), but there are minimal data from African settings where HIV, malaria and other environmental exposures may affect disease pathobiology and treatment targets. In this study, we used histology and high-dimensional imaging to characterize fatal lung disease in Malawian adults with ( n = 9) and without ( n = 7) COVID-19, and we generated single-cell transcriptomics data from lung, blood and nasal cells. Data integration with other cohorts showed a conserved COVID-19 histopathological signature, driven by contrasting immune and inflammatory mechanisms: in US, European and Asian cohorts, by type I/III interferon (IFN) responses, particularly in blood-derived monocytes, and in the Malawian cohort, by response to IFN-γ in lung-resident macrophages. HIV status had minimal impact on histology or immunopathology. Our study provides a data resource and highlights the importance of studying the cellular mechanisms of disease in underrepresented populations, indicating shared and distinct targets for treatment.
Multi-Section Magnetic Soft Robot with Multirobot Navigation System for Vasculature Intervention
Authors: Zhengyang Li, Qingsong Xu
Journal: Cyborg and Bionic Systems (2024)

Magnetic soft robots have recently become a promising technology that has been applied to minimally invasive cardiovascular surgery. This paper presents the analytical modeling of a novel multi-section magnetic soft robot (MS-MSR) with multi-curvature bending, which is maneuvered by an associated collaborative multirobot navigation system (CMNS) with magnetic actuation and ultrasound guidance targeted for intravascular intervention. The kinematic and dynamic analysis of the MS-MSR’s telescopic motion is performed using the optimized Cosserat rod model by considering the effect of an external heterogeneous magnetic field, which is generated by a mobile magnetic actuation manipulator to adapt to complex steering scenarios. Meanwhile, an extracorporeal mobile ultrasound navigation manipulator is exploited to track the magnetic soft robot’s distal tip motion to realize a closed-loop control. We also conduct a quadratic programming-based optimization scheme to synchronize the multi-objective task-space motion of CMNS with null-space projection. It allows the formulation of a comprehensive controller with motion priority for multirobot collaboration. Experimental results demonstrate that the proposed magnetic soft robot can be successfully navigated within the multi-bifurcation intravascular environment with a shape modeling error <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:mn>3.62</mml:mn> <mml:mo>±</mml:mo> <mml:msup> <mml:mn>1.28</mml:mn> <mml:mo>∘</mml:mo> </mml:msup> </mml:math> and a tip error of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:mn>1.08</mml:mn> <mml:mo>±</mml:mo> <mml:mn>0.45</mml:mn> <mml:mspace width="0.25em"/> <mml:mi>mm</mml:mi> </mml:math> under the actuation of a CMNS through in vitro ultrasound-guided vasculature interventional tests.
Nemvaleukin alfa, a modified interleukin-2 cytokine, as monotherapy and with pembrolizumab in patients with advanced solid tumors (ARTISTRY-1)
Authors: Ulka N Vaishampayan, Jameel Muzaffar, Ira Winer, Seth D Rosen, Christoper J Hoimes, Aman Chauhan, Anna Spreafico, Karl D Lewis, Debora S Bruno, Olivier Dumas, David F McDermott, James F Strauss, Quincy S Chu, Lucy Gilbert, Arvind Chaudhry, Emiliano Calvo, Rita Dalal, Valentina Boni, Marc S Ernstoff, Vamsidhar Velcheti
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor, preferentially activating CD8 + T cells and natural killer cells, with minimal expansion of regulatory T cells, thereby mitigating the risk of toxicities associated with high-affinity interleukin-2 receptor activation. Clinical outcomes with nemvaleukin are unknown. ARTISTRY-1 investigated the safety, recommended phase 2 dose (RP2D), and antitumor activity of nemvaleukin in patients with advanced solid tumors. Methods This was a three-part, open-label, phase 1/2 study: part A, dose-escalation monotherapy, part B, dose-expansion monotherapy, and part C, combination therapy with pembrolizumab. The study was conducted at 32 sites in 7 countries. Adult patients with advanced solid tumors were enrolled and received intravenous nemvaleukin once daily on days 1–5 (21-day cycle) at 0.1–10 µg/kg/day (part A), or at the RP2D (part B), or with pembrolizumab (part C). Primary endpoints were RP2D selection and dose-limiting toxicities (part A), and overall response rate (ORR) and safety (parts B and C). Results From July 2016 to March 2023, 243 patients were enrolled and treated (46, 74, and 166 in parts A, B, and C, respectively). The maximum tolerated dose was not reached. RP2D was determined as 6 µg/kg/day. ORR with nemvaleukin monotherapy was 10% (7/68; 95% CI 4 to 20), with seven partial responses (melanoma, n=4; renal cell carcinoma, n=3). Robust CD8 + T and natural killer cell expansion, and minimal regulatory T cell expansion were observed following nemvaleukin treatment. ORR with nemvaleukin plus pembrolizumab was 13% (19/144; 95% CI 8 to 20), with 5 complete and 14 partial responses; 6 responses were in PD-(L)1 inhibitor-approved and five in PD-(L)1 inhibitor-unapproved tumor types. Three responses were in patients with platinum-resistant ovarian cancer. The most common grade 3–4 treatment-related adverse events (TRAEs) in parts B and C, respectively, were neutropenia (49%, 21%) and anemia (10%, 11%); 4% of patients in each part discontinued due to TRAEs. Conclusions Nemvaleukin was well tolerated and demonstrated promising antitumor activity across heavily pretreated advanced solid tumors. Phase 2/3 studies of nemvaleukin are ongoing. Trial registration number NCT02799095 .
Biomineralized PEEK cages containing osteoinductive CaP bioceramics promote spinal fusion in goats
Authors: Qiujiang Li, Bowen Hu, Linan Wang, Lei Wang, Cong Feng, Zhuang Zhang, Zhipeng Deng, Yang Xiao, Bo Yuan, Xiangdong Zhu, Xiangfeng Li, Xi Yang, Yueming Song, Xingdong Zhang
Journal: Bioactive Materials (2024)
Noise-aware dynamic image denoising and positron range correction for Rubidium-82 cardiac PET imaging via self-supervision
Authors: Huidong Xie, Liang Guo, Alexandre Velo, Zhao Liu, Qiong Liu, Xueqi Guo, Bo Zhou, Xiongchao Chen, Yu-Jung Tsai, Tianshun Miao, Menghua Xia, Yi-Hwa Liu, Ian S Armstrong, Ge Wang, Richard E Carson, Albert J Sinusas, Chi Liu
Journal: Medical Image Analysis (2024)
War Exposure and DNA Methylation in Syrian Refugee Children and Adolescents
Authors: Demelza Smeeth, Simone Ecker, Olga Chervova, Fiona McEwen, Elie Karam, Stephan Beck, Michael Pluess
Journal: JAMA Psychiatry (2024)

Importance Exposure to war is associated with poor mental health outcomes. Adverse and traumatic experiences can lead to long-lasting DNA methylation changes, potentially mediating the link between adversity and mental health. To date, limited studies have investigated the impact of war on DNA methylation in children or adolescents, hampering our understanding of the biological impact of war exposure. Objective To identify salivary DNA methylation differences associated with war exposure in refugee children and adolescents. Design, Setting, and Participants This cohort study included Syrian refugee children and adolescents, and their primary caregiver were recruited from tented settlements in Lebanon. Data collection was carried out in 2 waves, 1 year apart, from October 2017 to January 2018 and October 2018 to January 2019. Children and their caregiver were interviewed, and children provided saliva samples for DNA extraction. Data analysis was conducted in 2022, 2023, and 2024. Exposure War exposure assessed by interviewing children and their caregiver using the War Events Questionnaire. Main Outcomes and Measures Salivary DNA methylation levels were assayed with the Infinium MethylationEPIC BeadChip (Illumina). Epigenetic aging acceleration was estimated using a set of preexisting epigenetic aging clocks. A literature search was conducted to identify previously reported DNA methylation correlates of childhood trauma. Results The study population included 1507 children and adolescents (mean [SD] age, 11.3 [2.4] years; age range, 6-19 years; 793 female [52.6%]). A total of 1449 children provided saliva samples for DNA extraction in year 1, and 872 children provided samples in year 2. Children who reported war events had a number of differentially methylated sites and regions. Enrichment analyses indicated an enrichment of gene sets associated with transmembrane transport, neurotransmission, and intracellular movement in genes that exhibited differential methylation. Sex-stratified analyses found a number of sex-specific DNA methylation differences associated with war exposure. Only 2 of 258 (0.8%) previously reported trauma-associated DNA methylation sites were associated with war exposure (B = −0.004; 95% CI, −0.005 to −0.003; Bonferroni P = .04 and B = −0.005; 95% CI, −0.006 to −0.004; Bonferroni P = .03). Any war exposure or bombardment was nominally associated with decreased epigenetic age using the Horvath multitissue clock (B = −0.39; 95% CI, −0.63 to −0.14; P = .007 and B = −0.42; 95% CI, −0.73 to −0.11; P = .002). Conclusions and Relevance In this cohort of Syrian refugee children and adolescents, war exposure was associated with a small number of distinct differences in salivary DNA methylation.