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Benzene is a recognized hematotoxin and leukemogen, but its mechanisms of action in humans are still uncertain. To provide insight into these processes, we carried out a cross-sectional study of 44 healthy workers currently exposed to benzene (median 8-hr time-weighted average; 31 ppm), and unexposed controls in Shanghai, China. Here we provide an overview of the study results on peripheral blood cells levels and somatic cell mutation frequency measured by the glycophorin A (GPA) gene loss assay and report on peripheral cytokine levels. All peripheral blood cells levels (i.e., total white blood cells, absolute lymphocyte count, platelets, red blood cells, and hemoglobin) were decreased among exposed workers compared to controls, with the exception of the red blood cell mean corpuscular volume, which was higher among exposed subjects. In contrast, peripheral cytokine levels (interleukin-3, interleukin-6, erythropoietin, granulocyte colony-stimulating factor, tissue necrosis factor-alpha) in a subset of the most highly exposed workers (n = 11) were similar to values in controls (n = 11), suggesting that benzene does not affect these growth factor levels in peripheral blood. The GPA assay measures stem cell or precursor erythroid cell mutations expressed in peripheral red blood cells of MN heterozygous subjects, identifying NN variants, which result from loss of the GPA M allele and duplication of the N allele, and N phi variants, which arise from gene inactivation. The NN (but not N phi) GPA variant cell frequency was elevated in the exposed workers compared with controls (mean +/- SD, 13.9 +/- 8.4 mutants per million cells versus 7.4 +/- 5.2 per million cells, (respectively; p = 0.0002), suggesting that benzene produces gene-duplicating but not gene-inactivating mutations at the GPA locus in bone marrow cells of exposed humans. These findings, combined with ongoing analyses of benzene macromolecular adducts and chromosomal aberrations, will provide an opportunity to comprehensively evaluate a wide range of early biologic effects associated with benzene exposure in humans.

Background: Anemia management in hemodialysis patients poses significant challenges. The present study explored the hypothesis that computerized dosing of intravenous erythropoietin (EPO) would increase the percentage of hemoglobin (Hb) values within the target range and reduce staff time spent on anemia management.Study Design: Retrospective cohort.Setting& Participants: In-center hemodialysis patients who received EPO at Dialysis Clinic Inc dialysis units for at least 3 months between October 1, 2005, and April 30, 2006.Quality Improvement Plan: Computerized decision support (CDS) for EPO dosing is compared with manual physician-directed dosing.Outcomes: Achieved monthly Hb values, quantity of EPO administered, and time spent by dialysis unit personnel.Measurements: Monthly Hb and quantity of EPO administered to 1,118 patients from 18 dialysis units treated using CDS and 7,823 patients from 125 dialysis units treated using manual dosing.Results: There was no difference in the likelihood of a monthly Hb level of 11-12 or 10-12 g/dL using CDS compared with manual dosing. The likelihood of an Hb level > 12 g/dL decreased and the likelihood of an Hb level < 10 g/dL increased using CDS. EPO use was 4% lower using CDS, although the difference was not statistically significant. CDS was associated with a nearly 50% decrease (P < 0.001) in the time spent by dialysis unit staff on anemia management.Limitations: Retrospective and nonrandomized.Conclusion: The number of monthly Hb values in an 11- (and 10-) to 12-g/dL target range and EPO use did not differ with EPO dosing using CDS compared with manual dosing. Staff resources devoted to anemia management decreased significantly using CDS. [ABSTRACT FROM AUTHOR]

BACKGROUND: The optimal hemoglobin target and possible toxicity of epoetin therapy in hemodialysis patients are controversial. Previous studies suggest that African American patients use higher doses of epoetin and have better survival compared with white hemodialysis patients. STUDY DESIGN: Retrospective longitudinal cohort. SETTING & PARTICIPANTS: Epoetin-exposed incident hemodialysis patients (N = 12,733; African Americans, n = 4,801; white, n = 7,386) treated in Dialysis Clinic Inc facilities during 2000 to 2006. PREDICTORS: Hemoglobin, epoetin, iron. OUTCOMES: Mortality, hospitalization. MEASUREMENTS: Proportional hazards models with time-varying covariates. RESULTS: Hemoglobin concentrations less than 10 g/dL in whites and less than 11 g/dL in African Americans were associated with increased mortality and hospitalization versus the referent hemoglobin level of 11 to 11.9 g/dL. Hemoglobin levels of 13 g/dL or greater in whites were associated with decreased noncardiovascular mortality. Six-month cumulative epoetin doses of 20,000 U/wk or greater were associated with increased mortality and hospitalization versus the referent group (8,000 to 12,499 U/wk). Epoetin doses less than 8,000 U/wk were associated with decreased risk. Higher epoetin doses were associated with increased mortality at hemoglobin concentrations of 10 to 12.9 g/dL and with increased hospitalization at all hemoglobin concentrations of 10 g/dL or greater. Higher epoetin doses were associated with increased mortality and hospitalization within each tertile of serum albumin concentration. These patterns did not differ by race. LIMITATIONS: Treatment-by-indication bias and unidentified confounders cannot be excluded. Small sample sizes in the highest and lowest hemoglobin strata decrease statistical power. CONCLUSIONS: Relationships between hemoglobin concentration and mortality differed between African Americans and whites. Additionally, the relationship of lower mortality with greater achieved hemoglobin concentration seen in white patients was observed for all-cause, but not cardiovascular, mortality. A higher cumulative epoetin dose was associated with worse outcomes, even in patients with albumin levels greater than 4 g/dL. There were no statistically significant interactions between race and epoetin dose. Further studies are needed to confirm and to define the mechanism of these findings. Copyright © 2009 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Aortic arch anomalies may have major clinical significance after birth. Prenatal diagnosis of an aortic arch anomaly creating a vascular ring was detected by two-dimensional ulatrasound and is presented in this case report. [ABSTRACT FROM AUTHOR]

Background: Health literacy is important in chronic conditions, such as kidney transplantation. Understanding patients' health literacy profiles can assist tailoring follow-up and educational programmes to the health literacy needs of vulnerable kidney transplant recipients. This approach enabled us to cluster patients according to their profiles of challenges and strengths in different health literacy domains., Objectives: This study aimed to identify different health literacy profiles within kidney transplant recipients and what characterized the different profiles., Design: Cross-sectional study., Participants: One hundred ninety-five kidney transplanted recipients were included., Measurements: We used the self-reported Health Literacy Questionnaire and analyzed using Ward's method (hierarchical cluster approach). We also collected background characteristics and clinical variables, including psychological distress (Hopkins Symptoms Checklist) and perceived health status (visual analogue scale, EuroQol-5D)., Results: The analysis revealed four clusters with substantial differences in health literacy profiles. One cluster's patients had the most challenges in all health literacy domains constituting 24% of the sample. Compared to the other three clusters, this cluster was associated with shorter duration of kidney disease, higher number of patients in dialysis before transplantation, higher percentage of male patients, lower number of kidneys from living donors, higher number of patients not working and higher representation of psychological distress. All four clusters reported the most challenges in the same domain: the ability to critically appraise health information., Conclusion: In kidney transplant recipients, profiling clusters with the Health Literacy Questionnaire and Ward's method aids in identifying health literacy needs in vulnerable groups, enabling transplant professionals to offer tailored health literacy support., (© 2024 The Author(s). Journal of Renal Care published by John Wiley & Sons Ltd on behalf of European Dialysis & Transplant Nurses Association/European Renal Care Association.)

The human vascular system, comprising endothelial cells (ECs) and mural cells, covers a vast surface area in the body, providing a critical interface between blood and tissue environments. Functional differences exist across specific vascular beds, but their molecular determinants across tissues remain largely unknown. In this study, we integrated single-cell transcriptomics data from 19 human organs and tissues and defined 42 vascular cell states from approximately 67,000 cells (62 donors), including angiotypic transitional signatures along the arterial endothelial axis from large to small caliber vessels. We also characterized organotypic populations, including splenic littoral and blood-brain barrier ECs, thus clarifying the molecular profiles of these important cell states. Interrogating endothelial-mural cell molecular crosstalk revealed angiotypic and organotypic communication pathways related to Notch, Wnt, retinoic acid, prostaglandin and cell adhesion signaling. Transcription factor network analysis revealed differential regulation of downstream target genes in tissue-specific modules, such as those of FOXF1 across multiple lung vascular subpopulations. Additionally, we make mechanistic inferences of vascular drug targets within different vascular beds. This open-access resource enhances our understanding of angiodiversity and organotypic molecular signatures in human vascular cells, and has therapeutic implications for vascular diseases across tissues., Competing Interests: Competing interests: In the past 3 years, S.A.T. has consulted for or been a member of scientific advisory boards (SABs) at Qiagen, OMass Therapeutics, Xaira Therapeutics and ForeSite Labs, and a non-executive director of 10x Genomics. She is a co-founder and equity holder of TransitionBio and Ensocell, and a part-time employee at GSK. R.E. is a co-founder and equity holder in Ensocell. The other authors declare no competing interests., (© 2024. The Author(s).)

Background: In organ donation from deceased donors, the interaction between the donor's relatives and intensive care personnel is an important factor. The organ donation (OD) process is complex, and patients' relatives play a vital role. Intensive care professionals need knowledge about how relatives perceive and experience the process to create a caring environment and support them throughout. Therefore, this collaborative project aims to explore both relatives' and intensive care personnel's perspectives of care in deceased organ donation in Scandinavia., Objective: This study aims to (1) investigate donor relatives' satisfaction and ICU personnel's perception of their own professional competence and (2) explore donor relatives' and ICU personnel's experiences in the OD process to design for care and support in OD., Methods: This protocol outlines a Scandinavian (Norway, Sweden, and Denmark) project, including 4 work packages. Work package 1 started in 2023 with the translation and validation of the Family Satisfaction in the Intensive Care Unit questionnaire into a Danish version and the translation of the Professional Competence in Organ Donation Questionnaire into a Swedish and Danish version. A cross-sectional survey measuring Scandinavian relatives' perception of support in and satisfaction with the organ donation process and a cross-sectional survey measuring Scandinavian intensive care personnel's competence in organ donation are the foundation for work package 2 (2024). The data from both surveys will be analyzed using descriptive and comparative analysis. The results will inform the interview guides in qualitative studies (work packages 3 and 4). Participants in the quantitative study will be invited to participate in in-depth interviews. In work package 3, in-depth interviews will be conducted to illuminate relatives' experiences in the organ donation process. The interviews will be analyzed using thematic analysis, according to Braun and Clarke. In work package 4 (2025-2026), 1 qualitative design study will be conducted to illuminate ICU personnel's experiences. Furthermore, the results from work packages 2 and 3 will inform the development of specific programs for care, support, and communication in the organ donation process., Results: The project was funded by the Norwegian Organ Donor Foundation in 2022 and Scandiatransplant in 2023. The Norwegian Nurses Organisation supports the project by funding a PhD student. The PhD student was employed by the University in Agder in May 2024., Conclusions: This project will provide new knowledge that will assist us in designing and establishing programs for care, support, and donor relatives' involvement in OD processes., International Registered Report Identifier (irrid): PRR1-10.2196/55643., (©Kathe B Meyer, Gudrun Rohde, Gro Frivold. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.11.2024.)

The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases 1,2 has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease 3 . Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated quality control approach (scAutoQC), leading to a healthy reference atlas with approximately 1.1 million cells and 136 fine-grained cell states. We anchor 12 gastrointestinal disease datasets spanning gastrointestinal cancers, coeliac disease, ulcerative colitis and Crohn's disease to this reference. Utilizing this 1.6 million cell resource (gutcellatlas.org), we discover epithelial cell metaplasia originating from stem cells in intestinal inflammatory diseases with transcriptional similarity to cells found in pyloric and Brunner's glands. Although previously linked to mucosal healing 4 , we now implicate pyloric gland metaplastic cells in inflammation through recruitment of immune cells including T cells and neutrophils. Overall, we describe inflammation-induced changes in stem cells that alter mucosal tissue architecture and promote further inflammation, a concept applicable to other tissues and diseases., Competing Interests: Competing interests: S.A.T. is a scientific advisory board member of ForeSite Labs, OMass Therapeutics, a co-founder and equity holder of TransitionBio and EnsoCell Therapeutics, a non-executive director of 10x Genomics and a part-time employee of GlaxoSmithKline. R.E. is an equity holder in EnsoCell. P.K. has consulted for AstraZeneca, UCB, Biomunex and Infinitopes. N.M.P reports consulting fees from Infinitopes. J.S.-R. reports funding from GSK, Pfizer and Sanofi and fees/honoraria from Travere Therapeutics, Stadapharm, Astex, Owkin, Pfizer, Moderna and Grunenthal. A.S. is the recipient of research grants from Roche-Genentech, Abbvie, GSK, Scipher Medicine, Pfizer, Alimentiv, Boehringer Ingelheim and Agomab and has received consulting fees from Genentech, GSK, Pfizer, HotSpot Therapeutics, Alimentiv, Agomab, Goodgut and Orikine. R.E. and S.A.T are inventors on the patent GB2412853.0 filed in the UK, some components of which are related to this work. All other authors declare no competing interests., (© 2024. The Author(s).)

Human embryonic bone and joint formation is determined by coordinated differentiation of progenitors in the nascent skeleton. The cell states, epigenetic processes and key regulatory factors that underlie lineage commitment of these cells remain elusive. Here we applied paired transcriptional and epigenetic profiling of approximately 336,000 nucleus droplets and spatial transcriptomics to establish a multi-omic atlas of human embryonic joint and cranium development between 5 and 11 weeks after conception. Using combined modelling of transcriptional and epigenetic data, we characterized regionally distinct limb and cranial osteoprogenitor trajectories across the embryonic skeleton and further described regulatory networks that govern intramembranous and endochondral ossification. Spatial localization of cell clusters in our in situ sequencing data using a new tool, ISS-Patcher, revealed mechanisms of progenitor zonation during bone and joint formation. Through trajectory analysis, we predicted potential non-canonical cellular origins for human chondrocytes from Schwann cells. We also introduce SNP2Cell, a tool to link cell-type-specific regulatory networks to polygenic traits such as osteoarthritis. Using osteolineage trajectories characterized here, we simulated in silico perturbations of genes that cause monogenic craniosynostosis and implicate potential cell states and disease mechanisms. This work forms a detailed and dynamic regulatory atlas of bone and cartilage maturation and advances our fundamental understanding of cell-fate determination in human skeletal development., Competing Interests: Competing interests: C.D.B. is a founder of Mestag Therapeutics. S.A.T. is a scientific advisory board member of ForeSite Labs, OMass Therapeutics, Qiagen, a co-founder and equity holder of TransitionBio and EnsoCell Therapeutics, a non-executive director of 10x Genomics and a part-time employee of GlaxoSmithKline. Sarah also holds equity in TransitionBio and options for equity in Element Biosciences, where she is a former SAB member.  All other authors declare no competing interests., (© 2024. The Author(s).)

Over the last decade, single-cell genomics has revealed remarkable heterogeneity and plasticity of cell types in the lungs and airways. The challenge now is to understand how these cell types interact in three-dimensional space to perform lung functions, facilitating airflow and gas exchange while simultaneously providing barrier function to avoid infection. An explosion in novel spatially resolved gene expression technologies, coupled with computational tools that harness machine learning and deep learning, now promise to address this challenge. Here, we review the most commonly used spatial analysis workflows, highlighting their advantages and limitations, and outline recent developments in machine learning and artificial intelligence that will augment how we interpret spatial data. Together these technologies have the potential to transform our understanding of the respiratory system in health and disease, and we showcase studies in lung development, COVID-19, lung cancer, and fibrosis where spatially resolved transcriptomics is already providing novel insights.

Single-cell data analysis can infer dynamic changes in cell populations, for example across time, space or in response to perturbation, thus deriving pseudotime trajectories. Current approaches comparing trajectories often use dynamic programming but are limited by assumptions such as the existence of a definitive match. Here we describe Genes2Genes, a Bayesian information-theoretic dynamic programming framework for aligning single-cell trajectories. It is able to capture sequential matches and mismatches of individual genes between a reference and query trajectory, highlighting distinct clusters of alignment patterns. Across both real world and simulated datasets, it accurately inferred alignments and demonstrated its utility in disease cell-state trajectory analysis. In a proof-of-concept application, Genes2Genes revealed that T cells differentiated in vitro match an immature in vivo state while lacking expression of genes associated with TNF signaling. This demonstrates that precise trajectory alignment can pinpoint divergence from the in vivo system, thus guiding the optimization of in vitro culture conditions., (© 2024. The Author(s).)

Here we propose "molecular connectomics" to link molecular and morphological cell features in three dimensions across scales, using machine learning and artificial intelligence to reveal emergent properties of complex biological systems., Competing Interests: In the past 3 years, S.A.T. has received remuneration for scientific advisory board membership from Sanofi, GlaxoSmithKline, Foresite Labs and Qiagen. S.A.T. is a co-founder and holds equity in Transition Bio and Ensocell. From 8 January 2024, S.A.T. is a part-time employee of GlaxoSmithKline., (Copyright: © 2024 Megas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited 1 . Here in our SARS-CoV-2 human challenge study, we used single-cell multi-omics profiling of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Our analyses revealed rapid changes in cell-type proportions and dozens of highly dynamic cellular response states in epithelial and immune cells associated with specific time points and infection status. We observed that the interferon response in blood preceded the nasopharyngeal response. Moreover, nasopharyngeal immune infiltration occurred early in samples from individuals with only transient infection and later in samples from individuals with sustained infection. High expression of HLA-DQA2 before inoculation was associated with preventing sustained infection. Ciliated cells showed multiple immune responses and were most permissive for viral replication, whereas nasopharyngeal T cells and macrophages were infected non-productively. We resolved 54 T cell states, including acutely activated T cells that clonally expanded while carrying convergent SARS-CoV-2 motifs. Our new computational pipeline Cell2TCR identifies activated antigen-responding T cells based on a gene expression signature and clusters these into clonotype groups and motifs. Overall, our detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection., (© 2024. The Author(s).)

Single-cell assay for transposase-accessible chromatin by sequencing (scATAC-seq) has emerged as a powerful tool for dissecting regulatory landscapes and cellular heterogeneity. However, an exploration of systemic biases among scATAC-seq technologies has remained absent. In this study, we benchmark the performance of eight scATAC-seq methods across 47 experiments using human peripheral blood mononuclear cells (PBMCs) as a reference sample and develop PUMATAC, a universal preprocessing pipeline, to handle the various sequencing data formats. Our analyses reveal significant differences in sequencing library complexity and tagmentation specificity, which impact cell-type annotation, genotype demultiplexing, peak calling, differential region accessibility and transcription factor motif enrichment. Our findings underscore the importance of sample extraction, method selection, data processing and total cost of experiments, offering valuable guidance for future research. Finally, our data and analysis pipeline encompasses 169,000 PBMC scATAC-seq profiles and a best practices code repository for scATAC-seq data analysis, which are freely available to extend this benchmarking effort to future protocols., (© 2023. The Author(s).)

Objective: This study aimed to evaluate the effect of a new health communication intervention focusing on knowledge management skills on health literacy and medication adherence during the first year following kidney transplantation., Methods: We randomized 195 patients during 2020-2021, to either intervention- or control group. Questionnaires were completed at baseline and at 12 months post-transplantation with a 12-month response rate of 84%. Health literacy was measured by the multidimensional Health Literacy Questionnaire (HLQ) instrument. Medication adherence was measured by the self-reported questionnaire (BAASIS©)., Results: Results showed that the intervention group had a significant increase in 2 HLQ domains compared to the control group capturing the "ability to appraise health information" Domain 5, (p-value = 0.002) and the "ability to navigate the healthcare system" Domain 7, (p-value <0.04). The effect sizes of SRM were 0.49 (Domain 5) and 0.33 (Domain 7). Medication adherence was comparable in the groups at any measure points., Conclusions: This study contributes to important knowledge about how a health communication intervention focusing on knowledge translation using motivational interviewing techniques positively strengthens health literacy in kidney transplant recipients., Practical Implications: Current patient education practice may benefit from focusing on knowledge translation in combination with motivational interview technique., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate health literacy (HL) and digital health literacy (eHL) among patients hospitalised in surgical and medical wards using a cluster analysis approach., Design: Cross-sectional study using Ward's hierarchical clustering method to measure cluster adequacy by evaluating distances between cluster centroids (a measure of cohesion). Different distances produced different cluster solutions., Setting and Participants: The study was conducted at a Norwegian university hospital. A total of 260 hospitalised patients were enrolled between 24 May and 6 June 2021., Data Collection: All data were collected by self-reported questionnaires. Data on HL and eHL were collected by the Health Literacy Questionnaire (HLQ) and the eHealth Literacy Questionnaire (eHLQ). We also collected data on background characteristics, health status and patient diagnosis., Results: We found six HLQ clusters to be the best solution of the sample, identifying substantial diversity in HL strengths and challenges. Two clusters, representing 21% of the total sample, reported the lowest HLQ scores in eight of nine HLQ domains. Compared with the other clusters, these two contained the highest number of women, as well as the patients with the highest mean age, a low level of education and the lowest proportion of being employed. One of these clusters also represented patients with the lowest health status score. We identified six eHL clusters, two of which represented 31% of the total sample with the lowest eHLQ scores in five of seven eHLQ domains, with background characteristics comparable to patients in the low-scoring HLQ clusters., Conclusions: This study provides new, nuanced knowledge about HL and eHL profiles in different clusters of patients hospitalised in surgical and medical wards. With such data, healthcare professionals can take into account vulnerable patients' HL needs and tailor information and communication accordingly., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Multisystem inflammatory syndrome in children is a post-infectious presentation SARS-CoV-2 associated with expansion of the T cell receptor Vβ21.3+ T-cell subgroup. Here we apply muti-single cell omics to compare the inflammatory process in children with acute respiratory COVID-19 and those presenting with non SARS-CoV-2 infections in children. Here we show that in Multi-Inflammatory Syndrome in Children (MIS-C), the natural killer cell and monocyte population demonstrate heightened CD95 (Fas) and Interleuking 18 receptor expression. Additionally, TCR Vβ21.3+ CD4+ T-cells exhibit skewed differentiation towards T helper 1, 17 and regulatory T cells, with increased expression of the co-stimulation receptors ICOS, CD28 and interleukin 18 receptor. We observe no functional evidence for NLRP3 inflammasome pathway overactivation, though MIS-C monocytes show elevated active caspase 8. This, coupled with raised IL18 mRNA expression in CD16- NK cells on single cell RNA sequencing analysis, suggests interleukin 18 and CD95 signalling may trigger activation of TCR Vβ21.3+ T-cells in MIS-C, driven by increased IL-18 production from activated monocytes and CD16- Natural Killer cells., (© 2024. The Author(s).)

Children infected with SARS-CoV-2 rarely progress to respiratory failure. However, the risk of mortality in infected people over 85 years of age remains high. Here we investigate differences in the cellular landscape and function of paediatric (<12 years), adult (30-50 years) and older adult (>70 years) ex vivo cultured nasal epithelial cells in response to infection with SARS-CoV-2. We show that cell tropism of SARS-CoV-2, and expression of ACE2 and TMPRSS2 in nasal epithelial cell subtypes, differ between age groups. While ciliated cells are viral replication centres across all age groups, a distinct goblet inflammatory subtype emerges in infected paediatric cultures and shows high expression of interferon-stimulated genes and incomplete viral replication. In contrast, older adult cultures infected with SARS-CoV-2 show a proportional increase in basaloid-like cells, which facilitate viral spread and are associated with altered epithelial repair pathways. We confirm age-specific induction of these cell types by integrating data from in vivo COVID-19 studies and validate that our in vitro model recapitulates early epithelial responses to SARS-CoV-2 infection., (© 2024. The Author(s).)

Skeletal muscle aging is a key contributor to age-related frailty and sarcopenia with substantial implications for global health. Here we profiled 90,902 single cells and 92,259 single nuclei from 17 donors to map the aging process in the adult human intercostal muscle, identifying cellular changes in each muscle compartment. We found that distinct subsets of muscle stem cells exhibit decreased ribosome biogenesis genes and increased CCL2 expression, causing different aging phenotypes. Our atlas also highlights an expansion of nuclei associated with the neuromuscular junction, which may reflect re-innervation, and outlines how the loss of fast-twitch myofibers is mitigated through regeneration and upregulation of fast-type markers in slow-twitch myofibers with age. Furthermore, we document the function of aging muscle microenvironment in immune cell attraction. Overall, we present a comprehensive human skeletal muscle aging resource ( https://www.muscleageingcellatlas.org/ ) together with an in-house mouse muscle atlas to study common features of muscle aging across species., (© 2024. The Author(s).)

Background: Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to modifiable lifestyle risk in the form of tobacco smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, 40% of which occur more than 15 years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk remain unclear. We thus set out to examine whether risk stratification in the clinic and in the general population can be improved upon by the addition of genetic data and to explore the mechanisms of the persisting risk in former smokers., Methods: We analysed transcriptomic data from accessible airway tissues of 487 subjects, including healthy volunteers and clinic patients of different smoking statuses. We developed a computational model to assess smoking-associated gene expression changes and their reversibility after smoking is stopped, comparing healthy subjects to clinic patients with and without lung cancer., Results: We find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune- and interferon-related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier., Conclusions: Our results provide initial evidence for germline-mediated personalized smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality., (© 2024. The Author(s).)

Background: Clinical practice guidelines emphasize shared decision-making for kidney replacement treatment, yet little is known about the influence of cultural differences on that process. We undertook a retrospective chart review to explore the process and timing of dialysis decision making and initiation in Chinese American patients to provide quality kidney care for this population., Design: Participants received outpatient care at Tufts Medical Center and dialysis at Dialysis Clinic, Inc. Boston or Somerville, MA from 2001-2021. Clinic chart review sourced demographic, clinical, and end-of-life care information from 180 participants (82 Chinese American, 98 other) from stage 4 chronic kidney disease (CKD) and dialysis initiation., Results: Chinese American participants were older (mean 70 vs. 59, p < 0.0001), less likely to speak English (12% vs. 87%, p < 0.0001), and used interpreter services more (80% vs. 11%, p < 0.0001). Chinese American participants had more visits (median 14 vs. 10, p = 0.005); were more often accompanied by family members (75% vs. 40%, p < 0.001); and had significantly lower rates of healthcare proxy documentation (35% vs. 55%, p = 0.006). There was no statistical difference in months between first CKD 4 visit and first dialysis. Both groups started dialysis at the same average eGFR and with similar rates of permanent dialysis access. Chinese American participants had significantly lower serum albumin at dialysis initiation (mean 3.3 g/dL vs 3.7 g/dL, p = 0.0003). Documentation reflected a low number of conversations about non-dialytic care, end-of-life planning, or palliative care in both groups across all visits., Conclusion: The time between CKD 4 and dialysis initiation was the same in both groups, suggesting a similar overall outcome of care. Chart documentation suggests that Chinese American participants had a significantly higher number of visits with nephrologists where discussion about dialysis was noted and were more likely to have a family member present at the visit. Fewer Chinese American participants completed healthcare proxies. Among all study participants, healthcare proxy, code status, and palliative care discussions were reported less frequently than expected. These findings highlight opportunities for collaboration between palliative care clinicians and nephrologists., (© 2024. The Author(s).)

Assessment of single-cell gene expression (single-cell RNA sequencing) and adaptive immune receptor (AIR) sequencing (scVDJ-seq) has been invaluable in studying lymphocyte biology. Here we introduce Dandelion, a computational pipeline for scVDJ-seq analysis. It enables the application of standard V(D)J analysis workflows to single-cell datasets, delivering improved V(D)J contig annotation and the identification of nonproductive and partially spliced contigs. We devised a strategy to create an AIR feature space that can be used for both differential V(D)J usage analysis and pseudotime trajectory inference. The application of Dandelion improved the alignment of human thymic development trajectories of double-positive T cells to mature single-positive CD4/CD8 T cells, generating predictions of factors regulating lineage commitment. Dandelion analysis of other cell compartments provided insights into the origins of human B1 cells and ILC/NK cell development, illustrating the power of our approach. Dandelion is available at https://www.github.com/zktuong/dandelion ., (© 2023. The Author(s).)

Harmonizing cell types across the single-cell community and assembling them into a common framework is central to building a standardized Human Cell Atlas. Here, we present CellHint, a predictive clustering tree-based tool to resolve cell-type differences in annotation resolution and technical biases across datasets. CellHint accurately quantifies cell-cell transcriptomic similarities and places cell types into a relationship graph that hierarchically defines shared and unique cell subtypes. Application to multiple immune datasets recapitulates expert-curated annotations. CellHint also reveals underexplored relationships between healthy and diseased lung cell states in eight diseases. Furthermore, we present a workflow for fast cross-dataset integration guided by harmonized cell types and cell hierarchy, which uncovers underappreciated cell types in adult human hippocampus. Finally, we apply CellHint to 12 tissues from 38 datasets, providing a deeply curated cross-tissue database with ∼3.7 million cells and various machine learning models for automatic cell annotation across human tissues., Competing Interests: Declaration of interests S.A.T. is a remunerated member of the Scientific Advisory Board, Foresite Labs, and Qiagen. She is co-founder and equity holder of Transition Bio., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a major site of mucosal immunity after birth. An unanswered question is whether tissue-resident immune cells play a role in shaping the tissue as it develops in utero. Here, we profiled human embryonic and fetal lung immune cells using scRNA-seq, smFISH, and immunohistochemistry. At the embryonic stage, we observed an early wave of innate immune cells, including innate lymphoid cells, natural killer cells, myeloid cells, and lineage progenitors. By the canalicular stage, we detected naive T lymphocytes expressing high levels of cytotoxicity genes and the presence of mature B lymphocytes, including B-1 cells. Our analysis suggests that fetal lungs provide a niche for full B cell maturation. Given the presence and diversity of immune cells during development, we also investigated their possible effect on epithelial maturation. We found that IL-1β drives epithelial progenitor exit from self-renewal and differentiation to basal cells in vitro. In vivo, IL-1β-producing myeloid cells were found throughout the lung and adjacent to epithelial tips, suggesting that immune cells may direct human lung epithelial development.