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Abstract Background The Manhattan Lupus Surveillance Program (MLSP), a population-based retrospective registry of patients with systemic lupus erythematosus (SLE), was used to investigate the prevalence of cardiovascular disease events (CVE) and compare rates among sex, age and race/ethnicity to population-based controls. Methods Patients with prevalent SLE in 2007 aged ≥ 20 years in the MLSP were included. CVE required documentation of a myocardial infarction or cerebrovascular accident. We calculated crude risk ratios and adjusted risk ratios (ARR) controlling for sex, age group, race and ethnicity, and years since diagnosis. Data from the 2009–2010 National Health and Nutrition Examination Survey (NHANES) and the 2013–2014 NYC Health and Nutrition Examination Survey (NYC HANES) were used to calculate expected CVE prevalence by multiplying NHANES and NYC HANES estimates by strata-specific counts of patients with SLE. Crude prevalence ratios (PRs) using national and NYC estimates and age standardized prevalence ratios (ASPRs) using national estimates were calculated. Results CVE occurred in 13.9% of 1,285 MLSP patients with SLE, and risk was increased among men (ARR:1.7, 95%CI:1.2–2.5) and older adults (age > 60 ARR:2.5, 95%CI:1.7–3.8). Compared with non-Hispanic Asian patients, CVE risk was elevated among Hispanic/Latino (ARR:3.1, 95%CI:1.4-7.0) and non-Hispanic Black (ARR:3.5, 95%CI1.6-7.9) patients as well as those identified as non-Hispanic and in another or multiple racial groups (ARR:4.2, 95%CI:1.1–15.8). Overall, CVE prevalence was higher among patients with SLE than nationally (ASPR:3.1, 95%CI:3.0-3.1) but did not differ by sex. Compared with national race and ethnicity-stratified estimates, CVE among patients with SLE was highest among Hispanics/Latinos (ASPR:4.3, 95%CI:4.2–4.4). CVE was also elevated among SLE registry patients compared with all NYC residents. Comparisons with age-stratified national estimates revealed PRs of 6.4 (95%CI:6.2–6.5) among patients aged 20–49 years and 2.2 (95%CI:2.1–2.2) among those ≥ 50 years. Male (11.3, 95%CI:10.5–12.1), Hispanic/Latino (10.9, 95%CI:10.5–11.4) and non-Hispanic Black (6.2, 95%CI:6.0-6.4) SLE patients aged 20–49 had the highest CVE prevalence ratios. Conclusions These population-based estimates of CVE in a diverse registry of patients with SLE revealed increased rates among younger male, Hispanic/Latino and non-Hispanic Black patients. These findings reinforce the need to appropriately screen for CVD among all SLE patients but particularly among these high-risk patients.

Abstract Medulloblastoma, the most common malignant pediatric brain tumor, is classified into four main molecular subgroups, but group 3 and group 4 tumors are difficult to subclassify and have a poor prognosis. Rapid point-of-care diagnostic and prognostic assays are needed to improve medulloblastoma risk stratification and management. N6-methyladenosine (m6A) is a common RNA modification and long non-coding RNAs (lncRNAs) play a central role in tumor progression, but their impact on gene expression and associated clinical outcomes in medulloblastoma are unknown. Here we analyzed 469 medulloblastoma tumor transcriptomes to identify lncRNAs co-expressed with m6A regulators. Using LASSO-Cox analysis, we identified a five-gene m6A-associated lncRNA signature (M6LSig) significantly associated with overall survival, which was combined in a prognostic clinical nomogram. Using expression of the 67 m6A-associated lncRNAs, a subgroup classification model was generated using the XGBoost machine learning algorithm, which had a classification accuracy > 90%, including for group 3 and 4 samples. All M6LSig genes were significantly correlated with at least one immune cell type abundance in the tumor microenvironment, and the risk score was positively correlated with CD4+ naïve T cell abundance and negatively correlated with follicular helper T cells and eosinophils. Knockdown of key m6A writer genes METTL3 and METTL14 in a group 3 medulloblastoma cell line (D425-Med) decreased cell proliferation and upregulated many M6LSig genes identified in our in silico analysis, suggesting that the signature genes are functional in medulloblastoma. This study highlights a crucial role for m6A-dependent lncRNAs in medulloblastoma prognosis and immune responses and provides the foundation for practical clinical tools that can be rapidly deployed in clinical settings.

Abstract Background Lymnaeid snails of the genus Austropeplea are an important vector of the liver fluke (Fasciola hepatica), contributing to livestock production losses in Australia and New Zealand. However, the species status within Austropeplea is ambiguous due to heavy reliance on morphological analysis and a relative lack of genetic data. This study aimed to characterise the mitochondrial genome of A. cf. brazieri, an intermediate host of liver fluke in eastern Victoria. Methods The mitochondrial genome was assembled and annotated from a combination of second- and third-generation sequencing data. For comparative purposes, we performed phylogenetic analyses of the concatenated nucleotide sequences of the mitochondrial protein-coding genes, cytochrome c oxidase subunit 1 and 16S genes. Results The assembled mt genome was 13,757 base pairs and comprised 37 genes, including 13 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes. The mt genome length, gene order and nucleotide compositions were similar to related species of lymnaeids. Phylogenetic analyses of the mt nucleotide sequences placed A. cf. brazieri within the same clade as Orientogalba ollula with strong statistical supports. Phylogenies of the cox1 and 16S mt sequences were constructed due to the wide availability of these sequences representing the lymnaeid taxa. As expected in both these phylogenies, A. cf. brazieri clustered with other Austropeplea sequences, but the nodal supports were low. Conclusions The representative mt genome of A. cf. brazieri should provide a useful resource for future molecular, epidemiology and parasitological studies of this socio-economically important lymnaeid species. Graphical abstract

Abstract Background A key step in nervous system development involves the coordinated control of neural progenitor specification and positioning. A long-standing model for the vertebrate CNS postulates that transient anatomical compartments – known as neuromeres – function to position neural progenitors along the embryonic anteroposterior neuraxis. Such neuromeres are apparent in the embryonic hindbrain – that contains six rhombomeres with morphologically apparent boundaries – but other neuromeres lack clear morphological boundaries and have instead been defined by different criteria, such as differences in gene expression patterns and the outcomes of transplantation experiments. Accordingly, the caudal hindbrain (CHB) posterior to rhombomere (r) 6 has been variably proposed to contain from two to five ‘pseudo-rhombomeres’, but the lack of comprehensive molecular data has precluded a detailed definition of such structures. Methods We used single-cell Multiome analysis, which allows simultaneous characterization of gene expression and chromatin state of individual cell nuclei, to identify and characterize CHB progenitors in the developing zebrafish CNS. Results We identified CHB progenitors as a transcriptionally distinct population, that also possesses a unique profile of accessible transcription factor binding motifs, relative to both r6 and the spinal cord. This CHB population can be subdivided along its dorsoventral axis based on molecular characteristics, but we do not find any molecular evidence that it contains multiple pseudo-rhombomeres. We further observe that the CHB is closely related to r6 at the earliest embryonic stages, but becomes more divergent over time, and that it is defined by a unique gene regulatory network. Conclusions We conclude that the early CHB represents a single neuromere compartment that cannot be molecularly subdivided into pseudo-rhombomeres and that it may share an embryonic origin with r6.

Abstract Background Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an inhibitory cell surface protein that functions through homophilic and heterophilic ligand binding. Its expression on immune cells in human tumors is poorly understood. Methods An antibody that distinguishes human CEACAM1 from other highly related CEACAM family members was labeled with 159Tb and inserted into a panel of antibodies that included specificity for programmed cell death protein 1 (PD1) and PD-L1, which are targets of immunotherapy, to gain a data-driven immune cell atlas using cytometry by time-of-flight (CyTOF). A detailed inventory of CEACAM1, PD1, and PD-L1 expression on immune cells in metastatic lesions to lymph node or soft tissues and peripheral blood samples from patients with treatment-naive and -resistant melanoma as well as peripheral blood samples from healthy controls was performed. Results CEACAM1 is absent or at low levels on healthy circulating immune cells but is increased on immune cells in peripheral blood and tumors of melanoma patients. The majority of circulating PD1-positive NK cells, innate T cells, B cells, monocytic cells, dendritic cells, and CD4+ T cells in the peripheral circulation of treatment-resistant disease co-express CEACAM1 and are demonstrable as discrete populations. CEACAM1 is present on distinct types of cells that are unique to the tumor microenvironment and exhibit expression levels that are highest in treatment resistance; this includes tumor-infiltrating CD8+ T cells. Conclusions To the best of our knowledge, this work represents the first comprehensive atlas of CEACAM1 expression on immune cells in a human tumor and reveals an important correlation with treatment-resistant disease. These studies suggest that agents targeting CEACAM1 may represent appropriate partners for PD1-related pathway therapies.

Abstract Organ on Chip platforms hold significant promise as alternatives to animal models or traditional cell cultures, both of which poorly recapitulate human pathophysiology and human level responses. Within the last 15 years, we have witnessed seminal scientific developments from academic laboratories, a flurry of startups and investments, and a genuine interest from pharmaceutical industry as well as regulatory authorities to translate these platforms. This Perspective identifies several fundamental design and process features that may act as roadblocks that prevent widespread dissemination and deployment of these systems, and provides a roadmap to help position this technology in mainstream drug discovery.

IntroductionCOVID-19 created a global need for healthcare worker (HCW) training. Initially, mass trainings focused on public health workers and physicians working in intensive care units. However, in resource-constrained settings, nurses and general practitioners provide most patient care, typically lacking the training and equipment to manage critically ill patients. We developed a massive open online course (MOOC) for HCWs in resource-constrained settings aimed at training bedside providers caring for COVID-19 patients. We describe the development, implementation and analysis of this MOOC.MethodsFrom May through June 2020, the course was developed by a multi-disciplinary team and launched on two online platforms in July. The 4-hour course comprises 6 video-based modules. Student knowledge was assessed using pre- and post-module quizzes and final exam, while demographics and user experience were evaluated by pre- and post-course surveys and learning platform data.ResultsFrom July 17th to September 24th, 30,859 students enrolled, 18,818 started, and 7,101 completed the course. Most participants worked in healthcare (78%) and resided in lower middle- (38%) or upper middle- (20%) income countries. Learners from upper middle-income and lower middle-income countries had higher completion rates. Knowledge gains were observed from pre-module to post-module quizzes and a final exam. Afterward, participants reported increased self-efficacy regarding course objectives, a 0.63 mean increase on a 4-point scale (95% CI [0.60,0.66]). Most participants (93%) would recommend the course to others.ConclusionThis article demonstrates the potential of MOOCs to rapidly provide access to emerging medical knowledge during a public health crisis, particularly for HCWs in high- and middle-income countries.

The mass production and the practical number of cryogenic quantum devices producible in a single chip are limited to the number of electrical contact pads and wiring of the cryostat or dilution refrigerator. It is, therefore, beneficial to contrast the measurements of hundreds of devices fabricated in a single chip in one cooldown process to promote the scalability, integrability, reliability, and reproducibility of quantum devices and to save evaluation time, cost and energy. Here, we used a cryogenic on-chip multiplexer architecture and investigated the statistics of the 0.7 anomaly observed on the first three plateaus of the quantized conductance of semiconductor quantum point contact (QPC) transistors. Our single chips contain 256 split gate field-effect QPC transistors (QFET) each, with two 16-branch multiplexed source-drain and gate pads, allowing individual transistors to be selected, addressed and controlled through an electrostatic gate voltage process. A total of 1280 quantum transistors with nano-scale dimensions are patterned in 5 different chips of GaAs heterostructures. From the measurements of 571 functioning QFETs taken at temperatures T = 1.4 K and T = 40 mK, it is found that the spontaneous polarisation model and Kondo effect do not fit our results. Furthermore, some of the features in our data largely agreed with van Hove model with short-range interactions. Our approach provides further insight into the quantum mechanical properties and microscopic origin of the 0.7 anomaly in QFETs, paving the way for the development of semiconducting quantum circuits and integrated cryogenic electronics, for scalable quantum logic control, readout, synthesis, and processing applications.

Summary: Background: Spinal degenerative disease represents a growing burden on our healthcare system, yet little is known about longitudinal trends in access and care. Our goal was to provide an essential portrait of surgical volume trends for degenerative spinal pathologies within Canada. Methods: The Canadian Institute for Health Information (CIHI) database was used to identify all patients receiving surgery for a degenerative spinal condition from 2006 to 2019. Trends in number of interventions, unscheduled vs scheduled hospitalizations, in-hours vs out-of-hours interventions, resource utilization and adverse events were analyzed retrospectively using linear regression models. Confidence intervals were reported in the expected count ratio scale (CR). Findings: A total of 338,629 spinal interventions and 256,360 hospitalizations between 2006 and 2019 were analyzed. The mean and SD of the annual mean age of patients was 55.5 (SD 1.6) for elective hospitalizations and 55.6 (SD 1.6) for emergent hospitalizations. The proportion of female patients was 47.8% (91,789/192,027) for elective hospitalizations and 41.4% (26,633/64,333) for emergent hospitalizations. Elective hospitalizations increased an average of 2.0% per year, with CR = 1.020 (95% CI 1.017–1.023, p

The aim of this study was to characterise paediatric emergency department presentations during the 2023 thunderstorm asthma (TA) epidemic, characterised by a sudden surge in wheeze presentations, with analysis of environmental factors.Wheeze presentations totalled 50 (28%) on 12 June and 18 (19%) 13 June. There was no prior asthma in 39 (57%) and no atopic disorders in 30 (44%). There was neither asthma nor atopic disorders in 8 (12%). 44 (65%) were severe or life-threatening. There were no endotracheal intubations and no deaths. High pollen and air pollution warnings were issued.TA poses a significant, sudden health threat, often in children without asthma. A surge strategy is required.

The use of vaporizers to inhale cannabis is a technique that has risen in popularity among the American public. There is a general perception that vaporizers are “safer” when compared to more traditional cannabis smoking via combustion (i.e., cigarettes). The inherent use of heated air in vaporizers might reduce the respiratory toxicants or protein toxins by heating cannabis to a temperature where active compounds form in vapor phase. Yet this temperature is below the point of combustion where smoke and associated toxicants are produced. The elemental impurities are a general concern in all botanical products including cannabis and cannabis-derived products (CCDPs). This study aimed to investigate the potential transfer of those metallic elements from cannabis material to cannabis vapor through the vaporization process. A Volcano Digit Vaporizer (Storz & Bickel) was used as the heating device to perform the vaporization. Three cannabis plant materials were evaluated with varying contents of cannabinoids, including a cannabis placebo (

Background and aimsDetailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.Approach and resultsA targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p

Background: Current measures to prevent spinal surgical site infection (SSI) lack compliance and lead to antimicrobial resistance. We aimed to examine the effectiveness of bundled preoperative intranasal photodynamic disinfection therapy (nPDT) and chlorhexidine gluconate (CHG) body wipes in the prophylaxis of spine SSIs in adults, as well as determine our institutional savings attributable to the use of this strategy and identify adverse events reported with nPDT-CHG. Methods: We performed a 14-year prospective observational interrupted time-series study in adult (age > 18 yr) patients undergoing emergent or elective spine surgery with 3 time-specific cohorts: before rollout of our institution's nPDT-CHG program (2006-2010), during rollout (2011-2014) and after rollout (2015-2019). We used unadjusted bivariate analysis to test for temporal changes across patient and surgical variables, and segmented regression to estimate the effect of nPDT-CHG on the annual SSI incidence rates per period. We used 2 models to estimate the cost of nPDT-CHG to prevent 1 additional SSI per year and the annual cumulative cost savings through SSI prevention. Results: Over the study period, 13 493 patients (mean 964 per year) underwent elective or emergent spine surgery. From 2006 to 2019, the mean age, mean Charlson Comorbidity Index (CCI) score and mean Spine Surgical Invasiveness Index (SSII) score increased from 48.4 to 58.1 years, from 1.7 to 2.6, and from 15.4 to 20.5, respectively (p < 0.001). Unadjusted analysis confirmed a significant decrease in the annual number (74.6 to 26.8) and incidence (7.98% to 2.67%) of SSIs with nPDT-CHG (p < 0.001). After adjustment for mean age, mean CCI score and mean SSII score, segmented regression showed an absolute reduction in the annual SSI incidence rate of 3.36% per year (p < 0.001). The estimated annual cost to prevent 1 additional SSI per year was about $1350-$1650, and the estimated annual cumulative cost savings were $2 484856-S2 495 016. No adverse events were reported with nPDT-CHG. Conclusion: Preoperative nPDT-CHG administration is an effective prophylactic strategy for spinal SSIs, with significant cost savings. Given its rapid action, minimal risk of antimicrobial resistance, broad-spectrum activity and high compliance rate, preoperative nPDT-CHG decolonization should be the standard of care for all patients undergoing emergent or elective spine surgery. Contexte : L'application des mesures de prévention des infections des plaies opératoires (IPO) du rachis laisse actuellement à désirer et pourrait contribuer à la résistance aux antibiotiques. Nous avons voulu vérifier l'efficacité de la thérapie photodynamique antimicrobienne (TPA) intranasale préopératoire alliée à l'utilisation de lingettes désinfectantes à la chlorhexidine (LDC) pour le corps en prophylaxie des IPO du rachis chez des adultes, calculer les économies réalisées par notre établissement grâce à la stratégie TPD-LDC et recenser ses effets indésirables. Méthodes : Nous avons procédé à une étude observationnelle de séries chronologiques interrompues échelonnée sur une période de 14 ans chez des adultes (âgés de >18 ans) soumis à une chirurgie urgente ou non urgente du rachis auprès de 3 cohortes chronologiques spécifiques : avant le déploiement de la stratégie dans notre établissement (2006-2010), puis durant (2011-2014) et après son déploiement (2015-2019). Nous avons appliqué une analyse bivariée non ajustée pour vérifier les changements dans le temps selon la patientèle et les paramètres chirurgicaux, et segmenté la régression pour estimer l'effet de la stratégie TPA-LDC sur les taux d'incidence annuels moyens d'IPO par période. Nous avons utilisé 2 modèles pour estimer le coût de la stratégie TPA-LDC apte à prévenir une IPO additionnelle par année et les économies cumulatives annuelles moyennes générées par la prévention des IPO. Résultats : Durant la période de l'étude, 13 493 malades (964 par année en moyenne) ont subi une chirurgie urgente ou non urgente du rachis. Entre 2006 et 2011 et entre 2015 et 2019, l'âge moyen, l'indice moyen de comorbidité de Charlson (ICC) et l'indice moyen d'invasivité de la chirurgie du rachis (IICR) sont passés de 48,4 à 58,1 ans, de 1,7 à 2,6 et de 15,4 à 20,5, respectivement (p < 0,001). L'analyse non ajustée a confirmé une baisse significative du nombre annuel (de 74,6 à 26,8) et de l'incidence (de 7,98% à 2,67%) des IPO associée à la stratégie TPA-LDC (p < 0,001). Après ajustement pour tenir compte de l'âge, de l'ICC et de l'IICR moyens, la régression segmentée a montré une réduction absolue du taux d'incidence annuel des IPO de 3,36% par année (p < 0,001). Le coût annuel moyen estimé pour prévenir une IPO additionnelle a été d'environ 1350$-1650$, et les économies cumulatives annuelles moyennes estimées ont été de 2484856 $-2 495 016$. Aucun effet indésirable n'a été signalé avec la stratégie TPA-LDC. Conclusion : L'application préopératoire de la stratégie TPA-LDC est une mesure prophylactique efficace pour les IPO du rachis, et donne lieu à des économies significatives. Compte tenu de sa rapidité d'action, du risque minimal de résistance aux antibiotiques, de son activité à large spectre et du taux d'observance élevé, la décolonisation préopératoire par TPA-LDC devrait être une norme de soins pour l'ensemble de la patientèle soumise à une chirurgie urgente ou non urgente du rachis., Surgical site infections (SSIs) are devastating postoperative complications associated with substantial morbidity, prolonged length of stay (LOS) and increased health care-related costs. (1) The rate of SSIs after spine surgery [...]