Vitamin A mediates conversion of monocyte-derived macrophages into tissue-resident macrophages during alternative activation.

It remains unclear whether activated inflammatory macrophages can adopt features of tissue-resident macrophages, or what mechanisms might mediate such a phenotypic conversion. Here we show that vitamin A is required for the phenotypic conversion of interleukin 4 (IL-4)-activated monocyte-derived F4/80intCD206+PD-L2+MHCII+ macrophages into macrophages with a tissue-resident F4/80hiCD206-PD-L2-MHCII-UCP1+ phenotype in the peritoneal cavity of mice and during the formation of liver granulomas in mice infected with Schistosoma mansoni. The phenotypic conversion of F4/80intCD206+ macrophages into F4/80hiCD206- macrophages was associated with almost complete remodeling of the chromatin landscape, as well as alteration of the transcriptional profiles. Vitamin A-deficient mice infected with S. mansoni had disrupted liver granuloma architecture and increased mortality, which indicates that failure to convert macrophages from the F4/80intCD206+ phenotype to F4/80hiCD206- may lead to dysregulated inflammation during helminth infection.

Strokes Averted by Intravenous Thrombolysis: A Secondary Analysis of a Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

OBJECTIVE: This study was undertaken to examine averted stroke in optimized stroke systems. METHODS: This secondary analysis of a multicenter trial from 2014 to 2020 compared patients treated by mobile stroke unit (MSU) versus standard management. The analytical cohort consisted of participants with suspected stroke treated with intravenous thrombolysis. The main outcome was a tissue-defined averted stroke, defined as a final diagnosis of stroke with resolution of presenting symptoms/signs by 24 hours attributed to thrombolysis and no acute infarction/hemorrhage on imaging. An additional outcome was stroke with early symptom resolution, defined as a final diagnosis of stroke with resolution of presenting symptoms/signs by 24 hours attributed to thrombolysis. RESULTS: Among 1,009 patients with a median last known well to thrombolysis time of 87 minutes, 159 (16%) had tissue-defined averted stroke and 276 (27%) had stroke with early symptom resolution. Compared with standard management, MSU care was associated with more tissue-defined averted stroke (18% vs 11%, adjusted odds ratio [aOR] = 1.82, 95% confidence interval [CI] = 1.13-2.98) and stroke with early symptom resolution (31% vs 21%, aOR = 1.74, 95% CI = 1.12-2.61). The relationships between thrombolysis treatment time and averted/early recovered stroke appeared nonlinear. Most models indicated increased odds for stroke with early symptom resolution but not tissue-defined averted stroke with earlier treatment. Additionally, younger age, female gender, hyperlipidemia, lower National Institutes of Health Stroke Scale, lower blood pressure, and no large vessel occlusion were associated with both tissue-defined averted stroke and stroke with early symptom resolution. INTERPRETATION: In optimized stroke systems, 1 in 4 patients treated with thrombolysis recovered within 24 hours and 1 in 6 had no demonstrable brain injury on imaging. ANN NEUROL 2024;95:347-361.

CSF-1 maintains pathogenic but not homeostatic myeloid cells in the central nervous system during autoimmune neuroinflammation.

The receptor for colony stimulating factor 1 (CSF-1R) is important for the survival and function of myeloid cells that mediate pathology during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). CSF-1 and IL-34, the ligands of CSF-1R, have similar bioactivities but distinct tissue and context-dependent expression patterns, suggesting that they have different roles. This could be the case in EAE, given that CSF-1 expression is up-regulated in the CNS, while IL-34 remains constitutively expressed. We found that targeting CSF-1 with neutralizing antibody halted ongoing EAE, with efficacy superior to CSF-1R inhibitor BLZ945, whereas IL-34 neutralization had no effect, suggesting that pathogenic myeloid cells were maintained by CSF-1. Both anti­CSF-1 and BLZ945 treatment greatly reduced the number of monocyte-derived cells and microglia in the CNS. However, anti­CSF-1 selectively depleted inflammatory microglia and monocytes in inflamed CNS areas, whereas BLZ945 depleted virtually all myeloid cells, including quiescent microglia, throughout the CNS. Anti­CSF-1 treatment reduced the size of demyelinated lesions and microglial activation in the gray matter. Lastly, we found that bone marrow­derived immune cells were the major mediators of CSF-1R­dependent pathology, while microglia played a lesser role. Our findings suggest that targeting CSF-1 could be effective in ameliorating MS pathology, while preserving the homeostatic functions of myeloid cells, thereby minimizing risks associated with ablation of CSF-1R­dependent cells.

Immune-mediated thrombocytopenia and IL-6-mediated thrombocytosis observed in idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare haematological disorder characterized by generalized lymphadenopathy with atypical histopathological features and systemic inflammation caused by a cytokine storm involving interleukin-6 (IL-6). Three clinical subtypes are recognized: thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly (iMCD-TAFRO); idiopathic plasmacytic lymphadenopathy (iMCD-IPL), involving thrombocytosis and hypergammaglobulinaemia; and iMCD-not otherwise specified (iMCD-NOS), which includes patients who do not meet criteria for the other subtypes. Disease pathogenesis is poorly understood, with potential involvement of infectious, clonal and/or autoimmune mechanisms. To better characterize iMCD clinicopathology and gain mechanistic insights into iMCD, we analysed complete blood counts, other clinical laboratory values and blood smear morphology among 63 iMCD patients grouped by clinical subtype. Patients with iMCD-TAFRO had large platelets, clinical severity associated with lower platelet counts and transfusion-resistant thrombocytopenia, similar to what is observed with immune-mediated destruction of platelets in immune thrombocytopenic purpura. Conversely, elevated platelet counts in iMCD-IPL were associated with elevated IL-6 and declined following anti-IL-6 therapy. Our data suggest that autoimmune mechanisms contribute to the thrombocytopenia in at least a portion of iMCD-TAFRO patients whereas IL-6 drives thrombocytosis in iMCD-IPL, and these mechanisms likely contribute to disease pathogenesis.

Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

BACKGROUND: Mobile stroke units (MSUs) are ambulances with staff and a computed tomographic scanner that may enable faster treatment with tissue plasminogen activator (t-PA) than standard management by emergency medical services (EMS). Whether and how much MSUs alter outcomes has not been extensively studied. METHODS: In an observational, prospective, multicenter, alternating-week trial, we assessed outcomes from MSU or EMS management within 4.5 hours after onset of acute stroke symptoms. The primary outcome was the score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes according to a patient value system, derived from scores on the modified Rankin scale of 0 to 6, with higher scores indicating more disability). The main analysis involved dichotomized scores on the utility-weighted modified Rankin scale (≥0.91 or <0.91, approximating scores on the modified Rankin scale of ≤1 or >1) at 90 days in patients eligible for t-PA. Analyses were also performed in all enrolled patients. RESULTS: We enrolled 1515 patients, of whom 1047 were eligible to receive t-PA; 617 received care by MSU and 430 by EMS. The median time from onset of stroke to administration of t-PA was 72 minutes in the MSU group and 108 minutes in the EMS group. Of patients eligible for t-PA, 97.1% in the MSU group received t-PA, as compared with 79.5% in the EMS group. The mean score on the utility-weighted modified Rankin scale at 90 days in patients eligible for t-PA was 0.72 in the MSU group and 0.66 in the EMS group (adjusted odds ratio for a score of ≥0.91, 2.43; 95% confidence interval [CI], 1.75 to 3.36; P<0.001). Among the patients eligible for t-PA, 55.0% in the MSU group and 44.4% in the EMS group had a score of 0 or 1 on the modified Rankin scale at 90 days. Among all enrolled patients, the mean score on the utility-weighted modified Rankin scale at discharge was 0.57 in the MSU group and 0.51 in the EMS group (adjusted odds ratio for a score of ≥0.91, 1.82; 95% CI, 1.39 to 2.37; P<0.001). Secondary clinical outcomes generally favored MSUs. Mortality at 90 days was 8.9% in the MSU group and 11.9% in the EMS group. CONCLUSIONS: In patients with acute stroke who were eligible for t-PA, utility-weighted disability outcomes at 90 days were better with MSUs than with EMS. (Funded by the Patient-Centered Outcomes Research Institute; BEST-MSU ClinicalTrials.gov number, NCT02190500.).

A novel cryopreservation and biobanking strategy to study lymphoid tissue stromal cells in human disease.

Nonhematopoietic lymph node stromal cells (LNSCs) regulate lymphocyte trafficking, survival, and function for key roles in host defense, autoimmunity, alloimmunity, and lymphoproliferative disorders. However, the study of LNSCs in human diseases is complicated by a dependence on viable lymphoid tissues, which are most often excised prior to establishment of a specific diagnosis. Here, we demonstrate that cryopreservation can be used to bank lymphoid tissue for the study of LNSCs in human disease. Using human tonsils and lymph nodes (LN), lymphoid tissue fragments were cryopreserved for subsequent enzymatic digestion and recovery of viable nonhematopoietic cells. Flow cytometry and single-cell transcriptomics identified comparable proportions of LN stromal cell types in fresh and cryopreserved tissue. Moreover, cryopreservation had little effect on transcriptional profiles, which showed significant overlap between tonsils and LN. The presence and spatial distribution of transcriptionally defined cell types were confirmed by in situ analyses. Our broadly applicable approach promises to greatly enable research into the roles of LNSCs in human disease.

Material Flow Analysis and Occupational Exposure Assessment in Additive Manufacturing End-of-Life Material Management.

Additive manufacturing (AM) offers a variety of material manufacturing techniques for a wide range of applications across many industries. Most efforts at process optimization and exposure assessment for AM are centered around the manufacturing process. However, identifying the material allocation and potentially harmful exposures in end-of-life (EoL) management is equally crucial to mitigating environmental releases and occupational health impacts within the AM supply chain. This research tracks the allocation and potential releases of AM EoL materials within the US through a material flow analysis. Of the generated AM EoL materials, 58% are incinerated, 33% are landfilled, and 9% are recycled by weight. The generated data set was then used to examine the theoretical occupational hazards during AM EoL material management practices through generic exposure scenario assessment, highlighting the importance of ventilation and personal protective equipment at all stages of AM material management. This research identifies pollution sources, offering policymakers and stakeholders insights to shape pollution prevention and worker safety strategies within the US AM EoL management pathways.

An Exploratory Analysis of ChatGPT Compared to Human Performance With the Anesthesiology Oral Board Examination: Initial Insights and Implications.

BACKGROUND: Chat Generative Pre-Trained Transformer (ChatGPT) has been tested and has passed various high-level examinations. However, it has not been tested on an examination such as the American Board of Anesthesiology (ABA) Standardized Oral Examination (SOE). The SOE is designed to assess higher-level competencies, such as judgment, organization, adaptability to unexpected clinical changes, and presentation of information. METHODS: Four anesthesiology fellows were examined on 2 sample ABA SOEs. Their answers were compared to those produced by the same questions asked to ChatGPT. All human and ChatGPT responses were transcribed, randomized by module, and then reproduced as complete examinations, using a commercially available software-based human voice replicator. Eight ABA applied examiners listened to and scored the topic and modules from 1 of the 4 versions of each of the 2 sample examinations. The ABA did not provide any support or collaboration with any authors. RESULTS: The anesthesiology fellow's answers were found to have a better median score than ChatGPT, for the module topics scores (P = .03). However, there was no significant difference in the median overall global module scores between the human and ChatGPT responses (P = .17). The examiners were able to identify the ChatGPT-generated answers for 23 of 24 modules (95.83%), with only 1 ChatGPT response perceived as from a human. In contrast, the examiners thought the human (fellow) responses were artificial intelligence (AI)-generated in 10 of 24 modules (41.67%). Examiner comments explained that ChatGPT generated relevant content, but were lengthy answers, which at times did not focus on the specific scenario priorities. There were no comments from the examiners regarding Chat GPT fact "hallucinations." CONCLUSIONS: ChatGPT generated SOE answers with comparable module ratings to anesthesiology fellows, as graded by 8 ABA oral board examiners. However, the ChatGPT answers were deemed subjectively inferior due to the length of responses and lack of focus. Future curation and training of an AI database, like ChatGPT, could produce answers more in line with ideal ABA SOE answers. This could lead to higher performance and an anesthesiology-specific trained AI useful for training and examination preparation.

Perspectives on the comparative benefits of body-powered and myoelectric upper limb prostheses.

BACKGROUND: Patient access to body-powered and myoelectric upper limb prostheses in the United States is often restricted by a healthcare system that prioritizes prosthesis prescription based on cost and perceived value. Although this system operates on an underlying assumption that design differences between these prostheses leads to relative advantages and disadvantages of each device, there is limited empirical evidence to support this view. MAIN TEXT: This commentary article will review a series of studies conducted by our research team with the goal of differentiating how prosthesis design might impact user performance on a variety of interrelated domains. Our central hypothesis is that the design and actuation method of body-powered and myoelectric prostheses might affect users' ability to access sensory feedback and account for device properties when planning movements. Accordingly, other domains that depend on these abilities may also be affected. While our work demonstrated some differences in availability of sensory feedback based on prosthesis design, this did not result in consistent differences in prosthesis embodiment, movement accuracy, movement quality, and overall kinematic patterns. CONCLUSION: Collectively, our findings suggest that performance may not necessarily depend on prosthesis design, allowing users to be successful with either device type depending on the circumstances. Prescription practices should rely more on individual needs and preferences than cost or prosthesis design. However, we acknowledge that there remains a dearth of evidence to inform decision-making and that an expanded research focus in this area will be beneficial.

Asthma policy in Illinois: A survey of school nursing and staff knowledge and implementation patterns.

OBJECTIVE: Our goal is to examine gaps in self-carry, asthma emergency protocol, and stock inhaler policy knowledge in Illinois schools. DESIGN: A 30-item REDCap cross-sectional survey developed by a team of stakeholders was disseminated. Questions assessed policy knowledge, awareness, and practices regarding asthma emergency protocols, self-carry, and stock inhalers. SAMPLE: Participants were Illinois school nurses belonging to a governmental organization listserv. MEASUREMENTS: Analysis utilized Chi-square tests, descriptive statistics, and t-tests. RESULTS: Nurses reported 36% of students on average self-carried asthma medication. Thirty percent of nurses were not aware of their emergency asthma policy and only 60% reported having an emergency asthma protocol in their school(s). Fifty-four percent of nurses were aware of stock inhaler programming. Of the 10.3% who reported a stock inhaler program, a lower frequency reported calling 911 for asthma emergencies. Perceived school asthma prevalence varied from 0%-87%. CONCLUSIONS: Our survey demonstrates large variation in knowledge and implementation of school-based asthma health policy. This is likely due to variations in health policy education dissemination. Future efforts should focus on the dissemination and implementation of school-based asthma health policies to improve their more universal adoption and better support school-based asthma management.

Antibody Duration After Infection From SARS-CoV-2 in the Texas Coronavirus Antibody Response Survey.

Understanding the duration of antibodies to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus that causes COVID-19 is important to controlling the current pandemic. Participants from the Texas Coronavirus Antibody Response Survey (Texas CARES) with at least 1 nucleocapsid protein antibody test were selected for a longitudinal analysis of antibody duration. A linear mixed model was fit to data from participants (n = 4553) with 1 to 3 antibody tests over 11 months (1 October 2020 to 16 September 2021), and models fit showed that expected antibody response after COVID-19 infection robustly increases for 100 days postinfection, and predicts individuals may remain antibody positive from natural infection beyond 500 days depending on age, body mass index, smoking or vaping use, and disease severity (hospitalized or not; symptomatic or not).

RUNX-1 haploinsufficiency causes a marked deficiency of megakaryocyte-biased hematopoietic progenitor cells.

Patients with familial platelet disorder with a predisposition to myeloid malignancy (FPDMM) harbor germline monoallelic mutations in a key hematopoietic transcription factor, RUNX-1. Previous studies of FPDMM have focused on megakaryocyte (Mk) differentiation and platelet production and signaling. However, the effects of RUNX-1 haploinsufficiency on hematopoietic progenitor cells (HPCs) and subsequent megakaryopoiesis remains incomplete. We studied induced pluripotent stem cell (iPSC)-derived HPCs (iHPCs) and Mks (iMks) from both patient-derived lines and a wild-type (WT) line modified to be RUNX-1 haploinsufficient (RUNX-1+/-), each compared with their isogenic WT control. All RUNX-1+/- lines showed decreased iMk yield and depletion of an Mk-biased iHPC subpopulation. To investigate global and local gene expression changes underlying this iHPC shift, single-cell RNA sequencing was performed on sorted FPDMM and control iHPCs. We defined several cell subpopulations in the Mk-biased iHPCs. Analyses of gene sets upregulated in FPDMM iHPCs indicated enrichment for response to stress, regulation of signal transduction, and immune signaling-related gene sets. Immunoblot analyses in FPDMM iMks were consistent with these findings, but also identified augmented baseline c-Jun N-terminal kinase (JNK) phosphorylation, known to be activated by transforming growth factor-ß1 (TGF-ß1) and cellular stressors. These findings were confirmed in adult human CD34+-derived stem and progenitor cells (HSPCs) transduced with lentiviral RUNX1 short hairpin RNA to mimic RUNX-1+/-. In both iHPCs and CD34+-derived HSPCs, targeted inhibitors of JNK and TGF-ß1 pathways corrected the megakaryopoietic defect. We propose that such intervention may correct the thrombocytopenia in patients with FPDMM.

A Systematic Search for the Adsorption Motif of All Stereoisomers of Propylene Glycol on a Palladium(111) Surface for Fuel Cell Applications.

Small organic molecules have been shown to produce sufficient power densities allowing them to be environmentally friendly renewable fuel sources and an important part of fuel cell research. Affiliated experimental work found propylene glycol, as a source of renewable fuel, produces viable power densities when utilized with an alkaline-acid fuel cell and a Pd(111) catalyst. There is limited theoretical work on propylene glycol's energy reaction pathway. Thus, the first step in understanding how propylene glycol reacts with the Pd(111) slab is understanding its adsorption. In this paper, we present the investigation of adsorption potential energies (APE) of propylene glycol stereoisomers (S)-propane-1,2-diol (1,2PGS), (R)-propane-1,2-diol (1,2PGR), and propane-1,3-diol (1,3PG) on Pd(111). The isomers are systematically scanned through different configurations to analyze the preferred stable orientation and positional motifs. Density functional theory (DFT) is used to optimize the molecular geometries and surface relaxations. The most stable configuration of the 1,2PG stereoisomers resulted in an APE of -0.97 eV. The most stable configuration of the 1,3PG resulted in an APE of -1.19 eV. Both the 1,2PG(S/R) and 1,3PG isomers favor a motif in which at least one hydroxyl oxygen atom interacts with the surface of the Pd(111) catalyst. The 1,2PG carbon backbone prefers to have the center carbon positioned away from the slab, while the 1,3PG prefers to have the center carbon positioned closer to the slab. The most stable 1,3PG differs from other reported 1,3PG and 1,2PG relaxed configurations in that both of the hydroxyl oxygen atoms interact with the Pd(111) surface. These results show more favorable APEs than previously reported calculations. This paper will discuss in detail the differences between the hydroxyl group motifs and their role in affecting adsorption.

Long-term immune response to SARS-CoV-2 infection and vaccination in children and adolescents.

BACKGROUND: This analysis examined the durability of antibodies present after SARS-CoV-2 infection and vaccination in children and adolescents. METHODS: Data were collected over 4 time points between October 2020-November 2022 as part of a prospective population-based cohort aged 5-to-19 years (N = 810). Results of the (1) Roche Elecsys® Anti-SARS-CoV-2 Immunoassay for detection of antibodies to the SARS-CoV-2 nucleocapsid protein (Roche N-test); and (2) qualitative and semi-quantitative detection of antibodies to the SARS CoV-2 spike protein receptor binding domain (Roche S-test); and (3) self-reported antigen/PCR COVID-19 test results, vaccination and symptom status were analyzed. RESULTS: N antibody levels reached a median of 84.10 U/ml (IQR: 20.2, 157.7) cutoff index (COI) ~ 6 months post-infection and increased slightly to a median of 85.25 (IQR: 28.0, 143.0) COI at 12 months post-infection. Peak S antibody levels were reached at a median of 2500 U/mL ~6 months post-vaccination and remained for ~12 months (mean 11.6 months, SD 1.20). CONCLUSIONS: This analysis provides evidence of robust durability of nucleocapsid and spike antibodies in a large pediatric sample up to 12 months post-infection/vaccination. This information can inform pediatric SARS-CoV-2 vaccination schedules. IMPACT: This study provided evidence of robust durability of both nucleocapsid and spike antibodies in a large pediatric sample up to 12 months after infection. Little is known about the long-term durability of natural and vaccine-induced SARS-CoV-2 antibodies in the pediatric population. Here, we determined the durability of anti-SARS-CoV-2 spike (S-test) and nucleocapsid protein (N-test) in children/adolescents after SARS-CoV-2 infection and/or vaccination lasts at least up to 12 months. This information can inform future SARS-CoV-2 vaccination schedules in this age group.

The impact of the COVID-19 pandemic on help-seeking behaviours of Indigenous and Black women experiencing intimate partner violence in the United States.

AIMS: This article discusses possible barriers to help-seeking that Indigenous and Black women encountered when seeking help related to experiences of intimate partner violence during the COVID-19 pandemic. DESIGN: This article is focused on understanding the impact of the COVID-19 pandemic on populations at highest risk for intimate partner violence in its most severe forms. DATA SOURCES: Literature sources range from 2010 to 2022. The article is also informed by the experiences of scholars and advocates working with Indigenous and Black women experiencing intimate partner violence in Wisconsin. In our write-up, we draw on Indigenous feminism and Black feminist thought. IMPLICATIONS FOR NURSING: Help seeking is contextual. The context in which help seeking occurs or does not occur for Indigenous and Black women, due to the barriers we discuss is vital for nurses to understand in order to provide efficient and meaningful nursing care. CONCLUSION: Our goal is to center the nursing profession in a leadership position in addressing the complex and unique needs of Indigenous and Black women who experience the highest rates of intimate partner violence and also experience the greatest barriers to care and support. IMPACT: We seek to contribute theory-driven knowledge that informs the work of nurses who are often the first to encounter survivors of intimate partner violence within the clinical setting. Help-seeking is often hindered by factors such as geographic and jurisdictional, economic, and structural response barriers. This knowledge will enhance nurses' ability to lead and advocate for clinical practice and policies that minimize the barriers women experience following intimate partner violence, especially during pandemics, disasters, and other extraordinary circumstances. PUBLIC CONTRIBUTIONS: This article is based on the collaboration of community advocates, nurse scientists, and public health scholars, who work closely with Indigenous and Black survivors of violence and seek to meet their needs and offer them meaningful support.

Review of generic scenario environmental release and occupational exposure models used in chemical risk assessment.

Under the Toxic Substances Control Act (TSCA), the United States Environmental Protection Agency (USEPA) is required to determine whether a new chemical substance poses an unreasonable risk to human health or the environment before the chemical is manufactured in or imported into the United States. This manuscript provides a review of the process used to evaluate the risk associated with a chemical based on the scenarios and models used in the evaluation. Specifically, the Generic Scenarios and Emission Scenario Documents developed by the USEPA were reviewed, along with background documentation prepared by USEPA to identify the core elements of the environmental release and occupational exposure scenarios used to assess the risk of the chemical being evaluated. Additionally, this contribution provides an overview of methods used to model occupational exposures and environmental releases as part of the chemical evaluation process used in other jurisdictions, along with work being performed to improve these models. Finally, the alternative methods to evaluate occupational exposures and environmental releases that may be used as part of the decision-making process regarding a chemical are identified. The contribution provides a path forward for reducing the time required and improving the chemical evaluation of the unreasonable risk determination regarding the manufacture or import of a chemical.

Genetic analysis for type 1 diabetes genes in juvenile dermatomyositis unveils genetic disease overlap.

OBJECTIVES: JDM is a serious autoimmune and complex genetic disease. Another autoimmune genetic disease, type 1 diabetes (T1D), has been observed for significantly increased prevalence in families with JDM, while increased JDM risk has also been observed in T1D cases. This study aimed to study whether these two autoimmune diseases, JDM and T1D, share common genetic susceptibility. METHODS: From 169 JDM families, 121 unrelated cases with European ancestry (EA) were identified by genome-wide genotyping, principal component analysis and identical-by-descent (IBD) analysis. T1D genetic risk score (GRS) were calculated in these cases and were compared with 361 EA T1D cases and 1943 non-diabetes EA controls. A total of 113 cases of the 121 unrelated European cases were sequenced by whole exome sequencing. RESULTS: We observed increased T1D GRS in JDM cases (P = 9.42E-05). Using whole exome sequencing, we uncovered the T1D genes, phospholipase B1, cystic fibrosis transmembrane conductance regulator, tyrosine hydroxylase, CD6 molecule, perforin 1 and dynein axonemal heavy chain 2, potentially associated with JDM by the burden test of rare functional coding variants. CONCLUSION: Novel mechanisms of JDM related to these T1D genes are suggested by this study, which may imply novel therapeutic targets for JDM and warrant further study.

The helminth glycoprotein omega-1 improves metabolic homeostasis in obese mice through type 2 immunity-independent inhibition of food intake.

Type 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta-inflammation and insulin resistance. Infection with the helminth parasite Schistosoma mansoni and treatment with its soluble egg antigens (SEA) induce a type 2 immune response in metabolic organs and improve insulin sensitivity and glucose tolerance in obese mice, yet, a causal relationship remains unproven. Here, we investigated the effects and underlying mechanisms of the T2 ribonuclease omega-1 (ω1), one of the major S mansoni immunomodulatory glycoproteins, on metabolic homeostasis. We show that treatment of obese mice with plant-produced recombinant ω1, harboring similar glycan motifs as present on the native molecule, decreased body fat mass, and improved systemic insulin sensitivity and glucose tolerance in a time- and dose-dependent manner. This effect was associated with an increase in white adipose tissue (WAT) type 2 T helper cells, eosinophils, and alternatively activated macrophages, without affecting type 2 innate lymphoid cells. In contrast to SEA, the metabolic effects of ω1 were still observed in obese STAT6-deficient mice with impaired type 2 immunity, indicating that its metabolic effects are independent of the type 2 immune response. Instead, we found that ω1 inhibited food intake, without affecting locomotor activity, WAT thermogenic capacity or whole-body energy expenditure, an effect also occurring in leptin receptor-deficient obese and hyperphagic db/db mice. Altogether, we demonstrate that while the helminth glycoprotein ω1 can induce type 2 immunity, it improves whole-body metabolic homeostasis in obese mice by inhibiting food intake via a STAT6-independent mechanism.

Temporal and spatial goal-directed reaching in upper limb prosthesis users.

Understanding the fundamental characteristics of prosthetic movement control is imperative in improving prosthesis design and training. This study quantified how using an upper limb prosthesis affected performance during goal-directed reaching tasks. Nine prosthesis users with unilateral transradial limb absence and nine healthy controls completed a series of goal-directed reaching movements with different goals: one spatial and three temporal with different goal frequencies. We quantified end-point accuracy, smoothness, and peak speed for the spatial task and temporal accuracy, horizontal distance, and speed for the temporal task. For the temporal task, we also used a goal-equivalent manifold (GEM) approach to decompose variability in movement distance and speed into those perpendicular and tangential to the GEM. Detrended fluctuation analysis (DFA) quantified the temporal persistence of each time series. For the spatial task, movements made with prostheses were less smooth, had larger end-point errors, and had slower peak speed compared to those with control limbs (p < 0.041). For the temporal task, movements made with prostheses and intact limbs of prosthesis users and control limbs were similar in distance and speed and had similar timing errors (p > 0.138). Timing errors, distance, speed, and GEM deviations were corrected similarly between prosthetic limbs and control limbs (p > 0.091). The mean and variability of distance, speed, and perpendicular deviations decreased with increased goal frequency (p < 0.001). Our results suggest that prosthesis users have a sufficient internal model to successfully complete ballistic movements but are unable to accurately complete movements requiring substantial feedback.

Identifying health-related quality of life cut-off scores that indicate the need for supportive care in young adults with cancer.

PURPOSE: Using patient-reported outcomes in routine cancer care may improve health outcomes. However, a lack of information about which scores are problematic in specific populations can impede use. To facilitate interpretation of the European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30), we identified cut-off scores that indicate need for support by comparing each scale to relevant items from the Supportive Care Needs Survey (SCNS-LF59) in a young adult (YA) population. METHODS: We conducted a cross-sectional survey amongst YAs with cancer ages 25-39 at diagnosis. Participants completed the EORTC QLQ-C30 and SCNS-LF59. Patient, clinician and research experts matched supportive care needs from the SCNS-LF59 to quality of life domains of the EORTC QLQ-C30. We evaluated the EORTC QLQ-C30 domain score's ability to detect patients with need using receiver operator characteristic (ROC) analysis, calculating the area under the ROC curve and sensitivity and specificity for selected cut-offs. Cut-offs were chosen by maximising Youden's J statistic and ensuring sensitivity passed 0.70. Sensitivity analyses were conducted to examine the variability of the cut-off scores by treatment status. RESULTS: Three hundred and forty-seven YAs took part in the survey. Six experts matched SCNS-LF59 items to ten EORTC QLQ-C30 domains. The AUC ranged from 0.78 to 0.87. Cut-offs selected ranged from 8 (Nausea and Vomiting and Pain) to 97 (Physical Functioning). All had adequate sensitivity (above 0.70) except the Financial Difficulties scale (0.64). Specificity ranged from 0.61 to 0.88. Four of the cut-off scores differed by treatment status. CONCLUSION: Cut-offs with adequate sensitivity were calculated for nine EORTC QLQ-C30 scales for use with YAs with cancer. Cut-offs are key to interpretability and use of the EORTC QLQ-C30 in routine care to identify patients with supportive care need.