Altered transcriptomic immune responses of maintenance hemodialysis patients to the COVID-19 mRNA vaccine.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusions: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD. Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Coordinated elimination of bacterial taxa optimally attenuates alloimmunity and prolongs allograft survival.

This study aimed to dissect the relationship between specific gut commensal bacterial subgroups, their functional metabolic pathways, and their impact on skin allograft outcome and alloimmunity. We previously showed that oral broad-spectrum antibiotic (Abx) pretreatment in mice delayed skin, heart, and lung allograft rejection and dampened alloimmune responses. Here, rationally designed Abx combinations targeting major bacterial groups were used to elucidate their individual contribution to modulating alloimmune responses. Abx cocktails targeting intestinal gram-negative, gram-positive, or anaerobic/gram-positive bacteria by oral gavage, all delayed skin allograft rejection, and reduced alloreactive T cell priming to different extents. Notably, the most pronounced extension of skin allograft survival and attenuation of alloimmunity were achieved when all gut bacterial groups were simultaneously targeted. These results suggest a model in which the strength of the alloimmune response is additively tuned up by gut microbial diversity. Shotgun metagenomic sequencing enabled strain-level resolution and identified a shared commensal, Parabacteroides distasonis, as the most enriched following all Abx treatments. Oral administration of P.distasonis to mice harboring a diverse microbiota significantly prolonged skin allograft survival, identifying a probiotic with therapeutic benefit in transplantation.

BORN TO WHEEZE OR LEARNED WHEN WE WERE YOUNG: MATERNAL AND ENVIRONMENTAL FACTORS INFLUENCE ATOPIC RISK.

The prevalence of atopic diseases is increasing globally, particularly in children. Heritable genetics can partially explain risk of disease. Evidence also points to acquired genetic material, in the form of the microbiome, as an important factor in disease pathogenesis. The acquisition of the microbiome dynamically changes in response to differences in lifestyle and environmental factors. Also, in utero, maternal and environmental factors influence atopic risk for allergic rhinitis, eczema, asthma, and food allergy. Combining the analytical power of omics, we focus on how the microbiota mediates effects between mother, environment, immunity, and risk of atopic disease. In parallel, we stress that health care disparities impact asthma morbidity and mortality. Efforts to improve asthma outcomes must include multidisciplinary strategies.

Virtual Dementia-Friendly Communities (Verily Connect) Stepped-Wedge Cluster-Randomised Controlled Trial: Improving Dementia Caregiver Wellbeing in Rural Australia.

Caring for people living with dementia often leads to social isolation and decreased support for caregivers. This study investigated the effect of a Virtual Dementia-Friendly Rural Communities (Verily Connect) model on social support and demand for caregivers of people living with dementia. The co-designed intervention entailed an integrated website and mobile application, peer-support videoconference, and technology learning hubs. This mixed-methods, stepped-wedge, cluster-randomised controlled trial was conducted with 113 participants from 12 rural communities in Australia. Caregiver data were collected using MOS-SSS and ZBI between 2018 and 2020. The relationship between post-intervention social support with age, years of caring, years since diagnosis, and duration of intervention were explored through correlation analysis and thin plate regression. Google Analytics were analysed for levels of engagement, and cost analysis was performed for implementation. Results showed that caregivers' perception of social support (MOS-SSS) increased over 32 weeks (p = 0.003) and there was a marginal trend of less care demand (ZBI) among caregivers. Better social support was observed with increasing caregiver age until 55 years. Younger caregivers (aged <55 years) experienced the greatest post-intervention improvement. The greatest engagement occurred early in the trial, declining sharply thereafter. The Verily Connect model improved caregivers' social support and appeared to ease caregiver demand.

Syncope and the Inability to Move: Was It the Magnesium?

Proton pump inhibitors (PPIs) were clinically introduced more than 30 years ago and have been a very safe and effective agent for the treatment of a variety of different acid-base disorders. PPIs work by inhibiting the final step in gastric acid synthesis production by covalently binding to the (H+,K+)-ATPase enzyme system at the level of the gastric parietal cells leading to the irreversible inhibition of gastric acid secretion until new enzymes are produced. This inhibition is useful in a wide variety of disorders, which include, but are not limited to, gastroesophageal reflux disease (GERD), peptic ulcer disease, erosive esophagitis, Helicobacter pylori infection, and pathological hypersecretory disorders. Despite PPIs' overall excellent safety profile, PPIs have raised concerns about both short- and long-term complications including multiple electrolyte derangements that can lead to life-threatening situations. We present a case of a 68-year-old male who presented to the emergency department after a syncopal episode with profound weakness and was found to have undetectable magnesium levels secondary to long-term omeprazole use. This case report highlights how important it is for clinicians to be aware of these electrolyte disturbances and the importance of monitoring electrolytes while being on these medications.

Microbiota-dependent and -independent effects of obesity on transplant rejection and hyperglycemia.

Obesity is associated with dysbiosis and a state of chronic inflammation that contributes to the pathogenesis of metabolic diseases, including diabetes. We have previously shown that obese mice develop glucose intolerance, increased alloreactivity, and accelerated transplant rejection. In the present study, we investigated the influence of the microbiota on diet-induced obesity (DIO)-associated transplant rejection and hyperglycemia. Antibiotic treatment prolonged graft survival and reduced fasting glycemia in high-fat diet (HFD)-fed specific-pathogen-free (SPF) mice, supporting a role for the microbiota in promoting accelerated graft rejection and hyperglycemia induced by DIO. Further supporting a microbiota-dependent effect, fecal microbiota transfer from DIO SPF mice into germ-free mice also accelerated graft rejection when compared with lean mice-fecal microbiota transfer. Notably, HFD could be also detrimental to the graft independently from microbiota, obesity, and hyperglycemia. Thus, whereas HFD-associated hyperglycemia was exclusively microbiota-dependent, HFD affected transplant outcomes via both microbiota-dependent and -independent mechanisms. Importantly, hyperglycemia in DIO SPF mice could be reduced by the addition of the gut commensal Alistipes onderdonkii, which alleviated both HFD-induced inflammation and glucose intolerance. Thus, microbial dysbiosis can be manipulated via antibiotics or select probiotics to counter some of the pathogenic effects of obesity in transplantation.

Patterns of mental healthcare provision in rural areas: A demonstration study in Australia and Europe.

Introduction: Mental healthcare systems are primarily designed to urban populations. However, the specific characteristics of rural areas require specific strategies, resource allocation, and indicators which fit their local conditions. This planning process requires comparison with other rural areas. This demonstration study aimed to describe and compare specialized rural adult mental health services in Australia, Norway, and Spain; and to demonstrate the readiness of the healthcare ecosystem approach and the DESDE-LTC mapping tool (Description and Evaluation of Services and Directories of Long Term Care) for comparing rural care between countries and across areas. Methods: The study described and classified the services using the DESDE-LTC. The analyses included context analysis, care availability, placement capacity, balance of care, and diversity of care. Additionally, readiness (Technology Readiness Levels - TRL) and impact analyses (Adoption Impact Ladder - AIL) were also assessed by two independent raters. Results: The findings demonstrated the usability of the healthcare ecosystem approach and the DESDE-LTC to map and identify differences and similarities in the pattern of care of highly divergent rural areas. Day care had a greater weight in the European pattern of care, while it was replaced by social outpatient care in Australian areas. In contrast, care coordination was more common in Australia, pointing to a more fragmented system that requires navigation services. The share between hospital and community residential care showed no differences between the two regions, but there were differences between catchment areas. The healthcare ecosystem approach showed a TRL 8 (the tool has been demonstrated in a real-world environment and it is ready for release and general use) and an AIL of 5 (the target public agencies provided resources for its completion). Two experts evaluated the readiness of the use of DESDE-LTC in their respective regional studies. All of them were classified using the TRL. Discussion: In conclusion, this study strongly supports gathering data on the provision of care in rural areas using standardized methods to inform rural service planning. It provides information on context and service availability, capacity and balance of care that may improve, directly or through subsequent analyses, the management and planning of services in rural areas.

Oral administration of the commensal Alistipes onderdonkii prolongs allograft survival.

Intestinal commensals can exert immunomodulatory effects on the host, with beneficial or detrimental consequences depending on underlying diseases. We have previously correlated longer survival of minor mismatched skin grafts in mice with the presence of an intestinal commensal bacterium, Alistipes onderdonkii. In this study, we investigated its sufficiency and mechanism of action. Oral administration of A onderdonkii strain DSM19147 but not DSM108265 was sufficient to prolong minor mismatched skin graft survival through inhibition of tumor necrosis factor production. Through metabolomic and metagenomic comparisons between DSM19147 and DSM108265, we identified candidate gene products associated with the anti-inflammatory effect of DSM19147. A onderdonkii DSM19147 can lower inflammation both at a steady state and after transplantation and may serve as an anti-inflammatory probiotic beneficial for transplant recipients.

Making Connections that Count - a Case Study of the Family Referral Service in Schools Program on the Central Coast, New South Wales, Australia.

Introduction: Adverse childhood experiences (ACEs) are associated with health and social problems in later life, with an early intervention highly desirable for better outcomes. Description: The Family-Referral-Services-In-Schools (FRSIS) is an early-intervention case management program for children and families with complex unmet needs, providing access to family support, housing, mental health care, and/or drug and alcohol services. The in-school trial setting was aimed at improving service uptake which was low in its community counterpart. Discussion: FRSIS was a well-regarded intervention that reduced barriers to access for vulnerable families. The school setting and non-government agency service provision led to increased acceptability and trust. The program reached 5% of the student population. Support was tailored to family need, which was often complex and involved both children and caregivers. Initially, the multi-agency partnership and governance oversight group championed the service and enabled the pilot to be established, however funding uncertainty and competing priorities saw leadership support ebb away despite operational success. Conclusion: The FRSIS model breaks down numerous barriers to accessing care for vulnerable families by its generalist nature and tailored approach and represents a high-trust approach to brokering appropriate care. Consistency in leadership support was a missed opportunity for program sustainability.

Immune response to the mRNA COVID-19 vaccine in hemodialysis patients: cohort study.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: A transcriptomic analysis of the immune response to the Covid-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells (PBMCs) was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and seven days after the second dose (V2D7) using anti-Spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified six months after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with predominant T cell activity in controls one week after the first vaccination dose, compared to predominant myeloid cell activity in HD at this time point. HD demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p < 0.05). Anti-spike IgG remained elevated above baseline at six months in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusion: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance hemodialysis subjects (HD) comparable to healthy controls (HC) and identify transcriptomic and clinical predictors of anti-Spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of end stage renal disease (ESRD). Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Trimer IgG and neutralising antibody response to COVID-19 mRNA vaccination in individuals with sarcoidosis.

Background: Individuals with sarcoidosis are at higher risk for infection owing to underlying disease pathogenesis and need for immunosuppressive treatment. Current knowledge as to how subjects with sarcoidosis respond to different forms of vaccination is limited. We examined quantitative and functional antibody response to COVID-19 vaccination in infection-naive subjects with and without sarcoidosis. Methods: Our prospective cohort study recruited 14 subjects with biopsy-proven sarcoidosis and 27 age-sex matched controls who underwent a two-shot series of the BNT162b2 mRNA vaccine at the University of Illinois at Chicago. Baseline, 4-week and 6-month trimer spike protein IgG and neutralising antibody (nAb) titres were assessed. Correlation and multivariate regression analysis was conducted. Results: Sarcoidosis subjects had a significant increase in short-term antibody production to a level comparable to controls; however, IgG titres significantly declined back to baseline levels by 6 months. Corresponding neutralising assays revealed robust nAb titres in sarcoidosis subjects that persisted at 6 months. A significant and strong correlation between IgG and nAb titres across all time points was observed in the control group. However within the sarcoidosis group, a significant but weak correlation between antibody levels was found. Overall, IgG levels were poor predictors of nAb titres at short- or long-term time points. Conclusions: Sarcoidosis subjects exhibit nAb induced by the BNT162b2 mRNA SARS-CoV-2 vaccine at levels comparable to controls that persists at 6 months indicating conferred immunity. Trimer IgG levels are poor predictors of nAb in subjects with sarcoidosis. Studies of further antibody immunoglobulins and subtypes warrant investigation.

Analysis of Exosomal MicroRNA Dynamics in Response to Rhinovirus Challenge in a Longitudinal Case-Control Study of Asthma.

Asthma symptoms are often exacerbated by the common-cold-causing rhinovirus (RV). In this study, we characterized the temporal behavior of circulating exosomal microRNAs (ExoMiRNAs) in a longitudinal bi-phasic case-control study of mild asthmatics (n = 12) and matched non-atopic healthy controls (n = 12) inoculated with rhinovirus. We aimed to define clinical and immunologic characteristics associated with differentially expressed (DE) miRNAs. In total, 26 DE ExoMiRNAs, including hsa-let-7f-5p, hsa-let-7a-5p, hsa-miR-122-5p, hsa-miR-101-3p, and hsa-miR-126-3p, were identified between asthmatic and healthy subjects after inoculation with RV. Time series clustering identified a unique Cluster of Upregulated DE ExoMiRNAs with augmenting mean expression and a distinct Cluster of Downregulated DE ExoMiRNAs with mean expression decline in asthmatic subjects upon RV challenge. Notably, the Upregulated Cluster correlated with Th1 and interferon-induced cytokines/chemokines (IFN-γ and IFN-γ-inducible protein-10) and interleukin-10 (IL-10). Conversely, the Downregulated Cluster correlated with IL-13, a Th2 cytokine, pulmonary function measurements (FVC%, FEV1%, and PEF%), and inflammatory biomarkers (FeNO, eosinophil%, and neutrophil%). Key ExoMiRNA-target gene and anti-viral defense mechanisms of the Upregulated and Downregulated Clusters were identified by network and gene enrichment analyses. Our findings provide insight into the regulatory role of ExoMiRNAs in RV-induced asthma.

Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis.

Introduction: In sarcoidosis, peripheral lymphopenia and anergy have been associated with increased inflammation and maladaptive immune activity, likely promoting development of chronic and progressive disease. However, the molecular mechanisms that lead to reduced lymphocyte proportions, particularly CD4+ T-cells, have not been fully elucidated. We posit that paradoxical peripheral lymphopenia is characterized by a dysregulated transcriptomic network associated with cell function and fate that results from altered transcription factor targeting activity. Methods: Messenger RNA-sequencing (mRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) from ACCESS study subjects with sarcoidosis and matched controls and findings validated on a sarcoidosis case-control cohort and a sarcoidosis case series. Preserved PBMC transcriptomic networks between case-control cohorts were assessed to establish cellular associations with gene modules and define regulatory targeting involved in sarcoidosis immune dysregulation utilizing weighted gene co-expression network analysis and differential transcription factor involvement analysis. Network centrality measures identified master transcriptional regulators of subnetworks related to cell proliferation and death. Predictive models of differential PBMC proportions constructed from ACCESS target gene expression corroborated the relationship between aberrant transcription factor regulatory activity and imputed and clinical PBMC populations in the validation cohorts. Results: We identified two unique and preserved gene modules significantly associated with sarcoidosis immune dysregulation. Strikingly, increased expression of a monocyte-driven, and not a lymphocyte-driven, gene module related to innate immunity and cell death was the best predictor of peripheral CD4+ T-cell proportions. Within the gene network of this monocyte-driven module, TLE3 and CBX8 were determined to be master regulators of the cell death subnetwork. A core gene signature of differentially over-expressed target genes of TLE3 and CBX8 involved in cellular communication and immune response regulation accurately predicted imputed and clinical monocyte expansion and CD4+ T-cell depletion. Conclusions: Altered transcriptional regulation associated with aberrant gene expression of a monocyte-driven transcriptional network likely influences lymphocyte function and survival. Although further investigation is warranted, this indicates that crosstalk between hyperactive monocytes and lymphocytes may instigate peripheral lymphopenia and underlie sarcoidosis immune dysregulation and pathogenesis. Future therapies selectively targeting master regulators, or their targets, may mitigate dysregulated immune processes in sarcoidosis and disease progression.

Men, suicide, and family and interpersonal violence: A mixed methods exploratory study.

Research has shown a link between gender, violence, and suicide. This relationship is complex, and few empirical studies have explored suicide and family and interpersonal violence perpetrated by men. Drawing on a coronial dataset of suicide cases and a mixed methods design, this study integrated a quantitative analysis of 155 suicide cases with a qualitative analysis of medico-legal reports from 32 cases. Findings showed different types and patterns of family and intimate partner violence for men who died by suicide. Men used violence in response to conflict, but also to dominate women. Cumulative, interwoven effects of violence, mental illness, alcohol and other drug use, socioeconomic, and psychosocial circumstances were observed in our study population. However, the use of violence and suicidal behaviour was also a deliberate and calculated response by which some men sought to maintain influence or control over women. Health and criminal justice interventions served as short-term responses to violence, mental illness, and suicidal behaviour, but were of limited assistance.

Web-Based Technologies to Support Carers of People Living With Dementia: Protocol for a Mixed Methods Stepped-Wedge Cluster Randomized Controlled Trial.

BACKGROUND: Informal carers play a significant role in supporting people living with dementia; however, carers in rural areas are often isolated, with limited access to support services. Although dementia-friendly communities provide valued support for carers, access to them is limited as they are few and geographically dispersed. OBJECTIVE: This study's aim was to increase support and services for rural informal carers of people living with dementia by using information and communication technologies accessed through an integrated website and mobile app-the Verily Connect app. The objective of this protocol is to detail the research design used in a complex study that was situated in a challenging real-world setting integrating web-based and on-ground technology and communication. Therefore, it is anticipated that this protocol will strengthen the research of others exploring similar complex concepts. METHODS: A stepped-wedge, open-cohort cluster randomized controlled trial was conducted to implement Verily Connect across 12 rural Australian communities. The Verily Connect intervention delivered web-based, curated information about dementia, a localized directory of dementia services and support, group and individual chat forums, and peer support through videoconference. During the implementation phase of 32 weeks, Verily Connect was progressively implemented in four 8-weekly waves of 3 communities per wave. Usual care, used as a comparator, was available to carers throughout the study period. Participants and researchers were unblinded to the intervention. There were 3 cohorts of participants: carers, volunteers, and staff; participants were recruited from their communities. The primary outcome measure was perceived carer social support measured using the Medical Outcomes Study-Social Support Survey. Volunteers and staff provided feedback on their participation in Verily Connect as qualitative data. Qualitative data were collected from all cohorts of participants through interviews and focus groups. Process evaluation data were collected through interviews and memos written by research staff. Data on the costs of implementing Verily Connect were collected by the research team members and evaluated by a health economist. RESULTS: Between August 2018 and September 2019, a total of 113 participants were recruited. There were 37 (32.7%) carers, 39 (34.5%) volunteers, and 37 (32.7%) health service staff. The study was complex because of the involvement of multiple and varied communities of carers, volunteers, health service staff, and research team members originating from 5 universities. Web-based technologies were used as intervention strategies to support carers and facilitate the process of undertaking the study. CONCLUSIONS: The Verily Connect trial enabled the testing and further development of a web-based approach to increasing support for carers of people living with dementia across a diverse rural landscape in Australia. This protocol provides an example of how to conduct a pragmatic evaluation of a complex and co-designed intervention involving multiple stakeholders. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618001213235; https://tinyurl.com/4rjvrasf. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/33023.

Healthful eating patterns, serum metabolite profile and risk of diabetes in a population-based prospective study of US Hispanics/Latinos.

AIMS/HYPOTHESIS: We aimed to evaluate associations of multiple recommended dietary patterns (i.e. the alternate Mediterranean diet [aMED], the Healthy Eating Index [HEI]-2015 and the healthful Plant-based Diet Index [hPDI]) with serum metabolite profile, and to examine dietary-pattern-associated metabolites in relation to incident diabetes. METHODS: We included 2842 adult participants free from diabetes, CVD and cancer during baseline recruitment of the Hispanic Community Health Study/Study of Latinos. Metabolomics profiling of fasting serum was performed using an untargeted approach. Dietary pattern scores were derived using information collected by two 24 h dietary recalls. Dietary-pattern-associated metabolites were identified using multivariable survey linear regressions and their associations with incident diabetes were assessed using multivariable survey Poisson regressions with adjustment for traditional risk factors. RESULTS: We identified eight metabolites (mannose, γ/ß-tocopherol, N1-methylinosine, pyrraline and four amino acids) that were inversely associated with all dietary scores. These metabolites were detrimentally associated with various cardiometabolic risk traits, especially insulin resistance. A score comprised of these metabolites was associated with elevated risk of diabetes (RRper SD 1.54 [95% CI 1.29, 1.83]), and this detrimental association appeared to be attenuated or eliminated by having a higher score for aMED (pinteraction = 0.0001), HEI-2015 (pinteraction = 0.020) or hPDI (pinteraction = 0.023). For example, RR (95% CI) of diabetes for each SD increment in the metabolite score was 1.99 (1.44, 2.37), 1.67 (1.17, 2.38) and 1.08 (0.86, 1.34) across the lowest to the highest tertile of aMED score, respectively. CONCLUSIONS/INTERPRETATION: Various recommended dietary patterns were inversely related to a group of metabolites that were associated with elevated risk of diabetes. Adhering to a healthful eating pattern may attenuate or eliminate the detrimental association between metabolically unhealthy serum metabolites and risk of diabetes.

Long non-coding RNAs (lncRNAs) NEAT1 and MALAT1 are differentially expressed in severe COVID-19 patients: An integrated single-cell analysis.

Hyperactive and damaging inflammation is a hallmark of severe rather than mild Coronavirus disease 2019 (COVID-19). To uncover key inflammatory differentiators between severe and mild COVID-19, we applied an unbiased single-cell transcriptomic analysis. We integrated two single-cell RNA-seq datasets with COVID-19 patient samples, one that sequenced bronchoalveolar lavage (BAL) cells and one that sequenced peripheral blood mononuclear cells (PBMCs). The combined cell population was then analyzed with a focus on genes associated with disease severity. The immunomodulatory long non-coding RNAs (lncRNAs) NEAT1 and MALAT1 were highly differentially expressed between mild and severe patients in multiple cell types. Within those same cell types, the concurrent detection of other severity-associated genes involved in cellular stress response and apoptosis regulation suggests that the pro-inflammatory functions of these lncRNAs may foster cell stress and damage. Thus, NEAT1 and MALAT1 are potential components of immune dysregulation in COVID-19 that may provide targets for severity related diagnostic measures or therapy.

Taurodeoxycholic acid and valine reverse obesity-associated augmented alloimmune responses and prolong allograft survival.

Obesity initiates a chronic inflammatory network linked to perioperative complications and increased acute rejection rates in organ transplantation. Bariatric surgery is the most effective treatment of obesity recommended for morbidly obese transplant recipients. Here, we delineated the effects of obesity and bariatric surgery on alloimmunity and transplant outcomes in diet-induced obese (DIO) mice. Allograft survival was significantly shorter in DIO-mice. When performing sleeve gastrectomies (SGx) prior to transplantation, we found attenuated T cell-derived alloimmune responses resulting in prolonged allograft survival. Administering taurodeoxycholic acid (TDCA) and valine, metabolites depleted in DIO-mice and restored through SGx, prolonged graft survival in DIO-mice comparable with SGx an dampened Th1 and Th17 alloimmune responses while Treg frequencies and CD4+ T cell-derived IL-10 production were augmented. Moreover, in recipient animals treated with TDCA/valine, levels of donor-specific antibodies had been reduced. Mechanistically, TDCA/valine restrained inflammatory M1-macrophage polarization through TGR5 that compromised cAMP signaling and inhibited macrophage-derived T cell activation. Consistently, administering a TGR5 agonist to DIO-mice prolonged allograft survival. Overall, we provide novel insights into obesity-induced inflammation and its impact on alloimmunity. Furthermore, we introduce TDCA/valine as a noninvasive alternative treatment for obese transplant patients.

Transmission Dynamics of Large Coronavirus Disease Outbreak in Homeless Shelter, Chicago, Illinois, USA, 2020.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential for rapid transmission in congregate settings. We describe the multidisciplinary response to an outbreak of coronavirus disease (COVID-19) in a large homeless shelter in Chicago, Illinois, USA. The response to the outbreak included 4 rounds of mass PCR testing of all staff and residents and subsequent isolation of persons who tested positive for SARS-CoV-2. We further describe the dynamics of the shelter outbreak by fitting a modified susceptible-exposed-infectious-recovered compartmental model incorporating the widespread SARS-CoV-2 testing and isolation measures implemented in this shelter. Our model demonstrates that rapid transmission of COVID-19 in the shelter occurred before the outbreak was detected; rates of transmission declined after widespread testing and isolation measures were put in place. Overall, we demonstrate the feasibility of mass PCR testing and isolation in congregate settings and suggest the necessity of prompt response to suspected COVID-19 outbreaks in homeless shelters.