Dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis.

BACKGROUND: Colitis caused by checkpoint inhibitors (CPI) is frequent and is treated with empiric steroids, but CPI colitis mechanisms in steroid-experienced or refractory disease are unclear. METHODS: Using colon biopsies and blood from predominantly steroid-experienced CPI colitis patients, we performed multiplexed single-cell transcriptomics and proteomics to nominate contributing populations. RESULTS: CPI colitis biopsies showed enrichment of CD4+resident memory (RM) T cells in addition to CD8+ RM and cytotoxic CD8+ T cells. Matching T cell receptor (TCR) clonotypes suggested that both RMs are progenitors that yield cytotoxic effectors. Activated, CD38+ HLA-DR+ CD4+ RM and cytotoxic CD8+ T cells were enriched in steroid-experienced and a validation data set of steroid-naïve CPI colitis, underscoring their pathogenic potential across steroid exposure. Distinct from ulcerative colitis, CPI colitis exhibited perturbed stromal metabolism (NAD+, tryptophan) impacting epithelial survival and inflammation. Endothelial cells in CPI colitis after anti-TNF and anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) upregulated the integrin α4ß7 ligand molecular vascular addressin cell adhesion molecule 1 (MAdCAM-1), which may preferentially respond to vedolizumab (anti-α4ß7). CONCLUSIONS: These findings nominate CD4+ RM and MAdCAM-1+ endothelial cells for targeting in specific subsets of CPI colitis patients.

Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis.

Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we perform single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

Maternal and child nutrition services associated with nutritional knowledge and practices, India.

Objective: To evaluate whether maternal and child nutrition activities provided through the Indian Integrated Child Development Services scheme in India were associated with improved nutritional knowledge and practices among beneficiary women. Methods: We used a multistage sampling design to randomly select 4400 pregnant women or mothers of children younger than 2 years for a cross-sectional telephone survey. The respondents were beneficiaries of the scheme from across 11 Indian states. We used multivariate regression models controlling for sociodemographic factors to estimate the association between: scheme activities and nutrition messages heard; and scheme activities and nutrition practices. We also estimated the proportion of the total association with nutrition practices which was mediated by nutrition messages. Results: Among 110 regression models testing unique pairs of seven activities and 18 nutrition messages, 103 showed a statistically significant positive relationship (median risk ratio, RR: 1.14). For activities and nine nutrition practices, 39 out of 54 tested pairs were significantly associated (median RR: 1.16). We observed statistically significant mediation through nutrition messages for 28 out of 42 tested pairs of activities and nutrition practices. Conclusion: Receipt of the scheme's activities was associated with improved nutrition knowledge and practices. Improvements in practices were statistically mediated by improvements in knowledge. These findings suggest that a large-scale nutrition scheme with a strong counselling component could successfully change beneficiary behaviours.

Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis.

Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we performed single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

Clinical and laboratory features of COVID-19 illness and outcomes in immunocompromised individuals during the first pandemic wave in Sydney, Australia.

People with immunocompromising conditions are at increased risk of SARS-CoV-2 infection and mortality, however early in the pandemic it was challenging to collate data on this heterogenous population. We conducted a registry study of immunocompromised individuals with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection from March-October 2020 in Sydney, Australia to understand clinical and laboratory outcomes in this population prior to the emergence of the Delta variant. 27 participants were enrolled into the study including people with a haematologic oncologic conditions (n = 12), secondary immunosuppression (N = 8) and those with primary or acquired immunodeficiency (i.e. HIV; N = 7). All participants had symptomatic COVID-19 with the most common features being cough (64%), fever (52%) and headache (40%). Five patients demonstrated delayed SARS-CoV-2 clearance lasting three weeks to three months. The mortality rate in this study was 7% compared to 1.3% in the state of New South Wales Australia during the same period. This study provides data from the first eight months of the pandemic on COVID-19 outcomes in at-risk patient groups.

Concomitant exposure to air pollution, green space, and noise and risk of stroke: a cohort study from Denmark.

Background: Air pollution, road traffic noise, and green space are correlated factors, associated with risk of stroke. We investigated their independent relationship with stroke in multi-exposure analyses and estimated their cumulative stroke burden. Methods: For all persons, ≥50 years of age and living in Denmark from 2005 to 2017, we established complete address histories and estimated running 5-year mean exposure to fine particles (PM2.5), ultrafine particles, elemental carbon, nitrogen dioxide (NO2), and road traffic noise at the most, and least exposed façade. For air pollutants, we estimated total, and non-traffic contributions. Green space around the residence was estimated from land use maps. Hazard ratios (HR) and 95% confidence limits (CL) were estimated with Cox proportional hazards models and used to calculate cumulative risk indices (CRI). We adjusted for the individual and sociodemographic covariates available in our dataset (which did not include information about individual life styles and medical conditions). Findings: The cohort accumulated 18,344,976 years of follow-up and 94,256 cases of stroke. All exposures were associated with risk of stroke in single pollutant models. In multi-pollutant analyses, only PM2.5 (HR: 1.058, 95% CI: 1.040-1.075) and noise at most exposed façade (HR: 1.033, 95% CI: 1.024-1.042) were independently associated with a higher risk of stroke. Both noise and air pollution contributed substantially to the CRI (1.103, 95% CI: 1.092-1.114) in the model with noise, green space, and total PM2.5 concentrations. Interpretation: Environmental exposure to air pollution and noise were both independently associated with risk of stroke. Funding: Health Effects Institute (HEI) (Assistance Award No. R-82811201).

Source-Specific Air Pollution Including Ultrafine Particles and Risk of Myocardial Infarction: A Nationwide Cohort Study from Denmark.

BACKGROUND: Air pollution is negatively associated with cardiovascular health. Impediments to efficient regulation include lack of knowledge about which sources of air pollution contributes most to health burden and few studies on effects of the potentially more potent ultrafine particles (UFP). OBJECTIVE: The authors aimed to investigate myocardial infarction (MI) morbidity and specific types and sources of air pollution. METHODS: We identified all persons living in Denmark in the period 2005-2017, age >50 y and never diagnosed with MI. We quantified 5-y running time-weighted mean concentrations of air pollution at residencies, both total and apportioned to traffic and nontraffic sources. We evaluated particulate matter (PM) with aerodynamic diameter ≤2.5µm (PM2.5), <0.1µm (UFP), elemental carbon (EC), and nitrogen dioxide (NO2). We used Cox proportional hazards models, with adjustment for time-varying exposures, and personal and area-level demographic and socioeconomic covariates from high-quality administrative registers. RESULTS: In this nationwide cohort of 1,964,702 persons (with 18 million person-years of follow-up and 71,285 cases of MI), UFP and PM2.5 were associated with increased risk of MI with hazard ratios (HRs) per interquartile range (IQR) of 1.040 [95% confidence interval (CI): 1.025, 1.055] and 1.053 (95% CI: 1.035, 1.071), respectively. HRs per IQR of UFP and PM2.5 from nontraffic sources were similar to the total (1.034 and 1.051), whereas HRs for UFP and PM2.5 from traffic sources were smaller (1.011 and 1.011). The HR for EC from traffic sources was 1.013 (95% CI: 1.003, 1.023). NO2 from nontraffic sources was associated with MI (HR=1.048; 95% CI: 1.034, 1.062) but not from traffic sources. In general, nontraffic sources contributed more to total air pollution levels than national traffic sources. CONCLUSIONS: PM2.5 and UFP from traffic and nontraffic sources were associated with increased risk of MI, with nontraffic sources being the dominant source of exposure and morbidity. https://doi.org/10.1289/EHP10556.

Mortality and costs related to severe acute pancreatitis in the intensive care units of Australia and New Zealand (ANZ), 2003-2020.

BACKGROUND AND OBJECTIVE: Comprehensive data on the burden of severe acute pancreatitis (SAP) in global intensive care units (ICUs) and trends over time are lacking. Our objective was to compare trends in hospital and ICU mortality, in-hospital and ICU length of stay, and costs related to ICU admission in Australia and New Zealand (ANZ) for SAP. METHODS: We performed a retrospective, observational, cohort study of ICU admissions reported to the ANZ Intensive Care Society Adult Patient Database over three consecutive six-year time periods from 2003 to 2020. RESULTS: 12,635 patients with SAP from 189 ICUs in ANZ were analysed. No difference in adjusted hospital mortality (11.4% vs 11.5% vs 11.0%, p = 0.85) and ICU mortality rates (7.5% vs 8.0% vs 8.1%, p = 0.73) were noted over the study period. Median length of hospital admission reduced over time (13.9 days in 2003-08, 13.1 days in 2009-14 and 12.5 days in 2015-20; p < 0.01). No difference in length of ICU stay was noted over the study period (p = 0.13). The cost of managing SAP in ANZ ICUs remained constant over the three time periods. CONCLUSIONS: In critically-ill SAP patients in ANZ, no change in mortality has been noted over nearly two decades. There was a slight reduction in hospital stay (1 day), while the length of ICU stay remained unchanged. Given the significant costs related to care of patients with SAP in ICU, these findings highlight the need to prioritise resource allocation for healthcare delivery and targeted clinical research to identify treatments aimed at reducing mortality.

Effects of Sociodemographic Characteristics, Comorbidity, and Coexposures on the Association between Air Pollution and Type 2 Diabetes: A Nationwide Cohort Study.

BACKGROUND: Exposure to air pollution has been associated with a higher risk of type 2 diabetes (T2D), but studies investigating whether deprived groups are more susceptible to the harmful effects of air pollution are inconsistent. OBJECTIVES: We aimed to investigate whether the association between air pollution and T2D differed according to sociodemographic characteristics, comorbidity, and coexposures. METHODS: We estimated residential exposure to PM2.5, ultrafine particles (UFP), elemental carbon, and NO2 for all persons living in Denmark in the period 2005-2017. In total, 1.8 million persons 50-80 y of age were included for main analyses of whom 113,985 developed T2D during follow-up. We conducted additional analyses on 1.3 million persons age 35-50 y. Using Cox proportional hazards model (relative risk) and Aalens additive hazard model (absolute risk), we calculated associations between 5-y time-weighted running means of air pollution and T2D in strata of sociodemographic variables, comorbidity, population density, road traffic noise, and green space proximity. RESULTS: Air pollution was associated with T2D, especially among people age 50-80 y, with hazard ratios of 1.17 [95% confidence interval (CI): 1.13, 1.21] per 5 µg/m3 PM2.5 and 1.16 (95% CI: 1.13, 1.19) per 10,000 UFP/cm3. In the age 50-80 y population, we found higher associations between air pollution and T2D among men in comparison with women, people with lower education vs. individuals with high education, people with medium income vs. those with low or high income, people cohabiting vs. those living alone, and people with comorbidities vs. those without comorbidities. We observed no marked changes according to occupation, population density, road noise, or surrounding greenness. In the age 35-50 y population, similar tendencies were observed, except in relation to sex and occupation, where we observed associations with air pollution only among women and blue-collar workers. DISCUSSION: We found stronger associations between air pollution and T2D among people with existing comorbidities and weaker associations among people with high socioeconomic status in comparison with those with lower socioeconomic status. https://doi.org/10.1289/EHP11347.

SARS-CoV-2 infection of airway organoids reveals conserved use of Tetraspanin-8 by Ancestral, Delta, and Omicron variants.

Ancestral SARS coronavirus-2 (SARS-CoV-2) and variants of concern (VOC) caused a global pandemic with a spectrum of disease severity. The mechanistic explaining variations related to airway epithelium are relatively understudied. Here, we biobanked airway organoids (AO) by preserving stem cell function. We optimized viral infection with H1N1/PR8 and comprehensively characterized epithelial responses to SARS-CoV-2 infection in phenotypically stable AO from 20 different subjects. We discovered Tetraspanin-8 (TSPAN8) as a facilitator of SARS-CoV-2 infection. TSPAN8 facilitates SARS-CoV-2 infection rates independently of ACE2-Spike interaction. In head-to-head comparisons with Ancestral SARS-CoV-2, Delta and Omicron VOC displayed lower overall infection rates of AO but triggered changes in epithelial response. All variants shared highest tropism for ciliated and goblet cells. TSPAN8-blocking antibodies diminish SARS-CoV-2 infection and may spur novel avenues for COVID-19 therapy.

Oral iron supplementation and anaemia in children according to schedule, duration, dose and cosupplementation: a systematic review and meta-analysis of 129 randomised trials.

INTRODUCTION: WHO guidelines on iron supplementation among children call for further research to identify the optimal schedule, duration, dose and cosupplementation regimen. METHODS: A systematic review and meta-analysis of randomised controlled trials was undertaken. Randomised controlled trials providing ≥30 days of oral iron supplementation versus placebo or control to children and adolescents aged <20 years were eligible. Random-effects meta-analysis was used to summarise the potential benefits and harms of iron supplementation. Meta-regression was used to estimate iron effect heterogeneity. RESULTS: 129 trials with 201 intervention arms randomised 34 564 children. Frequent (3-7/week) and intermittent (1-2/week) iron regimens were similarly effective at decreasing anaemia, iron deficiency and iron deficiency anaemia (p heterogeneity >0.05), although serum ferritin levels and (after adjustment for baseline anaemia) haemoglobin levels increased more with frequent supplementation. Shorter (1-3 months) versus longer (7+ months) durations of supplementation generally showed similar benefits after controlling for baseline anaemia status, except for ferritin which increased more with longer duration of supplementation (p=0.04). Moderate-dose and high-dose supplements were more effective than low-dose supplements at improving haemoglobin (p=0.004), ferritin (p=0.008) and iron deficiency anaemia (p=0.02), but had similar effects to low-dose supplements for overall anaemia. Iron supplementation provided similar benefits when administered alone or in combination with zinc or vitamin A, except for an attenuated effect on overall anaemia when iron was cosupplemented with zinc (p=0.048). CONCLUSIONS: Weekly and shorter duration iron supplementation at moderate or high doses might be optimal approaches for children and adolescents at risk of deficiency. TRIAL REGISTRATION NUMBER: CRD42016039948.

Prioritizing outcome measures after aneurysmal subarachnoid hemorrhage: A q-sort survey of patients, health care providers and researchers.

Objective: To understand which outcome measures patients and their families, health care providers, and researchers prioritize after aneurysmal subarachnoid hemorrhage (aSAH). Methods: We conducted a cross-sectional q-sort survey with participants from three key stakeholder groups. Potential outcomes were identified from interviews and focus groups. Participants were purposively sampled to achieve diversity based on stakeholder group, geography, and profession. Respondents sorted 27 outcomes in a quasi-normally distributed grid (Q-Sort) from most to least important. Principal components analysis was used to determine similarities in the way participants sorted the outcome measures resulting in distinct groupings. Overall rankings were also reported. Results: 112 participants were invited. 70 responded and 64 participants from 25 different countries completed a Q-sort. Balanced stakeholder representation was achieved. Five distinct patterns were identified based on survival, pathophysiological, psychological, resource use, and functional outcome measures. Quality of life as reported by the patient was the highest ranked outcome measure followed by independence and functional measures. Survival and biomedical outcomes were ranked in the middle and cost measures last. Conclusions: In this diverse sample of key stakeholders, we characterized several distinct perspectives with respect to outcome measure selection in aSAH. We did not identify a clear pattern of opinion based on stakeholder group or other participant characteristics. Patient-reported measure of quality of life was ranked the most important overall with function and independence also highly rated. These results will assist study design and inform efforts to improve outcome selection in aSAH research.

Frontline workers: Mediators of mucosal immunity in community acquired pneumonia and COVID-19.

The current COVID-19 pandemic has highlighted a need to further understand lung mucosal immunity to reduce the burden of community acquired pneumonia, including that caused by the SARS-CoV-2 virus. Local mucosal immunity provides the first line of defence against respiratory pathogens, however very little is known about the mechanisms involved, with a majority of literature on respiratory infections based on the examination of peripheral blood. The mortality for severe community acquired pneumonia has been rising annually, even prior to the current pandemic, highlighting a significant need to increase knowledge, understanding and research in this field. In this review we profile key mediators of lung mucosal immunity, the dysfunction that occurs in the diseased lung microenvironment including the imbalance of inflammatory mediators and dysbiosis of the local microbiome. A greater understanding of lung tissue-based immunity may lead to improved diagnostic and prognostic procedures and novel treatment strategies aimed at reducing the disease burden of community acquired pneumonia, avoiding the systemic manifestations of infection and excess morbidity and mortality.

Made to measure-Selecting outcomes in aneurysmal subarachnoid hemorrhage research.

There has been limited new high-level evidence generated to guide aneurysmal subarachnoid hemorrhage (aSAH) management in the past decade. The choice of outcome measures used in aSAH clinical trials may be one of the factors hindering progress. In this narrative review we consider the current process for determining "what" to measure in aSAH and identify some of the shortcomings of these approaches. A consideration of the unique clinical course of aSAH is then discussed and how this impacts on selecting the best timepoints to assess change in the chosen constructs. We also review the how to critically appraise different measurement instruments and some of the issues with how these are applied in the context of aSAH. We conclude with current initiatives to improve outcome selection in aSAH and future directions in the research agenda.

Magnetic Bloch oscillations and domain wall dynamics in a near-Ising ferromagnetic chain.

When charged particles in periodic lattices are subjected to a constant electric field, they respond by oscillating. Here we demonstrate that the magnetic analogue of these Bloch oscillations are realised in a ferromagnetic easy axis chain. In this case, the "particles" undergoing oscillatory motion in the presence of a magnetic field are domain walls. Inelastic neutron scattering reveals three distinct components of the low energy spin-dynamics including a signature Bloch oscillation mode. Using parameter-free theoretical calculations, we are able to account for all features in the excitation spectrum, thus providing detailed insights into the complex dynamics in spin-anisotropic chains.

Risk of community- and hospital-acquired bacteremia and profile of antibiotic resistance in children hospitalized with severe acute malnutrition in Niger.

OBJECTIVE: To estimate the prevalence and antibiotic resistance profile of community- and hospital-acquired bacteremia among hospitalized children with severe acute malnutrition in Niger. METHODS: A descriptive, longitudinal study was conducted in an intensive nutritional rehabilitation center in Madarounfa, Niger. Children aged 6 to 59 months admitted for inpatient treatment of complicated severe acute malnutrition (n=2187) had blood specimens drawn at admission to assess prevalence of community-acquired bacteremia. Subsequent specimens were drawn per physician discretion to assess incidence of hospital-acquired bacteremia. Antibiotic susceptibility testing was performed on positive blood cultures. RESULTS: The prevalence of community-acquired bacteremia at admission was at least 9.1% (95% confidence interval [CI]: 8.1, 10.4%), with non-typhoid Salmonella identified in over half (57.8%) of cases. The cumulative incidence of hospital-acquired bacteremia was estimated at 1.2% (95% CI: 0.8, 1.7%), among which the most common organisms were Klebsiella pneumoniae (19.4%), Acinetobacter baumannii (16.1%), Enterococcus faecalis (12.9%), and Escherichia coli (12.9%). In community-acquired bacteremia, 58% cases were resistant to amoxicillin-clavulanate; 100% of hospital-acquired bacteremia cases were resistant to amoxicillin and amoxicillin-clavulanate. Mortality risk was elevated among children with hospital-acquired bacteremia (risk ratio [RR] = 9.32) and community-acquired bacteremia (RR = 2.67). CONCLUSION: Bacteremia was a significant contributor to mortality. Antibiotic resistance poses a challenge to effective clinical management of severe acute malnutrition.

Assessing public financing for nutrition in Bhutan, Nepal and Sri Lanka.

The objective of this study was to assess public financing for nutrition in Bhutan, Nepal and Sri Lanka to identify limitations of available data and to discuss policy implications. A variant of the Scaling Up Nutrition Movement methodology was used. Budget allocations and expenditures for relevant government ministries during 2012-2018 were identified. Nutrition-related line items were tagged using definitions of nutrition-specific and nutrition-sensitive interventions. Data were aggregated by year and calculated in constant United States dollars (USD). Expenditures by year were presented as a proportion of gross domestic product and general government expenditures. The percent utilization of budget allocations and proportion of funding from central government sources were determined. Per capita expenditures on nutrition-specific interventions varied from USD 1.08-8.76 and for nutrition-sensitive interventions varied from USD 20.22-51.20. Nutrition-specific expenditures as a percent of gross domestic product ranged from 0.08% in Sri Lanka in 2017% to 0.34% in Nepal in 2016. The median utilization rate was 64% for nutrition-specific and 84% for nutrition-sensitive interventions. Nutrition-specific funding financed by the central government was 90.7% in Bhutan and 99.4% in Sri Lanka. This study revealed the need to prioritize and invest in evidence-based interventions, including balancing investments in nutrition-specific versus -sensitive interventions. Challenges in estimation of nutrition expenditures and cross-country comparison were also observed, highlighting the need for appropriate nutrition line item tagging and standardized systems for data collection.

Iron supplementation and paediatric HIV disease progression: a cohort study among children receiving routine HIV care in Dar es Salaam, Tanzania.

BACKGROUND: Anaemia is common among HIV-infected children and iron supplementation is prescribed routinely for the prevention and management of anaemia among children. Limited evidence suggests iron supplementation may have adverse effects among HIV-infected populations. We aimed to estimate the effect of iron supplement use on mortality, disease progression and haematological outcomes among HIV-infected children in Dar es Salaam, Tanzania. METHODS: A prospective cohort study was conducted among HIV-infected children (aged 0-14 years) receiving antiretroviral treatment or supportive care between October 2004 and September 2014. Clinical data were recorded on morbidity and vital status, haematological status and prescriptions at each clinical visit. Cox proportional hazards models adjusted for time-varying covariates were used to estimate the association of time-varying iron supplementation on the hazard rate of mortality, HIV disease stage progression, tuberculosis incidence and anaemia and microcytosis persistence. RESULTS: In all, 4229 children were observed during 149 260 clinic visits for a mean follow-up of 2.9 years. After adjustment for time-varying clinical covariates, time-varying iron supplementation was associated with a 2.87 times higher hazard rate of mortality (95% CI: 1.70, 4.87) and a 1.48 times higher hazard rate of HIV disease stage progression (95% CI: 1.10, 1.98). Iron supplementation was also associated with a lower rate of anaemia persistence (HR = 0.47; 95% CI: 0.37, 0.61). No differences in the association between iron supplementation and clinical outcomes were observed by antiretroviral therapy or anaemia status. CONCLUSIONS: Iron supplementation may increase the risk of HIV disease stage progression and mortality among HIV-infected children, while reducing the risk of anaemia.