Shared neutrophil and T cell dysfunction is accompanied by a distinct interferon signature during severe febrile illnesses in children.

Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children.

Cell type- and layer-specific plasticity of olfactory bulb interneurons following olfactory sensory neuron ablation.

Lifelong neurogenesis endows the mouse olfactory system with a capacity for regeneration that is unique in the mammalian nervous system. Throughout life, olfactory sensory neurons (OSNs) are generated from olfactory epithelium (OE) stem cells in the nose, while the subventricular zone generates neuroblasts that migrate to the olfactory bulb (OB) and differentiate into multiple populations of inhibitory interneurons. Methimazole (MMZ) selectively ablates OSNs, but OE neurogenesis enables OSN repopulation and gradual recovery of OSN input to the OB within 6 weeks. However, it is not known how OB interneurons are affected by this loss and subsequent regeneration of OSN input following MMZ treatment. We found that dopaminergic neuron density was significantly reduced 7-14 days post-MMZ but recovered substantially at 35 days. The density of parvalbumin-expressing interneurons was unaffected by MMZ; however, their soma size was significantly reduced at 7-14 days post-MMZ, recovering by 35 days. Surprisingly, we found a transient increase in the density of calretinin-expressing neurons in the glomerular and external plexiform layers, but not the granule cell layer, 7 days post-MMZ. This could not be accounted for by increased neurogenesis but may result from increased calretinin expression. Together, our data demonstrate cell type- and layer-specific changes in OB interneuron density and morphology after MMZ treatment, providing new insight into the range of plasticity mechanisms employed by OB circuits during loss and regeneration of sensory input.

Lifting COVID-19-associated non-pharmaceutical interventions: potential impact on notifications of infectious diseases transmitted from person to person in 2022 in Bavaria, Germany.

Background: The COVID-19 pandemic and associated non-pharmaceutical interventions (NPIs) have led to substantial decreases in case numbers of infectious diseases in several countries worldwide. As NPIs were gradually lifted, intense or out-of-season outbreaks of respiratory and gastrointestinal diseases were reported, raising the hypothesis of a potential catch-up effect of infections. By analysing surveillance data from the federal reporting system for notifiable infectious diseases, we aimed to assess the potential impact of lifting COVID-19 associated NPIs on notifications of selected infectious diseases in Bavaria, 2022. Methods: We compared influenza, chickenpox, norovirus gastroenteritis, rotavirus gastroenteritis weekly case numbers in a pre-pandemic period (2016-2019) and 2022 using two time series analyses approaches: (i) a predictive model forecasting weekly case numbers for the pandemic years 2020-2022, based on 2016-2019 data, (ii) interrupted time series model, based on 2016-2022 data, including a term per pandemic period. Results: In 2022, incidence rates were higher compared to pre-pandemic period for influenza (IRR = 3.47, 95%CI: 1.49-7.94) and rotavirus gastroenteritis (IRR = 1.36, 95%CI: 0.95-1.93), though not significant for rotavirus gastroenteritis. Conversely, case numbers remained significantly below pre-pandemic levels for chickenpox (IRR = 0.52, 95%CI: 0.41-0.65) and norovirus gastroenteritis (IRR = 0.59, 95%CI: 0.42-0.82). Seasonality changed notably for influenza, showing an earlier influenza wave compared to pre-pandemic periods. Conclusion: The lifting of NPIs was associated with heterogenic epidemiological patterns depending on the selected disease. The full impact of NPIs and their discontinuation may only become clear with continued monitoring and assessment of potential additional contributing factors.

Coverage and determinants of COVID-19 child vaccination in Munich, Germany in October 2022-January 2023: Results of the COVIP-Virenwächter study.

COVID-19 vaccination reduces the risk of severe disease, in children as well as adults. We studied COVID-19 vaccination coverage among children, parental COVID-19 vaccination intent for their children and determinants of vaccination among children to inform communication strategies. We invited parents of children aged 6 months-11 years in Munich, Germany, to an anonymous online survey between 13.10.2022 and 15.01.2023. Parents reported COVID-19 vaccination status and, for unvaccinated children, vaccination intent per child. We determined vaccination coverage (≥ 1 dose) and parental intent, and subsequently used logistic regression to identify determinants of vaccination, including the 5C psychological antecedents of vaccination (confidence, complacency, constraints, calculation, collective responsibility). In total, 339 parents reported on 591 children. Vaccination coverage was 7% (6/86) amongst 6-months-4-year-olds and 59% (295/498) amongst 5-11-year-olds. For unvaccinated 6-months-4-year-olds, 31% of parents reported high, 13% medium, 56% low vaccination intent; for 5-11-year-olds 8% reported high, 20% medium, 71% low intent. Positive determinants of vaccination were older child age, child belonging to a clinically vulnerable group, as well as parental COVID-19 vaccination, higher education level, country of birth Germany, and high level of trust in official guidelines; a negative determinant was previous vaccination refusal. For 5-11-year-olds, additional positive determinants were higher confidence and lower complacency.    Conclusion: While a substantial proportion of 5-11-year-olds were vaccinated against COVID-19, coverage was low among 6-months-4-year-olds. Parental vaccination intent for unvaccinated children was low. Vaccination communication should take into account parental socio-demographic characteristics and specifically address individual risks and benefits of child vaccination. What is Known: • COVID-19 vaccination lowers severe disease risk in all ages. • Germany recommends vaccination for 5-11-years-olds since December 2021 and for 6 months-4 year-olds since November 2022. What is New: • In Munich, vaccine uptake was high in 5-11-year-olds but parental intent for not yet vaccinated children was low; the opposite was the case for 6-months-4-year-olds; vaccination determinants were eligibility, parental education, birth country and general vaccination hesitancy; psychological antecedents were confidence and complacency. • Tailored interventions should address guidelines, health literacy, cultural sensitivity, and boost confidence in vaccines and institutions while raising awareness of COVID-19 risks for children.

Describing Elephants: An Update on the Immunopathology of Multisystem Inflammatory Syndrome in Children.

First described in 2020, multi-system inflammatory syndrome in children (MIS-C) is an, initially life-threatening, disease characterised by severe inflammation and following exposure to SARS-CoV-2. The immunopathology of MIS-C involves a hyperinflammation characterised by a cytokine storm and activation of both the innate and adaptive immune system, eventually leading to multi-organ failure. Several etiological theories are described in literature. Firstly, it is suggested that the gut plays an important role in the translocation of microbial products to the systemic circulation. Additionally, the production of autoantibodies that develop after the initial infection with SARS-CoV-2 might lead to many of its broad clinical symptoms. Finally, the superantigen theory where non-specific binding of the SARS-CoV-2 spike glycoprotein to the T-cell receptor leads to a subsequent activation of T cells, generating a powerful immune response. Despite the sudden outbreak of MIS-C and alarming messages, as of 2024, cases have declined drastically and subsequently show a less severe clinical spectrum. However, subacute cases not meeting current diagnostic criteria might be overlooked even though they represent a valuable research population. In the future, research should focus on adjusting these criteria to better understand the broad pathophysiology of MIS-C, aiding early detection, therapy, and prediction.

Rapid Market Screening to assess lead concentrations in consumer products across 25 low- and middle-income countries.

Lead exposure can have serious consequences for health and development. The neurological and behavioral effects of lead are considered irreversible. Young children are particularly vulnerable to lead poisoning. In 2020, Pure Earth and UNICEF estimated that one in three children had elevated blood lead levels above 5 µg/dL. The sources of lead exposure vary around the world and can range from household products, such as spices or foodware, to environmental pollution from nearby industries. The aim of this study was to analyze common products from markets in low- and middle-income countries (LMICs) for their lead content to determine whether they are plausible sources of exposure. In 25 LMICs, the research teams systematically collected consumer products (metal foodware, ceramics, cosmetics, paints, toys, spices and other foods). The items were analyzed on site for detectable lead above 2 ppm using an X-ray fluorescence analyzer. For quality control purposes, a subset of the samples was analyzed in the USA using inductively coupled plasma mass spectrometry. The lead concentrations of the individual product types were compared with established regulatory thresholds. Out of 5007 analyzed products, threshold values (TV) were surpassed in 51% for metal foodware (TV 100 ppm), 45% for ceramics (TV 100 ppm), and 41% for paints (TV 90 ppm). Sources of exposure in LMICs can be diverse, and consumers in LMICs lack adequate protection from preventable sources of lead exposure. Rapid Market Screening is an innovative, simple, and useful tool to identify risky products that could be sources of lead exposure.

Acetaminophen overdose: analysis of 2018 US nationwide emergency database.

INTRODUCTION: Recognized risk factors for acetaminophen overdose include alcohol, opioids, and mood disorders. The aim of this study is to assess additional risk factors for acetaminophen overdose evaluated in the emergency department (ED). METHODS: A retrospective study was performed using the 2018 US Nationwide Emergency Department Sample (NEDS). All adult ED visits for acetaminophen overdose were included in the study group and those without it were taken as control. STATA, 16.1 was used to perform multivariable logistic regression analysis and adjusted odds ratios (ORadj) were reported. RESULTS: We identified 27,792 ED visits for acetaminophen overdose. Relative to non-acetaminophen ED visits, this group was younger (median age 32 vs 47 years; p < 0.0001), more often female (66.1% vs 57.0%; p < 0.0001), had higher ED charges ($3,506 vs $2,714; p < 0.0001), higher proportion of alcohol-related disorders (15.8% vs 3.5%; p < 0.0001), anxiety disorders (30.2% vs 8.3%; p < 0.0001), cannabis use (8.7% vs 1.4%; p < 0.0001), hematology/oncology diagnoses (13.3% vs 10.9%; p < 0.0001), mood disorders (52.4% vs 7.9%; p < 0.0001), opioid-related disorders (4.1% vs 1.0%; p < 0.0001), and suicide attempt/ideation (12.2% vs 1.1%; p < 0.0001). Multivariable analysis showed alcohol-related disorders (ORadj 2.67), anxiety disorders (ORadj 1.24), cannabis (ORadj 1.63), females (ORadj 1.45), Income Q3 (ORadj 1.09), hematology/oncology diagnoses (ORadj 1.40), mood disorders (ORadj 10.07), opioid-related disorders (ORadj 1.20), and suicide attempt/ideation (ORadj 1.68) were associated with acetaminophen overdose. CONCLUSION: In addition to previously recognized risks, our study demonstrated that cannabis use and hematologic/oncologic comorbidities were more common among acetaminophen-overdose ED visits. These new findings are concerning because of rapid legalization of cannabis and the increasing incidence of cancer worldwide. Additional investigation into these risks should be a priority for clinicians, policymakers, and researchers.

The effects of the COVID-19 pandemic on PICU admissions for severe asthma exacerbations: A single-center experience.

BACKGROUND: The incidence of severe asthma exacerbations (SAE) requiring a pediatric intensive care unit (PICU) admission during the coronavirus disease 2019 (COVID-19) pandemic (and its association with public restrictions) is largely unknown. We examined the trend of SAE requiring PICU admission before, during, and after COVID-19 restrictions in Amsterdam, the Netherlands, and its relationship with features such as environmental triggers and changes in COVID-19 restriction measures. METHODS: In this single-center, retrospective cohort study, all PICU admissions of children aged ≥2 years for severe asthma at the Amsterdam UMC between 2018 and 2022 were included. The concentrations of ambient fine particulate matter (PM2.5 ) and pollen were obtained from official monitoring stations. RESULTS: Between January 2018 and December 2022, 228 children were admitted to the PICU of the Amsterdam UMC for SAE. While we observed a decrease in admissions during periods of more stringent restriction, there was an increase in the PICU admission rate for SAE in some periods following the lifting of restrictions. In particular, following the COVID-19 restrictions in 2021, we observed a peak incidence of admissions from August to November, which was higher than any other peak during the indicated years. No association with air pollution or pollen was observed. CONCLUSION: We hypothesize that an increase in clinically diagnosed viral infections after lockdown periods was the reason for the altered incidence of SAE at the PICU in late 2021, rather than air pollution and pollen concentrations.

Epidemiology of common infectious diseases before and during the COVID-19 pandemic in Bavaria, Germany, 2016 to 2021: an analysis of routine surveillance data.

BackgroundUnprecedented non-pharmaceutical interventions to control the COVID-19 pandemic also had an effect on other infectious diseases.AimWe aimed to determine their impact on transmission and diagnosis of notifiable diseases other than COVID-19 in Bavaria, Germany, in 2020 and 2021.MethodsWe compared weekly cases of 15 notifiable infectious diseases recorded in Bavaria between 1 January 2016 and 31 December 2021 in time series analyses, median age and time-to-diagnosis using Wilcoxon rank sum test and hospitalisation rates using univariable logistic regression during three time periods: pre-pandemic (weeks 1 2016-9 2020), pandemic years 1 (weeks 10-52 2020) and 2 (2021).ResultsWeekly case numbers decreased in pandemic year 1 for all diseases assessed except influenza, Lyme disease and tick-borne encephalitis; markedly for norovirus gastroenteritis (IRR = 0.15; 95% CI: 0.12-0.20) and pertussis (IRR = 0.22; 95% CI: 0.18-0.26). In pandemic year 2, influenza (IRR = 0.04; 95% CI: 0.02-0.09) and pertussis (IRR = 0.11; 95% CI: 0.09-0.14) decreased markedly, but also chickenpox, dengue fever, Haemophilus influenzae invasive infection, hepatitis C, legionellosis, noro- and rotavirus gastroenteritis and salmonellosis. For enterohaemorrhagic Escherichia coli infections, median age decreased in pandemic years 1 and 2 (4 years, interquartile range (IQR): 1-32 and 3 years, IQR: 1-18 vs 11 years, IQR: 2-42); hospitalisation proportions increased in pandemic year 1 (OR = 1.60; 95% CI: 1.08-2.34).ConclusionReductions for various infectious diseases and changes in case characteristics in 2020 and 2021 indicate reduced transmission of notifiable diseases other than COVID-19 due to interventions and under-detection.

The influence of disparities on intensive care outcomes in children with respiratory diseases: A systematic review.

CONTEXT: The negative effects of socioeconomic, environmental and ethnic inequalities on childhood respiratory diseases are known in the development of persistent asthma and can result in adverse outcomes. However, little is known about the effects of these disparities on pediatric intensive care unit (PICU) outcomes in respiratory diseases. OBJECTIVE: The purpose of this systematic review is to evaluate the literature on disparities in socioeconomic, environmental and ethnic determinants and PICU outcomes. We hypothesize that these disparities negatively influence the outcomes of children's respiratory diseases at the PICU. METHODS: A literature search (in PubMed, Embase.com and Web of Science Core Collection) was performed up to September 30, 2022. Two authors extracted the data and independently evaluated the risk of bias with appropriate assessment methods. Articles were included if the patients were below 18 years of age (excluding neonatal intensive care unit admissions), they concerned respiratory diseases and incorporated socioeconomic, ethnic or environmental disparities. RESULTS: Eight thousand seven hundred fourty-six references were reviewed, and 15 articles were included; seven articles on the effect of socioeconomic status, five articles on ethnicity, one on the effect of sex and lastly two on environmental factors. All articles but one showed an unfavorable outcome at the PICU. CONCLUSION: Disparities in socioeconomic (such as a low-income household, public health insurance), ethnic and environmental factors (such as exposure to tobacco smoke and diet) have been assessed as risk factors for the severity of children's respiratory diseases and can negatively influence the outcomes of these children admitted and treated at the PICU.

Pediatric Toxicology: An Updated Review.

Pediatricians should be familiar with principles of medical toxicology given that intentional and unintentional ingestions are commonly encountered in different medical settings. Most exploratory ingestions are well tolerated and do not cause significant health effects, but a few noteworthy exceptions can lead to serious illness and death. This article reviews common medications and household products likely to cause significant toxicity in pediatric patients, even in small, exploratory ingestions. Increasing cannabis exposures among children and adolescents are also reviewed. Additionally, indications for gastric decontamination with activated charcoal are reviewed. Finally, poisoning prevention strategies are reviewed. [Pediatr Ann. 2023;52(4):e139-e145.].

Fomepizole as an adjunctive therapy for acetaminophen poisoning: cases reported to the toxicology investigators consortium (ToxIC) database 2015-2020.

INTRODUCTION: Fomepizole inhibits formation of toxic acetaminophen (APAP) metabolites and may prevent or reverse mitochondrial toxicity. Given these mechanisms, it may be beneficial in patients with severe APAP toxicity. Current patterns of use for this indication are not well-studied. METHODS: This is a secondary analysis of patients enrolled in the Toxicology Investigators Consortium (ToxIC) database from January 2015 to July 2020. We queried cases in which APAP was listed as an ingested agent and fomepizole was also administered. We excluded cases in which APAP was not the primary agent, N-acetylcysteine (NAC) was not administered, or fomepizole was explicitly administered for another indication. Additionally, we sent a survey to each ToxIC site that administered fomepizole for APAP toxicity to better understand when, why, and how they were using it for this indication. RESULTS: Twenty-five cases of fomepizole administration following an APAP ingestion met our inclusion criteria. There were one to four cases per year between 2015 and 2019 and eight cases in 2020. Seventeen of 25 (68%) cases were for a known acute ingestion. Eighteen of 25 (72%) patients developed hepatotoxicity (AST or ALT > 1000 IU/L) and 10 of 25 (40%) developed coagulopathy (PT > 15s). This was an ill patient population, with 18 of 25 (72%) developing metabolic acidosis (pH <7.20), 12 of 25 (48%) were intubated, 9 of 25 (36%) receiving vasopressors, and 6 of 25 (24%) receiving continuous renal replacement therapy. Overall, mortality was 24%. CONCLUSION: The use of fomepizole is increasing in frequency in a small subset of critically ill and acutely APAP-poisoned patients.

Severe acute asthma at the pediatric intensive care unit: can we link the clinical phenotypes to immunological endotypes?

INTRODUCTION: The clinical phenotype of severe acute asthma at the pediatric intensive care unit (PICU) is highly heterogeneous. However, current treatment is still based on a 'one-size-fits-all approach'. AREAS COVERED: We aim to give a comprehensive description of the clinical characteristics of pediatric patients with severe acute asthma admitted to the PICU and available immunological biomarkers, providing the first steps toward precision medicine for this patient population. A literature search was performed using PubMed for relevant studies on severe acute (pediatric) asthma. EXPERT OPINION: Omics technologies should be used to investigate the relationship between cellular molecules and pathways, and their clinical phenotypes. Inflammatory phenotypes might guide bedside decisions regarding the use of corticosteroids, neutrophil modifiers and/or type of beta-agonist. A next step toward precision medicine should be inclusion of these patients in clinical trials on biologics.

Antimicrobial Resistance in Isolates from Cattle with Bovine Respiratory Disease in Bavaria, Germany.

Patterns of antimicrobial resistance (AMR) regarding Pasteurella multocida (n = 345), Mannheimia haemolytica (n = 273), Truperella pyogenes (n = 119), and Bibersteinia trehalosi (n = 17) isolated from calves, cattle and dairy cows with putative bovine respiratory disease syndrome were determined. The aim of this study was to investigate temporal trends in AMR and the influence of epidemiological parameters for the geographic origin in Bavaria, Germany, between July 2015 and June 2020. Spectinomycin was the only antimicrobial agent with a significant decrease regarding not susceptible isolates within the study period (P. multocida 88.89% to 67.82%, M. haemolytica 90.24% to 68.00%). Regarding P. multocida, significant increasing rates of not susceptible isolates were found for the antimicrobials tulathromycin (5.56% to 26.44%) and tetracycline (18.52% to 57.47%). The proportions of multidrug-resistant (MDR) P. multocida isolates (n = 48) increased significantly from 3.70% to 22.90%. The proportions of MDR M. haemolytica and P. multocida isolates (n = 62) were significantly higher in fattening farms (14.92%) compared to dairy farms (3.29%) and also significantly higher on farms with more than 300 animals (19.49%) compared to farms with 100 animals or less (6.92%). The data underline the importance of the epidemiological farm characteristics, here farm type and herd size regarding the investigation of AMR.

Tuberculosis contact investigation following the stone-in-the-pond principle in the Netherlands - Did adjusted guidelines improve efficiency?

BackgroundIn low tuberculosis (TB) incidence countries, contact investigation (CI) requires not missing contacts with TB infection or disease without unnecessarily evaluating non-infected contacts.AimWe assessed whether updated guidelines for the stone-in-the-pond principle and their promotion improved CI practices.MethodsThis retrospective study used surveillance data to compare CI outcomes before (2011-2013) and after (2014-2016) the guideline update and promotion. Using negative binomial regression and logistic regression models, we compared the number of contacts invited for CI per index patient, the number of CI scaled-up according to the stone-in-the-pond principle, the TB and latent TB infection (LTBI) testing coverage, and yield.ResultsPre and post update, 1,703 and 1,489 index patients were reported, 27,187 and 21,056 contacts were eligible for CI, 86% and 89% were tested for TB, and 0.70% and 0.73% were identified with active TB, respectively. Post update, the number of casual contacts invited per index patient decreased statistically significantly (RR = 0.88; 95% CI: 0.79-0.98), TB testing coverage increased (OR = 1.4; 95% CI: 1.2-1.7), and TB yield increased (OR = 2.0; 95% CI: 1.0-3.9). The total LTBI yield increased from 8.8% to 9.8%, with statistically significant increases for casual (OR = 1.2; 95% CI: 1.0-1.5) and community contacts (OR = 2.0; 95% CI: 1.6-3.2). The proportion of CIs appropriately scaled-up to community contacts increased statistically significantly (RR = 1.8; 95% CI: 1.3-2.6).ConclusionThis study shows that promoting evidence-based CI guidelines strengthen the efficiency of CIs without jeopardising effectiveness. These findings support CI is an effective TB elimination intervention.

Temperature-Dependent Low-Frequency Modes in the Active Site of Bovine Carbonic Anhydrase II Probed by 2D-IR Spectroscopy.

Enzyme catalysis achieves tremendous rate accelerations. Enzyme reaction centers provide a constraint geometry that preferentially binds an activated form of the substrate and thus lowers the energy barrier. However, this transition state picture neglects the flexibility of proteins and its role in enzymatic catalysis. Especially for proton transfer reactions, it has been suggested that motions of the protein modulate the donor-acceptor distance and prepare a tunneling-ready state. We report the detection of frequency fluctuations of an azide anion (N3-) bound in the active site of the protein carbonic anhydrase II, where a low-frequency mode of the protein has been proposed to facilitate proton transfer over two water molecules during the catalyzed reaction. 2D-IR spectroscopy resolves an underdamped low-frequency mode at about 1 THz (30 cm-1). We find its frequency to be viscosity- and temperature-dependent and to decrease by 6 cm-1 between 230 and 320 K, reporting the softening of the mode's potential.

Collaborative tuberculosis/HIV activities in the European Region.

INTRODUCTION: An estimated 12% of tuberculosis (TB) patients are co-infected with HIV in the World Health Organization European Region (the Region). Reducing morbidity and mortality from HIV-associated TB requires strong collaboration between TB and HIV services at all levels with integrated people-centred models of care. METHODS: We collected information on the current models of integration of TB and HIV services in the Region via a comprehensive survey among the TB and HIV National Focal Points, and identified challenges and opportunities. RESULTS: 47 out of 55 (85%) countries responded. HIV testing in all TB patients and screening for active TB in all people living with HIV (PLHIV) was recommended in 40 (85%) and 34 (72%) countries, respectively. 30 (64%) countries recommended latent TB infection (LTBI) screening in all PLHIV, while 13 (28%) had a selective approach and four (9%) did not recommend LTBI screening. In most countries, testing for HIV and screening for active TB and LTBI was done by the specialist treating the patient, i.e. TB patients were tested for HIV by a TB specialist in 42 (89%) countries and PLHIV were screened for active TB by an HIV specialist in 34 (72%) countries. CONCLUSIONS: TB and HIV care are well integrated in policies of especially high TB and high HIV burden countries; however, implementation needs to be improved. Continuous monitoring of TB and HIV services integration enables assessing the quality of TB/HIV care and to identify where further improvements are needed.

Smad7 in intestinal CD4+ T cells determines autoimmunity in a spontaneous model of multiple sclerosis.

Environmental triggers acting at the intestinal barrier are thought to contribute to the initiation of autoimmune disorders. The transforming growth factor beta inhibitor Smad7 determines the phenotype of CD4+ T cells. We hypothesized that Smad7 in intestinal CD4+ T cells controls initiation of opticospinal encephalomyelitis (OSE), a murine model of multiple sclerosis (MS), depending on the presence of gut microbiota. Smad7 was overexpressed or deleted in OSE CD4+ T cells to determine the effect on clinical progression, T cell differentiation, and T cell migration from the intestine to the central nervous system (CNS). Smad7 overexpression worsened the clinical course of OSE and increased CNS inflammation and demyelination. It favored expansion of intestinal CD4+ T cells toward an inflammatory phenotype and migration of intestinal CD4+ T cells to the CNS. Intestinal biopsies from MS patients revealed decreased transforming growth factor beta signaling with a shift toward inflammatory T cell subtypes. Smad7 in intestinal T cells might represent a valuable therapeutic target for MS to achieve immunologic tolerance in the intestine and suppress CNS inflammation.