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ObjectivesAim of this study was to investigate the expression of interleukin (IL)-40, a new cytokine associated with B cells homoeostasis and immune response, in primary Sjögren syndrome (pSS) and in pSS-associated lymphomas.Methods29 patients with pSS and 24 controls were enrolled. Minor salivary gland (MSG) biopsies from patients, controls and parotid gland biopsies from pSS-associated lymphoma were obtained. Quantitative gene expression analysis by TaqMan real-time PCR and immunohistochemistry for IL-40 were performed on MSG. MSG cellular sources of IL-40 were determined by flow-cytometry and immunofluorescence. Serum concentration of IL-40 was assessed by ELISA and cellular sources of IL-40 were determined by flow-cytometry. An in vitro assay with recombinant IL-40 (rIL-40) was performed to detect the effect on cytokine production from peripheral blood mononuclear cells (PBMCs).ResultsIL-40 was significantly increased in the lymphocytic infiltrated MSG of patients with pSS and correlated with focus score and with IL-4 and transforming growth factor-β expression. In addition, IL-40 was increased in the serum of pSS and its levels correlated with the EULAR Sjögren’s Syndrome Disease Activity Index score. B cells from patients were shown to be the major source of IL-40 at both tissue and peripheral level. PBMCs from patients, exposed to rIL-40 in vitro, released proinflammatory cytokines, specifically interferon-γ from B cells and T-CD8+and tumour necrosis factor-α and IL-17 from both T-CD4+and T-CD8+. IL-40 expression in parotid glands of pSS-associated lymphomas was also increased. Moreover, IL-40-driven NETosis was evidenced in neutrophils obtained from pSS.ConclusionOur results suggest that IL-40 may play a role in pSS pathogenesis and pSS-associated lymphomas.

Women with HIV (WWH) have heightened heart failure risk. Plasma OPN (osteopontin) is a powerful predictor of heart failure outcomes in the general population. Limited data exist on relationships between plasma OPN and surrogates of HIV-associated heart failure risk.Prospective, cross-sectional.We analyzed relationships between plasma OPN and cardiac structure/function (assessed using cardiovascular magnetic resonance imaging) and immune activation (biomarkers and flow cytometry) among 20 WWH and 14 women without HIV (WWOH).Plasma OPN did not differ between groups. Among WWH, plasma OPN related directly to the markers of cardiac fibrosis, growth differentiation factor-15 (ρ = 0.51, P = 0.02) and soluble interleukin 1 receptor-like 1 (ρ = 0.45, P = 0.0459). Among WWH (but not among WWOH or the whole group), plasma OPN related directly to both myocardial fibrosis (ρ = 0.49, P = 0.03) and myocardial steatosis (ρ = 0.46, P = 0.0487). Among the whole group and WWH (and not among WWOH), plasma OPN related directly to the surface expression of C-X3-C motif chemokine receptor 1 (CX3CR1) on nonclassical (CD14-CD16+) monocytes (whole group: ρ = 0.36, P = 0.04; WWH: ρ = 0.46, P = 0.04). Further, among WWH and WWOH (and not among the whole group), plasma OPN related directly to the surface expression of CC motif chemokine receptor 2 (CCR2) on inflammatory (CD14+CD16+) monocytes (WWH: ρ = 0.54, P = 0.01; WWOH: ρ = 0.60, P = 0.03), and in WWH, this held even after controlling for HIV-specific parameters.Among WWH, plasma OPN, a powerful predictor of heart failure outcomes, related to myocardial fibrosis and steatosis and the expression of CCR2 and CX3CR1 on select monocyte subpopulations. OPN may play a role in heart failure pathogenesis among WWH.NCT02874703.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease in the world. It is known that there is a pathogenic relation between liver damage and the inflammatory and oxidative environment present in Metabolic Syndrome (MS). background: Non-alcoholic fatty liver disease (NAFLD) is the world's most frequent cause of chronic liver disease. It is known there is a pathogenic relation between liver damage and the inflammatory and oxidative environment present in Metabolic Syndrome (MS). Objective: To study the pharmacological action of atorvastatin and metformin in an experimental model of MS. objective: To study the pharmacological action of atorvastatin and metformin in an experimental model of MS. Methods: We used 40 male rats (Wistar) divided into the following groups: Control (A)(n=8), induced MS (B)(n=8), MS + atorvastatin treatment (C)(n=8), MS + metformin treatment (D)(n=8) and MS + combined treatment (E)(n=8). MS was induced by administering 10% fructose in drinking water for 45 days. Atorvastatin 0.035mg/day/rat, metformin 1.78mg/day/rat, and a combination of both drugs were administered for 45 days. Metabolic, oxidative (nitric oxide, myeloperoxidase and superoxide dismutase) and inflammatory (fibrinogen) parameters were determined. Histological sections of liver were analyzed by light microscopy. method: We used 40 male rats (Wistar) divided into the following groups: Control (A)(n=8), induced MS (B)(n=8), MS + atorvastatin treatment (C)(n=8), MS + metformin treatment (D)(n=8) and MS + combined treatment (E)(n=8). MS was induced by administering 10% fructose in drinking water for 45 days. Atorvastatin 0.035mg/day/rat, metformin 1.78mg/day/rat, and a combination of both drugs were administered for 45 days. Metabolic, oxidative (nitric oxide, myeloperoxidase, and superoxide dismutase) and inflammatory (fibrinogen) parameters were determined. Histological sections of the liver were analyzed by light microscopy. Comparisons of all possible combinations of pairs of means were made by multivariate ANOVA and Hotelling (as a post hoc test). A significance level of p Results: The glycemia, lipid profile and TG/HDL-C index were altered in MS group. After pharmacological treatment, metabolic parameters improve significantly in all treated groups. Inflammatory and oxidative stress biomarkers increase in MS. Treated groups showed an increase in NO bioavailability, no difference in MPO activity and an increase in fibrinogen. Atorvastatin showed a decrease in SOD while Metformin and combination treatment showed an increase in SOD compared to MS. In MS, we observed histological lesions consistent with NAFLD. However, after a combined treatment, we observed total regression of these lesions. Conclusion: Our results showed that there is an important synergy between atorvastatin and metformin in improving liver involvement in MS.

Background: Chamaenerion latifolium is a perennial herbaceous plant of the Onagraceae family. The purpose of this study was to evaluate and compare the volatile chemical components of the aerial parts of Chamaenerion latifolium growing in the Republic of Kazakhstan. Method: The leaves and stems of Chamaenerion latifolium were extracted with hexane and analysed by gas chromatography-mass spectrometry (GC-MS). Results: The regularisation of peak areas method was used to calculate the concentrations of the sixty-five identified compounds. Conclusion: Among them, the major components are alkanes (leaves 31.339%, stems 48.158%), esters (leaves 10.216%, stems 12.196%), alcohols (leaves 5.483% and stems 5.14%), aldehydes (leaves 3.155%, stems 1.592%), triterpenoids (leaves 2.247% stems 3.785%).

Aim: The in vitro effects of commonly used first-line anti-arthritic drugs on early stages of T-cell activation were examined. Methods: The 2B4.11 murine T cell hybridoma cell line recognizing pigeon cytochrome c (PCC) as the antigen was co-cultured with the histocompatible antigen presenting B cell hybridoma line LK35.2, PCC, and anti-arthritic drugs, including methotrexate, hydroxychloroquine, salazopyrine, cyclosporin, and leflunomide. After 16 hours of incubation, the supernatant was removed, and cytokines were assayed. Results: Anti-arthritic drugs inhibited the production of pro-inflammatory cytokines IL-2, IL-6, IFN-γ, GM-CSF, and TNF-α (Th1 cytokines) to a varying extent. Surprisingly, leflunomide, salazopyrine, prednisone and indomethacin as well as blocking Th1 cytokines, stimulated the production of the anti-inflammatory cytokine IL-10, a Th2 cytokine. Conclusion: Anti-arthritic medications can inhibit the production of pro-inflammatory cytokines and in some cases, incite a Th2 response that could potentially inhibit the progression of the immune response.

Abstract: Osteoarthritis is the most common human joint disease in the world. It is also one of the most common skeletal muscle defects, destructive joint changes, and the leading cause of disability and reduced quality of life. Destructive changes in inflammatory joints are associated with a range of biochemical events, including the overproduction of inflammatory cytokines. Cytokines are protein compounds that play an essential role in causing and regulating inflammation. A balance between pro-inflammatory and anti-inflammatory cytokines is crucial in maintaining a stable body. In some inflammatory diseases, including osteoarthritis, the balance between these compounds is disturbed, and the balance shifts to pre-inflammatory cytokines. For this reason, researchers today are trying to find an effective way to reduce inflammation and treat osteoarthritis by using certain compounds. Current treatments for osteoarthritis, including nonsteroidal antiinflammatory drugs, glucocorticoids, and hyaluronic acid, are mainly based on reducing pain and inflammation. However, they have limited effects in controlling symptoms and improving the patient's quality of life. Also, due to the high level of side effects, synthetic drugs have led to the identification of compounds of natural origin to give patients a chance to use painkillers and antiinflammatory drugs with fewer side effects. This review study aimed to present the role of quercetin as a natural compound in reducing the expression of pro-inflammatory cytokines in osteoarthritis. This study also discusses the relationship between inflammation and cartilage destruction and other inflammation-related factors caused by cytokines.

Introduction: The coronavirus pandemic has disproportionately affected older adults and has provided an incentive to find alternatives to emergency department attendance to avoid unnecessary exposure to the SARS-CoV-2 virus. To address this issue, a specialist geriatric multidisciplinary team at Queen Elizabeth Hospital set up a novel telemedicine approach to the ambulance service with the aim of reducing unnecessary emergency department attendance for older adults. This study provides a service evaluation in its first year of use. Methods: Service evaluation in the first year of the ‘Ask OPAL’ (older person Assessment and liaison) hotline for ambulance paramedics, run by a multidisciplinary acute geriatrics team at the Queen Elizabeth Hospital, Birmingham. Data on the number, patient demographics, intervention, and outcome of the calls, were recorded Results: During the study period, 2552 ‘Ask OPAL’ calls were conducted. Of the 2552 calls carried out, 1755 patients (69%) remained at home. Of the patients who remained at home, 76% received verbal advice only, while 24% were referred to community services in addition to receiving verbal advice. Conclusion: In conclusion, the use of an integrated multidisciplinary team communicating with paramedics via telemedicine appears to be successful in preventing avoidable hospital admissions in complex patients.

Background: Diabetes mellitus (DM) is a metabolic disorder characterized by progressive β cell dysfunction. Sheng-Mai Injection (SMI), a Traditional Chinese medicine preparation, is widely used for DM and its related complications. Objective: This meta-analysis aimed to summarize the applications of SMI in DM and related complications. Methods: Eight databases were searched, and meta-analyses were performed. Results: Fifteen studies, including 1273 participants, were included. All studies and participants included were from China. Pooled effects showed that SMI might reduce glycated hemoglobin (MD -0.46%; 95% CI -0.89 to -0.03; P < 0.01), fasting blood glucose (MD -0.83 mmol/L; 95% CI -1.30 to -0.36; P < 0.01), two-hour postprandial glucose (MD -1.27 mmol/L; 95% CI -1.96 to -0.58; P < 0.01), 24-hour urinary protein (MD -0.28 mg; 95% CI -0.51 to -0.06; P = 0.01), blood urea nitrogen (MD -1.31 mg; 95% CI -2.08 to -0.54; P < 0.05), Scr (MD -2.60; 95% CI -3.43 to -1.77; P < 0.05), ulnar nerve motor nerve conduction velocity (MNCV) (MD 1.45; 95% CI 0.03 to 2.87; P < 0.05), and tibial nerve sensory nerve conduction velocity (SNCV) (MD 1.84; 95% CI 0.1 to 3.58; P < 0.05). There was no evidence of an effect on common peroneal nervous MNCV and SNCV, tibial nerve MNCV, median nerve MNCV, and SNCV. Adverse effects included less frequent gastrointestinal reactions, elevated transaminase, leucopenia, fever, and rash. Conclusion: Combination use of SMI based on conventional hypoglycemic treatment can significantly improve HbA1c, FBG, and 2hPG in DM and reduce 24-hour urinary protein, Scr, and BUN in DM patients. SMI was found to have no effect on the neurological function of diabetic peripheral neuropathy.

Background: The Italian population’s habits changed dramatically during the “COVID- 19 lockdown” due to physical distancing and self-isolation. Moreover, medical consultations of patients with chronic diseases, such as type 2 diabetes (T2D), were suspended or postponed, unless urgent or semi-urgent, for several consecutive months. Thus, it is expected that the lockdown could have affected glucometabolic control in T2D. Purpose: The aim of the study was to assess changes in glucometabolic control in a cohort of T2D patients before (T1) and after (T2) the COVID-19 lockdown (March-May 2020). Methods: The study was approved by the Ethics Committee of the University of Bari, and all patients provided informed written consent to participate. Medical history, complete physical examination, and laboratory assessment were conducted as real-life clinical practice. Changes in clinical and laboratory variables between T1 and T2 were calculated. Results: In detail, 13 patients were on metformin as monotherapy, 36 on GLP-1RA, 12 on sodiumglucose transporter 2 inhibitors (SGLT-2i), and 2 on dipeptidyl-peptidase 4 inhibitors (DPP4i). The mean age was 65.3 years (43-83). Study participants were mainly men (73%). The body weight (BW) ranged from 56 to 145 kg, and the waist circumference ranged from 88 to 146 cm. The mean HbA1c was 51.0 mmol/mol. At T2, no statistically significant changes were observed from baseline except for BW [-1.6 (-2.60 to -0.62)] and HbA1c [-2.90 (-4.69; -1.12)]. Conclusion: We evaluated the effects of the COVID-19 lockdown on glucometabolic control in patients with background well-controlled T2D. We found that the lockdown had no adverse effects on metabolic profile regardless of background clinical characteristics and antihyperglycemic management. Despite limitations due to the nature of this study (sample size, retrospective observation, lack of data on lifestyle changes in our patients' everyday lives), T2D patients managed in our Diabetes Centers faced the lockdown-related restrictions without any detrimental consequence.

The objective of the study was to gain an insight into the perceptions and experiences of patients with rheumatoid arthritis and a high cardiovascular disease risk (CVD-RA) when undergoing an exercise intervention aimed at improving their cardiorespiratory fitness. This qualitative study was part of a pilot study, which investigated the effects of an exercise intervention on cardiorespiratory fitness in patients with CVD-RA. Six patients were invited to participate in face-to-face semi-structured interviews. We invited patients who completed the exercise intervention as well as patients who withdrew from the exercise intervention. The interviews were analyzed according to the method of thematic analysis. Six patients were interviewed, of whom four patients completed and two patients discontinued the exercise intervention. The mean (SD) age was 58 (9.7) years, the median disease duration was 10 years, and five patients were female. The analyses revealed seven themes that provided insight into perceptions and experiences: (1) ability to understand reasons for actions; (2) the need to be seen; (3) reaching their maximum effort; (4) experiencing their limits; (5) wanting personalized exercise therapy; (6) happy to be physically active; (7) benefits of exercise. Patients perceived that they were able to perform a cardiopulmonary exercise test with maximum effort and achieved the prescribed intensity of the exercise intervention. They also experienced an improvement in their physical activity by incorporating physical activity in their daily live. Overarching principles that re-occurred in the themes were: the need to be viewed as a person and the importance of feeling safe.

Abstract: Diaminopyrimidine compounds having the following general structure (I), compositions comprising an effective amount of a diaminopyrimidine compound, and methods for treating or preventing fibrotic liver disorders or other diseases associated with the JNK pathway are discussed in this patent study.

Abstract: Tirzepatide (mounjaro®) is a derivative of the human glucose-dependent insulinotropic polypeptide (GIP) hormone with a position-20 being modified with 1,20- eicosanedioic acid via a chemical linker. It acts as a glucagon-like peptide-1 (GLP-1) receptor and GIP receptor agonist. It has recently been approved by FDA as an adjunct therapy to exercise and diet to improve glycemic control in patients with type II diabetes mellitus (T2DM). It represents a new transforming paradigm in the management of T2DM. This mini-review will shed light on its different pharmacokinetic and pharmacodynamic aspects.

Background: Allergic asthma is a chronic inflammatory illness of the respiratory system characterized by an increase in the number of inflammatory cells in the airways and trouble breathing. Mesenchymal stem cells (MSCs) have the potential to be used in inflammatory diseases as a cellular immunosuppressive treatment. They express calcitriol receptors and communicate with other immunocytes, which increases their anti-inflammatory activity. This study aimed to determine the effects of calcitriol-treated MSC treatment on allergic asthma pathways in a mouse model. Methods: To generate a mouse model of asthma, the mice were sensitized intraperitoneally with ovalbumin (OVA) and aluminum hydroxide emulsion and then challenged intra-nasally with OVA. On day 14, experimental mice received tail vein injections of calcitriol-treated MSCs in PBS prior to allergen exposure. The cytokines assays including IL-4, 10, 12, 17, TGF-β and IFN-γ, splenocytes proliferation, and histological examination of lungs samples were performed. The mice were sensitized with OVA and the response to dexamethasone treatment was compared. Results: Calcitriol-treated MSCs significantly increased the levels of IL-12, TGF-β, and IFN-γ compared to non-treated MSCs groups. Moreover, calcitriol-treated and non-treated MSCs significantly decreased IL-4 and IL-17 compared to asthmatic groups. The results of the histopathological examination showed that calcitriol-treated MSCs reduced the accumulation of inflammatory cells and bronchial wall thickening in comparison with the asthma group. Conclusion: Using the allergic asthma model, we were able to show that calcitriol-treated MSCs had an inhibitory impact on airway inflammation. Our findings suggest that the injection of calcitrioltreated MSCs may be a viable treatment option for allergic asthma.

Aim: The study aims to show that sodium selenite (Ss) would have an immunomodulatory effect on the functional activity of proinflammatory macrophages (Mφs) during their extended extracellular activation at the onset of human type 1 diabetes (T1D). Background: Exacerbated activation of proinflammatory “M1” macrophages (Mϕs) can promote chronic local pancreatic islet inflammation and T1D development. Objective: We investigated the ex vivo effects of Ss on the immune modulation of global/extended activation of human proinflammatory M1-like Mϕs. Methods: Experiments were carried out on primary monocytes-derived Mϕs (MDMs). Results: The levels of IL-1β, TNF-α, H2O2 and intracellular free calcium ions (ifCa2+), and the ratios of IL-1β-to-IL-10 and TNF-α-to-IL-10 were markedly increased in T1D Mϕs than in healthy control Mϕs. Conversely, both IL-10 production and arginase 1 (ARG1) activity were downregulated in T1D Mϕs. Additionally, Ss treatment induced a marked downregulation of respiratory burst, ifCa2+ levels, M1-like Mϕ-associated inducible nitric oxide (NO) synthase (iNOS) activity, cell necrosis and related necroinflammation biomarkers, including IL-1β and TNF-α, CD14 expression, and the ratios of iNOS-to-ARG1, IL-1β-to-IL-10, and TNF-α-to-IL-10. Moreover, Ss upregulated anti-inflammatory “M2-like” Mϕ activity as demonstrated by ARG1 activity and IL-10 production, as well as phagocytosis capacity. Conclusions: Ss exerts a potent immunomodulatory role on functional activities of human proinflammatory T1D M1-like Mϕs subjected to extended activation, as well as on the M1-like/M2-like dichotomy. Additionally, the current study provides a novel therapeutic approach using Ss to promote the anti-inflammatory function of Mϕs at the onset of T1D.

To establish the incidence, risk factors and prognostic effect of anemia in children living with HIV (CLWH).Retrospective nested case-control study of patients 0-18 years in five centers in sub-Saharan Africa, 2004-2014.Incident cases of anemia were identified from electronic records and matched with CLWH without anemia. We calculated the incidence density of anemia and used conditional logistic regression to evaluate its association with risk factors, stratified by severity and type of anemia. We used a Cox proportional hazards model to evaluate the impact of anemia on survival.Two thousand, one hundred and thirty-seven children were sampled. The incidence density of anemia was 1 per 6.6 CLWH-years. Anemia was moderate in 31.8% and severe in 17.3% of anemia cases, which had 10-year mortality hazards of 3.4 and 4.5, respectively. Microcytic anemia (36% cases) was associated with 2.3-fold hazard of 10-year mortality, and with malnutrition and CD4 + suppression. Normocytic anemia (50.5% cases) was associated with 2.6-fold hazards of 10-year mortality, and with more severe malnutrition, CD4 + suppression, and WHO stage, but inversely associated with lamivudine and nevirapine therapy. Macrocytic anemia (13.5% cases) was neither associated with higher 10-year mortality nor with severe malnutrition or CD4 + suppression but was associated with WHO stage II/III and negatively associated with lamivudine therapy.This large multicountry study of CLWH found a high incidence density of anemia. Higher severity, normocytic and microcytic types of anemia were independently associated with long-term mortality. Laboratory studies are needed to decipher the mechanisms of anemia and how it impacts mortality in CLWH.

Identify key features of IL-33 immunobiology important in allergic and nonallergic airway inflammatory diseases and potential therapeutic strategies to reduce disease burden.PubMed, clinicaltrials.gov.A systematic and focused literature search was conducted of PubMed from March 2021 to December 2021 using keywords to either PubMed or BioMed Explorer including IL-33/ST2, genetic polymorphisms, transcription, translation, post-translation modification, nuclear protein, allergy, asthma, and lung disease. Clinical trial information on IL-33 was extracted from clinicaltrials.gov in August 2021.In total, 72 publications with relevance to IL-33 immunobiology and/or clinical lung disease were identified (allergic airway inflammation/allergic asthmaAn integral role of IL-33 in the pathogenesis of allergic and nonallergic airway inflammatory disease is evident with several emerging clinical trials investigating therapeutic approaches. Current data support a critical role of IL-33 in damage signaling, repair and regeneration of lungs.

Multidrug-resistant organisms (MDROs) are prevalent in transplant recipients and associated with poor outcomes. We review recent cases of phage therapy used to treat recalcitrant infections in transplant recipients and explore the future role of such therapy in this setting.Individual case reports and small case series suggest possible efficacy of phage therapy for the treatment of MDRO infections in pre and posttransplant patients. Importantly, there have been no serious safety concerns in the reported cases that we reviewed. There are no applicable randomized controlled trials (RCTs) to better guide phage therapy at this time.Given the safety and possibility of successful salvage therapy of MDRO infections using bacteriophages, it is reasonable to pursue phage therapy for difficult-to-treat infections on a compassionate use basis, but RCT data are critically needed to better inform management.

Assess the impact of pre-treatment high-frequency and low-frequency drug-resistant HIV variants on long-term outcomes of first-line efavirenz-based antiretroviral therapy (ART).Prospective observational study.Participants' pre-treatment plasma RNA had two sections of HIV pol encoding reverse transcriptase sequenced (Illumina, MiSeq) using unique molecular identifiers to detect wild-type (pre-treatment drug-resistant variants less than 1% of viral quasispecies), low-frequency (1-9%) or high-frequency drug-resistant variants (10-100%). Associations between pre-treatment drug resistance and virologic outcomes over 24 months of efavirenz-based ART were assessed for the number and frequency of mutations by drug class and other resistance parameters.Virologic failure was detected in 30 of 352 (9%) and pre-treatment drug-resistant variants were detected in the viral quasispecies of 31 of 352 (9%) participants prescribed efavirenz-based ART. Survival analyses revealed statistically significant associations between pre-treatment drug resistance at low (P 0.0001) and high (P 0.001) frequencies, at oligonucleotide ligation assay (OLA) (P 0.00001) and non-OLA (P 0.01) codons, to a single-antiretroviral class (P 0.00001), and a shorter time to virologic failure of efavirenz-based ART. Regression analyses detected independent effects across resistance categories, including both low-frequency (P 0.01) and high-frequency (P 0.001) drug-resistant variants.We observed that pre-treatment HIV drug resistance detected at low frequencies increased the risk of virologic failure over 24 months of efavirenz-based ART, but that most failures, regardless of drug-resistant variants' frequencies, were detected within a year of ART initiation. These observations suggest that when efavirenz-based ART is prescribed, screening for pre-treatment drug resistance by an assay capable of detecting low-frequency variants, including OLA, may guide clinicians to prescribe more effective ART.

There are four conditions caused by Kaposi sarcoma herpesvirus (KSHV): Kaposi sarcoma, KSHV-associated multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and KSHV inflammatory cytokine syndrome (KICS). These KSHV-associated disorders (KADs) often occur in people with HIV and can lead to multiorgan dysfunction requiring admission to the ICU. However, little is known about patient outcomes in this setting.A retrospective study of patients with KADs admitted to the ICU between 2010 and 2021 was conducted, examining KAD admission diagnoses, HIV characteristics, selected cytokine profiles, and ICU interventions. Primary outcomes were 60-day and median overall survival from ICU admission to death from any cause.Forty-seven patients (all but one with HIV coinfection) were included. At ICU admission, 44 patients (94%) were on antiretroviral therapy with a median CD4 + count of 88 cells/μl and HIV viral load of 23 copies/ml. The most common presentation was respiratory failure alone (19%) or with hypotension (17%). Twenty-two (47%) patients had presumed KICS (with or without Kaposi sarcoma) at admission and an additional KAD was diagnosed in 36% of these patients. IL-6 levels did not vary across KAD subtype. Twenty (43%) patients received KAD-directed therapy in the ICU. Sixty-day survival was 70% and median overall survival was 9 months.The majority of patients with HIV and KADs admitted to the ICU had well controlled HIV. Additional KAD were diagnosed during ICU admission in a proportion of patients who presented with presumed KICS. Critical illness did not preclude a subset of patients from receiving KAD-directed therapy in the ICU.

School based asthma programs have demonstrated that preventive asthma therapy administered in school reduces asthma morbidity. The burden of co-morbid allergic disease on asthma outcomes in a large school based asthma cohort has been unexplored.Evaluate the prevalence of allergic rhinitis (AR) in historically minoritized school children with persistent asthma, and determine if AR is an independent risk factor for asthma morbidity.We evaluated the prevalence of AR in children enrolled in 3 NIH funded school based asthma programs in Rochester, NY. We used linear regression and multivariate analyses to compare asthma outcomes for children whose caregivers did and did not report AR.We used data from 1,029 children with asthma (mean age 7.4, 60.4% Black, 29.5% Hispanic, 72.8% insured with Medicaid). 63% of children reported AR. Children with AR had significantly fewer symptom free days over 2 weeks compared to children without AR (7.2 vs. 8.3,Among a large school-based cohort of minoritized children with asthma, we found that the majority of children have comorbid allergic rhinitis, which was associated with increased asthma morbidity. Inadequate recognition and treatment for allergic rhinitis likely represents substantial preventable morbidity for this group.

To examine type 2 diabetes mellitus incidence and associated risk factors among people with HIV (PWH).A retrospective clinical cohort study of PWH at a Southeastern US academic HIV clinic between 2008 and 2018.PWH who attended at least two clinic visits were evaluated with demographic and clinical data extracted from the electronic medical record (EMR). Diabetes was defined as: hemoglobin A1C ≥6.5% and/or 2 glucose results200 mg/dl (at least 30 days apart), diagnosis of diabetes in the EMR, or exposure to diabetes medication. Time to diabetes incidence was computed from the entire clinic population for each year. Multivariable Cox proportional hazard regression models with time-dependent covariates were created to evaluate the independent association between covariates and time to incident diabetes.Among 4113 PWH, we identified 252 incident cases of diabetes. Incidence increased from 1.04 incidents per 1000 person years (PY) in 2008, to 1.55 incidents per 1000 PY in 2018. Body mass index (hazard ratio [HR] 10.5 (6.2, 17.7)), liver disease (HR 1.9 (1.2, 3.1)), steroid exposure (HR 1.5 (1.1, 1.9)), and use of integrase inhibitors (HR 1.5 (1.1, 2.0)) were associated with incident diabetes. Additional associated factors included lower CD4 + cell counts, duration of HIV infection, exposure to nonstatin lipid-lowering therapy, and dyslipidemia.Rapidly increasing incident diabetes rates among PWH were associated with both traditional and HIV-related associated risk factors, particularly body weight, steroid exposure, and use of Integrase Inhibitors. Notably, several of the risk factors identified are modifiable and can be targeted for intervention.

This Pillars of Immunology article is a commentary on “Positive Selection of Natural Autoreactive B Cells,” a pivotal article written by K. Hayakawa, M. Asano, S. A. Shinton, M. Gui, D. Allman, C. L. Stewart, J. Silver, and R. R. Hardy, and published in Science, in 1999. https://doi.org/10.1126/science.285.5424.113.

The Wnt signalling antagonist Dickkopf-1 (DKK1) inhibits osteoblast differentiation and function and has been described to play a central role in promoting bone loss, while blockade of DKK1 increases bone formation. We investigated the effects of DKK1 on periosteal new bone formation in two murine models of inflammatory arthritis, the antigen-induced arthritis (AIA) and K/BxN serum transfer arthritis (STA) models.The flare variant of AIA was induced in wild-type mice and a blocking antibody to DKK1, control rat immunoglobulin G (IgG), or phosphate-buffered saline (PBS) was administered starting on day 14, a time at which inflammation and erosions are known to be established. Knees were assessed for histological inflammation and periosteal new bone formation was quantitated. In addition, STA was generated in transgenic (Tg) mice with osteoblast-specific overexpression ofiDkk1/iand littermate controls. New bone formation around the wrists of these mice was quantified by micro-computed tomography.Blockade of DKK1 in arthritic mice resulted in significantly more periosteal new bone formation compared to mice treated with control rat IgG or PBS. Conversely, in the setting of increasediDkk1/iexpression, arthriticiDkk1/iTg mice developed significantly less periosteal new bone than arthritic controls.DKK1 is a regulator of periosteal bone formation in inflammatory arthritis. Thus, regulation of DKK1 may be considered as a therapeutic approach in inflammatory diseases in which patients suffer from excessive periosteal bone formation, such as spondyloarthritis.

Leptospira species are difficult to culture. Thus, when there is suspicion for an infectious etiology to uveitis, bacterial cultures may fail to identify Leptospira. We describe a case of leptospirosis-associated uveitis that evaded culture and molecular assays. DNA sequencing of the aqueous fluid showed the presence of Leptospira spp.Retrospective case review of clinical and laboratory features of a patient with ocular leptospirosis is presented.DNA sequencing identified the genome of Leptospirosis spp. in the aqueous humor.Metagenomic sequencing, by virtue of its unbiased nature, can be a helpful adjunctive test when a strong clinical suspicion for intraocular infection persists despite negative routine culture and molecular assays.

The School Inner-City Asthma Intervention Study 2 (SICAS 2) tested interventions to reduce exposures in classrooms of students with asthma. The objective of thisPre-intervention dust samples were collected at the beginning of the school year from classrooms and corresponding homes of students with asthma (For those students with a higher Group 1 mold level in their pre-intervention classroom than home (HEPA intervention in classrooms reduced Group 1 and ERMI values, which corresponded to improvements in the students' FEV1% test results.

In antibody-mediated allograft rejection, donor-reactive antibodies cause transplant injury in part via complement activation. New mechanistic insights indicate complement also modulates development of humoral immune responses. Herein we review recent data that describes how complement affects antibody formation and we discuss therapeutic implications.Extravasating T cells interacting with integrins express and activate intracellular complement that drives immune-metabolic adaptations vital for CD4 + helper cells. Marginal zone B cells can acquire intact major histocompatibility complexes from dendritic cells via complement-dependent trogocytosis for presentation to T cells. Activated B cells in germinal centers receive co-stimulatory signals from T-helper cells. These germinal center B cells undergo coordinate shifts in surface complement regulator expression that permit complement receptor signaling on the germinal center B cells required for affinity maturation. The positively selected, high-affinity B cells can differentiate into plasma cells that produce donor-HLA-reactive antibodies capable of ligating endothelial, among other, graft cells. Subsequent sublytic complement attack can stimulate endothelial cells to activate CD4 + and CD8 + T cells, promoting cellular and humoral rejection. Newly developed complement inhibitors are being tested to prevent/treat transplant rejection.The complement system influences T-cell, B-cell and endothelial-cell activation, and thereby contributes allograft injury. Emerging therapeutic strategies targeting complement activation have the potential to prevent or abrogate transplant injury and improve transplant outcomes.

The current population-based study examines the association between county-level ambient air pollution and childhood asthma. Data from the nationally representative 2010–2015 National Health Interview Survey were linked to nationwide fine particulate matter (PM2.5) air pollution data at the county-level from the National Environmental Public Health Tracking Network which utilizes air quality monitoring stations and modeled PM2.5 measurements (Downscaler model data) and adjusted by county-level socioeconomic characteristics data from the 2010–2015 American Community Survey. Multilevel modeling techniques were used to assess the association between PM2.5 annual concentrations (quartiles < 8.11, 8.11–9.50, 9.51–10.59, ≥ 10.60 µg/m3) and current childhood asthma along with two asthma outcomes (episode in the past year, emergency room (ER) visit due to asthma). From 2010 to 2015, there were significant declines in PM2.5 concentrations and asthma outcomes. In unadjusted models, children living in areas with higher PM2.5 concentrations were more likely to have current asthma, ≥1 asthma episode in the past year, and ≥1 ER visit due to asthma compared with children living in areas with the lowest quartile (< 8.11 µg/m3). After adjusting for characteristics at the county, geographic, and child and family-level, significant associations remained for asthma episode, and ER visit among children living in areas with PM2.5 annual concentrations between 9.51 and 10.59 µg/m3 (3rd quartile) compared with children living in areas with the lowest quartile. This study adds to the limited literature by incorporating nationally representative county-, child-, and family-level data to provide a multi-level analysis of the associations between air pollution and childhood asthma in the U.S.

Fracture rates have been reported to be higher among older women living with HIV (WLWH) than HIV- women. Hormone therapy with estrogen can reduce vasomotor symptoms (VMS) associated with menopause and prevent fractures. As data are limited on the benefits of hormone therapy use in WLWH, we examined associations of hormone therapy, use and fractures.A prospective study of 1765 (1350 WLWH and 415 HIV-) postmenopausal Women's Interagency HIV Study (WIHS) participants was performed, including self-reported hormone therapy, use and fracture data from 2003 to 2017. Proportional hazard models determined predictors of new fractures at any site or at typical fragility fracture sites (hip, spine, wrist).At the first postmenopausal visit, the median (IQR) age of WLWH was slightly younger than HIV- women [49.8 (46.4-53) vs. 50.7 (47.5-54), P = 0.0002] and a smaller proportion of WLWH reported presence of VMS (17% vs. 26%, P 0.0001). A greater proportion of WLWH than HIV- women reported hormone therapy use (8% vs. 4%, P = 0.007) at the first postmenopausal visit. In multivariate analyses, white race and smoking were significant predictors of incident fracture at any site but hormone therapy ( P = 0.69) and HIV status ( P = 0.53) were not.Our study did not find evidence of benefit or harm with regards to fracture outcomes in postmenopausal WLWH receiving hormone therapy. Further research is needed to determine whether hormone therapy has benefits beyond treatment of VMS, such as prevention of adverse aging-associated outcomes.

Inflammation is a biological process that dynamically alters the surrounding microenvironment, including participating immune cells. As a well-protected organ surrounded by specialized barriers and with immune privilege properties, the central nervous system (CNS) tightly regulates immune responses. Yet in neuroinflammatory conditions, pathogenic immunity can disrupt CNS structure and function. T cells in particular play a key role in promoting and restricting neuroinflammatory responses, while the inflamed CNS microenvironment can influence and reshape T cell function and identity. Still, the contraction of aberrant T cell responses within the CNS is not well understood. Using autoimmunity as a model, here we address the contribution of CD4 T helper (Th) cell subsets in promoting neuropathology and disease. To address the mechanisms antagonizing neuroinflammation, we focus on the control of the immune response by regulatory T cells (Tregs) and describe the counteracting processes that preserve their identity under inflammatory challenges. Finally, given the influence of the local microenvironment on immune regulation, we address how CNS-intrinsic signals reshape T cell function to mitigate abnormal immune T cell responses.

Many individuals living with the human immunodeficiency virus (HIV) infection and receiving antiretroviral therapy (ART) reside in areas at high risk for malaria but how malaria affects clinical outcomes is not well described in this population. We evaluated the burden of malaria infection and clinical malaria, and impact on HIV viral load and CD4 + cell count among adults on ART.We recruited Malawian adults on ART who had an undetectable viral load and ≥250 CD4 + cells/μl to participate in this randomized trial to continue daily trimethoprim-sulfamethoxazole (TS), discontinue daily co-trimoxazole, or switch to weekly chloroquine (CQ).We defined clinical malaria as symptoms consistent with malaria and positive blood smear, and malaria infection as Plasmodium falciparum DNA detected from dried blood spots (collected every 4-12 weeks). CD4 + cell count and viral load were measured every 24 weeks. We used Poisson regression and survival analysis to compare the incidence of malaria infection and clinical malaria. Clinicaltrials.gov NCT01650558.Among 1499 participants enrolled, clinical malaria incidence was 21.4/100 person-years of observation (PYO), 2.4/100 PYO and 1.9/100 PYO in the no prophylaxis, TS, and CQ arms, respectively. We identified twelve cases of malaria that led to hospitalization and all individuals recovered. The preventive effect of staying on prophylaxis was approximately 90% compared to no prophylaxis (TS: incidence rate ratio [IRR] 0.11, 95% confidence interval [CI] 0.08, 0.15 and CQ: IRR 0.09, 95% CI 0.06, 0.13). P. falciparum infection prevalence among all visits was 187/1475 (12.7%), 48/1563 (3.1%), and 29/1561 (1.9%) in the no prophylaxis, TS, and CQ arms, respectively. Malaria infection and clinical malaria were not associated with changes in CD4 + cell count or viral load.In clinically stable adults living with HIV on ART, clinical malaria was common after chemoprophylaxis stopped. However, neither malaria infection nor clinical illness appeared to affect HIV disease progression.

Older donors have the potential to close the gap between demand and supply in solid organs transplantation. Utilizing older organs, at the same time, has been associated with worse short- and long-term outcomes. Here, we introduce potential mechanisms on how treatments during machine perfusion (MP) may safely improve the utilization of older organs.Consequences of ischemia reperfusion injury (IRI), a process of acute, sterile inflammation leading to organ injury are more prominent in older organs. Of relevance, organ age and IRI seem to act synergistically, leading to an increase of damage associated molecular patterns that trigger innate and adaptive immune responses. While cold storage has traditionally been considered the standard of care in organ preservation, accumulating data support that both hypothermic and normothermic MP improve organ quality, particularly in older organs. Furthermore, MP provides the opportunity to assess the quality of organs while adding therapeutic agents. Experimental data have already demonstrated the potential of applying treatments during MP. New experimental show that the depletion of senescent cells that accumulate in old organs improves organ quality and transplant outcomes.As the importance of expanding the donor pool is increasing, MP and novel treatments bear the potential to assess and regenerate older organs, narrowing the gap between demand and supply.

Purpose of review: There is no widely accepted single ethical principle for the fair allocation of scarce donor organs for transplantation. Although most allocation systems use combinations of allocation principles, there is a particular tension between 'prioritizing the worst-off' and 'maximizing total benefits'. It is often suggested that empirical research on public preferences should help solve the dilemma between equity and efficiency in allocation policy-making. Recent findings: This review shows that the evidence on public preferences for allocation principles is limited, and that the normative role of public preferences in donor organ allocation policy making is unclear. The review seeks to clarify the ethical dilemma to the transplant community, and draws attention to recent attempts at balancing and rank-ordering of allocation principles. Summary: This review suggests that policy makers should make explicit the relative weights attributed to equity and efficiency considerations in allocation policies, and monitor the effects of policy changes on important ethics outcomes, including equitable access among patient groups. Also, it draws attention to wider justice issues associated not with the distribution of donor organs among patients on waiting lists, but with barriers in referral for transplant evaluation and disparities among patient groups in access to waiting lists.

The role of nutrition is increasingly recognized in the management of chronic immune diseases. However, the role of an immune-supportive diet as adjuvant therapy in the management of allergic disease has not been similarly explored. This review assesses the existing evidence for a relationship between nutrition, immune function, and allergic disease from a clinical perspective. In addition, the authors propose an immune-supportive diet to enhance dietary interventions and complementing other therapeutic options for allergic disease from early life to adulthood. A narrative review of the literature was conducted, to determine the evidence of the relationship between nutrition and immune function, overall health, epithelial barrier function, and gut microbiome, particularly in relation to allergy. Studies on food supplements were excluded. The evidence was assessed and utilized to develop a sustainable immune-supportive diet to complement other therapies in allergic disease. The proposed diet consists of a highly diverse range of fresh, whole, and minimally processed plant-based and fermented foods supplemented with moderate amounts of nuts, omega-3-rich foods and animal-based products in proportional amounts of the EAT-Lancet diet, such as (fatty) fish, (fermented) milk products which may be full-fat and eggs, lean meat or poultry, which may be free-range or organic.

Active ingredients of sunscreens, or UV filters, have increased in use because public awareness of sun safety has risen. In addition to this intentional use, unintentional exposures to UV filters also occur through application of personal care products, where the filters are incorporated into the product. There are 2 main types of UV filters: organic (chemical) filters and the 2 inorganic (mineral) filters, titanium dioxide and zinc oxide. Both allergic contact dermatitis (ACD) and photoallergic contact dermatitis (PACD) have been caused by organic filters; oxybenzone (benzophenone-3) is the most frequently reported contact and photocontact allergen compared with all other UV filters. There are no reports of ACD or PACD to the inorganic (physical) UV filters. Here, we review the categories of sunscreens available, currently marketed UV filters, and their corresponding ACD and PACD.