BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.

The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.

Single-Cell Transcriptomics of Regulatory T Cells Reveals Trajectories of Tissue Adaptation.

Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, their respective draining lymph nodes (LNs) and spleen. In these tissues, we identified Treg cell subpopulations with distinct degrees of NLT phenotype. Subpopulation pseudotime ordering and gene kinetics were consistent in recruitment to skin and colon, yet the initial NLT-priming in LNs and the final stages of NLT functional adaptation reflected tissue-specific differences. Predicted kinetics were recapitulated using an in vivo melanoma-induction model, validating key regulators and receptors. Finally, we profiled human blood and NLT Treg and Tmem cells, and identified cross-mammalian conserved tissue signatures. In summary, we describe the relationship between Treg cell heterogeneity and recruitment to NLTs through the combined use of computational prediction and in vivo validation.

Autoimmunity Against Surfactant Protein B Is Associated with Pneumonitis During Checkpoint Blockade.

RATIONALE: Immune checkpoint inhibitor-related pneumonitis is a serious autoimmune event affecting up to 20% of patients with non-small cell lung cancer, yet the factors underpinning its development in some patients and not others are poorly understood. OBJECTIVES: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. METHODS: The study cohort consisted of non-small cell lung cancer patients who gave blood samples before and during immune checkpoint inhibitor treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with non-small cell lung cancer and patients with melanoma. MEASUREMENTS AND MAIN RESULTS: Across both cohorts, patients who developed pneumonitis had higher pre-treatment levels of immunoglobulin G autoantibodies targeting surfactant protein-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ interferon-gamma-positive surfactant protein B-specific T cells, and expanding T cell clonotypes recognizing this protein, accompanied by a pro-inflammatory serum proteomic profile. CONCLUSIONS: Our data suggest that the co-occurrence of surfactant protein-B-specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pre-treatment levels of these antibodies may represent a potential biomarker for elevated risk of developing pneumonitis and on-treatment levels may provide a diagnostic aid. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Individual T helper cells have a quantitative cytokine memory.

The probabilistic expression of cytokine genes in differentiated T helper (Th) cell populations remains ill defined. By single-cell analyses and mathematical modeling, we show that one stimulation featured stable cytokine nonproducers as well as stable producers with wide cell-to-cell variability in the magnitude of expression. Focusing on interferon-γ (IFN-γ) expression by Th1 cells, mathematical modeling predicted that this behavior reflected different cell-intrinsic capacities and not mere gene-expression noise. In vivo, Th1 cells sort purified by secreted IFN-γ amounts preserved a quantitative memory for both probability and magnitude of IFN-γ re-expression for at least 1 month. Mechanistically, this memory resulted from quantitatively distinct transcription of individual alleles and was controlled by stable expression differences of the Th1 cell lineage-specifying transcription factor T-bet. Functionally, Th1 cells with graded IFN-γ production competence differentially activated Salmonella-infected macrophages for bacterial killing. Thus, individual Th cells commit to produce distinct amounts of a given cytokine, thereby generating functional intrapopulation heterogeneity.

Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage.

Tissue damage caused by viral hepatitis is a major cause of morbidity and mortality worldwide. Using a mouse model of viral hepatitis, we identified virus-induced early transcriptional changes in the redox pathways in the liver, including downregulation of superoxide dismutase 1 (Sod1). Sod1(-/-) mice exhibited increased inflammation and aggravated liver damage upon viral infection, which was independent of T and NK cells and could be ameliorated by antioxidant treatment. Type I interferon (IFN-I) led to a downregulation of Sod1 and caused oxidative liver damage in Sod1(-/-) and wild-type mice. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against virus-induced liver damage. These results delineate IFN-I mediated oxidative stress as a key mediator of virus-induced liver damage and describe a mechanism of innate-immunity-driven pathology, linking IFN-I signaling with antioxidant host defense and infection-associated tissue damage. VIDEO ABSTRACT.

Postarrest Care Bundle Improves Quality of Care and Clinical Outcomes in the Normothermia Era.

PURPOSE: Temperature targets in patients with cardiac arrest and return of spontaneous circulation (ROSC) have changed. Changes to higher temperature targets have been associated with higher breakthrough fevers and mortality. A post-ROSC normothermia bundle was developed to improve compliance with temperature targets. METHODS: In August 2021, "ad hoc" normothermia at the discretion of the attending intensivist was initiated. In December 2021, a post-ROSC normothermia protocol was implemented, incorporating a rigorous, stepwise approach to fever prevention (temperature ≥ 37.8). We conducted a before-after cohort study of all adult patients post-ROSC who survived to intensive care unit admission between August 1, 2021, and April 1, 2022. They were divided into "ad hoc" and "protocol" groups. Clinical outcomes compared included fevers, active cooling, and paralytic use. RESULTS: Fifty-eight post-ROSC patients were admitted; 24 in the "ad hoc" and 34 in the "protocol" groups. Patient demographics were similar between groups. The "ad hoc" group had more shockable rhythms (67% vs 24%, P = .001) and cardiac catheterizations (42% vs 15%, P = .03). The "protocol" group were significantly less likely to have a fever at 40 h (6% vs 40%, P < .001) and 72 h (14% vs 65%, P ≤ .001). Patients in the normothermia "protocol" used significantly less neuromuscular blocking agents (24% vs 50%, P = .05). The normothermia "protocol" resulted in similar mortality (56% vs 58%, P = 1.0). CONCLUSION: Use of a normothermia "protocol" resulted in fewer fevers and less neuromuscular blocker administration compared to "ad hoc" management. A protocolized approach for improved quality of care should be considered in institutions adopting normothermia.

Wafer-scale development, characterization, and high temperature stabilization of epitaxial Cr2O3 films grown on Ru(0001).

This work outlines conditions suitable for the heteroepitaxial growth of Cr2O3(0001) films (1.5-20 nm thick) on a Ru(0001)-terminated substrate. Optimized growth is achieved by sputter deposition of Cr within a 4 mTorr Ar/O2 20% ambient at Ru temperatures ranging from 450 to 600 °C. The Cr2O3 film adopts a 30° rotated honeycomb configuration with respect to the underlying Ru(0001) substrate and exhibits a hexagonal lattice parameter consistent with that for bulk Cr2O3(0001). Heating to 700 °C within the same environment during film preparation leads to Ru oxidation. Exposure to temperatures at or above 400 °C in a vacuum, Ar, or Ar/H2 3% leads to chromia film degradation characterized by increased Ru 3d XPS intensity coupled with concomitant Cr 2p and O 1s peak attenuations when compared to data collected from unannealed films. An ill-defined but hexagonally well-ordered RuxCryOz surface structure is noted after heating the film in this manner. Heating within a wet Ar/H2 3% environment preserves the Cr2O3(0001)/Ru(0001) heterolayer structure to temperatures of at least 950 °C. Heating an Ru-Cr2O3-Ru heterostacked film to 950 °C within this environment is shown by cross-sectional scanning/transmission electron microscopy (S/TEM) to provide clear evidence of retained epitaxial bicrystalline oxide interlayer structure, interlayer immiscibility, and epitaxial registry between the top and bottom Ru layers. Subtle effects marked by O enrichment and O 1s and Cr 2p shifts to increased binding energies are noted by XPS in the near-Ru regions of Cr2O3(0001)/Ru(0001) and Ru(0001)/Cr2O3(0001)/Ru(0001) films after annealing to different temperatures in different sets of environmental conditions.

Characterizing the impact of thermoregulation in patients after cardiac arrest: a retrospective cohort study.

PURPOSE: Core body temperature has been extensively investigated as a thereuptic target in care after cardiac arrest. Nevertheless, the integrity of thermoregulation in patients after cardiac arrest has not been well studied. We sought to evaluate whether low spontaneous body temperature after cardiac arrest is associated with increased death and a worse neurologic outcome, and whether patients with low spontaneous body temperature exhibit features suggestive of impaired thermoregulation. METHODS: We conducted a single-centre retrospective cohort study. We included all adult patients who underwent temperature control with hypothermia after cardiac arrest between 1 January 2014 and 30 June 2020. The primary exposure was low spontaneous core body temperature (< 35 °C) at initiation of hypothermia therapy. The primary outcome was in-hospital death and the secondary outcome was poor neurologic outcomes at discharge. RESULTS: Five hundred and ninety-seven adult patients, comprising both in- and out-of-hospital cardiac arrests, were included. Patients with low spontaneous body temperature also had slightly lower average temperature, and more frequent transient but controlled breakthrough fever episodes in the first 24 hr. In the multivariable logistic regression analysis, low spontaneous body temperature was associated with higher odds of in-hospital death (odds ratio, 2.9; 95% confidence interval, 1.9 to 4.2; P < 0.001). CONCLUSION: In this single-centre retrospective cohort study, low spontaneous core body temperature was associated with poor outcomes in patients after cardiac arrest. Patients with low spontaneous body temperature also exhibited features suggestive of impaired thermoregulation. Further research is needed to determine whether body temperature upon presentation reflects the robustness of the patient's underlying physiology and severity of brain insult after a cardiac arrest.

RéSUMé: OBJECTIF: La température corporelle centrale a fait l'objet d'études approfondies en tant que cible thérapeutique dans les soins après un arrêt cardiaque. Néanmoins, l'intégrité de la thermorégulation après un arrêt cardiaque n'a pas été bien étudiée. Nous avons cherché à évaluer si une température corporelle spontanément basse après un arrêt cardiaque était associée à une augmentation de la mortalité et à une issue neurologique plus grave, et si les individus ayant une température corporelle spontanément basse présentaient des caractéristiques suggérant une altération de la thermorégulation. MéTHODE: Nous avons mené une étude de cohorte rétrospective monocentrique. Nous avons inclus tou·tes les patient·es adultes ayant bénéficié d'un contrôle de température lors d'une hypothermie après un arrêt cardiaque entre le 1er janvier 2014 et le 30 juin 2020. L'exposition principale était une température corporelle centrale spontanément basse (< 35 °C) au début du traitement de l'hypothermie. Le critère d'évaluation principal était le décès à l'hôpital, et le critère d'évaluation secondaire était de mauvaises issues neurologiques à la sortie de l'hôpital. RéSULTATS: Cinq cent quatre-vingt-dix-sept patient·es adultes, ayant subi des arrêts cardiaques à l'hôpital ou hors de l'hôpital, ont été inclus·es. Les patient·es ayant une température corporelle spontanément basse avaient également une température moyenne légèrement plus basse et des épisodes de fièvre paroxystique transitoires mais contrôlés plus fréquents au cours des premières 24 heures. Dans l'analyse de régression logistique multivariée, une température corporelle spontanément basse était associée à une probabilité plus élevée de décès à l'hôpital (rapport de cotes, 2,9; intervalle de confiance à 95 %, 1,9 à 4,2; P < 0,001). CONCLUSION: Dans cette étude de cohorte rétrospective monocentrique, une température corporelle centrale spontanément basse a été associée à de mauvais devenirs après un arrêt cardiaque. Les patient·es présentant une température corporelle spontanément basse présentaient également des caractéristiques suggérant une altération de la thermorégulation. D'autres recherches sont nécessaires pour déterminer si la température corporelle lors de la présentation reflète la robustesse de la physiologie sous-jacente des patient·es et la gravité de la lésion cérébrale après un arrêt cardiaque.

Th2 cells lacking T-bet suppress naive and memory T cell responses via IL-10.

Exacerbated immune responses and loss of self-tolerance lead to the development of autoimmunity and immunopathology. Novel therapies to target autoreactive T cells are still needed. Here, we report that Th2-polarized T cells lacking the transcription factor T-bet harbor strong immunomodulatory potential and suppress antigen-specific CD8+ T cells via IL-10. Tbx21-/- Th2 cells protected mice against virus-induced type 1 diabetes development and suppressed not only naive but also memory CD8+ T cell responses. IL-10-producing, but not IL-10-deficient Tbx21-/- Th2 cells down-regulated costimulatory molecules on dendritic cells and reduced their IL-12 production after lymphocytic choriomeningitis virus infection. Impaired dendritic cell activation hindered effector and cytotoxic CD8+ T cell development after infection. These findings indicate that Tbx21-/- Th2 cells strongly suppress proinflammatory responses of naive and memory T cells via IL-10. Thus, in vivo IL-10-secreting Th2 cells could harbor a therapeutic potential for the treatment of T cell-mediated inflammatory disorders.

Synthesis, DFT, molecular dynamics, and Monte Carlo simulation of a novel thiourea derivative with extraordinary inhibitive properties for mild steel in 0.5 M sulphuric acid.

A novel thiourea derivative has been successfully synthesized via green routes and fully characterized by FT-IR, 1H, 13C-NMR, and elemental analysis. The synthetic inhibitor 2-amino-N-(phenylcarbamothioyl) benzamide (APCB) was assessed as a corrosion inhibitor for mild steel (MS) in 0.5 M H2SO4. Various electrochemical techniques, such as electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization (PDP), have been used to evaluate inhibition efficiency. As a result, EIS and PDP agreed with each other, indicating that APCB exhibits an inhibition performance that exceeds 96% at a concentration of 2 × 10-4 M and increases with an increase in temperature up to 98% at 333 K. However, PDP measurements showed that APCB is a mixed type of inhibitor. In addition, SEM, EDX, AFM, and contact angle measurements were used as a topological surface characterization technique that confirmed the formation of a protective layer over the MS surface. Additionally, the complex formation was thoroughly confirmed by UV-Vis measurements. The adsorption of APCB proved the highest compliance with the Langmuir adsorption isotherm. Furthermore, density functional theory (DFT) calculations were conducted to establish the correlation between the electronic structure and excellent inhibition efficiency. Moreover, molecular dynamics (MD) simulations were used to find interaction energy in different media. Finally, the adsorption affinity of the MS surface for different concentrations of APCB was verified via Monte Carlo (MC) simulations. Owing to the outcomes of this study, it is remarkable that APCB, with its low cost and simple synthesis, might be an exceptionally prominent option for mild steel protection.

Point-of-care lung and cardiac ultrasound (LUCAS) study in hip fracture patients: a prospective cohort study.

PURPOSE: A clinical conflict often presented with hip fracture patients is whether to proceed with timely surgery or delay surgery until a formal echocardiogram is conducted. This study aimed to assess the impact of incorporating point-of-care lung and cardiac ultrasound (LUCAS) scans as part of the preoperative assessment for hip fracture patients. METHODS: We recruited 225 consecutive adult patients booked for urgent hip arthroplasty surgery. A LUCAS scan was performed for each patient. The anesthesiologists were asked to provide their anesthetic plans before and after acknowledging the results of the LUCAS scans. The primary endpoint was a composite outcome of changes to the anesthetic plan. The secondary outcomes included anesthesiologists' opinions of the LUCAS scans. RESULTS: One-hundred-ninety-eight patients were included. The majority of LUCAS findings were not severe. A common abnormal finding was hypovolemia (31%). One-hundred-and-six anesthetic management decisions were changed, with 59 of these changes being an escalation of the anesthetic plan, and 47 of these changes being a de-escalation. Eighty-three percent of anesthesiologists agreed that LUCAS affirmed their anesthetic plans and should be an integral part of the perioperative assessment. CONCLUSION: This study found that LUCAS scans did not significantly alter the anesthetic plan for hip fracture patients. Nevertheless, LUCAS scans can rule out severe cardiopulmonary conditions and allow for both escalation and de-escalation of care. In the setting of early hip surgery, LUCAS presents a viable option in selected patients to address the unmet need to allow for both timely surgery and comprehensive patient evaluation. STUDY REGISTRATION: ClinicalTrials.gov (NCT03275129); registered 8 July 2018.

RéSUMé: OBJECTIF: Une interrogation clinique qui existe souvent avec les patient·es se présentant avec une fracture de hanche est de savoir s'il faut procéder à une intervention chirurgicale rapidement ou retarder la chirurgie jusqu'à ce qu'un échocardiogramme formel soit réalisé. Cette étude visait à évaluer l'impact de l'intégration de l'échographie ciblée pulmonaire et cardiaque (LUCAS, Lung and Cardiac ultrasound) dans le cadre de l'évaluation préopératoire des personnes ayant subi une fracture de la hanche. MéTHODE: Nous avons recruté 225 patient·es adultes consécutif·ves devant bénéficier d'une arthroplastie urgente de la hanche. Une échographie de type LUCAS a été réalisée pour chaque patient·e. On a demandé aux anesthésiologistes de fournir leurs plans anesthésiques avant et après avoir pris connaissance des résultats des échographies de type LUCAS. Le critère d'évaluation principal était un résultat composite des modifications apportées au plan anesthésique. Les critères d'évaluation secondaires comprenaient les opinions des anesthésiologistes sur les échographies de type LUCAS. RéSULTATS: Cent quatre-vingt-dix-huit patient·es ont été inclus·es. La majorité des résultats de l'échographie de type LUCAS n'étaient pas graves. Un résultat anormal courant était l'hypovolémie (31 %). Cent six décisions de prise en charge anesthésique ont été modifiées, 59 de ces changements étant une escalade du plan anesthésique et 47 de ces changements étant une réduction. Quatre-vingt-trois pour cent des anesthésiologistes ont convenu que l'échographie de type LUCAS confirmait leurs plans anesthésiques et devrait faire partie intégrante de l'évaluation périopératoire. CONCLUSION: Cette étude a révélé que les échographies de type LUCAS ne modifiaient pas de manière significative le plan anesthésique pour les patient·es se présentant avec une fracture de hanche. Néanmoins, les échographies de type LUCAS peuvent exclure des affections cardiopulmonaires graves et permettre à la fois d'augmenter ou de réduire les soins périopératoires. Dans le cadre d'une chirurgie précoce de la hanche, l'échographie de type LUCAS présente une option viable chez une patientèle sélectionnée pour répondre à un besoin non satisfait afin de permettre à la fois une chirurgie rapide et une évaluation complète des patient·es. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT03275129); enregistrée le 8 juillet 2018.

Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism.

AIMS: Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism. METHODS AND RESULTS: Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels. CONCLUSION: Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.

Residual homing of α4ß7-expressing ß1+PI16+ regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab.

OBJECTIVE: The anti-α4ß7 integrin antibody vedolizumab is administered at a fixed dose for the treatment of IBDs. This leads to a wide range of serum concentrations in patients and previous studies had suggested that highest exposure levels are associated with suboptimal clinical response. We aimed to determine the mechanisms underlying these non-linear exposure-efficacy characteristics of vedolizumab. DESIGN: We characterised over 500 samples from more than 300 subjects. We studied the binding of vedolizumab to T cells and investigated the functional consequences for dynamic adhesion, transmigration, gut homing and free binding sites in vivo. Employing single-cell RNA sequencing, we characterised α4ß7 integrin-expressing T cell populations 'resistant' to vedolizumab and validated our findings in vitro and in samples from vedolizumab-treated patients with IBD. We also correlated our findings with a post-hoc analysis of the Gemini II and III studies. RESULTS: Regulatory T (TReg) cells exhibited a right-shifted vedolizumab binding profile compared with effector T (TEff) cells. Consistently, in a certain concentration range, the residual adhesion, transmigration, homing of and availability of functional α4ß7 on TReg cells in vivo was higher than that of/on TEff cells. We identified a vedolizumab-'resistant' α4ß7-expressing ß1+PI16+ TReg cell subset with pronounced regulatory properties as the substrate for this effect. Our observations correlated with exposure-efficacy data from Gemini II and III trials. CONCLUSION: Completely blocking TEff cell trafficking with vedolizumab, while simultaneously permitting residual homing of powerful TReg cells in an optimal 'therapeutic window' based on target exposure levels might be a strategy to optimise treatment outcomes in patients with IBD.

The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes.

After being activated by antigen, helper T lymphocytes switch from a resting state to clonal expansion. This switch requires inactivation of the transcription factor Foxo1, a suppressor of proliferation expressed in resting helper T lymphocytes. In the early antigen-dependent phase of expansion, Foxo1 is inactivated by antigen receptor-mediated post-translational modifications. Here we show that in the late phase of expansion, Foxo1 was no longer post-translationally regulated but was inhibited post-transcriptionally by the interleukin 2 (IL-2)-induced microRNA miR-182. Specific inhibition of miR-182 in helper T lymphocytes limited their population expansion in vitro and in vivo. Our results demonstrate a central role for miR-182 in the physiological regulation of IL-2-driven helper T cell-mediated immune responses and open new therapeutic possibilities.

Anti-SARS-CoV2 antibody-mediated cytokine release syndrome in a patient with acute promyelocytic leukemia.

BACKGROUND: Passive immunization against SARS-CoV-2 limits viral burden and death from COVID-19; however, it poses a theoretical risk of disease exacerbation through antibody-dependent enhancement (ADE). ADE after anti-SARS-CoV2 antibody treatment has not been reported, and therefore the potential risk and promoting factors remain unknown. CASE PRESENTATION: A 75-year-old female was admitted to the emergency room with recurrent, unexplained bruises and leukocytopenia, anemia, and thrombocytopenia. Evaluation of a bone marrow biopsy established the diagnosis of an acute promyelocytic leukemia (APL). SARS-CoV-2 RT-PCR testing of nasal and throat swabs on admission was negative. During the routine SARS-CoV-2 testing of inpatients, our patient tested positive for SARS-CoV-2 on day 14 after admission without typical COVID-19 symptoms. Due to disease- and therapy-related immunosuppression and advanced age conferring a high risk of progressing to severe COVID-19, casirivimab and imdevimab were administered as a preemptive approach. The patient developed immune activation and cytokine release syndrome (CRS) occurring within four hours of preemptive anti-SARS-CoV2 antibody (casirivimab/imdevimab) infusion. Immune activation and CRS were evidenced by a rapid increase in serum cytokines (IL-6, TNFα, IL-8, IL-10), acute respiratory insufficiency, and progressive acute respiratory distress syndrome. DISCUSSION AND CONCLUSION: The temporal relationship between therapeutic antibody administration and the rapid laboratory, radiological, and clinical deterioration suggests that CRS was an antibody-related adverse event, potentially exacerbated by APL treatment-mediated differentiation of leukemic blasts and promyelocytes. This case highlights the need for careful assessment of life-threatening adverse events after passive SARS-CoV-2 immunization, especially in the clinical context of patients with complex immune and hematological landscapes.

Standardized statement for the ethical use of human cadaveric tissues in anatomy research papers: Recommendations from Anatomical Journal Editors-in-Chief.

Human cadaveric donors are essential for research in the anatomical sciences. However, many research papers in the anatomical sciences often omit a statement regarding the ethical use of the donor cadavers or, as no current standardized versions exist, use language that is extremely varied. To rectify this issue, 22 editors-in-chief of anatomical journals, representing 17 different countries, developed standardized and simplified language that can be used by authors of studies that use human cadaveric tissues. The goal of these editor recommendations is to standardize the writing approach by which the ethical use of cadaveric donors is acknowledged in anatomical studies that use donor human cadavers. Such sections in anatomical papers will help elevate our discipline and promote standardized language use in others non anatomy journals and also other media outlets that use cadaveric tissues.

Curcumin and ustekinumab cotherapy alleviates induced psoriasis in rats through their antioxidant, anti-inflammatory, and antiproliferative effects.

INTRODUCTION: Psoriasis is a chronic multifactorial inflammatory disease that affects 3% of people worldwide. Ustekinumab is a selective anti-IL-12/23 biologic that alleviates psoriasis, and curcumin is a natural, effective dietary turmeric extract applied to treat numerous diseases through its antioxidant and anti-inflammatory effects. OBJECTIVE: The current study evaluated the therapeutic effects of curcumin and ustekinumab cotherapy (CUC) on imiquimod (IQ)-induced psoriasis in a rat model. MATERIALS AND METHODS: Twenty rats were divided into four groups, G1 (control group), G2 (IQ-treated group), G3 (IQ + ustekinumab), and G4 (IQ + CUC). Clinical, histopathological (HP), immunohistochemical (IHC), antioxidant, and biochemical investigations evaluated the efficacy of these drugs for treating IQ induced-psoriasis. RESULTS: Rats of G2 exhibited clinical signs of psoriatic skin lesions (erythema, scaling, and skin thickening) with epidermal changes (acanthosis and parakeratosis). Additionally, the biochemical analysis revealed significant (p < 0.05) reductions in the levels of antioxidant biomarkers (SOD, GPx, and CAT) with significant (p < 0.05) elevations in psoriasis-related cytokines (TNF-α, IL-17A, IL-12P40, and IL-23). In contrast, CUC alleviated the psoriatic changes in G4 better than ustekinumab monotherapy in G3. CONCLUSIONS: Ustekinumab inhibits the inflammatory cytokines IL-12P40 and IL-23, while curcumin has antioxidant effects (increasing SOD, GPx, and CAT levels) with anti-inflammatory effects (decreasing the proinflammatory cytokine TNF-α and IL-17). Therefore, CUC could be an excellent cost-effective regimen that can improve the treatment of psoriasis by the synergistic effects of CUC.HighlightsIQ-induces psoriasis by elevating TNF-α, IL-17A, IL-12, and IL-23 and decreasing GPx, SOD, and CATUstekinumab exhibits anti-inflammatory effects by inhibiting IL-12 and IL-23Curcumin inhibits TNF-α and IL-17A, and increases GPx, SOD, and CAT levelsCUC mitigates psoriasis by synergistic antioxidant and anti-inflammatory effectsCUC inhibits TNF-α, IL-17A, IL-12, and IL-23 and increases GPx, SOD, and CAT levels.

[How T lymphocytes coordinate rheumatic inflammation]. / Wie T-Lymphozyten rheumatische Entzündung koordinieren.

Helper T (Th) cells play a decisive role in triggering and maintaining chronic rheumatic inflammation. Via secretion of proinflammatory cytokines and expression of costimulatory cell surface molecules, Th lymphocytes coordinate the recruitment and activation of effector cells, which are ultimately responsible for the immunopathology and tissue destruction. However, therapeutic approaches aimed at eliminating Th cells were unsuccessful due to their lack of selectivity. At the German Rheumatism Research Center (Deutsches Rheuma-Forschungszentrum, DRFZ), we are working to improve the understanding of the Th cells involved in chronic inflammatory reactions. Based on this understanding, our aim is to develop novel treatment strategies that selectively target the pathogenic Th lymphocytes causing rheumatic inflammation. The current article summarizes the DRFZ's research activities on this subject.

Eprosartan: A closer insight into its neuroprotective activity in rats with focal cerebral ischemia-reperfusion injury.

Eprosartan (EPRO), an angiotensin receptor type-1 (AT-1) blocker, exhibited neuroprotective activities in ischemic stroke resulting from focal cerebral ischemia in rats. The current study aimed to clarify the neuroprotective role of EPRO in middle carotid artery occlusion (MCAO)-induced ischemic stroke in rats. Fifty-six male Wistar rats were divided into four groups (n = 14 per group): sham-operated group, sham receiving EPRO (60 mg/kg/day, po) group, ischemia-reperfusion (IR) group, and IR receiving EPRO (60 mg/kg/day, po) group. MCAO led to a remarkable impairment in motor function together with stimulation of inflammatory and apoptotic pathways in the hippocampus of rats. After MCAO, the AT1 receptor in the brain was stimulated, resulting in activation of Janus kinase 2/signal transducers and activators of transcription 3 signaling generating more neuroinflammatory milieu and destructive actions on the hippocampus. Augmentation of caspase-3 level by MCAO enhanced neuronal apoptosis synchronized with neurodegenerative effects of oxidative stress biomarkers. Pretreatment with EPRO opposed motor impairment and decreased oxidative and apoptotic mediators in the hippocampus of rats. The anti-inflammatory activity of EPRO was revealed by downregulation of nuclear factor-kappa B and tumor necrosis factor-ß levels and (C-X-C motif) ligand 1 messenger RNA (mRNA) expression. Moreover, the study confirmed the role of EPRO against a unique pathway of hypoxia-inducible factor-1α and its subsequent inflammatory mediators. Furthermore, upregulation of caveolin-1 mRNA level was also observed along with decreased oxidative stress marker levels and brain edema. Therefore, EPRO showed neuroprotective effects in MCAO-induced cerebral ischemia in rats via attenuation of oxidative, apoptotic, and inflammatory pathways.

Canadian recommendations for training and performance in basic perioperative point-of-care ultrasound: recommendations from a consensus of Canadian anesthesiology academic centres.

Point-of-care ultrasound (POCUS) uses ultrasound at the bedside to aid decision-making in acute clinical scenarios. The increased use of ultrasound for regional anesthesia and vascular cannulation, together with more anesthesiologists trained in transesophageal echocardiography have contributed to the widespread use of POCUS in perioperative care. Despite the support of international experts, the practice of POCUS in perioperative care is variable as Canadian guidelines for anesthesiologists do not currently exist. Using a Delphi process of online surveys and a face-to-face national Canadian meeting, we developed a consensus statement for basic POCUS (bPOCUS) performance and training with a group of national experts from all Canadian universities. The group of experts consisted of 55 anesthesiologists from 12 Canadian universities considered local leaders in the field. An initial exploratory online survey of 47 statements was conducted. These statements were derived from previous generic guidelines or consensus conferences, or were based on current literature. Fourteen statements reached full consensus, 19 had 90-100% agreement, and 14 had less than 90% agreement. Eight new statements were proposed during the national meeting, and all statements without full agreement were discussed. A second online survey included 42 modified or new statements. From this second survey, 16 statements obtained full consensus, 39 had very good agreement, and one had good agreement. The final document includes 56 statements that define the scope of practice and necessary training for perioperative bPOCUS. The statements include five bPOCUS domains: cardiac, lung, airway, gastric, and abdomen. The use of bPOCUS is evolving and will play a significant role in perioperative medicine. This consensus statement aims to define a Canadian national standard on which curricula may be based. It also provides a framework to allow further development of bPOCUS in the perioperative setting.

RéSUMé: L'échographie ciblée (POCUS) utilise l'échographie au chevet des patients pour faciliter la prise de décisions dans les situations cliniques urgentes. L'utilisation accrue de l'échographie pour l'anesthésie régionale et la cannulation vasculaire, ainsi que l'augmentation du nombre d'anesthésologistes formés à l'échocardiographie transesophagienne, ont contribué à l'utilisation généralisée de l'échographie ciblée dans les soins périopératoires. Malgré son endossement par des experts internationaux, la pratique de l'échographie ciblée en soins périopératoires est variable, car il n'existe pas, à l'heure actuelle, de lignes directrices canadiennes destinées aux anesthésiologistes. À l'aide d'un processus Delphi de sondages en ligne et d'une réunion nationale canadienne en personne, un groupe d'experts nationaux provenant de toutes les universités canadiennes a élaboré une déclaration consensuelle pour la formation de base en et l'exécution de l'échographie ciblée (bPOCUS). Le groupe d'experts était composé de 55 anesthésiologistes issus de 12 universités canadiennes considérés comme des chefs de file locaux dans le domaine. Un premier sondage exploratoire en ligne comportant 47 énoncés a été réalisé. Ces énoncés étaient dérivés de lignes directrices antérieures ou de conférences consensuelles, ou étaient fondés sur la littérature actuelle. Quatorze énoncés ont obtenu un consensus complet, 19 ont atteint un taux de 90 à 100 %, et 14 ont obtenu moins de 90 % d'accord. Huit nouveaux énoncés ont été proposés au cours de la réunion nationale, et tous les énoncés n'ayant pas obtenu d'accord complet ont été discutés. Un deuxième sondage en ligne comprenait 42 énoncés modifiés ou nouveaux. Dans ce deuxième sondage, 16 énoncés ont obtenu un consensus total, 39 un très bon accord et un énoncé un bon accord. Le document final comporte 56 énoncés qui définissent le champ de pratique et la formation nécessaire pour l'échographie ciblée périopératoire de base. Les énoncés portent sur cinq domaines de l'échographie ciblée de base : échographie cardiaque, pulmonaire, des voies respiratoires, gastrique et abdominale. L'utilisation de l'échographie ciblée de base évolue et jouera un rôle important en médecine périopératoire. Cette déclaration consensuelle vise à définir une norme nationale canadienne sur laquelle les programmes d'études pourront s'appuyer. Elle fournit également un cadre pour encourager le développement ultérieur de l'échographie ciblée de base dans un contexte périopératoire.