Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rß1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL- 12–dependent IFN-? immunity and IL-23–dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL- 12Rß2 or IL-23R deficiency, lacking responses to IL-12 or IL- 23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that aß T, ?d T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-? in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-? in response to IL-23. We also show that the development of IFN-?–producing CD4+ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RA-CCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rß2 or IL-23R deficiency, relative to IL-12Rß1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R– and IL-12Rß2–deficient than IL-12Rß1–deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-?, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-?–dependent immunity to mycobacteria, both individually and much more so cooperatively

MOESM1 of Nonsurgical therapy for hydrocephalus: a comprehensive and critical review

Additional file 1. Table 1: Summary of brain protection experiments in animal models of hydrocephalus including details of animal, age, drug intervention, outcome parameters, weaknesses, and overall strength of conclusions

Nimodipine treatment does not benefit juvenile ferrets with kaolin-induced hydrocephalus

Abstract Prior research on 3-week hydrocephalic rats showed that behavioral deficits and white matter damage could be reduced by treatment with Ca2+ channel blocker nimodipine. We hypothesized that treatment with nimodipine would be also beneficial to young ferrets with kaolin-induced hydrocephalus. Hydrocephalus was induced at 14 days of age and animals were treated either with vehicle, low dose nimodipine (3.2 mg/kg/day), or high dose nimodipine (16 mg/kg/day) for 2 weeks from 38 to 52 days age. Hydrocephalic ferrets developed progressive ventriculomegaly, behavioral changes, and in some cases cortical blindness. These changes were not ameliorated by nimodipine. Histological examination showed damage in periventricular white matter, corpus callosum thinning, axonal damage, reactive astroglial changes, and suppressed cell proliferation compared to non-hydrocephalic controls. Treatment with nimodipine was not beneficial for any of the pathological changes mentioned above; only low dose nimodipine treatment was associated with normalized content of glial fibrillary acidic protein, despite larger ventricles. We conclude that young hydrocephalic ferrets experience behavioral impairments and structural brain damage that are not consistently improved by intermittent nimodipine treatment. Continuous delivery should be considered in further preclinical studies

Left atrial strain predicts postoperative atrial fibrillation in patients undergoing major orthopaedic surgery

Background: Atrial fibrillation (AF) is an arrhythmia that often occurred in patients after orthopaedic surgery; the presence of AF affects prognosis and prolongs hospitalization of these patients. Speckle tracking echocardiography (STE) is a new echocardiographic technique that has recently shown to predict the occurrence of AF. The aim of this study was to investigate left atrial (LA) function by STE in patients undergoing orthopaedic surgery and to correlate results with the incidence of post-operative AF. Methods: One-hundred and fifteen patients (mean age 74±12 years), undergoing elective (n=39; 41.9%) or post-traumatic (n=54; 58.0%) orthopaedic surgery, were prospectively enrolled. Both conventional echocardiographic parameters and STE parameters were measured in all subjects the day before surgery. The occurrence of AF was monitored until discharge. Results: Of 115 patients screened, 93 met eligibility criteria; 49 underwent hip surgery, 28 knee surgery and 16 surgery of the shoulder/elbow. All patients received a standard postoperative care. No major surgical complications were recorded. Postoperative AF occurred in 26 patients (27.9%). Among all clinical and echocardiographic variables analyzed, global PALS demonstrated the highest diagnostic accuracy (AUC of 0.88) and, with a cutoff value less than 15.3%, good sensitivity and specificity of 89% and 90%, respectively, to predict postoperative AF episodes. LA volume indexed and E/e’ ratio had lower diagnostic accuracy (AUC 0.70 and 0.49, respectively). Conclusions: STE analysis of LA myocardial deformation could be considered a promising tool for the evaluation of AF risk prediction in patients undergoing orthopaedic surgery