Current trends in autoimmunity and the nervous system

In the broad field of autoimmunity and clinical immunology, experimental evidence over the past few years have demonstrated several connections between the immune system and the nervous system, both central and peripheral, leading to the definition of neuroimmunology and of an immune-brain axis. Indeed, the central nervous system as an immune-privileged site, thanks to the blood-brain barrier, is no longer a dogma as the barrier may be altered during chronic inflammation with disruptive changes of endothelial cells and tight junctions, largely mediated by adenosine receptors and the expression of CD39/CD73. The diseases that encompass the neuroimmunology field vary from primary nervous diseases such as multiple sclerosis to systemic conditions with neuropsychiatric complications, such as systemic lupus erythematosus or vasculitidies. Despite potentially similar clinical manifestations, the pathogenesis of each condition is different, but the interaction between the ultra-specialized structure that is the nervous system and inflammation mediators are crucial. Two examples come from anti-dsDNA cross-reacting with anti-N-Methyl-D-Aspartate receptor (NMDAR) antibodies in neuropsychiatric lupus or the new family of antibody-associated neuronal autoimmune diseases including classic paraneoplastic syndromes with antibodies directed to intracellular antigens (Hu, Yo, Ri) and autoimmune encephalitis. In the case of multiple sclerosis, the T cell paradigm is now complicated by the growing evidence of a B cell involvement, particularly via aquaporin antibodies, and their influence on Th1 and Th17 lineages. Inspired by a productive AARDA-sponsored colloquium among experts we provide a critical review of the literature on the pathogenesis of different immune-mediated diseases with neurologic manifestations and we discuss the basic immunology of the central nervous system and the interaction between immune cells and the peripheral nervous system

Cross-continental emergence of Nannizziopsis barbatae disease may threaten wild Australian lizards

Members of the genus Nannizziopsis are emerging fungal pathogens of reptiles that have been documented as the cause of fatal mycoses in a wide range of reptiles in captivity. Cases of severe, proliferative dermatitis, debility and death have been detected in multiple free-living lizard species from locations across Australia, including a substantial outbreak among Eastern water dragons (Intellagama lesueurii) in Brisbane, Queensland. We investigated this disease in a subset of severely affected lizards and identified a clinically consistent syndrome characterized by hyperkeratosis, epidermal hyperplasia, dermal inflammation, necrosis, ulceration, and emaciation. Using a novel fungal isolation method, histopathology, and molecular techniques, we identified the etiologic agent as Nannizziopsis barbatae, a species reported only once previously from captive lizards in Australia. Here we report severe dermatomycosis caused by N. barbatae in five species of Australian lizard, representing the first cases of Nannizziopsis infection among free-living reptiles, globally. Further, we evaluate key pathogen and host characteristics that indicate N. barbatae-associated dermatomycosis may pose a concerning threat to Australian lizards

Height and risk of death among men and women: aetiological implications of associations with cardiorespiratory disease and cancer mortality

OBJECTIVES: Height is inversely associated with cardiovascular disease mortality risk and has shown variable associations with cancer incidence and mortality. The interpretation of findings from previous studies has been constrained by data limitations. Associations between height and specific causes of death were investigated in a large general population cohort of men and women from the West of Scotland. DESIGN: Prospective observational study. SETTING: Renfrew and Paisley, in the West of Scotland. SUBJECTS: 7052 men and 8354 women aged 45-64 were recruited into a study in Renfrew and Paisley, in the West of Scotland, between 1972 and 1976. Detailed assessments of cardiovascular disease risk factors, morbidity and socioeconomic circumstances were made at baseline. MAIN OUTCOME MEASURES: Deaths during 20 years of follow up classified into specific causes. RESULTS: Over the follow up period 3347 men and 2638 women died. Height is inversely associated with all cause, coronary heart disease, stroke, and respiratory disease mortality among men and women. Adjustment for socioeconomic position and cardiovascular risk factors had little influence on these associations. Height is strongly associated with forced expiratory volume in one second (FEV1) and adjustment for FEV1 considerably attenuated the association between height and cardiorespiratory mortality. Smoking related cancer mortality is not associated with height. The risk of deaths from cancer unrelated to smoking tended to increase with height, particularly for haematopoietic, colorectal and prostate cancers. Stomach cancer mortality was inversely associated with height. Adjustment for socioeconomic position had little influence on these associations. CONCLUSION: Height serves partly as an indicator of socioeconomic circumstances and nutritional status in childhood and this may underlie the inverse associations between height and adulthood cardiorespiratory mortality. Much of the association between height and cardiorespiratory mortality was accounted for by lung function, which is also partly determined by exposures acting in childhood. The inverse association between height and stomach cancer mortality probably reflects Helicobacter pylori infection in childhood resulting inor being associated withshorter height. The positive associations between height and several cancers unrelated to smoking could reflect the influence of calorie intake during childhood on the risk of these cancers

High pTp_{T} non-photonic electron production in pp+pp collisions at s\sqrt{s} = 200 GeV

We present the measurement of non-photonic electron production at high transverse momentum ($p_T >$ 2.5 GeV/$c$) in $p$ + $p$ collisions at $\sqrt{s}$ = 200 GeV using data recorded during 2005 and 2008 by the STAR experiment at the Relativistic Heavy Ion Collider (RHIC). The measured cross-sections from the two runs are consistent with each other despite a large difference in photonic background levels due to different detector configurations. We compare the measured non-photonic electron cross-sections with previously published RHIC data and pQCD calculations. Using the relative contributions of B and D mesons to non-photonic electrons, we determine the integrated cross sections of electrons ($\frac{e^++e^-}{2}$) at 3 GeV/$c < p_T <~$10 GeV/$c$ from bottom and charm meson decays to be ${d\sigma_{(B\to e)+(B\to D \to e)} \over dy_e}|_{y_e=0}$ = 4.0$\pm0.5$({\rm stat.})$\pm1.1$({\rm syst.}) nb and ${d\sigma_{D\to e} \over dy_e}|_{y_e=0}$ = 6.2$\pm0.7$({\rm stat.})$\pm1.5$({\rm syst.}) nb, respectively.Comment: 17 pages, 17 figure

Structural basis of glycan276-dependent recognition by HIV-1 broadly neutralizing antibodies

Recognition of N-linked glycan at residue N276 (glycan276) at the periphery of the CD4-binding site (CD4bs) on the HIV-envelope trimer is a formidable challenge for many CD4bs-directed antibodies. To understand how this glycan can be recognized, here we isolate two lineages of glycan276-dependent CD4bs antibodies. Antibody CH540-VRC40.01 (named for donor-lineage.clone) neutralizes 81% of a panel of 208 diverse strains, while antibody CH314-VRC33.01 neutralizes 45%. Cryo-electron microscopy (cryo-EM) structures of these two antibodies and 179NC75, a previously identified glycan276-dependent CD4bs antibody, in complex with HIV-envelope trimer reveal substantially different modes of glycan276 recognition. Despite these differences, binding of glycan276-dependent antibodies maintains a glycan276 conformation similar to that observed in the absence of glycan276-binding antibodies. By contrast, glycan276-independent CD4bs antibodies, such as VRC01, displace glycan276 upon binding. These results provide a foundation for understanding antibody recognition of glycan276 and suggest its presence may be crucial for priming immunogens seeking to initiate broad CD4bs recognition

Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial

Background: Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. Methods: We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30–85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194. Findings: Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37–54) and median BMI was 29·8 kg/m2 (IQR 27·0–34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2–8·2) in participants who received metformin and 10·4% (7·8–12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39–0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15–0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59–1·64) or fluvoxamine (1·36, 0·78–2·34) compared with placebo. Interpretation: Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe. Funding: Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences

TESS Reveals HD 118203 b to be a Transiting Planet

The exoplanet HD 118203 b, orbiting a bright (V = 8.05) host star, was discovered using the radial velocity method by da Silva et al., but was not previously known to transit. Transiting Exoplanet Survey Satellite (TESS) photometry has revealed that this planet transits its host star. Nine planetary transits were observed by TESS, allowing us to measure the radius of the planet to be 1.136-0.028 +0.029 R J, and to calculate the planet mass to be 2.166-0.079 +0.074 M J. The host star is slightly evolved with an effective temperature of T eff=5683-85 +84 K and a surface gravity of log\,g=3.889 0.018-0.017. With an orbital period of 6.134985-0.000030 +0.000029 days and an eccentricity of 0.314 ± 0.017, the planet occupies a transitional regime between circularized hot Jupiters and more dynamically active planets at longer orbital periods. The host star is among the 10 brightest known to have transiting giant planets, providing opportunities for both planetary atmospheric and asteroseismic studies