Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

Systematic review of the effectiveness of remifentanil in term breech pregnancies undergoing external cephalic version

BackgroundExternal cephalic version (ECV) is a moderately painful procedure used to turn a fetus from a non-vertex to cephalic position. This systematic review and meta-analysis compared intravenous remifentanil with other analgesia or no analgesia or placebo on the success rate and associated pain of ECV.MethodsSystematic searches for randomised controlled trials using remifentanil during ECV for non-cephalic term singleton pregnancies were conducted in EMBASE, MEDLINE and Cochrane Library to October 2021. The primary outcomes were successful ECV and maternal pain; secondary outcomes included mode of delivery and adverse effects. The Cochrane Risk of Bias tool was used and meta-analysis undertaken if there were ≥2 comparable studies.ResultsFour trials were identified, three placebo-controlled and one vs no analgesia, totalling 482 participants. Comparisons against nitrous oxide or neuraxial anaesthesia were not analysed. Two studies had a low overall risk of bias, and two had some concern for bias. Remifentanil compared with placebo increased the success of ECV by 43% (risk ratio [RR] 1.43; 95% confidence interval [CI] 1.14 to 1.78). Pain scores (0–10) were lower (mean difference −1.97; 95% CI −2.49 to −1.46) whilst there was no impact on caesarean delivery rate (RR 0.97; 95% CI 0.81 to 1.17). Adverse events were rare, with fetal bradycardia observed less often with remifentanil than placebo.ConclusionsRemifentanil increases the procedural success of ECV and reduces pain compared with placebo. Trials were at low risk of bias and contained a sufficient number of participants to have reasonable confidence in this finding

Effects of an acute enteric disease challenge on IGF-1 and IGFBP-3 gene expression in porcine skeletal muscle

Eighteen pigs (initial weight 25 lb and approximately 5 wk of age) were used in a 14-d trial to determine the effects of an acute Salmonella enterica serotype typhimurium (ST) disease challenge on both circulating insulinlike growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) and steady-state IGF-1 and IGFBP-3 mRNA levels in skeletal muscle. Muscle biopsies and blood samples were obtained from all pigs on d 0, 3, 7, and 14 relative to ST-challenge. Results suggest that an acute ST-challenge decreased circulating IGF-1 levels on d 3 and 7 but did not affect circulating IGFBP-3 concentrations. Additionally, ST-challenge had no effect on steady-state IGF-1 and IGFBP-3 mRNA levels in skeletal muscle following the onset of disease. These data suggest that an acute enteric disease insult can lower circulating IGF-1 but more chronic conditions may be necessary to affect local IGF-1 levels in skeletal muscle. Additionally, the increased muscle IGF-1 mRNA without increased IGFBP-3 levels on d 14 most likely results in increased IGF-1 synthesis that contributes to circulating IGF-1 concentrations

Low-dose cyclophosphamide enhances helper-to-non-helper ratios

This study was conducted to analyze the effect of different doses of cyclophosphamide (CY) on the lymphocyte populations in the rat. Monoclonal antibodies against rat determinants were used: W3/13 (T lymphocytes), W3/25 (T helper), OX-8 (non-helper), and OX-33 (B lymphocytes). Blood samples were collected on days 0, 3, 7, and 14 from four groups of F-344 Fisher rats (n = 4): three that received 25, 50, or 75 mg/kg of CY and a control group. The duration and severity of lymphocyte depletion were dose-related and were evident for both helper and non-helper cells (p less than 0.02). The helper-to-non-helper ratio increased for the group that received 25 mg/kg when compared with control and other groups, but was only significantly changed when compared with the 75 mg/kg group (p = 0.004). This effect was transitory and was only seen on day 3. The control and the 25 mg/kg groups gained weight; the other two groups lost weight (p less than 0.05). Lower doses of CY were associated with a transitory immunostimulatory effect and no morbidity when compared with higher doses