The Neuroimmune Pharmacology of SARS-CoV-2

This guest commentary introduces “The Neuroimmune Pharmacology of SARS-CoV-2,” a special theme issue for The Journal of Neuroimmune Pharmacology led by the Society on NeuroImmune Pharmacology. The issue builds on the Society’s Virtual Workshop on COVID-19 held April 9, 2021.

Graphical abstract

Top row from left: Drs. Santosh Kumar, Sowmya Yelamanchili, Pankaj Seth, Jean M. Bidlack; Bottom row from left: Drs. Gurudutt Pendyala, Sanjay Maggirwar, and Sulie L. Chang.

     

Meta-analysis of self-gripping mesh (Progrip) versus sutured mesh in open inguinal hernia repair

BackgroundThis metaanalysis was designed to systematically analyse all published randomized controlled trials comparing self-gripping mesh (ProGrip) and sutured mesh to analyse early and long term outcomes for open inguinal hernia repair.MethodsA literature search was performed using the Cochrane Colorectal Cancer Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in the Cochrane Library, MEDLINE, Embase and Science Citation Index Expanded. Randomized trials comparing self-gripping mesh with sutured mesh were included. Statistical analysis was performed using Review Manager Version 5.2 software. The primary outcome measures were hernia recurrence and chronic pain after operation. Secondary outcome measures included surgical time, wound complications and perioperative complications.ResultsFive randomized trials were identified as suitable, including 1170 patients. There was no significant difference between the two types of mesh repairs in perioperative complications, wound haematoma, chronic groin pain and hernia recurrence. Wound infection was lower in self gripping mesh group compared to sutured mesh but this was not statistically significant (risk ratio (RR) 0.57, 95% confidence interval 0.30–1.06, P = 0.08). The duration of operation was significantly shorter with self-gripping mesh compared to sutured mesh with a mean difference of ?5.48 min [?9.31, ?1.64] Z = 2.80 (P = 0.005).ConclusionSelf-gripping mesh was associated with shorter operative time compared to sutured mesh. Both types of mesh repairs have comparable perioperative and long term outcomes.     

A randomized cross-over trial to define neurophysiological correlates of AV-101 N-methyl-d-aspartate receptor blockade in healthy veterans

The kynurenine pathway (KP) is a strategic metabolic system that combines regulation of neuronal excitability via glutamate receptor function and neuroinflammation via other KP metabolites. This pathway has great promise in treatment of depression and suicidality. The KP modulator AV-101 (4-chlorokynurenine, 4-Cl-KYN), an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), an N-methyl-d-aspartate receptor (NMDAR) glycine site antagonist, and of 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HAA), a suppressor of NMDAR agonist quinolinic acid (QUIN), is a promising potential antidepressant that targets glutamate functioning via the KP. However, a recent placebo-controlled clinical trial of AV-101 in depression found negative results. This raises the question of whether AV-101 can penetrate the brain and engage the NMDAR and KP effectively. To address this problem, ten healthy US military veterans (mean age = 32.6 years ± 6.11; 1 female) completed a phase-1 randomized, double-blind, placebo-controlled, crossover study to examine dose-related effects of AV-101 (720 and 1440 mg) on NMDAR engagement measured by γ-frequency band auditory steady-state response (40 Hz ASSR) and resting EEG. Linear mixed models revealed that 1440 mg AV-101, but not 720 mg, increased 40 Hz ASSR and 40 Hz ASSR γ-inter-trial phase coherence relative to placebo. AV-101 also increased 4-Cl-KYN, 7-Cl-KYNA, 4-Cl-3-HAA, 3-HAA, and KYNA in a dose-dependent manner, without affecting KYN and QUIN. AV-101 was safe and well tolerated. These results corroborate brain target engagement of 1440 mg AV-101 in humans, consistent with blockade of interneuronal NMDAR blockade. Future studies should test higher doses of AV-101 in depression. Suicidal behavior, which has been associated with high QUIN and low KYNA, is also a potential target for AV-101.Subject terms: Biomarkers, Neurophysiology, Neuroscience     

Air Transport of Patients with Unstable Aortic Aneurysms Directly into Operating Rooms

Objective. The purpose of this study was to describe an air transport service's protocol for direct transport of patients with abdominal aortic aneurysm leak (AAAL) into receiving hospital operating rooms (ORs). Methods. This retrospective consecutive-case analysis examined AAAL patients undergoing nurse-paramedic Boston MedFlight (BMF) transport during 1999–2004, who were taken directly into ORs at four academic centers. BMF uses a rotating roster system to assign receiving hospitals when referring physicians have no preidentified receiving facility, but this practice may prolong patient transport or be associated with less diagnostic certainty, andthus more delay, at receiving hospitals. Thus, the study compared “Roster” versus “Non-roster” patients' time andoutcome end points. Continuous nonparametric data (e.g., time intervals) were described with median andinterquartile range (IQR). Chi-square andKruskal-Wallis tests were used for univariate comparisons; regression analysis assessed dependent variables while adjusting for covariates (e.g., transport mileage). Results. There were 29 direct-to-OR transports, with median distance of 30 miles. All patients had AAAL diagnosis confirmed; 51.7% survived. System performance for end points was similar as assessed between Roster versus Non-roster patients. Conclusions. Interfacility direct-to-OR transport of AAAL patients is feasible. Use of a roster system allows for timely transport facilitation for patients needing specialized care; roster patients achieve similar end points as did patients who had already-identified receiving hospitals upon air medical transport request.     

Gossypiboma mimicking posterior urethral stricture

INTRODUCTIONForeign bodies in the urogenital tract are not uncommon. Hairpins, glass rods, umbilical tapes, ball point pen are described in lower urogenital tract. Retained gauze piece (gossypiboma) in posterior urethra may cause diagnostic dilemma. Symptoms and investigations may mimic stricture of posterior urethra.PRESENTATION OF CASETwo cases of retained gauze pieces in the urethra are described here. The micturating cystourethrogram was suggestive of posterior urethral stricture.DISCUSSIONTwo cases described here had retained gauze piece as a cause of filling defect and abnormal appearance in the micturating cystourethrogram. Gossypiboma may be a possibility where posterior urethral stricture are seen after previous surgery in paediatric age group.CONCLUSIONIn the setting of previous urogenital surgery gossypiboma should be kept in the differential diagnosis where posterior urethral stricture are seen in the paediatric age group.     

Heterogeneity in Rhesus Macaque Complement Factor H Binding to Meningococcal Factor H Binding Protein (FHbp) Informs Selection of Primates To Assess Immunogenicity of FHbp-Based Vaccines

Neisseria meningitidis causes disease only in humans. An important mechanism underlying this host specificity is the ability of the organism to resist complement by recruiting the complement downregulator factor H (FH) to the bacterial surface. In previous studies, binding of FH to one of the major meningococcal FH ligands, factor H binding protein (FHbp), was reported to be specific for human FH. Here we report that sera from 23 of 73 rhesus macaques (32%) tested had high FH binding to FHbp. Similar to human FH, binding of macaque FH to the meningococcal cell surface inhibited the complement alternative pathway by decreasing deposition of C3b. FH contains 20 domains (or short consensus repeats), with domains 6 and 7 being responsible for binding of human FH to FHbp. DNA sequence analyses of FH domains 6 and 7 from macaques with high or low FH binding showed a polymorphism at residue 352 in domain 6, with Tyr being associated with high binding and His with low binding. A recombinant macaque FH 6,7/Fc fragment with Tyr352 showed higher binding to FHbp than the corresponding fragment with His352. In previous studies in human FH transgenic mice, binding of FH to FHbp vaccines decreased protective antibody responses, and mutant FHbp vaccines with decreased FH binding elicited serum antibodies with greater protective activity. Thus, macaques with high FH binding to FHbp represent an attractive nonhuman primate model to investigate further the effects of FH binding on the immunogenicity of FHbp vaccines.     

Hypertrophic cardiomyopathy and ultra-endurance running - two incompatible entities?

Regular and prolonged exercise is associated with increased left ventricular wall thickness that can overlap with hypertrophic cardiomyopathy (HCM). Differentiating physiological from pathological hypertrophy has important implications, since HCM is the commonest cause of exercise-related sudden cardiac death in young individuals. Most deaths have been reported in intermittent ''start-stop'' sports such as football (soccer) and basketball. The theory is that individuals with HCM are unable to augment stroke volume sufficiently to meet the demands of endurance sports and are accordingly ''selected-out'' of participation in such events. We report the case of an ultra-endurance athlete with 25 years of > 50 km competitive running experience, with genetically confirmed HCM; thereby demonstrating that these can be two compatible entities.