SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings from the COV-AD Study

Background

Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood.

Objectives

COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination.

Methods

Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs.

Results

A total of 5.6% (n?=?320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n?=?168) compared with 100% of healthy controls (n?=?205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p?=?0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p?=?0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine.

Conclusion

SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection.

     

Evaluation of Trauma Care Resources in Health Centers and Referral Hospitals in Cambodia

Background  The aim of this study was to evaluate the available resources for trauma care at health centers (HCs) and referral hospitals (RHs) in rural Cambodia and to examine whether the resources at HCs are allocated on the basis of actual need based on the referral distance and number of severely injured patients referred to RHs. Methods  We conducted a cross-sectional facility survey by phone interview or mail using structured questionnaires at nationally representative samples of 85 HCs and 17 RHs from December 2006 to April 2007. The questionnaire included a modified checklist of the guidelines for essential trauma care as well as questions on distance for referral and the number of injured patients received and referred during the last 3 months. We analyzed the association between resource availability at HCs and their need using multivariate linear regression. Results  Median (interquartile range) numbers of available resources at HCs and RHs were 25.5 (22.0–27.5) and 35 (28–41) among 37 and 62 essential items, respectively. Basic equipment, including both consumable supplies and durable devices and life-saving knowledge/skills, were not satisfactory at either HCs or RHs. A longer distance to the RH was associated with more knowledge/skills but not with equipment supplies; the number of referred patients was not associated with equipment or knowledge/skills. Conclusions  Staff training emphasizing life-saving knowledge/skills and better organization and planning to supply physical resources are needed. There is a gap between resource allocation and need, which should be addressed through clear policies to prioritize remote areas and to allocate resources based on reliable injury data. Part of this study was presented at an annual conference of the Japan Association for the Surgery of Trauma, Okinawa, May 2008.     

Molecular diversity of Glanzmann thrombasthenia in southern India: new insights into mRNA splicing and structure-function correlations of alphaIIbbeta3 integrin (ITGA2B, ITGB3)

The molecular basis of Glanzmann thrombasthenia (GT) was studied in 40 families from southern India. Of 23 identified mutations (13 in the alphaIIb (ITGA2B) gene and 10 in the beta3 (ITGB3) gene), 20 were novel and three were described previously. Three mutations in the beta3 gene-p.Leu143Trp (Leu117Trp), p.Tyr307Stop (Tyr281Stop), and p.Arg119Gln (Arg93Gln)-were detected in 12, three, and two families, respectively, with definite founder effects observed for the first two mutations. Alternative splicing was predicted in silico for the normal variant and a missense variant of the beta3 gene, and for 10/11 frameshift or nonsense mutations in alphaIIb or beta3. The prediction was confirmed experimentally for a c.2898_2902dupCCCCT mutation in exon 28 of the alphaIIb gene that induced exon skipping. Seven out of nine missense mutations substituted highly conserved amino acids buried in the proteins' cores, predicting structural abnormalities. Among these, a beta3 substitution, p.Cys39Gly (Cys13Gly) was found to cause intracellular degradation of the beta3 subunit, in contrast to previous findings that mutations at Cys435, the partner of Cys13 in a disulfide bond, cause constitutive activation of alphaIIbbeta3. The two patients with a beta3 Arg93Gln mutation had normal clot retraction, consistent with a recent finding that this substitution is associated with normal surface expression of alphaIIbbeta3. In conclusion, this study demonstrates that a variety of mutations account for GT in southern Indian patients, provides new insights into mRNA splicing, and highlights the role of specific amino acids in structure-function correlations of alphaIIbbeta3.     

High-frequency hearing loss and wideband middle ear impedance in children with otitis media histories

OBJECTIVE: This study was undertaken to determine the relationship between extended-high-frequency (EHF) hearing losses and wideband middle ear impedance in children with chronic otitis media (OM) histories. DESIGN: Children with OM histories were selected from a prospective study cohort if they had normal tympanograms, no air-bone gaps, and no otoscopic evidence of active OM at the time of testing. OM subjects were divided into two groups, those with Better Hearing in the EHF range and those with Worse Hearing in the EHF range. The OM groups were compared with an age-matched, healthy Control group that had no more than five documented episodes of OM and no more than two in any 1 yr. All children were 9 to 16 yr of age. Subjects were tested by standard audiometric methods in the conventional audiometric range (0.25 to 8.0 kHz) and the EHF range (8 to 20 kHz). Middle ear impedance and reflectance were measured with an experimental system over the frequency range 0.25 to 10.08 kHz. RESULTS: The Worse Hearing OM group had slightly poorer hearing in the conventional audiometric frequency range compared with the other two groups. The Better Hearing OM group and the Control group had nearly identical EHF hearing. The Worse Hearing OM group had significantly poorer EHF hearing compared with the other two groups, the difference increasing exponentially with frequency. Middle ear impedance differences among groups were confined to low frequencies (<2 kHz). The Control group had significantly higher negative reactance than the two OM groups. There were no significant group differences in impedance or reflectance in the high frequencies (2 to 10 kHz). CONCLUSIONS: The results of this study confirm those of previous reports that children who have recovered from chronic OM have significantly poorer hearing in the EHF range compared with children without significant OM histories. The EHF hearing losses that occur in children with OM histories are strongly frequency dependent, suggesting a preferential effect on the base of the cochlea. Middle ear impedance and reflectance differences do not account for the EHF hearing losses observed in children with OM histories. The results support the hypothesis that OM-related EHF hearing losses are cochlear in origin.     

Monitoring of mannitol phase behavior during freeze-drying using non-invasive Raman spectroscopy

In this study, the feasibility of using Raman spectroscopy as a fast, non-invasive, non-destructive technique to monitor crystallization and polymorphic transformations during freeze-drying is assessed using mannitol as the model compound. In-line process monitoring was achieved by interfacing a Raman spectrometer with a fiber-optically coupled, long-working-distance probe to a freeze-drier. By analyzing the process data using principal component analysis, it was possible to extract valuable information pertaining to ice and mannitol crystallization points, the polymorphic form of mannitol, and dehydration of the mannitol hydrate. In conclusion, Raman spectroscopy is a potentially useful technique to monitor physical changes during freeze-drying.     

Influence of the antacid Maalox on the pharmacokinetics of capecitabine in cancer patients

Purpose: In the present study the possible influence of the antacid Maalox on the pharmacokinetics of capecitabine (Xeloda) and its metabolites was investigated in cancer patients. Methods: A total of 12 patients with solid, predominantly metastatic tumors of various origin received a single oral dose of 1250 mg/m² of capecitabine (treatment A), a single oral dose of 1250 mg/m² of capecitabine followed immediately by 20 ml of Maalox (treatment B), and a single oral dose of 1250 mg/m² of capecitabine followed 2 h later by 20 ml of Maalox (treatment C) in an open, randomized, three-way cross over fashion. Serial blood and urine samples were collected for up to 24 h after each administration. Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chromatography/mass spectrometry and in urine using nuclear magnetic resonance spectroscopy. Results: Administration of Maalox either concomitantly with capecitabine or delayed by 2 h did not influence the time to peak plasma concentrations (C_max) or the elimination half-lives of capecitabine and its metabolites. Unexpectedly, moderate increases in the C_max and AUC_0–∞ values obtained for capecitabine and 5′-deoxy-5-fluorocytidine were observed when Maalox was given together with capecitabine. However, these increases, which ranged between 10% and 31%, were not statistically significant (P > 0.05) and are not of clinical significance. There was no indication of consistent changes in the plasma concentrations of the other metabolites 5′-deoxy-5′-fluorouridine (5′-DFUR), 5-fluorouracil, and α-fluoro-β-alanine. The C_max and AUC_0–∞ values recorded for these three metabolites increased and decreased in a stochastic manner. The magnitude of these changes was low (<13%) and not statistically significant. The primary statistical analysis of the AUC_0–∞obtained for 5′-DFUR provided a P value of 0.4524 and clearly indicated no significant difference between the treatments. The addition of Maalox had no influence on the overall urinary recovery or the proportion of the dose recovered as capecitabine or its metabolites from urine. Conclusion: At the dose used in this study, the effect of concomitantly delivered Maalox on the extent and rate of gastrointestinal absorption of capecitabine is not clinically significant. Therefore, there is no need to adjust the dose or timing of capecitabine administration in patients treated with Maalox. Received: 11 May 1998 / Accepted: 17 August 1998     

Qualind: A method for assessing the accuracy of automated tests

As audiology strives for cost containment, standardization, accuracy of tests, and accountability, greater use of automated tests is likely. Highly skilled audiologists employ quality control factors that contribute to test accuracy, but they are not formally included in test protocols, resulting in a wide range of accuracy, owing to the various skill and experience levels of clinicians. A method that incorporates validated quality indicators may increase accuracy and enhance access to accurate hearing tests. This report describes a quality assessment method that can be applied to any test that (1) requires behavioral or physiologic responses, (2) is associated with factors that correlate with accuracy, and (3) has an available independent measure of the dimension being assessed, including tests of sensory sensitivity, cognitive function, aptitude, academic achievement, and personality. In this report the method is applied to AMTAS, an automated method for diagnostic pure-tone audiometry.