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.

     

A systematic review of the relationship between glycemic control and necrobiosis lipoidica diabeticorum in patients with diabetes mellitus

The association of specific skin disorders with diabetes mellitus (DM) has been well established. Current literature suggests that approximately 30–91% of patients with diabetes will experience at least one cutaneous manifestation of this systemic disease in their lifetime. To date, there are limited articles summarizing the link between necrobiosis lipoidica diabeticorum (NLD) prognosis and glycemic control in patients with diabetes. The objective of the study is to summarize and appraise the available evidence assessing the relationship between glycemic control and NLD. A literature search was conducted based on MEDLINE (1946–2015), EMBASE (1980–2015), Google Scholar, and PubMed for publications that described the results of diabetes control and NLD. Further studies were identified from bibliographies of all relevant studies, gray literature, and annual scientific assemblies. All studies investigating the relationship between DM (type 1 and type 2) management and NLD were included. Two reviewers independently extracted data including demographics, type of diabetes management measures (glucose, HbA1c, insulin), comorbidities, and outcome. A total of 622 studies were identified, and 10 studies met the inclusion and exclusion criteria: two case series and eight case reports. Of the 24 patients with NLD, 13 patients reported resolution of NLD after implementing various methods of glycemic control (diabetic diet consisting of 1600 kcal/day [1 patient], insulin regimen [3 patients], and pancreatic transplantation [9 patients]). Glycemic control may have a role in influencing the prognosis of necrobiosis lipoidica in patients with diabetes; however, there is currently insufficient evidence to support or refute this claim.     

Uterine carcinosarcomas and grade 3 endometrioid cancers: evidence for distinct tumor behavior

OBJECTIVE: To compare the clinical behavior and outcome of uterine carcinosarcomas and grade 3 endometrioid carcinomas. METHODS: Data on patients with grade 3 endometrioid adenocarcinomas and uterine carcinosarcomas, from 1988 to 2004, was obtained from the Surveillance, Epidemiology, and End Results database. Mortality was analyzed using Cox proportional hazards models. Survival analysis was performed with the Kaplan-Meier method and log rank test. RESULTS: The cohort included 8,986 women with 5,024 (56%) grade 3 endometrioid carcinomas and 3,962 (44%) uterine carcinosarcomas. Women with uterine carcinosarcomas were older (aged 70 years compared with 66 years; P<.001) and more often nonwhite (23% compared with 15%; P<.001). These women presented with more advanced disease (stage III/IV 41% compared with 31%; P<.001). Multivariable analysis demonstrated that uterine carcinosarcoma histology, advanced age, nonwhite race, and advanced stage were independent predictors of poor survival. Cancer-specific mortality was 45% lower in women with grade 3 endometrioid carcinomas (hazard ratio 0.55; 95% confidence interval [CI] 0.5-0.6). The 5-year cancer-specific survival was lower for women with uterine carcinosarcoma for each disease stage. Survival for stage IC was 38% (95% CI 33-45%) for uterine carcinosarcoma compared with 68% (95% CI 63-73%) for grade 3 endometrioid carcinoma. For stage III, survival was 22% (95% CI 19-26%) for uterine carcinosarcoma compared with 45% (95% CI 41-49%) for grade 3 endometrioid carcinoma. CONCLUSION: Carcinosarcomas present at more advanced stage and have worse survival than grade 3 endometrioid carcinomas. Carcinosarcomas may represent a distinct biologic entity. LEVEL OF EVIDENCE: II.     

Cytodiagnosis of actinomycetoma

Mycetoma is a late clinical manifestation of a subcutaneous infection produced by bacteria (actinomycetoma) or fungi (eumycetoma). The distinction between eumycetoma and actinomycetoma in Fine Needle Aspiration Cytology (FNAC) is as accurate as histopathology. A 55 year old man presented with a slow growing swelling on the plantar aspect of the right foot which was present for the last 10 years. A clinical diagnosis of soft tissue tumor was made and FNAC was advised. Smears revealed mixed inflammatory infiltrate and foreign body type of giant cells along with clumps of fibrillar organisms. Gram stain done later demonstrated gram positive thin branching filaments. A diagnosis of actinomycetoma was rendered. Histopathology of the excised specimen confirmed the cytologic diagnosis of actinomycetoma. Mycetoma can be accurately diagnosed by FNAC, which is a simple, inexpensive technique for rapid diagnosis. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Receptor‐interacting protein (RIP) and Sirtuin‐3 (SIRT3) are on opposite sides of anoikis and tumorigenesis

BACKGROUND:

Regulating cross‐talk between anoikis and survival signaling pathways is crucial to regulating tissue processes and mitigating diseases like cancer. Previously, the authors demonstrated that anoikis activates a signaling pathway involving the CD95/Fas‐mediated signaling pathway that is regulated by receptor‐interacting protein (RIP), a kinase that shuttles between Fas‐mediated cell death and integrin/focal adhesion kinase (FAK)‐mediated survival pathways. Because it is known that sirtuin‐3 (SIRT3), a nicotinamide adenine dinucleotide‐dependent deacetylase, regulates cell survival, metabolism, and tumorigenesis, the authors hypothesized that SIRT3 may engage in cross‐talk with Fas/RIP/integrin/FAK survival‐death pathways in cancer cell systems.

METHODS:

Using immunohistochemical staining, immunoblotting, human tissue microarrays, and overexpression and suppression approaches in vitro and in vivo, the roles of RIP and SIRT3 were examined in oral squamous cell carcinoma (OSCC) anoikis resistance and tumorigenesis.

RESULTS:

RIP and SIRT3 had opposite expression profiles in OSCC cells and tissues. Stable suppression of RIP enhanced SIRT3 levels, whereas stable suppression of SIRT3 did not impact RIP levels in OSCC cells. The authors observed that, as OSCC cells became anoikis‐resistant, they formed multicellular aggregates or oraspheres in suspension conditions, and their expression of SIRT3 increased as their RIP expression decreased. Also, anoikis‐resistant OSCC cells with higher SIRT3 and low RIP expression induced an increased tumor burden and incidence in mice, unlike their adherent OSCC cell counterparts. Furthermore, stable suppression of SIRT3 inhibited anoikis resistance and reduced tumor incidence.

CONCLUSIONS:

The current results indicted that RIP is a likely upstream, negative regulator of SIRT3 in anoikis resistance, and an anoikis‐resistant orasphere phenotype defined by higher SIRT3 and low RIP expression contributes to a more aggressive phenotype in OSCC development. Cancer 2012. © 2012 American Cancer Society.     

Clinical Activity and Polymerase Chain Reaction Evidence of Chlamydial Infection after Repeated Mass Antibiotic Treatments for Trachoma

It is unclear how the prevalence of clinically active trachoma correlates with the prevalence of ocular chlamydial infection at the community level. In 24 villages from a cluster-randomized clinical trial of mass azithromycin distributions in Ethiopia, the correlation between the prevalence of clinical activity (on examination) and chlamydial infection (by polymerase chain reaction) was moderately strong before mass antibiotic treatments (Pearson''s correlation coefficient r = 0.75, 95% confidence interval [CI] = 0.52–0.87), but decreased at each time point during four biannual treatments (at 24 months, r = 0.15, 95% CI = −0.14–0.41). One year after the final treatment, the correlation coefficient had increased, but not to the pre-treatment level (r = 0.55, 95% CI = 0.30–0.73). In a region with hyperendemic trachoma, conjunctival examination was a useful indicator of the prevalence of chlamydial infection before treatments, less useful during mass treatments, but regained utility by one year after treatments had stopped.     

Complement C3 isoforms in Austrelaps superbus

Complement C3 plays a pivotal role in both classical and alternate pathways. Lower organisms (urochordates and fishes) have multiple isoforms whereas higher organisms have a single C3 gene. In cobras, a closely related protein cobra venom factor (CVF) is expressed in their venom gland. We have recently shown that Austrelaps superbus contains two isoforms (AVF-1 and AVF-2) of CVF-like proteins in the venom gland. To understand the origin of these proteins and their similarity to C3 protein, we examined C3-like proteins in the liver. Here we describe the complete cDNA sequences of two isoforms (AsC3-1 and AsC3-2) of complement C3 found in A. superbus liver. This is the first report of molecular isoforms of C3 in a reptilian organism. These isoforms display the overall domain structure of complement C3 proteins. Real-time quantitative analysis shows that there is a 144-fold difference in their mRNA expression levels. We also demonstrate by Southern blot experiments that the venom gland isoforms (AVF-1 and AVF-2) and the liver isoforms (AsC3-1 and AsC3-2) are the products of four individual genes. The putative promoter regions of these four genes are highly similar ( approximately 99% identical) to each other. These genes represent a unique case where despite being identical at the genomic level, exhibit tissue specificity and differential gene regulation. These genes offer a system to identify the tissue-specific regulatory proteins that are responsible for the constitutive expression of complement C3 in liver and inducible expression of AVF genes in the venom gland of A. superbus.