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.

     

The patellar ligament: A comprehensive review

The patellar ligament (PL) is an epiphyseal ligament and is part of the extensor complex of the knee. The ligament has gained attention due to its clinical relevance to autograft and tendinopathy. A variety of anatomical variations of the PL such as aplasia, numerical variations, and vascularity are being reported recently by clinicians and anatomists. The aim of this literature was to review the available literature to provide a consensus regarding anatomic variations of the PL, neurovasculature surrounding the PL, histology of the PL, and various aspects of PL measurements with relevance to the surgical considerations and sex and age-related differences. A narrative review of the patellar ligament was performed by conducting a detailed literature search and review of relevant articles. A total of 90 articles on the patellar ligament were included and were categorized into studies based on anatomical variations, neurovasculature, morphometrics, microanatomy, sex and age-related difference, and ACL reconstruction. The anatomical variations and morphometrics of the PL were found to correlate with the frequency of strain injuries, tendinopathy, and efficacy of the PL autograft in anterior cruciate ligament reconstruction. The sex differences in PL measurements and the effect of estrogen on collagen synthesis explained a higher incidence of patellar tendinopathy in women. An awareness of its variations enables careful selection of surgical incisions, thereby avoiding complications related to nerve injury. Accurate knowledge of the PL microanatomy assists in understanding the mechanism of ligament degeneration, rupture, autograft harvesting, and ligamentization results.     

Beta1-integrin and IL-1alpha expression as bystander effect of medium from irradiated cells: the pilot study

Bystander effects have been proposed as a third action pathway of ionising radiation besides direct and indirect effects. The purpose of the study was to investigate whether expression of interleukin-1alpha (IL-1alpha) and beta1-integrin is elevated in bystander cells as a marker for bystander effects in comparison with classical markers such as the clonogenic assay, apoptosis and the presence of micronuclei. The hybrid cell line E.A. hy.926 obtained by fusion of HUVEC cells with the epithelial cell line A 459 was irradiated with 0-5 Gy. Bystander effects were established via medium transfer at 45 min and 4 h after irradiation from irradiated to nonirradiated cell populations. In order to exclude effects of the irradiated medium itself, irradiated medium only was also used for transfer to nonirradiated cells. Then, cells were fixed at 1, 2, 6, and 24 h after irradiation or medium transport and IL-1alpha and beta1-integrin were detected and evaluated. A higher number of beta1-integrin-positive cells was observed in both irradiated and bystander cell populations than in the control group at 1 and 24 h after irradiation with 1 Gy or medium transfer. Significantly higher numbers of IL-1alpha-positive cells were found at 1, 2, and 6 h after irradiation with 1 Gy or medium transfer as well as at 2 and 6 h after irradiation with 5 Gy or medium transfer. Clonogenic survival decreased dependently on the dose in irradiated cells but did not show any significant difference between the bystander cell populations and sham-irradiated cells. The irradiated medium itself did not have any effect. It is concluded that beta1-integrin and IL-1alpha expression may serve as more sensitive markers of post-irradiation responses in bystander cell populations than the classical radiobiological markers. Moreover, overexpression of beta1-integrin and IL-1alpha may induce increased susceptibility to inflammation of bystander cells.     

2-dimensional MEMS dielectrophoresis device for osteoblast cell stimulation

A fixed microelectrode device for cell stimulation has been designed and fabricated using micro-electro-mechanical systems (MEMS) technology. Dielectrophoretic forces obtained from non-uniform electric fields were used for manipulating and positioning osteoblasts. The experiments show that the osteoblasts experience positive dielectrophoresis (p-DEP) when suspended in iso-osmotic culture medium and exposed to AC fields at 5 MHz frequency. Negative dielectrophoresis (n-DEP) is obtained at 0.1 MHz. The viability of osteoblasts under dielectrophoresis has been investigated. The viability values for cells exposed to DEP are nearly three times higher than the control values, indicating that dielectrophoresis may have an anabolic effect on osteoblasts.     

A comparison of primary intraperitoneal chemotherapy to consolidation intraperitoneal chemotherapy in optimally resected advanced ovarian cancer

Objective

To compare survival outcomes for patients with advanced epithelial ovarian cancer (EOC) who received primary intravenous/intraperitoneal (IV/IP) chemotherapy to those who received IV followed by consolidation (treatment given to patients in remission) IP chemotherapy.

Methods

Data were analyzed and compared for all patients with stage III–IV EOC who underwent optimal primary cytoreduction (residual disease ≤ 1 cm) followed by cisplatin-based consolidation IP chemotherapy (1/2001–12/2005) or primary IV/IP chemotherapy (1/2005–7/2011).

Results

We identified 224 patients; 62 (28%) received IV followed by consolidation IP chemotherapy and 162 (72%) received primary IV/IP chemotherapy. The primary IP group had significantly more patients with serous tumors. The consolidation IP group had a significantly greater median preoperative platelet count, CA-125, and amount of ascites. There were no differences in residual disease at the end of cytoreduction between both groups. The median progression-free survival (PFS) was greater for the primary IP group; however, this did not reach statistical significance (23.7 months vs 19.7 months; HR 0.78; 95% CI, 0.57–1.06; p = 0.11). The median overall survival (OS) was significantly greater for the primary IP group (78.8 months vs 57.5 months; HR 0.56; 95% CI, 0.38–0.83; p = 0.004). On multivariate analysis, after adjusting for confounders, the difference in PFS was not significant (HR 0.78; 95% CI, 0.56–1.11; p = 0.17), while the difference in OS remained significant (HR 0.59; 95% CI, 0.39–0.89; p = 0.01).

Conclusions

In our study, primary IV/IP chemotherapy was associated with improved OS compared to IV followed by consolidation IP chemotherapy in patients with optimally cytoreduced advanced EOC.     

Absorption and release of protein from hydroxyapatite-polylactic acid (HA-PLA) membranes

Objectives

The aim of this study was to investigate the kinetics of protein interactions with a novel hydroxyapatite-polylactide (HA-PLA) composite membrane material.

Methods

Trilayer PLA and HA-PLA composite membranes reinforced with PLA fibres were used to absorb and release protein which was measured by a BioRad assay. The proteins used were fetal calf serum and bovine serum albumin. PLA and HA-PLA composite films were manufactured to test permeability.

Results

Maximal protein absorption was seen within 5 min of treating materials; a nearly 8-fold increase in total absorption was seen with HA-containing composites compared to those without HA. These also exhibited a more gradual and sustained release of protein for periods of up to 96 h, for example at 24 h protein concentrations released were 2.20 ± 2.80 and 0.49 ± 5.38 μg/ml for membranes with and without HA respectively. In addition low pressure and temperature used during production of membranes also allowed greater and more sustained protein release. HA-PLA composite films also showed marked increased permeability compared to plain PLA films, for example after 24 h PLA only films 3.64 ± 1.01 μg/ml, PLA film with 25% HA: 44.99 ± 35.61 μg/ml, PLA film with 75% HA: 153.12 ± 65.57 μg/ml.

Conclusions

The results demonstrate that these composite membranes rapidly absorb protein and that the absorbed protein is released slowly for periods of up to 96 h, dependent on constituents of the material and the manufacturing conditions. Incorporation of HA into these membranes was the key factor for improved protein kinetics and membrane permeability.     

Oligopeptide inhibitors of HIV-induced syncytium formation

The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein is essential for virus entry and the formation of multinucleated giant cells by cell fusion, one of the major virus-induced cytopathic effects. To study the effects of potential fusion inhibitors, a vaccinia virus recombinant expressing the envelope glycoprotein was generated and used to infect HeLa CD4+ cells. Syncytium induction was observed as early as 4 h postinfection and continued until the entire monolayer was fused. The N-terminus of the gp41 subunit of the HIV envelope protein is very hydrophobic, and appears to be involved in virus-induced membrane fusion. We synthesized several oligopeptide analogs of the N-terminal region of gp41 and determined their ability to inhibit HIV-induced cell fusion in CD4+ HeLa cells. A hexapeptide which was identical in amino acid sequence to the N-terminus of gp41 was found to completely inhibit cell fusion, whereas peptides with altered sequences showed reduced inhibitory activity. These peptides had no effect on protein synthesis, processing, or transport to the cell surface, and showed no signs of toxicity to cells even at very high concentrations. These results indicate that oligopeptides which are homologous to the fusion peptide of HIV inhibit virus-induced cytopathology, and should be evaluated further as potential antiviral agents.     

Predictors of time to requiring dopaminergic treatment in 2 Parkinson's disease cohorts

The rate of progression of Parkinson's disease (PD) is highly variable. Knowledge of factors associated with disease milestones and commonly used research outcome measures helps with patient counseling and guides the design and interpretation of clinical studies. The objective of the study was to identify prognostic factors for time to acquiring disability requiring dopaminergic therapy that are reproducible within 2 large prospectively followed cohorts. Potential prognostic factors were identified using data from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial, and their reproducibility was examined using data from the Parkinson Research Examination of CEP‐1347 trial (PRECEPT). In multivariable analyses of the DATATOP cohort, higher baseline Unified Parkinson's Disease Rating Scale (UPDRS) scores, full‐time employment, a lesser smoking history, and onset on the left side were associated with a shorter time to disability requiring dopaminergic therapy. PRECEPT data confirmed the associations of higher baseline UPDRS scores and full‐time employment with shorter time to requiring treatment. Any clinical trial using the end point of time to disability requiring dopaminergic therapy should ensure that groups are well balanced with respect to baseline UPDRS scores and the proportion of subjects employed full time and should consider including these variables as covariates in the statistical model for primary analysis of treatment effects. We suspect that individuals employed full time may have a lower threshold for requiring dopaminergic therapy because of occupational demands. © 2011 Movement Disorder Society