Effect of Prior ChAdOx1 COVID-19 Immunisation on T-Cell Responses to ChAdOx1-HBV.

There are varying data concerning the effect of prior anti-vector immunity on the T-cell response induced by immunisation with an identical vectored vaccine containing a heterologous antigen insert. To determine whether prior exposure to ChAdOx1-SARS-CoV2 immunisation (Vaxzevria®) impacts magnitudes of antigen-specific T-cell responses elicited by subsequent administration of the same viral vector (encoding HBV antigens, ChAdOx1-HBV), healthy volunteers that had received Vaxzevria® (n = 15) or the Pfizer or Moderna mRNA COVID-19 vaccine (n = 11) between 10 and 18 weeks prior were recruited to receive a single intramuscular injection of ChAdOx1-HBV. Anti-ChAdOx1-neutralising antibody titers were determined, and vector or insert-specific T-cell responses were measured by a gamma-interferon ELISpot and intracellular cytokine staining (ICS) assay using multiparameter flow cytometry. Participants were followed for three months after the ChAdOx1-HBV injection, which was well-tolerated, and no dropouts occurred. The baseline ChAdOx1 neutralisation titers were higher in the Vaxzevria® cohort (median of 848) than in the mRNA cohort (median of 25). T-cell responses to HBV antigens, measured by ELISpot, were higher on day 28 in the mRNA group (p = 0.013) but were similar between groups on day 84 (p = 0.441). By ICS, these differences persisted at the last time point. There was no clear correlation between the baseline responses to the adenoviral hexon and the subsequent ELISpot responses. As vaccination within 3 months using the same viral vector backbone affected the insert-specific T-cell responses, a greater interval after prior adenoviral immunisation using heterologous antigens may be warranted in settings in which these cells play critical roles.

Pre-Clinical Development of an Adenovirus Vector Based RSV and Shingles Vaccine Candidate.

Respiratory syncytial virus (RSV) infection and shingles are two viral diseases that affect older adults, and a combined vaccine to protect against both could be beneficial. RSV infection causes hospitalisations and significant morbidity in both children and adults and can be fatal in the elderly. The RSV fusion (F) envelope glycoprotein induces a strong RSV-neutralising antibody response and is the target of protective immunity in the first RSV vaccine for older adults, recently approved by the FDA. An initial childhood infection with the varicella zoster virus (VZV) results in chickenpox disease, but reactivation in older adults can cause shingles. This reactivation in sensory and autonomic neurons is characterized by a skin-blistering rash that can be accompanied by prolonged pain. The approved protein-in-adjuvant shingles vaccine induces VZV glycoprotein E (gE)-fspecific antibody and CD4+ T cell responses and is highly effective. Here we report the evaluation of RSV/shingles combination vaccine candidates based on non-replicating chimpanzee adenovirus (ChAd) vectors. We confirmed the cellular and humoral immunogenicity of the vaccine vectors in mice using T cell and antibody assays. We also carried out an RSV challenge study in cotton rats which demonstrated protective efficacy following a homologous prime-boost regimen with our preferred vaccine candidate.

Treatment of axial spondyloarthritis with biologic and targeted synthetic DMARDs: British Society for Rheumatology guideline scope.

Pharmacological management has advanced considerably since the 2015 British Society for Rheumatology axial spondyloarthritis (axSpA) guideline to incorporate new classes of biologic DMARDs (bDMARDs, including biosimilars), targeted synthetic DMARDs (tsDMARDs) and treatment strategies such as drug tapering. The aim of this guideline is to provide an evidence-based update on pharmacological management of adults with axSpA (including AS and non-radiographic axSpA) using b/tsDMARDs. This guideline is aimed at health-care professionals in the UK who care directly for people with axSpA, including rheumatologists, rheumatology specialist nurses, allied health professionals, rheumatology specialty trainees and pharmacists; people living with axSpA; and other stakeholders, such as patient organizations and charities.

Intravenous administration of viral vectors expressing prostate cancer antigens enhances the magnitude and functionality of CD8+ T cell responses.

BACKGROUND: The use of immunotherapeutic vaccination in prostate cancer is a promising approach that likely requires the induction of functional, cytotoxic T cells . The experimental approach described here uses a well-studied adenovirus-poxvirus heterologous prime-boost regimen, in which the vectors encode a combination of prostate cancer antigens, with the booster dose delivered by either the intravenous or intramuscular (IM) route. This prime-boost regimen was investigated for antigen-specific CD8+ T cell induction. METHODS: The coding sequences for four antigens expressed in prostate cancer, 5T4, PSA, PAP, and STEAP1, were inserted into replication-incompetent chimpanzee adenovirus Oxford 1 (ChAdOx1) and into replication-deficient modified vaccinia Ankara (MVA). In four strains of mice, ChAdOx1 prime was delivered intramuscularly, with an MVA boost delivered by either IM or intravenous routes. Immune responses were measured in splenocytes using ELISpot, multiparameter flow cytometry, and a targeted in vivo killing assay. RESULTS: The prime-boost regimen was highly immunogenic, with intravenous administration of the boost resulting in a sixfold increase in the magnitude of antigen-specific T cells induced and increased in vivo killing relative to the intramuscular boosting route. Prostate-specific antigen (PSA)-specific responses were dominant in all mouse strains studied (C57BL/6, BALBc, CD-1 and HLA-A2 transgenic). CONCLUSION: This quadrivalent immunotherapeutic approach using four antigens expressed in prostate cancer induced high magnitude, functional CD8+ T cells in murine models. The data suggest that comparing the intravenous versus intramuscular boosting routes is worthy of investigation in humans.

Standards of Practice for Occupational Therapy.

This document defines minimum standards for the practice of occupational therapy. According to the Occupational Therapy Practice Framework: Domain and Process (4th ed.; OTPF-4), occupational therapy is defined as the therapeutic use of everyday life occupations with persons, groups, or populations (i.e., the client) for the purpose of enhancing or enabling participation. . . . Occupational therapy services are provided for habilitation, rehabilitation, and promotion of health and wellness for clients with disability- and non-disability-related needs. These services include acquisition and preservation of occupational identity for clients who have or are at risk for developing an illness, injury, disease, disorder, condition, impairment, disability, activity limitation, or participation restriction. (American Occupational Therapy Association [AOTA], 2020c, p. 1).

Baclofen bridging, weaning protocol and pain management of a person with T6 paraplegia who required removal of intrathecal baclofen pump due to wound infection.

Intrathecal baclofen is recognised as an effective treatment option for severe symptoms of segmental spasticity after spinal cord injury. We present our experience of a case of a patient who was admitted to our centre for elective intrathecal baclofen pump revision surgery, but postsurgical complications of a blocked catheter and subsequent wound infections meant the pump had to be removed. In this case, treatment of severe spasticity and nociceptive pain was required while avoiding potentially lethal side effects of sudden baclofen withdrawal. We suggest an effective bridging and weaning protocol for oral drug titration to treat spasticity and pain as a blended syndrome in this challenging situation.

Treatment of psoriatic arthritis with biologic and targeted synthetic DMARDs: British Society for Rheumatology guideline scope.

The aim of this guideline is to provide an update on evidence-based recommendations for treatment of adult patients with PsA. The previous BSR guidelines for PsA were published in 2012 and since that time, there have been many new advanced therapies licensed for PsA. This update will provide practical guidance for clinicians on the optimal selection of advanced therapies taking into account different domains of PsA (arthritis, enthesitis, dactylitis, axial disease and psoriasis) and key associated comorbidities. It will also update guidance on treatment strategy including the use of a treat-to-target approach. The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol. (1) This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence (NICE) accreditation.

Intrinsic Type 1 Interferon (IFN1) Profile of Uncultured Human Bone Marrow CD45lowCD271+ Multipotential Stromal Cells (BM-MSCs): The Impact of Donor Age, Culture Expansion and IFNα and IFNß Stimulation.

Skeletal aging is associated with reduced proliferative potential of bone marrow (BM) multipotential stromal cells (MSCs). Recent data suggest the involvement of type 1 interferon (IFN1) signalling in hematopoietic stem cell (HSC) senescence. Considering that BM-HSCs and BM-MSCs share the same BM niche, we investigated IFN1 expression profile in human BM-MSCs in relation to donor age, culture-expansion and IFN1 (α and ß) stimulation. Fluorescence-activated cell sorting was used to purify uncultured BM-MSCs from younger (19-41, n = 6) and older (59-89, n = 6) donors based on the CD45lowCD271+ phenotype, and hematopoietic-lineage cells (BM-HLCs, CD45+CD271-) were used as controls. Gene expression was analysed using integrated circuits arrays in sorted fractions as well as cultured/stimulated BM-MSCs and Y201/Y202 immortalised cell lines. IFN1 stimulation led to BM-MSC growth arrest and upregulation of many IFN1-stimulated genes (ISGs), with IFNß demonstrating stronger effects. Uncultured MSCs were characterised by a moderate-level ISG expression similar to Y201 cells. Age-related changes in ISG expression were negligible in BM-MSCs compared to BM-HLCs, and intracellular reactive oxygen species (ROS) levels in BM-MSCs did not significantly correlate with donor age. Antiaging genes Klotho and SIRT6 correlated with more ISGs in BM-MSCs than in BM-HLCs. In patients with osteoarthritis (OA), BM-MSCs expressed considerably lower levels of several ISGs, indicating that their IFN1 signature is affected in a pathological condition. In summary, BM-MSCs possess homeostatic IFN1 gene expression signature in health, which is sensitive to in vitro culture and external IFN1 stimulation. IFN signalling may facilitate in vivo BM-MSC responses to DNA damage and combating senescence and aberrant immune activation.

A case control study of the implementation of change model versus passive dissemination of practice guidelines for compliance in monitoring for metabolic syndrome.

We developed an intervention to improve compliance with guidelines for monitoring metabolic syndrome and compared compliance prior to intervention and three times post-intervention at three community mental health clinics in Texas. One test clinic received intervention and two other clinics served as controls. Fifty random charts were reviewed from each clinic for three specific, 1-2 weeks periods over the course of 18 months. There were significant improvements in the ordering of labs, the presence of lab results in the chart, and documentation of blood pressure, body mass index and waist circumference in the intervention clinic over time in comparison to the control clinics. Documented evidence of physician action with respect to out of range values remained low. Metabolic monitoring is a multi-step process. Removing barriers, creating specific procedures, and dedicating staff resources can improve compliance with monitoring.

Bilateral asynchronous renal cell carcinoma with metastatic involvement of the tongue.

Renal cell carcinoma (RCC) has a propensity for distant organ metastasis and late recurrence, involving not only the ipsilateral but also contralateral kidney. Lingual metastasis by RCC is rare. We present an unusual case of bilateral asynchronous RCC. Involvement of the right kidney was discovered only after a metastatic tongue lesion was diagnosed. The original RCC had been treated by left nephrectomy 14 years previously. Due to end-stage primary pulmonary malignancy, and poor function of the remaining kidney, immunotherapy was unsuitable. Palliative local resection of the lingual metastasis alleviated functional difficulties and was preventative against airway obstruction, but the patient died five months later.