Search

Abstract Background Medical training program and hospital response to the COVID-19 pandemic has varied greatly and has impacted trainee well-being. Which factors have specifically related to trainee wellness, however, has not yet been examined in depth. The aim of the study was to understand trainee perspectives on the individual psychiatry trainee programs’ hospitals’ objective COVID-19 preparedness management. We also sought and to gauge how program changes, and general pandemic-related concerns, have been associated with trainee satisfaction and burnout. Methods A cross-sectional survey study of psychiatric trainees was distributed electronically throughout the country via various psychiatry residency program listservs in April 2020. Statistical analyses were performed utilizing simple linear regression. Results From 352 respondents (346 complete responses and 6 partial responses), the most frequent program changes were “decreased number of rotations requiring in-person patient care” and “increased call hours or duties.” Of pandemic-related concerns surveyed, the two greatest were “spreading COVID-19 to family/friends” and “co-residents’ burnout and anxiety.” A positive relationship was found between trainee satisfaction with perceived COVID-19 departmental response and comfort level of residents/fellows in expressing concerns with attending clinicians and department leadership. Conclusions Since the start of the COVID-19 pandemic, trainees have experienced a variety of changes to trainee program policies and guidelines. Overall, poor communication and trainee dissatisfaction with departmental response correlated with concern of infection and anxiety/burnout. Insights garnered from this study could provide scaffolding for the best practices to reduce trainee physician anxiety/burnout for the current and future pandemics of this variety and magnitude.

Objective: Endoplasmic reticulum aminopeptidase 1 (ERAP‐1) and ERAP‐2, encoded on chromosome 5q15, trim endogenous peptides for HLA‐mediated presentation to the immune system. Polymorphisms in ERAP1 and/or ERAP2 are strongly associated with several immune‐mediated diseases with specific HLA backgrounds, implicating altered peptide handling and presentation as prerequisites for autoreactivity against an arthritogenic peptide. Given the thorough characterization of disease risk–associated polymorphisms that alter ERAP activity, this study aimed instead to interrogate the expression effect of chromosome 5q15 polymorphisms to determine their effect on ERAP isoform and protein expression. Methods: RNA sequencing and genotyping across chromosome 5q15 were performed to detect genetic variants in ERAP1 and ERAP2 associated with altered total gene and isoform‐specific expression. The functional implication of a putative messenger RNA splice‐altering variant on ERAP‐1 protein levels was validated using mass spectrometry. Results: Polymorphisms associated with ankylosing spondylitis (AS) significantly influenced the transcript and protein expression of ERAP‐1 and ERAP‐2. Disease risk–associated polymorphisms in and around both genes were also associated with increased gene expression. Furthermore, key risk‐associated ERAP1 variants were associated with altered transcript splicing, leading to allele‐dependent alternate expression of 2 distinct isoforms and significant differences in the type of ERAP‐1 protein produced. Conclusion: In accordance with studies demonstrating that polymorphisms that increase aminopeptidase activity predispose to immune disease, the increased risk also attributed to increased expression of ERAP1 and ERAP2 supports the notion of using aminopeptidase inhibition to treat AS and other ERAP‐associated conditions. [ABSTRACT FROM AUTHOR]

Background: Ankylosing spondylitis (AS) is characterised by immune-mediated arthritis and osteoproliferation, ultimately leading to joint ankylosis. Whether inflammation is necessary for osteoproliferation is controversial, fuelled by the unclear efficacy of anti-inflammatory treatments on radiographic progression. In proteoglycan-induced spondylitis (PGISp), a mouse model of AS, inflammation is the prerequisite for osteoproliferation as osteoproliferation was only observed following inflammation-driven intervertebral disc (IVD) destruction. We hypothesised that early intervention with a potent anti-inflammatory therapy would protect IVD integrity and consequently alter disease progression.Methods: PGISp mice received vehicle or a combination of etanercept (ETN) plus prednisolone (PRD) therapy for 2 or 6 weeks initiated at an early disease stage. Peripheral arthritis was scored longitudinally. Spinal disease was assessed using a semi-quantitative histological scoring regimen including inflammation, joint destruction and excessive tissue formation.Results: ETN + PRD therapy significantly delayed the onset of peripheral arthritis. IVD integrity was significantly protected when treatment was commenced in early disease. Six-weeks of treatment resulted in trends towards reductions in intervertebral joint damage and excessive tissue formation. IVD score distribution was dichotomized, likely reflecting the extent of axial disease at initiation of therapy. In the sub-group of mice with high IVD destruction scores, ETN + PRD treatment significantly reduced IVD destruction severity, inflammation and bone erosion and reduced cartilage damage and excessive tissue formation.Conclusions: Early intervention with anti-inflammatory treatment not only improved inflammatory symptoms but also ameliorated structural damage of spine in PGISp mice. This preclinical observation suggests that early anti-inflammatory intervention may slow radiographic progression in AS patients. [ABSTRACT FROM AUTHOR]

Mutations of UDP-N-acetyl-alpha-D-galactosamine polypeptide N-acetyl galactosaminyl transferase 3 (GALNT3) result in familial tumoural calcinosis (FTC) and the hyperostosis-hyperphosphataemia syndrome (HHS), which are autosomal recessive disorders characterised by soft-tissue calcification and hyperphosphataemia. To facilitate in vivo studies of these heritable disorders of phosphate homeostasis, we embarked on establishing a mouse model by assessing progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU), and identified a mutant mouse, TCAL, with autosomal recessive inheritance of ectopic calcification, which involved multiple tissues, and hyperphosphataemia; the phenotype was designated TCAL and the locus, Tcal. TCAL males were infertile with loss of Sertoli cells and spermatozoa, and increased testicular apoptosis. Genetic mapping localized Tcal to chromosome 2 (62.64--71.11 Mb) which contained the Galnt3. DNA sequence analysis identified a Galnt3 missense mutation (Trp589Arg) in TCAL mice. Transient transfection of wild-type and mutant Galnt3- enhanced green fluorescent protein (EGFP) constructs in COS-7 cells revealed endoplasmic reticulum retention of the Trp589Arg mutant and Western blot analysis of kidney homogenates demonstrated defective glycosylation of Galnt3 in Tcal/Tcal mice. Tcal/Tcal mice had normal plasma calcium and parathyroid hormone concentrations; decreased alkaline phosphatase activity and intact Fgf23 concentrations; and elevation of circulating 1,25-dihydroxyvitamin D. Quantitative reverse transcriptase-PCR (qRT-PCR) revealed that Tcal/Tcal mice had increased expression of Galnt3 and Fgf23 in bone, but that renal expression of Klotho, 25-hydroxyvitamin D-1α-hydroxylase (Cyp27b1), and the sodium- phosphate cotransporters type-IIa and -IIc was similar to that in wild-type mice. Thus, TCAL mice have the phenotypic features of FTC and HHS, and provide a model for these disorders of phosphate metabolism. [ABSTRACT FROM AUTHOR]