A Frameshift Mutation in Golden Retriever Dogs with Progressive Retinal Atrophy Endorses SLC4A3 as a Candidate Gene for Human Retinal Degenerations

Progressive retinal atrophy (PRA) in dogs, the canine equivalent of retinitis pigmentosa (RP) in humans, is characterised by vision loss due to degeneration of the photoreceptor cells in the retina, eventually leading to complete blindness. It affects more than 100 dog breeds, and is caused by numerous mutations. RP affects 1 in 4000 people in the Western world and 70% of causal mutations remain unknown. Canine diseases are natural models for the study of human diseases and are becoming increasingly useful for the development of therapies in humans. One variant, prcd-PRA, only accounts for a small proportion of PRA cases in the Golden Retriever (GR) breed. Using genome-wide association with 27 cases and 19 controls we identified a novel PRA locus on CFA37 (praw = 1.94×10−10, pgenome = 1.0×10−5), where a 644 kb region was homozygous within cases. A frameshift mutation was identified in a solute carrier anion exchanger gene (SLC4A3) located within this region. This variant was present in 56% of PRA cases and 87% of obligate carriers, and displayed a recessive mode of inheritance with full penetrance within those lineages in which it segregated. Allele frequencies are approximately 4% in the UK, 6% in Sweden and 2% in France, but the variant has not been found in GRs from the US. A large proportion of cases (approximately 44%) remain unexplained, indicating that PRA in this breed is genetically heterogeneous and caused by at least three mutations. SLC4A3 is important for retinal function and has not previously been associated with spontaneously occurring retinal degenerations in any other species, including humans

Determinants of well-being and their interconnections in Australian general practitioners: a qualitative study

Objectives The well-being of doctors is recognised as a major priority in healthcare, yet there is little research on how general practitioners (GPs) keep well. We aimed to address this gap by applying a positive psychology lens, and exploring what determines GPs’ well-being, as opposed to burnout and mental ill health, in Australia.Design Semi-structured qualitative interviews. From March to September 2021, we interviewed GPs working in numerous settings, using snowball and purposive sampling to expand recruitment across Australia. 20 GPs participated individually via Zoom. A semi-structured interview-guide provided a framework to explore well-being from a personal, organisational and systemic perspective. Recordings were transcribed verbatim, and inductive thematic analysis was performed.Results Eleven female and nine male GPs with diverse experience, from urban and rural settings were interviewed (mean 32 min). Determinants of well-being were underpinned by GPs’ sense of identity. This was strongly influenced by GPs seeing themselves as a distinct but often undervalued profession working in small organisations within a broader health system. Both personal finances, and funding structures emerged as important moderators of the interconnections between these themes. Enablers of well-being were mainly identified at a personal and practice level, whereas systemic determinants were consistently seen as barriers to well-being. A complex balancing act between all determinants of well-being was evidenced.Conclusions GPs were able to identify targets for individual and practice level interventions to improve well-being, many of which have not been evaluated. However, few systemic aspects were suggested as being able to promote well-being, but rather seen as barriers, limiting how to develop systemic interventions to enhance well-being. Finances need to be a major consideration to prioritise, promote and support GP well-being, and a sustainable primary care workforce

IgG4 subclass antibodies impair antitumor immunity in melanoma

Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10–driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22(+) B cells and IgG4(+)-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell–mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches