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The risk of revision surgery after trainee-led primary total hip replacement.
INTRODUCTION: The aim of this study was to determine the impact of operating surgeon grade and level of supervision on the incidence of one-year patient mortality and all-cause revision following elective primary total hip replacement (THR). METHODS: National Joint Registry data from 2005 to 2020 for a single University Teaching Hospital were used, with analysis performed on the 15-year dataset divided into 5-year block periods (B1, 2005-2010; B2, 2010-2015; B3, 2015-2020). Outcome measures were mortality and revision surgery at one year, in relation to lead surgeon grade, and level of supervision for trainee-led (TL) operations. RESULTS: A total of 9,999 eligible primary THRs were performed, of which 5,526 (55.3%) were consultant-led (CL), and 4,473 (44.7%) TL. Of TL, 2,404 (53.7%) were nonconsultant-supervised (TU) and 2,069 (46.3%) consultant-supervised (TS). The incidence of one-year patient mortality was 2.05% (n=205), and all-cause revision was 1.11% (n=111). There was no difference in one-year mortality between TL and CL operations (p=0.20, odds ratio (OR) 0.78, confidence interval (CI) 0.55-1.10). The incidence of one-year revision was not different for TL and CL operations (p=0.15, OR 1.37, CI 0.89-2.09). Overall, there was no temporal change for either outcome measure between TL or CL operations. A significant increase in revision within one-year was observed in B3 between TU compared with CL operations (p=0.005, OR 2.81, CI 1.35-5.87). CONCLUSIONS: We found no difference in overall one-year mortality or all-cause revision rate between TL and CL primary THR. Despite a reduction in unsupervised THR in the latest five-year period (2015-2020), unsupervised TL THR resulted in an increased risk of early revision.
Roadmap for alleviating the manifestations of ageing in the cardiovascular system.
Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.
Hypercoagulation after Hospital Discharge in Acute Severe Ulcerative Colitis: A Prospective Study.
BACKGROUND & AIMS: Venous thromboembolism is a serious complication during and following hospitalization with acute severe ulcerative colitis (ASUC). We evaluated serial thrombotic profiles of patients with ASUC from the point of hospitalization up to 12 weeks postdischarge and compared these with control patients with quiescent ulcerative colitis. METHODS: Twenty-seven patients with ASUC and 25 control patients with quiescent ulcerative colitis were recruited. Thrombin generation (endogenous thrombin potential), rotational thromboelastometry (EXTEM and FIBTEM maximum clot firmness), procoagulant factors, anticoagulant factors, and fibrinolytic markers were assessed for those with ASUC on admission (Day 1), Day 5, 4 weeks, and at 8-12 weeks. These assessments were performed on a single occasion for control patients. RESULTS: Endogenous thrombin potential and maximum clot firmness were significantly elevated in patients with ASUC compared with control subjects and remained significantly elevated for 4 weeks and for 8-12 weeks after admission (P < .05), respectively. Von Willebrand factor antigen, factor VIII, Clauss fibrinogen concentration, and platelet count were significantly increased from presentation to 8-12 weeks and are likely to account for changes in the global hemostatic profile. CONCLUSIONS: Global measures of hemostasis demonstrated that patients with ASUC were prothrombotic compared with control subjects with quiescent colitis. This difference was maintained 8-12 weeks after the initial presentation, supporting clinical observations that patients with ASUC have an elevated risk of venous thromboembolism after hospital discharge.
The role and uses of antibodies in COVID-19 infections: a living review.
Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity.
Mucosal immune responses in COVID19 - a living review.
COVID-19 was initially characterized as a disease primarily of the lungs, but it is becoming increasingly clear that the SARS-CoV2 virus is able to infect many organs and cause a broad pathological response. The primary infection site is likely to be a mucosal surface, mainly the lungs or the intestine, where epithelial cells can be infected with virus. Although it is clear that virus within the lungs can cause severe pathology, driven by an exaggerated immune response, infection within the intestine generally seems to cause minor or no symptoms. In this review, we compare the disease processes between the lungs and gastrointestinal tract, and what might drive these different responses. As the microbiome is a key part of mucosal barrier sites, we also consider the effect that microbial species may play on infection and the subsequent immune responses. Because of difficulties obtaining tissue samples, there are currently few studies focused on the local mucosal response rather than the systemic response, but understanding the local immune response will become increasingly important for understanding the mechanisms of disease in order to develop better treatments.
Weaving and loom terminology in Japhug
We describe the yarn preparation and weaving tradition of the Japhug people of Sichuan Province, China, speakers of a Rgyalrongic language belonging to the Sino-Tibetan family. We discuss the practical aspects of the loom and its operation, as well as the terms used to describe it. Our analysis shows that the terms are mostly a mixture of autochthonous Rgyalrongic and borrowings from Tibetan. The loom is a version of the frameless body-tensioned loom, an ancient and widespread type in East Asia and Southeast Asia, used by many Sino-Tibetan language speakers. We provide a simple guide for researchers interested in recording weaving traditions in the field, and we briefly discuss the implications of our findings for the study of the languages and ethnography of the Sino-Tibetan peoples generally.
Defining an ageing-related pathology, disease or syndrome: International Consensus Statement.
Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased health span. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand and meet the healthcare, workforce, well-being and socioeconomic needs of ageing populations, whilst supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies. The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19, 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥ 70% for approval. The accepted criteria for an ageing-related pathology, disease or syndrome were (1) develops and/or progresses with increasing chronological age; (2) should be associated with, or contribute to, functional decline or an increased susceptibility to functional decline and (3) evidenced by studies in humans. Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.
T cell phenotypes in COVID-19 - a living review.
COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients' long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation.
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
The immune-epithelial-stromal interactions underpinning intestinal damage in celiac disease (CD) are incompletely understood. To address this, we performed single-cell transcriptomics (RNA sequencing; 86,442 immune, parenchymal and epithelial cells; 35 participants) and spatial transcriptomics (20 participants) on CD intestinal biopsy samples. Here we show that in CD, epithelial populations shifted toward a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T cells showed numeric and functional changes in regulatory and follicular helper-like CD4+ T cells, intraepithelial lymphocytes, CD8+ and γδ T cell subsets, with skewed T cell antigen receptor repertoires. Mucosal changes remained detectable despite treatment, representing a persistent immune-epithelial 'scar'. Spatial transcriptomics defined transcriptional niches beyond those captured in conventional histological scores, including CD-specific lymphoid aggregates containing T cell-B cell interactions. Receptor-ligand spatial analyses integrated with disease susceptibility gene expression defined networks of altered chemokine and morphogen signaling, and provide potential therapeutic targets for CD prevention and treatment.
A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease.
Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohn's disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas represents the largest cellular census of perturbation with the most common biologic treatment, anti-TNF, across multiple inflammatory diseases.
Sexual dimorphisms in fat distribution: investigating oestradiol’s depot-specific effects on preadipocyte and macrophage interactions
Fat distribution is a key regulator of cardiometabolic disease risk, with biological females typically favouring fat storage in the gluteofemoral region, while males tend to store fat around the abdomen. Accumulation of gluteofemoral adiposity, particularly through hyperplastic expansion, is metabolically favourable and is thought to be promoted by the sex hormone oestradiol in females. Alterations in oestradiol concentrations, such as those occurring at menopause or during oestradiol therapy, are associated with shifts in fat distribution and subsequent changes in cardiometabolic risk. However, the mechanisms underlying these oestradiol-induced changes remain poorly understood and are complicated by the controversial literature surrounding the effects of oestradiol on adipose tissue expansion. Given the documented role of oestradiol in modulating the inflammatory phenotypes of other cells within the adipose tissue stromovascular fraction (SVF), particularly macrophages, it is essential to investigate how oestradiol may influence signalling between adipocytes and macrophages to promote depot-specific changes in adipose expansion, favouring gluteofemoral adipose tissue growth and abdominal adipose tissue regression. This thesis aimed to first characterize the depot-specific SVF population landscape using single-cell RNA sequencing (scRNASeq) on paired abdominal and gluteal adipose tissue biopsies. It then assessed oestradiol signalling in abdominal and gluteal preadipocytes using in-vitro models, and established an in-vitro co-culture system between preadipocytes and macrophages. This system facilitated the identification of oestradiol-primed communication signals that may modulate depot-specific expansion through RNA sequencing approaches. The results reveal unique transcriptional landscapes of abdominal and gluteal adipose tissue SVF and demonstrate that preadipocyte responses to oestradiol are highly depot-specific. Additionally, this work identified a range of candidate signals exchanged between preadipocytes and macrophages that may contribute to oestradiol-primed, depots-specific adipose tissue expansion. Future research should aim to functionally test these signals using the in-vitro systems developed here.