Tubulointerstitial nephritis and uveitis (TINU) syndrome::a systematic review of its epidemiology, demographics and risk factors

Abstract Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare oculorenal inflammatory condition that was first described in 1975. In 2001 a major review identified 133 cases in the world literature and proposed key diagnostic criteria for the condition. Although acknowledged as rare, the limited data available prevented reliable estimates of the prevalence of the condition, and hampered elucidation of the relationship between genetic and environmental factors that contribute to its pathogenesis. In this review we have performed a systematic search on the epidemiology, demographics and proposed risk factors for TINU. Estimates of prevalence based on studies that explicitly report TINU cases suggest that it is diagnosed in 0.2–2% of patients attending specialist uveitis services, with variation reflecting a number of factors including level of diagnostic certainty required. The prevalence of uveitis in patients with tubulointerstitial nephritis (TIN) may be higher than currently recognised, particularly in the paediatric population. The prevalence of TINU is higher in younger age groups and there is a female preponderance although this gender effect appears weaker than suggested by early studies. Although important genetic contributions have been proposed, the small size of studies and variation between reports currently preclude identification of a ‘pro-TINU’ haplotype. Drugs and infections have been proposed as the leading acquired risk factors for the development of TINU; whilst the small size of TINU cohorts and issues of study design limit interpretation of many studies. Larger datasets from the renal literature suggest that the majority of these cases are precipitated by a drug-induced hypersensitivity reaction; however in many ophthalmic cases no clear precipitant is identified

Longitudinal studies of patients with ANCA vasculitis demonstrate concurrent reactivity to complementary PR3 protein segments cPR3m and cPR3C and with no reactivity to cPR3N

Antibodies recognizing the complement of the middle of PR3 (cPR3m) occur in ~30% of PR3-ANCA-vasculitis patients and immunization of animals with a peptide complementary to the middle of PR3 (cPR3m) induces not only anti-complementary PR3 antibodies, but also anti-PR3 antibodies derived through an anti-idiotypic response. PR3 epitopes recognized by patient ANCA however, are not restricted to the middle of PR3. This prompted us to test for antibodies that react with proteins complementary to the terminal regions of PR3 (cPR3C and cPR3N) in PR3-ANCA patients. Anti-cPR3C reactivity was detected in 28% of patients but anti-cPR3N reactivity in only 15%. Ranked anti-cPR3C and anti-cPR3m reactivity correlated in the cohort, whereas there was no significant relationship between cPR3C and cPR3N reactivity. Serial samples from three patients’ revealed that anti-cPR3C and anti-cPR3m reactivity followed a similar pattern over time. Serial samples from a fourth patient demonstrated an anti-cPR3N response without concurrent cPR3m or cPR3C reactivity. Epitope determination by mass spectrometry identified a thirteen amino acid sequence on cPR3C that contained a common binding site recognized by antibodies from three patients. This peptide sequence contains a “PHQ” motif which was reported to be the basis for cross-reactivity of anti-cPR3m antibodies with plasminogen. Why these antibodies are detected in only ~30% of the patients remains unclear. The data reveal it is not due to lack of inclusion of flanking regions of complementary PR3 during screening. Instead, quite unexpectedly, the data demonstrate that patients’ antibodies react with a restricted epitope that exists in both cPR3m and cPR3C

Endothelial SARS-CoV-2 infection is not the underlying cause of COVID-19-associated vascular pathology in mice

Endothelial damage and vascular pathology have been recognized as major features of COVID-19 since the beginning of the pandemic. Two main theories regarding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) damages endothelial cells and causes vascular pathology have been proposed: direct viral infection of endothelial cells or indirect damage mediated by circulating inflammatory molecules and immune mechanisms. However, these proposed mechanisms remain largely untested in vivo. In the present study, we utilized a set of new mouse genetic tools developed in our lab to test both the necessity and sufficiency of endothelial human angiotensin-converting enzyme 2 (hACE2) in COVID-19 pathogenesis. Our results demonstrate that endothelial ACE2 and direct infection of vascular endothelial cells do not contribute significantly to the diverse vascular pathology associated with COVID-19

Short-term efficacy and safety of rituximab therapy in refractory systemic lupus erythematosus: results from the British Isles Lupus Assessment Group Biologics Register.

OBJECTIVES: To describe the baseline characteristics of SLE patients requiring biologic therapy in the UK and to explore short term efficacy and infection rates associated with rituximab (RTX) use. METHODS: Patients commencing biologic therapy for refractory SLE and who consented to join BILAG-BR were analysed. Baseline characteristics, disease activity (BILAG 2004/SLEDAI-2K) and rates of infection over follow-up were analysed. Response was defined as loss of all A and B BILAG scores to ⩽ 1 B score with no new A/B scores in other organ systems at 6 months. RESULTS: Two hundred and seventy SLE patients commenced biologic therapy from September 2010 to September 2015, most commonly RTX (n = 261). Two hundred and fifty (93%) patients were taking glucocorticoids at baseline at a median [interquartile range (IQR)] oral dose of 10 mg (5-20 mg) daily. Response rates at 6 months were available for 68% of patients. The median (IQR) BILAG score was 15 (10-23) at baseline and 3 (2-12) at 6 months (P < 0.0001). The median (IQR) SLEDAI-2K reduced from 8 (5-12) to 4 (0-7) (P < 0.001). Response was achieved in 49% of patients. There was also a reduction in glucocorticoid use to a median (IQR) dose of 7.5 mg (5-12 mg) at 6 months (P < 0.001). Serious infections occurred in 26 (10%) patients, being more frequent in the first 3 months post-RTX therapy. A higher proportion of early infections were non-respiratory (odds ratio = 1.98, 95% CI: 0.99, 3.9; P = 0.049). CONCLUSION: RTX is safe and is associated with improvement in disease activity in refractory SLE patients with concomitant reductions in glucocorticoid use. Early vigilance for infection post-infusion is important to further improve treatment risks and benefits

Serotonin Reduction in Post-acute Sequelae of Viral Infection

Post-acute sequelae of COVID-19 (PASC, Long COVID ) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes

Priorities for research in soil ecology

The ecological interactions that occur in and with soil are of consequence in many ecosystems on the planet. These interactions provide numerous essential ecosystem services, and the sustainable management of soils has attracted increasing scientific and public attention. Although soil ecology emerged as an independent field of research many decades ago, and we have gained important insights into the functioning of soils, there still are fundamental aspects that need to be better understood to ensure that the ecosystem services that soils provide are not lost and that soils can be used in a sustainable way. In this perspectives paper, we highlight some of the major knowledge gaps that should be prioritized in soil ecological research. These research priorities were compiled based on an online survey of 32 editors of Pedobiologia – Journal of Soil Ecology. These editors work at universities and research centers in Europe, North America, Asia, and Australia. The questions were categorized into four themes: (1) soil biodiversity and biogeography, (2) interactions and the functioning of ecosystems, (3) global change and soil management, and (4) new directions. The respondents identified priorities that may be achievable in the near future, as well as several that are currently achievable but remain open. While some of the identified barriers to progress were technological in nature, many respondents cited a need for substantial leadership and goodwill among members of the soil ecology research community, including the need for multi-institutional partnerships, and had substantial concerns regarding the loss of taxonomic expertise

Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo

Meeting Abstracts: Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo Clearwater Beach, FL, USA. 9-11 June 201