Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism. CONCLUSIONS Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy.

SumlTlaryAsthma is a chronic life-threatening disease of worldwide importance. Although allergic asthma and related atopic conditions correlate strongly with immune sensitization to house dust mites, it is unclear why antigens from mites provoke such powerful allergic immune responses. We have characterized the protease activity of Der p I, the group I protease allergen of the house dust mite Dermatophagoides pteronyssinus, and here report that it cleaves the low-affinity immunoglobulin (Ig) E Fc receptor (CD23) from the surface of human B lymphocytes. Derp I selectively cleaves CD23 and has no effect on the expression of any other B cell surface molecules tested. We speculate that this loss of cell surface CD23 from IgE-secreting B cells may promote and enhance IgE immune responses by ablating an important feedback inhibitory mechanism that normally limits IgE synthesis. Furthermore, since soluble CD23 is reported to promote IgE production, fragments of CD23 released by Der p I may directly enhance the synthesis of IgE. cel-Antiprotease, a pulmonary antiprotease, is also shown to inhibit the cleavage of CD23 by Derp I. This may be significant in the etiopathogenesis of asthma, because other indoor pollutants associated with asthma are known to potently inhibit this antiprotease. These data suggest that the proteolytic activity of Derp I, the group I allergen of the house dust mite D. pteronyssinus, is mechanistically linked to the potent allergenicity of house dust mites. Furthermore, inhibition of Der p I by cq-antiprotease suggests a mechanism by which confounding factors, such as tobacco smoke, may act as a risk factor for allergic asthma.

Introduction Increased mortality has been demonstrated in older adults with COVID-19, but the effect of frailty has been unclear. Methods This multi-centre cohort study involved patients aged 18 years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty, and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation, and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS), and delirium on risk of increased care requirements on discharge, adjusting for the same variables. Results Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, IQR 54–83; 55.2% male). The risk of death increased independently with increasing age (>80 vs 18–49: HR 3.57, CI 2.54–5.02), frailty (CFS 8 vs 1–3: HR 3.03, CI 2.29–4.00) inflammation, renal disease, cardiovascular disease, and cancer, but not delirium. Age, frailty (CFS 7 vs 1–3: OR 7.00, CI 5.27–9.32), delirium, dementia, and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9. Conclusions Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age.

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In a survey of the mite fauna in 30 homes in Oxfordshire, Dermatophagoides pteronyssinus and Euroglyphus maynei were found to be the most abundant species but D. farinae was absent. Of a total of 14 parameters investigated for their influence on mite numbers, relative humidity was apparently the most important factor. Bedrooms with humidities above 64% contained significantly more mites in mattresses than those with lower humidities. Bedroom humidity and thus mattress mite numbers were apparently related and were influenced by the bedroom minimum temperature, the age of the house and the use of central heating. These trends were not seen in the numbers of mites found in living-room carpets. Atopic and non-atopic participants involved in this study did not differ significantly in the numbers of mites found in their homes.

This article addresses the debate over mediation as an alternative to litigation by reviewing the literature on custody mediation in the context of domestic violence and by examining the “fit” between the process of mediation and domestic violence participants. The evidence shows that mandatory custody mediation is inappropriate in the context of wife abuse.

Wood mice Apodemus sylvaticus are potentially useful indicators of change in arable ecosystems. Here we focus on changes resulting from removal of land from arable production under the set-aside scheme. Wood mice were radio-tracked to compare: (a) their use of set-aside, crop and hedgerow before and after harvest; (b) set-aside con®gured as margins and as a 3 ha block; (c) cut and uncut 20-m wide set-aside margins. Males had larger home ranges, and were more mobile than females. Ranges were larger, and animals more mobile, before harvest than afterwards. There were no differences in range sizes of breeding and nonbreeding animals after harvest, suggesting that changes in habitat use were not a function of cessation of breeding. Before harvest, wood mice used habitats within their ranges at random, and their ranges contained a high proportion of cropped area. After harvest they preferred hedgerow and avoided margin set-aside within their ranges, but did not similarly avoid the set-aside block. The proportion of cropped area within their ranges decreased after harvest, and the proportion of margin increased. Our evidence suggests wood mice avoided using the area adjacent to the hedgerow, perhaps to avoid predators. Uncut set-aside patches were favoured and cut patches avoided, possibly in response to differences in food availability and levels of protection from predators. These results con®rm that wood mice are useful indicators of change in arable landscapes.