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Background:. Primary sclerosing cholangitis is a progressive inflammatory liver disease characterized by biliary and liver fibrosis. Vascular adhesion protein-1 (VAP-1) is important in the inflammatory process driving liver fibrosis. We evaluated the safety and efficacy of VAP-1 blockade with a monoclonal antibody (timolumab, BTT1023) in patients with primary sclerosing cholangitis. Methods:. BUTEO was a prospective, single-arm, open-label, multicenter, phase II trial, conducted in 6 centers in the United Kingdom. Patients with primary sclerosing cholangitis aged 18–75 years had an alkaline phosphatase value of >1.5 times the upper limit of normal. The dose-confirmatory stage aimed to confirm the safety of timolumab through the incidence of dose-limiting toxicity and sufficient trough levels of circulating antibody to block VAP-1 function. The primary outcome of the dose-expansion portion of the trial was patient’s response to timolumab at day 99, as measured by a reduction in serum alkaline phosphatase by 25% or more from baseline to day 99. Results:. Twenty-three patients were recruited: 7 into the initial dose-confirmatory stage and a further 16 into an expansion stage. Timolumab (8 mg/kg) was confirmed to be safe for the duration of administration with sufficient circulating levels. Only 2 of the 18 evaluable patients (11.1%) achieved a reduction in alkaline phosphatase levels of 25% or more, and both the proportion of circulating inflammatory cell populations and biomarkers of fibrosis remained unchanged from baseline. Conclusions:. The BUTEO trial confirmed 8 mg/kg timolumab had no short-term safety signals and resulted in sufficient circulating levels of VAP-1 blocking timolumab. However, the trial was stopped after an interim assessment due to a lack of efficacy as determined by no significant change in serum liver tests.

Abstract Although increased temperatures are known to reinforce the effects of habitat destruction at local to landscape scales, evidence of their additive or interactive effects is limited, particularly over larger spatial extents and longer timescales. To address these deficiencies, we created a dataset of land-use changes over 75 years, documenting the loss of over half (>3000 km2) the semi-natural grassland of Great Britain. Pairing this dataset with climate change data, we tested for relationships to distribution changes in birds, butterflies, macromoths, and plants (n = 1192 species total). We show that individual or additive effects of climate warming and land conversion unambiguously increased persistence probability for 40% of species, and decreased it for 12%, and these effects were reflected in both range contractions and expansions. Interactive effects were relatively rare, being detected in less than 1 in 5 species, and their overall effect on extinction risk was often weak. Such individualistic responses emphasise the importance of including species-level information in policies targeting biodiversity and climate adaptation.

Introduction The non-intoxicating plant-derived cannabinoid, cannabidiol (CBD), has demonstrated therapeutic potential in a number of clinical conditions. Most successful clinical trials have used relatively high (≥300 mg) oral doses of CBD. Relatively few studies have investigated the efficacy of lower (

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is associated with liver and cardiovascular morbidity and mortality. Recently published NAFLD Quality Standards include 11 key performance indicators (KPIs) of good clinical care. This national study, endorsed by British Association for the Study of the Liver (BASL) and British Society of Gastroenterology (BSG), aimed to benchmark NAFLD care in UK hospitals against these KPIs. Methods: This study included all new patients with NAFLD reviewed in the outpatient clinic in the months of March 2019 and March 2022. Participating UK hospitals self-registered for the study through BASL/BSG. KPI outcomes were compared using Fisher’s exact or Chi-square tests. Results: Data from 776 patients with NAFLD attending 34 hospitals (England [25], Scotland [four], Wales [three], Northern Ireland [two]) were collected. A total of 85.3% of hospitals reported established local liver disease assessment pathways, yet only 27.9% of patients with suspected NAFLD had non-invasive fibrosis assessment documented at the point of referral to secondary care. In secondary care, 79.1% of patients had fibrosis assessment. Assessment of cardiometabolic risk factors including obesity, type 2 diabetes, hypertension, and smoking were conducted in 73.2%, 33.0%, 19.3%, and 54.9% of all patients, respectively. There was limited documentation of diet (35.7%) and exercise advice (55.1%). Excluding those on statins, only 9.1% of patients with NAFLD at increased cardiovascular risk (T2DM and/or QRISK-3 >10%) had documented discussion of statin treatment. Significant KPI improvements from 2019 to 2022 were evident in use of non-invasive fibrosis assessment before secondary care referral, statin recommendations, and diet and exercise recommendations. Conclusions: This national study identified substantial variation in NAFLD management in the UK with clear areas for improvement, particularly fibrosis risk assessment before secondary care referral and management of associated cardiometabolic risk factors. Impact and implications: This study identified significant variation in the management of NAFLD in the UK. Only 27.9% of patients with suspected NAFLD had non-invasive fibrosis assessment performed to identify those at greater risk of advanced liver disease before specialist referral. Greater emphasis is needed on the management of associated cardiometabolic risk factors in individuals with NAFLD. Hospitals with multidisciplinary NAFLD service provision had higher rates of fibrosis evaluation and assessment and management of cardiometabolic risk than hospitals without multidisciplinary services. Further work is needed to align guideline recommendations and real-world practice in NAFLD care.

Summary: Opportunistic species sightings submitted by citizen science volunteers are a valuable source of species data for trends analysis, as used in biodiversity indicators. However, projects collecting these data give people flexibility where and when to make records, and the recording behaviour of participants varies between individuals. Here we tested the effect of recorder behaviour on outputs of the analysis of temporal biodiversity trends. Using a large (c. 3 million records), 20 year unstructured citizen science dataset of butterfly records in Great Britain, we manipulated recorder behaviour by constructing biased 50% subsamples of the dataset by preferentially including different types of recorders (based on high and low values of four metrics independently describing the temporal, spatial and taxonomic attributes of recorder behaviour). We found that, in general, the three outputs (namely: occupancy trend, precision of the trend, and the estimate of occupancy) showed relatively little deviation from random expectation across most of the different types of recorder behaviour. Occupancy trends showed least deviation, while estimates of occupancy itself showed greatest deviation from the random expectation. Regarding the recorder behaviours, the outputs were most sensitive to variation in ‘recorder potential’, which describes the difference between ‘thorough’ and ‘incidental’ recorders. Importantly, by demonstrating the robustness of occupancy trends to differences in recorder behaviour, this study provides support for the appropriate use of occupancy trend modelling for unstructured citizen science. However, we did not consider change in recorder behaviour over time, so further research is required to assess the impact of this on trend modelling. This study highlights the value of developing solutions to further increase the robustness of biodiversity trend analysis. These solutions should include both analytical developments and enhancements in project design to engage participants.

Abstract Background The involvement of Besnoitia bennetti in skin pathologies was investigated in a series of 20 donkeys from the Donkey Sanctuary in England, in the 2013–2019 period. Methods The initial histopathological finding of Besnoitia cysts in skin lumps that were presumed to be sarcoids in 2013 triggered our cognisance of this parasite and resulted in identification of a total of 20 cases. Histopathological examination of surgical biopsy samples collected from 8 live donkeys and tissue specimens from 12 deceased donkeys at post-mortem examination revealed the presence of Besnoitia cysts in all 20 donkeys. The indirect fluorescent antibody test (IFAT) and immunoblotting analysis showed the presence of anti-Besnoitia antibodies in archived serum samples from 4 deceased donkeys. Additionally, infection was evidenced in one live donkey based on IFAT and immunoblot analysis of tissue fluid of a dermal mass containing Besnoitia cysts, and real-time (RT)-PCR analysis and microsatellite genotyping of DNA isolated from the tissue of the same dermal mass confirmed the infection specifically as B. bennetti. Results Both serological and microsatellite analyses confirmed the aetiology to be B. bennetti. Our findings suggested that in cases of skin masses such as sarcoids, the suspicion of B. bennetti infection should be borne in mind even when clinical and histopathology examination results are negative in order to avoid misdiagnosis. Conclusions This case series documents, to our knowledge, the first report of B. bennetti infection in donkeys in the UK, indicating that donkey besnoitiosis has become noteworthy in the UK. Further investigations of the occurrence, epidemiological characteristics, and clinical manifestations of B. bennetti infection in donkeys and other equids are warranted.

Many species’ life cycles have moved earlier in the year because of climate change, but we do not know the consequences for range expansions. The authors show that these advances promote range expansions in species with multiple reproductive cycles per year, but not in species with only one.

The link between family, fear and women’s bodies has a complicated history in Indonesia, tied to both international aid and economic development—as well as, in more recent years, to consumerism and transnational capital. Yet, if the ‘small happy and prosperous family norm’ is now the aspiration of many young Balinese, this was not always the case. Today advertisements for family planning technology encourage women to overcome fears of discomfort and physical side-effects in order to realize ‘the family of their dreams’. But the fears of earlier days were not so easily allayed—incited by stories of infertility, infection and death resulting from use of the IUD. What do older Balinese remember of the early days of the KB program? How does this compare with the aspirations of younger Balinese as they pursue the pleasures of life in a ‘small family’ and experience its anxieties? This article presents preliminary reflections on a new project exploring how Balinese differing in gender, generation and social class talk about and act on their plans for the future. Given its importance for both state bureaucratic and commercial representations of domestic life, the ideal of the patriarchal nuclear family figures centrally in these reflections.

ObjectiveOrgan radiation dose from a CT scan, calculated by CT dosimetry software, can be combined with cancer risk data to estimate cancer incidence resulting from CT exposure. We aim to determine to what extent the use of improved anatomical representation of the adult human body "phantom" in CT dosimetry software impacts estimates of radiation dose and cancer incidence, to inform comparison of past and future research.MethodsWe collected 20 adult cases for each of three CT protocols (abdomen/pelvis, chest and head) from each of five public hospitals (random sample) (January-April inclusive 2010) and three private clinics (self-report). Organ equivalent and effective dose were calculated using both ImPACT (mathematical phantom) and NCICT (voxelised phantom) software. Bland-Altman plots demonstrate agreement and Passing-Bablok regression reports systematic, proportional or random differences between results. We modelled the estimated lifetime attributable risk of cancer from a single exposure for each protocol, using age-sex specific risk-coefficients from the Biologic Effects of Ionizing Radiation VII report.ResultsFor the majority of organs used in epidemiological studies of cancer incidence, the NCICT software (voxelised) provided higher dose estimates. Across the lifespan NCICT resulted in cancer estimates 2.9%-6.6% and 14.8%-16.3% higher in males and females (abdomen/pelvis) and 7.6%-19.7% and 12.9%-26.5% higher in males and females respectively (chest protocol). For the head protocol overall cancer estimates were lower for NCICT, but with greatest disparity, >30% at times.ConclusionWhen the results of previous studies estimating CT dose and cancer incidence are compared to more recent, or future, studies the dosimetry software must be considered. Any change in radiation dose or cancer risk may be attributable to the software and phantom used, rather than-or in addition to-changes in scanning practice. Studies using dosimetry software to estimate radiation dose should describe software comprehensively to facilitate comparison with past and future research.

Abstract Artificial light at night (ALAN) is an increasingly important driver of global change. Lighting directly affects plants, but few studies have investigated indirect effects mediated by interacting organisms. Nocturnal Lepidoptera are globally important pollinators, and pollen transport by moths is disrupted by lighting. Many street lighting systems are being replaced with novel, energy‐efficient lighting, with unknown ecological consequences. Using the wildflower Silene latifolia, we compared pollination success and quality at experimentally lit and unlit plots, testing two major changes to street lighting technology: in lamp type, from high‐pressure sodium lamps to light‐emitting diodes, and in lighting regime, from full‐night (FN) to part‐night (PN) lighting. We predicted that lighting would reduce pollination. S. latifolia was pollinated both diurnally and nocturnally. Contrary to our predictions, flowers under FN lighting had higher pollination success than flowers under either PN lighting or unlit controls, which did not significantly differ from each other. Lamp type, lighting regime, and distance from the light all significantly affected aspects of pollination quality. These results confirm that street lighting could affect plant reproduction through indirect effects mediated by nocturnal insects, and further highlight the possibility for novel lighting technologies to mitigate the effects of ALAN on ecosystems.