Clinical Approach to Immune-Mediated Hemolytic Anemia and Thrombocytopenia.

Primary immune mediated hemolytic anemia (IMHA) and thrombocytopenia (IMTP) are rare in horses with the conditions more commonly occurring secondary to underlying disease. Several case reports have suggested a link between neoplasia and immune-mediated destruction of platelets and red blood cells. Diagnostic investigations should therefore focus on identifying possible underlying causes such as infections and neoplasia. Immunosuppressive therapy with corticosteroids and azathioprine is the mainstay of treatment but should be used cautiously in cases where underlying infection has not been excluded. Given the frequent association of secondary IMHA and IMTP cases with neoplasia, primary cases generally have a better prognosis.

Hospitality Work as Social Reproduction: Embodied and Emotional Labour during COVID-19.

This article focuses on how the imaginary of a 'safe' environment was visualised and conveyed within the hospitality sector during the COVID-19 pandemic, drawing on diaries and interviews with 21 workers in the UK. Our findings show increased workloads for hospitality staff, compounded by anxieties of risk and individualised COVID-19 regulation work. This includes workers' negotiations of corporeal boundaries and distancing from customers, the visible cleaning of communal areas and recuperation and care work for their own bodies and others in shared living spaces. We draw on conceptualisations of embodied and emotional labour to understand these experiences, reflecting on the importance of the actions performed by workers in maintaining community spaces and creating customer confidence in safely enjoying a 'hospitable' environment. This article contributes to social science scholarship of embodied and emotional labour, hospitality and social reproduction.

Risk-Adapted Breast Screening for Women at Low Predicted Risk of Breast Cancer: An Online Discrete Choice Experiment.

BACKGROUND: A risk-stratified breast screening program could offer low-risk women less screening than is currently offered by the National Health Service. The acceptability of this approach may be enhanced if it corresponds to UK women's screening preferences and values. OBJECTIVES: To elicit and quantify preferences for low-risk screening options. METHODS: Women aged 40 to 70 y with no history of breast cancer took part in an online discrete choice experiment. We generated 32 hypothetical low-risk screening programs defined by 5 attributes (start age, end age, screening interval, risk of dying from breast cancer, and risk of overdiagnosis), the levels of which were systematically varied between the programs. Respondents were presented with 8 choice sets and asked to choose between 2 screening alternatives or no screening. Preference data were analyzed using conditional logit regression models. The relative importance of attributes and the mean predicted probability of choosing each program were estimated. RESULTS: Participants (N = 502) preferred all screening programs over no screening. An older starting age of screening, younger end age of screening, longer intervals between screening, and increased risk of dying had a negative impact on support for screening programs (P < 0.01). Although the risk of overdiagnosis was of low relative importance, a decreased risk of this harm had a small positive impact on screening choices. The mean predicted probabilities that risk-adapted screening programs would be supported relative to current guidelines were low (range, 0.18 to 0.52). CONCLUSIONS: A deintensified screening pathway for women at low risk of breast cancer, especially one that recommends a later screening start age, would run counter to women's breast screening preferences. Further research is needed to enhance the acceptability of offering less screening to those at low risk of breast cancer. HIGHLIGHTS: Risk-based breast screening may involve the deintensification of screening for women at low risk of breast cancer.Low-risk screening pathways run counter to women's screening preferences and values.Longer screening intervals may be preferable to a later start age.Work is needed to enhance the acceptability of a low-risk screening pathway.

Association between emergency department attendances, sociodemographic factors and long-term health conditions in the population of Norfolk and Waveney, England: Cross sectional study.

INTRODUCTION: Demand for urgent and emergency health care in England has grown over the last decade, for reasons that are not clear. Changes in population demographics may be a cause. This study investigated associations between individuals' characteristics (including socioeconomic deprivation and long term health conditions (LTC)) and the frequency of emergency department (ED) attendances, in the Norfolk and Waveney subregion of the East of England. METHODS: The study population was people who were registered with 91 of 106 Norfolk and Waveney general practices during one year from 1 April 2022 to 31 March 2023. Linked primary and secondary care and geographical data included each individual's sociodemographic characteristics, and number of ED attendances during the same year and, for some individuals, LTCs and number of general practice (GP) appointments. Associations between these factors and ED attendances were estimated using Poisson regression models. RESULTS: 1,027,422 individuals were included of whom 57.4% had GP data on the presence or absence of LTC, and 43.1% had both LTC and general practitioner appointment data. In the total population ED attendances were more frequent in individuals aged under five years, (adjusted Incidence Rate Ratio (IRR) 1.25, 95% confidence interval 1.23 to 1.28) compared to 15-35 years); living in more socioeconomically deprived areas (IRR 0.61 (0.60 to 0.63)) for least deprived compared to most deprived,and living closer to the nearest ED. Among individuals with LTC data, each additional LTC was also associated with increased ED attendances (IRR 1.16 (1.15 to 1.16)). Among individuals with LTC and GP appointment data, each additional GP appointment was also associated with increased ED attendances (IRR 1.03 (1.026 to 1.027)). CONCLUSIONS: In the Norfolk and Waveney population, ED attendance rates were higher for young children and individuals living in more deprived areas and closer to EDs. In individuals with LTC and GP appointment data, both factors were also associated with higher ED attendance.

Heterogeneity in the Definitions of Proximal Junctional Kyphosis and Failure in Spinal Deformity Literature: A Tower of Babel.

STUDY DESIGN: Systematic review. OBJECTIVE: To describe the various definitions of PJK and PJF used in spinal deformity literature and their utility over time. SUMMARY OF BACKGROUND DATA: Proximal junctional kyphosis or failure (PJK/PJF) is among the most common complication after long-segment fusions, but there is no consensus on their definitions. This presents challenges in understanding risk factors, management, and prevention strategies. METHODS: A systematic literature review was performed on studies specifying a definition of PJK and/or PJF. PJK definitions were categorized as radiographic vs non-radiographic and data was collected on PJK criteria including threshold for proximal junctional angle (PJA), change in PJA, vertebra selection for PJA measurement, and follow-up timepoints. PJF definitions were categorized as structural failure, need for revision, symptomatic failure, and radiographic (angular). RESULTS: 359 studies defining PJK and/or PJF were identified. While 56% of studies used the definition PJA>10° and PJA change from baseline>10°, the remainder expressed significant heterogeneity with respect to criteria for magnitude of PJA and degree of PJA change. The most common vertebrae assessed were UIV/UIV+2 (74%) and most common minimum follow-up (mFU) listed was 2 years (60%). Mean FUs for studies varied considerably even in studies with the same mFU, from 2.1-8.9 years (2-year mFU) and 1.1-4.0 years (1-year mFU). PJF definitions were most commonly structural (58%) or defined as a need for revision (48%), with a much less common use of PJA thresholds (23%). CONCLUSIONS: The challenges faced in preventing proximal junctional complications are mired in the heterogenous groundwork by which PJK and PJF are defined. Most definitions of PJK use radiographic thresholds without consideration of clinical relevance and variations in individual alignment. Conversely, definitions of PJF are based on clinical criteria, which are often subjective. Future research should focus on understanding the mechanisms of PJK/PJF, as only then will we be able to accurately define and prevent these complications.

Phase contrast micro-CT with adjustable in-slice spatial resolution at constant magnification.

Objective.To report on a micro computed tomography (micro-CT) system capable of x-ray phase contrast imaging and of increasing spatial resolution at constant magnification.Approach.The micro-CT system implements the edge illumination (EI) method, which relies on two absorbing masks with periodically spaced transmitting apertures in the beam path; these split the beam into an array of beamlets and provide sensitivity to the beamlets' directionality, i.e. refraction. In EI, spatial resolution depends on the width of the beamlets rather than on the source/detector point spread function (PSF), meaning that resolution can be increased by decreasing the mask apertures, without changing the source/detector PSF or the magnification.Main results.We have designed a dedicated mask featuring multiple bands with differently sized apertures and used this to demonstrate that resolution is a tuneable parameter in our system, by showing that increasingly small apertures deliver increasingly detailed images. Phase contrast images of a bar pattern-based resolution phantom and a biological sample (a mouse embryo) were obtained at multiple resolutions.Significance.The new micro-CT system could find application in areas where phase contrast is already known to provide superior image quality, while the added tuneable resolution functionality could enable more sophisticated analyses in these applications, e.g. by scanning samples at multiple scales.

Diversity of Microbial Mats in the Makgadikgadi Salt Pans, Botswana.

The Makgadikgadi Salt Pans are the remnants of a mega paleo-lake system in the central Kalahari, Botswana. Today, the Makgadikgadi Basin is an arid to semi-arid area receiving water of meteoric origin during the short, wet season. Large microbial mats, which support primary production, are formed due to desiccation during the dry season. This study aimed to characterise the microbial diversity of the microbial mats and the underlying sediment. The focus was the Ntwetwe Pan, located west of the Makgadikgadi Basin. Metagenomic analyses demonstrated that the mats consisted of a high relative abundance of Cyanobacteriota (synonym Cyanobacteria) (20.50-41.47%), Pseudomonadota (synonym Proteobacteria) (15.71 to 32.18%), and Actinomycetota (synonym Actinobacteria) (8.53-32.56%). In the underlying sediments, Pseudomonadota, Actinomycetota, and Euryarchaeota represented over 70% of the community. Localised fluctuations in water content and pH did not significantly affect the microbial diversity of the sediment or the mats.

Protein engineering enables a soakable crystal form of human CDK7 primed for high-throughput crystallography and structure-based drug design.

Cyclin dependent kinase 7 (CDK7) is an important therapeutic kinase best known for its dual role in cell cycle regulation and gene transcription. Here, we describe the application of protein engineering to generate constructs leading to high resolution crystal structures of human CDK7 in both active and inactive conformations. The active state of the kinase was crystallized by incorporation of an additional surface residue mutation (W132R) onto the double phosphomimetic mutant background (S164D and T170E) that yielded the inactive kinase structure. A novel back-soaking approach was developed to determine crystal structures of several clinical and pre-clinical inhibitors of this kinase, demonstrating the potential utility of the crystal system for structure-based drug design (SBDD). The crystal structures help to rationalize the mode of inhibition and the ligand selectivity profiles versus key anti-targets. The protein engineering approach described here illustrates a generally applicable strategy for structural enablement of challenging molecular targets.

Enabling synthesis in fragment-based drug discovery (FBDD): microscale high-throughput optimisation of the medicinal chemist's toolbox reactions.

Miniaturised high-throughput experimentation (HTE) is widely employed in industrial and academic laboratories for rapid reaction optimisation using material-limited, multifactorial reaction condition screening. In fragment-based drug discovery (FBDD), common toolbox reactions such as the Suzuki-Miyaura and Buchwald-Hartwig cross couplings can be hampered by the fragment's intrinsic heteroatom-rich pharmacophore which is required for ligand-protein binding. At Astex, we are using microscale HTE to speed up reaction optimisation and prevent target down-prioritisation. By identifying catalyst/base/solvent combinations which tolerate unprotected heteroatoms we can rapidly optimise key cross-couplings and expedite route design by avoiding superfluous protecting group manipulations. However, HTE requires extensive upfront training, and this modern automated synthesis technique largely differs to the way organic chemists are traditionally trained. To make HTE accessible to all our synthetic chemists we have developed a semi-automated workflow enabled by pre-made 96-well screening kits, rapid analytical methods and in-house software development, which is empowering chemists at Astex to run HTE screens independently with minimal training.

The People vs the NHS: Biosexual citizenship and hope in stories of PrEP activism.

Discourses of pre-exposure prophylaxis (PrEP) revel in its radical potential as a global HIV prevention technology, offering a promise of change for the broader landscape of HIV prevention. In 2018, the British Broadcasting Corporation (BBC) aired The People vs The NHS: Who Gets the Drugs?, a documentary focused on the 'battle' to make PrEP available in England. In this article we explore how the BBC documentary positions PrEP, PrEP biosexual citizen-activists, as well as the wider role of the NHS in HIV prevention and the wellbeing of communities affected by HIV in the UK. We consider how biosexual citizenship (Epstein 2018) is configured through future imaginaries of hope, and the spectral histories of AIDS activism. We describe how The People crafts a story of PrEP activism in the context of an imagined gay community whose past, present, and hopeful future is entangled within the complexities and contractions of a state-funded health system. Here, PrEP functions as a 'happiness pointer' (Ahmed 2011), to orient imagined gay communities towards a hopeful future by demanding and accessing essential medicines and ensuring the absence of needless HIV transmissions. This biomedical success emerges from a shared traumatic past and firmly establishes the salvatory trajectory of PrEP and an imagined gay community who have continued to be affected by HIV. However, campaigns about the individual's right to access PrEP construct the availability and consumption of PrEP as an end goal to their activism, where access to PrEP is understood as an individual's right as a pharmaceutical consumer.