Orthopaedic surgery

Over the past fifty years orthopaedic surgery made giant strides forward. It developed from a discipline that dealt primarily with the treatment of fractures, bone infections and tendon transfers and that treated degenerate joints by fusing them to one of such sophistication as to be able to treat fractures by internal fixation and early mobilisation. It is now possible to replace most joints in the body and to benefit from the results of stem cell research that hold promise of yet further exciting developments, the more important but by no means exclusive advances in orthopaedic surgery are presented.peer-reviewe

Proximal femoral focal deficiency : a case report

Proximal Femoral Focal Deficiency (PFFD) is a rare and complex congenital anomaly (1:50,000-200,000 population) that results in varying degrees of femoral hypoplasia with limb shortening and pelvic abnormalities. It may be present bilaterally in association with other malformations/deficiencies of the lower limbs, and the upper limbs may also be involved. Other anomalies may also be present such as cleft palate, congenital heart defects, and spinal anomalies. The aetiology is unknown. We present a case of PFFD who was born locally.peer-reviewe

Graves-PCD: protocol for a randomised, dose-finding, adaptive trial of the plasma cell-depleting agent daratumumab in severe Graves\u27 disease

\ua9 Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ. INTRODUCTION: Severe Graves\u27 disease is a life-changing condition with poor outcomes from currently available treatments. It is caused by directly pathogenic thyroid-stimulating hormone receptor-stimulating antibodies (TRAb), which are secreted from plasma cells. The human anti-CD38 monoclonal antibody daratumumab was developed to target plasma cells which express high levels of CD38, and is currently licensed for treatment of the plasma cell malignancy, myeloma. However, it can also deplete benign plasma cells with the potential to reduce TRAb and alter the natural history of severe Graves\u27 disease. This study aims to establish proof of concept that daratumumab has efficacy in patients with severe Graves\u27 disease and will provide important data to inform a choice of dosing regimen for subsequent trials. METHODS AND ANALYSIS: The Graves-PCD trial aims to determine if daratumumab modulates the humoral immune response in patients with severe Graves\u27 disease, and if so, over what time period, and to find an optimal dose. It is a single-blinded, randomised, dose-finding, adaptive trial using four different doses of daratumumab or placebo in 30 adult patients. Part 1 of the trial is dose-finding and, following an interim analysis, in part 2, the remaining patients will be randomised between the chosen dose(s) from the interim analysis or placebo. The primary outcome is the percentage change in serum TRAb from baseline to 12 weeks. ETHICS AND DISSEMINATION: The trial received a favourable ethical opinion from London-Hampstead Research Ethics Committee (reference 21/LO/0449). The results of this trial will be disseminated at international meetings, in the peer-reviewed literature and through partner patient group newsletters and presentations at patient education events. TRIAL REGISTRATION NUMBER: ISRCTN81162400

Diversity and abundance of solitary and primitively eusocial bees in an urban centre: a case study from Northampton (England)

The apparent reduction of solitary and primitively eusocial bees populations has remained a huge concern over the past few decades and urbanisation is considered as one of the factors affecting bees at different scales depending on bee guild. As urbanisation is increasing globally it necessitates more research to understand the complex community dynamics of solitary and primitively eusocial bees in urban settings. We investigated the urban core of a British town for diversity and abundance of solitary bees using standardized methods, and compared the results with nearby meadows and nature reserves. The study recorded 48 species within the town, about 22 % of the total species and 58 % of the genera of solitary bees in the United Kingdom. Furthermore we found the urban core to be more diverse and abundant in solitary and primitively eusocial bees compared to the meadows and nature re-serves. Of particular note was an urban record of the nationally rare Red Data Book species Coelioxys quadridentata and its host Anthophora quadrimaculata. This research demonstrates that urban settings can contribute significantly to the conservation of solitary and primitively eusocial bees in Britain

Quantitative Historical Change in Bumblebee (Bombus spp.) Assemblages of Red Clover Fields

Flower visiting insects provide a vitally important pollination service for many crops and wild plants. Recent decline of pollinating insects due to anthropogenic modification of habitats and climate, in particular from 1950's onwards, is a major and widespread concern. However, few studies document the extent of declines in species diversity, and no studies have previously quantified local abundance declines. We here make a quantitative assessment of recent historical changes in bumblebee assemblages by comparing contemporary and historical survey data. species observed in the 1930's, five species were not observed at present. The latter were all long-tongued, late-emerging species.Because bumblebees are important pollinators, historical changes in local bumblebee assemblages are expected to severely affect plant reproduction, in particular long-tubed species, which are pollinated by long-tongued bumblebees

Exploring contemporary patterns of cultural consumption : offline and online film watching in the UK

This paper focuses on patterns of film consumption within cultural consumption more broadly to assess trends in consumerism such as eclectic consumption, individualised consumption and omnivorous/univorous consumption and whether economic background and status feature in shaping cultural consumption. We focus on film because it is widely consumed, online and offline, and has many genres that vary in terms of perceived artistic and entertainment value. In broad terms, film is differentiated between mainstream commercially driven film such as Hollywood blockbusters, middlebrow ‘feel good’ movies and independent arthouse and foreign language film. Our empirical statistical analysis shows that film consumers watch a wide range of genres. However, films deemed to hold artistic value such as arthouse and foreign language feature as part of broad and wide-ranging pattern of consumption of film that attracts its own dedicated consumers. Though we found that social and economic factors remain predictors of cultural consumption the overall picture is more complex than a simple direct correspondence and perceptions of other cultural forms also play a role. Those likely to consume arthouse and foreign language film consume other film genres and other cultural forms genres and those who ‘prefer’ arthouse and foreign language film have slightly more constrained socio-economic characteristics. Overall, we find that economic and cultural factors such income, education, and wider consumption of culture are significant in patterns of film consumption

Prediction of risk and incidence of dry eye in critical patients

Objectives: to estimate the incidence of dry eye, to identify risk factors and to establish a risk prediction model for its development in adult patients admitted to the intensive care unit of a public hospital. Method: concurrent cohort, conducted between March and June, 2014, with 230 patients admitted to an intensive care unit. Data were analyzed by bivariate descriptive statistics, with multivariate survival analysis and Cox regression. Results: 53% out of 230 patients have developed dry eye, with onset mean time of 3.5 days. Independent variables that significantly and concurrently impacted the time for dry eye to occur were: O2 in room air, blinking more than five times per minute (lower risk factors) and presence of vascular disease (higher risk factor). Conclusion: dry eye is a common finding in patients admitted to adults intensive care units, and care for its prevention should be established

A nationwide study of adults admitted to hospital with diabetic ketoacidosis or hyperosmolar hyperglycaemic state and COVID‐19

AimsTo investigate characteristics of people hospitalized with coronavirus-disease-2019 (COVID-19) and diabetic ketoacidosis (DKA) or hyperosmolar hyperglycaemic state (HHS), and to identify risk factors for mortality and intensive care admission.Materials and methodsRetrospective cohort study with anonymized data from the Association of British Clinical Diabetologists nationwide audit of hospital admissions with COVID-19 and diabetes, from start of pandemic to November 2021. The primary outcome was inpatient mortality. DKA and HHS were adjudicated against national criteria. Age-adjusted odds ratios were calculated using logistic regression.ResultsIn total, 85 confirmed DKA cases, and 20 HHS, occurred among 4073 people (211 type 1 diabetes, 3748 type 2 diabetes, 114 unknown type) hospitalized with COVID-19. Mean (SD) age was 60 (18.2) years in DKA and 74 (11.8) years in HHS (p < .001). A higher proportion of patients with HHS than with DKA were of non-White ethnicity (71.4% vs 39.0% p = .038). Mortality in DKA was 36.8% (n = 57) and 3.8% (n = 26) in type 2 and type 1 diabetes respectively. Among people with type 2 diabetes and DKA, mortality was lower in insulin users compared with non-users [21.4% vs. 52.2%; age-adjusted odds ratio 0.13 (95% CI 0.03-0.60)]. Crude mortality was lower in DKA than HHS (25.9% vs. 65.0%, p = .001) and in statin users versus non-users (36.4% vs. 100%; p = .035) but these were not statistically significant after age adjustment.ConclusionsHospitalization with COVID-19 and adjudicated DKA is four times more common than HHS but both associate with substantial mortality. There is a strong association of previous insulin therapy with survival in type 2 diabetes-associated DKA

An Analysis of Mechanisms for Cellular Uptake of miRNAs to Enhance Drug Delivery and Efficacy in Cancer Chemoresistance

Up until recently, it was believed that pharmaceutical drugs and their metabolites enter into the cell to gain access to their targets via simple diffusion across the hydrophobic lipid cellular membrane, at a rate which is based on their lipophilicity. An increasing amount of evidence indicates that the phospholipid bilayer-mediated drug diffusion is in fact negligible, and that drugs pass through cell membranes via proteinaceous membrane transporters or carriers which are normally used for the transportation of nutrients and intermediate metabolites. Drugs can be targeted to specific cells and tissues which express the relevant transporters, leading to the design of safe and efficacious treatments. Furthermore, transporter expression levels can be manipulated, systematically and in a high-throughput manner, allowing for considerable progress in determining which transporters are used by specific drugs. The ever-expanding field of miRNA therapeutics is not without its challenges, with the most notable one being the safe and effective delivery of the miRNA mimic/antagonist safely to the target cell cytoplasm for attaining the desired clinical outcome, particularly in miRNA-based cancer therapeutics, due to the poor efficiency of neo-vascular systems revolting around the tumour site, brought about by tumour-induced angiogenesis. This acquisition of resistance to several types of anticancer drugs can be as a result of an upregulation of efflux transporters expression, which eject drugs from cells, hence lowering drug efficacy, resulting in multidrug resistance. In this article, the latest available data on human microRNAs has been reviewed, together with the most recently described mechanisms for miRNA uptake in cells, for future therapeutic enhancements against cancer chemoresistance

Evidence for the Role of the Mitochondrial ABC Transporter MDL1 in the Uptake of Clozapine and Related Molecules into the Yeast Saccharomyces cerevisiae

Clozapine is an antipsychotic drug whose accumulation in white cells can sometimes prove toxic; understanding the transporters and alleles responsible is thus highly desirable. We used a strategy in which a yeast (Saccharomyces cerevisiae) CRISPR-Cas9 knock-out library was exposed to cytotoxic concentrations of clozapine to determine those transporters whose absence made it more resistant; we also recognised the structural similarity of the fluorescent dye safranin O (also known as safranin T) to clozapine, allowing it to be used as a surrogate marker. Strains lacking the mitochondrial ABC transporter MDL1 (encoded by YLR188W) showed substantial resistance to clozapine. MDL1 overexpression also conferred extra sensitivity to clozapine and admitted a massive increase in the cellular and mitochondrial uptake of safranin O, as determined using flow cytometry and microscopically. Yeast lacking mitochondria showed no such unusual accumulation. Mitochondrial MDL1 is thus the main means of accumulation of clozapine in S. cerevisiae. The closest human homologue of S. cerevisiae MDL1 is ABCB10.</jats:p