Ethical and Policy Issues Raised by Uterus Transplants

Introduction: In 2014, Brännström and colleagues reported the first human live birth following uterine transplantation (UTx). Research into this treatment for absolute uterine factor infertility has since grown with clinical trials currently taking place across centers in at least thirteen countries worldwide. Sources of data: This review summarizes and critiques the academic literature on ethical and policy issues raised by UTx. Areas of agreement: There is general agreement on the importance of risk reduction and, in principle, to the sharing and maintenance of patient data on an international registry. Areas of controversy: There are numerous areas of controversy ranging from whether it is ethically justified to carry out uterus transplants at all (considering the associated health risks) to how deceased donor organs for transplant should be allocated. This review focuses on three key issues: the choice between deceased and living donors, ensuring valid consent to the procedure and access to treatment. Growing points; UTx is presently a novel and rare procedure but is likely to become more commonplace in the foreseeable future, given the large number of surgical teams working on it worldwide. Areas timely for developing research: Uterus transplantation requires us to re-examine fundamental questions about the ethical and social value of gestation. If eventually extended to transgender women or even to men, it may also require us to reconceptualize what it is to be a ‘father’ or to be a ‘mother’, and the definition of these terms in law

Labour efficiency on-farm

End of project reportImprovements in milking efficiency have a greater influence than any other aspect of the dairy farmers work on overall farm labour inputs (Whipp, 1992). In order to facilitate the examination of milking process labour inputs, the milking process may be divided into the following three components: herding pre and post milking (transfer of cows to and from the milking parlour); milking (milking tasks / work routines within the parlour); and washing (washing of milking machine and yard). Meanwhile, within milking specifically, the number of cows milked per operator per hour is the best measure of both the performance of the operator and the milking installation (Clough, 1978). This is affected by the following three factors: the milking times of the cows, the number and arrangement of the milking units, and the operator’s work routine (Whipp, 1992). The addition of extra milking units will only increase milking performance if the operator has idle time during milking (Hansen, 1999)

Welfare and health of dairy cattle on out-wintering pads or in cubicle housing with or without cushioned flooring.

End of Project ReportThe first study described in this report involved housing 66 spring calving heifers in one of three systems during the winter, namely, (i) a conventional cubicle house, (ii) a cubicle house with cushioned flooring covering the slats (slat mats) in the passageway and (iii) on a wood-chip out-wintering pad. Behaviour, health and performance indicators were measured on all animals while pregnant from housing in November 2003 until calving in January 2004. Additionally, data were collected on the first 15 animals to calve in each treatment for the first four weeks of lactation in the spring. The slat mats resulted in some improvements to hoof health compared to the conventional cubicle house. Furthermore, it increased feeding times although this had no effect on feed intake or performance. The results also indicated that heifers have a preference for standing on cushioned flooring rather than on concrete during late pregnancy. Both groups indoors differed greatly from the outdoor heifers in several respects. The outdoor animals had healthier feet and were less affected by injuries to the limbs. They also had a more diverse behaviour repertoire and slipped and tripped less. However, their welfare was adversely affected by inclement weather conditions with indications of immunosuppression combined with a reduction in average daily gain being recorded. Furthermore, they were dirtier and spent less time lying down. None of these factors influenced milk yield, quality or composition in early lactation. Welfare problems associated with the pad were weather and management dependent and hence could be addressed by more frequent cleaning of the pad and/or an increase in space allowance combined with the provision of shelter. Hence, the potential for good welfare in dairy heifers was higher on the pad than indoors in a cubicle system even when slat mats were provided. In the second study, 62 autumn calving pluriparous dairy cows were housed in September 2004 in a cubicle system with either solid concrete floors or solid concrete floors covered by a rubber mat and cleaned by an automatic scrapper. Behaviour, locomotion and foot lesion scores were recorded from at least 3 weeks prior to calving until at least 16 weeks post-partum. Furthermore, in-depth measures of oestrous behaviour and reproductive performance were recorded. The cushioned flooring had no effect on sole or white line lesion scores or on dermatitis scores. However, it reduced the rate of wear of the heels in early lactation. Cows on cushioned flooring spent more time standing, but not feeding, at the feed face while cows on concrete stood in the cubicles instead. It appears that where cows have access to spacious, well-designed cubicles they can use them for standing to get relief for their feet from the concrete. Similar to the previous study this also indicates that cows prefer to stand on cushioned flooring than on bare concrete and emphasises the importance of at least providing cows with mats or mattresses in their cubicles. There were no effects of the cushioned flooring on oestrous behaviour or reproductive performance, which was poor in both treatments. It is suggested that the reasons for this were that the cushioned flooring did not provide sufficient traction for the cows and so they were as reluctant as the cows on concrete to perform mounting behaviour.European Union Structural Fun

Non-exercise equations to estimate fitness in white European and South Asian men

Cardiorespiratory fitness is a strong, independent predictor of health, whether it is measured in an exercise test or estimated in an equation. The purpose of this study was to develop and validate equations to estimate fitness in middle-aged white European and South Asian men.Multiple linear regression models (n=168, including 83 white European and 85 South Asian men) were created using variables that are thought to be important in predicting fitness (VO2 max, mL⋅kg⋅min): age (years); BMI (kg·m); resting heart rate (beats⋅min); smoking status (0=never smoked, 1=ex or current smoker); physical activity expressed as quintiles (0=quintile 1, 1=quintile 2, 2=quintile 3, 3=quintile 4, 4=quintile 5), categories of moderate- to vigorous-intensity physical activity (0=<75 min⋅wk, 1=75-150 min⋅wk, 2=>150-225 min⋅wk, 3=>225-300 min⋅wk, 4=>300 min⋅wk), or minutes of moderate- to vigorous-intensity physical activity (min⋅wk); and, ethnicity (0=South Asian, 1=white). The leave-one-out-cross-validation procedure was used to assess the generalizability and the bootstrap and jackknife resampling techniques were used to estimate the variance and bias of the models.Around 70% of the variance in fitness was explained in models with an ethnicity variable, such as: VO2 max = 77.409 - (age*0.374) - (BMI*0.906) - (ex or current smoker*1.976) + (physical activity quintile coefficient) - (resting heart rate*0.066) + (white ethnicity*8.032), where physical activity quintile 1 is 1, 2 is 1.127, 3 is 1.869, 4 is 3.793, and 5 is 3.029. Only around 50% of the variance was explained in models without an ethnicity variable. All models with an ethnicity variable were generalizable and had low variance and bias.These data demonstrate the importance of incorporating ethnicity in non-exercise equations to estimate cardiorespiratory fitness in multi-ethnic populations

Presumed Dissent?:Opt-out organ donation and the routine exclusion of organs and tissues

It is often claimed that a legitimate approach to organ donation is an opt-out system, also known as ‘presumed consent’, ‘deemed consent’, or ‘deemed authorisation’, whereby individuals are presumed or deemed willing to donate at least some of their organs and tissues after death unless they have explicitly refused permission. While sharing a default in favour of donation, such systems differ in several key respects, such as the role and importance assigned to the family members of prospective donors and their preferences, and exclusions and safeguards which often specify the demographic groups, purposes, or organs and tissues which will remain outside the scope of the opt-out system. Using the recent shift to opt-out in England, Scotland, and Northern Ireland as a case study, and by reference to the key goals motivating this shift across the UK, this paper asks whether and, if so, why, and how, opt-out systems for post-mortem organ donation should restrict the types of organs and tissues for which consent is deemed. In other words, ought opt-out systems for post-mortem organ donation presume dissent regarding the donation of certain organs and tissues

In vitro development of chemotherapy and targeted therapy drug-resistant cancer cell lines: a practical guide with case studies

The development of a drug-resistant cell line can take from 3 to 18 months. However, little is published on the methodology of this development process. This article will discuss key decisions to be made prior to starting resistant cell line development; the choice of parent cell line, dose of selecting agent, treatment interval, and optimizing the dose of drug for the parent cell line. Clinically relevant drug-resistant cell lines are developed by mimicking the conditions cancer patients experience during chemotherapy and cell lines display between two- and eight-fold resistance compared to their parental cell line. Doses of drug administered are low, and a pulsed treatment strategy is often used where the cells recover in drug-free media. High-level laboratory models are developed with the aim of understanding potential mechanisms of resistance to chemotherapy agents. Doses of drug are higher and escalated over time. It is common to have difficulty developing stable clinically relevant drug-resistant cell lines. A comparative selection strategy of multiple cell lines or multiple chemotherapeutic agents mitigates this risk and gives insight into which agents or type of cell line develops resistance easily. Successful selection strategies from our research are presented. Pulsed-selection produced platinum or taxane-resistant large cell lung cancer (H1299 and H460) and temozolomide-resistant melanoma (Malme-3M and HT144) cell lines. Continuous selection produced a lapatinib-resistant breast cancer cell line (HCC1954). Techniques for maintaining drug-resistant cell lines are outlined including; maintaining cells with chemotherapy, pulse treating with chemotherapy, or returning to master drug-resistant stocks. The heterogeneity of drug-resistant models produced from the same parent cell line with the same chemotherapy agent is explored with reference to P-glycoprotein. Heterogeneity in drug-resistant cell lines reflects the heterogeneity that can occur in clinical drug resistance

Learning from Consortia: Programme story and reflections

The Learning from Consortia programme was set-up to improve international development practice by learning with and supporting 13 UK Aid Connect (UKAC) consortia. The programme aimed to learn from their experiences and insights to draw out good practice in consortium working, as well as helping organisations and donors understand how they can best support consortia. Led by Bond, The Partnering Initiative (TPI) and an academic advisory board, the programme was fully funded by the UK’s Foreign, Commonwealth and Development Office (FCDO). Research was conducted through a participatory process with UKAC consortia, drawing on their experiences from working in diverse partnerships and implementing programmes in the UK, Africa and Asia. There was a focus on five themes – community engagement, consortium working, gender, innovation and value for money – each addressing a set of “learning questions”. The themes had both academic and thematic advisers who worked with the consortia, helping to guide their research and conduct in-depth analysis. The learning and evidence from the programme have been collated into a number of resources and knowledge products, along with a public event held in March 2021. These resources can be accessed through the Learning from Consortia programme’s webpage. (https://www.bond.org.uk/resources-support/learning-from-consortia) In late April 2021, FCDO took the decision to close the Learning from Consortia programme early, as part of the wide-ranging UK Aid cuts. Read Bond’s statement about this decision here. (https://www.bond.org.uk/press-releases/2021/05/government-cuts-50-of-its-funding-to-bond-the-uk-network-for-organisations

Genome-wide analysis of self-reported risk-taking behaviour and cross-disorder genetic correlations in the UK Biobank cohort

Risk-taking behaviour is a key component of several psychiatric disorders and could influence lifestyle choices such as smoking, alcohol use, and diet. As a phenotype, risk-taking behaviour therefore fits within a Research Domain Criteria (RDoC) approach, whereby identifying genetic determinants of this trait has the potential to improve our understanding across different psychiatric disorders. Here we report a genome-wide association study in 116,255 UK Biobank participants who responded yes/no to the question “Would you consider yourself a risk taker?” Risk takers (compared with controls) were more likely to be men, smokers, and have a history of psychiatric disorder. Genetic loci associated with risk-taking behaviour were identified on chromosomes 3 (rs13084531) and 6 (rs9379971). The effects of both lead SNPs were comparable between men and women. The chromosome 3 locus highlights CADM2, previously implicated in cognitive and executive functions, but the chromosome 6 locus is challenging to interpret due to the complexity of the HLA region. Risk-taking behaviour shared significant genetic risk with schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, and post-traumatic stress disorder, as well as with smoking and total obesity. Despite being based on only a single question, this study furthers our understanding of the biology of risk-taking behaviour, a trait that has a major impact on a range of common physical and mental health disorders

Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with MDD, anxiety disorder and schizophrenia

Mood instability is a core clinical feature of affective and psychotic disorders. In keeping with the Research Domain Criteria approach, it may be a useful construct for identifying biology that cuts across psychiatric categories. We aimed to investigate the biological validity of a simple measure of mood instability and evaluate its genetic relationship with several psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, attention deficit hyperactivity disorder (ADHD), anxiety disorder and post-traumatic stress disorder (PTSD). We conducted a genome-wide association study (GWAS) of mood instability in 53,525 cases and 60,443 controls from UK Biobank, identifying four independently associated loci (on chromosomes 8, 9, 14 and 18), and a common single-nucleotide polymorphism (SNP)-based heritability estimate of ~8%. We found a strong genetic correlation between mood instability and MDD (r g = 0.60, SE = 0.07, p = 8.95 × 10−17) and a small but significant genetic correlation with both schizophrenia (r g = 0.11, SE = 0.04, p = 0.01) and anxiety disorders (r g = 0.28, SE = 0.14, p = 0.04), although no genetic correlation with BD, ADHD or PTSD was observed. Several genes at the associated loci may have a role in mood instability, including the DCC netrin 1 receptor (DCC) gene, eukaryotic translation initiation factor 2B subunit beta (eIF2B2), placental growth factor (PGF) and protein tyrosine phosphatase, receptor type D (PTPRD). Strengths of this study include the very large sample size, but our measure of mood instability may be limited by the use of a single question. Overall, this work suggests a polygenic basis for mood instability. This simple measure can be obtained in very large samples; our findings suggest that doing so may offer the opportunity to illuminate the fundamental biology of mood regulation