Acute effects of a ketone monoester, whey protein, or their coingestion on mTOR trafficking and protein-protein colocalization in human skeletal muscle.

We recently demonstrated that acute oral ketone monoester intake induces a stimulation of postprandial myofibrillar protein synthesis rates comparable to that elicited following the ingestion of 10 g whey protein or their coingestion. The present investigation aimed to determine the acute effects of ingesting a ketone monoester, whey protein, or their coingestion on mechanistic target of rapamycin (mTOR)-related protein-protein colocalization and intracellular trafficking in human skeletal muscle. In a randomized, double-blind, parallel group design, 36 healthy recreationally active young males (age: 24.2 ± 4.1 yr) ingested either: 1) 0.36 g·kg-1 bodyweight of the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KET), 2) 10 g whey protein (PRO), or 3) the combination of both (KET + PRO). Muscle biopsies were obtained in the overnight postabsorptive state (basal conditions), and at 120 and 300 min in the postprandial period for immunofluorescence assessment of protein translocation and colocalization of mTOR-related signaling molecules. All treatments resulted in a significant (Interaction: P < 0.0001) decrease in tuberous sclerosis complex 2 (TSC2)-Ras homolog enriched in brain (Rheb) colocalization at 120 min versus basal; however, the decrease was sustained at 300 min versus basal (P < 0.0001) only in KET + PRO. PRO and KET + PRO increased (Interaction: P < 0.0001) mTOR-Rheb colocalization at 120 min versus basal; however, KET + PRO resulted in a sustained increase in mTOR-Rheb colocalization at 300 min that was greater than KET and PRO. Treatment intake increased mTOR-wheat germ agglutinin (WGA) colocalization at 120 and 300 min (Time: P = 0.0031), suggesting translocation toward the fiber periphery. These findings demonstrate that ketone monoester intake can influence the spatial mechanisms involved in the regulation of mTORC1 in human skeletal muscle.NEW & NOTEWORTHY We explored the effects of a ketone monoester (KET), whey protein (PRO), or their coingestion (KET + PRO) on mTOR-related protein-protein colocalization and intracellular trafficking in human muscle. All treatments decreased TSC2-Rheb colocalization at 120 minutes; however, KET + PRO sustained the decrease at 300 min. Only PRO and KET + PRO increased mTOR-Rheb colocalization; however, the increase at 300 min was greater in KET + PRO. Treatment intake increased mTOR-WGA colocalization, suggesting translocation to the fiber periphery. Ketone bodies influence the spatial regulation of mTOR.

Comparing the psychological outcomes of donor and non-donor conceived people: A systematic review.

BACKGROUND: Over 70 000 donor-conceived (DC) people have been born in the UK since 1991. Little is known about their long-term psychological outcomes and no systematic review has assessed these. OBJECTIVES: To conduct a systematic review of the psychological experiences of DC people through childhood and adulthood (Prospero: CRD42021257863). SEARCH STRATEGY: Searches of Cumulative Index to Nursing and Allied Health Literature (CINHAL), the Excerpta Medica database (Embase), MEDLINE® and PsycINFO, conducted on 4 January 2024. SELECTION CRITERIA: Quantitative and qualitative studies were included if: there were five or more participants; they were peer reviewed; and any DC psychological outcomes were assessed. No limits on date, language or country were applied. DATA COLLECTION AND ANALYSIS: Double screening, selection, data extraction and quality assessment were performed, using Joanna Briggs Institute (JBI) scoring. MAIN RESULTS: Fifty studies (with 4666 DC participants), mostly from high-income anglophone countries, with heterogeneity of design, populations and outcome measures, were included. Of 19 comparative studies, 14 found no difference in outcomes between DC and non-DC people, ten found better outcomes (in health, well-being, self-esteem and emotional warmth) and six found worse outcomes (increased autism spectrum disorder and attention deficit hyperactivity disorder, addiction issues, mental illness, disruptive behaviour and identity problems). Qualitative data revealed common themes relating to identity formation, mistrust and concerns regarding genetic heritage. The evidence regarding adulthood outcomes was very limited. CONCLUSIONS: The research on DC individuals presents a nuanced picture, with most studies suggesting comparable or improved outcomes in terms of well-being and relationships, but with a notable minority indicating higher rates of mental health and identity struggles. Qualitative findings underscore common negative experiences, whereas the early disclosure of DC status appears beneficial for psychological well-being.

Leucine ingestion promotes mTOR translocation to the periphery and enhances total and peripheral RPS6 phosphorylation in human skeletal muscle.

The activation of the mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of protein synthesis, by anabolic stimuli (such as muscle contraction or essential amino acids) involves its translocation to the cell periphery. Leucine is generally considered the most anabolic of amino acids for its ability to independently modulate muscle protein synthesis. However, it is currently unknown if free leucine impacts region-specific mTORC1-mediated phosphorylation events and protein-protein interactions. In this clinical trial (NCT03952884; registered May 16, 2019), we used immunofluorescence methods to investigate the role of dietary leucine on the postprandial regulation of mTORC1 and ribosomal protein S6 (RPS6), an important downstream readout of mTORC1 activity. Eight young, healthy, recreationally active males (n = 8; 23 ± 3 yrs) ingested 2 g of leucine with vastus lateralis biopsies collected at baseline, 30, 60, and 180 min postprandial. Leucine promoted mTOR translocation to the periphery (~ 18-29%; p ≤ 0.012) and enhanced mTOR localization with the lysosome (~ 16%; both p = 0.049) at 30 and 60 min post-feeding. p-RPS6Ser240/244 staining intensity, a readout of mTORC1 activity, was significantly elevated at all postprandial timepoints in both the total fiber (~ 14-30%; p ≤ 0.032) and peripheral regions (~ 16-33%; p ≤ 0.014). Additionally, total and peripheral p-RPS6Ser240/244 staining intensity at 60 min was positively correlated (r = 0.74, p = 0.036; r = 0.80, p = 0.016, respectively) with rates of myofibrillar protein synthesis over 180 min. The ability of leucine to activate mTORC1 in peripheral regions favors an enhanced rate of MPS, as this is the intracellular space thought to be replete with the cellular machinery that facilitates this anabolic process.

Commitment devices: beyond the medical ethics of nudges.

Commitment devices (CDs) can help people overcome self-control problems to act on their plans and preferences. In these arrangements, people willingly make one of their options worse in order to change their own future behaviour, often by setting aside a sum of money that they will forfeit it if they fail to complete the planned action. Such applications of behavioural science have been used to help people stick to healthier lifestyle choices, overcome addictions and adhere to medication; they are acceptable to many patients and even relatively small sums can be effective. Some authors have objected to the use of nudges in healthcare. Engelen has listed nine potential objections to nudges in relation to means (why nudge rather than persuade?), ends (what action is being promoted?) and agents (who is nudging whom?). These objections are shown to lack force in the context of CDs. Instead, an analysis specific to the ethical issues in CDs is employed. CDs exclude certain groups including so-called 'naifs' and risk increasing health inequality. CDs may promote the wrong behaviour and people might legitimately change their minds. Intermediaries might encounter perverse incentives. Approaches to overcoming these problems are described and eight key ethical considerations for those considering implementing CDs in the future are described. Altogether this paper illustrates the advantages of appraising the ethics of behavioural science in medicine on a case-by-case basis.

How should institutions help clinicians to practise greener anaesthesia: first-order and second-order responsibilities to practice sustainably.

There is a need for all industries, including healthcare, to reduce their greenhouse gas emissions. In anaesthetic practice, this not only requires a reduction in resource use and waste, but also a shift away from inhaled anaesthetic gases and towards alternatives with a lower carbon footprint. As inhalational anaesthesia produces greenhouse gas emissions at the point of use, achieving sustainable anaesthetic practice involves individual practitioner behaviour change. However, changing the practice of healthcare professionals raises potential ethical issues. The purpose of this paper is twofold. First, we discuss what moral duties anaesthetic practitioners have when it comes to practices that impact the environment. We argue that behaviour change among practitioners to align with certain moral responsibilities must be supplemented with an account of institutional duties to support this. In other words, we argue that institutions and those in power have second-order responsibilities to ensure that practitioners can fulfil their first-order responsibilities to practice more sustainably. The second goal of the paper is to consider not just the nature of second-order responsibilities but the content. We assess four different ways that second-order responsibilities might be fulfilled within healthcare systems: removing certain anaesthetic agents, seeking consensus, education and methods from behavioural economics. We argue that, while each of these are a necessary part of the picture, some interventions like nudges have considerable advantages.

Technology Matters: Digital micro interventions to support parenting: Evaluating time out apps.

Digital interventions to support parenting skills are popular but engagement can be low. Digital micro interventions such as apps targeting specific aspects of parenting are a novel development with the potential to overcome this challenge. Time out is an evidence-based component of many parenting skills training programmes and is an appropriate target for digital micro intervention. We describe the eight requirements of high-quality time out according to the literature and how these can be supported by an app. Searches of the App Store, Google Play, and Alexa Skills in the UK identified six apps designed to support time out. Current time out apps all promoted consistency, but they all risked low-quality time out through inappropriate initiation, duration, and termination. Professionals in child and adolescent mental health should explore the details of any digital micro interventions being used by parents for time out and provide appropriate counselling. We recommend that all future digital micro interventions in this area should incorporate evidence-based guidance.

RPS6 phosphorylation occurs to a greater extent in the periphery of human skeletal muscle fibers, near focal adhesions, after anabolic stimuli.

Following anabolic stimuli (mechanical loading and/or amino acid provision), the mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of protein synthesis, translocates toward the cell periphery. However, it is unknown if mTORC1-mediated phosphorylation events occur in these peripheral regions or before translocation (i.e., in central regions). We therefore aimed to determine the cellular location of a mTORC1-mediated phosphorylation event, RPS6Ser240/244, in human skeletal muscle following anabolic stimuli. Fourteen young, healthy males either ingested a protein-carbohydrate beverage (0.25 g/kg protein and 0.75 g/kg carbohydrate) alone [n = 7; 23 ± 5 yr; 76.8 ± 3.6 kg; and 13.6 ± 3.8% body fat (BF), FED] or following a whole body resistance exercise bout (n = 7; 22 ± 2 yr; 78.1 ± 3.6 kg; and 12.2 ± 4.9%BF, EXFED). Vastus lateralis muscle biopsies were obtained at rest (PRE) and 120 and 300 min following anabolic stimuli. RPS6Ser240/244 phosphorylation measured by immunofluorescent staining or immunoblot was positively correlated (r = 0.76, P < 0.001). Peripheral staining intensity of p-RPS6Ser240/244 increased above PRE in both FED and EXFED at 120 min (∼54% and ∼138%, respectively, P < 0.05) but was greater in EXFED at both poststimuli time points (P < 0.05). The peripheral-to-central ratio of p-RPS6240/244 staining displayed a similar pattern, even when corrected for total RPS6 distribution, suggesting RPS6 phosphorylation occurs to a greater extent in the periphery of fibers. Moreover, p-RPS6Ser240/244 intensity within paxillin-positive regions, a marker of focal adhesion complexes, was elevated at 120 min irrespective of stimulus (P = 0.006) before returning to PRE at 300 min. These data confirm that RPS6Ser240/244 phosphorylation occurs in the region of human muscle fibers to which mTOR translocates following anabolic stimuli and identifies focal adhesion complexes as a potential site of mTORC1 regulation in vivo.

Identification of underexplored mesenchymal and vascular-related cell populations in human skeletal muscle.

Skeletal muscle repair and maintenance are directly and indirectly supported by interstitial cell populations such as vascular cells and fibro-adipogenic progenitors (FAPs), a subset of which express Twist2 and possess direct myogenic potential. Furthermore, work in rodents has highlighted the potential of pericytes to act as progenitor cells, giving rise to muscle cells and transdifferentiating into endothelial cells. However, less is understood about these populations in human skeletal muscle. Here, we performed single-cell RNA sequencing (scRNAseq) on ∼2,000 cells isolated from the human semitendinosus muscle of young individuals. This demonstrated the presence of a vascular-related cell type that expressed pericyte and pan-endothelial genes that we localized to large blood vessels within skeletal muscle cross sections and termed endothelial-like pericytes (ELPCs). RNA velocity analysis indicated that ELPCs may represent a "transition state" between endothelial cells and pericytes. Analysis of published scRNAseq data sets revealed evidence for ELPCs in trunk and heart musculature, which showed transcriptional similarity. In addition, we identified a subset of FAPs expressing TWIST2 mRNA and protein. Human TWIST2-expressing cells were anatomically and transcriptionally comparable to mouse Twist2 cells as they were restricted to the myofiber interstitium, expressed fibrogenic genes but lacked satellite cell markers, and colocalized with the FAPs marker PDGFRα in human muscle cross sections. Taken together, these results highlight the complexity of stromal cells residing in human skeletal muscle and support the utility of scRNAseq for discovery and characterization of poorly described cell populations.

Challenges of rapamycin repurposing as a potential therapeutic candidate for COVID-19: implications for skeletal muscle metabolic health in older persons.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that has spread worldwide, resulting in over 6 million deaths as of March 2022. Older people have been disproportionately affected by the disease, as they have a greater risk of hospitalization, are more vulnerable to severe infection, and have higher mortality than younger patients. Although effective vaccines have been rapidly developed and administered globally, several clinical trials are ongoing to repurpose existing drugs to combat severe infection. One such drug, rapamycin, is currently under study for this purpose, given its immunosuppressant effects that are mediated by its inhibition of the mechanistic target of rapamycin (mTOR), a master regulator of cell growth. Consistent with this premise, acute rapamycin administration in young healthy humans blocks or attenuates mTOR and its downstream effectors, leading to the inhibition of muscle protein synthesis (MPS). Skeletal muscle mass declines when MPS is chronically lower than muscle protein breakdown. This is consequential for older people who are more susceptible to anabolic resistance (i.e., the blunting of MPS) due to reduced activity, sedentariness, or bed rest such as that associated with COVID-19 hospitalization, and who have also demonstrated a delayed or blunted ability to regain inactivity-induced muscle loss. The lack of studies investigating rapamycin administration on skeletal muscle in older people, and the emergence of effective antiviral medications against severe infection, may indicate the reduced relevance of drug repurposing for present or future pandemics.

Differences between sperm sharing and egg sharing are morally relevant.

Sperm sharing arrangements involve a man ('the sharer') allowing his sperm to be used by people seeking donor sperm ('the recipients') in exchange for reduced price in vitro fertilisation. Clinics in the UK have offered egg sharing since the 1990s and the arrangement has been subjected to regulatory oversight and significant ethical analysis. By contrast, until now no published ethical or empirical research has analysed sperm sharing. Moreover the Human Fertilisation and Embryology Authority (HFEA) does not record the number of sperm sharing arrangements taking place.This paper describes the sperm sharing process providing an analysis of all the UK clinics advertising sperm sharing services. The ethical rationale for egg sharing is described: reducing the number of women exposed to the risks of stimulation and retrieval. This advantage is absent in sperm sharing where donation has no physical drawbacks. The key adverse social and emotional outcome of gamete sharing arises when the sharer's own treatment is unsuccessful and the recipient's is successful. This outcome is more likely in sperm sharing than in egg sharing given sperm from sharers can be used by up to 10 families whereas shared eggs only go to one other family.Given its morally relevant differences from egg sharing, sperm sharing requires its own ethical analysis. The HFEA should begin recording sperm sharing arrangements in order to enable meaningful ethical and policy scrutiny.

A muscle-centric view of time-restricted feeding for older adults.

PURPOSE OF REVIEW: The practice of time-restricted feeding (TRF) has received fervent interest in recent years as a strategy to mitigate obesity and metabolic disease. We sought to review the implications of TRF for skeletal muscle health and function in aging. RECENT FINDINGS: TRF has high adherence and can promote body weight loss in older populations. Body weight reductions favor fat mass in the young, however, there is also the potential for undesirable losses in lean mass. There is currently no evidence to support TRF for skeletal muscle function and metabolism in older persons, and only tentative findings in the young. With a narrow eating window of 6-8 h and a prolonged fasting period to minimize daily insulin exposure, TRF may contradict recommended dietary practices for optimizing skeletal muscle anabolism in older people. SUMMARY: TRF might represent a promising intervention to address obesity and its associated metabolic diseases, however, at present there is insufficient evidence for optimizing skeletal muscle mass or health in older individuals. Further research is needed to: (1) ascertain the impact of TRF on body composition, skeletal muscle anabolism, and autophagy in aging, and; (2) delineate the potentially myoprotective roles of dietary protein and exercise within the framework of TRF in older persons.

Incorporation of Dietary Amino Acids Into Myofibrillar and Sarcoplasmic Proteins in Free-Living Adults Is Influenced by Sex, Resistance Exercise, and Training Status.

BACKGROUND: Acute exercise increases the incorporation of dietary amino acids into de novo myofibrillar proteins after a single meal in controlled laboratory studies in males. It is unclear whether this extends to free-living settings or is influenced by training or sex. OBJECTIVES: We determined the effects of exercise, training status, and sex on 24-hour free-living dietary phenylalanine incorporation into skeletal muscle proteins. METHODS: In a parallel group design, recreationally active males (mean ± SD age, 23 ± 3 years;  BMI. 23.4 ± 2.9 kg/m2; n = 10) and females (age 24 ± 5 years;  BMI, 23.1 ± 3.9 kg/m2; n = 9) underwent 8 weeks of whole-body resistance exercise 3 times a week. Controlled diets containing 1.6 g/kg-1/d-1 (amino acids modelled after egg), enriched to 10% with [13C6] or [2H5]phenylalanine, were consumed before and after an acute bout of resistance exercise. Fasted muscle biopsies were obtained before [untrained, pre-exercise condition (REST ] and 24 hours after an acute bout of resistance exercise in untrained (UT) and trained (T) states to determine dietary phenylalanine incorporation into myofibrillar (ΔMyo) and sarcoplasmic (ΔSarc) proteins, intracellular mechanistic target of rapamycin (mTOR) colocalization with ulex europaeus agglutinin-1 (UEA-1; capillary marker; immunofluorescence), and amino acid transporter expression (Western blotting). RESULTS: The ΔMyo values were ∼62% greater (P < 0.01) in females than males at REST. The ΔMyo values increased above REST by ∼51% during UT and ∼30% in T (both P < 0.01) in males, remained unchanged in females during UT, and were ∼33% lower at T when compared to UT (P = 0.013). Irrespective of sex, ΔMyo and ΔSarc were decreased at T compared to UT (P ≤ 0.026). Resistance training increased mTOR colocalization with UEA-1 (P = 0.004), while L amino acid transporter 1, which was greater in males (P < 0.01), and sodium-coupled neutral amino acid transporter 2 protein expression were not affected by acute exercise (P ≥ 0.33) or training (P ≥ 0.45). CONCLUSIONS: The exercise-induced incorporation of dietary phenylalanine into myofibrillar and sarcoplasmic proteins is attenuated after training regardless of sex, suggesting a reduced reliance on dietary amino acids for postexercise skeletal muscle remodeling in the T state.

More than just a garbage can: emerging roles of the lysosome as an anabolic organelle in skeletal muscle.

Skeletal muscle is a highly plastic tissue capable of remodeling in response to a range of physiological stimuli, including nutrients and exercise. Historically, the lysosome has been considered an essentially catabolic organelle contributing to autophagy, phagocytosis, and exo-/endocytosis in skeletal muscle. However, recent evidence has emerged of several anabolic roles for the lysosome, including the requirement for autophagy in skeletal muscle mass maintenance, the discovery of the lysosome as an intracellular signaling hub for mechanistic target of rapamycin complex 1 (mTORC1) activation, and the importance of transcription factor EB/lysosomal biogenesis-related signaling in the regulation of mTORC1-mediated protein synthesis. We, therefore, propose that the lysosome is an understudied organelle with the potential to underpin the skeletal muscle adaptive response to anabolic stimuli. Within this review, we describe the molecular regulation of lysosome biogenesis and detail the emerging anabolic roles of the lysosome in skeletal muscle with particular emphasis on how these roles may mediate adaptations to chronic resistance exercise. Furthermore, given the well-established role of amino acids to support muscle protein remodeling, we describe how dietary proteins "labeled" with stable isotopes could provide a complementary research tool to better understand how lysosomal biogenesis, autophagy regulation, and/or mTORC1-lysosomal repositioning can mediate the intracellular usage of dietary amino acids in response to anabolic stimuli. Finally, we provide avenues for future research with the aim of elucidating how the regulation of this important organelle could mediate skeletal muscle anabolism.

Protein-carbohydrate ingestion alters Vps34 cellular localization independent of changes in kinase activity in human skeletal muscle.

NEW FINDINGS: What is the central question of the study? Is Vps34 a nutrient-sensitive activator of mTORC1 in human skeletal muscle? What is the main finding and its importance? We show that altering nutrient availability, via protein-carbohydrate feeding, does not increase Vps34 kinase activity in human skeletal muscle. Instead, feeding increased Vps34-mTORC1 co-localization in parallel to increased mTORC1 activity. These findings may have important implications in the understanding nutrient-induced mTORC1 activation in skeletal muscle via interaction with Vps34. ABSTRACT: The Class III PI3Kinase, Vps34, has recently been proposed as a nutrient sensor, essential for activation of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). We therefore investigated the effects of increasing nutrient availability through protein-carbohydrate (PRO-CHO) feeding on Vps34 kinase activity and cellular localization in human skeletal muscle. Eight young, healthy males (21 ± 0.5 yrs, 77.7 ± 9.9 kg, 25.9 ± 2.7 kg/m2 , mean ± SD) ingested a PRO-CHO beverage containing 20/44/1 g PRO/CHO/FAT respectively, with skeletal muscle biopsies obtained at baseline and 1 h and 3 h post-feeding. PRO-CHO feeding did not alter Vps34 kinase activity, but did stimulate Vps34 translocation toward the cell periphery (PRE (mean ± SD) - 0.273 ± 0.040, 1 h - 0.348 ± 0.061, Pearson's Coefficient (r)) where it co-localized with mTOR (PRE - 0.312 ± 0.040, 1 h - 0.348 ± 0.069, Pearson's Coefficient (r)). These alterations occurred in parallel to an increase in S6K1 kinase activity (941 ± 466% of PRE at 1 h post-feeding). Subsequent in vitro experiments in C2C12 and human primary myotubes displayed no effect of the Vps34-specific inhibitor SAR405 on mTORC1 signalling responses to elevated nutrient availability. Therefore, in summary, PRO-CHO ingestion does not increase Vps34 activity in human skeletal muscle, whilst pharmacological inhibition of Vps34 does not prevent nutrient stimulation of mTORC1 in vitro. However, PRO-CHO ingestion promotes Vps34 translocation to the cell periphery, enabling Vps34 to associate with mTOR. Therefore, our data suggests that interaction between Vps34 and mTOR, rather than changes in Vps34 activity per se may be involved in PRO-CHO activation of mTORC1 in human skeletal muscle.

Landscapes of practice in medical education.

Sociocultural learning theories play an important part in medical education. When Etienne Wenger-Trayner described 'communities of practice' oriented around three common features (mutual engagement, joint enterprise, shared repertoire), his approach was enthusiastically embraced across a range of fields, including those of clinical medicine and medical education. However, this model is limited by its focus on a single community. Recently, leading sociocultural learning theorists including Wenger-Trayner have proposed the landscape of practice as a model for how learner identities develop, but this theory has not yet been utilised in medical education. In this Cross-cutting Edge paper, I describe the key features of landscapes of practice. The landscape of practice encompasses all the communities of practice, and learners can move between these. The boundaries between communities of practice are particularly fertile settings for learning, either through occasional forays across borders or through complete multimembership of two or more communities of practice. The capacity to navigate knowledge acquisition and identity formation across the landscape, known as 'knowledgeability,' therefore becomes crucial. This paper concludes by describing possible applications of the landscapes of practice model in medical education practice and research. The model provides a rich framework for approaching cross-discipline learning, although it has been criticised for failing to address the difficulties created by wide disparities in power within communities and for an unrealistically collaborative (rather than competitive) view of boundary relations. Nevertheless, it provides a novel way of understanding the identity formation of medical trainees and students.

Postmortem non-directed sperm donation: quality matters.

In our paper 'The ethical case for non-directed postmortem sperm donation' we argued that it would be ethical for men to donate sperm after death for use by strangers. In their thoughtful response Fredrick and Ben Kroon lay out practical concerns regarding our proposal. They raise issues regarding the quality of sperm collected postmortem based on empirical studies. Second, they claim that concerns about quality would make women unlikely to use sperm collected after death. In this response we explore issues of sperm quality in both living and dead donors. We consider whether there might be ways to ensure quality in both. Finally, we question whether quality should be a barrier to women choosing to use sperm donated after death.

Is one narrative enough? Analytical tools should match the problems they address.

Jeff Nisker describes his personal experience of a diagnosis of advanced prostate cancer and the kindnesses he received from friendly doctors. He claims that this narrative account supports the promotion of Prostate Specific Antigen (PSA) screening for asymptomatic men and impugns statisticians, mistakenly thinking that their opposition to PSA screening derives from concerns about financial cost. The account inadvertently demonstrates the danger of over-reliance on a single ethical tool for critical analysis. In the first part of this response, we describe the statistical evidence. The most reliable Cochrane meta-analyses have not shown that PSA screening saves lives overall. Moreover, the high false positive rate of PSA screening leads to overinvestigation which results in unnecessary anxiety and increased cases of unnecessary sepsis, urinary incontinence and sexual dysfunction. Then we describe how narrative ethics alone is an insufficient tool to make claims about policies, such as PSA screening, which have hidden harms. Although Nisker's story-telling is compelling and evokes emotions, narrative ethics of this sort have an inherent bias against people who would be harmed by the counterfactual. Particular care must be taken to look for and consider those untellable stories. Ethicists who only consider narratives which are readily at hand risk harming those who are voiceless or protected by the status quo. PSA screening is the wrong tool to reduce prostate cancer deaths and narrative ethics is the wrong tool to appraise this policy. It is vital that the correct theoretical tools are applied to the medical and ethical questions under scrutiny.

Confused out of care: unanticipated consequences of a 'Hostile Environment'.

The UK's 2014 Immigration Act aimed to create a 'Hostile Environment' for migrants to the UK. One aspect of this was the restriction of access to secondary care for overseas visitors to the UK, although it remains the case that everybody living in the UK has the legal right to access primary care. In this paper, we argue that the effects of this policy extend beyond secondary care, including preventing eligible people from registering with a General Practice (GP), although as an unintended consequence. This problem arises from misinterpretation of policy wording, misleading GP websites and gatekeeping behaviour from front-line staff, even though there are no grounds in the current guidelines or law to support this. Free access to primary healthcare among refugees and asylum seekers living in deprived populations is particularly important in protecting patient health, given the burden of ill-health in this population and the multiple barriers to accessing early intervention they face. The medical profession has a duty to communicate their rights to this patient group-their legal entitlement to access free healthcare, and the vital importance of doing so.

The ethical case for non-directed postmortem sperm donation.

In this article we outline and defend the concept of voluntary non-directed postmortem sperm donation. This approach offers a potential means of increasing the quantity and heterogeneity of donor sperm. This is pertinent given the present context of a donor sperm shortage in the UK. Beyond making the case that it is technically feasible for dead men to donate their sperm for use in reproduction, we argue that this is ethically permissible. The inability to access donor sperm and the suffering this causes, we argue, justifies allowing access to sperm donated after death. Moreover, it is known that individuals and couples have desires for certain sperm donor characteristics which may not be fulfilled when numbers of sperm donors are low. Enacting these preferences contributes significantly to the well-being of intended parents, so we argue that this provides a pro tanto reason for respecting them. Finally, we explore the benefits and possible disadvantages of such a system for the various parties affected.