Gillick competence: an inadequate guide to the ethics of involving adolescents in decision-making.

Developmentally, adolescence sits in transition between childhood and adulthood. Involving adolescents in their medical decision-making prompts important and complex ethical questions. Originating in the UK, the concept of Gillick competence is a dominant framework for navigating adolescent medical decision-making from legal, ethical and clinical perspectives and is commonly treated as comprehensive. In this paper, we argue that its utility is far more limited, and hence over-reliance on Gillick risks undermining rather than promoting ethically appropriate adolescent involvement. We demonstrate that Gillick only provides guidance in the limited range of cases where legal decisional authority needs to be clarified. The range of cases where use of Gillick actually promotes adolescent involvement is narrower still, because several features must be present for Gillick to be enacted. Each of these features can, and do, act as barriers to adolescent involvement. Within these limited situations, we argue that Gillick is not specific or strong enough and is reliant on ethically contestable principles. Moreover, in most situations in adolescent healthcare, Gillick is silent on the ethical questions around involving adolescents. This is because it focuses on decisional authority-having the final say in decision-making-which is one small subset of the many ways adolescents could be involved in decision-making. The implication of our analysis is that use of Gillick competence tends to limit or undermine adolescent involvement opportunities. We propose that those working with adolescents should be judicious in seeking Gillick's guidance, instead drawing on and developing alternative frameworks that provide a comprehensive model for adolescent involvement.

Reconceiving Reproduction: Removing "Rearing" From the Definition-and What This Means for ART.

The predominant position in the reproductive rights literature argues that access to assisted reproductive technologies (ART) forms part of an individual's right to reproduce. On this reasoning, refusal of treatment by clinicians (via provision) violates a hopeful parent's reproductive right and discriminates against the infertile. I reject these views and suggest they wrongly contort what reproductive freedom entitles individuals to do and demand of others. I suggest these views find their origin, at least in part, in the way we define "reproduction" itself. This paper critically analyses two widely accepted definitions of human reproduction and demonstrates that both are fundamentally flawed. While the process of reproduction includes the biological acts of begetting and bearing a child, I argue that it does not extend to include rearing. This reworked definition has little impact in the realm of sexual reproduction. However, it has significant ethical implications for the formulation and assignment of reproductive rights and responsibilities in the non-sexual realm in two important ways. First, a claim to access ART where one has an intention to rear a child (but does not beget or bear) cannot be grounded in reproductive rights. Second, lacking an intention to rear does not extinguish the reproductive rights and responsibilities for those who collaborate in the process. I conclude that clinicians collaborate in non-sexual reproduction at the point of triggering conception (begetting) and therefore have the right to refuse to be involved in non-sexual reproduction, in some instances, as do all reproductive collaborators.

Design of a Real-World Observational Study in Previously Untreated and Minimally Treated Hemophilia A Patients: Protect-NOW.

Background The efficacy, safety, and immunogenicity of each of Octapharma's factor VIII (FVIII) products, Nuwiq, octanate, and wilate, have been investigated in previously untreated patients (PUPs) with severe hemophilia A in prospective clinical trials. The aim of the Protect-NOW study is to evaluate the effectiveness, safety, and utilization patterns of Nuwiq, octanate, and wilate in PUPs and minimally treated patients (MTPs; <5 exposure days [EDs] to FVIII concentrates or other blood products containing FVIII) with severe hemophilia A in a real-world setting. Real-world data provide valuable information that complement data obtained from interventional clinical trials. Methods Protect-NOW (ClinicalTrials.gov identifier: NCT03695978; ISRCTN identifier: 11492145) is a real-world study in PUPs and MTPs treated with either the human cell line-derived recombinant FVIII Nuwiq (simoctocog alfa) or a plasma-derived FVIII concentrate containing von Willebrand factor (octanate or wilate). It is a prospective and (partly) retrospective, observational, international, noncontrolled, noninterventional study. A total of 140 PUPs and MTPs with severe hemophilia A will be enrolled across around 50 specialized centers worldwide and followed for either 100 EDs or a maximum period of 3 years from ED1. The primary objectives are to assess effectiveness in the prevention and treatment of bleeding episodes and overall safety, including inhibitor development. The secondary objectives are to assess utilization patterns (including dosage and frequency of administration) and the effectiveness in surgical prophylaxis. Conclusions The Protect-NOW study will provide information on the treatment of PUPs and MTPs in routine clinical practice, which will help guide clinical decision making for treating these patients in the future.

A little bit pregnant: towards a pluralist account of non-sexual reproduction.

Fertility clinicians participate in non-sexual reproductive projects by providing assisted reproductive technology (ART) to those hoping to reproduce, in support of their reproductive goals. In most countries where ART is available, the state regulates ART as a form of medical treatment. The predominant position in the reproductive rights literature frames the clinician's role as medical technician, and the state as a third party with limited rights to interfere. These roles broadly align with established functions of clinician and state in Western liberal democracies, where doctors have duties to provide safe, beneficial and legal healthcare to all who seek it. Recognised state responsibilities include safeguarding equitable access to medical services and protecting and promoting reproductive liberty.I argue against this normative moral framing of clinician and state involvement in non-sexual reproduction, suggesting that clinician and state join the non-sexual reproductive project at the point of triggering conception. Begetting a child is more than just the provision and regulation of healthcare; it generates rights and confers responsibilities on all who join this morally significant project. All who collaborate have the right to join or refuse to join the project. I suggest this is intuitively understood in the sexual realm, but not in the non-sexual realm. My key substantive claim is that non-sexual reproduction is a pluralist pursuit that morally implicates more than the genetic and gestational contributors. I find that while the moral basis of a clinician or the state's right to refuse to join the ART project is the same as for those providing gestational or genetic input, the reasons that morally underpin their refusal differs.

Emicizumab prophylaxis in haemophilia A with inhibitors: Three years follow-up from the UK Haemophilia Centre Doctors' Organisation (UKHCDO).

INTRODUCTION: The UK National Haemophilia Database (NHD) collects data from all UK persons with haemophilia A with inhibitors (PwHA-I). It is well-placed to investigate patient selection, clinical outcomes, drug safety and other issues not addressed in clinical trials of emicizumab. AIMS: To determine safety, bleeding outcomes and early effects on joint health of emicizumab prophylaxis in a large, unselected cohort using national registry and patient reported Haemtrack (HT) data between 01 January 2018 and 30 September 2021. METHODS: Prospectively collected bleeding outcomes were analysed in people with ≥6 months emicizumab HT data and compared with previous treatment if available. Change in paired Haemophilia Joint Health Scores (HJHS) were analysed in a subgroup. Adverse events (AEs) reports were collected and adjudicated centrally. RESULTS: This analysis includes 117 PwHA-I. Mean annualised bleeding rate (ABR) was .32 (95% CI, .18; .39) over a median 42 months treatment with emicizumab. Within-person comparison (n = 74) demonstrated an 89% reduction in ABR after switching to emicizumab and an increase in zero treated bleed rate from 45 to 88% (p < .01). In a subgroup of 37 people, total HJHS improved in 36%, remained stable in 46% and deteriorated in 18%, with a median (IQR) within-person change of -2.0 (-9, 1.5) (p = .04). Three arterial thrombotic events were reported, two possibly drug related. Other AEs were generally non-severe and usually limited to early treatment, included cutaneous reactions (3.6%), headaches (1.4%), nausea (2.8%) and arthralgia (1.4%). CONCLUSIONS: Emicizumab prophylaxis is associated with sustained low bleeding rates and was generally well-tolerated in people with haemophilia A and inhibitors.

Reproduction misconceived: why there is no right to reproduce and the implications for ART access.

Reproduction is broadly recognised as fundamental to human flourishing. The presumptive priority of reproductive freedom forms the predominant position in the literature, translating in the non-sexual reproductive realm as an almost inviolable right to access assisted reproductive technology (ART). This position largely condemns refusal or restriction of ART by clinicians or the state as discriminatory. In this paper, I critically analyse the moral rights individuals assert in reproductive pursuit to explore whether reproductive rights entitle hopeful parents to ART. I demonstrate that none of the protected actions performed, or entitlements generated are sui generis 'reproductive' rights, leading to the claim that there is no such thing as a right to reproduce. Under scrutiny, the reproductive right is a far narrower and weaker rights assertion than is recognised in the literature. I argue that the predominant position is grounded in a fundamental misunderstanding of the scope and strength of reproductive claims.I also highlight a significant conceptual inconsistency in the literature. On one hand, there is broad consensus that reproductive rights are predominantly negative, yet access to fertility treatment is framed as a component of the right. This wrongly contorts the negative nature of reproductive rights into a positive claim-right to ART. I conclude that this mistakenly frames ART access as sitting within the scope of reproductive freedom. I offer a revised conceptual paradigm of reproductive rights that has important clinical and policy implications for the provision and regulation of ART.

Management of children and adults with all stages of nodular lymphocyte predominant Hodgkin lymphoma - All StAGEs: A consensus-based position paper from the Hodgkin lymphoma subgroup of the UK National Cancer Research Institute.

A consensus statement for the management for patients of all ages with all stages of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) - All StAGEs - is proposed by representatives of the UK National Cancer Research Institute (NCRI) Hodgkin lymphoma study group and the Children's Cancer & Leukaemia Group. Based on current practices and published evidence, a consensus has been reached regarding diagnosis, staging and risk-ik7 stratified management which includes active surveillance, low- and standard-dose immunochemotherapy and radiotherapy.

Bi-allelic mutation of CTNNB1 causes a severe form of syndromic microphthalmia, persistent foetal vasculature and vitreoretinal dysplasia.

BACKGROUND: Inherited vitreoretinopathies arise as a consequence of congenital retinal vascularisation abnormalities. They represent a phenotypically and genetically heterogeneous group of disorders that can have a major impact on vision. Several genes encoding proteins and effectors of the canonical Wnt/ß-catenin pathway have been associated and precise diagnosis, although difficult, is essential for proper clinical management including syndrome specific management where appropriate. This work aimed to investigate the molecular basis of disease in a single proband born to consanguineous parents, who presented with microphthalmia, persistent foetal vasculature, posterior lens vacuoles, vitreoretinal dysplasia, microcephaly, hypotelorism and global developmental delay, and was registered severely visually impaired by 5 months of age. METHODS: Extensive genomic pre-screening, including microarray comparative genomic hybridisation and sequencing of a 114 gene panel associated with cataract and congenital ophthalmic disorders was conducted by an accredited clinical laboratory. Whole exome sequencing (WES) was undertaken on a research basis and in vitro TOPflash transcriptional reporter assay was utilised to assess the impact of the putative causal variant. RESULTS: In the proband, WES revealed a novel, likely pathogenic homozygous mutation in the cadherin-associated protein beta-1 gene (CTNNB1), c.884C>G; p.(Ala295Gly), which encodes a co-effector molecule of the Wnt/ß-catenin pathway. The proband's parents were shown to be heterozygous carriers but ophthalmic examination did not detect any abnormalities. Functional assessment of the missense variant demonstrated significant reduction of ß-catenin activity. CONCLUSIONS: This is the first report of a biallelic disease-causing variation in CTNNB1. We conclude that this biallelic, transcriptional inactivating mutation of CTNNB1 causes a severe, syndromic form of microphthalmia, persistent foetal vasculature and vitreoretinal dysplasia that results in serious visual loss in infancy.

Retrospective evaluation of systemic hypertension in dogs with nonassociative (primary) immune-mediated hemolytic anemia (December 2016 to April 2019): 26 cases.

OBJECTIVE: To report the prevalence of arterial hypertension in a population of dogs with nonassociative immune-mediated hemolytic anemia (IMHA) on presentation and during hospitalization. To determine the relationships of systolic blood pressure (SBP) with mortality and a prognostic indicator, the canine hemolytic anemia objective score. DESIGN: Retrospective observational study (December 2016 to April 2019). SETTING: University teaching hospital. ANIMALS: Twenty-six clinical dogs presenting to the ICU with nonassociative (primary) IMHA and a control group of 23 clinical dogs with idiopathic epilepsy hospitalized in the ICU for seizure treatment or monitoring. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hypertension was defined as SBP ≥ 160 mm Hg and severe hypertension as SBP ≥ 180 mm Hg. Mean SBP was significantly increased in IMHA dogs (161 mm Hg, SD = 21) compared to ICU control dogs (138 mm Hg, SD = 14; P < 0.005). Hypertension was present in 13 of 26 (50.0%) dogs across the period of hospitalization and was severe in three of 26 (11.5%). During at least 1 day of hospitalization, 18 of 26 (69.2%) dogs were hypertensive and eight of 26 (34.6%) were severely hypertensive. Hypertension was not associated with short-term mortality or canine hemolytic anemia objective score. CONCLUSIONS: In this retrospective study, hypertension was more prevalent in dogs with nonassociative IMHA than a control population of ICU-hospitalized dogs. An association between autoimmune conditions and hypertension has been previously reported in people but not within a canine population. Hypertension in dogs may have an inflammatory or autoimmune etiology. SBP should be monitored closely in canine IMHA, in case antihypertensive treatment is required.

Arterial malformations leading to bilateral spontaneous renal hemorrhage in a dog.

OBJECTIVE: To describe the clinical presentation, diagnostic imaging, management, and follow-up of a dog that presented with sequential, bilateral, spontaneous, subcapsular and perirenal hemorrhage (Wunderlich syndrome) due to bilateral renal arterial malformations. CASE SUMMARY: A 9-year-old intact male Field Spaniel presented for acute onset abdominal pain following a possible syncopal episode. Abdominal ultrasonography, contrast-enhanced ultrasound, and computed tomography (CT) revealed right-sided perirenal hemorrhage that extended into the peritoneum. The dog was discharged following stabilization with analgesia, fluid therapy, and tranexamic acid. One month later, the patient presented with identical clinical signs. A CT scan at this stage revealed bilateral kidney infarcts with new left-sided perirenal hemorrhage. Abdominal ultrasound and contrast-enhanced ultrasound were repeated and showed similar findings. Follow up with four-dimensional CT angiography revealed bilateral renal arterial malformations, likely causing spontaneous renal hemorrhage and secondary subcapsular hematomas , retroperitoneal and peritoneal hemorrhage. UNIQUE INFORMATION PROVIDED: This is the first reported case of both bilateral renal arterial malformations and bilateral spontaneous subcapsular and perirenal hemorrhage in the absence of neoplasia, coagulopathy, or trauma in a dog. Advanced imaging modalities, including selective angiography, were required to diagnose this condition successfully. Arterial malformations should be considered as a differential diagnosis in cases of hemoretroperitoneum. Nephrectomy due to perirenal hemorrhage should be cautiously considered, especially in the absence of angiography, because of the sequential bilateral nature of this case. Conservative management in this case resulted in a good long-term outcome 10 months later.

Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia.

Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We, therefore, investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of cell state accounts for a significant component of bottleneck selection during induction chemotherapy.

Immune tolerance induction in severe haemophilia A: A UKHCDO inhibitor and paediatric working party consensus update.

INTRODUCTION: In good risk patients (historic inhibitor peak < 200BU), the International Immune Tolerance Study demonstrated equal efficacy to induce tolerance between high (200iu/kg/day) and low dose (50iu/kg ×3 times/week) immune tolerance induction (ITI) regimens. However, the trial stopped early on account of the excessive bleed rate in the low dose ITI arm. METHODS: United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) Paediatric and Inhibitor working parties considered available ITI data alongside the bi-phenotypic antibody emicizumab (Hemlibra®) efficacy and safety data to develop a consensus guideline for the future UK ITI guideline. RESULTS: This revision of UKHCDO ITI guidance incorporates the recommendation to use emicizumab as a prophylaxis haemostatic agent to reduce bleeding rates and to facilitate low dose and reduced frequency of FVIII CFC for ITI in the majority of children. CONCLUSION: This consensus protocol will facilitate future evaluation of ITI outcomes in the evolving landscape of haemophilia therapeutics and ITI strategies.

Retrospective evaluation of refeeding syndrome in cats: 11 cases (2013-2019).

OBJECTIVES: The aim of this study was to describe the clinicopathological findings, management and outcome of cats with refeeding syndrome (RS) following prolonged starvation. METHODS: Records from four referral hospitals were searched between May 2013 and November 2019 and retrospectively evaluated. Inclusion criteria were the presence of a risk factor for RS, such as severe weight loss or emaciation following a period of presumed starvation, hypophosphataemia or a delta phosphorous exceeding 30% reduction following refeeding, being treated on the basis of a clinical diagnosis of RS and one or more derangement of hypokalaemia, hypoglycaemia or hyperglycaemia. RESULTS: Eleven cats were identified, which had been missing for a median of 6 weeks (range 3-104 weeks). Mean ± SD percentage weight loss was 46% ± 7% (n = 8). Eight of 11 cats developed hypophosphataemia with a mean delta phosphorous of -47% ± 9%. All cats were documented to be hypokalaemic. During hospitalisation, 10/11 cats developed hyperglycaemia and 7/11 cats developed hypoglycaemia. Cardiovascular, gastrointestinal and neurological signs were common. Eight of 11 cats displayed new or progressive neurological deficits after refeeding, including mentation changes and cerebellar dysfunction. All cats became anaemic and seven cats required a blood transfusion. Eight cats survived to discharge after a mean of 14 ± 4 days of hospitalisation. Six cats developed acute kidney injury (AKI; International Renal Interest Society stage 1). The presence of AKI (P = 0.024) was associated with non-survival and maximum bilirubin concentration was significantly higher in non-survivors (P = 0.018). CONCLUSIONS AND RELEVANCE: Cats with RS in this cohort had been missing, presumed starved, for more than 3 weeks. In addition to hypophosphataemia and hypokalaemia, altered glucose homeostasis and organ damage involving the liver and kidneys were common. Cats with RS appear to have a good prognosis, but prolonged intensive care is required.

A single centre retrospective study of low dose prophylaxis with extended half-life factor IX for severe haemophilia B.

INTRODUCTION: Extended half-life factor IX concentrates (EHL-FIX) can be administered weekly to prevent bleeding for persons with severe haemophilia B. We report the experience of a large UK haemophilia comprehensive care centre using low dose EHL-FIX for persons with severe haemophilia B. AIM: The low doses used in real world are approximately half of the doses used in clinical trials. We aim to assess the efficacy and safety of low dose EHL-FIX. METHODS: Data from a cohort of 13 patients who were switched from standard half-life factor IX (SHL-FIX) to Alprolix® (mean dose 31.5 IU/kg) and seven patients who switched from standard half-life factor IX to Idelvion® (mean dose 20.2 IU/kg) were included. RESULTS: The median annualized bleeding rate was similar for SHL-FIX (median 3, interquartile range [IQR] 1-5) and EHL-FIX (median 3, IQR 1-5.25). Quality of life scores, measured using the European Quality of Life 5 Dimensions assessment were similar for SHL-FIX (median 0.76, IQR: 0.63-0.84) and EHL-FIX (median 0.79, IQR: 0.58-0.88). CONCLUSION: This study shows that EHL-FIX given at low doses can be effective for prevention of bleeding for persons with severe haemophilia B.

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders.

PURPOSE: A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). METHODS: Two hundred one unrelated children (0-5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011-2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. RESULTS: The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). CONCLUSION: Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.

Clinical and genetic variability in children with partial albinism.

Individuals who have ocular features of albinism and skin pigmentation in keeping with their familial background present a considerable diagnostic challenge. Timely diagnosis through genomic testing can help avert diagnostic odysseys and facilitates accurate genetic counselling and tailored specialist management. Here, we report the clinical and gene panel testing findings in 12 children with presumed ocular albinism. A definitive molecular diagnosis was made in 8/12 probands (67%) and a possible molecular diagnosis was identified in a further 3/12 probands (25%). TYR was the most commonly mutated gene in this cohort (75% of patients, 9/12). A disease-causing TYR haplotype comprised of two common, functional polymorphisms, TYR c.[575 C > A;1205 G > A] p.[(Ser192Tyr);(Arg402Gln)], was found to be particularly prevalent. One participant had GPR143-associated X-linked ocular albinism and another proband had biallelic variants in SLC38A8, a glutamine transporter gene associated with foveal hypoplasia and optic nerve misrouting without pigmentation defects. Intriguingly, 2/12 individuals had a single, rare, likely pathogenic variant in each of TYR and OCA2 - a significant enrichment compared to a control cohort of 4046 individuals from the 100,000 genomes project pilot dataset. Overall, our findings highlight that panel-based genetic testing is a clinically useful test with a high diagnostic yield in children with partial/ocular albinism.

The psychosocial and service delivery impact of genomic testing for inherited retinal dystrophies.

Next-generation sequencing (NGS) provides diagnostic information for many rare conditions. The evolution of NGS for panel, exome, and genome testing is set to be the platform for transforming genomic diagnosis in the National Health Service (NHS). Inherited retinal dystrophies (IRDs) are a highly genetically heterogeneous disease group causing progressive visual impairment. IRDs are ideal for an NGS panel approach due to phenotypic overlap and were one of the first diagnostic panels to be developed in the NHS. While diagnostic yield for patients with IRD has improved significantly with NGS, a proportion of patients remain without a diagnosis. The clinical value of NGS testing is well understood; however, the patient experience of panel testing is not well documented. Semi-structured qualitative telephone interviews were conducted with 23 participants with IRD who had undergone NGS testing. Interviews were transcribed verbatim and analysed using interpretative phenomenological analysis. Participants' experiences were interpreted to explore the psychosocial and service delivery impact of this testing technology, inclusive of those who received a pathogenic, negative, carrier status or variant of uncertain significance result. Collectively, three core themes were identified: (1) the journey towards a genomic diagnosis, (2) the impact of NGS testing, (3) service delivery of NGS tests. Disclosure of results had no reported adverse implications. Participants appreciated an open discussion about the potential for an uncertain or unexpected result, prior to testing. They valued pre-test counselling discussions, expert opinions and on-going care from genomic services.