Brain stimulation for treatment and enhancement in children: an ethical analysis

Davis (2014) called for "extreme caution" in the use of non-invasive brain stimulation (NIBS) to treat neurological disorders in children, due to gaps in scientific knowledge. We are sympathetic to his position. However, we must also address the ethical implications of applying this technology to minors. Compensatory trade-offs associated with NIBS present a challenge to its use in children, insofar as these trade-offs have the effect of limiting the child's future options. The distinction between treatment and enhancement has some normative force here. As the intervention moves away from being a treatment toward being an enhancement-and thus toward a more uncertain weighing of the benefits, risks, and costs-considerations of the child's best interests (as judged by the parents) diminish, and the need to protect the child's (future) autonomy looms larger. NIBS for enhancement involving trade-offs should therefore be delayed, if possible, until the child reaches a state of maturity and can make an informed, personal decision. NIBS for treatment, by contrast, is permissible insofar as it can be shown to be at least as safe and effective as currently approved treatments, which are themselves justified on a best interests standard

An empirical bioethical examination of Norwegian and British doctors' views of responsibility and (de)prioritization in healthcare

In a world with limited resources, allocation of resources to certain individuals and conditions inevitably means fewer resources allocated to other individuals and conditions. Should a patient's personal responsibility be relevant to decisions re- garding allocation? In this project we combine the normative and the descriptive, conducting an empirical bioethical examination of how both Norwegian and British doctors think about principles of responsibility in allocating scarce healthcare re- sources. A large proportion of doctors in both countries supported including re- sponsibility for illness in prioritization decisions. This finding was more prominent in zero‐sum scenarios where allocation to one patient means that another patient is denied treatment. There was most support for incorporating prospective responsi- bility (through patient contracts), and low support for integrating responsibility into co‐payments (i.e. through requiring responsible patients to pay part of the costs of treatment). Finally, some behaviours were considered more appropriate grounds for deprioritization (smoking, alcohol, drug use)—potentially because of the certainty of impact and direct link to ill health. In zero‐sum situations, prognosis also influenced prioritization (but did not outweigh responsibility). Ethical implications are discussed. We argue that the role that responsibility constructs appear to play in doctors' decisions indicates a needs for more nuanced—and clear—policy. Such policy should account for the distinctions we draw between responsibility‐sensitive and prog- nostic justifications for deprioritization

Prospective intention-based lifestyle contracts: mHealth technology and responsibility in healthcare

As the rising costs of lifestyle-related diseases place increasing strain on public healthcare systems, the individual’s role in disease may be proposed as a healthcare rationing criterion. Literature thus far has largely focused on retrospective responsi- bility in healthcare. The concept of prospective responsibility, in the form of a life- style contract, warrants further investigation. The responsibilisation in healthcare debate also needs to take into account innovative developments in mobile health technology, such as wearable biometric devices and mobile apps, which may change how we hold others accountable for their lifestyles. Little is known about public atti- tudes towards lifestyle contracts and the use of mobile health technology to hold people responsible in the context of healthcare. This paper has two components. Firstly, it details empirical findings from a survey of 81 members of the United Kingdom general public on public attitudes towards individual responsibility and rationing healthcare, prospective and retrospective responsibility, and the acceptabil- ity of lifestyle contracts in the context of mobile health technology. Secondly, we draw on the empirical findings and propose a model of prospective intention-based lifestyle contracts, which is both more aligned with public intuitions and less ethi- cally objectionable than more traditional, retrospective models of responsibility in healthcare

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Implementation of corticosteroids in treating COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK:prospective observational cohort study

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. FUNDING: UK National Institute for Health Research and UK Medical Research Council

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Tiina Paunio on työryhmän UK10K jäsen.The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.Peer reviewe

Whole-genome sequence-based analysis of thyroid function

Tiina Paunio on työryhmän UK10K Consortium jäsen.Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N = 2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF >= 1%) associated with TSH and FT4 (N = 16,335). For TSH, we identify a novel variant in SYN2 (MAF = 23.5%, P = 6.15 x 10(-9)) and a new independent variant in PDE8B (MAF = 10.4%, P = 5.94 x 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/ SLC25A52 (MAF = 3.2%, P = 1.27 x 10(-9)) tagging a rare TTR variant (MAF = 0.4%, P = 2.14 x 10(-11)). All common variants explain >= 20% of the variance in TSH and FT4. Analysis of rare variants (MAFPeer reviewe