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Abstract It seems probable that some form of medically-assisted dying will become legal in England and Wales in the foreseeable future. Assisted dying Bills are at various stages of preparation in surrounding jurisdictions (Scotland, Republic of Ireland, Isle of Man, Jersey), and activists campaign unceasingly for a change in the law in England and Wales. There is generally uncritical supportive media coverage, and individual autonomy is seen as the unassailable trump card: ‘my life, my death’. However, devising a law which is ‘fit for purpose’ is not an easy matter. The challenge is to achieve an appropriate balance between compassion and patient autonomy on the one hand, and respect for human life generally and medical autonomy on the other. More people should benefit from a change in the law than be harmed. In relation to medically-assisted dying, this may not be possible. Protecting the vulnerable is a key issue. Likewise, not impacting negatively on societal attitudes towards the disabled and frail elderly, particularly those with dementia. This paper compares three existing models of physician-assisted suicide: Switzerland, Oregon (USA), and Victoria (Australia). Vulnerability and autonomy are discussed, and concern expressed about the biased nature of much of the advocacy for assisted dying, tantamount to disinformation. A ‘hidden’ danger of assisted dying is noted, namely, increased suffering as more patients decline referral to palliative-hospice care because they fear they will be ‘drugged to death’. Finally, suggestions are made for a possible ‘least worse’ way forward. One solution would seem to be for physician-assisted suicide to be the responsibility of a stand-alone Department for Assisted Dying overseen by lawyers or judges and operated by technicians. Doctors would be required only to confirm a patient’s medical eligibility. Palliative-hospice care should definitely not be involved, and healthcare professionals must have an inviolable right to opt out of involvement. There is also an urgent need to improve the provision of care for all terminally ill patients.

Abstract Background The effects of Anabolic Androgenic Steroids (AAS) are largely illustrated through Androgen Receptor induced gene transcription, yet RNA-Seq has yet to be conducted on human whole blood and skeletal muscle. Investigating the transcriptional signature of AAS in blood may aid AAS detection and in muscle further understanding of AAS induced hypertrophy. Methods Males aged 20–42 were recruited and sampled once: sedentary controls (C), resistance trained lifters (RT) and resistance trained current AAS users (RT-AS) who ceased exposure ≤ 2 or ≥ 10 weeks prior to sampling. RT-AS were sampled twice as Returning Participants (RP) if AAS usage ceased for ≥ 18 weeks. RNA was extracted from whole blood and trapezius muscle samples. RNA libraries were sequenced twice, for validation purposes, on the DNBSEQ-G400RS with either standard or CoolMPS PE100 reagents following MGI protocols. Genes were considered differentially expressed with FDR

Abstract We have several major concerns about this article [Guastella et al 2021]. Although it states that it is about palliative sedation, it is not. Rather, it is about the French Claeys Leonetti Law about Continuous Deep Sedation (CDS) at the end of life [Loi n°2016-87].

Lanthipeptide synthetases are present in all domains of life. They catalyze a crucial step during lanthipeptide biosynthesis by introducing thioether linkages during posttranslational peptide modification. Lanthipeptides have a wide range of functions, including antimicrobial and morphogenetic activities. Intriguingly, several Clostridium species contain lanthipeptide synthetase-like genes of the class II (lanM) family but lack other components of the lanthipeptide biosynthetic machinery. In all instances, these genes are located immediately downstream of putative agr quorum sensing operons. The physiological role and mode of action of the encoded LanM-like proteins remain uncertain as they lack conserved catalytic residues. Here we show for the industrial organism Clostridium acetobutylicum that the LanM-like protein CA_C0082 is not required for the production of active AgrD-derived signaling peptide but nevertheless acts as an effector of Agr quorum sensing. Expression of CA_C0082 was shown to be controlled by the Agr system and is a prerequisite for granulose (storage polymer) formation. The accumulation of granulose, in turn, was shown to be required for maximal spore formation but also to reduce early solvent formation. CA_C0082 and its putative homologs appear to be closely associated with Agr systems predicted to employ signaling peptides with six-membered ring structures and may represent a new subfamily of LanM-like proteins. This is the first time their contribution to bacterial Agr signaling has been described.

Exploiting biological processes to recycle renewable carbon into high value platform chemicals provides a sustainable and greener alternative to current reliance on petrochemicals. In this regard Cupriavidus necator H16 represents a particularly promising microbial chassis due to its ability to grow on a wide range of low-cost feedstocks, including the waste gas carbon dioxide, whilst also naturally producing large quantities of polyhydroxybutyrate (PHB) during nutrient-limited conditions. Understanding the complex metabolic behaviour of this bacterium is a prerequisite for the design of successful engineering strategies for optimising product yields. We present a genome-scale metabolic model (GSM) of C. necator H16 (denoted iCN1361), which is directly constructed from the BioCyc database to improve the readability and reusability of the model. After the initial automated construction, we have performed extensive curation and both theoretical and experimental validation. By carrying out a genome-wide essentiality screening using a Transposon-directed Insertion site Sequencing (TraDIS) approach, we showed that the model could predict gene knockout phenotypes with a high level of accuracy. Importantly, we indicate how experimental and computational predictions can be used to improve model structure and, thus, model accuracy as well as to evaluate potential false positives identified in the experiments. Finally, by integrating transcriptomics data with iCN1361 we create a condition-specific model, which, importantly, better reflects PHB production in C. necator H16. Observed changes in the omics data and in-silico-estimated alterations in fluxes were then used to predict the regulatory control of key cellular processes. The results presented demonstrate that iCN1361 is a valuable tool for unravelling the system-level metabolic behaviour of C. necator H16 and can provide useful insights for designing metabolic engineering strategies.

Abstract There are continued challenges in achieving effective pain management for children and young people (CYP). Research has found several barriers to effective CYP pain management, which include, but are not limited to, deficiencies in knowledge among nurses and other healthcare professionals. Calls for improvements in and an increase in pain education ensue, in the expectation that an increase in knowledge will lead to an improved pain care for patients. Educational initiatives, as reported in the literature, have tended to focus on increasing empirical knowledge which has not resulted in the anticipated improvements in practice. An exploration of Carper's and Chinn & Kramer's five ways of knowing helps demonstrate why an over‐reliance on empirics fails to equip nurses for the realities of clinical practice and does not facilitate knowledge mobilization or improvements in pain care for CYP. In this paper, we explore these ways of knowing to produce a model for knowledge mobilization in (pain) education. Our model puts forward a multifaceted approach to education using the active learning principles which supports and equip nurses to become effective pain practitioners.

Morita et al. are to be thanked for their attempt to bring greater clarity to the subject of sedation at the end of life, more specifically in relation to continuous deep sedation (CDS) as an extreme (?far-reaching?) form of palliative sedation.1 Of the four types they describe, three are variations of proportional sedation, only the fourth is irreversible CDS from start to death. They comment that this ?may be an essentially separate medical practice from the other three types.? I agree, and suggest that it falls outside the definition of palliative sedation. As emphasized in The Principles of Revised Clinical Guidelines about Palliative Sedation Therapy of the Japanese Society for Palliative Medicine, palliative sedation should, like all therapeutic measures, be proportional to need.2 Even in a catastrophic situation, for example, a massive cancer-related arterial hemorrhage, proportionality is still relevant even though the initial dose of sedatives will almost certainly be higher than those used in less dramatic circumstances. Morita et al. suggest that the inclusion of ?intent to reduce consciousness? in earlier descriptions of palliative sedation should be abandoned because of the difficulty in evaluating this.1 However, there is always intention in therapeutics, and in this situation the intention is to palliate suffering, not to shorten life. As noted in the revised Japanese guidelines, ?It is ethically unacceptable to enforce palliative sedation intended to shorten life, which is different from foreseeing the foreshortening of life.?2 Morita et al. suggest that we should speak of ?treatment goal? rather than ?intention.? For me, the two terms are synonymous, but the former increases clarity and thus is preferable. For most people, a reducing level of consciousness is part of the natural dying process: progressive organ failure results in the accumulation of toxic metabolites, leading to depression of both cerebral cortex and brainstem. Sedatives will tend to accelerate and potentiate both a reduction in level of consciousness and cardiorespiratory failure. In those very close to death, the relative contributions of sedative medication and of natural dying to the reduced consciousness are impossible to determine. In Japan, the estimated prognosis of patients requiring CDS typically seems to be only a few days.2,3 This suggests that the typical clinical context for CDS in Japan could be different from, for example, that in The Netherlands, even though guidelines in both countries permit CDS in patients with an estimated prognosis of less than or equal to two weeks. Thus, for comparative purposes, it is essential for any treatment protocol used for monitoring and research purposes to record the physical status of the patients when CDS is started, and the time until death. It is also important that research is undertaken to identify the reasons for the gross disparity between the incidence of CDS in some nationwide studies (15?25%), particularly in countries where medically assisted dying is permitted (euthanasia, assisted suicide), and that reported by some palliative care services (1?3%).4