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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].

The efficient synthesis of a N,N'‐bis(2,6‐terphenyl) substituted N‐heterocyclic carbene (NHC) is reported. The gain in efficiency and total yield, compared to traditional synthesis, is the result of a high yielding and scalable double Suzuki coupling step, affording a 2,6‐terphenyl aniline, catalyzed by a Pd β‐diketiminate complex. A stereoelectronic study revealed the new NHC to be very similar to the only other N,N'‐bis(2,6‐terphenyl) substituted NHC. Application to the stabilization of Group 13 trihydrides gives acceptable outcomes but inferior to those observed when the bulky IPr* NHC is deployed. [ABSTRACT FROM AUTHOR]

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.

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.

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.

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

Background The most effective method and modality for measuring glenoid version for different shoulder conditions is uncertain. Computed tomography (CT) imaging exposes the patient to radiation, and standard magnetic resonance imaging (MRI) does not consistently image the entire scapula. This study investigates the reliability of a new method for assessing glenoid version using routine shoulder MRI. Methods MRI images of 20 patients undergoing arthroscopy for shoulder instability were independently assessed by 3 clinicians for osseous and chondrolabral glenoid version. To assess glenoid version, a line was drawn from medial corner of the glenoid body to midpoint of the glenoid face. A line perpendicular to this was the reference against which to measure glenoid version. Measurements were repeated after 3 months to assess intra- and interobserver reliability. Reliability was determined using intraclass correlation coefficients (ICCs). Results Interclass correlation coefficients showed at least good reliability for most estimates of intraobserver reliability (ICC ≥ .66) and excellent reliability for most estimates of interobserver reliability (ICC ≥ .84), with the exception of some inferior glenoid measurements where ICC was poor (ICC ≤.41). Discussion We propose that this new method of measuring glenoid on standard axial MRI can be used as a simple, practical, and reliable method in shoulder instability patients, which will reduce the requirement for CT in this group.

We read with interest the article by Ramos-Rincon and colleagues about patients with COVID-19 dying in acute medical wards in a Spanish University hospital [...]

The integration of augmented reality (AR) technology into personal computing is happening fast, and augmented workplaces for professionals in areas such as Industry 4.0 or digital health can reasonably be expected to form liminal zones that push the boundary of what currently possible. The application potential in the creative industries, however, is vast and can target broad audiences, so with UNBODY, we set out to push boundaries of a different kind and depart from the graphic-centric worlds of AR to explore textual and aural dimensions of an extended reality, in which words haunt and re-create our physical selves. UNBODY is an AR installation for smart glasses that embeds poetry in the user’s surroundings. The augmented experience turns reality into a medium where holographic texts and film clips spill from dayglow billboards and totems. In this paper, we develop a blueprint for an AR escape room dedicated to the spoken and written word, with its open source code facilitating uptake by others into existing or new AR escape rooms. We outline the user-centered process of designing, building, and evaluating UNBODY. More specifically, we deployed a system usability scale (SUS) and a spatial interaction evaluation (SPINE) in order to validate its wider applicability. In this paper, we also describe the composition and concept of the experience, identifying several components (trigger posters, posters with video overlay, word dropper totem, floating object gallery, and a user trail visualization) as part of our first version before evaluation. UNBODY provides a sense of situational awareness and immersivity from inside an escape room. The recorded average mean for the SUS was 59.7, slightly under the recommended 68 average but still above ‘OK’ in the zone of low marginal acceptable. The findings for the SPINE were moderately positive, with the highest scores for output modalities and navigation support. This indicated that the proposed components and escape room concept work. Based on these results, we improved the experience, adding, among others, an interactive word composer component. We conclude that a poetry escape room is possible, outline our co-creation process, and deliver an open source technical framework as a blueprint for adding enhanced support for the spoken and written word to existing or coming AR escape room experiences. In an outlook, we discuss additional insight on timing, alignment, and the right level of personalization.

Abstract In worldwide conditions of increasingly antibiotic-resistant hospital infections, it is important to research alternative therapies. Bdellovibrio bacteriovorus bacteria naturally prey on Gram-negative pathogens, including antibiotic-resistant strains and so B. bacteriovorus have been proposed as “living antibiotics” to combat antimicrobially-resistant pathogens. Predator-prey interactions are complex and can be altered by environmental components. To be effective B. bacteriovorus predation needs to work in human body fluids such as serum where predation dynamics may differ to that studied in laboratory media. Here we combine mathematical modelling and lab experimentation to investigate the predation of an important carbapenem-resistant human pathogen, Klebsiella pneumoniae, by B. bacteriovorus in human serum versus buffer. We show experimentally that B. bacteriovorus is able to reduce prey numbers in each environment, on different timescales. Our mathematical model captures the underlying dynamics of the experimentation, including an initial predation-delay at the predator-prey-serum interface. Our research shows differences between predation in buffer and serum and highlights both the potential and limitations of B. bacteriovorus acting therapeutically against K. pneumoniae in serum, informing future research into the medicinal behaviours and dosing of this living antibacterial.

‘Palliation sedation’ is a widely used term to describe the intentional administration of sedatives to reduce a dying person’s consciousness to relieve intolerable suffering from refractory symptoms. Research studies generally focus on either ‘continuous sedation until death’ or ‘continuous deep sedation’. It is not always clear whether instances of secondary sedation (i.e. caused by specific symptom management) have been excluded. Continuous deep sedation is controversial because it ends a person’s ‘biographical life’ (the ability to interact meaningfully with other people) and shortens ‘biological life’. Ethically, continuous deep sedation is an exceptional last resort measure. Studies suggest that continuous deep sedation has become ‘normalized’ in some countries and some palliative care services. Of concern is the dissonance between guidelines and practice. At the extreme, there are reports of continuous deep sedation which are best described as non-voluntary (unrequested) euthanasia. Other major concerns relate to its use for solely non-physical (existential) reasons, the under-diagnosis of delirium and its mistreatment, and not appreciating that unresponsiveness is not the same as unconsciousness (unawareness). Ideally, a multiprofessional palliative care team should be involved before proceeding to continuous deep sedation. Good palliative care greatly reduces the need for continuous deep sedation.