A dicer-related helicase opposes the age-related pathology from SKN-1 activation in ASI neurons.

Coordination of cellular responses to stress is essential for health across the lifespan. The transcription factor SKN-1 is an essential homeostat that mediates survival in stress-inducing environments and cellular dysfunction, but constitutive activation of SKN-1 drives premature aging thus revealing the importance of turning off cytoprotective pathways. Here, we identify how SKN-1 activation in two ciliated ASI neurons in Caenorhabditis elegans results in an increase in organismal transcriptional capacity that drives pleiotropic outcomes in peripheral tissues. An increase in the expression of established SKN-1 stress response and lipid metabolism gene classes of RNA in the ASI neurons, in addition to the increased expression of several classes of noncoding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a unique regulator of the SKN-1 homeostat that mediates SKN-1 abundance within intestinal cells. Moreover, RNAi-independent activity of the dicer-related DExD/H-box helicase, drh-1, in the intestine, can oppose the effects of aberrant SKN-1 transcriptional activation and delays age-dependent decline in health. Taken together, our results uncover a cell nonautonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system.

In vitro quality parameters of whole blood-derived platelets pooled using two different platelet pooling sets and stored up to 7 days are similar.

BACKGROUND: Increasing the number of collections of whole blood-derived platelets (WBDP) and lengthening the allowable storage time may alleviate platelet (PLT) shortages. There is a need for new PLT pooling sets that can provide acceptable quality on Day 7 of storage. STUDY DESIGN AND METHODS: This pool-and-split study compared WBDP prepared using the platelet-rich plasma method with the novel IMUGARD WB PLT pooling set and a control pooling set. After pooling and filtration, PLT products were tested on Days 1, 5, and 7. Large volume delayed sampling (LVDS) cultures were taken on Day 2. RESULTS: The median postfiltration residual white blood cell (rWBC) content was 0.18 million per product (maximum 1.26 million; n = 69) with mean PLT recovery of 88.5 ± 2.8% for the new set and median 0.23 million (maximum 1.83 million) rWBC with 87.5 ± 2.5% recovery for the control. Day 5 mean pH22°C were 7.18 ± 0.12 and 7.13 ± 0.10 for the new and control set, respectively. Day 5 in vitro quality parameters were within 20% between the two pooling sets. The new set Day 7 pH22°C was acceptable (7.07 ± 0.17, 100% ≥ 6.3), and most parameters were within 20% of Day 5 values. CONCLUSION: WBDP quality for the new pooling set is acceptable across a battery of in vitro tests when stored up to 7 days and meets FDA regulatory criteria. The quality parameters were similar between the new pooling set and the control set on Day 5. This new set is compatible with LVDS.

Tailored leadership training in emergency medicine: qualitative exploration of the impact of the EMLeaders programme on consultants and trainees in England.

BACKGROUND: Emergency medicine (EM) consultants are expected to provide leadership to facilitate optimal clinical results, effective teamwork and learning. To foster leadership skills, the Emergency Medicine Leadership Programme (EMLeaders) was launched in 2018 by the Royal College of Emergency Medicine (RCEM), Health Education England and National Health Service England. A mixed-methods evaluation of EMLeaders was commissioned to assess the impact at the strategic, team and individual levels. This paper reports the qualitative evaluation component. METHODS: Qualitative data collected from 2021 to 2022 were drawn from an online survey of RCEM members in England, which included four open questions about leadership training. At the end of the survey, participants were asked to share contact details if willing to undertake an in-depth qualitative interview. Interviews explored perceptions of the programme and impact of curriculum design and delivery. Data were analysed thematically against the Kirkpatrick framework, providing in-depth understanding. RESULTS: There were 417 survey respondents, of whom 177 had participated in EMLeaders. Semistructured interviews were completed with 13 EM consultants, 13 trainees and 1 specialty and associate specialist doctor. EMLeaders was highly valued by EM consultants and trainees, particularly group interaction, expert facilitation and face-to-face practical scenario work. Consultant data yielded the themes: we believe in it; EM relevance is key; on a leadership journey; shaping better leaders; and a broken system. Challenges were identified in building engagement within a pressured workplace system and embedding workplace role modelling. Trainees identified behavioural shift in themselves following the programme but wanted more face-to-face discussions with senior colleagues. Key trainee themes included value in being together, storytelling in leadership, headspace for the leadership lens and survival in a state of collapse. CONCLUSION: The development of leadership skills in EM is considered important. The EMLeaders programme can support leadership learning but further embedding is needed.

Circulating small RNA signatures differentiate accurately the subtypes of muscular dystrophies: small-RNA next-generation sequencing analytics and functional insights.

Muscular dystrophies are a group of rare and severe inherited disorders mainly affecting the muscle tissue. Duchene Muscular Dystrophy, Myotonic Dystrophy types 1 and 2, Limb Girdle Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy are some of the members of this family of disorders. In addition to the current diagnostic tools, there is an increasing interest for the development of novel non-invasive biomarkers for the diagnosis and monitoring of these diseases. miRNAs are small RNA molecules characterized by high stability in blood thus making them ideal biomarker candidates for various diseases. In this study, we present the first genome-wide next-generation small RNA sequencing in serum samples of five different types of muscular dystrophy patients and healthy individuals. We identified many small RNAs including miRNAs, lncRNAs, tRNAs, snoRNAs and snRNAs, that differentially discriminate the muscular dystrophy patients from the healthy individuals. Further analysis of the identified miRNAs showed that some miRNAs can distinguish the muscular dystrophy patients from controls and other miRNAs are specific to the type of muscular dystrophy. Bioinformatics analysis of the target genes for the most significant miRNAs and the biological role of these genes revealed different pathways that the dysregulated miRNAs are involved in each type of muscular dystrophy investigated. In conclusion, this study shows unique signatures of small RNAs circulating in five types of muscular dystrophy patients and provides a useful resource for future studies for the development of miRNA biomarkers in muscular dystrophies and for their involvement in the pathogenesis of the disorders.

Low Prevalence of NOTCH2NLC GGC Repeat Expansion in White Patients with Movement Disorders.

BACKGROUND: The objective of this study was to determine the prevalence of the GGC-repeat expansion in NOTCH2NLC in whites presenting with movement disorders. METHODS: We searched for the GGC-repeat expansion in NOTCH2NLC using repeat-primed polymerase chain reaction in 203 patients with essential tremor, 825 patients with PD, 194 patients with spinocerebellar ataxia, 207 patients with "possible" or "probable" MSA, and 336 patients with pathologically confirmed MSA. We also screened 30,008 patients enrolled in the 100,000 Genomes Project for the same mutation using ExpansionHunter, followed by repeat-primed polymerase chain reaction. All possible expansions were confirmed by Southern blotting and/or long-read sequencing. RESULTS: We identified 1 patient who carried the NOTCH2NLC mutation in the essential tremor cohort, and 1 patient presenting with recurrent encephalopathy and postural tremor/parkinsonism in the 100,000 Genomes Project. CONCLUSIONS: GGC-repeat expansion in NOTCH2NLC is rare in whites presenting with movement disorders. In addition, existing whole-genome sequencing data are useful in case ascertainment. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Using practical wisdom to facilitate ethical decision-making: a major empirical study of phronesis in the decision narratives of doctors.

BACKGROUND: Medical ethics has recently seen a drive away from multiple prescriptive approaches, where physicians are inundated with guidelines and principles, towards alternative, less deontological perspectives. This represents a clear call for theory building that does not produce more guidelines. Phronesis (practical wisdom) offers an alternative approach for ethical decision-making based on an application of accumulated wisdom gained through previous practice dilemmas and decisions experienced by practitioners. Phronesis, as an 'executive virtue', offers a way to navigate the practice virtues for any given case to reach a final decision on the way forward. However, very limited empirical data exist to support the theory of phronesis-based medical decision-making, and what does exist tends to focus on individual practitioners rather than practice-based communities of physicians. METHODS: The primary research question was: What does it mean to medical practitioners to make ethically wise decisions for patients and their communities? A three-year ethnographic study explored the practical wisdom of doctors (n = 131) and used their narratives to develop theoretical understanding of the concepts of ethical decision-making. Data collection included narrative interviews and observations with hospital doctors and General Practitioners at all stages in career progression. The analysis draws on neo-Aristotelian, MacIntyrean concepts of practice- based virtue ethics and was supported by an arts-based film production process. RESULTS: We found that individually doctors conveyed many different practice virtues and those were consolidated into fifteen virtue continua that convey the participants' 'collective practical wisdom', including the phronesis virtue. This study advances the existing theory and practice on phronesis as a decision-making approach due to the availability of these continua. CONCLUSION: Given the arguments that doctors feel professionally and personally vulnerable in the context of ethical decision-making, the continua in the form of a video series and app based moral debating resource can support before, during and after decision-making reflection. The potential implications are that these theoretical findings can be used by educators and practitioners as a non-prescriptive alternative to improve ethical decision-making, thereby addressing the call in the literature, and benefit patients and their communities, as well.

Activities of daily living in myotonic dystrophy type 1.

OBJECTIVES: The objective of this cross-sectional, observational study was to investigate performance of activities of daily living in patients with myotonic dystrophy type 1 (DM1). MATERIALS AND METHODS: Adults with genetically confirmed DM1 were recruited from Newcastle University (Newcastle upon Tyne, UK) and University College London Hospitals NHS Foundation Trust (London, UK). Data on activities of daily living were recorded through the DM1-ActivC (scale scores range between 0 and 100, where a higher/lower score indicates a higher/lower ability). RESULTS: Our sample comprised 192 patients with DM1 (mean age: 46 years; 51% female). Patients reported most difficulties with running, carrying and putting down heavy objects, and standing on one leg, and least difficulties with eating soup, washing upper body, and taking a shower. Irrespective of the disease duration (mean: 20 years), most patients were able to perform basic and instrumental activities of daily living (eg personal hygiene and grooming, showering, eating, cleaning and shopping), with the exception of functional mobility/transfer tasks (eg walking uphill and running). The mean DM1-ActivC total score was estimated at 71 (95% CI: 68-74). Estimated progenitor cytosine-thymine-guanine repeat length and age explained 27% of the variance in DM1-ActivC total scores (P < .001). CONCLUSIONS: We show that DM1 impairs performance of activities of daily living, in particular those requiring a high degree of muscle strength, stability and coordination. Yet, across the evolution of the disease, the majority of patients will still be able to independently perform most basic and instrumental activities of daily living.

Phronesis in Medical Ethics: Courage and Motivation to Keep on the Track of Rightness in Decision-Making.

Ethical decision making in medicine has recently seen calls to move towards less prescriptive- based approaches that consider the particularities of each case. The main alternative call from the literature is for better understanding of phronesis (practical wisdom) concepts applied to decision making. A well-cited phronesis-based approach is Kaldjian's five-stage theoretical framework: goals, concrete circumstances, virtues, deliberation and motivation to act. We build on Kaldjian's theory after using his framework to analyse data collected from a three-year empirical study of phronesis and the medical community. The data are a set of narratives collected in response to asking a medical community (131 doctors at various stages of their careers) what making ethically wise decisions means to them. We found that Kaldjian's five concepts are present in the accounts to some extent but that one of the elements, motivation, is constructed as playing a different, though still crucial role. Rather than being an end-stage of the process as Kaldjian's framework suggests, motivation was constructed as initiating the process and maintaining the momentum of taking a phronesis-based approach. The implications for medical ethics decision-making education are significant as motivation itself is a highly complex concept. We therefore theorise that motivation is required for leading in, continuing and completing the actions of the ethical decision taken. Appreciating the central importance of motivation through the whole of Kaldjian's framework has implications for cultivating the virtues of phronesis and courage to take the right course of action.

A model to predict ventilator requirement in myotonic dystrophy type 1.

INTRODUCTION: Respiratory failure is one of the most common causes of mortality in myotonic dystrophy type 1 (DM1). The variation in the DM1 phenotype causes difficulty in clinically predicting the severity of respiratory involvement, and variables such as daytime somnolence are insensitive for identifying patients who require continuous or bilevel nocturnal positive airway pressure (NPAP). METHODS: We retrospectively analyzed a cohort of 126 adult onset patients with DM1 at the point of their first respiratory assessment to identify significant factors in predicting ventilator requirement. RESULTS: Triplet repeat years score and Muscle Impairment Rating Scale were significantly linearly related to NPAP and, thus, formed the model. DISCUSSION: We devised a simple model to aid clinicians in predicting at first visit those patients with DM1 who are likely to require NPAP. We also describe the causes of failure to tolerate NPAP in DM1. Muscle Nerve 59:683-687, 2019.

Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy.

INTRODUCTION: Earlier small case series and clinical observations reported on chronic pain playing an important role in facioscapulohumeral dystrophy (FSHD). The aim of this study was to determine the characteristics and impact of pain on quality of life (QoL) in patients with FSHD. METHODS: We analyzed patient reported outcome measures collected through the U.K. FSHD Patient Registry. RESULTS: Of 398 patients, 88.6% reported pain at the time of study. The most frequent locations were shoulders and lower back. A total of 203 participants reported chronic pain, 30.4% of them as severe. The overall disease impact on QoL was significantly higher in patients with early onset and long disease duration. Chronic pain had a negative impact on all Individualised Neuromuscular Quality of Life Questionnaire domains and overall disease score. DISCUSSION: Our study shows that pain in FSHD type 1 (FSHD1) is frequent and strongly impacts on QoL, similar to other chronic, painful disorders. Management of pain should be considered when treating FSHD1 patients. Muscle Nerve 57: 380-387, 2018.

Myotonic dystrophy: diagnosis, management and new therapies.

PURPOSE OF REVIEW: Myotonic dystrophies type 1 and type 2 are progressive multisystem genetic disorders with clinical and genetic features in common. Myotonic dystrophy type 1 is the most prevalent muscular dystrophy in adults and has a wide phenotypic spectrum. The average age of death in myotonic dystrophy type 1 is in the fifth decade. In comparison, myotonic dystrophy type 2 tends to cause a milder phenotype with later onset of symptoms and is less common than myotonic dystrophy type 1. Historically, patients with myotonic dystrophy type 1 have not received the medical and social input they need to maximize their quality and quantity of life. This review describes the improved understanding in the molecular and clinical features of myotonic dystrophy type 1 as well as the screening of clinical complications and their management. We will also discuss new potential genetic treatments. RECENT FINDINGS: An active approach to screening and management of myotonic dystrophies type 1 and type 2 requires a multidisciplinary medical, rehabilitative and social team. This process will probably improve morbidity and mortality for patients. Genetic treatments have been successfully used in in-vitro and animal models to reverse the physiological, histopathological and transcriptomic features. SUMMARY: Molecular therapeutics for myotonic dystrophy will probably bridge the translational gap between bench and bedside in the near future. There will still be a requirement for clinical screening of patients with myotonic dystrophy with proactive and systematic management of complications.

A multicentre postal survey investigating the contribution of illness perceptions, coping and optimism to quality of life and mood in adults with muscle disease.

OBJECTIVE: To replicate the finding that illness perceptions influence quality of life in adults with muscle disease and to explore the additional influence of coping and optimism on quality of life and mood. DESIGN: A postal survey including questionnaires recording quality of life, mood, illness perceptions, optimism, coping and functional impairment. SETTING: National Health Service muscle clinics in the United Kingdom. PARTICIPANTS: A convenience sample of adults with muscle disease. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Individualised Neuromuscular Quality of Life Questionnaire, Hospital Anxiety and Depression Scale. RESULTS: A total of 226 completed questionnaires were returned. Although functional impairment explained most of the variance in three out of eight quality of life domains, psychological factors explained greater amounts of variance (between 19% and 52% of variance) in all other quality of life domains and in both mood domains (between 45% and 48% of variance). Overall, illness perceptions explained much of the variance in quality of life and mood score (between 5% and 37% of variance), while coping (up to 8% of variance) and optimism (up to 15% of variance) explained smaller amounts of variance. CONCLUSION: The results confirm that illness perceptions are associated with quality of life in muscle disease and suggest that they also influence mood. The addition of optimism and coping variables into the analysis yielded small increases in the proportions of variance in quality of life and mood which were explained. These results have implications for the composition of future psychological interventions.

Disrupting the SKN-1 homeostat: mechanistic insights and phenotypic outcomes.

The mechanisms that govern maintenance of cellular homeostasis are crucial to the lifespan and healthspan of all living systems. As an organism ages, there is a gradual decline in cellular homeostasis that leads to senescence and death. As an organism lives into advanced age, the cells within will attempt to abate age-related decline by enhancing the activity of cellular stress pathways. The regulation of cellular stress responses by transcription factors SKN-1/Nrf2 is a well characterized pathway in which cellular stress, particularly xenobiotic stress, is abated by SKN-1/Nrf2-mediated transcriptional activation of the Phase II detoxification pathway. However, SKN-1/Nrf2 also regulates a multitude of other processes including development, pathogenic stress responses, proteostasis, and lipid metabolism. While this process is typically tightly regulated, constitutive activation of SKN-1/Nrf2 is detrimental to organismal health, this raises interesting questions surrounding the tradeoff between SKN-1/Nrf2 cryoprotection and cellular health and the ability of cells to deactivate stress response pathways post stress. Recent work has determined that transcriptional programs of SKN-1 can be redirected or suppressed to abate negative health outcomes of constitutive activation. Here we will detail the mechanisms by which SKN-1 is controlled, which are important for our understanding of SKN-1/Nrf2 cytoprotection across the lifespan.

Myotonic dystrophy type 1: palliative care guidelines.

Palliative care for adults with neuromuscular conditions is an emerging field. Previous guidelines regarding myotonic dystrophy and palliative care have only mentioned end-of-life care and little else. The following guidelines have been written using national experts as a description of best practice as part of the Dystrophia Myotonica National Care Guidelines Consortium.

A dicer-related helicase opposes the age-related pathology from SKN-1 activation in ASI neurons.

Coordination of cellular responses to stress are essential for health across the lifespan. The transcription factor SKN-1 is an essential homeostat that mediates survival in stress-inducing environments and cellular dysfunction, but constitutive activation of SKN-1 drives premature aging thus revealing the importance of turning off cytoprotective pathways. Here we identify how SKN-1 activation in two ciliated ASI neurons in C. elegans results in an increase in organismal transcriptional capacity that drives pleiotropic outcomes in peripheral tissues. An increase in the expression of established SKN-1 stress response and lipid metabolism gene classes of RNA in the ASI neurons, in addition to the increased expression of several classes of non-coding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a novel regulator of the SKN-1 homeostat that mediates SKN-1 abundance within intestinal cells. Moreover, RNAi-independent activity of the dicer-related DExD/H-box helicase, drh-1 , in the intestine, can oppose the e2ffects of aberrant SKN-1 transcriptional activation and delays age-dependent decline in health. Taken together, our results uncover a cell non-autonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system. SIGNIFICANCE STATEMENT: Unlike activation, an understudied fundamental question across biological systems is how to deactivate a pathway, process, or enzyme after it has been turned on. The irony that the activation of a transcription factor that is meant to be protective can diminish health was first documented by us at the organismal level over a decade ago, but it has long been appreciated that chronic activation of the human ortholog of SKN-1, NRF2, could lead to chemo- and radiation resistance in cancer cells. A colloquial analogy to this biological idea is a sink faucet that has an on valve without a mechanism to shut the water off, which will cause the sink to overflow. Here, we define this off valve.

Scale-Up of flat plate photobioreactors considering diffuse and direct light characteristics.

This study investigates the scaling of photobioreactor productivity based on the growth of Nannochloropsis salina incorporating the effects of direct and diffuse light. The scaling and optimization of photobioreactor geometry was analyzed by determining the growth response of a small-scale system designed to represent a core sample of a large-scale photobioreactor. The small-scale test apparatus was operated at a variety of light intensities on a batch time scale to generate a photosynthetic irradiance (PI) growth dataset, ultimately used to inform a PI growth model. The validation of the scalability of the PI growth model to predict productivity in large-scale systems was done by comparison with experimental growth data collected from two geometrically different large-scale photobioreactors operated at a variety of light intensities. For direct comparison, the small-scale and large-scale experimental systems presented were operated similarly and in such a way to incorporate cultivation relevant time scales, light intensities, mixing, and nutrient loads. Validation of the scalability of the PI growth model enables the critical evaluation of different photobioreactor geometries and design optimization incorporating growth effects from diffuse and direct light. Discussion focuses on the application of the PI growth model to assess the effect of diffuse light growth compared to direct light growth for the evaluation of photobioreactors followed by the use of the model for photobioreactor geometry optimization on the metric of areal productivity.

Diabetes mellitus and periodontal disease: the profession's choices.

This paper reviews why doctors rarely refer their diabetic patients for a dental opinion and suggests strategies to teach them the importance of controlling periodontal disease as part of a system of joint care. A pro forma to share results and define diabetic risks for doctors, dentists and patients has been developed. Periodontal risks could be better defined if the community periodontal index of treatment needs score of 2 for calculus is divided into 2 for supra-gingival and 2* for sub-gingival types.

An overview of heart rhythm disorders and management in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is the most common adult form of muscular dystrophy, presenting with a constellation of systemic findings secondary to a CTG triplet expansion of the noncoding region of the DMPK gene. Cardiac involvement is frequent, with conduction disease and supraventricular and ventricular arrhythmias being the most prevalent cardiac manifestations, often developing from a young age. The development of cardiac arrhythmias has been linked to increased morbidity and mortality, with sudden cardiac death well described. Strategies to mitigate risk of arrhythmic death have been developed. In this review, we outline the current knowledge on the pathophysiology of rhythm abnormalities in patients with myotonic dystrophy and summarize available knowledge on arrhythmic risk stratification. We also review management strategies from an electrophysiological perspective, attempting to underline the substantial unmet need to address residual arrhythmic risks for this population.

A Normal Electrocardiogram Does Not Exclude Infra-Hisian Conduction Disease in Patients With Myotonic Dystrophy Type 1.

OBJECTIVES: This study aimed to identify electrocardiographic (ECG) predictors of a prolonged His-ventricular (HV) interval in patients with type 1 myotonic dystrophy (DM1). BACKGROUND: Patients with DM1 have an increased risk of sudden cardiac death. The presence of His-Purkinje system disease/prolonged HV interval (≥70 ms) is associated with a higher risk of potentially life-threatening bradyarrhythmic events. METHODS: Electrophysiology studies (EPSs) were performed in all DM1 patients referred to 2 tertiary centers for routine cardiac assessment. In a subgroup of patients, the EPS was repeated at varying intervals. RESULTS: A total of 154 patients (mean age: 43.7 ± 13.3; 58.1% male) underwent 202 diagnostic EPSs. HV ≥70 ms was found on 58 EPSs (28.7%); 9 of 59 patients (15.2%) with PR <200 ms and QRS interval <110 ms on baseline ECG had an HV ≥70 ms on EPS. Among those with PR ≥200 ms and/or QRS interval ≥100 ms, only 33.9% had an HV ≥70 ms on EPS. There were 38 patients who underwent repeated EPS, in which 28.8% demonstrated a prolongation of the HV interval overall compared with baseline. QRS duration demonstrated the most powerful discriminative capacity for HV ≥70 ms (area under the receiver operating characteristic curve: 0.76; 95% confidence interval [CI]: 0.68 to 0.84; p < 0.001). On multivariate analysis, QRS interval ≥112 ms had the highest predictive value for HV ≥70 ms (odds ratio: 7.94; 95% CI: 3.85 to 16.37. CONCLUSIONS: ECG parameters have a poor predictive value for infra-Hisian conduction block in DM1 patients. QRS and PR intervals are normal in up to 15.2% of DM1 patients with prolonged HV, and 66.1% of those with PR ≥200 ms and/or QRS ≥100 ms do not have advanced His-Purkinje conduction system disease on EPS. Electrophysiology testing should be a mandatory part of screening for all patients to guide prophylactic pacemaker implantation.