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Abstract This case report describes the first reported overdose of the dihydropyridine calcium channel blocker (CCB) lercanidipine. A 49 yr old male presented to the Emergency Department 3 hrs after the ingestion of 560 mg of lercanidipine. In the department he had a witnessed seizure within 15 minutes of arrival attributed to the overdose. Following immediate recovery of consciousness after the seizure, he had refractory hypotension and bradycardia which failed to respond to fluid resuscitation, glucagon therapy, and intravenous calcium. He went on to require vasopressor support with noradrenaline and was treated with high dose insulin therapy which was successful in achieving cardiovascular stability. Vasopressor therapy was no longer required within one half life of lercanidipine, and the total stay on intensive care was one day before transfer to a ward. Calcium channel blocker overdose is an uncommon but life-threatening overdose. Treatment for severe toxicity is similar to b-blocker overdose. Hypotension is treated with intravenous fluid therapy, intravenous calcium and possibly glucagon with vasopressor or inotropic support as required. Atropine is used to attempt reversal of bradycardia. High doses of intravenous insulin with intravenous dextrose as required (hyperinsulinaemic euglycaemia or HIET), has also been successfully reported. Experimental animal data suggests that HIET is of benefit and potentially superior to fluid therapy, calcium, glucagon and potentially vasopressor therapy. HIET effectively and sustainably reverses hypotension, bradycardia and improves myocardial contractility and metabolism. Current advice in calcium channel blocker overdose is to begin therapy early in toxicity, starting with a 1.0 IU/kg insulin bolus followed by an infusion of 0.5 IU/kg/hr of insulin and dextrose as required titrated to clinical response.

Introduction: People with learning disabilities experience worse healthcare outcomes than the general population. There is evidence that they are more likely to experience avoidable mortality and less likely to receive critical care interventions during an acute illness. Decisions regarding critical care admission or intervention must be based on evidence of whether a patient will receive lasting benefit from a critical care admission. We therefore investigated outcomes from critical care admissions in people with learning disabilities and compared them to general critical care patients., Methods: People with learning disabilities who were admitted to our critical care unit were identified via our coding department, from the Intensive Care National Audit and Research Centre (ICNARC) database and from our local electronic patient record. Mortality and length of stay outcomes for people with learning disabilities were recorded following critical care admission over a 5 years period and compared with the general critical care cohort over the same 5 years period. Longer term survival of patients with learning disabilities was also recorded., Results: 297 critical care admissions in 176 people with learning disabilities were identified. The general critical care cohort included 6224 admissions in 4976 patients. The standardised mortality rate in people with learning disabilities admitted to critical care was 0.59 compared to the general critical care cohort which was 0.98. Mortality outcomes remained better in patients with learning disabilities compared to the general critical care cohort in invasively ventilated patients and in people with profound and multiple learning disability. Critical care length of stay was longer in people with learning disabilities. 12 month mortality was 14.8% in the learning disability cohort. By the end of the study, 23.9% of people with learning disabilities had died after a mean of 482 days following their first critical care admission. Patients who are currently still alive after having survived to hospital discharge following critical care admission have lived an average of 1129 days. After only 7.4% of critical care admissions in people with learning disabilities was there an increase in dependence on assistance in activities of daily living., Discussion: We have shown that people with learning disabilities are more likely to survive following a critical care admission than general critical care patients. This is regardless of whether they were invasively ventilated or whether they had profound and multiple learning disabilities. Critical care admission and invasive ventilation are associated with good short and longer term mortality., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Intensive Care Society 2024.)

Introduction: The purpose of this study is to evaluate the use of a varenicline solution nasal spray (VNS) for reducing the signs and symptoms of dry eye following laser in situ keratomileusis (LASIK)., Methods: Subjects electing to undergo LASIK were randomized to VNS (study group) or placebo/vehicle (control group) and initiated treatment with the nasal spray twice daily 28 days prior to surgery with continued treatment for 84 days following LASIK. After initiation of treatment, subjects were seen on the day of surgery and postoperatively on Days 1, 7, 28, 84 (3 months) and 168 (6 months). The primary outcome measure was the mean change in NEI-VFQ-25, a 25-item dry eye questionnaire, from baseline to 3 months. The second primary outcome measure was the mean change in corneal fluorescein staining. Secondary outcome measures included evaluation of tear break-up time, Schirmer testing, tear osmolarity and eye dryness score (EDS)., Results: Twenty subjects were enrolled in each group and successfully underwent LASIK. Both groups demonstrated an improvement in the National Eye Institute Visual Function Questionnaire (NEI-VFQ) at 3 months. The study group demonstrated improved corneal staining scores at months 1 and 3. Similarly, the study group demonstrated improvement in tear osmolarity scores versus the placebo group at the same time points. Although the study group was numerically greater than placebo for each time point for both corneal staining and tear osmolarity, the differences were not statistically significant for any primary or secondary outcome measures., Conclusion: VNS is a dry eye treatment option for patients following LASIK and may have potential benefit for patients hoping to avoid additional topical medications. The results were not statistically significant compared to placebo in this trial, and further investigation of the use of VNS following LASIK in a larger trial would be beneficial., (© 2024. The Author(s).)

Background: Motor Neurone Disease (MND) leads to muscle weakening, affecting movement, speech, and breathing. Home mechanical ventilation, particularly non-invasive ventilation (NIV), is used to alleviate symptoms and support breathing in people living with MND. While home mechanical ventilation can alleviate symptoms and improve survival, it does not slow the progression of MND. This study addresses gaps in understanding end-of-life decision-making in those dependent on home mechanical ventilation, considering the perspectives of patients, family members, and bereaved families., Methods: A UK-wide qualitative study using flexible interviews to explore the experiences of people living with MND (n = 16), their family members (n = 10), and bereaved family members (n = 36) about the use of home mechanical ventilation at the end of life., Results: Some participants expressed a reluctance to discuss end-of-life decisions, often framed as a desire to "live for the day" due to the considerable uncertainty faced by those with MND. Participants who avoided end-of-life discussions often engaged in 'selective decision-making' related to personal planning, involving practical and emotional preparations. Many faced challenges in hypothesising about future decisions given the unpredictability of the disease, opting to make 'timely decisions' as and when needed. For those who became dependent on ventilation and did not want to discuss end of life, decisions were often 'defaulted' to others, especially once capacity was lost. 'Proactive decisions', including advance care planning and withdrawal of treatment, were found to empower some patients, providing a sense of control over the timing of their death. A significant proportion lacked a clear understanding of the dying process and available options., Conclusions: The study highlights the complexity and evolution of decision-making, often influenced by the dynamic and uncertain nature of MND. The study emphasises the need for a nuanced understanding of decision-making in the context of MND., (© 2024. The Author(s).)

Significant inconsistencies in respiratory care provision for Duchenne muscular dystrophy (DMD) are reported across different specialist neuromuscular centres in the UK. The absence of robust clinical evidence and expert consensus is a barrier to the implementation of care recommendations in public healthcare systems as is the need to increase awareness of key aspects of care for those living with DMD. Here, we provide evidenced-based and/or consensus-based best practice for the respiratory care of children and adults living with DMD in the UK, both as part of routine care and in an emergency., Methodology: Initiated by an expert working group of UK-based respiratory physicians (including British Thoracic Society (BTS) representatives), neuromuscular clinicians, physiotherapist and patient representatives, draft guidelines were created based on published evidence, current practice and expert opinion. After wider consultation with UK respiratory teams and neuromuscular services, consensus was achieved on these best practice recommendations for respiratory care in DMD., Result: The resulting recommendations are presented in the form of a flow chart for assessment and monitoring, with additional guidance and a separate chart setting out key considerations for emergency management. The recommendations have been endorsed by the BTS., Conclusions: These guidelines provide practical, reasoned recommendations for all those managing day-to-day and acute respiratory care in children and adults with DMD. The hope is that this will support patients and healthcare professionals in accessing high standards of care across the UK., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Depending on the definitional criteria used, approximately 5% to 10% of critical adults will require prolonged mechanical ventilation with longer-term outcomes that are worse than those ventilated for a shorter duration. Outcomes are affected by patient characteristics before critical illness and its severity but also by organizational characteristics and care models. Definitive trials of interventions to inform care activities, such as ventilator weaning, upper airway management, rehabilitation, and nutrition specific to the prolonged mechanical ventilation patient population, are lacking. A structured and individualized approach developed by the multiprofessional team in discussion with the patient and their family is warranted., Competing Interests: Disclosure The authors have no potential conflicts of interest to declare relevant to this publication., (Copyright © 2024 Elsevier Inc. All rights reserved.)

(1) Background: High-flow nasal therapy (HFNT) has shown several benefits in addressing respiratory failure. However, the quality of evidence and the guidance for safe practice are lacking. This survey aimed to understand HFNT practice and the needs of the clinical community to support safe practice. (2) Method: A survey questionnaire was developed and distributed to relevant healthcare professionals through national networks in the UK, USA and Canada; responses were collected between October 2020 and April 2021. (3) Results: In the UK and Canada, HFNT was used in 95% of hospitals, with the highest use being in the emergency department. HNFT was widely used outside of a critical care setting. HFNT was mostly used to treat acute type 1 respiratory failure (98%), followed by acute type 2 respiratory failure and chronic respiratory failure. Guideline development was felt to be important (96%) and urgent (81%). Auditing of practice was lacking in 71% of hospitals. In the USA, HFNT was broadly similar to UK and Canadian practice. (4) Conclusions: The survey results reveal several key points: (a) HFNT is used in clinical conditions with limited evidence; (b) there is a lack of auditing; (c) it is used in wards that may not have the appropriate skill mix; and (d) there is a lack of guidance for HFNT use.

This paper assesses and reports the experience of ten teams working to port, validate, and benchmark several High Performance Computing applications on a novel GPU-accelerated Arm testbed system. The testbed consists of eight NVIDIA Arm HPC Developer Kit systems, each one equipped with a server-class Arm CPU from Ampere Computing and two data center GPUs from NVIDIA Corp. The systems are connected together using InfiniBand interconnect. The selected applications and mini-apps are written using several programming languages and use multiple accelerator-based programming models for GPUs such as CUDA, OpenACC, and OpenMP offloading. Working on application porting requires a robust and easy-to-access programming environment, including a variety of compilers and optimized scientific libraries. The goal of this work is to evaluate platform readiness and assess the effort required from developers to deploy well-established scientific workloads on current and future generation Arm-based GPU-accelerated HPC systems. The reported case studies demonstrate that the current level of maturity and diversity of software and tools is already adequate for large-scale production deployments.

Guidelines suggest that exhaled gases do not reach the outlet of noninvasive ventilators in clinical use. In this study, when tidal volumes exceeded 800 mL, exhaled gases did reach the ventilator, leading to a risk of cross-infection between users. https://bit.ly/3EdvtY6., Competing Interests: Conflict of interest: B. Messer reports personal fees from Fisher & Paykel outside the submitted work. Conflict of interest: A.D. Armstrong reports personal fees from Fisher & Paykel and grants from Breas, outside the submitted work. Conflict of interest: N.D. Lane reports grants from the ResMed Foundation and Bright Northumbria, and nonfinancial support from Chiesi, outside the submitted work. Conflict of interest: A. Robb has nothing to disclose. Conflict of interest: R.E. Bullock has nothing to disclose., (Copyright ©The authors 2022.)

Background: The COVID-19 pandemic has resulted in increased admissions with respiratory failure and there have been reports of oxygen failure and shortages of machines to deliver ventilation and Continuous Positive Airway Pressure (CPAP). Domiciliary ventilators which entrain room air have been widely used during the pandemic. Poor outcomes reported with non-invasive respiratory support using ventilators which lack an oxygen blender could be related to an unreliable Fraction of inspired O 2 (FiO 2 ). Additionally, with concerns about oxygen failure, the variety of ventilator circuits used as well as differing peak inspiratory flow rates (PIFR) could impact on the FiO 2 delivered during therapy with domiciliary ventilators., Methods: In a series of bench tests, we tested the effect of choice of circuit and different PIFR on the FiO 2 achieved during simulation of ventilation and CPAP therapy using domiciliary ventilators., Results: FiO 2 was highly dependent upon the type of circuit used with circuits with an active exhalation valve achieving similar FiO 2 at lower oxygen flow rates than circuits using an exhalation port. During CPAP therapy, high PIFR resulted in significantly lower FiO 2 than low PIFR., Conclusions: This study has implications for oxygen usage as well as delivery of non-invasive respiratory support during therapy with domiciliary ventilators when these are used during the second wave of COVID-19., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Intensive Care Society 2020.)

Introduction: Pseudomonas aeruginosa increases morbidity and mortality in respiratory disease. To date the long-term ventilation population does not have clear guidelines regarding its management., Method: We undertook a retrospective observational study in a regional long-term ventilation population (837 patients). We defined the primary outcome as P. aeruginosa isolation. In addition positive cultures for copathogens ( Serratia , Proteus species, Stenotrophomonas , Burkholderia cepacia complex and nontuberculous mycobacteria) were recorded . Logistic regression and odds ratios were calculated., Results: 17.6% of the cohort isolated P. aeruginosa , and this pathogen was cultured more frequently in patients with a tracheostomy (logistic regression coefficient 2.90, p≤0.0001) and cystic fibrosis/bronchiectasis (logistic regression coefficient 2.48, p≤0.0001). 6.3% of patients were ventilated via tracheostomy. In the P. aeruginosa positive cohort 46.9% of patients were treated with a long-term macrolide, 36.7% received a nebulised antibiotic and 21.1% received both. Tracheostomised P. aeruginosa positive patients received a nebulised antibiotic more frequently (OR 2.63, 95% CI 1.23-5.64, p=0.013). Copathogens were isolated in 33.3% of the P. aeruginosa cohort. In this cohort patients with a tracheostomy grew a copathogen more frequently than those without (OR 2.75, 95% CI 1.28-5.90)., Conclusions: P. aeruginosa isolation is common within the adult long-term ventilation population and is significantly associated with tracheostomy, cystic fibrosis and bronchiectasis. Further research and international guidelines are needed to establish the prognostic impact of P. aeruginosa and to guide on antimicrobial management. The increased risk of P. aeruginosa should be considered when contemplating long-term ventilation via tracheostomy., Competing Interests: Conflict of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. B. Messer reports speakers’ fees from Fisher and Paykel outside the submitted work. A. De Soyza has received fees/grants from AstraZeneca, Bayer, GSK, Novartis, Grifols, Gilead and Zambon., (Copyright ©The authors 2022.)

Importance: Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies., Objective: To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure., Design, Setting, and Participants: A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021., Interventions: Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475)., Main Outcomes and Measures: The primary outcome was a composite of tracheal intubation or mortality within 30 days., Results: The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, -8% [95% CI, -15% to -1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, -1% [95% CI, -8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group., Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings., Trial Registration: isrctn.org Identifier: ISRCTN16912075.

Introduction: Motor neurone disease (MND) is characterized by rapidly progressive motor neurone degeneration which leads to muscle wasting. Mortality and morbidity are due to respiratory muscle failure which may be offset by ventilation. The aim of this observational study was to quantify the number and characteristics of patients living with MND choosing tracheostomy ventilation (TV) in the UK. Methods : Long-term ventilation services in the UK were invited to undertake a retrospective 5-year audit of MND patients under their care between April 2013 and March 2018 who had TV. Patient characteristics, the time spent on ventilation, hospital length of stay, discharge destination, and survival data were collected. Results : Sixty-eight MND patients were initiated on TV over the 5-year period. Eighty-one percent of patients received TV in an emergency setting with more than a third of these undiagnosed at presentation. Patients choosing elective TV were more likely to be male (85%) have a bulbar presentation (54%) and an increased survival of 10 months over the observation period. The mean length of hospital stay post TV was 136 days. Two-thirds of patients were discharged to their own home. Conclusion : Very few patients living with MND in the UK are currently receiving TV. In those who choose TV, there may be a survival advantage to planning an elective procedure. Despite the long inpatient stay and high care costs involved a majority of patients survived and were discharged to their own home.

Introduction: Sialorrhoea is a debilitating symptom in neurological disease and there is a growing literature for the use of intrasalivary gland Botulinum Toxin (botox) injections in its management. However, provision of intrasalivary gland botox remains inconsistent and sialorrhoea is often poorly controlled in motor neuron disease (MND).Sialorrhoea in association with bulbar dysfunction can cause intolerance of non-invasive ventilation (NIV) and respiratory infection, so its treatment is critical within a home ventilation service (HVS).This treatment can also be used to enable tracheostomy cuff deflation to facilitate weaning from ventilation. We report on the outcomes of intrasalivary gland botox in our HVS., Methods: In 2015, we set up an intrasalivary gland botox service for patients under our HVS. Under ultrasound guidance, we injected submandibular gland(SMG), parotid gland (PG) or both., Results: 109 intrasalivary gland botox procedures were performed in 72 patients. Diagnostic groups included MND 32Cerebral Palsy 8 and Weaning 14. Glands injected were, SMG (6%), PG (47%) and both (47%). The majority (84%) received the Dysport preparation with mean dose 273 units. 94% were ultrasound guided. 81% of injections resulted in a positive treatment effect, with 47% patients requesting repeat injections. Complications were angioedema (0.9%) and worsening dysphagia (3.7% following SMG injection). Mean survival following treatment was 40 months with 53% patients still alive., Conclusions: Intrasalivary gland botox appears effective across a range of neurological conditions requiring long-term NIV with few complications. Dysphagia may be an important complication of SMG injection. A randomised controlled trial may help establish the evidence base., Competing Interests: Competing interests: BM reports speaker fees from Fisher and Paykel outside the submitted work. AdS reports grants and personal fees from AstraZeneca, Bayer, Boehringer, Chiesi, Forest labs, GSK, Grifols, Insmed, Teva, Zambon, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Isolated diaphragmatic palsy in the absence of progressive neuromuscular disease is uncommon. It poses diagnostic challenges and limited data are available regarding prognosis. We present retrospective cohort data from two large teaching hospitals in the United Kingdom., Method: 60 patients who were assessed either as inpatients or outpatients were included in this study. Patients with progressive neuromuscular disease were excluded. Clinical presentation, tests of respiratory muscle function (sitting/supine vital capacity, maximal expiratory pressure (MEP), maximal inspiratory pressure (MIP) and sniff nasal inspiratory pressure (SNIP)) and outcomes were recorded., Results: For patients with diaphragmatic palsy, mean±sd seated and supine vital capacity pre-noninvasive ventilation (NIV) were reduced at 1.7±1.2 L and 1.1±0.9 L, respectively, with a mean±sd postural fall in vital capacity of 42±0.16%. The mean MEP/MIP and MEP/SNIP ratios for diaphragmatic palsy were 3 and 3.5, respectively. After a year of treatment with NIV, mean±sd upright and supine vital capacity had increased to 2.1±0.9 L and 1.8±1 L, respectively, and the mean±sd fall in vital capacity from sitting to supine reduced to 29±0.17%. MEP/MIP and MEP/SNIP ratios reduced to 2.6 and 2.9, respectively, from the pre-NIV values. The values of postural fall in vital capacity correlated (p<0.05) with MEP/MIP and MEP/SNIP ratio (r 2 =0.86 and r 2 =0.7, respectively)., Conclusion: Tests of respiratory muscle strength are valuable in the diagnostic workup of patients with unexplained dyspnoea. A triad of 1) orthopnoea, with 2) normal lung imaging and 3) MEP/MIP and/or MEP/SNIP ratio ≥2.7 points towards isolated diaphragmatic palsy. This needs to be confirmed by prospective studies., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2021.)

Competing Interests: None

Long-term dependence on non-invasive ventilation (NIV) without time for advance care planning can result in significant complications that may require innovative management strategies. We present the case of a man who was admitted with respiratory failure and required NIV. Despite effective treatment for community acquired pneumonia, attempts to wean NIV failed. While dependent on NIV, a diagnosis of motor neuron disease was made. Time without ventilation was not tolerated and consequently complications of: facial pressure ulceration, nasal septal prolapse, inspissated secretions and failure to feed occurred. This case illustrates the severity of complications that can result from NIV dependence; however, it also details how these can be effectively managed by the hospice multidisciplinary team, with support from experts both within and external to the hospice enabling the acquisition of appropriate skills and knowledge., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Evidence has suggested that when senior doctors are less approachable, junior staff are less likely to raise safety issues. There are limited existing data on whether the name by which junior doctors address their seniors reflects approachability and if this varies between grade and specialties., Methods: An online survey was conducted in a large teaching hospital. Respondents were asked about their use of first names when addressing consultants and whether they felt this reflected their perceptions of the consultants' approachability., Results: Four-hundred and twenty-three responses were received from a cohort of approximately 800 junior doctors. Of these, 410 were included in this analysis. Respondents came from 57 different subspecialties and all years of training. Overall, junior doctors addressed 43% of consultants by their first name; 71% of junior doctors perceived these consultants to be more approachable. There were significant differences in the results between grades and specialty of junior doctor., Conclusion: Throughout all specialties, the majority of junior doctors consider the consultants that they address informally to be more approachable., (© Royal College of Physicians 2020. All rights reserved.)

It is recommended that developers of Point Of Care Tests (POCTs) assess the care pathway of the patient population of interest in order to understand if the POCT fits within the pathway and has the potential to improve it. If the variation of the pathway across potential hospitals is large, then it is likely that the evaluation of effectiveness is harder and the route towards large-scale takes adoption longer. Evaluating care pathways can be a time-consuming activity when conducted through clinical audits or interviews with healthcare professionals. We have developed a more rapid methodology which extrapolates the care pathway from local hospital guidelines and assesses their variation. Sepsis kills 46,000 people per year in the UK with societal costs of up to £10 billion. Therefore, there is a clinical need for an optimized pathway. By applying our method in this field, we were able to assess the variation in current hospital guidelines for sepsis and infer the potential impact this may have on the evidence development on innovations in this applications. We obtained 15 local sepsis guidelines. Two independent reviewers extracted: use of the national early warning score (NEWS), signs and risk factors informing the decision to prescribe antibiotics, and the number of decisional steps up to this point. Considerable variation was observed in all the variables, which is likely to have an impact on future clinical and economic evaluations and adoption of POCT for the identification of patients with sepsis.

As noted in Wikipedia, skin in the game refers to having 'incurred risk by being involved in achieving a goal', where ' skin is a synecdoche for the person involved, and game is the metaphor for actions on the field of play under discussion'. For exascale applications under development in the US Department of Energy Exascale Computing Project, nothing could be more apt, with the skin being exascale applications and the game being delivering comprehensive science-based computational applications that effectively exploit exascale high-performance computing technologies to provide breakthrough modelling and simulation and data science solutions. These solutions will yield high-confidence insights and answers to the most critical problems and challenges for the USA in scientific discovery, national security, energy assurance, economic competitiveness and advanced healthcare. This article is part of a discussion meeting issue 'Numerical algorithms for high-performance computational science'.

Objectives: Mechanical ventilation (MV) has been shown to improve survival and quality of life in motor neuron disease (MND). However, during the progression of MND, there may come a point when MV is no longer felt appropriate. Association of Palliative Medicine Guidelines have been recently published to help clinicians withdraw MV at the request of patients with MND in a safe and compassionate manner to ensure that symptoms of distress and dyspnoea are minimised., Methods: In this report, we discuss the palliative and ventilatory management of six ventilator-dependent patients with MND who had requested the withdrawal of MV as part of their end-of-life care., Results: We have withdrawn MV from six patients with MND at their request and our practice has been influenced by the Association of Palliative Medicine Guidelines., Conclusion: Withdrawal of MV in MND at a patient's request is challenging but is also a fundamental responsibility of healthcare teams. We discuss the lessons we have learnt which will influence our practice and help other teams in the future., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Elucidating the relationship between the folding landscape of enzymes and their catalytic power has been one of the challenges of modern enzymology. The present work explores this issue by using a simplified folding model to generate the free-energy landscape of an enzyme and then to evaluate the activation barriers for the chemical step in different regions of the landscape. This approach is used to investigate the recent finding that an engineered monomeric chorismate mutase exhibits catalytic efficiency similar to the naturally occurring dimer even though it exhibits the properties of an intrinsically disordered molten globule. It is found that the monomer becomes more confined than its native-like counterpart upon ligand binding but still retains a wider catalytic region. Although the overall rate acceleration is still determined by reduction of the reorganization energy, the detailed contribution of different barriers yields a more complex picture for the chemical process than that of a single path. This work provides insight into the relationship between folding landscapes and catalysis. The computational approach used here may also provide a powerful strategy for modeling single-molecule experiments and designing enzymes.

The possible relationship between the thermal stability and the catalytic power of enzymes is of great current interest. In particular, it has been suggested that thermophilic or hyperthermophilic (Tm) enzymes have lower catalytic power at a given temperature than the corresponding mesophilic (Ms) enzymes, because the thermophilic enzymes are less flexible (assuming that flexibility and catalysis are directly correlated). These suggestions presume that the reduced dynamics of the thermophilic enzymes is the reason for their reduced catalytic power. The present paper takes the specific case of dihydrofolate reductase (DHFR) and explores the validity of the above argument by simulation approaches. It is found that the Tm enzymes have restricted motions in the direction of the folding coordinate, but this is not relevant to the chemical process, since the motions along the reaction coordinate are perpendicular to the folding motions. Moreover, it is shown that the rate of the chemical reaction is determined by the activation barrier and the corresponding reorganization energy, rather than by dynamics or flexibility in the ground state. In fact, as far as flexibility is concerned, we conclude that the displacement along the reaction coordinate is larger in the Tm enzyme than in the Ms enzyme and that the general trend in enzyme catalysis is that the best catalyst involves less motion during the reaction than the less optimal catalyst. The relationship between thermal stability and catalysis appears to reflect the fact that to obtain small electrostatic reorganization energy it is necessary to invest some folding energy in the overall preorganization process. Thus, the optimized catalysts are less stable. This trend is clearly observed in the DHFR case.

The ability to predict the thermal stability of proteins based on their corresponding sequence is a problem of great fundamental and practical importance. Here we report an approach for calculating the electrostatic contribution to protein stability based on the use of the semimacroscopic protein dipole Langevin dipole (PDLD/S) in its linear response approximation version for self-energy with a dielectric constant, (epsilon(p)) and an effective dielectric for charge-charge interactions (epsilon(eff)). The method is applied to the test cases of ubiquitin, lipase, dihydrofolate reductase and cold shock proteins with series of epsilon(p) and epsilon(eff). It is found that the optimal values of these dielectric constants lead to very promising results, both for the relative stability and the absolute folding energy. Consideration of the specific values of the optimal dielectric constants leads to an exciting conceptual description of the reorganization effect during the folding process. Although this description should be examined by further microscopic studies, the practical use of the current approach seems to offer a powerful tool for protein design and for studies of the energetics of protein folding.

Rationally controlled growth of inorganic semiconductor nanowires is important for their applications in nanoscale electronics and photonics. In this article, we discuss the rational growth, physical properties, and integration of nanowires based on the results from the authors' laboratory. The composition, diameter, growth position, and orientation of the nanowires are controlled based on the vapor-solid-liquid (VLS) crystal growth mechanism. The thermal stability and optical properties of these semiconductor nanowires are investigated. Particularly, ZnO nanowires with well-defined end surfaces can function as room-temperature ultraviolet nanolasers. In addition, a novel microfluidic-assisted nanowire integration (MANI) process was developed for the hierarchical assembly of nanowire building blocks into functional devices and systems.

Patients begin to formulate their expectations of the postoperative hospitalization during the preadmission program. The challenge is to better understand the factors patients consider when formulating judgments about the quality of preadmission education. For example, it may be that perceptions of the preadmission program are influenced by what patients believe about their postoperative pain and functional abilities. Specific attention needs to be given both preoperatively and postoperatively to instructing patients on realistic expectations for recovery. One other method of measuring patient outcomes is with the Health Status Profile (SF-36) (Response Healthcare Information Management, 1995). The SF-36 approach emphasizes the outcome of medical care as the patient sees it, in addition to a clinical evaluation of successful health care. This form is currently initiated in the physician's office and returned for scanning at the preadmission class. The patient then completes another SF-36 at 6 months and every year thereafter to compare measurable outcomes. Patients intending to have elective total joint replacements experience anxiety and require much support and education. An effective preadmission program is a major investment in a patient's recovery, as well as a unique marketing tool to customers. Preadmission programs can be viewed as an opportunity to enhance customer satisfaction. Preadmission clinics are an excellent means for nurses to improve the quality of patient care through patient education. the overall goal of preadmission testing programs is to ensure patient preparedness while increasing quality health care and overall customer satisfaction. To enhance program effectiveness, health care providers must lead collaborative efforts to improve the efficiency of systems.

Expression of protein kinase C-epsilon was examined in the human monoblastoid U937 cell. This cell type contained the alpha, beta, and epsilon isoforms of protein kinase C (PKC). While PKC-epsilon content was slightly higher in the cytosolic than in the particulate fraction, the amount contained in the particulate fraction was higher than the alpha and beta isoforms which were predominantly localized to the cytosol. After an acute exposure to tetradecanoyl-13-phorbol acetate (TPA), PKC-epsilon translocated to the particulate fraction. Acute or chronic exposure to ionomycin did not alter content of the epsilon isoform. Longer exposures to TPA decreased PKC-epsilon in both cellular fractions. PKC-epsilon displayed a similar sensitivity to TPA-induced down-regulation as did PKC-beta while PKC-alpha was more resistant to this effect. After a 72-h exposure to 0.1 nM TPA, increases in the alpha and beta isoforms but not in PKC-epsilon were observed. However, 1,25-dihydroxy vitamin D3 and dibutyryl cyclic AMP which induce U937 differentiation enhanced PKC-epsilon expression.