Adoption of high-sensitivity cardiac troponin for risk stratification of patients with suspected myocardial infarction: a multicentre cohort study.

Background: Guidelines recommend high-sensitivity cardiac troponin to risk stratify patients with possible myocardial infarction and identify those eligible for discharge. Our aim was to evaluate adoption of this approach in practice and to determine whether effectiveness and safety varies by age, sex, ethnicity, or socioeconomic deprivation status. Methods: A multi-centre cohort study was conducted in 13 hospitals across the United Kingdom from November 1st, 2021, to October 31st, 2022. Routinely collected data including high-sensitivity cardiac troponin I or T measurements were linked to outcomes. The primary effectiveness and safety outcomes were the proportion discharged from the Emergency Department, and the proportion dead or with a subsequent myocardial infarction at 30 days, respectively. Patients were stratified using peak troponin concentration as low (<5 ng/L), intermediate (5 ng/L to sex-specific 99th percentile), or high-risk (>sex-specific 99th percentile). Findings: In total 137,881 patients (49% [67,709/137,881] female) were included of whom 60,707 (44%), 42,727 (31%), and 34,447 (25%) were stratified as low-, intermediate- and high-risk, respectively. Overall, 65.8% (39,918/60,707) of low-risk patients were discharged from the Emergency Department, but this varied from 26.8% [2200/8216] to 93.5% [918/982] by site. The safety outcome occurred in 0.5% (277/60,707) and 11.4% (3917/34,447) of patients classified as low- or high-risk, of whom 0.03% (18/60,707) and 1% (304/34,447) had a subsequent myocardial infarction at 30 days, respectively. A similar proportion of male and female patients were discharged (52% [36,838/70,759] versus 54% [36,113/67,109]), but discharge was more likely if patients were <70 years old (61% [58,533/95,227] versus 34% [14,428/42,654]), from areas of low socioeconomic deprivation (48% [6697/14,087] versus 43% [12,090/28,116]) or were black or asian compared to caucasian (62% [5458/8877] and 55% [10,026/18,231] versus 46% [35,138/75,820]). Interpretation: Despite high-sensitivity cardiac troponin correctly identifying half of all patients with possible myocardial infarction as being at low risk, only two-thirds of these patients were discharged. Substantial variation in the discharge of patients by age, ethnicity, socioeconomic deprivation, and site was observed identifying important opportunities to improve care. Funding: UK Research and Innovation.

Strategies to identify medical patients suitable for management through Same Day Emergency Care Services: A Systematic Review.

Same Day Emergency Care (SDEC) in unplanned and emergency care is an NHSE priority. Optimal use of these services requires rapid identification of suitable patients. NHSE suggests the use of one tool for this purpose. This systematic review compares studies which evaluate the performance of selection tools for SDEC pathways. Nine studies met the inclusion criteria. Three scores were evaluated: the Amb score (7 studies), Glasgow Admission Prediction Score (GAPS)(6 studies) and Sydney Triage to Admission Risk Tool (START)(2 studies). There was heterogeneity in the populations assessed, exclusion criteria used, and definitions used for SDEC suitability, with proportions of patients deemed 'suitable' for SDEC ranging from 20-80%. Reported score sensitivity and specificity ranged between 18-99% and 10-89%. Score performance could not be compared due to heterogeneity between studies. No studies assessed clinical implementation. The current evidence to support the use of a specific tool for SDEC is limited and requires further evaluation.

A novel in vitro cell model of the proteinase/antiproteinase balance observed in alpha-1 antitrypsin deficiency.

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting from mutations in the alpha-1 antitrypsin (AAT) protein, a major systemic antiproteinase, resulting in reduced/no release of AAT, disrupting the proteinase/antiproteinase balance. A sustained imbalance can cause structural changes to the lung parenchyma, leading to emphysema. Predicting and assessing human responses to potential therapeutic candidates from preclinical animal studies have been challenging. Our aims were to develop a more physiologically relevant in vitro model of the proteinase/antiproteinase balance and assess whether the data generated could better predict the efficacy of pharmacological candidates to inform decisions on clinical trials, together with expected biomarker responses. Methods: We developed an in vitro model assessing the proteinase/antiproteinase balance by the changes in the fibrinogen cleavage products of neutrophil elastase (NE) and proteinase 3 (PR3). This allowed the assessment of physiological and pharmaceutical neutrophil serine proteinase (NSP) inhibitors to determine the putative threshold at which the maximal effect is achieved. Results: AAT significantly reduced NE and PR3 activity footprints, with the maximal reduction achieved at concentrations above 10 µM. The inhibitor MPH966 alone also significantly reduced NE footprint generation in a concentration-dependent manner, leveling out above 100 nM but had no effect on the PR3 footprint. At levels of AAT consistent with AATD, MPH966 had an additive effect, reducing the NE activity footprint more than either inhibitor alone. Conclusion: Our results support an inhibitor threshold above which the activity footprint generation appears resistant to increasing dosage. Our model can support the testing of inhibitors, confirming activity biomarkers as indicators of likely pharmaceutical efficacy, the assessment of NSP activity in the pathophysiology of emphysema, and the likely function of biological or pharmacological inhibitors in disease management.

Acute frailty services: results of a national day of care survey.

INTRODUCTION: Older people living with frailty are at high risk of emergency hospital admission and often have complex care needs which may not be adequately met by conventional models of acute care. This has driven the introduction of adaptations to acute care pathways designed to improve outcomes in this patient group. The identification of differences in the organisational approach to frailty may highlight opportunities for quality improvement. METHODS: The Society for Acute Medicine Benchmarking audit is a national service evaluation which uses a single day-of-care methodology to record patient and organisational level data. All acute hospitals in the United Kingdom are eligible to participate. Emergency admissions referred to acute medical services between 00:00 and 23:59 on Thursday 23rd June 2022 were recorded. Information on the structure and operational design of acute frailty services was collected. The use of a validated frailty assessment tool, clinical frailty scale within the first 24 h of admission, assessment by an acute frailty service and clinical outcomes were reported in patients aged 70 year and above. A mixed effect generalised linear model was used to determine factors associated same-day discharge without overnight stay in patients with frailty. RESULTS: A total of 152 hospitals participated. There was significant heterogeneity in the operational design and staffing model of acute frailty services. The presence of an acute frailty unit was reported in 57 (42.2%) hospitals. The use of validated frailty assessment tools was reported in 117 (90.0%) hospitals, of which 107 (91.5%) used the clinical frailty scale. Patient-level data were recorded for 3604 patients aged 70 years and above. At the patient level, 1626 (45.1%) were assessed using a validated tool during the admission process. Assessment by acute frailty services was associated with an increased likelihood of same-day discharge (adjusted OR 1.55, 95%CI 1.03- 2.39). CONCLUSION: There is significant variation in the provision of acute frailty services. Frailty-related policies and services are common at the organisational level but implemented inconsistently at the patient level. Older people with frailty or geriatric syndromes assessed by acute frailty services were more likely to be discharged without the need for overnight bed-based admission.

Towards personalised anti-microbial and immune approaches to infections in acute care. Can real-time genomic-informed diagnosis of pathogens, and immune-focused therapies improve outcomes for patients? An observational, experimental study protocol.

INTRODUCTION: Infection causes a vast burden of disease, with significant mortality, morbidity and costs to health-care systems. However, identifying the pathogen causative infection can be challenging, resulting in high use of broad-spectrum antibiotics, much of which may be inappropriate. Novel metagenomic methods have potential to rapidly identify pathogens, however their clinical utility for many infections is currently unclear. Outcome from infection is also impacted by the effectiveness of immune responses, which can be impaired by age, co-morbidity and the infection itself. The aims of this study are twofold: To compare diversity of organisms identified and time-to-result using metagenomic methods versus traditional culture -based techniques, to explore the potential clinical role of metagenomic approaches to pathogen identification in a range of infections.To characterise the ex vivo function of immune cells from patients with acute infection, exploring host and pathogen-specific factors which may affect immune function and overall outcomes. METHODS: This is a prospective observational study of patients with acute infection. Patients with symptoms suggestive of an acute infection will be recruited, and blood and bodily fluid relevant to the site of infection collected (for example, sputum and naso-oropharyngeal swabs for respiratory tract infections, or urine for a suspected urinary tract infection). Metagenomic analysis of samples will be compared to traditional microbiology, alongside the antimicrobials received. Blood and respiratory samples such as bronchoalveolar lavage will be used to isolate immune cells and interrogate immune cell function. Where possible, similar samples will be collected from matched participants without a suspected infection to determine the impact of infection on both microbiome and immune cell function.

Development and evaluation of a tool to optimise inhaler selection prior to hospital discharge following an exacerbation of COPD.

Introduction: Rates of mortality and re-admission after a hospitalised exacerbation of COPD are high and resistant to change. COPD guidelines do not give practical advice about the optimal selection of inhaled drugs and device in this situation. We hypothesised that a failure to optimise inhaled drug and drug delivery prior to discharge from hospital after an exacerbation would be associated with a modifiable increased risk of re-admission and death. We designed a study to 1) develop a practical inhaler selection tool to use at the point of hospital discharge and 2) implement this tool to understand the potential impact on modifying inhaler prescriptions, clinical outcomes, acceptability to clinicians and patients, and the feasibility of delivering a definitive trial to demonstrate potential benefit. Methods: We iteratively developed an inhaler selection tool for use prior to discharge following a hospitalised exacerbation of COPD using surveys with multiprofessional clinicians and a focus group of people living with COPD. We surveyed clinicians to understand their views on the minimum clinically important difference (MCID) for death and re-admission following a hospitalised exacerbation of COPD. We conducted a mixed-methods implementation feasibility study using the tool at discharge, and collated 30- and 90-day follow-up data including death and re-admissions. Additionally, we observed the tool being used and interviewed clinicians and patients about use of the tool in this setting. Results: We completed the design of an inhaler selection tool through two rounds of consultations with 94 multiprofessional clinicians, and a focus group of four expert patients. Regarding MCIDs, there was majority consensus for the following reductions from baseline being the MCID: 30-day readmissions 5-10%, 90-day readmissions 10-20%, 30-day mortality 5-10% and 90-day mortality 5-10%. 118 patients were assessed for eligibility and 26 had the tool applied. A change in inhaled medication was recommended in nine (35%) out of 26. Re-admission or death at 30 days was seen in 33% of the switch group and 35% of the no-switch group. Re-admission or death at 90 days was seen in 56% of the switch group and 41% of the no-switch group. Satisfaction with inhalers was generally high, and switching was associated with a small increase in the Feeling of Satisfaction with Inhaler questionnaire of 3 out of 50 points. Delivery of a definitive study would be challenging. Conclusion: We completed a mixed-methods study to design and implement a tool to aid optimisation of inhaled pharmacotherapy prior to discharge following a hospitalised exacerbation of COPD. This was not associated with fewer re-admissions, but was well received and one-third of people were eligible for a change in inhalers.

How far back do we need to look to capture diagnoses in electronic health records? A retrospective observational study of hospital electronic health record data.

OBJECTIVES: Analysis of routinely collected electronic health data is a key tool for long-term condition research and practice for hospitalised patients. This requires accurate and complete ascertainment of a broad range of diagnoses, something not always recorded on an admission document at a single point in time. This study aimed to ascertain how far back in time electronic hospital records need to be interrogated to capture long-term condition diagnoses. DESIGN: Retrospective observational study of routinely collected hospital electronic health record data. SETTING: Queen Elizabeth Hospital Birmingham (UK)-linked data held by the PIONEER acute care data hub. PARTICIPANTS: Patients whose first recorded admission for chronic obstructive pulmonary disease (COPD) exacerbation (n=560) or acute stroke (n=2142) was between January and December 2018 and who had a minimum of 10 years of data prior to the index date. OUTCOME MEASURES: We identified the most common International Classification of Diseases version 10-coded diagnoses received by patients with COPD and acute stroke separately. For each diagnosis, we derived the number of patients with the diagnosis recorded at least once over the full 10-year lookback period, and then compared this with shorter lookback periods from 1 year to 9 years prior to the index admission. RESULTS: Seven of the top 10 most common diagnoses in the COPD dataset reached >90% completeness by 6 years of lookback. Atrial fibrillation and diabetes were >90% coded with 2-3 years of lookback, but hypertension and asthma completeness continued to rise all the way out to 10 years of lookback. For stroke, 4 of the top 10 reached 90% completeness by 5 years of lookback; angina pectoris was >90% coded at 7 years and previous transient ischaemic attack completeness continued to rise out to 10 years of lookback. CONCLUSION: A 7-year lookback captures most, but not all, common diagnoses. Lookback duration should be tailored to the conditions being studied.

Structural Predictors of Lung Function Decline in Young Smokers with Normal Spirometry.

Rationale: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. Objectives: We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. Methods: We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age, and sex, was related to the initial QCT appearances and symptoms, measured using the CAT. Measurements and Main Results: There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability-defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV1 decline, as was a higher CAT score. Conclusions: Radiological abnormalities on CT are already established in young smokers with normal lung function and are associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. Clinical trial registered with www.clinicaltrials.gov (NCT03480347).

E-cigarette vapor renders neutrophils dysfunctional due to filamentous actin accumulation.

BACKGROUND: Electronic cigarette (e-cigarette) use continues to rise despite concerns of long-term effects, especially the risk of developing lung diseases such as chronic obstructive pulmonary disease. Neutrophils are central to the pathogenesis of chronic obstructive pulmonary disease, with changes in phenotype and function implicated in tissue damage. OBJECTIVE: We sought to measure the impact of direct exposure to nicotine-containing and nicotine-free e-cigarette vapor on human neutrophil function and phenotype. METHODS: Neutrophils were isolated from the whole blood of self-reported nonsmoking, nonvaping healthy volunteers. Neutrophils were exposed to 40 puffs of e-cigarette vapor generated from e-cigarette devices using flavorless e-cigarette liquids with and without nicotine before functions, deformability, and phenotype were assessed. RESULTS: Neutrophil surface marker expression was altered, with CD62L and CXCR2 expression significantly reduced in neutrophils treated with e-cigarette vapor containing nicotine. Neutrophil migration to IL-8, phagocytosis of Escherichia coli and Staphylococcus aureus pHrodo bioparticles, oxidative burst response, and phorbol 12-myristate 13-acetate-stimulated neutrophil extracellular trap formation were all significantly reduced by e-cigarette vapor treatments, independent of nicotine content. E-cigarette vapor induced increased levels of baseline polymerized filamentous actin levels in the cytoplasm, compared with untreated controls. CONCLUSIONS: The significant reduction in effector neutrophil functions after exposure to high-power e-cigarette devices, even in the absence of nicotine, is associated with excessive filamentous actin polymerization. This highlights the potentially damaging impact of vaping on respiratory health and reinforces the urgency of research to uncover the long-term health implications of e-cigarettes.

Acute care models for older people living with frailty: a systematic review and taxonomy.

BACKGROUND: The need to improve the acute care pathway to meet the care needs of older people living with frailty is a strategic priority for many healthcare systems. The optimal care model for this patient group is unclear. METHODS: A systematic review was conducted to derive a taxonomy of acute care models for older people with acute medical illness and describe the outcomes used to assess their effectiveness. Care models providing time-limited episodes of care (up to 14 days) within 48 h of presentation to patients over the age of 65 with acute medical illness were included. Care models based in hospital and community settings were eligible. Searches were undertaken in Medline, Embase, CINAHL and Cochrane databases. Interventions were described and classified in detail using a modified version of the TIDIeR checklist for complex interventions. Outcomes were described and classified using the Core Outcome Measures in Effectiveness Trials (COMET) taxonomy. Risk of bias was assessed using RoB2 and ROBINS-I. RESULTS: The inclusion criteria were met by 103 articles. Four classes of acute care model were identified, acute-bed based care, hospital at home, emergency department in-reach and care home models. The field is dominated by small single centre randomised and non-randomised studies. Most studies were judged to be at risk of bias. A range of outcome measures were reported with little consistency between studies. Evidence of effectiveness was limited. CONCLUSION: Acute care models for older people living with frailty are heterogenous. The clinical effectiveness of these models cannot be conclusively established from the available evidence. TRIAL REGISTRATION: PROSPERO registration (CRD42021279131).

Exploring fraity and sarcopenia in older adults admitted to acute medical unit, looking at prevalence, trajectory, and outcomes: A protocol testing the feasibility and acceptability of the TYSON study.

BACKGROUND: Frailty and sarcopenia are common in older people and are associated with adverse outcomes including increased mortality and morbidity. It is unclear whether screening for frailty and sarcopenia would identify specific populations most at risk of poor outcomes during unplanned hospital admissions, which screening tools should be used and what the trajectory of both conditions are over the course of an admission. The TYSON study is an observational cohort study aiming to determine the prevalence, trajectory and outcomes associated with frailty and sarcopenia in different patient cohorts. This protocol tests the feasibility and acceptability of TYSON processes. OBJECTIVES: To determine in acutely admitted medical patients who are older adults: Primary: The feasibility and acceptability of frailty and sarcopenia assessments; Secondary: (1) Differences in community and hospital frailty assessments, as assessed by the medical team, the patient and elderly care physicians, (2) The dynamic changes in frailty and sarcopenia during a hospital admission, and patient outcomes; Exploratory: Inflammatory and metabolic mediators associated with frailty and sarcopenia. METHODS: A single centre, prospective observational study including patients aged ≥ 65 years admitted to an acute medical unit. Frailty assessments include the Rockwood clinical frailty and e-frailty index. Sarcopenia assessments include the Bilateral Anterior Thigh Thickness (BATT) measurement. Each participant will be asked to complete 5 visits, at day 0, day 3, day 7, month 3 and month 6. Blood samples will be collected to explore inflammatory and metabolic markers associated with frailty and sarcopenia. The study and protocol have been ethically approved by the Health Research Authority (REC 20/WA/0263). DISCUSSION: The study will determine the feasibility and acceptability of frailty and sarcopenia assessments in an acute hospital setting, and inform on the prevalence, trajectory and associated outcomes of frailty and sarcopenia in this group of patients. An inflammatory and metabolic profile will be explored in frailty and sarcopenia.

Small airways dysfunction: The importance of utilising Z-scores to define MMEF abnormalities in clinical practice.

Background: The small airways comprise the largest cross-sectional area of the lungs, however, assessing and reporting abnormalities for this region of the bronchial tree has been practically and scientifically uncertain. Methods: Using routinely collected spirometry data for patients with either asthma or COPD, the accuracy of % predicted values for defining small airways dysfunction was assessed. A z-score of ≤ -1.645 of the maximal-mid expiratory flow (MMEF) was used as the gold standard for defining abnormality in the small airways. Results: Records of 3396 patients were included in the analysis. The false positive (FP) rates were 24.6 %, 16.1 %, 11.5 %, or 7.9 % when the % predicted value of 80 %, 70 %, 65 %, or 60 % were used, respectively. Sex, age, and BMI were associated with FP rates. Males were more likely to be categorised as FP with odds ratio (OR) between 1.10 and 1.49 across % predicted groups. Age was associated with FP rates with an OR between 1.01 and 1.08. The BMI was also associated with FP rates with an OR of 1.03 across all % predicted groups. Assessing the association of age groups with FP rate showed that those above 60 years old were more likely to be categorised as FP with an OR between 1.23 and 73.2 compared to those less than 30 years old. Conclusion: When assessing the small airways in clinical practice or for scientific purposes, the % predicted values overestimate the actual impairment leading to FP interpretation. Utilising z-score values are recommended to assess the small airways using the spirometric index, MMEF.

The value of standards for health datasets in artificial intelligence-based applications.

Artificial intelligence as a medical device is increasingly being applied to healthcare for diagnosis, risk stratification and resource allocation. However, a growing body of evidence has highlighted the risk of algorithmic bias, which may perpetuate existing health inequity. This problem arises in part because of systemic inequalities in dataset curation, unequal opportunity to participate in research and inequalities of access. This study aims to explore existing standards, frameworks and best practices for ensuring adequate data diversity in health datasets. Exploring the body of existing literature and expert views is an important step towards the development of consensus-based guidelines. The study comprises two parts: a systematic review of existing standards, frameworks and best practices for healthcare datasets; and a survey and thematic analysis of stakeholder views of bias, health equity and best practices for artificial intelligence as a medical device. We found that the need for dataset diversity was well described in literature, and experts generally favored the development of a robust set of guidelines, but there were mixed views about how these could be implemented practically. The outputs of this study will be used to inform the development of standards for transparency of data diversity in health datasets (the STANDING Together initiative).

Observational cohort study protocol: neutrophil function and energetics in adults with pneumonia and sepsis - Pneumonia Metabolism in Ageing (PUMA).

INTRODUCTION: Community-acquired pneumonia has high mortality and is associated with significant healthcare costs. In older adults with community-acquired pneumonia neutrophil dysfunction has been identified and is associated with poor outcomes for patients. Immunometabolism is a rapidly developing field which links immune cell function to metabolism. This study aims to explore neutrophil metabolism in community-acquired pneumonia. METHODS AND ANALYSIS: Pneumonia Metabolism in Ageing study is a prospective observational study recruiting older adults hospitalised with community-acquired pneumonia to examine neutrophil function and metabolic status. Controls will be older adults with no acute illness. The primary endpoint is neutrophil chemotaxis. ETHICS AND DISSEMINATION: The study has ethical approval from the Research Ethics Committee Wales, reference 19/WA/0299. This study involves participants who may lack the capacity to consent to research involvement, in this situation, personal or professional assent will be sought. The results from this study will be submitted for publication in peer-reviewed journals and disseminated at local and international conferences.

Mapping inpatient care pathways for patients with COPD: an observational study using routinely collected electronic hospital record data.

Introduction: Respiratory specialist ward care is associated with better outcomes for patients with COPD exacerbations. We assessed patient pathways and associated factors for people admitted to hospital with COPD exacerbations. Methods: We analysed routinely collected electronic health data for patients admitted with COPD exacerbation in 2018 to Queen Elizabeth Hospital, Birmingham, UK. We extracted data on demographics, deprivation index, Elixhauser comorbidities, ward moves, length of stay, and in-hospital and 1-year mortality. We compared care pathways with recommended care pathways (transition from initial assessment area to respiratory wards or discharge). We used Markov state transition models to derive probabilities of following recommended pathways for patient subgroups. Results: Of 42 555 patients with unplanned admissions during 2018, 571 patients were admitted at least once with an exacerbation of COPD. The mean±sd age was 51±11 years; 313 (55%) were women, 337 (59%) lived in the most deprived neighbourhoods and 45 (9%) were from non-white ethnic backgrounds. 428 (75.0%) had ≥4 comorbidities. Age >70 years was associated with higher in-hospital and 1-year mortality, more places of care (wards) and longer length of stay; having ≥4 comorbidities was associated with higher mortality and longer length of stay. Older age was associated with a significantly lower probability of following a recommended pathway (>70 years: 0.514, 95% CI 0.458-0.571; ≤70 years: 0.636, 95% CI 0.572-0.696; p=0.004). Conclusions: Only older age was associated with a lower chance of following recommended hospital pathways of care. Such analyses could help refine appropriate care pathways for patients with COPD exacerbations.

A single bout of prior resistance exercise attenuates muscle atrophy and declines in myofibrillar protein synthesis during bed-rest in older men.

Impairments in myofibrillar protein synthesis (MyoPS) during bed rest accelerate skeletal muscle loss in older adults, increasing the risk of adverse secondary health outcomes. We investigated the effect of prior resistance exercise (RE) on MyoPS and muscle morphology during a disuse event in 10 healthy older men (65-80 years). Participants completed a single bout of unilateral leg RE the evening prior to 5 days of in-patient bed-rest. Quadriceps cross-sectional area (CSA) was determined prior to and following bed-rest. Serial muscle biopsies and dual stable isotope tracers were used to determine rates of integrated MyoPS (iMyoPS) over a 7 day habitual 'free-living' phase and the bed-rest phase, and rates of acute postabsorptive and postprandial MyoPS (aMyoPS) at the end of bed rest. Quadriceps CSA at 40%, 60% and 80% of muscle length significantly decreased in exercised (EX) and non-exercised control (CTL) legs with bed-rest. The decline in quadriceps CSA at 40% and 60% of muscle length was attenuated in EX compared with CTL. During bed-rest, iMyoPS rates decreased from habitual values in CTL, but not EX, and were significantly different between legs. Postprandial aMyoPS rates increased above postabsorptive values in EX only. The change in iMyoPS over bed-rest correlated with the change in quadriceps CSA in CTL, but not EX. A single bout of RE attenuated the decline in iMyoPS rates and quadriceps atrophy with 5 days of bed-rest in older men. Further work is required to understand the functional and clinical implications of prior RE in older patient populations. KEY POINTS: Age-related skeletal muscle deterioration, linked to numerous adverse health outcomes, is driven by impairments in muscle protein synthesis that are accelerated during periods of disuse. Resistance exercise can stimulate muscle protein synthesis over several days of recovery and therefore could counteract impairments in this process that occur in the early phase of disuse. In the present study, we demonstrate that the decline in myofibrillar protein synthesis and muscle atrophy over 5 days of bed-rest in older men was attenuated by a single bout of unilateral resistance exercise performed the evening prior to bed-rest. These findings suggest that concise resistance exercise intervention holds the potential to support muscle mass retention in older individuals during short-term disuse, with implications for delaying sarcopenia progression in ageing populations.

Road map for clinicians to develop and evaluate AI predictive models to inform clinical decision-making.

BACKGROUND: Predictive models have been used in clinical care for decades. They can determine the risk of a patient developing a particular condition or complication and inform the shared decision-making process. Developing artificial intelligence (AI) predictive models for use in clinical practice is challenging; even if they have good predictive performance, this does not guarantee that they will be used or enhance decision-making. We describe nine stages of developing and evaluating a predictive AI model, recognising the challenges that clinicians might face at each stage and providing practical tips to help manage them. FINDINGS: The nine stages included clarifying the clinical question or outcome(s) of interest (output), identifying appropriate predictors (features selection), choosing relevant datasets, developing the AI predictive model, validating and testing the developed model, presenting and interpreting the model prediction(s), licensing and maintaining the AI predictive model and evaluating the impact of the AI predictive model. The introduction of an AI prediction model into clinical practice usually consists of multiple interacting components, including the accuracy of the model predictions, physician and patient understanding and use of these probabilities, expected effectiveness of subsequent actions or interventions and adherence to these. Much of the difference in whether benefits are realised relates to whether the predictions are given to clinicians in a timely way that enables them to take an appropriate action. CONCLUSION: The downstream effects on processes and outcomes of AI prediction models vary widely, and it is essential to evaluate the use in clinical practice using an appropriate study design.

Real-time assessment of neutrophil metabolism and oxidative burst using extracellular flux analysis.

Neutrophil responses are critical during inflammatory and infective events, and neutrophil dysregulation has been associated with poor patient outcomes. Immunometabolism is a rapidly growing field that has provided insights into cellular functions in health and disease. Neutrophils are highly glycolytic when activated, with inhibition of glycolysis associated with functional deficits. There is currently very limited data available assessing metabolism in neutrophils. Extracellular flux (XF) analysis assesses real time oxygen consumption and the rate of proton efflux in cells. This technology allows for the automated addition of inhibitors and stimulants to visualise the effect on metabolism. We describe optimised protocols for an XFe96 XF Analyser to (i) probe glycolysis in neutrophils under basal and stimulated conditions, (ii) probe phorbol 12-myristate 13-acetate induced oxidative burst, and (iii) highlight challenges of using XF technology to examine mitochondrial function in neutrophils. We provide an overview of how to analyze XF data and identify pitfalls of probing neutrophil metabolism with XF analysis. In summary we describe robust methods for assessing glycolysis and oxidative burst in human neutrophils and discuss the challenges around using this technique to assess mitochondrial respiration. XF technology is a powerful platform with a user-friendly interface and data analysis templates, however we suggest caution when assessing neutrophil mitochondrial respiration.