Development of respiratory care guidelines for Duchenne muscular dystrophy in the UK: key recommendations for clinical practice.

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.

Skeletal muscle angiogenic, regulatory, and heat shock protein responses to prolonged passive hyperthermia of the human lower limb.

Passive hyperthermia induces a range of physiological responses including augmenting skeletal muscle mRNA expression. This experiment aimed to examine gene and protein responses to prolonged passive leg hyperthermia. Seven young participants underwent 3 h of resting unilateral leg heating (HEAT) followed by a further 3 h of rest, with the contralateral leg serving as an unheated control (CONT). Muscle biopsies were taken at baseline (0 h), and at 1.5, 3, 4, and 6 h in HEAT and 0 and 6 h in CONT to assess changes in selected mRNA expression via qRT-PCR, and HSP72 and VEGFα concentration via ELISA. Muscle temperature (Tm) increased in HEAT plateauing from 1.5 to 3 h (+3.5 ± 1.5°C from 34.2 ± 1.2°C baseline value; P < 0.001), returning to baseline at 6 h. No change occurred in CONT. Endothelial nitric oxide synthase (eNOS), Forkhead box O1 (FOXO-1), Hsp72, and VEGFα mRNA increased in HEAT (P < 0.05); however, post hoc analysis identified that only Hsp72 mRNA statistically increased (at 4 h vs. baseline). When peak change during HEAT was calculated angiopoietin 2 (ANGPT-2) decreased (-0.4 ± 0.2-fold), and C-C motif chemokine ligand 2 (CCL2) (+2.9 ± 1.6-fold), FOXO-1 (+6.2 ± 4.4-fold), Hsp27 (+2.9 ± 1.7-fold), Hsp72 (+8.5 ± 3.5-fold), Hsp90α (+4.6 ± 3.7-fold), and VEGFα (+5.9 ± 3.1-fold) increased from baseline (all P < 0.05). At 6 h Tm were not different between limbs (P = 0.582; CONT = 32.5 ± 1.6°C, HEAT = 34.3 ± 1.2°C), and only ANGPT-2 (P = 0.031; -1.3 ± 1.4-fold) and VEGFα (P = 0.030; 1.1 ± 1.2-fold) differed between HEAT and CONT. No change in VEGFα or HSP72 protein concentration were observed over time; however, peak change in VEGFα did increase (P < 0.05) in HEAT (+140 ± 184 pg·mL-1) versus CONT (+7 ± 86 pg·mL-1). Passive hyperthermia transiently augmented ANGPT-2, CCL2, eNOS, FOXO-1, Hsp27, Hsp72, Hsp90α and VEGFα mRNA, and VEGFα protein.

Long COVID: mechanisms, risk factors and recovery.

NEW FINDINGS: What is the topic of this review? The emerging condition of long COVID, its epidemiology, pathophysiological impacts on patients of different backgrounds, physiological mechanisms emerging as explanations of the condition, and treatment strategies being trialled. The review leads from a Physiological Society online conference on this topic. What advances does it highlight? Progress in understanding the pathophysiology and cellular mechanisms underlying Long COVID and potential therapeutic and management strategies. ABSTRACT: Long COVID, the prolonged illness and fatigue suffered by a small proportion of those infected with SARS-CoV-2, is placing an increasing burden on individuals and society. A Physiological Society virtual meeting in February 2022 brought clinicians and researchers together to discuss the current understanding of long COVID mechanisms, risk factors and recovery. This review highlights the themes arising from that meeting. It considers the nature of long COVID, exploring its links with other post-viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome, and highlights how long COVID research can help us better support those suffering from all post-viral syndromes. Long COVID research started particularly swiftly in populations routinely monitoring their physical performance - namely the military and elite athletes. The review highlights how the high degree of diagnosis, intervention and monitoring of success in these active populations can suggest management strategies for the wider population. We then consider how a key component of performance monitoring in active populations, cardiopulmonary exercise training, has revealed long COVID-related changes in physiology - including alterations in peripheral muscle function, ventilatory inefficiency and autonomic dysfunction. The nature and impact of dysautonomia are further discussed in relation to postural orthostatic tachycardia syndrome, fatigue and treatment strategies that aim to combat sympathetic overactivation by stimulating the vagus nerve. We then interrogate the mechanisms that underlie long COVID symptoms, with a focus on impaired oxygen delivery due to micro-clotting and disruption of cellular energy metabolism, before considering treatment strategies that indirectly or directly tackle these mechanisms. These include remote inspiratory muscle training and integrated care pathways that combine rehabilitation and drug interventions with research into long COVID healthcare access across different populations. Overall, this review showcases how physiological research reveals the changes that occur in long COVID and how different therapeutic strategies are being developed and tested to combat this condition.

Metabolic phenotype of skeletal muscle in early critical illness.

OBJECTIVES: To characterise the sketetal muscle metabolic phenotype during early critical illness. METHODS: Vastus lateralis muscle biopsies and serum samples (days 1 and 7) were obtained from 63 intensive care patients (59% male, 54.7±18.0 years, Acute Physiology and Chronic Health Evaluation II score 23.5±6.5). MEASUREMENTS AND MAIN RESULTS: From day 1 to 7, there was a reduction in mitochondrial beta-oxidation enzyme concentrations, mitochondrial biogenesis markers (PGC1α messenger mRNA expression (-27.4CN (95% CI -123.9 to 14.3); n=23; p=0.025) and mitochondrial DNA copy number (-1859CN (IQR -5557-1325); n=35; p=0.032). Intramuscular ATP content was reduced compared tocompared with controls on day 1 (17.7mmol/kg /dry weight (dw) (95% CI 15.3 to 20.0) vs. 21.7 mmol/kg /dw (95% CI 20.4 to 22.9); p<0.001) and decreased over 7 days (-4.8 mmol/kg dw (IQR -8.0-1.2); n=33; p=0.001). In addition, the ratio of phosphorylated:total AMP-K (the bioenergetic sensor) increased (0.52 (IQR -0.09-2.6); n=31; p<0.001). There was an increase in intramuscular phosphocholine (847.2AU (IQR 232.5-1672); n=15; p=0.022), intramuscular tumour necrosis factor receptor 1 (0.66 µg (IQR -0.44-3.33); n=29; p=0.041) and IL-10 (13.6 ng (IQR 3.4-39.0); n=29; p=0.004). Serum adiponectin (10.3 µg (95% CI 6.8 to 13.7); p<0.001) and ghrelin (16.0 ng/mL (IQR -7-100); p=0.028) increased. Network analysis revealed a close and direct relationship between bioenergetic impairment and reduction in muscle mass and between intramuscular inflammation and impaired anabolic signaling. ATP content and muscle mass were unrelated to lipids delivered. CONCLUSIONS: Decreased mitochondrial biogenesis and dysregulated lipid oxidation contribute to compromised skeletal muscle bioenergetic status. In addition, intramuscular inflammation was associated with impaired anabolic recovery with lipid delivery observed as bioenergetically inert. Future clinical work will focus on these key areas to ameliorate acute skeletal muscle wasting. TRIAL REGISTRATION NUMBER: NCT01106300.

How is physical activity measured in lung cancer?A systematic review of outcome measures and their psychometric properties.

Physical activity (PA) levels are low in patients with lung cancer. Emerging evidence supports the use of interventions to increase PA in this population. We aimed to (1) identify and synthesize outcome measures which assess PA levels in patients with lung cancer and (2) to evaluate, synthesize and compare the psychometric properties of these measures. A systematic review of articles from searches was conducted of five electronic databases and personal records. Eligible studies were those which assessed PA using either performance-based or patient-reported measures. For aim 2, studies identified in aim 1 reporting on at least one psychometric property (validity, reliability, responsiveness or measurement error) were included. Two independent reviewers assessed eligibility and risk of bias with the COnsensus-based Standards for the selection of health status Measurement INstruments. Thirty-four studies using 21 different measures of PA were identified. Seventeen studies used performance-based measures. The Godin Leisure Time Exercise Questionnaire (GLTEQ) was the most frequently used patient-reported measure. Psychometric properties were reported for 13 of these measures and most frequently for movement sensors. Two studies reported on properties of the GLTEQ. Quality ratings for risk of bias were low. There is significant heterogeneity amongst studies regarding method of PA measurement along the lung cancer continuum. Greater consensus could be achieved by using a consensus approach such as a Delphi process. Future studies should include assessment of psychometric properties of the measurement tool being used. Currently, it is recommended where feasible, both performance-based and patient-reported measurements of PA should be undertaken.

Mechanisms underlying exercise intolerance in long COVID: An accumulation of multisystem dysfunction.

The pathogenesis of exercise intolerance and persistent fatigue which can follow an infection with the SARS-CoV-2 virus ("long COVID") is not fully understood. Cases were recruited from a long COVID clinic (N = 32; 44 ± 12 years; 10 (31%) men), and age-/sex-matched healthy controls (HC) (N = 19; 40 ± 13 years; 6 (32%) men) from University College London staff and students. We assessed exercise performance, lung and cardiac function, vascular health, skeletal muscle oxidative capacity, and autonomic nervous system (ANS) function. Key outcome measures for each physiological system were compared between groups using potential outcome means (95% confidence intervals) adjusted for potential confounders. Long COVID participant outcomes were compared to normative values. When compared to HC, cases exhibited reduced oxygen uptake efficiency slope (1847 (1679, 2016) vs. 2176 (1978, 2373) mL/min, p = 0.002) and anaerobic threshold (13.2 (12.2, 14.3) vs. 15.6 (14.4, 17.2) mL/kg/min, p < 0.001), and lower oxidative capacity, measured using near infrared spectroscopy (τ: 38.7 (31.9, 45.6) vs. 24.6 (19.1, 30.1) s, p = 0.001). In cases, ANS measures fell below normal limits in 39%. Long COVID is associated with reduced measures of exercise performance and skeletal muscle oxidative capacity in the absence of evidence of microvascular dysfunction, suggesting mitochondrial pathology. There was evidence of attendant ANS dysregulation in a significant proportion. These multisystem factors might contribute to impaired exercise tolerance in long COVID sufferers.

When months matter; modelling the impact of the COVID-19 pandemic on the diagnostic pathway of Motor Neurone Disease (MND).

BACKGROUND: A diagnosis of MND takes an average 10-16 months from symptom onset. Early diagnosis is important to access supportive measures to maximise quality of life. The COVID-19 pandemic has caused significant delays in NHS pathways; the majority of GP appointments now occur online with subsequent delays in secondary care assessment. Given the rapid progression of MND, patients may be disproportionately affected resulting in late stage new presentations. We used Monte Carlo simulation to model the pre-COVID-19 diagnostic pathway and then introduced plausible COVID-19 delays. METHODS: The diagnostic pathway was modelled using gamma distributions of time taken: 1) from symptom onset to GP presentation, 2) for specialist referral, and 3) for diagnosis reached after neurology appointment. We incorporated branches to simulate delays: when patients did not attend their GP and when the GP consultation did not result in referral. An emergency presentation was triggered when diagnostic pathway time was within 30 days of projected median survival. Total time-to-diagnosis was calculated over 100,000 iterations. The pre-COVID-19 model was estimated using published data and the Improving MND Care Survey 2019. We estimated COVID-19 delays using published statistics. RESULTS: The pre-COVID model reproduced known features of the MND diagnostic pathway, with a median time to diagnosis of 399 days and predicting 5.2% of MND patients present as undiagnosed emergencies. COVID-19 resulted in diagnostic delays from 558 days when only primary care was 25% delayed, to 915 days when both primary and secondary care were 75%. The model predicted an increase in emergency presentations ranging from 15.4%-44.5%. INTERPRETATIONS: The model suggests the COVID-19 pandemic will result in later-stage diagnoses and more emergency presentations of undiagnosed MND. Late-stage presentations may require rapid escalation to multidisciplinary care. Proactive recognition of acute and late-stage disease with altered service provision will optimise care for people with MND.

Renin-angiotensin system blockade: a novel therapeutic approach in chronic obstructive pulmonary disease.

ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin II receptor blockers) are already widely used for the treatment and prevention of cardiovascular disease and their potential role in other disease states has become increasingly recognized. COPD (chronic obstructive pulmonary disease) is characterized by pathological inflammatory processes involving the lung parenchyma, airways and vascular bed. The aim of the present review is to outline the role of the RAS (renin-angiotensin system) in the pathogenesis of COPD, including reference to results from fibrotic lung conditions and pulmonary hypertension. The review will, in particular, address the emerging evidence that ACE inhibition could have a beneficial effect on skeletal muscle function and cardiovascular co-morbidity in COPD patients. The evidence to support the effect of RAS blockade as a novel therapeutic approach in COPD will be discussed.

Inappropriate Ventilatory Homeostatic Responses in Hospitalized COVID-19 Patients.

Background: The clinical presentation of COVID-19 suggests altered breathing control - tachypnoea, relative lack of dyspnoea, and often a discrepancy between severity of clinical and radiological findings. Few studies characterize and analyse the contribution of breathing drivers and their ventilatory and perceptual responses. Aim: To establish the prevalence of inappropriate ventilatory and perceptual response in COVID-19, by characterizing the relationships between respiratory rate (RR), dyspnoea and arterial blood gas (ABG) in a cohort of COVID-19 patients at presentation to hospital, and their post-Covid respiratory sequelae at follow-up. Methods: We conducted a retrospective cohort study including consecutive adult patients admitted to hospital with confirmed COVID-19 between 1st March 2020 and 30th April 2020. In those with concurrent ABG, RR and documented dyspnoea status on presentation, we documented patient characteristics, disease severity, and outcomes at hospital and 6-week post-discharge. Results: Of 492 admissions, 194 patients met the inclusion criteria. Tachypnoea was present in 75% pronounced (RR>30) in 36%, and persisted during sleep. RR correlated with heart rate (HR) (r = 0.2674), temperature (r = 0.2824), CRP (r = 0.2561), Alveolar-arterial (A-a) gradient (r = 0.4189), and lower PaO2/FiO2 (PF) ratio (r = -0.3636). RR was not correlated with any neurological symptoms. Dyspnoea was correlated with RR (r = 0.2932), A-a gradient (r = 0.1723), and lower PF ratio (r = -0.1914), but not correlated with PaO2 (r = -0.1095), PaCO2 (r = -0.0598) or any recorded neurological symptom except for altered consciousness. Impaired ventilatory homeostatic control of pH/PaCO2 [tachypnoea (RR>20), hypocapnia (PaCO2 <4.6 kPa), and alkalosis (pH>7.45)] was observed in 29%. This group, of which 37% reported no dyspnoea, had more severe respiratory disease (A-a gradient 38.9 vs. 12.4 mmHg; PF ratio 120 vs. 238), and higher prevalence of anosmia (21 vs. 15%), dysgeusia (25 vs. 12%), headache (33 vs. 23%) and nausea (33 vs. 14%) with similar rates of new anxiety/depression (26 vs. 23%), but lower incidence of past neurological or psychiatric diagnoses (5 vs. 21%) compared to appropriate responders. Only 5% had hypoxia sufficiently severe to drive breathing (i.e. PaO2 <6.6 kPa). At 6 weeks post-discharge, 24% (8/34) showed a new breathing pattern disorder with no other neurological findings, nor previous respiratory, neurological, or psychiatric disorder diagnoses. Conclusions: Impaired homeostatic control of ventilation i.e., tachypnoea, despite hypocapnia to the point of alkalosis appears prevalent in patients admitted to hospital with COVID-19, a finding typically accompanying more severe disease. Tachypnoea prevalence was between 12 and 29%. Data suggest that excessive tachypnoea is driven by both peripheral and central mechanisms, but not hypoxia. Over a third of patients with impaired homeostatic ventilatory control did not experience dyspnoea despite tachypnoea. A subset of followed-up patients developed post-covid breathing pattern disorder.

Implementing a novel protocol for withdrawal of CPAP support in COVID-19 patients: a case series.

BACKGROUND: No published protocol to guide the withdrawal of continuous positive airway pressure (CPAP) for patients with COVID-19 exists. CASE SERIES: Description of the introduction of a novel protocol, developed by consensus to guide the withdrawal of CPAP for patients diagnosed as dying with COVID-19 in an acute hospital. OUTCOME: 19 patients died on the high-dependency respiratory unit following treatment with CPAP. 89% died with CPAP withdrawn. The dying trajectory was difficult to predict. Symptoms were managed promptly and effectively with a combination of opioids, benzodiazepines and close medical supervision. No concerns were raised by families regarding the decision making or withdrawal process. DISCUSSION: The use of the protocol ensures a comfortable and dignified death and supports the delivery of individualised care at the end of life. Future research on this topic should focus on qualitative outcomes and consider the applicability of this protocol in other patient groups.

Post-COVID-19 assessment in a specialist clinical service: a 12-month, single-centre, prospective study in 1325 individuals.

INTRODUCTION: Post-COVID-19 complications require simultaneous characterisation and management to plan policy and health system responses. We describe the 12-month experience of the first UK dedicated post-COVID-19 clinical service to include hospitalised and non-hospitalised patients. METHODS: In a single-centre, observational analysis, we report the demographics, symptoms, comorbidities, investigations, treatments, functional recovery, specialist referral and rehabilitation of 1325 individuals assessed at the University College London Hospitals post-COVID-19 service between April 2020 and April 2021, comparing by referral route: posthospitalised (PH), non-hospitalised (NH) and post emergency department (PED). Symptoms associated with poor recovery or inability to return to work full time were assessed using multivariable logistic regression. RESULTS: 1325 individuals were assessed (PH: 547, 41.3%; PED: 212, 16%; NH: 566, 42.7%). Compared with the PH and PED groups, the NH group were younger (median 44.6 (35.6-52.8) years vs 58.3 (47.0-67.7) years and 48.5 (39.4-55.7) years), more likely to be female (68.2%, 43.0% and 59.9%), less likely to be of ethnic minority (30.9%, 52.7% and 41.0%) or seen later after symptom onset (median (IQR): 194 (118-298) days, 69 (51-111) days and 76 (55-128) days; all p<0.0001). All groups had similar rates of onward specialist referral (NH 18.7%, PH 16.1% and PED 18.9%, p=0.452) and were more likely to require support for breathlessness (23.7%, 5.5% and 15.1%, p<0.001) and fatigue (17.8%, 4.8% and 8.0%, p<0.001). Hospitalised patients had higher rates of pulmonary emboli, persistent lung interstitial abnormalities and other organ impairment. 716 (54.0%) individuals reported <75% optimal health (median 70%, IQR 55%-85%). Less than half of employed individuals could return to work full time at first assessment. CONCLUSION: Post-COVID-19 symptoms were significant in PH and NH patients, with significant ongoing healthcare needs and utilisation. Trials of interventions and patient-centred pathways for diagnostic and treatment approaches are urgently required.

Expiratory muscle strength training improves measures of pressure generation and cough strength in a patient with myotonic dystrophy type 1.

Expiratory muscle strength training (EMST) exercise programmes aim to improve respiratory function by increasing the force generating capability of expiratory muscles by resistance training. In neuromuscular conditions, in which cough flow generation is often decreased, there is increasing interest in EMST as a therapeutic intervention. We present data showing efficacy of EMST in a patient with adult onset Myotonic Dystrophy Type 1 (DM1). A domiciliary training programme (5 days per week over 32 weeks) resulted in increases in maximum expiratory mouth pressure (from 15 cmH2O to 38 cmH2O) and peak cough flow (300 L/min to 390 L/min). Improvements were also seen in maximum inspiratory mouth pressure (26 cmH2O to 52 cmH2O) and sniff nasal inspiratory pressure (40 cmH2O to 69 cmH2O). No changes were detected in speech or swallowing. This novel study demonstrates that cough flow generation in DM1 may be increased by a programme of expiratory muscle training. A clinical trial of EMST in DM1 is warranted.

Anaemia secondary to critical illness: an unexplained phenomenon.

Almost all patients suffering critical illness become anaemic during their time in intensive care. The cause of this anaemia and its management has been a topic of debate in critical care medicine for the last two decades. Packed red cell transfusion has an associated cost and morbidity such that decreasing the number of units transfused would be of great benefit. Our understanding of the aetiology and importance of this anaemia is improving with recent and ongoing work to establish the cause, effect and best treatment options. This review aims to describe the current literature whilst suggesting that the nature of the anaemia should be considered with reference to the time point in critical illness. Finally, we suggest that using haemoglobin concentration as a measure of oxygen-carrying capacity has limitations and that ways of measuring haemoglobin mass should be explored.

No evidence for a local renin-angiotensin system in liver mitochondria.

The circulating, endocrine renin-angiotensin system (RAS) is important to circulatory homeostasis, while ubiquitous tissue and cellular RAS play diverse roles, including metabolic regulation. Indeed, inhibition of RAS is associated with improved cellular oxidative capacity. Recently it has been suggested that an intra-mitochondrial RAS directly impacts on metabolism. Here we sought to rigorously explore this hypothesis. Radiolabelled ligand-binding and unbiased proteomic approaches were applied to purified mitochondrial sub-fractions from rat liver, and the impact of AngII on mitochondrial function assessed. Whilst high-affinity AngII binding sites were found in the mitochondria-associated membrane (MAM) fraction, no RAS components could be detected in purified mitochondria. Moreover, AngII had no effect on the function of isolated mitochondria at physiologically relevant concentrations. We thus found no evidence of endogenous mitochondrial AngII production, and conclude that the effects of AngII on cellular energy metabolism are not mediated through its direct binding to mitochondrial targets.