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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.

IntroductionPost-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.MethodsIn 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.Results1325 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 pConclusionPost-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.

BackgroundComplications following SARS-CoV-2 infection 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 clinical service to include both hospitalised and non-hospitalised patients.MethodsIn a single-centre, observational analysis, we report outcomes for 1325 individuals assessed in the University College London Hospitals NHS Foundation Trust Post-COVID service between April 2020 and April 2021. Demography, symptoms, comorbidities, investigations, treatments, functional recovery, specialist referral and rehabilitation were compared by referral route (“post hospitalisation”, 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.Findings1325 individuals were assessed (PH 547 [41.3%], PED 212 [16%], NH 566 [42.7%]. Compared with PH and PED groups, NH were younger (median 44.6 [35.6-52.8] vs 58.3 [47.0-67.7] and 48.5 [39.4-55.7] years), more likely to be female (68.2%, 43.0% and 59.9%), less likely to be from an ethnic minority (30.9%, 52.7% and 41.0%) and seen later after symptom onset (median [IQR]:194 [118-298], 69 [51-111] and 76 [55-128] days) (all pInterpretationSymptoms following SARS-CoV-2 infection were significant in both post- and non-hospitalised patients, with significant ongoing healthcare needs and utilisation. Trials of interventions and patient-centred pathways for diagnostic and treatment approaches are urgently required.FundingUCLH/UCL BRCResearch in contextPrevious evidenceLong COVID and post-COVID syndrome were first identified in April 2020. We searched PubMed and medrxiv for articles published up to April 30th, 2021, using the keywords “long COVID”, “post-COVID syndrome”, “persistent symptoms”, “hospitalised”, “community” and “non-hospitalised”. We identified 17 articles and 7 systematic reviews. Fifteen studies have considered symptoms, multi-organ or functional impairment but only one study to-date has considered all these variables in non-hospitalised COVID patients. No studies have compared symptom burden and management between non-hospitalised and hospitalised individuals as systematically assessed and managed in a dedicated post-COVID service.Added value of this studyFor the first time, we report the baseline characteristics, investigation and outcomes of initial assessment of all eligible patients in a dedicated multi-professional post-COVID service, including 547 post-hospitalisation, 566 non-hospitalised and 212 patients discharged from emergency department. Despite relatively low comorbidity and risk factor burden in non-hospitalised patients, we show that both non-hospitalised and hospitalised patients presenting with persistent symptoms after SARS-CoV2 infection have high rates of functional impairment, specialist referral and rehabilitation, even 6-12 months after the acute infection. These real-world data will inform models of care during and beyond the pandemic.Implications of all the available evidenceThe significant, long-lasting health and social consequences of SARS-CoV-2 infection are not confined to those who required hospitalisation. As with other long-term conditions, care of patients experiencing Long COVID or specific end-organ effects require consistent, integrated, patient-centred approaches to investigation and management. At public health and policy level, burden of post-COVID morbidity demands renewed focus on effective infection suppression for all age groups.

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.

BackgroundA 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.MethodsThe 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.ResultsThe 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%.InterpretationsThe 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.FundingThis research was supported and funded by a grant from the Reta Lila Weston Trust. NS was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.

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.

Purpose: We evaluate the effect of an exercised prehabilitation programme on tumour response in rectal cancer patients following neoadjuvant chemoradiotherapy (NACRT). Patients and Methods: Rectal cancer patients with (MRI-defined) threatened resection margins who completed standardized NACRT were prospectively studied in a post hoc, explorative analysis of two previously reported clinical trials. MRI was performed at Weeks 9 and 14 post-NACRT, with surgery at Week 15. Patients undertook a 6-week preoperative exercise-training programme. Oxygen uptake (VO2) at anaerobic threshold (AT) wasmeasured at baseline (pre-NACRT), after completion of NACRT and at week 6 (post-NACRT). Tumour related outcome variables: MRI tumour regression grading (ymrTRG) at Week 9 and 14; histopathological T-stage (ypT); and tumour regression grading (ypTRG)) were compared. Results: 35 patients (26 males) were recruited. 26 patients undertook tailored exercise-training with 9 unmatched controls. NACRT resulted in a fall in VO2 at AT −2.0 ml/kg −1 /min −1 (−1.3,−2.6), p < 0.001. Exercise was shown to reverse this effect. VO2 at AT increased between groups, (post-NACRT vs. week 6) by +1.9 ml/kg −1 /min −1 (0.6, 3.2), p = 0.007. A significantly greater ypTRG in the exercise group at the time of surgery was found (p = 0.02). Conclusion: Following completion of NACRT, exercise resulted in significant improvements in fitness and augmented pathological tumour regression.

ObjectivesTo characterise the sketetal muscle metabolic phenotype during early critical illness.MethodsVastus 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 resultsFrom 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); pConclusionsDecreased 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 numberNCT01106300.

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.

Background: Chemotherapy improves outcomes for patients with gastrointestinal cancer, but carries associated morbidity. Platinum-based chemotherapy adversely impacts fitness, invivo mitochondrial function, and cellular redox status in humans, however the mechanisms are poorly understood. Exercise interventions mitigate against this, but interactions between the effect of the cancer, chemotherapy, and exercise intervention are poorly understood. Using a colorectal cancer (CRC) mouse model we investigated changes in skeletal muscle oxidative phosphorylation (OxPhos) capacity and redox biology with chemotherapy and exercise. Method: SCID mice (n=48) were randomized to laparotomy with (Ca) or without (NCa) orthotopic caecal injection of DLD-1 CRC cells. CRC established over 8 weeks then mice were randomized to 1) 3 cycles of intra-peritoneal (IP) chemotherapy (Chemo; 5FU 5mg/kg, Oxaliplatin 10mg/kg and Leucovorin 90mg/kg) followed by interval exercise-training 2) Chemo and no exercise 3) IP saline sham (Sal) with exercise or 4) Sal with no exercise. Blood was collected pre and post-Chemo and at death (post-exercise), and markers of oxidative stress measured. Soleus muscle mitochondrial function was analyzed using high-resolution respirometry. Measurements included maximum OxPhos capacity (PI+II+β), Complex I and II capacities and the ratio of octanoyl-carnitine to pyruvate-supported respiration (FAO). Histopathological caecal examination was undertaken to determine cancer response. Results: Chemotherapy alone resulted in 37% lower OxPhos capacities in sham mice (p=0.011), whilst FAO was 40% lower (p=0.004). Cancer alone resulted in 38% lower OxPhos capacities (p=0.012). In combination with cancer, chemotherapy resulted in OxPhos capacities that were 42% lower than in mice with cancer but no chemotherapy (p=0.007), along with 51% lower Complex I (p Conclusion: Chemotherapy and cancer alone were associated with a loss of oxidative capacity, with a greater reduction when combined. Chemotherapy alone and with cancer caused a shift away from FAO and reduction in TPPC. Though we demonstrated an exercise effect in sham mice, exercise did not increase OxPhos capacity, nor did it ameliorate the effects of cancer and chemotherapy. A more intense exercise intervention may be required. Citation Format: Malcolm Andrew West, Alexandrina Roman, Ronan Astin, Sian Pugh, Bernadette Fernandez, Annette Hayden, Judith Cave, Eleanor Jaynes, John N. Primrose, Sandy Jack, Michael P. Grocott, Andrew Murray, Martin Feelisch, Alexander Mirnezami, Timothy Underwood. Altered skeletal muscle mitochondrial function and redox biology with chemotherapy and exercise in a colorectal cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1488. doi:10.1158/1538-7445.AM2017-1488

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.

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.

Background and Aims In severe sepsis, early mitochondrial dysfunction in skeletal muscle is associated with decreased biogenesis and adverse patient outcome. We hypothesised that reduction in mitochondrial content during critical illness would be balanced by enhanced capacity to produce ATP achieved by switching from glucose to fatty acid oxidation as the preferred metabolic substrate. Methods 30 critically ill patients (70% male, age 56.4 ± 19.7 years, APACHE II score 22.4 ± 6.6) were prospectively recruited Results There were reduction in both skeletal muscle mtDNA (p = 0.04) and PGC1-α (p = 0.02) from day 1 to day 7, with fold change in PGC1α correlated with the fold change in mtDNA (r 2 = 0.65, p 0.1). Protein levels of mitochondrial respiratory complexes I-V did not change significantly from day 1 to day 7 and mtDNA fold change did not correlate with fold change in complex I-V (p > 0.1). There was a weak positive correlation between feeding (protein delivered) and fold change in complex I (r 2 = 0.20, p = 0.014) and complex III protein level (r 2 = 0.20, p = 0.016). Overall levels of mitochondrial β-oxidation pathway proteins (CPT1, MCAD, ETF, DecR1) did not change whilst peroxisomal MEFII increased significantly (p Conclusion These data suggest decreased mitochondrial biogenesis over the first week of critical illness. The increase in β-oxidation proteins combined with the lack of change in respiratory chain complex concentrations during the first week suggests that the oxidative capacity of the remaining mitochondria was enhanced with increased capacity to metabolise fatty acids. These data support our hypothesis that the decreased cellular energy utilisation accompanying decreased mitochondrial biogenesis is offset by increased capacity to produce ATP through the β-oxidation of fats.

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.