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Objectives To investigate the experience of people who continue to be unwell after acute COVID-19, often referred to as ‘long COVID’, both in terms of their symptoms and their interactions with healthcare. Design We conducted a mixed-methods analysis (quantitative and qualitative) of responses to a survey accessed through a UK online post-COVID support and information hub between April 2020 and December 2020 about people’s experiences after having acute COVID-19. Participants Of 3290 respondents, 78% were female, median age range 45-54 years, 92.1% reported white ethnicity; 12.7% had been hospitalised. 494 respondents (16.5%) completed the survey between 4 and 8 weeks of the onset of their symptoms, 641 (21.4%) between 8 and 12 weeks and 1865 (62.1%) more than 12 weeks after. Results The ongoing symptoms most frequently reported were; breathing problems (92.1%), fatigue (83.3%), muscle weakness or joint stiffness (50.6%), sleep disturbances (46.2%), problems with mental abilities (45.9%) changes in mood, including anxiety and depression (43.1%) and cough (42.3%). Symptoms did not appear to be related to the severity of the acute illness or to the presence of pre-existing medical conditions. Analysis of free text responses revealed three main themes (1) Experience of living with COVID-19 – physical and psychological symptoms that fluctuate unpredictably; (2) Interactions with healthcare; (3) Implications for the future – their own condition, society and the healthcare system and the need for research Conclusion People living with persistent problems after the acute phase of COVID-19 report multiple and varying symptoms that are not necessarily associated with initial disease severity or the presence of pre-existing health conditions. Many have substantial unmet needs and experience barriers to accessing healthcare. Consideration of patient perspective and experiences will assist in the planning of services to address this. Ethical approval Ethical approval was granted by Imperial College Research and Integrity Team (IREC; 20IC6625).

Participating in singing is considered to have a range of social and psychological benefits. However, the physiological demands of singing, whether it can be considered exercise, and its intensity as a physical activity are not well understood. We therefore compared cardiorespiratory parameters while completing components of Singing for Lung Health (SLH) sessions, with treadmill walking at differing speeds (2, 4, and 6km/hr). Eight healthy adults were included, none of whom reported regular participation in formal singing activities. Singing induced physiological responses that were consistent with moderate intensity activity (METS: median 4.12, IQR 2.72 - 4.78), with oxygen consumption, heart rate, and volume per breath above those seen walking at 4km/hr. Minute ventilation was higher during singing (median 22.42L/min, IQR 16.83 - 30.54) than at rest (11L/min, 9 - 13), lower than 6km/hr walking (30.35L/min, 26.94 - 41.11), but not statistically different from 2km/hr (18.77L/min, 16.89 - 21.35) or 4km/hr (23.27L/min, 20.09 - 26.37) walking. Our findings suggest the metabolic demands of singing may contribute to the health and wellbeing benefits attributed to participation. However, if physical training benefits result remains uncertain. Further research including different singing styles, singers, and physical performance impacts when used as a training modality is encouraged.

Reduced physical performance reduces quality of life in patients with chronic obstructive pulmonary disease (COPD). Impaired physical performance is, in part, a consequence of reduced muscle mass and function, which is accompanied by mitochondrial dysfunction. We recently showed that miR-542-3p and miR-542-5p were elevated in a small cohort of COPD patients and more markedly in critical care patients. In mice, these microRNAs (miRNAs) promoted mitochondrial dysfunction suggesting that they would affect physical performance in patients with COPD, but we did not explore the association of these miRNAs with disease severity or physical performance further. We therefore quantified miR-542-3p/5p and mitochondrial rRNA expression in RNA extracted from quadriceps muscle of patients with COPD and determined their association with physical performance. As miR-542-3p inhibits ribosomal protein synthesis its ability to inhibit protein synthesis was also determined in vitro. Both miR-542-3p expression and -5p expression were elevated in patients with COPD (5-fold P < 0.001) and the degree of elevation associated with impaired lung function (transfer capacity of the lung for CO in % and forced expiratory volume in 1 s in %) and physical performance (6-min walk distance in %). In COPD patients, the ratio of 12S rRNA to 16S rRNA was suppressed suggesting mitochondrial ribosomal stress and mitochondrial dysfunction and miR-542-3p/5p expression was inversely associated with mitochondrial gene expression and positively associated with p53 activity. miR-542-3p suppressed RPS23 expression and maximal protein synthesis in vitro. Our data show that miR-542-3p and -5p expression is elevated in COPD patients and may suppress physical performance at least in part by inhibiting mitochondrial and cytoplasmic ribosome synthesis and suppressing protein synthesis. NEW & NOTEWORTHY miR-542-3p and -5p are elevated in the quadriceps muscle of patients with chronic obstructive pulmonary disease (COPD) in proportion to the severity of their lung disease. These microRNAs inhibit mitochondrial and cytoplasmic protein synthesis suggesting that they contribute to impaired exercise performance in COPD.

Skeletal muscle dysfunction is a frequent extra-pulmonary manifestation of Chronic Obstructive Pulmonary Disease (COPD) with implications for both quality of life and survival. The underlying biology nevertheless remains poorly understood. We measured global gene transcription in the quadriceps using Affymetrix HuGene1.1ST arrays in an unselected cohort of 79 stable COPD patients in secondary care and 16 healthy age- and gender-matched controls. We detected 1,826 transcripts showing COPD-related variation. Eighteen exhibited ≥2fold changes (SLC22A3, FAM184B, CDKN1A, FST, LINC01405, MUSK, PANX1, ANKRD1, C12orf75, MYH1, POSTN, FRZB, TNC, ACTC1, LINC00310, MYH3, MYBPH and AREG). Thirty-one transcripts possessed previous reported evidence of involvement in COPD through genome-wide association, including FAM13A. Network analysis revealed a substructure comprising 6 modules of co-expressed genes. We identified modules with mitochondrial and extracellular matrix features, of which IDH2, a central component of the mitochondrial antioxidant pathway, and ABI3BP, a proposed switch between proliferation and differentiation, represent hubs respectively. COPD is accompanied by coordinated patterns of transcription in the quadriceps involving the mitochondria and extracellular matrix and including genes previously implicated in primary disease processes.

Background Loss of muscle mass and strength are important sequelae of chronic disease, but the response of individuals is remarkably variable, suggesting important genetic and epigenetic modulators of muscle homeostasis. Such factors are likely to modify the activity of pathways that regulate wasting, but to date, few such factors have been identified. Methods The effect of miR‐422a on SMAD4 expression and transforming growth factor (TGF)‐β signalling were determined by western blotting and luciferase assay. miRNA expression was determined by qPCR in plasma and muscle biopsy samples from a cross‐sectional study of patients with chronic obstructive pulmonary disease (COPD) and a longitudinal study of patients undergoing aortic surgery, who were subsequently admitted to the intensive care unit (ICU). Results miR‐422a was identified, by a screen, as a microRNA that was present in the plasma of patients with COPD and negatively associated with muscle strength as well as being readily detectable in the muscle of patients. In vitro, miR‐422a suppressed SMAD4 expression and inhibited TGF‐beta and bone morphogenetic protein‐dependent luciferase activity in muscle cells. In male patients with COPD and those undergoing aortic surgery and on the ICU, a model of ICU‐associated muscle weakness, quadriceps expression of miR‐422a was positively associated with muscle strength (maximal voluntary contraction r = 0.59, P

ispartof: Journal of Medical Internet Research status: accepted

Introduction Skeletal muscle dysfunction is a clinically important complication of pulmonary arterial hypertension (PAH). Growth/differentiation factor 15 (GDF-15), a prognostic marker in PAH, has been associated with muscle loss in other conditions. We aimed to define the associations of GDF-15 and muscle wasting in PAH, to assess its utility as a biomarker of muscle loss and to investigate its downstream signalling pathway as a therapeutic target. Methods GDF-15 levels and measures of muscle size and strength were analysed in the monocrotaline (MCT) rat, Sugen/hypoxia mouse and in 30 patients with PAH. In C2C12 myotubes the downstream targets of GDF-15 were identified. The pathway elucidated was then antagonised in vivo. Results Circulating GDF-15 levels correlated with tibialis anterior (TA) muscle fibre diameter in the MCT rat (Pearson r=−0.61, p=0.003). In patients with PAH, plasma GDF-15 levels of

Background: a loss of muscle mass occurs as a consequence of a range of chronic and acute diseases as well as in older age. This wasting results from an imbalance of protein synthesis and degradation with a reduction in synthesis and resistance to anabolic stimulation often reported features. Ribosomes are required for protein synthesis, so changes in the control of ribosome synthesis are potential contributors to muscle wasting. MicroRNAs (miRNAs) are known regulators of muscle phenotype and have been shown to modulate components of the protein synthetic pathway. One miRNA that is predicted to target a number of components of protein synthetic pathway is miR-424-5p, which is elevated in the quadriceps of patients with chronic obstructive pulmonary disease (COPD).Methods: targets of miR-424-5p were identified by Argonaute2 pull down, and the effects of the miRNA on RNA and protein expression were determined by quantitative polymerase chain reaction and western blotting in muscle cells in vitro. Protein synthesis was determined by puromycin incorporation in vitro. The miRNA was over-expressed in the tibialis anterior muscle of mice by electroporation and the effects quantified. Finally, quadriceps expression of the miRNA was determined by quantitative polymerase chain reaction in patients with COPD and intensive care unit (ICU)-acquired weakness and in patients undergoing aortic surgery as well as in individuals from the Hertfordshire Sarcopenia Study.Results: pull-down assays showed that miR-424-5p bound to messenger RNAs encoding proteins associated with muscle protein synthesis. The most highly enriched messenger RNAs encoded proteins required for the Pol I RNA pre-initiation complex required for ribosomal RNA (rRNA) transcription, (PolR1A and upstream binding transcription factor). In vitro, miR-424-5p reduced the expression of these RNAs, reduced rRNA levels, and inhibited protein synthesis. In mice, over-expression of miR-322 (rodent miR-424 orthologue) caused fibre atrophy and reduced upstream binding transcription factor expression and rRNA levels. In humans, elevated miR-424-5p associated with markers of disease severity in COPD (FEV1%), in patients undergoing aortic surgery (LVEF%), and in patients with ICU-acquired weakness (days in ICU). In patients undergoing aortic surgery, preoperative miR-424-5p expression in skeletal muscle was associated with muscle loss over the following 7 days.Conclusions: these data suggest that miR-424-5p regulates rRNA synthesis by inhibiting Pol I pre-initiation complex formation. Increased miR-424-5p expression in patients with conditions associated with muscle wasting is likely to contribute to the inhibition of protein synthesis and loss of muscle mass.

OBJECTIVES: Continuous positive airway pressure (CPAP) improves upper airway obstruction in patients with obstructive sleep apnoea (OSA), who often are overweight-obese. Although it is thought that CPAP improves long-term blood pressure control (BP), the impact of acute and short-term CPAP use on the cardiovascular system in obese patients has not been described in detail.METHODS: Obese patients (body mass index, BMI > 25 kg/m2) with OSA were studied awake, supine during incremental CPAP titration (4-20 cmH2O, +2 cmH2O/3 mins). BP was measured continuously with a beat-to-beat BP monitor (Ohmeda 2300, Finapres Medical Systems, Amsterdam/NL), BP variability (BPV) was calculated as the standard deviation of BP at each CPAP level, the 95% confidence interval (95%CI) was calculated and changes in BP and BPV were reported.RESULTS: 15 patients (12 male, 48 ± 10) years, BMI 38.9 ± 5.8 kg/m2) were studied; the baseline BP was 131.0 ± 10.2/85.1 ± 9.1 mmHg. BP and BPV increased linearly with CPAP titration (systolic BP r = 0.960, p CONCLUSION: Short-term incremental CPAP leads to significant increases in BP and BPV in obese patients with OSA while awake. Careful titration of pressures is required to minimise the risk of nocturnal awakenings while improving BP control.

Obstructive sleep apnoea (OSA) is characterised by a loss of neuromuscular tone of the upper airway dilator muscles while asleep. Positive airway pressure is a well-established long-term treatment, but patient compliance is limited. Alternative treatment options include the use of electrical current for hypoglossal nerve stimulation. This study investigated the effectiveness of transcutaneous electrical stimulation in patients with OSA. The current study was a randomised, sham-controlled and double blind cross-over trial using transcutaneous electrical stimulation of the upper airway dilator muscles in patients with OSA. Patients underwent a baseline polysomnography to assess the severity of OSA, followed by two randomly assigned nights of sham stimulation and active treatment. The primary outcome was the 4% oxygen desaturation index (ODI). 36 patients were recruited, the mean age was 50.8 (SD 11.2) years, 30 males, body-mass-index (BMI) mean 29.6 (SD 8.0) kg/m 2 , ODI median 25.7 (interquartile range, IQR 16.0-49.1) /hour. The ODI improved when comparing sham stimulation to active treatment (ODI median 26.9 (IQR 17.5-39.5) vs 19.5 (IQR 11.6-40.0) /hour; p=0.026) without affecting sleep architecture. Patients tolerated stimulation well, without adverse events. Responders (47.2%) were predominantly from the mild-moderate OSA category. In this subgroup, the oxygen desaturation index was reduced by 10.0 (95%CI 3.9-16.0) /hour (p Transcutaneous electrical stimulation of the pharyngeal dilators in patients with OSA can be delivered throughout the whole night. It is well tolerated and improves upper airway obstruction.

Introduction: Transcutaneous electrical stimulation (TES) provides neuromuscular tone to the pharyngeal dilator muscles of the upper airway (UA) while asleep, but feasibility of this method to treat obstructive sleep apnoea (OSA) throughout the whole night has not been tested. Patients&Methods: We conducted a sham-controlled, randomised and controlled cross-over trial using TES of the UA muscles in 36 patients with confirmed OSA to assess patients9 acceptance of the method and the potential side effect profile. Patients were studied using polysomnography during randomly assigned nights of sham-stimulation and active treatment following titration of the stimulation while awake. Assessment of patients9 acceptance and experience of side effects was measured using a visual analogue scale (0-10 points). Data were compared using the Wilcoxon test. Results: None of the patients reported skin discomfort, unpleasant tongue sensations or morning headache (p=n.s.). There was no difference in patients9 perceived sleep quality (p=n.s.), but patients reported a 30% reduction in mouth dryness following the night of active treatment (p=0.007). The total sleep time was not different between the treatment arms (p=n.s.). During the trial, there were no severe adverse events. Conclusion: TES of the UA dilator muscles in OSA can be delivered throughout the night with few side effects and does not lead to arousal from sleep, if appropriately titrated.