Recent advances in skeletal muscle physiology

Skeletal muscle is the largest mass of tissue in the body, accounting for 50%–75% of total body proteins and approximately 40% of total body weight. It plays key roles in motor function, heat generation, substrate storage, and glucose metabolism, perturbations of which leads to disease states. The basics of skeletal muscle physiology have been previously reviewed in this journal. Some of the key concepts are revisited in this review to help understand the recent advances in the field, together with their clinical importance

Academic anaesthesiology: a global perspective on training, support, and future development of early career researchers

As anaesthesiologists face increasing clinical demands and a limited and competitive funding environment for academic work, the sustainability of academic anaesthesiologists has never been more tenuous. Yet, the speciality needs academic anaesthesiologists in many roles, extending beyond routine clinical duties. Anaesthesiologist educators, researchers, and administrators are required not only to train future generations but also to lead innovation and expansion of anaesthesiology and related specialities, all to improve patient care. This group of early career researchers with geographically distinct training and practice backgrounds aim to highlight the diversity in clinical and academic training and career development pathways for anaesthesiologists globally. Although multiple routes to success exist, one common thread is the need for consistent support of strong mentors and sponsors. Moreover, to address inequitable opportunities, we emphasise the need for diversity and inclusivity through global collaboration and exchange that aims to improve access to research training and participation. We are optimistic that by focusing on these fundamental principles, we can help build a more resilient and sustainable future for academic anaesthesiologists around the world

Penicillin allergy de-labelling ahead of elective surgery: feasibility and barriers

Background: Around 10–15% of the in-patient population carry unsubstantiated ‘penicillin allergy’ labels, the majority incorrect when tested. These labels are associated with harm from use of broad-spectrum non-penicillin antibiotics. Current testing guidelines incorporate both skin and challenge tests; this is prohibitively expensive and time-consuming to deliver on a large scale. We aimed to establish the feasibility of a rapid access de-labelling pathway for surgical patients, using direct oral challenge. Methods: ‘Penicillin allergic’ patients, recruited from a surgical pre-assessment clinic, were risk-stratified using a screening questionnaire. Patients at low risk of true, immunoglobulin E (IgE)-mediated allergy were offered direct oral challenge using incremental amoxicillin to a total dose of 500 mg. A 3-day course was completed at home. De-labelled patients were followed up to determine antibiotic use in surgery, and attitudes towards de-labelling were explored. Results: Of 219 patients screened, 74 were eligible for inclusion and offered testing. We subsequently tested 56 patients; 55 were de-labelled. None had a serious reaction to the supervised challenge, or thereafter. On follow-up, 17 of 19 patients received appropriate antimicrobial prophylaxis during surgery. Only three of 33 de-labelled patients would have been happy for the label to be removed without prior specialist testing. Conclusion: Rapid access de-labelling, using direct oral challenge in appropriately risk-stratified patients, can be incorporated into the existing surgical care pathway. This provides immediate and potential long-term benefit for patients. Interest in testing is high among patients, and clinicians appear to follow clinic recommendations. Patients are unlikely to accept removal of their allergy label on the basis of history alone

alpha'-exact entropies for BPS and non-BPS extremal dyonic black holes in heterotic string theory from ten-dimensional supersymmetry

We calculate near-horizon solutions for four-dimensional 4-charge and five-dimensional 3-charge black holes in heterotic string theory from the part of the ten-dimensional tree-level effective action which is connected to gravitational Chern-Simons term by supersymmetry. We obtain that the entropies of large black holes exactly match the alpha'-exact statistical entropies obtained from microstate counting (D=4) and AdS/CFT correspondence (D=5). Especially interesting is that we obtain agreement for both BPS and non-BPS black holes, contrary to the case of R^2-truncated (four-derivative) actions (D-dimensional N=2 off-shell supersymmetric or Gauss-Bonnet) were used, which give the entropies agreeing (at best) just for BPS black holes. The key property of the solutions, which enabled us to tackle the action containing infinite number of terms, is vanishing of the Riemann tensor \bar{R}_{MNPQ} obtained from torsional connection defined with \bar{\Gamma} = \Gamma - H/2. Morover, if every monomial of the remaining part of the effective action would contain at least two Riemanns \bar{R}_{MNPQ}, it would trivially follow that our solutions are exact solutions of the full heterotic effective action in D=10. The above conjecture, which appeared (in this or stronger form) from time to time in the literature, has controversial status, but is supported by the most recent calculations of Richards (arXiv:0807.3453 [hep-th]). Agreement of our results for the entropies with the microscopic ones supports the conjecture. As for small black holes, our solutions in D=5 still have singular horizons.Comment: 28 pages; v2: minor changes, references added; v3: extended discussion on small black holes in sec. 5.4, more references added, accepted in JHE

Prognostic significance of troponin in patients with malignancy ( NIHR Health Informatics Collaborative TROP-MALIGNANCY study )

Background: Cardiac troponin is commonly raised in patients presenting with malignancy. The prognostic significance of raised troponin in these patients is unclear. Objectives: We sought to investigate the relation between troponin and mortality in a large, well characterised cohort of patients with a routinely measured troponin and a primary diagnosis of malignancy. Methods: We used the National Institute for Health Research (NIHR) Health Informatics Collaborative data of 5571 patients, who had troponin levels measured at 5 UK cardiac centres between 2010 and 2017 and had a primary diagnosis of malignancy. Patients were classified into solid tumour or haematological malignancy subgroups. Peak troponin levels were standardised as a multiple of each laboratory’s 99th -percentile upper limit of normal (xULN). Results: 4649 patients were diagnosed with solid tumours and 922 patients with haematological malignancies. Raised troponin was an independent predictor of mortality in all patients (Troponin > 10 vs. <1 adjusted HR 2.01, 95% CI 1.73 to 2.34), in solid tumours (HR 1.84, 95% CI 1.55 to 2.19), and in haematological malignancy (HR 2.72, 95% CI 1.99 to 3.72). There was a significant trend in increasing mortality risk across troponin categories in all three subgroups (p < 0.001). Conclusion: Raised troponin level is associated with increased mortality in patients with a primary diagnosis of malignancy regardless of cancer subtype. Mortality risk is stable for patients with a troponin level below the ULN but increases as troponin level increases above the ULN in the absence of acute coronary syndrome

Developing expert international consensus statements for opioid-sparing analgesia using the Delphi method

Introduction: The management of postoperative pain in anaesthesia is evolving with a deeper understanding of associating multiple modalities and analgesic medications. However, the motivations and barriers regarding the adoption of opioid-sparing analgesia are not well known. Methods: We designed a modified Delphi survey to explore the perspectives and opinions of expert panellists with regard to opioid-sparing multimodal analgesia. 29 anaesthetists underwent an evolving three-round questionnaire to determine the level of agreement on certain aspects of multimodal analgesia, with the last round deciding if each statement was a priority. Results: The results were aggregated and a consensus, defined as achievement of over 75% on the Likert scale, was reached for five out of eight statements. The panellists agreed there was a strong body of evidence supporting opioid-sparing multimodal analgesia. However, there existed multiple barriers to widespread adoption, foremost the lack of training and education, as well as the reluctance to change existing practices. Practical issues such as cost effectiveness, increased workload, or the lack of supply of anaesthetic agents were not perceived to be as critical in preventing adoption. Conclusion: Thus, a focus on developing specific guidelines for multimodal analgesia and addressing gaps in education may improve the adoption of opioid-sparing analgesia

Ryanodine receptor leak triggers fiber Ca²⁺ redistribution to preserve force and elevate basal metabolism in skeletal muscle

Muscle contraction depends on tightly regulated Ca2+ release. Aberrant Ca2+ leak through ryanodine receptor 1 (RyR1) on the sarcoplasmic reticulum (SR) membrane can lead to heatstroke and malignant hyperthermia (MH) susceptibility, as well as severe myopathy. However, the mechanism by which Ca2+ leak drives these pathologies is unknown. Here, we investigate the effects of four mouse genotypes with increasingly severe RyR1 leak in skeletal muscle fibers. We find that RyR1 Ca2+ leak initiates a cascade of events that cause precise redistribution of Ca2+ among the SR, cytoplasm, and mitochondria through altering the Ca2+ permeability of the transverse tubular system membrane. This redistribution of Ca2+ allows mice with moderate RyR1 leak to maintain normal function; however, severe RyR1 leak with RYR1 mutations reduces the capacity to generate force. Our results reveal the mechanism underlying force preservation, increased ATP metabolism, and susceptibility to MH in individuals with gain-of-function RYR1 mutations