Blood Biomarkers of Long COVID: A Systematic Review.

BACKGROUND: Long coronavirus disease (COVID; LC) affects millions of people worldwide. The exact mechanisms which result in a broad, undulating and detrimental symptom profile remain unknown. Blood biomarkers associated with LC have been described; however, consensus on these remains elusive, in part due to a lack of continuity between studies on a universally accepted definition of LC. This systematic review aimed to consolidate current knowledge of blood biomarkers associated with the prevalence of LC on the basis of the World Health Organisation (WHO) clinical definition of this condition. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Observational, cross-sectional, and randomised control studies published in the English language that studied blood biomarkers associated with the WHO definition of LC. All studies included participants who were ≥ 18 years old and group sizes ≥ 10 participants, and were compared against a control group without any known co-morbidities. METHODS: A systematic literature search was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and prospectively registered on Prospero (ID: CRD42022373121). The Cochrane, Embase, PubMed and Web of Science databases were searched from inception to January 2024. Search results were gathered using Rayyan software and data extracted using Microsoft Excel. The reporting recommendations for tumour markers prognostic studies (REMARK) questionnaire was used to assess the quality of the included studies. RESULTS: A total of 45 observational and one interventional study comprising 4415 participants were included in this review which identified 525 blood biomarkers thought to be associated with LC. Three blood biomarker subtypes were associated with the development of LC: (1) immunological and inflammatory dysfunction, (2) endothelial/vascular dysfunction and (3) metabolic and clotting abnormalities. DISCUSSION AND CONCLUSIONS: Our data are consistent with previous findings; however, no single biomarker was sufficiently associated with LC prevalence and instead a profile of biomarkers across various physiological systems may be more clinically useful. In all, 196 studies were excluded due to a lack of an adequately healthy comparator group and/or failure to meet the WHO LC definition. This demonstrates a need for further research incorporating a universal LC definition across all disease severity groups and symptom profiles, and longitudinal data reflecting the relapsing and remitting nature of this condition. Further investigation into blood biomarkers of LC, including clear reporting of healthy comparator groups and the investigation of acute and chronic biomarker changes, within the context of medical practice, may support the development of curative/restorative approaches.

Exploring the utility of ultrasound to assess disuse atrophy in different muscles of the lower leg.

BACKGROUND: Skeletal muscle is a highly plastic tissue crucial for many functions associated with whole-body health across the life course. Magnetic resonance imaging (MRI) is the current gold standard for measuring skeletal muscle size. However, MRI is expensive, and access to facilities is often limited. B-mode ultrasonography (U/S) has been proposed as a potential alternative to MRI for the assessment of muscle size. However, to date, no work has explored the utility of U/S to assess disuse muscle atrophy (DMA) across muscles with different atrophy susceptibility profiles, an omission which may limit the clinical application of previous work. METHODS: To address this significant knowledge gap, 10 young men (22 ±  years, 24.1 ± 2.3 kg/m2) underwent 15-day unilateral leg immobilization using a knee-brace and air boot. Cross-sectional area (CSA) and muscle thickness (MT) of the tibialis anterior (TA) and medial gastrocnemius (MG) were assessed via U/S before and after immobilization, with CSA and muscle volume assessed via MRI. RESULTS: With both muscles combined, there were good correlations between each U/S and MRI measure, both before (e.g., CSAMRI vs. MTU/S and CSAU/S: r = 0.88 and 0.94, respectively, both P < 0.0001) and after (e.g., VOLMRI vs. MTU/S and CSAU/S: r = 0.90 and 0.96, respectively, both P < 0.0001) immobilization. The relationship between the methods was notably stronger for MG than TA at each time-point (e.g., CSAMRI vs. MTU/S: MG, r = 0.70, P = 0.0006; TA, r = 0.37, P = 0.10). There was no relationship between the degree of DMA determined by the two methods in either muscle (e.g., TA pre- vs. post-immobilization, VOLMRI: 136 ± 6 vs. 133 ± 5, P = 0.08; CSAU/S: 6.05 ± 0.3 vs. 5.92 ± 0.4, P = 0.70; relationship between methods: r = 0.12, P = 0.75). CONCLUSIONS: Both MTU/S and CSAU/S provide comparable static measures of lower leg muscle size compared with MRI, albeit with weaker agreement in TA compared to MG. Although both MTU/S and CSAU/S can discern differences in DMA susceptibility between muscles, neither can reliably assess degree of DMA. Based on the growing recognition of heterogeneous atrophy profiles between muscles, and the topical importance of less commonly studied muscles (i.e., TA for falls prevention in older adults), future research should aim to optimize accessible methods to determine muscle losses across the body.

The effect of pre-operative exercise training on post-operative cognitive function: a systematic review.

BACKGROUND: With population aging and advances in surgical and anesthetic procedures, the incidence of surgery in patients over the age of 65 years is increasing. One post-operative complication often encountered by older surgical patients is post-operative cognitive dysfunction (POCD). Preoperative exercise training can improve the overall physiological resilience of older surgical patients, yet its impact on post-operative cognition is less well-established. METHODS: Six databases (Medline (OVID); EMBASE (OVID); EMCARE (OVID); CINAHL (EBSCOHost), the Cochrane Library, and PubMed) were searched for studies reporting the effect of pre-operative physical training on post-operative cognition. The quality of evidence was assessed using the Mixed Methods Assessment Tool. RESULTS: A total of 3983 studies were initially identified, three of which met the inclusion criteria for this review. Two studies were pilot randomized trials, and one was a prospective randomized trial. Two of the studies were high-quality. Each study used a different type of physical exercise and cognition assessment tool. Across the studies, post-operative cognition (p = 0.005) and attention (p = 0.04) were found to be better in the intervention groups compared to control, with one study reporting no difference between the groups. CONCLUSION: Preoperative physical training may improve post-operative cognitive function, although more research with a consistent endpoint is required. Future studies should focus on patients at high risk of POCD, such as older adults, and explore the impact of different exercise regimes, including frequency, intensity, time, and type.

Skeletal muscle dysfunction with advancing age.

As a result of advances in medical treatments and associated policy over the last century, life expectancy has risen substantially and continues to increase globally. However, the disconnect between lifespan and 'health span' (the length of time spent in a healthy, disease-free state) has also increased, with skeletal muscle being a substantial contributor to this. Biological ageing is accompanied by declines in both skeletal muscle mass and function, termed sarcopenia. The mechanisms underpinning sarcopenia are multifactorial and are known to include marked alterations in muscle protein turnover and adaptations to the neural input to muscle. However, to date, the relative contribution of each factor remains largely unexplored. Specifically, muscle protein synthetic responses to key anabolic stimuli are blunted with advancing age, whilst alterations to neural components, spanning from the motor cortex and motoneuron excitability to the neuromuscular junction, may explain the greater magnitude of function losses when compared with mass. The consequences of these losses can be devastating for individuals, their support networks, and healthcare services; with clear detrimental impacts on both clinical (e.g., mortality, frailty, and post-treatment complications) and societal (e.g., independence maintenance) outcomes. Whether declines in muscle quantity and quality are an inevitable component of ageing remains to be completely understood. Nevertheless, strategies to mitigate these declines are of vital importance to improve the health span of older adults. This review aims to provide an overview of the declines in skeletal muscle mass and function with advancing age, describes the wide-ranging implications of these declines, and finally suggests strategies to mitigate them, including the merits of emerging pharmaceutical agents.

Metabolic effects of very-low calorie diet, Semaglutide, or combination of the two, in individuals with type 2 diabetes mellitus.

BACKGROUND & AIMS: Very-low calorie diets (VLCD) and the glucagon-like peptide-1 receptor agonist (GLP1RA) Semaglutide induce significant weight loss and improve glycaemic control in individuals with type 2 diabetes (T2D). This pilot study was conducted to explore the comparative short-term effects of these interventions individually, and in combination, on weight, body composition and metabolic outcomes. METHODS: Thirty individuals with T2D (age 18-75 years, BMI 27-50  kg m-2) were randomly assigned to receive Semaglutide (SEM), 800 kilocalorie/day VLCD (VLCD), or both in combination (COMB) for 12 weeks. Measurement of weight and glycated haemoglobin (HbA1c), dual energy X-ray absorptiometry, and intravenous glucose tolerance tests (IVGTT) were performed at baseline and post-intervention. Diet diaries were utilised to assess compliance. Insulin first phase response during IVGTT provided a marker of pancreatic beta-cell function, and insulin sensitivity was estimated using HOMA-IR. RESULTS: Significantly greater reductions in body weight and fat mass were observed in VLCD and COMB, than SEM (p < 0.01 v both). VLCD and COMB resulted in a 5.4 and 7 percentage-point greater weight loss than SEM, respectively. HbA1c and fasting glucose reduced significantly in all groups, however fasting insulin and HOMA-IR improved in VLCD and COMB only. Insulin first phase response during IVGTT increased in SEM and COMB, and this increase was significantly greater in COMB than VLCD (p < 0.01). CONCLUSION: VLCD elicited greater short-term losses of weight and fat mass than Semaglutide. Adding VLCD to Semaglutide stimulated further weight loss than Semaglutide alone. The combination did not yield any additive effects on weight and body composition above VLCD alone, but did provoke greater improvements in pancreatic beta-cell function. Thus, combination of Semaglutide and VLCD warrants further exploration as a novel approach to T2D management.

Sex disparities of human neuromuscular decline in older humans.

Females typically live longer than males but, paradoxically, spend a greater number of later years in poorer health. The neuromuscular system is a critical component of the progression to frailty, and motor unit (MU) characteristics differ by sex in healthy young individuals and may adapt to ageing in a sex-specific manner due to divergent hormonal profiles. The purpose of this study was to investigate sex differences in vastus lateralis (VL) MU structure and function in early to late elderly humans. Intramuscular electromyography signals from 50 healthy older adults (M/F: 26/24) were collected from VL during standardized submaximal contractions and decomposed to quantify MU characteristics. Muscle size and neuromuscular performance were also measured. Females had higher MU firing rate (FR) than males (P = 0.025), with no difference in MU structure or neuromuscular junction transmission (NMJ) instability. All MU characteristics increased from low- to mid-level contractions (P < 0.05) without sex × level interactions. Females had smaller cross-sectional area of VL, lower strength and poorer force steadiness (P < 0.05). From early to late elderly, both sexes showed decreased neuromuscular function (P < 0.05) without sex-specific patterns. Higher VL MUFRs at normalized contraction levels previously observed in young are also apparent in old individuals, with no sex-based difference of estimates of MU structure or NMJ transmission instability. From early to late elderly, the deterioration of neuromuscular function and MU characteristics did not differ between sexes, yet function was consistently greater in males. These parallel trajectories underscore the lower initial level for older females and may offer insights into identifying critical intervention periods. KEY POINTS: Females generally exhibit an extended lifespan when compared to males, yet this is accompanied by a poorer healthspan and higher rates of frailty. In healthy young people, motor unit firing rate (MUFR) at normalized contraction intensities is widely reported to be higher in females than in age-matched males. Here we show in 50 people that older females have higher MUFR than older males with little difference in other MU parameters. The trajectory of decline from early to late elderly does not differ between sexes, yet function is consistently lower in females. These findings highlight distinguishable sex disparities in some MU characteristics and neuromuscular function, and suggest early interventions are needed for females to prevent functional deterioration to reduce the ageing health-sex paradox.

Exploring the utility of bedside tests for predicting cardiorespiratory fitness in older adults.

Objectives: Cardiorespiratory fitness (CRF) declines with advancing and has also, independent of age, been shown to be predictive of all-cause mortality, morbidity, and poor clinical outcomes. In relation to the older patient, there is a particular wealth of evidence highlighting the relationship between low CRF and poor surgical outcomes. Cardiopulmonary exercise testing (CPET) is accepted as the gold-standard measure of CRF. However, this form of assessment has significant personnel and equipment demands and is not feasible for those with certain age-associated physical limitations, including joint and cardiovascular comorbidities. As such, alternative ways to assess the CRF of older patients are very much needed. Methods: Sixty-four participants (45% female) with a median age of 74 (65-90) years were recruited to this study via community-based advertisements. All participants completed three tests of physical function: (1) a step-box test; (2) handgrip strength dynamometry; and (3) a CPET on a cycle ergometer; and also had their muscle architecture (vastus lateralis) assessed by B-mode ultrasonography to provide measures of muscle thickness, pennation angle, and fascicle length. Multivariate linear regression was then used to ascertain bedside predictors of CPET parameters from the alternative measures of physical function and demographic (age, gender, body mass index (BMI)) data. Results: There was no significant association between ultrasound-assessed parameters of muscle architecture and measures of CRF. VO2peak was predicted to some extent from fast step time during the step-box test, gender, and BMI, leading to a model that achieved an R 2 of 0.40 (p < 0.001). Further, in aiming to develop a model with minimal assessment demands (i.e., using handgrip dynamometry rather than the step-box test), replacing fast step time with non-dominant HGS led to a model which achieved an R 2 of 0.36 (p < 0.001). Non-dominant handgrip strength combined with the step-box test parameter of fast step time and BMI delivered the most predictive model for VO2peak with an R 2 of 0.45 (p < 0.001). Conclusions: Our findings show that simple-to-ascertain patient characteristics and bedside assessments of physical function are able to predict CPET-derived CRF. Combined with gender and BMI, both handgrip strength and fast step time during a step-box test were predictive for VO2peak. Future work should apply this model to a clinical population to determine its utility in this setting and to explore if simple bedside tests are predictive of important clinical outcomes in older adults (i.e., post-surgical complications).

Common synaptic inputs and persistent inward currents of vastus lateralis motor units are reduced in older male adults.

Although muscle atrophy may partially account for age-related strength decline, it is further influenced by alterations of neural input to muscle. Persistent inward currents (PIC) and the level of common synaptic inputs to motoneurons influence neuromuscular function. However, these have not yet been described in the aged human quadriceps. High-density surface electromyography (HDsEMG) signals were collected from the vastus lateralis of 15 young (mean ± SD, 23 ± 5 y) and 15 older (67 ± 9 y) men during submaximal sustained and 20-s ramped contractions. HDsEMG signals were decomposed to identify individual motor unit discharges, from which PIC amplitude and intramuscular coherence were estimated. Older participants produced significantly lower knee extensor torque (p < 0.001) and poorer force tracking ability (p < 0.001) than young. Older participants also had lower PIC amplitude (p = 0.001) and coherence estimates in the alpha frequency band (p < 0.001) during ramp contractions when compared to young. Persistent inward currents and common synaptic inputs are lower in the vastus lateralis of older males when compared to young. These data highlight altered neural input to the clinically and functionally important quadriceps, further underpinning age-related loss of function which may occur independently of the loss of muscle mass.

Remote ischemic conditioning for stroke: A critical systematic review.

Remote ischemic conditioning (RIC) is the application of brief periods of ischemia to an organ or tissue with the aim of inducing protection from ischemia in a distant organ. It was first developed as a cardioprotective strategy but has been increasingly investigated as a neuroprotective intervention. The mechanisms by which RIC achieves neuroprotection are incompletely understood. Preclinical studies focus on the hypothesis that RIC can protect the brain from ischemia reperfusion (IR) injury following the restoration of blood flow after occlusion of a large cerebral artery. However, increasingly, a role of chronic RIC (CRIC) is being investigated as a means of promoting recovery following an ischemic insult to the brain. The recent publication of two large, randomized control trials has provided promise that RIC could improve functional outcomes after acute ischemic stroke, and that there may be a role for CRIC in the prevention of recurrent stroke. Although less developed, there is also proof-of-concept to suggest that RIC may be used to reduce vasospasm after subarachnoid hemorrhage or improve cognitive outcomes in vascular dementia. As a cheap, well-tolerated and almost universally applicable intervention, the motivation for investigating possible benefit of RIC in patients with cerebrovascular disease is great. In this review, we shall review the current evidence for RIC as applied to cerebrovascular disease.

Long COVID quality of life and healthcare experiences in the UK: a mixed method online survey.

PURPOSE: The complexity of long COVID and its diverse symptom profile contributes to unprecedented challenges for patients, clinicians, and healthcare services. The threat of long COVID remains ignored by Governments, the media and public health messaging, and patients' experiences must be heard through understanding of the lived experience. This study aimed to understand the lived experience of those living with long COVID. METHODS: An online web-based survey was designed using Patient and Public Involvement and Engagement (PPIE) to increase understanding of the lived experiences of long COVID, and was distributed through PPIE groups, social media, and word of mouth. The survey used closed and open questions relating to demographics, pre- and post-COVID-19 health quality of life, daily activities and long COVID experiences. RESULTS: Within our sample of 132 people living with long COVID, the findings highlight that individuals are being severely impacted by their symptoms and are unable to or limited in participating in their daily activities, reducing quality of life. Long COVID places strain on relationships, the ability to live life fully and is detrimental to mental health. Varying health care experiences are described by participants, with reports of medical gaslighting and inadequate support received. CONCLUSIONS: Long COVID has a severe impact on the ability to live life fully, and strains mental health. The appropriate mechanisms and support services are needed to support those living with long COVID and manage symptoms.

Molecular mechanisms underpinning favourable physiological adaptations to exercise prehabilitation for urological cancer surgery.

BACKGROUND: Surgery for urological cancers is associated with high complication rates and survivors commonly experience fatigue, reduced physical ability and quality of life. High-intensity interval training (HIIT) as surgical prehabilitation has been proven effective for improving the cardiorespiratory fitness (CRF) of urological cancer patients, however the mechanistic basis of this favourable adaptation is undefined. Thus, we aimed to assess the mechanisms of physiological responses to HIIT as surgical prehabilitation for urological cancer. METHODS: Nineteen male patients scheduled for major urological surgery were randomised to complete 4-weeks HIIT prehabilitation (71.6 ± 0.75 years, BMI: 27.7 ± 0.9 kg·m2) or a no-intervention control (71.8 ± 1.1 years, BMI: 26.9 ± 1.3 kg·m2). Before and after the intervention period, patients underwent m. vastus lateralis biopsies to quantify the impact of HIIT on mitochondrial oxidative phosphorylation (OXPHOS) capacity, cumulative myofibrillar muscle protein synthesis (MPS) and anabolic, catabolic and insulin-related signalling. RESULTS: OXPHOS capacity increased with HIIT, with increased expression of electron transport chain protein complexes (C)-II (p = 0.010) and III (p = 0.045); and a significant correlation between changes in C-I (r = 0.80, p = 0.003), C-IV (r = 0.75, p = 0.008) and C-V (r = 0.61, p = 0.046) and changes in CRF. Neither MPS (1.81 ± 0.12 to 2.04 ± 0.14%·day-1, p = 0.39) nor anabolic or catabolic proteins were upregulated by HIIT (p > 0.05). There was, however, an increase in phosphorylation of AS160Thr642 (p = 0.046) post-HIIT. CONCLUSIONS: A HIIT surgical prehabilitation regime, which improved the CRF of urological cancer patients, enhanced capacity for skeletal muscle OXPHOS; offering potential mechanistic explanation for this favourable adaptation. HIIT did not stimulate MPS, synonymous with the observed lack of hypertrophy. Larger trials pairing patient-centred and clinical endpoints with mechanistic investigations are required to determine the broader impacts of HIIT prehabilitation in this cohort, and to inform on future optimisation (i.e., to increase muscle mass).

Acute COVID-19, the Lived Experience, and Lessons to Learn for Future Pandemics.

OBJECTIVES: The study aimed to increase the understanding of the lived experience of patients during the acute phase of a coronavirus disease 2019 (COVID-19) infection. METHOD: A Web-based survey was distributed through established patient and public engagement and involvement groups and networks, social media, and by means of word of mouth. The survey covered questions relating to patient demographics, COVID-19 diagnosis, symptom profile, and patient experience during acute COVID-19. RESULTS: The findings demonstrate the varying symptom profiles experienced by people in the acute stage of COVID-19 infection, with participants sharing how they managed care at home, and/or accessed medical advice. Findings also highlight themes that people were concerned with being unable to receive care and believed they needed to rely heavily on family, with extreme thoughts of death. CONCLUSIONS: Although the urgent threat to public health has been negated by efficacious vaccines and enhanced treatment strategies, there are key lessons from the lived experience of COVID-19 that should be used to prepare for future pandemics and public health emergencies.

The student patient alliance: development and formative evaluation of an initiative to support collaborations between patient and public involvement partners and doctoral students.

BACKGROUND: While the integration of patient and public involvement (PPI) in clinical research is now widespread and recommended as standard practice, meaningful PPI in pre-clinical, discovery science research is more difficult to achieve. One potential way to address this is by integrating PPI into the training programmes of discovery science postgraduate doctoral students. This paper describes the development and formative evaluation of the Student Patient Alliance (SPA), a programme developed at the University of Birmingham that connects PPI partners with doctoral students. METHODS: Following a successful pilot of the SPA by the Rheumatology Research Group at the University of Birmingham, the scheme was implemented across several collaborating Versus Arthritis / Medical Research Council (MRC) centres of excellence. Doctoral students were partnered with PPI partners, provided with initial information and guidance, and then encouraged to work together on research and public engagement activities. After six months, students, their PPI partners and the PPI coordinators at each centre completed brief surveys about their participation in the SPA. RESULTS: Both doctoral students and their PPI partners felt that taking part in SPA had a positive impact on understanding, motivation and communication skills. Students reported an increased understanding of PPI and patient priorities and reported improved public engagement skills. Their PPI partners reported a positive impact of the collaboration with the students. They enjoyed learning about the student's research and contributing to the student's personal development. PPI coordinators also highlighted the benefits of the SPA, but noted some challenges they had experienced, such as difficulties matching students with PPI partners. CONCLUSIONS: The SPA was valued by students and PPI partners, and it is likely that initiatives of this kind would enhance students' PPI and public engagement skills and awareness of patients' experiences on a wider scale. However, appropriate resources are needed at an institutional level to support the implementation of effective programmes of this kind on a larger scale.

Menstrual Cycle Associated Alteration of Vastus Lateralis Motor Unit Function.

BACKGROUND: Estrogen and progesterone are the primary female sex hormones and have net excitatory and inhibitory effects, respectively, on neuronal function. Fluctuating concentrations across the menstrual cycle has led to several lines of research in relation to neuromuscular function and performance; however evidence from animal and cell culture models has yet to be demonstrated in human motor units coupled with quantification of circulating hormones. Intramuscular electromyography was used to record motor unit potentials and corresponding motor unit potential trains from the vastus lateralis of nine eumenorrheic females during the early follicular, ovulation and mid luteal phases of the menstrual cycle, alongside assessments of neuromuscular performance. Multi-level regression models were applied to explore effects of time and of contraction level. Statistical significance was accepted as p < 0.05. RESULTS: Knee extensor maximum voluntary contraction, jump power, force steadiness, and balance did not differ across the menstrual phases (all p > 0.4). Firing rate of low threshold motor units (10% maximum voluntary contraction) was lower during the ovulation and mid luteal phases (ß = - 0.82 Hz, p < 0.001), with no difference in motor unit potentials analysed from 25% maximum voluntary contraction contractions. Motor unit potentials were more complex during ovulation and mid luteal phase (p < 0.03), with no change in neuromuscular junction transmission instability (p > 0.3). CONCLUSIONS: Assessments of neuromuscular performance did not differ across the menstrual cycle. The suppression of low threshold motor unit firing rate during periods of increased progesterone may suggest a potential inhibitory effect and an alteration of recruitment strategy; however this had no discernible effect on performance. These findings highlight contraction level-dependent modulation of vastus lateralis motor unit function over the eumenorrheic cycle, occurring independently of measures of performance.

Bisphosphonates attenuate age-related muscle decline in Caenorhabditis elegans.

BACKGROUND: Age-related muscle decline (sarcopenia) associates with numerous health risk factors and poor quality of life. Drugs that counter sarcopenia without harmful side effects are lacking, and repurposing existing pharmaceuticals could expedite realistic clinical options. Recent studies suggest bisphosphonates promote muscle health; however, the efficacy of bisphosphonates as an anti-sarcopenic therapy is currently unclear. METHODS: Using Caenorhabditis elegans as a sarcopenia model, we treated animals with 100 nM, 1, 10, 100 and 500 µM zoledronic acid (ZA) and assessed lifespan and healthspan (movement rates) using a microfluidic chip device. The effects of ZA on sarcopenia were examined using GFP-tagged myofibres or mitochondria at days 0, 4 and 6 post-adulthood. Mechanisms of ZA-mediated healthspan extension were determined using combined ZA and targeted RNAi gene knockdown across the life-course. RESULTS: We found 100 nM and 1 µM ZA increased lifespan (P < 0.001) and healthspan [954 ± 53 (100 nM) and 963 ± 48 (1 µM) vs. 834 ± 59% (untreated) population activity AUC, P < 0.05]. 10 µM ZA shortened lifespan (P < 0.0001) but not healthspan (758.9 ± 37 vs. 834 ± 59, P > 0.05), whereas 100 and 500 µM ZA were larval lethal. ZA (1 µM) significantly improved myofibrillar structure on days 4 and 6 post-adulthood (83 and 71% well-organized myofibres, respectively, vs. 56 and 34% controls, P < 0.0001) and increased well-networked mitochondria at day 6 (47 vs. 16% in controls, P < 0.01). Genes required for ZA-mediated healthspan extension included fdps-1/FDPS-1 (278 ± 9 vs. 894 ± 17% population activity AUC in knockdown + 1 µM ZA vs. untreated controls, respectively, P < 0.0001), daf-16/FOXO (680 ± 16 vs. 894 ± 17%, P < 0.01) and agxt-2/BAIBA (531 ± 23 vs. 552 ± 8%, P > 0.05). Life/healthspan was extended through knockdown of igdb-1/FNDC5 (635 ± 10 vs. 523 ± 10% population activity AUC in gene knockdown vs. untreated controls, P < 0.01) and sir-2.3/SIRT-4 (586 ± 10 vs. 523 ± 10%, P < 0.05), with no synergistic improvements in ZA co-treatment vs. knockdown alone [651 ± 12 vs. 635 ± 10% (igdb-1/FNDC5) and 583 ± 9 vs. 586 ± 10% (sir-2.3/SIRT-4), both P > 0.05]. Conversely, let-756/FGF21 and sir-2.2/SIRT-4 were dispensable for ZA-induced healthspan [630 ± 6 vs. 523 ± 10% population activity AUC in knockdown + 1 µM ZA vs. untreated controls, P < 0.01 (let-756/FGF21) and 568 ± 9 vs. 523 ± 10%, P < 0.05 (sir-2.2/SIRT-4)]. CONCLUSIONS: Despite lacking an endoskeleton, ZA delays Caenorhabditis elegans sarcopenia, which translates to improved neuromuscular function across the life course. Bisphosphonates might, therefore, be an immediately exploitable anti-sarcopenia therapy.

A focus on leucine in the nutritional regulation of human skeletal muscle metabolism in ageing, exercise and unloading states.

Muscle protein synthesis (MPS) and muscle protein breakdown (MPB) are influenced through dietary protein intake and physical (in)activity, which it follows, regulate skeletal muscle (SKM) mass across the lifespan. Following consumption of dietary protein, the bio-availability of essential amino acids (EAA), and primarily leucine (LEU), drive a transient increase in MPS with an ensuing refractory period before the next MPS stimulation is possible (due to the "muscle full" state). At the same time, MPB is periodically constrained via reflex insulin actions. Layering exercise on top of protein intake increases the sensitivity of SKM to EAA, therefore extending the muscle full set-point (∼48 h), to permit long-term remodelling (e.g., hypertrophy). In contrast, ageing and physical inactivity are associated with a premature muscle full set-point in response to dietary protein/EAA and contractile activity. Of all the EAA, LEU is the most potent stimulator of the mechanistic target of rapamycin complex 1 (mTORC1)-signalling pathway, with the phosphorylation of mTORC1 substrates increasing ∼3-fold more than with all other EAA. Furthermore, maximal MPS stimulation is also achieved following low doses of LEU-enriched protein/EAA, negating the need for larger protein doses. As a result, LEU supplementation has been of long term interest to maximise muscle anabolism and subsequent net protein accretion, especially when in tandem with resistance exercise. This review highlights current knowledge vis-à-vis the anabolic effects of LEU supplementation in isolation, and in enriched protein/EAA sources (i.e., EAA and/or protein sources with added LEU), in the context of ageing, exercise and unloading states.

Nutritional interventions in prehabilitation for cancer surgery.

PURPOSE OF REVIEW: Nutrition remains a key focus in the preoptimization of patients undergoing cancer surgery. Given the catabolic nature of cancer, coupled with the physiological insult of surgery, malnutrition (when assessed) is prevalent in a significant proportion of patients. Therefore, robust research on interventions to attenuate the detrimental impact of this is crucial. RECENT FINDINGS: As a unimodal prehabilitation intervention, assessment for malnutrition is the first step, as universal supplementation has not been shown to have a significant impact on outcomes. However, targeted nutritional therapy, whether that is enteral or parenteral, has been shown to improve the nutritional state of patients' presurgery, potentially reducing the rate of postoperative complications such as nosocomial infections. As part of multimodal prehabilitation, the situation is more nuanced given the difficulty in attribution of effects to the differing components, and vast heterogeneity in intervention and patient profiles. SUMMARY: Multimodal prehabilitation is proven to improve length of hospital stay and postoperative outcomes, with nutrition forming a significant part of the therapy given. Further work is required to look at not only the interplay between the optimization of nutritional status and other prehabilitation interventions, but also how to best select which patients will achieve significant benefit.

Forming a consensus opinion to inform long COVID support mechanisms and interventions: a modified Delphi approach.

Background: Current approaches to support patients living with post-COVID condition, also known as Long COVID, are highly disparate with limited success in managing or resolving a well-documented and long-standing symptom burden. With approximately 2.1 million people living with the condition in the UK alone and millions more worldwide, there is a desperate need to devise support strategies and interventions for patients. Methods: A three-round Delphi consensus methodology was distributed internationally using an online survey and was completed by healthcare professionals (including clinicians, physiotherapists, and general practitioners), people with long COVID, and long COVID academic researchers (round 1 n = 273, round 2 n = 186, round 3 n = 138). Across the three rounds, respondents were located predominantly in the United Kingdom (UK), with 17.3-15.2% (round 1, n = 47; round 2 n = 32, round 2 n = 21) of respondents located elsewhere (United States of America (USA), Austria, Malta, United Arab Emirates (UAE), Finland, Norway, Malta, Netherlands, Iceland, Canada, Tunisie, Brazil, Hungary, Greece, France, Austrailia, South Africa, Serbia, and India). Respondents were given ∼5 weeks to complete the survey following enrolment, with round one taking place from 02/15/2022 to 03/28/22, round two; 05/09/2022 to 06/26/2022, and round 3; 07/14/2022 to 08/09/2022. A 5-point Likert scale of agreement was used and the opportunity to include free text responses was provided in the first round. Findings: Fifty-five statements reached consensus (defined as >80% agree and strongly agree), across the domains of i) long COVID as a condition, ii) current support and care available for long COVID, iii) clinical assessments for long COVID, and iv) support mechanisms and rehabilitation interventions for long COVID, further sub-categorised by consideration, inclusion, and focus. Consensus reached proposes that long COVID requires specialised, comprehensive support mechanisms and that interventions should form a personalised care plan guided by the needs of the patients. Supportive approaches should focus on individual symptoms, including but not limited to fatigue, cognitive dysfunction, and dyspnoea, utilising pacing, fatigue management, and support returning to daily activities. The mental impact of living with long COVID, tolerance to physical activity, emotional distress and well-being, and research of pre-existing conditions with similar symptoms, such as myalgic encephalomyelitis, should also be considered when supporting people with long COVID. Interpretation: We provide an outline that achieved consensus with stakeholders that could be used to inform the design and implementation of bespoke long COVID support mechanisms. Funding: None.

Exploring the variability of sarcopenia prevalence in a research population using different disease definitions.

BACKGROUND: Sarcopenia is the progressive loss of muscle mass and function with age. A number of different sarcopenia definitions have been proposed and utilised in research. This study aimed to investigate how the prevalence of sarcopenia in a research cohort of older adults is influenced by the use of independent aspects of these different definitions. METHODS: Data from 255 research participants were compiled. Defining criteria by the European Working Group on Sarcopenia in Older People, the International Working Group on Sarcopenia (IWGS), and the Foundation for the National Institutes of Health were applied. RESULTS: Prevalence of sarcopenia using muscle mass ranged from 4 to 22%. Gait speed and handgrip strength criteria identified 4-34% and 4-16% of participants as sarcopenic, respectively. CONCLUSION: Prevalence of sarcopenia differs substantially depending on the criteria used. Work is required to address the impact of this for sarcopenia research to be usefully translated to inform on clinical practice.

The effect of combined ß-lactoglobulin supplementation and resistance exercise training prior to limb immobilisation on muscle protein synthesis rates in healthy young adults: study protocol for a randomised controlled trial.

BACKGROUND: The decline in skeletal muscle mass experienced following a short-term period (days to weeks) of muscle disuse is mediated by impaired rates of muscle protein synthesis (MPS). Previous RCTs of exercise or nutrition prehabilitation interventions designed to mitigate disuse-induced muscle atrophy have reported limited efficacy. Hence, the aim of this study is to investigate the impact of a complex prehabilitation intervention that combines ß-lactoglobulin (a novel milk protein with a high leucine content) supplementation with resistance exercise training on disuse-induced changes in free-living integrated rates of MPS in healthy, young adults. METHODS/DESIGN: To address this aim, we will recruit 24 healthy young (18-45 years) males and females to conduct a parallel, double-blind, 2-arm, randomised placebo-controlled trial. The intervention group will combine a 7-day structured resistance exercise training programme with thrice daily dietary supplementation with 23 g of ß-lactoglobulin. The placebo group will combine the same training programme with an energy-matched carbohydrate (dextrose) control. The study protocol will last 16 days for each participant. Day 1 will be a familiarisation session and days 2-4 will be the baseline period. Days 5-11 represent the 'prehabilitation period' whereby participants will combine resistance training with their assigned dietary supplementation regimen. Days 12-16 represent the muscle disuse-induced 'immobilisation period' whereby participants will have a single leg immobilised in a brace and continue their assigned dietary supplementation regimen only (i.e. no resistance training). The primary endpoint of this study is the measurement of free-living integrated rates of MPS using deuterium oxide tracer methodology. Measurements of MPS will be calculated at baseline, over the 7-day prehabilitation period and over the 5-day immobilisation period separately. Secondary endpoints include measurements of muscle mass and strength that will be collected on days 4 (baseline), 11 (end of prehabilitation) and 16 (end of immobilisation). DISCUSSION: This novel study will establish the impact of a bimodal prehabilitation strategy that combines ß-lactoglobulin supplementation and resistance exercise training in modulating MPS following a short-term period of muscle disuse. If successful, this complex intervention may be translated to clinical practice with application to patients scheduled to undergo, for example, hip or knee replacement surgery. TRIAL REGISTRATION: NCT05496452. Registered on August 10, 2022. PROTOCOL VERSION: 16-12-2022/1.