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.

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.

Photoelectrochemical CO2 Reduction to CO Enabled by a Molecular Catalyst Attached to High-Surface-Area Porous Silicon.

A high-surface-area p-type porous Si photocathode containing a covalently immobilized molecular Re catalyst is highly selective for the photoelectrochemical conversion of CO2 to CO. It gives Faradaic efficiencies of up to 90% for CO at potentials of -1.7 V (versus ferrocenium/ferrocene) under 1 sun illumination in an acetonitrile solution containing phenol. The photovoltage is approximately 300 mV based on comparisons with similar n-type porous Si cathodes in the dark. Using an estimate of the equilibrium potential for CO2 reduction to CO under optimized reaction conditions, photoelectrolysis was performed at a small overpotential, and the onset of electrocatalysis in cyclic voltammograms occurred at a modest underpotential. The porous Si photoelectrode is more stable and selective for CO production than the photoelectrode generated by attaching the same Re catalyst to a planar Si wafer. Further, facile characterization of the porous Si-based photoelectrodes using transmission mode FTIR spectroscopy leads to highly reproducible catalytic performance.

Neurodiversity and disability: what is at stake?

Neurodiversity has come hugely to the fore in recent years in a variety of contexts, and is now subject to academic debate, activist discussion, and increasingly embedded in a range of institutional and corporate settings in the Global North, from workplaces to early years education, from psychotherapy to mainstream political discourses. The term has gained traction in Medical Humanities, as well as debate within bioethics, philosophy of psychology, and of law. Institutionally, it is now relied on in therapeutic practice, autism service provision, as well as in higher education, in particular. In this conceptual article we examine what is at stake in these usages and the implications in need of scrutiny. We resituate neurodiversity in relation to questions of disability by examining the deployment of neurology as the basis for identity, rights and benefits. The emergence of the term and the understandings to which it gives rise, we argue, leave out urgent questions of what is at stake for disabled people in a political climate of increasing harshness and ableism.

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.

Mixed methods study of attitudes on location of gynaecological oncology outpatient care: a patient and healthcare professional questionnaire.

OBJECTIVE: Gynaecological oncology place of care is often based on evolution of services, along historical professional boundaries, rather than user needs or preferences. We aimed to assess existing evidence, gather views of patients in the UK on their preferred place of outpatient care for gynaecological malignancies and evaluate alignment with preferences of healthcare professionals (HCP). METHODS: We performed a mixed methods study, including a scoping review, a patient survey and a healthcare practitioner questionnaire. We collected quantitative and qualitative data, performing content analysis to determine current practice and impact on patients. RESULTS: No studies were identified in our scoping review. We received responses from 159 patients and 54 gynaecological oncology HCPs. There was a strong preference for a dedicated gynaecological oncology setting (89% somewhat or very happy) (p<0.0001). Fifty-three percent of patients were somewhat or very unhappy to have care colocated with general obstetrics and gynaecology services. Specifically, two key themes were identified through content analysis of qualitative data from patients: 'environment and getting this right is vital'; and 'our cancer should be the priority'. HCPs underestimated the strong patient preference to be seen in dedicated units. Of those who see patients within general obstetrics and gynaecology, only 50% said patients were seen at separate times/locations from obstetric patients. CONCLUSION: This study demonstrates the significant impact of place of care on gynaecological oncology patients, which may be underestimated by HCPs.

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.

Acute adaptation of central and peripheral motor unit features to exercise-induced fatigue differs with concentric and eccentric loading.

NEW FINDINGS: What is the central question of this study? Conflicting evidence exists on motor unit (MU) firing rate in response to exercise-induced fatigue, possibly due to the contraction modality used: Do MU properties adapt similarly following concentric and eccentric loading? What is the main finding and its importance? MU firing rate increased following eccentric loading only despite a decline in absolute force. Force steadiness deteriorated following both loading methods. Central and peripheral MU features are altered in a contraction type-dependant manner, which is an important consideration for training interventions. ABSTRACT: Force output of muscle is partly mediated by the adjustment of motor unit (MU) firing rate (FR). Disparities in MU features in response to fatigue may be influenced by contraction type, as concentric (CON) and eccentric (ECC) contractions demand variable amounts of neural input, which alters the response to fatigue. This study aimed to determine the effects of fatigue following CON and ECC loading on MU features of the vastus lateralis (VL). High-density surface (HD-sEMG) and intramuscular (iEMG) electromyography were used to record MU potentials (MUPs) from bilateral VLs of 12 young volunteers (six females) during sustained isometric contractions at 25% and 40% of the maximum voluntary contraction (MVC), before and after completing CON and ECC weighted stepping exercise. Multi-level mixed effects linear regression models were performed with significance assumed as P < 0.05. MVC decreased in both CON and ECC legs post-exercise (P < 0.0001), as did force steadiness at both 25% and 40% MVC (P < 0.004). MU FR increased in ECC at both contraction levels (P < 0.001) but did not change in CON. FR variability increased in both legs at 25% and 40% MVC following fatigue (P < 0.01). From iEMG measures at 25% MVC, MUP shape did not change (P > 0.1) but neuromuscular junction transmission instability increased in both legs (P < 0.04), and markers of fibre membrane excitability increased following CON only (P = 0.018). These data demonstrate that central and peripheral MU features are altered following exercise-induced fatigue and differ according to exercise modality. This is important when considering interventional strategies targeting MU function.

Exploring the thermal behaviour of the solvated structures of nifedipine.

Understanding the solvation and desolvation of pharmaceutical materials is an important part of materials discovery and development. In situ structural data are vital to understand the changes to crystal form that may occur in the system. In this study, the isolation and characterization of seven solvates of the L-type calcium channel antagonist, nifedipine, is described using variable-temperature powder X-ray diffraction so that the structural evolution as a function of temperature can be followed. The solvates reported herein can be split into those that are structurally similar to the previously reported dimethyl sulfoxide (DMSO) and dioxane solvates and those that have a novel packing arrangement. Of particular note is the solvate with tetrahydrofuran (THF) which has a hydrogen-bonding motif between the nifedipine molecules very similar to that of metastable ß-nifedipine. In addition to variable-temperature X-ray diffraction, the stability of the solid forms was assessed using differential scanning calorimetry and thermogravimetric analysis and indicates that in all cases desolvation results in the thermodynamically stable α-polymorph of nifedipine even with the THF solvate. From the diffraction data the pathway of desolvation during heating of the DMF solvate showed conversion to another likely 1:1 polymorph before desolvation to α-nifedipine. The desolvation of this material indicated a two-stage process; first the initial loss of 90% of the solvent before the last 10% is lost on melting. The methanol solvate shows interesting negative thermal expansion on heating, which is rarely reported in organic materials, but this behaviour can be linked back to the winerack-type hydrogen-bonding pattern of the nifedipine molecules.

Contrast-enhanced ultrasound repeatability for the measurement of skeletal muscle microvascular blood flow.

NEW FINDINGS: What is the central question of this study? Contrast-enhanced ultrasound (CEUS) can be used to directly assess skeletal muscle perfusion but its day-to-day repeatability over time has not yet been validated: is CEUS a repeatable method for the measurement of skeletal muscle microvascular blood flow (MBF) at rest and in response to exercise, across independent assessment sessions? What is the main finding and its importance? A strong agreement between CEUS MBF measures across sessions suggests it is a repeatable method for assessing skeletal muscle perfusion over time. This validation provides confidence for incorporating these measures into longitudinal studies such as a chronic intervention or disease progression to gain further knowledge of skeletal muscle microvascular function. ABSTRACT: Contrast-enhanced ultrasound (CEUS) can be used to directly assess skeletal muscle perfusion. However, its repeatability over time has not yet been validated and therefore its use in longitudinal measures (i.e., exploring the impact of a chronic intervention or disease progression) is limited. This study aimed to determine the repeatability of CEUS for the measurement of skeletal muscle microvascular blood flow (MBF) at baseline and in response to exercise, across independent assessment sessions. Ten healthy volunteers (five female; 30 ± 6 years) had CEUS of the right vastus lateralis recorded in two separate sessions, 14 days apart. Measurements were taken at baseline, during an isometric leg extension and during recovery. Acoustic intensity data from a region of interest were plotted as a replenishment curve to obtain blood volume (A) and flow velocity (ß) values from a one-phase association non-linear regression of mean tissue echogenicity. Linear regression and Bland-Altman analyses of A and ß values were performed, with significance assumed as P < 0.05. Strong positive correlations were observed across sessions for all A and ß values (both P < 0.0001). Bland-Altman analysis showed a bias (SD) of -0.013 ± 1.24 for A and -0.014 ± 0.31 for ß. A bias of 0.201 ± 0.770 at baseline, 0.527 ± 1.29 during contraction and -0.203 ± 1.29 at recovery was observed for A, and -0.0328 ± 0.0853 (baseline), -0.0446 ± 0.206 (contraction) and 0.0382 ± 0.233 (recovery) for ß. A strong agreement between CEUS MBF measures across independent sessions suggests it to be a repeatable method for assessing skeletal muscle perfusion over time, and therefore facilitates wider use in longitudinal studies.

Molecular Identification of Asian Hornet Vespa velutina nigrithorax Prey from Larval Gut Contents: A Promising Method to Study the Diet of an Invasive Pest.

The Asian hornet, Vespa velutina nigrithorax (Hymenoptera: Vespidae), is an invasive hornet that was accidentally introduced into Europe in 2004. It mainly preys on other invertebrates and arthropod species, and often targets honey bee (Apis mellifera) colonies. The introduction of these hornets may damage indigenous fauna and apiculture. Knowledge of V. velutina prey preference and the species composition of their diet is relatively limited. In this study, we assessed methodologies for the molecular identification of prey using dissected larvae from destroyed nests. Ten larval samples were taken from five nests in areas where the hornets had not yet established: two from the Channel Islands and three in the mainland UK. DNA was extracted from the gut contents and sequenced and analysed by metabarcoding with Oxford Nanopore Technologies' Flongle and MinION devices. Numerous taxa were detected in each larval sample with the species composition varying by individual and by nest. Between 15 and 26 species were found per nest, with wasps (Vespula spp.), spiders, honey bees and blow flies being the most abundant taxa. These results demonstrate that metabarcoding larval gut contents can be used to study the Asian hornet diet and give a first snapshot of the prey items captured by V. v. nigrithorax in the UK. This method could be used for future large-scale testing of the gut contents of hornet nests, in order to provide a greater insight into the foraging behaviour of this predator across Europe and elsewhere.

"Knowing the Noise That Surrounds the Athlete": A Qualitative Study Exploring the Health-Seeking Behaviors of Athletes With Limb Deficiency Drawing on the Experiences and Perceptions of the Medical Staff and Athletes.

OBJECTIVE: The aim of the study is to explore the health-seeking behaviors of athletes with limb deficiency, drawing on the experiences and perception of the sports medicine team and athletes. DESIGN: The study used an interpretive hermeneutic phenomenological methodology with a subtle realist paradigmatic view to investigate commonality in unique experiences within reality. Data collection was completed with two focus groups in December 2019 and March 2020. Thirteen participants took part including athletes and sports medicine team members (physiotherapists, doctors, and strength and conditioning coaches) working in parasports. Focus group manuscripts were transcribed verbatim from audio recordings. An inductive, iterative process was used to identify themes and subthemes, with processes in place to establish rigor. RESULTS: Two themes and five subthemes emerged in relation to the "internalization and adjustment to social identity" and "the importance and impact of factors, which impact the athlete social identity." CONCLUSIONS: Health-seeking behaviors of athletes with limb deficiency were influenced by a unique blend of personal and environmental factors that contribute toward social identity. The sports medicine team require specific awareness of factors that may diminish health-seeking behaviors to deliver a personalized approach and negate consequences.

Effect of colonisation with Neisseria lactamica on cross-reactive anti-meningococcal B-cell responses: a randomised, controlled, human infection trial.

BACKGROUND: Pharyngeal colonisation by the commensal bacterium Neisseria lactamica inhibits colonisation by Neisseria meningitidis and has an inverse epidemiological association with meningococcal disease. The mechanisms that underpin this relationship are unclear, but could involve the induction of cross-reactive immunity. In this study, we aimed to evaluate whether colonisation with N lactamica induces N lactamica-specific B-cell responses that are cross-reactive with N meningitidis. METHODS: In this randomised, placebo-controlled, human infection trial at University Hospital Southampton Clinical Research Facility (Southampton, UK), healthy adults aged 18-45 years were randomly assigned (2:1) to receive intranasal inoculation with either 105 colony-forming units of N lactamica in 1 mL phosphate-buffered saline (PBS) or 1 mL PBS alone. Participants and researchers conducting participant sampling and immunological assays were masked to allocation. The primary endpoint was the frequency of circulating N lactamica-specific plasma cells and memory B cells after N lactamica inoculation (day 7-28) compared with baseline values (day 0), measured using enzyme-linked immunospot assays. The secondary endpoint was to measure the frequency of N meningitidis-specific B cells. In a second study, we measured the effect of duration of N lactamica colonisation on seroconversion by terminating carriage at either 4 days or 14 days with single-dose oral ciprofloxacin. The studies are now closed to participants. The trials are registered with ClinicalTrials.gov, NCT03633474 and NCT03549325. FINDINGS: Of 50 participants assessed for eligibility between Sept 5, 2018, and March 3, 2019, 31 were randomly assigned (n=20 N lactamica, n=11 PBS). Among the 17 participants who were colonised with N lactamica, the median baselines compared with peak post-colonisation N lactamica-specific plasma-cell frequencies (per 105 peripheral blood mononuclear cells) were 0·0 (IQR 0·0-0·0) versus 5·0 (1·5-10·5) for IgA-secreting plasma cells (p<0·0001), and 0·0 (0·0-0·0) versus 3·0 (1·5-9·5) for IgG-secreting plasma cells (p<0·0001). Median N lactamica-specific IgG memory-B-cell frequencies (percentage of total IgG memory B cells) increased from 0·0024% (0·0000-0·0097) at baseline to 0·0384% (0·0275-0·0649) at day 28 (p<0·0001). The frequency of N meningitidis-specific IgA-secreting and IgG-secreting plasma cells and memory B cells also increased signficantly in participants who were colonised with N lactamica. Upper respiratory tract symptoms were reported in ten (50%) of 20 participants who were inoculated with N lactamica and six (55%) of 11 participants who were inoculated with PBS (p>0·99). Three additional adverse events (two in the N lactamica group and one in the PBS group) and no serious adverse events were reported. In the second study, anti-N lactamica and anti-N meningitidis serum IgG titres increased only in participants who were colonised with N lactamica for 14 days. INTERPRETATION: Natural immunity to N meningitidis after colonisation with N lactamica might be due to cross-reactive adaptive responses. Exploitation of this microbial mechanism with a genetically modified live vector could protect against N meningitidis colonisation and disease. FUNDING: Wellcome Trust, Medical Research Council, and NIHR Southampton Biomedical Research Centre.

Serum CA125 and HE4 as Biomarkers for the Detection of Endometrial Cancer and Associated High-Risk Features.

Early detection of endometrial cancer improves survival. Non-invasive diagnostic biomarkers would improve triage of symptomatic women for investigations. This study aimed to determine the diagnostic accuracy of serum Cancer Antigen 125 (CA125) and Human Epididymis 4 (HE4) for endometrial cancer and associated high-risk features. Serum samples from women investigated for gynaecological symptoms or diagnosed with endometrial cancer were analysed for CA125 and HE4. Conventional diagnostic metrics were calculated. In total, 755 women were included; 397 had endometrial cancer. Serum CA125 and HE4 were significantly elevated in cases compared with controls (both p < 0.001), and with pathological markers of disease severity (p < 0.05). A combination of CA125 and HE4 detected endometrial cancer with an area under the curve (AUC) of 0.77 (95% CI: 0.74−0.81). In a model with body mass index (BMI) and parity, HE4 predicted endometrial cancer in pre-menopausal women with an AUC of 0.91 [sensitivity = 84.5%, specificity = 80.9% (p < 0.001)]. In women with abnormal ultrasound, HE4 ≥ 77 pmol/L improved specificity compared with imaging alone [68.6% (95% CI: 75.0−83.6) vs. 34.4% (95% CI: 27.1−42.3), respectively], but at a cost to sensitivity. HE4 ≥ 77 pmol/L improved the detection of myometrial invasion ≥50% in women with stage I disease compared with magnetic resonance imaging (MRI) alone [sensitivity = 100% (95% CI: 54.1−100)]. CA125 ≥ 35 U/mL did not add to imaging. HE4 is a good predictor of poor prognostic features which could assist staging investigations.

Training-induced improvements in knee extensor force accuracy are associated with reduced vastus lateralis motor unit firing variability.

NEW FINDINGS: What is the central question of this study? Can bilateral knee extensor force accuracy be improved following 4 weeks of unilateral force accuracy training and are there any subsequent alterations to central and/or peripheral motor unit features? What is the main finding and its importance? In the trained limb only, knee extensor force tracking accuracy improved with reduced motor unit firing rate variability in the vastus lateralis, and there was no change to neuromuscular junction transmission instability. Interventional strategies to improve force accuracy may be directed to older/clinical populations where such improvements may aid performance of daily living activities. ABSTRACT: Muscle force output during sustained submaximal isometric contractions fluctuates around an average value and is partly influenced by variation in motor unit (MU) firing rates. MU firing rate (FR) variability seemingly reduces following exercise training interventions; however, much less is known with respect to peripheral MU properties. We therefore investigated whether targeted force accuracy training could lead to improved muscle functional capacity and control, in addition to determining any alterations of individual MU features. Ten healthy participants (seven females, three males, 27 ± 6 years, 170 ± 8 cm, 69 ± 16 kg) underwent a 4-week supervised, unilateral knee extensor force accuracy training intervention. The coefficient of variation for force (FORCECoV ) and sinusoidal wave force tracking accuracy (FORCESinu ) were determined at 25% maximal voluntary contraction (MVC) pre- and post-training. Intramuscular electromyography was utilised to record individual MU potentials from the vastus lateralis (VL) muscles at 25% MVC during sustained contractions, pre- and post-training. Knee extensor muscle strength remained unchanged following training, with no improvements in unilateral leg-balance. FORCECoV and FORCESinu significantly improved in only the trained knee extensors by ∼13% (P = 0.01) and ∼30% (P < 0.0001), respectively. MU FR variability significantly reduced in the trained VL by ∼16% (n = 8; P = 0.001), with no further alterations to MU FR or neuromuscular junction transmission instability. Our results suggest muscle force control and tracking accuracy is a trainable characteristic in the knee extensors, which is likely explained by the reduction in MU FR variability which was apparent in the trained limb only.

Tetraspanin CD82 restrains phagocyte migration but supports macrophage activation.

Phagocytes migrate into tissues to combat infection and maintain tissue homeostasis. As dysregulated phagocyte migration and function can lead to inflammation or susceptibility to infection, identifying molecules that control these processes is critical. Here, we show that the tetraspanin CD82 restrains the migration of neutrophils and macrophages into tissues. Cd82 -/- phagocytes exhibited excessive migration during in vivo models of peritoneal inflammation, superfusion of CXCL1, retinopathy of prematurity, and infection with the protozoan parasite L. mexicana. However, with the latter, while Cd82 -/- macrophages infiltrated infection sites at higher proportions, cutaneous L. mexicana lesions were larger and persisted, indicating a failure to control infection. Analyses of in vitro bone-marrow-derived macrophages showed CD82 deficiency altered cellular morphology, and impaired gene expression and metabolism in response to anti-inflammatory activation. Altogether, this work reveals an important role for CD82 in restraining phagocyte infiltration and mediating their differentiation in response to stimulatory cues.

FARGO-360: a multi-disciplinary survey of practice and perspectives on provision of care for patients with frailty presenting with gynecological cancers in the UK and Ireland.

OBJECTIVES: Frailty has been associated with worse cancer-related outcomes for people with gynecological cancers. However, the lack of clear guidance on how to assess and modify frailty prior to instigating active treatments has the potential to lead to large variations in practice and outcomes. This study aimed to evaluate current practice and perspectives of healthcare practitioners on the provision of care for patients with frailty and a gynecological cancer. METHODS: Data were collected via a questionnaire-based survey distributed by the Audit and Research in Gynecological Oncology (ARGO) collaborative to healthcare professionals who identified as working with patients with gynecological malignancies in the United Kingdom (UK) or Ireland. Study data were collected using REDCap software hosted at the University of Manchester. Responses were collected over a 16 week period between January and April 2021. RESULTS: A total of 206 healthcare professionals (30 anesthetists (14.6%), 30 pre-operative nurses (14.6%), 51 surgeons (24.8%), 34 cancer specialist nurses (16.5%), 21 medical/clinical oncologists (10.2%), 25 physiotherapists/occupational therapists (12.1%) and 15 dieticians (7.3%)) completed the survey. The respondents worked at 19 hospital trusts across the UK and Ireland. Frailty scoring was not routinely performed in 63% of care settings, yet the majority of practitioners reported modifying their practice when providing and deciding on care for patients with frailty. Only 16% of organizations surveyed had a dedicated pathway for assessment and management of patients with frailty. A total of 37% of respondents reported access to prehabilitation services, 79% to enhanced recovery, and 27% to community rehabilitation teams. CONCLUSION: Practitioners from all groups surveyed considered that appropriate training, dedicated pathways for optimization, frailty specific performance indicators and evidence that frailty scoring had an impact on clinical outcomes and patient experience could all help to improve care for frail patients.

'Building back better' in the context of multi-hazards in the Caribbean.

The multi-hazard vulnerability of Small Island Developing States in the Caribbean has underpinned the repeated saga of destructive natural and anthropogenic events that have disrupted land, livelihoods, the economy, and society over the past several decades. Preparedness and response have been the focus of national governments and regional entities and the repeated battering calls into question the concept of recovery and 'building back better'. This paper examines the concept of recovery and 'building back better' in the context of the Caribbean, paying particular attention to the experience of the selected countries of Antigua and Barbuda, the Bahamas, Dominica, Guyana, Jamaica, and Saint Vincent and the Grenadines. These nations have recently been impacted by different disasters, ranging from storms to earthquakes to volcanic eruptions. This paper also explores the similarities among the recommendations concerning recovery needs, presenting key insights into suggested approaches for an inclusive people-centred recovery process that 'builds back better'.

Ageing and exercise-induced motor unit remodelling.

A motor unit (MU) comprises the neuron cell body, its corresponding axon and each of the muscle fibres it innervates. Many studies highlight age-related reductions in the number of MUs, yet the ability of a MU to undergo remodelling and to expand to rescue denervated muscle fibres is also a defining feature of MU plasticity. Remodelling of MUs involves two coordinated processes: (i) axonal sprouting and new branching growth from adjacent surviving neurons, and (ii) the formation of key structures around the neuromuscular junction to resume muscle-nerve communication. These processes rely on neurotrophins and coordinated signalling in muscle-nerve interactions. To date, several neurotrophins have attracted focus in animal models, including brain-derived neurotrophic factor and insulin-like growth factors I and II. Exercise in older age has demonstrated benefits in multiple physiological systems including skeletal muscle, yet evidence suggests this may also extend to peripheral MU remodelling. There is, however, a lack of research in humans due to methodological limitations which are easily surmountable in animal models. To improve mechanistic insight of the effects of exercise on MU remodelling with advancing age, future research should focus on combining methodological approaches to explore the in vivo physiological function of the MU alongside alterations of the localised molecular environment.

Neuromuscular recruitment strategies of the vastus lateralis according to sex.

AIM: Despite males typically exhibiting greater muscle strength and fatigability than females, it remains unclear if there are sex-based differences in neuromuscular recruitment strategies e.g. recruitment and modulation of motor unit firing rate (MU FR) at normalized forces and during progressive increases in force. METHODS: The study includes 29 healthy male and 31 healthy female participants (18-35 years). Intramuscular electromyography (iEMG) was used to record individual motor unit potentials (MUPs) and near-fibre MUPs from the vastus lateralis (VL) during 10% and 25% maximum isometric voluntary contractions (MVC), and spike-triggered averaging was used to obtain motor unit number estimates (MUNE) of the VL. RESULTS: Males exhibited greater muscle strength (P < .001) and size (P < .001) than females, with no difference in force steadiness at 10% or 25% MVC. Females had 8.4% and 6.5% higher FR at 10% and 25% MVC, respectively (both P < .03), while the MUP area was 33% smaller in females at 10% MVC (P < .02) and 26% smaller at 25% MVC (P = .062). However, both sexes showed similar increases in MU size and FR when moving from low- to mid-level contractions. There were no sex differences in any near-fibre MUP parameters or in MUNE. CONCLUSION: In the vastus lateralis, females produce muscle force via different neuromuscular recruitment strategies to males which is characterized by smaller MUs discharging at higher rates. However, similar strategies are employed to increase force production from low- to mid-level contractions. These findings of similar proportional increases between sexes support the use of mixed sex cohorts in studies of this nature.