Effect of immobilisation on human forearm fuel metabolism

Worldwide it has been estimated that physical inactivity causes between 6-10% of global deaths, with low physical activity levels directly linked to 25-27% of the incidence of type 2 diabetes, 21-25% of breast and colon cancers, and approximately 30% of ischaemic heart disease. Thus, elucidating the underlying mechanisms between physical inactivity and the associated negative implications for health is imperative to establish and implement effective countermeasures. Currently bed rest and limb immobilisation represent the most popular experimental models used to investigate the functional and metabolic perturbations associated with physical inactivity. Forearm immobilisation was employed in each of the studies presented in this thesis, a model which allows the contralateral, non-immobilised arm to act as a within volunteer control. Furthermore, upper limb immobilisation facilitates the exploration of the reduced muscle use without the confounding effects of decreasing overall levels of physical activity and has a decreased risk of deep vein thrombosis compared to lower limb immobilisation. The studies included in this thesis aimed to investigate the time course of metabolic and physiological changes in response to forearm immobilisation. Initial pilot work was conducted to determine which post-sampling processing methods are most appropriate to produce accurate and stable measures of whole blood glucose concentration in conjunction with the arterialised venous-venous substrate difference technique. Previous studies have shown intermittent bouts of resistance exercise during forearm immobilisation are not sufficient to protect against the decline in insulin stimulated muscle glucose uptake, a marker of insulin sensitivity, measured 36-48 hrs after the last bout of exercise. Thus, the first study in this thesis aimed to elucidate the time course of changes in insulin sensitivity over 3 days of immobilisation in 10 healthy, male volunteers and the findings revealed a marked decline (38%) in insulin sensitivity within 24 hrs of immobilisation. This reduction was sustained throughout the immobilisation period, and was not accompanied by parallel decrements in brachial artery blood flow and insulin concentration. The second study included 9 healthy, young males and aimed to investigate the impact of 2 days of immobilisation on forearm lipid clearance, for which no effect was observed. This study also aimed to identify any additional impact of increasing dietary lipid supply on decrements in insulin sensitivity and demonstrated increased dietary lipid supply does not affect the magnitude of decline in insulin sensitivity during forearm immobilisation. Overall, findings from the first two studies indicate impairments driving the rapid decline in insulin sensitivity associated with forearm immobilisation reside within the muscle. To further investigate the role of reduced muscle contraction on muscle glucose uptake during forearm immobilisation, a pilot study was carried out to determine whether regular low-grade electrically-evoked muscle contraction could blunt the immobilisation induced changes in muscle glucose uptake in response to an oral glucose challenge. The findings from this pilot study suggest that frequent muscle contraction, elicited via PES, throughout the immobilisation period is unable to prevent this decline in forearm glucose uptake. A growing body of work links the accumulation of intramyocellular lipid during muscle disuse with reduced insulin sensitivity, thus the third study aimed to investigate any relationship between decreased insulin sensitivity with increased lipid content of forearm muscle, assessed via proton magnetic resonance spectroscopy (1H-MRS), during16 days of limb immobilisation in 5 healthy male volunteers. Additionally, changes in forearm muscle cross section area and handgrip strength were also assessed. The major findings from this study support those of the earlier studies demonstrating rapid and marked decrements in muscle insulin sensitivity, which are sustained over 8 days of immobilisation. Forearm muscle cross sectional area and handgrip strength also significantly declined, however, decrements in strength were of a much greater magnitude than muscle cross sectional area. Despite extensive method development, the scanning protocol established was unable to obtain sufficient quality data to evaluate changes in forearm lipid content associated with immobilisation. Thus, due to the small volume and structure of forearm muscles, the lower limb remains the optimal model for obtaining quality spectra using 1H-MRS

The right of the child to be heard? Professional experiences of child care proceedings in the Irish District Court

Article 12 of the United Nations Convention on the Rights of the Child 1989 provides that all children capable of forming views should have those views seriously considered in any decisions that affect them. Once expressed, the views of the child should be afforded due weight in accordance with his or her age and maturity. Every day in Ireland, decisions are made in the District Court concerning where a child will live and who they will live with in cases where their wellbeing is considered to be at risk. In such cases, the child's views should form a key component of the assessment of their best interests. This article presents the findings of a national empirical study which explores the individual perspectives of professionals who are directly involved in such proceedings. In particular, it aims to highlight the extent to which children are actually heard in such cases and whether the current legal framework and its practical implementation are Article 12-compliant. Based on professional experiences, the manner in which children are heard in practice in this adversarial setting will be explored with a view to reform

Child care proceedings in non-specialist courts: the experience in Ireland

It is widely accepted that court proceedings concerning child protection are a particularly sensitive type of court proceedings that warrant a different approach to other types of proceedings. Consequently, the use of specialized family or children’s judges or courts is commonplace across Europe and in common law jurisdictions. By contrast, in Ireland, proceedings under the Child Care Act 1991 are heard in the general courts system by judges who mostly do not specialize in child or family law. In principle, the Act itself and the associated case law accept that the vulnerability of the parties and the sensitivity of the issues involved are such that they need to be singled out for a different approach to other court proceedings. However, it is questionable whether this aspiration has been realized in a system where child care proceedings are mostly heard in a general District Court, using the same judges and the same physical facilities used for proceedings such as minor crime and traffic offences. This article draws on the first major qualitative analysis of professional perspectives on child care proceedings in the Irish District Court. It examines evidence from judges, lawyers, social workers, and guardians ad litem and asks whether non-specialist courts are an appropriate venue for proceedings on an issue as complex and sensitive as child protection, or whether the establishment of specialist family courts with dedicated staff and facilities provides a better solution

Representation and participation in child care proceedings: what about the voice of the parents?

In Ireland, the Constitution guarantees very strong rights to parents and the family, and there has been a long and unfortunate history of failures to adequately protect children at risk. As a result, there has been much discussion in recent years about the need to improve legal mechanisms designed to protect the rights of children. By comparison, little attention has been given to establishing whether the theoretically strong rights of parents translate into strongly protected rights in practice. This paper presents new empirical evidence on the manner in which child care proceedings in Ireland balance the rights and interests of children and parents, including the rates at which orders are granted, the frequency of and conditions in which legal representation is provided, and the extent to which parents are able to actively participate in proceedings. A number of systemic issues are identified that restrict the capacity of the system to emphasise parental rights and hear the voice of parents to the extent that would be expected when looking at the legal provisions in isolation

What social workers talk about when they talk about child care proceedings in the District Court in Ireland

Court proceedings are a fundamental and increasingly time-consuming aspect of social work practice. However, to date, there is a relatively modest body of literature considering the experiences of social workers in instituting child care proceedings and giving evidence in court. This paper draws on data gathered as part of an in-depth qualitative study of professional experiences of District Court child care proceedings in Ireland and presents findings regarding the experiences of social workers in bringing court applications for child protection orders. It seeks to answer 2 key questions: First, how do child protection and welfare social workers experience the adversarial nature of child care proceedings in the District Court? Second, what are the views of child protection and welfare social workers on the strengths and weaknesses of child care proceedings as a decision-making model for children and young people? The main findings are that social workers expressed significant reservations about the predominantly adversarial model that currently operates in Irish child care proceedings and about the level of respect that social workers are afforded within the operation of the system

Relative contribution of intramyocellular lipid to whole-body fat oxidation is reduced with age but subsarcolemmal lipid accumulation and insulin resistance are only associated with overweight individuals

Insulin resistance is closely related to intramyocellular lipid (IMCL) accumulation, and both are associated with increasing age. It remains to be determined to what extent perturbations in IMCL metabolism are related to the aging process per se. On two separate occasions, whole-body and muscle insulin sensitivity (euglycemic-hyperinsulinemic clamp with 2-deoxyglucose) and fat utilization during 1 h of exercise at 50% VO2max ([U-13C]palmitate infusion combined with electron microscopy of IMCL) were determined in young lean (YL), old lean (OL), and old overweight (OO) males. OL displayed IMCL content and insulin sensitivity comparable with those in YL, whereas OO were markedly insulin resistant and had more than twofold greater IMCL in the subsarcolemmal (SSL) region. Indeed, whereas the plasma free fatty acid Ra and Rd were twice those of YL in both OL and OO, SSL area only increased during exercise in OO. Thus, skeletal muscle insulin resistance and lipid accumulation often observed in older individuals are likely due to lifestyle factors rather than inherent aging of skeletal muscle as usually reported. However, age per se appears to cause exacerbated adipose tissue lipolysis, suggesting that strategies to reduce muscle lipid delivery and improve adipose tissue function may be warranted in older overweight individuals

Immobilisation induces sizeable and sustained reductions in forearm glucose uptake in just 24h but does not change lipid uptake in healthy men

© 2021 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society Key points: The trajectory, magnitude and localisation of metabolic perturbations caused by immobilisation (IMM) are unresolved. Forearm glucose uptake (FGU) in response to glucose feeding was determined in healthy men before and during 72h of forearm IMM, and the same measurements were made in the non-IMM contralateral limb at baseline and 72h. In a similar study design, FGU and forearm lipid uptake were determined after a high fat mixed-meal (HFMM) in IMM and non-IMM limbs. FGU was reduced by 38%, 57% and 46% following 24, 48 and 72h IMM, respectively, but was unchanged in the non-IMM limb. A similar FGU response to IMM was observed after a HFMM, and forearm lipid uptake was unchanged. A sizeable reduction in FGU occurs in just 24h of IMM, which is sustained thereafter and specific to the IMM limb, making unloading per se the likely rapid driver of dysregulation. Abstract: The trajectory and magnitude of metabolic perturbations caused by muscle disuse are unknown yet central to understanding the mechanistic basis of immobilisation-associated metabolic dysregulation. To address this gap, forearm glucose uptake (FGU) was determined in 10healthy men (age 24.9±0.6years, weight 71.9±2.6 kg, BMI 22.6±0.6kg/m2) during a 180min oral glucose challenge before (0) and after 24, 48 and 72h of arm immobilisation, and before and after 72h in the contralateral non-immobilised arm (Study A). FGU was decreased from baseline at 24h (38%, P=0.04), 48h (57%, P=0.01) and 72h (46%, P=0.06) of immobilisation, and was also 63% less than the non-immobilised limb at 72h (P=0.002). In a second study, FGU and forearm lipid uptake were determined in ninehealthy men (age 22.4±1.3years, weight 71.4±2.8kg, BMI 22.6±0.8kg/m2) during a 420min mixed-meal challenge before (0) and after 24 and 48h of arm immobilisation and before and after 72h in the contralateral non-immobilised arm (Study B). FGU responses were similar to Study A, and forearm lipid uptake was unchanged from pre-immobilisation in both arms over the study. A sizeable decrement in FGU in response to glucose feeding occurred within 24h of immobilisation that was sustained and specific to the immobilised limb. Increasing lipid availability had no additional impact on the rate or magnitude of these responses or on lipid uptake. These findings highlight a lack of muscle contraction per se as a fast-acting physiological insult to FGU

Osteoarthritis: 119. The Effectiveness of Exercise Therapy with and without Manual Therapy for Hip Osteoarthritis: A Multicentre Randomised Controlled Trial

Background: Current evidence indicates that exercise therapy (ET) has a short and medium-term benefit for hip osteoarthritis (OA), but evidence is inconclusive regarding the effect of manual therapy (MT). The primary aim of this randomised controlled trial was to determine the effectiveness of ET with and without MT on clinical outcomes for individuals with hip OA. A secondary aim was to ascertain the effect of an 8-week waiting period on outcomes. Methods: 131 men and women with hip OA recruited in four hospitals were initially randomised to one of three groups: ET (n = 45), a combination of ET and MT (n = 43) and wait-list control (n = 43). The two intervention groups underwent individualised ET or ET/MT for 8 weeks. Patients in the control group waited 8 weeks and were randomised to receive either ET or ET/MT after 9 week follow-up, and pooled with original treatment group data: ET (n = 66) and ET/ MT (n = 65). All participants were followed up at 9 and 18 weeks and the control group was reassessed at 27 weeks (18 weeks post-treatment) by the same blinded assessor. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Other outcomes included sit-to-stand, 50-foot walk test, pain severity, hip range of motion (ROM), anxiety, depression, quality of life (QOL), analgesic usage, physical activity, patient-perceived change and patient satisfaction. Intention-to-treat analysis was performed to determine within-group change and between-group differences for the three groups at baseline and 9 weeks, and the two treatment groups at baseline, 9 and 18 weeks. Results: Eight patients (6.1%) were lost to follow-up at 9 weeks and 19 (14.5%) were lost to follow-up by 18 weeks. Both ET (n = 66) and ET/MT groups (n = 65) showed significant within-group improvements in WOMAC, pain severity, sit-to-stand and HROM measures at 9 weeks, which were still evident at 18 weeks. There was no significant within-group change in anxiety, depression, QOL, analgesic usage, 50-foot walk test or physical activity. There was no significant difference between the two intervention groups for any of the outcomes. Regarding the results of the original ET, ET/MT and control group allocation, there was a significant improvement in one or both ET and ET/MT groups compared with the control group in the same outcomes, as well as patient perceived improvement at 9 weeks. There was no significant difference between the three groups in analgesic usage, WOMAC stiffness subscale, sit-to-stand and 50 foot walk tests, QOL and physical activity. There was an overall deterioration in anxiety and depression scores. Conclusions: The addition of MT to an 8 week programme of ET for hip OA resulted in similar improvements in pain, function and ROM at 9 and 18 weeks. The significant improvement which occurred in the same outcomes in the two treatment groups compared with a wait-list control of 8 weeks has implications for waiting list management Disclosure statement: The authors have declared no conflicts of interes

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707