Devices for remote continuous monitoring of people with Parkinson's disease: a systematic review and cost-effectiveness analysis.

Background: Parkinson's disease is a brain condition causing a progressive loss of co ordination and movement problems. Around 145,500 people have Parkinson's disease in the United Kingdom. Levodopa is the most prescribed treatment for managing motor symptoms in the early stages. Patients should be monitored by a specialist every 6-12 months for disease progression and treatment of adverse effects. Wearable devices may provide a novel approach to management by directly monitoring patients for bradykinesia, dyskinesia, tremor and other symptoms. They are intended to be used alongside clinical judgement. Objectives: To determine the clinical and cost-effectiveness of five devices for monitoring Parkinson's disease: Personal KinetiGraph, Kinesia 360, KinesiaU, PDMonitor and STAT-ON. Methods: We performed systematic reviews of all evidence on the five devices, outcomes included: diagnostic accuracy, impact on decision-making, clinical outcomes, patient and clinician opinions and economic outcomes. We searched MEDLINE and 12 other databases/trial registries to February 2022. Risk of bias was assessed. Narrative synthesis was used to summarise all identified evidence, as the evidence was insufficient for meta-analysis. One included trial provided individual-level data, which was re-analysed. A de novo decision-analytic model was developed to estimate the cost-effectiveness of Personal KinetiGraph and Kinesia 360 compared to standard of care in the UK NHS over a 5-year time horizon. The base-case analysis considered two alternative monitoring strategies: one-time use and routine use of the device. Results: Fifty-seven studies of Personal KinetiGraph, 15 of STAT-ON, 3 of Kinesia 360, 1 of KinesiaU and 1 of PDMonitor were included. There was some evidence to suggest that Personal KinetiGraph can accurately measure bradykinesia and dyskinesia, leading to treatment modification in some patients, and a possible improvement in clinical outcomes when measured using the Unified Parkinson's Disease Rating Scale. The evidence for STAT-ON suggested it may be of value for diagnosing symptoms, but there is currently no evidence on its clinical impact. The evidence for Kinesia 360, KinesiaU and PDMonitor is insufficient to draw any conclusions on their value in clinical practice. The base-case results for Personal KinetiGraph compared to standard of care for one-time and routine use resulted in incremental cost-effectiveness ratios of £67,856 and £57,877 per quality-adjusted life-year gained, respectively, with a beneficial impact of the Personal KinetiGraph on Unified Parkinson's Disease Rating Scale domains III and IV. The incremental cost-effectiveness ratio results for Kinesia 360 compared to standard of care for one-time and routine use were £38,828 and £67,203 per quality-adjusted life-year gained, respectively. Limitations: The evidence was limited in extent and often low quality. For all devices, except Personal KinetiGraph, there was little to no evidence on the clinical impact of the technology. Conclusions: Personal KinetiGraph could reasonably be used in practice to monitor patient symptoms and modify treatment where required. There is too little evidence on STAT-ON, Kinesia 360, KinesiaU or PDMonitor to be confident that they are clinically useful. The cost-effectiveness of remote monitoring appears to be largely unfavourable with incremental cost-effectiveness ratios in excess of £30,000 per quality-adjusted life-year across a range of alternative assumptions. The main driver of cost-effectiveness was the durability of improvements in patient symptoms. Study registration: This study is registered as PROSPERO CRD42022308597. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135437) and is published in full in Health Technology Assessment; Vol. 28, No. 30. See the NIHR Funding and Awards website for further award information.

Parkinson's disease is a brain condition causing loss of co-ordination and movement problems. Levodopa is the most prescribed treatment for early disease. Patients should be seen by a specialist every 6­12 months to assess their treatment needs. Wearable devices (like smart watches) may aid management by directly monitoring patients for disease symptoms including tremor and slowness of movement (bradykinesia), or side effects of treatment like involuntary movement (dyskinesia). This assessment considered the clinical and economic value of five wearable devices: Personal KinetiGraph, STAT-ON, Kinesia 360, KinesiaU and PDMonitor. We searched medical databases to find all studies of the five devices. We assessed the quality of these studies and reviewed their results. We found 77 studies of the devices. There was some evidence to suggest that Personal KinetiGraph can accurately measure bradykinesia and dyskinesia, leading to treatment modification in some patients, and a possible improvement in symptoms. The evidence for STAT-ON suggested it may be of value for diagnosing symptoms, but there is currently no evidence on its clinical value. There was insufficient evidence for Kinesia 360, KinesiaU and PDMonitor to draw any conclusions. An economic analysis was conducted to investigate whether using any of these technologies is economically viable. The economic analysis found that the quality-of-life benefits generated by remote monitoring devices were small relative to the additional costs of implementing them in the NHS. As such, none of the remote monitoring devices were good value for money when compared with the current standard of care.

Using economic analysis to inform health resource allocation: lessons from Malawi.

Despite making remarkable strides in improving health outcomes, Malawi faces concerns about sustaining the progress achieved due to limited fiscal space and donor dependency. The imperative for efficient health spending becomes evident, necessitating strategic allocation of resources to areas with the greatest impact on mortality and morbidity. Health benefits packages hold promise in supporting efficient resource allocation. However, despite defining these packages over the last two decades, their development and implementation have posed significant challenges for Malawi. In response, the Malawian government, in collaboration with the Thanzi la Onse Programme, has developed a set of tools and frameworks, primarily based on cost-effectiveness analysis, to guide the design of health benefits packages likely to achieve national health objectives. This review provides an overview of these tools and frameworks, accompanied by other related analyses, aiming to better align health financing with health benefits package prioritization. The paper is organized around five key policy questions facing decision-makers: (i) What interventions should the health system deliver? (ii) How should resources be allocated geographically? (iii) How should investments in health system inputs be prioritized? (iv) How should equity considerations be incorporated into resource allocation decisions? and (v) How should evidence generation be prioritized to support resource allocation decisions (guiding research)? The tools and frameworks presented here are intended to be compatible for use in diverse and often complex healthcare systems across Africa, supporting the health resource allocation process as countries pursue Universal Health Coverage.

Mechanism and spectrum of inhibition of a 4´-cyano modified nucleotide analog against diverse RNA polymerases of prototypic respiratory RNA viruses.

The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRp) of prototypic respiratory viruses. GS-646939 is the active 5'-triphosphate (TP) metabolite of a 4'-cyano modified C-adenosine analog phosphoramidate prodrug GS-7682. Enzyme kinetics show that the RdRps of human rhinovirus type 16 (HRV-16) and enterovirus 71 (EV-71) incorporate GS-646939 with unprecedented selectivity; GS-646939 is incorporated 20-50-fold more efficiently than its natural ATP counterpart. The RdRp complex of respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) incorporate GS-646939 and ATP with similar efficiency. In contrast, influenza B RdRp shows a clear preference for ATP and human mitochondrial RNA polymerase (h-mtRNAP) does not show significant incorporation of GS-646939. Once incorporated into the nascent RNA strand, GS-646939 acts as a chain-terminator although higher NTP concentrations can partially overcome inhibition for some polymerases. Modeling and biochemical data suggest that the 4'-modification inhibits RdRp translocation. Comparative studies with GS-443902, the active triphosphate form of the 1'-cyano modified prodrugs remdesivir and obeldesivir, reveal not only different mechanisms of inhibition, but also differences in the spectrum of inhibition of viral polymerases. In conclusion, 1'-cyano and 4'-cyano modifications of nucleotide analogs provide complementary strategies to target the polymerase of several families of respiratory RNA viruses.

Time Course of Neuromuscular Fatigue During Different Resistance Exercise Loadings in Power Athletes, Strength Athletes, and Nonathletes.

ABSTRACT: Kotikangas, J, Walker, S, Peltonen, H, and Häkkinen, K. Time course of neuromuscular fatigue during different resistance exercise loadings in power athletes, strength athletes, and nonathletes. J Strength Cond Res 38(7): 1231-1242, 2024-Training background may affect the progression of fatigue and neuromuscular strategies to compensate for fatigue during resistance exercises. Thus, our aim was to examine how training background affects the time course of neuromuscular fatigue in response to different resistance exercises. Power athletes (PA, n = 8), strength athletes (SA, n = 8), and nonathletes (NA, n = 7) performed hypertrophic loading (HL, 5 × 10 × 10RM), maximal strength loadings (MSL, 7 × 3 × 3RM) and power loadings (PL, 7 × 6 × 50% of 1 repetition maximum) in back squat. Average power (AP), average velocity (VEL), surface electromyography (sEMG) amplitude (sEMGRMS), and sEMG mean power frequency (sEMGMPF) were measured within all loading sets. During PL, greater decreases in AP occurred from the beginning of SET1 to SET7 and in VEL to both SET4 and SET7 in NA compared with SA (p < 0.01, g > 1.84). During HL, there were various significant group × repetition interactions in AP within and between sets (p < 0.05, ηp2 > 0.307), but post hoc tests did not indicate significant differences between the groups (p > 0.05, g = 0.01-0.93). During MSL and HL, significant within-set and between-set decreases occurred in AP (p < 0.001, ηp2 > 0.701) and VEL (p < 0.001, ηp2 > 0.748) concurrently with increases in sEMGRMS (p < 0.01, ηp2 > 0.323) and decreases in sEMGMPF (p < 0.01, ηp2 > 0.242) in all groups. In conclusion, SA showed fatigue resistance by maintaining higher AP and VEL throughout PL. During HL, PA tended to have the greatest initial fatigue response in AP, but between-group comparisons were nonsignificant despite large effect sizes (g > 0.8). The differences in the progression of neuromuscular fatigue may be related to differing neural activation strategies between the groups, but further research confirmation is required.

The Health Impact of Waiting for Elective Procedures in the NHS in England: A Modeling Framework Applied to Coronary Artery Bypass Graft and Total Hip Replacement.

INTRODUCTION: The aim of this study is to demonstrate a practical framework that can be applied to estimate the health impact of changes in waiting times across a range of elective procedures in the National Health Service (NHS) in England. We apply this framework by modeling 2 procedures: coronary artery bypass graft (CABG) and total hip replacement (THR). METHODS: We built a Markov model capturing health pre- and postprocedure, including the possibility of exiting preprocedure to acute NHS care or self-funded private care. We estimate the change in quality-adjusted life-years (QALYs) over a lifetime horizon for 10 subgroups defined by sex and Index of Multiple Deprivation quintile groups and for 7 alternative scenarios. We include 18 wk as a baseline waiting time consistent with current NHS policy. The model was populated with data from routinely collected data sets where possible (Hospital Episode Statistics, Patient-Reported Outcome Measures, and Office for National Statistics Mortality records), supplemented by the academic literature. RESULTS: Compared with 18 wk, increasing the wait time to 36 wk resulted in a mean discounted QALY loss in the range of 0.034 to 0.043 for CABG and 0.193 to 0.291 for THR. The QALY impact of longer NHS waits was greater for those living in more deprived areas, partly as fewer patients switch to private care. DISCUSSION/CONCLUSION: The proposed framework was applied to 2 different procedures and patient populations. If applied to an expanded group of procedures, it could provide decision makers with information to inform prioritization of waiting lists. There are a number of limitations in routine data on waiting for elective procedures, primarily the lack of information on people still waiting. HIGHLIGHTS: We present a modeling framework that allows for an estimation of the health impact (measured in quality-adjusted life-years) of waiting for elective procedures in the NHS in England.We apply our model to waiting for coronary artery bypass graft (CABG) and total hip replacement (THR). Increasing the wait for THR results in a larger health loss than an equivalent increase in wait for CABG.This model could potentially be used to estimate the impact across an expanded group of procedures to inform prioritization of activities to reduce waiting times.

Effects of short and long - term nutrition and progesterone supplementation on the success of fixed - time artificial insemination in the ewe.

The success of fixed - time artificial insemination (AI) in the ewe is variable due to poor synchrony of estrus. We examined the effects of long-term nutrition (LTN; low, medium, high - 6 months), short-term nutrition (STN; 1.0 M, 1.5 M - 14 days) and progesterone supplementation (P; single pessary, replacement on Day 9) on synchrony and reproductive outcomes. High LTN advanced (P < 0.05) estrus, increased (P = 0.06) pregnancy (range 71.1 - 81.1%) and improved (P < 0.01) litter size (range 1.30 - 1.50). STN increased (P < 0.05) pregnancy (79.0 versus 72.3%) but not litter size or timing of estrus. A LTN x STN interaction (P < 0.01) for time of estrus indicates that the effects of LTN were moderated by STN depending on the level of LTN. Pessary replacement delayed (P < 0.05) the onset of estrus, improved synchrony but did not affect pregnancy or litter size. High LTN increased (P < 0.05) the number of large (≥ 3.8 mm) and medium - size follicles (2.0 - 3.7 mm) but the diameter of large follicles tended to be reduced (P = 0.08) on Day 12. STN did not affect follicle number or size whilst P reduced (P < 0.05) the diameter of large follicles on Day 12 (4.83 versus 5.10 mm) and increased the number of medium - size follicles (3.56 versus 2.74 mm). In conclusion, both LTN and STN are major sources of variability in AI programs whilst pessary replacement has potential to reduce variability.

D3/Penta 21 clinical trial design: A randomised non-inferiority trial with nested drug licensing substudy to assess dolutegravir and lamivudine fixed dose formulations for the maintenance of virological suppression in children with HIV-1 infection, aged 2 to 15 years.

BACKGROUND: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing. METHODS: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm. DISCUSSION: D3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial. TRIAL REGISTRATION: International Standard Randomised Clinical Trial Number Register: ISRCTN17157458. European Clinical Trials Database: 2020-001426-57. CLINICALTRIALS: gov: NCT04337450.

Cortical and spinal responses to short-term strength training and detraining in young and older adults in rectus femoris muscle.

INTRODUCTION: Strength training mitigates the age-related decline in strength and muscle activation but limited evidence exists on specific motor pathway adaptations. METHODS: Eleven young (22-34 years) and ten older (66-80 years) adults underwent five testing sessions where lumbar-evoked potentials (LEPs) and motor-evoked potentials (MEPs) were measured during 20 and 60% of maximum voluntary contraction (MVC). Ten stimulations, randomly delivered, targeted 25% of maximum compound action potential for LEPs and 120, 140, and 160% of active motor threshold (aMT) for MEPs. The 7-week whole-body resistance training intervention included five exercises, e.g., knee extension (5 sets) and leg press (3 sets), performed twice weekly and was followed by 4 weeks of detraining. RESULTS: Young had higher MVC (~ 63 N·m, p = 0.006), 1-RM (~ 50 kg, p = 0.002), and lower aMT (~ 9%, p = 0.030) than older adults at baseline. Young increased 1-RM (+ 18 kg, p < 0.001), skeletal muscle mass (SMM) (+ 0.9 kg, p = 0.009), and LEP amplitude (+ 0.174, p < 0.001) during 20% MVC. Older adults increased MVC (+ 13 N·m, p = 0.014), however, they experienced decreased LEP amplitude (- 0.241, p < 0.001) during 20% MVC and MEP amplitude reductions at 120% (- 0.157, p = 0.034), 140% (- 0.196, p = 0.026), and 160% (- 0.210, p = 0.006) aMT during 60% MVC trials. After detraining, young and older adults decreased 1-RM, while young adults decreased SMM. CONCLUSION: Higher aMT and MEP amplitude in older adults were concomitant with lower baseline strength. Training increased strength in both groups, but divergent modifications in cortico-spinal activity occurred. Results suggest that the primary locus of adaptation occurs at the spinal level.

Heat stress from current and predicted increases in temperature impairs lambing rates and birth weights in the Australian sheep flock.

Livestock heat stress threatens production, particularly in semi-arid, arid and tropical regions. Using established temperature thresholds for sheep, we modelled +1 °C and +3 °C temperature increases over the historical baseline, estimating that 2.1 million potential lambs are lost annually due to heat stress alone, increasing to 2.5 and 3.3 million, respectively, as temperatures rise. Heat stress poses risks at key periods of the reproductive cycle, with consequences across the Australian sheep flock.

Social Decision-Making Analysis: A General Approach to Inform Decisions on Resources in the Public Sector.

OBJECTIVES: Public expenditure aims to achieve social objectives by improving a range of socially valuable attributes of benefit (arguments in a social welfare function). Public expenditure is typically allocated to public sector budgets, where budget holders are tasked with meeting a subset of social objectives. METHODS: Decision makers require an evidence-based assessment of whether a proposed investment is likely to be worthwhile given existing levels of public expenditure. However, others also require some assessment of whether the overall level and allocation of public expenditure are appropriate. This article proposes a more general theoretical framework for economic evaluation that addresses both these questions. RESULTS: Using a stylized example of the economic evaluation of a new intervention in a simplified UK context, we show that this more general framework can support decisions beyond the approval or rejection of single projects. It shows that broader considerations about the level and allocation of public expenditure are possible and necessary when evaluating specific investments, which requires evidence of the range of benefits offered by marginal changes in different types of public expenditure and normative choices of how the attributes of benefit gained and forgone are valued. CONCLUSIONS: The proposed framework shows how to assess the value of a proposed investment and whether and how the overall level of public expenditure and its allocation across public sector budgets might be changed. It highlights that cost-benefit analysis and cost-effectiveness analysis can be viewed as special cases of this framework, identifying the weakness with each.

Two-week step-reduction has limited negative effects on physical function and metabolic health in older adults.

PURPOSE: This study determined the effects of a 2-week step-reduction period followed by 4-week exercise rehabilitation on physical function, body composition, and metabolic health in 70-80-year-olds asymptomatic for injury/illness. METHODS: A parallel-group randomized controlled trial (ENDURE-study, NCT04997447) was used, where 66 older adults (79% female) were randomized to either intervention or control group. The intervention group reduced daily steps to < 2000, monitored by accelerometer, for two weeks (Period I) and then step-reduction requirement was removed with an additional exercise rehabilitation 4 times per week for 4 weeks (Period II). The control group continued their habitual physical activity throughout with no additional exercise intervention. Laboratory tests were performed at baseline, after Period I and Period II. The primary outcome measure was leg lean mass (LLM). Secondary outcomes included total lean and fat mass, blood glucose and insulin concentration, LDL cholesterol and HDL cholesterol concentration, maximal isometric leg press force (MVC), and chair rise and stair climb performance. RESULTS: LLM remained unchanged in both groups and no changes occurred in physical function nor body composition in the intervention group in Period I. HDL cholesterol concentration reduced after Period I (from 1.62 ± 0.37 to 1.55 ± 0.36 mmol·L-1, P = 0.017) and returned to baseline after Period II (1.66 ± 0.38 mmol·L-1) in the intervention group (Time × Group interaction: P = 0.065). MVC improved after Period II only (Time × Group interaction: P = 0.009, Δ% = 15%, P < 0.001). CONCLUSION: Short-term step-reduction in healthy older adults may not be as detrimental to health or physical function as currently thought.

Circulating metabolome landscape in Lynch syndrome.

Circulating metabolites systemically reflect cellular processes and can modulate the tissue microenvironment in complex ways, potentially impacting cancer initiation processes. Genetic background increases cancer risk in individuals with Lynch syndrome; however, not all carriers develop cancer. Various lifestyle factors can influence Lynch syndrome cancer risk, and lifestyle choices actively shape systemic metabolism, with circulating metabolites potentially serving as the mechanical link between lifestyle and cancer risk. This study aims to characterize the circulating metabolome of Lynch syndrome carriers, shedding light on the energy metabolism status in this cancer predisposition syndrome.This study consists of a three-group cross-sectional analysis to compare the circulating metabolome of cancer-free Lynch syndrome carriers, sporadic colorectal cancer (CRC) patients, and healthy non-carrier controls. We detected elevated levels of circulating cholesterol, lipids, and lipoproteins in LS carriers. Furthermore, we unveiled that Lynch syndrome carriers and CRC patients displayed similar alterations compared to healthy non-carriers in circulating amino acid and ketone body profiles. Overall, cancer-free Lynch syndrome carriers showed a unique circulating metabolome landscape.This study provides valuable insights into the systemic metabolic landscape of Lynch syndrome individuals. The findings hint at shared metabolic patterns between cancer-free Lynch syndrome carriers and CRC patients.

Strength-trained adults demonstrate greater corticoreticular activation versus untrained controls.

The rapid increase in strength following strength-training involves neural adaptations, however, their specific localisation remains elusive. Prior focus on corticospinal responses prompts this study to explore the understudied cortical/subcortical adaptations, particularly cortico-reticulospinal tract responses, comparing healthy strength-trained adults to untrained peers. Fifteen chronically strength-trained individuals (≥2 years of training, mean age: 24 ± 7 years) were compared with 11 age-matched untrained participants (mean age: 26 ± 8 years). Assessments included maximal voluntary force (MVF), corticospinal excitability using transcranial magnetic stimulation (TMS), spinal excitability (cervicomedullary stimulation), voluntary activation (VA) and reticulospinal tract (RST) excitability, utilizing StartReact responses and ipsilateral motor-evoked potentials (iMEPs) for the flexor carpi radialis muscle. Trained participants had higher normalized MVF (6.4 ± 1.1 N/kg) than the untrained participants (4.8 ± 1.3 N/kg) (p = .003). Intracortical facilitation was higher in the strength-trained group (156 ± 49%) (p = .02), along with greater VA (98 ± 3.2%) (p = .002). The strength-trained group displayed reduced short-interval-intracortical inhibition (88 ± 8.0%) compared with the untrained group (69 ± 17.5%) (p < .001). Strength-trained individuals exhibited a greater normalized rate of force development (38.8 ± 10.1 N·s-1/kg) (p < .009), greater reticulospinal gain (2.5 ± 1.4) (p = .02) and higher ipsilateral-to-contralateral MEP ratios compared with the untrained group (p = .03). Strength-trained individuals displayed greater excitability within the intrinsic connections of the primary motor cortex and the RST. These results suggest greater synaptic input from the descending cortico-reticulospinal tract to α-motoneurons in strength-trained individuals, thereby contributing to the observed increase in VA and MVF.

Differential modulation of corticomotor excitability in older compared to young adults following a single bout of strength -exercise.

Evidence shows corticomotor plasticity diminishes with age. Nevertheless, whether strength-training, a proven intervention that induces corticomotor plasticity in younger adults, also takes effect in older adults, remains untested. This study examined the effect of a single-session of strength-exercise on corticomotor plasticity in older and younger adults. Thirteen older adults (72.3 ± 6.5 years) and eleven younger adults (29.9 ± 6.9 years), novice to strength-exercise, participated. Strength-exercise involved four sets of 6-8 repetitions of a dumbbell biceps curl at 70-75% of their one-repetition maximum (1-RM). Muscle strength, cortical, corticomotor and spinal excitability, before and up to 60-minutes after the strength-exercise session were assessed. We observed significant changes over time (p < 0.05) and an interaction between time and age group (p < 0.05) indicating a decrease in corticomotor excitability (18% p < 0.05) for older adults at 30- and 60-minutes post strength-exercise and an increase (26% and 40%, all p < 0.05) in younger adults at the same time points. Voluntary activation (VA) declined in older adults immediately post and 60-minutes post strength-exercise (36% and 25%, all p < 0.05). Exercise had no effect on the cortical silent period (cSP) in older adults however, in young adults cSP durations were shorter at both 30- and 60- minute time points (17% 30-minute post and 9% 60-minute post, p < 0.05). There were no differences in short-interval cortical inhibition (SICI) or intracortical facilitation (ICF) between groups. Although the corticomotor responses to strength-exercise were different within groups, overall, the neural responses seem to be independent of age.

Adapting Economic Evaluation Methods to Shifting Global Health Priorities: Assessing the Value of Health System Inputs.

OBJECTIVES: We highlight the importance of undertaking value assessments for health system inputs if allocative efficiency is to be achieve with health sector resources, with a focus on low- and middle-income countries. However, methodological challenges complicated the application of current economic evaluation techniques to health system input investments. METHODS: We undertake a review of the literature to examine how assessments of investments in health system inputs have been considered to date, highlighting several studies that have suggested ways to address the methodological issues. Additionally, we surveyed how empirical economic evaluations of health system inputs have approached these issues. Finally, we highlight the steps required to move toward a comprehensive standardized framework for undertaking economic evaluations to make value assessments for investments in health systems. RESULTS: Although the methodological challenges have been illustrated, a comprehensive framework for value assessments of health system inputs, guiding the evidence required, does not exist. The applied literature of economic evaluations of health system inputs has largely ignored the issues, likely resulting in inaccurate assessments of cost-effectiveness. CONCLUSIONS: A majority of health sector budgets are spent on health system inputs, facilitating the provision of healthcare interventions. Although economic evaluation methods are a key component in priority setting for healthcare interventions, such methods are less commonly applied to decision making for investments in health system inputs. Given the growing agenda for investments in health systems, a framework will be increasingly required to guide governments and development partners in prioritizing investments in scarce health sector budgets.

The Rac-GEF Tiam1 controls integrin-dependent neutrophil responses.

Rac GTPases are required for neutrophil adhesion and migration, and for the neutrophil effector responses that kill pathogens. These Rac-dependent functions are impaired when neutrophils lack the activators of Rac, Rac-GEFs from the Prex, Vav, and Dock families. In this study, we demonstrate that Tiam1 is also expressed in neutrophils, governing focal complexes, actin cytoskeletal dynamics, polarisation, and migration, in a manner depending on the integrin ligand to which the cells adhere. Tiam1 is dispensable for the generation of reactive oxygen species but mediates degranulation and NETs release in adherent neutrophils, as well as the killing of bacteria. In vivo, Tiam1 is required for neutrophil recruitment during aseptic peritonitis and for the clearance of Streptococcus pneumoniae during pulmonary infection. However, Tiam1 functions differently to other Rac-GEFs. Instead of promoting neutrophil adhesion to ICAM1 and stimulating ß2 integrin activity as could be expected, Tiam1 restricts these processes. In accordance with these paradoxical inhibitory roles, Tiam1 limits the fMLP-stimulated activation of Rac1 and Rac2 in adherent neutrophils, rather than activating Rac as expected. Tiam1 promotes the expression of several regulators of small GTPases and cytoskeletal dynamics, including αPix, Psd4, Rasa3, and Tiam2. It also controls the association of Rasa3, and potentially αPix, Git2, Psd4, and 14-3-3ζ/δ, with Rac. We propose these latter roles of Tiam1 underlie its effects on Rac and ß2 integrin activity and on cell responses. Hence, Tiam1 is a novel regulator of Rac-dependent neutrophil responses that functions differently to other known neutrophil Rac-GEFs.

Contraction intensity modulates spinal excitability during transcranial magnetic stimulation-evoked silent period in rectus femoris muscle.

PURPOSE: Reduced spinal excitability during the transcranial magnetic stimulation (TMS) silent period (SP) has recently been shown to last longer than previously thought in the upper limbs, as assessed via spinal electrical stimulation. Further, there is reason to expect that contraction intensity affects the duration of the reduced spinal excitability. METHODS: This study investigated spinal excitability at different time delays within the TMS-evoked SP in m.rectus femoris. Fifteen participants performed non-fatiguing isometric knee extensions at 25%, 50% and 75% of maximum voluntary contraction (MVC). Lumbar stimulation (LS) induced a lumbar-evoked potential (LEP) of 50% resting M-max. TMS stimulator output induced a SP lasting ~ 200 ms. In each contraction, a LEP (unconditioned) was delivered ~ 2-3 s prior to TMS, which was followed by a second LEP (conditioned) 60, 90, 120 or 150 ms into the silent period. Five contractions were performed at each contraction intensity and for each time delay in random order. RESULTS: Compared to the unconditioned LEP, the conditioned LEP amplitude was reduced (- 28 ± 34%, p = 0.007) only at 60 ms during 25% of MVC. Conditioned LEP amplitudes during 50% and 75% of MVC were reduced at 60 ms (- 37 ± 47%, p = 0.009 and - 37 ± 42%, p = 0.005, respectively) and 150 ms (- 30% ± 37%, p = 0.0083 and - 37 ± 43%, p = 0.005, respectively). LEP amplitude at 90 ms during 50% of MVC also reduced (- 25 ± 35%, p = 0.013). CONCLUSION: Reduced spinal excitability is extended during 50% and 75% of MVC. In future, paired TMS-LS could be a potential method to understand changes in spinal excitability during SP (at different contraction intensities) when testing various neurophysiological phenomena.

Body composition in male lifelong trained strength, sprint and endurance athletes and healthy age-matched controls.

Introduction: Aging involves many physiological processes that lead to decreases in muscle mass and increases in fat mass. While regular exercise can counteract such negative body composition outcomes, masters athletes maintain high levels of exercise throughout their lives. This provides a unique model to assess the impact of inherent aging. The present study compared lean mass and fat mass in young and masters athletes from different sports to age-matched non-athletic individuals. Methods: Participants included young (20-39 years, n = 109) and older (70-89 years, n = 147) competitive male athletes, and 147 healthy age-matched controls (young = 53, older = 94 males). Athletes were separated into strength (e.g., weightlifters, powerlifters), sprint (e.g., sprint runners, jumpers) and endurance (e.g., long-distance runners, cross-country skiers) athletic disciplines. Body composition was assessed by dual-energy x-ray absorptiometry (DXA). Upper and lower limb lean mass was combined for appendicular lean mass as well as appendicular lean mass index (ALMI; kg/m2). Individuals' scores were assessed against established cut-offs for low muscle mass, obesity, and sarcopenic obesity to determine prevalence in each group. Results: ALMI was greater in young strength (0.81-2.36 kg/m2, ∼15% and 1.24-2.74 kg/m2, ∼19%) and sprint (95% CI = 0.51-1.61 kg/m2, ∼11% and 0.96-1.97 kg/m2, ∼15%) athletes than in endurance and controls, respectively (all P < 0.001). In masters athletes, only strength athletes had greater ALMI than endurance athletes, but both older strength and sprint athletes had greater ALMI than older controls (0.42-1.27 kg/m2, ∼9% and 0.73-1.67 kg/m2, ∼13%, respectively, both P < 0.001). Fat mass was significantly lower in sprint and endurance athletes compared to strength athletes and controls in both age-groups. Sarcopenic obesity was identified in one young (2%) and eighteen (19%) older controls, while only two older endurance athletes (3%) and one older strength athlete (2%) were identified. Discussion: Lifelong competitive sport participation leads to lower prevalence of sarcopenic obesity than a recreationally active lifestyle. This is achieved in strength athletes by emphasizing muscle mass, while sprint and endurance athletes demonstrate low fat mass levels. However, all older athlete groups showed higher fat mass than the young groups, suggesting that exercise alone may not be sufficient to manage fat mass.

Physical qualities and body composition predictors of running performance in national level women's official soccer matches.

The purpose of the study was to (1) determine match running performance, anthropometry and various physical qualities of national level women soccer players and (2) identify key physical qualities and anthropometric predictors of match running profile during a competitive season. Twenty-five national level Finnish soccer players participated in the study. Players performed countermovement jump, loaded squat jumps, 30-meter sprint, maximum isokinetic knee flexor and extensor contractions, an incremental treadmill test and underwent body composition assessment in the lab. Match running performance was analyzed from 115 match observations during competitive league matches over 11 weeks after the laboratory tests. Pearson's correlation was used to determine bivariate relationships between match running variables and physical qualities and anthropometric variables. Identified significant bivariate relationships were then entered into multiple regression analyses to identify the best predictors of match running performance. Physical qualities and anthropometric variables predicted 65% of very high-intensity (VHIR) (> 19 km/h) and 63% of high-intensity (HIR) (13-19 km/h) running distances covered during matches, but only 22% of low-intensity (LIR) and 43% of total distances. Body fat percentage and high-speed knee flexor concentric strength were the most important predictors to VHIR and HIR while aerobic capacity-related variables were most important predictors to LIR and total distance. Physical qualities and anthropometry can predict a large portion of players' VHIR and HIR performance during matches in women's national level soccer. To increase player's VHIR and HIR distance, coaches could aim to develop players' high-speed (especially knee flexor concentric) strength and optimize player's body composition.

A multicomponent intervention to reduce daily sitting time in office workers: the SMART Work & Life three-arm cluster RCT.

Background: Office workers spend 70-85% of their time at work sitting. High levels of sitting have been linked to poor physiological and psychological health. Evidence shows the need for fully powered randomised controlled trials, with long-term follow-up, to test the effectiveness of interventions to reduce sitting time. Objective: Our objective was to test the clinical effectiveness and cost-effectiveness of the SMART Work & Life intervention, delivered with and without a height-adjustable workstation, compared with usual practice at 12-month follow-up. Design: A three-arm cluster randomised controlled trial. Setting: Councils in England. Participants: Office workers. Intervention: SMART Work & Life is a multicomponent intervention that includes behaviour change strategies, delivered by workplace champions. Clusters were randomised to (1) the SMART Work & Life intervention, (2) the SMART Work & Life intervention with a height-adjustable workstation (i.e. SMART Work & Life plus desk) or (3) a control group (i.e. usual practice). Outcome measures were assessed at baseline and at 3 and 12 months. Main outcome measures: The primary outcome was device-assessed daily sitting time compared with usual practice at 12 months. Secondary outcomes included sitting, standing, stepping time, physical activity, adiposity, blood pressure, biochemical measures, musculoskeletal issues, psychosocial variables, work-related health, diet and sleep. Cost-effectiveness and process evaluation data were collected. Results: A total of 78 clusters (756 participants) were randomised [control, 26 clusters (n = 267); SMART Work & Life only, 27 clusters (n = 249); SMART Work & Life plus desk, 25 clusters (n = 240)]. At 12 months, significant differences between groups were found in daily sitting time, with participants in the SMART Work & Life-only and SMART Work & Life plus desk arms sitting 22.2 minutes per day (97.5% confidence interval -38.8 to -5.7 minutes/day; p = 0.003) and 63.7 minutes per day (97.5% confidence interval -80.0 to -47.4 minutes/day; p < 0.001), respectively, less than the control group. Participants in the SMART Work & Life plus desk arm sat 41.7 minutes per day (95% confidence interval -56.3 to -27.0 minutes/day; p < 0.001) less than participants in the SMART Work & Life-only arm. Sitting time was largely replaced by standing time, and changes in daily behaviour were driven by changes during work hours on workdays. Behaviour changes observed at 12 months were similar to 3 months. At 12 months, small improvements were seen for stress, well-being and vigour in both intervention groups, and for pain in the lower extremity and social norms in the SMART Work & Life plus desk group. Results from the process evaluation supported these findings, with participants reporting feeling more energised, alert, focused and productive. The process evaluation also showed that participants viewed the intervention positively; however, the extent of engagement varied across clusters. The average cost of SMART Work & Life only and SMART Work & Life plus desk was £80.59 and £228.31 per participant, respectively. Within trial, SMART Work & Life only had an incremental cost-effectiveness ratio of £12,091 per quality-adjusted life-year, with SMART Work & Life plus desk being dominated. Over a lifetime, SMART Work & Life only and SMART Work & Life plus desk had incremental cost-effectiveness ratios of £4985 and £13,378 per quality-adjusted life-year, respectively. Limitations: The study was carried out in one sector, limiting generalisability. Conclusions: The SMART Work & Life intervention, provided with and without a height-adjustable workstation, was successful in changing sitting time. Future work: There is a need for longer-term follow-up, as well as follow-up within different organisations. Trial registration: Current Controlled Trials ISRCTN11618007.

Office workers spend a large proportion of their day sitting. High levels of sitting have been linked to diseases, such as type 2 diabetes, heart disease and some cancers. The SMART Work & Life intervention is designed to reduce office workers' sitting time inside and outside work. The SMART Work & Life intervention involves organisational, environmental, group and individual strategies to encourage a reduction in sitting time and was designed to be delivered with and without a height-adjustable workstation (which allows the user to switch between sitting and standing while working). To test whether or not the SMART Work & Life intervention worked, we recruited 756 office workers from councils in Leicester/Leicestershire, Greater Manchester and Liverpool, UK. Participants were from 78 office groups. One-third of the participants received the intervention, one-third received the intervention with a height-adjustable workstation and one-third were a control group (and carried on as usual). Workplace champions in each office group were given training and resources to deliver the intervention. Data were collected at the start of the study, with follow-up measurements at 3 and 12 months. We measured sitting time using a small device worn on the thigh and collected data on weight, body fat, blood pressure, blood sugar and cholesterol levels. We asked participants about their health and work and spoke to participants to find out what they thought of the intervention. Our results showed that participants who received the intervention without workstation sat for 22 minutes less per day, and participants who received the intervention with workstation sat for 64 minutes less per day, than participants in the control group. Levels of stress, well-being, vigour (i.e. personal and emotional energy and cognitive liveliness) and pain in the lower extremity appeared to improve in the intervention groups. Participants viewed the intervention positively and reported several benefits, such as feeling more energised, alert, focused and productive; however, the extent to which participants engaged with the intervention varied across groups.