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Background Stroke is a leading cause of mortality and disability. In higher-income countries, mortality and disability have been reduced with advances in stroke care and early access to rehabilitation services. However, access to such services and the subsequent impact on stroke outcomes in the Philippines, which is a lower- and middle-income countries (LMIC), is unclear. Understanding gaps in service delivery and underpinning research from acute to chronic stages post-stroke will allow future targeting of resources. Aims This scoping review aimed to map available literature on stroke services in the Philippines, based on Arksey and O’Malley’s five-stage-process. Summary of review A targeted strategy was used to search relevant databases (Focused: MEDLINE (ovid), EMBASE (ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO (ebsco); broad-based: Scopus; review-based: Cochrane Library, International Prospective Register of Systematic Reviews (PROSPERO), JBI (formerly Joanna Briggs Institute) as well as grey literature (Open Grey, Google scholar). The searches were conducted between 12/2022-01/2023 and repeated 12/2023. Literature describing adults with stroke in the Philippines and stroke services that aimed to maximize well-being, participation and function were searched. Studies were selected if they included one or more of: (a) patient numbers and stroke characteristics (b) staff numbers, qualifications and role (c) service resources (e.g., access to a rehabilitation unit) (d) cost of services and methods of payment) (e) content of stroke care (f) duration of stroke care/rehabilitation and interventions undertaken (g) outcome measures used in clinical practice. A total of 70 papers were included. Articles were assessed, data extracted and classified according to structure, process, or outcome related information. Advances in stroke services, including stroke ready hospitals providing early access to acute care such as thrombectomy and thrombolysis and early referral to rehabilitation coupled with rehabilitation guidelines have been developed. Gaps exist in stroke services structure (e.g., low number of neurologists and neuroimaging, lack of stroke protocols and pathways, inequity of stroke care across urban and rural locations), processes (e.g., delayed arrival to hospital, lack of stroke training among health workers, low awareness of stroke among public and non-stroke care workers, inequitable access to rehabilitation both hospital and community) and outcomes (e.g., low government insurance coverage resulting in high out-of-pocket expenses, limited data on caregiver burden, absence of unified national stroke registry to determine prevalence, incidence and burden of stroke). Potential solutions such as increasing stroke knowledge and awareness, use of mobile stroke units, TeleMedicine, TeleRehab, improving access to rehabilitation, upgrading PhilHealth and a unified national long-term stroke registry representing the real situation across urban and rural were identified. Conclusion This scoping review describes the existing evidence-base relating to structure, processes and outcomes of stroke services for adults within the Philippines. Developments in stroke services have been identified however, a wide gap exists between the availability of stroke services and the high burden of stroke in the Philippines. Strategies are critical to address the identified gaps as a precursor to improving stroke outcomes and reducing burden. Potential solutions identified within the review will require healthcare government and policymakers to focus on stroke awareness programs, primary and secondary stroke prevention, establishing and monitoring of stroke protocols and pathways, sustainable national stroke registry, and improve access to and availability of rehabilitation both hospital and community. What is already known? Stroke services in the Philippines are inequitable, for example, urban versus rural due to the geography of the Philippines, location of acute stroke ready hospitals and stroke rehabilitation units, limited transport options, and low government healthcare insurance coverage resulting in high out-of-pocket costs for stroke survivors and their families. What are the new findings? The Philippines have a higher incidence of stroke in younger adults than other LMICs, which impacts the available workforce and the country’s economy. There is a lack of data on community stroke rehabilitation provision, the content and intensity of stroke rehabilitation being delivered and the role and knowledge/skills of those delivering stroke rehabilitation, unmet needs of stroke survivors and caregiver burden and strain, What do the new findings imply? A wide gap exists between the availability of stroke services and the high burden of stroke. The impact of this is unclear due to the lack of a compulsory national stroke registry as well as published data on community or home-based stroke services that are not captured/published. What does this review offer? This review provides a broad overview of existing evidence-base of stroke services in the Philippines. It provides a catalyst for a) healthcare government to address stroke inequities and burden; b) development of future evidence-based interventions such as community-based rehabilitation; c) task-shifting e.g., training non-neurologists, barangay workers and caregivers; d) use of digital technologies and innovations e.g., stroke TeleRehab, TeleMedicine, mobile stroke units.

Regular exercise has widespread health benefits. Fundamental to these beneficial effects is the ability of the heart to intermittently and substantially increase its performance without incurring damage, but the underlying homeostatic mechanisms are unclear. We identify the ROS-generating NADPH oxidase-4 (Nox4) as an essential regulator of exercise performance in mice. Myocardial Nox4 levels increase during acute exercise and trigger activation of the transcription factor Nrf2, with the induction of multiple endogenous antioxidants. Cardiomyocyte-specific Nox4-deficient (csNox4KO) mice display a loss of exercise-induced Nrf2 activation, cardiac oxidative stress and reduced exercise performance. Cardiomyocyte-specific Nrf2-deficient (csNrf2KO) mice exhibit similar compromised exercise capacity, with mitochondrial and cardiac dysfunction. Supplementation with an Nrf2 activator or a mitochondria-targeted antioxidant effectively restores cardiac performance and exercise capacity in csNox4KO and csNrf2KO mice respectively. The Nox4/Nrf2 axis therefore drives a hormetic response that is required for optimal cardiac mitochondrial and contractile function during physiological exercise.

Dysregulation of redox homeostasis is implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H 2 O 2 in vivo, we established a redox-shifted model by manipulating levels of the H 2 O 2 -degrading enzyme catalase in Drosophila . Here we report that ubiquitous over-expression of catalase robustly extends lifespan in females. As anticipated, these flies are strongly resistant to a range of oxidative stress challenges, but interestingly are sensitive to starvation, which could not be explained by differences in levels of energy reserves. This led us to explore the contribution of autophagy, which is an important mechanism for organismal survival in response to starvation. We show that autophagy is essential for the increased lifespan by catalase upregulation, as the survival benefits are completely abolished upon global autophagy knock-down. Furthermore, using a specific redox-inactive knock-in mutant, we highlight the in vivo role of a key regulatory cysteine residue in Atg4a, which is required for the lifespan extension in our catalase model. Altogether, these findings confirm the redox regulation of autophagy in vivo as an important modulator of longevity. Redox signalling is emerging as an important regulator of metabolism and physiology, which is dysregulated in ageing and disease. Here, the authors show that redox regulation of a key redox sensitive cysteine in Atg4a induces autophagy in vivo and extends lifespan in female Drosophila .

ObjectiveTo identify the available guidance and training to implement telerehabilitation movement assessments for people (adults and children) with a physical disability, including those recovering from COVID-19.DesignRapid scoping review.Included sources and articlesPubMed, CINAHL, PsychInfo, Cochrane, Embase, Web of Science, PEDro, UK Health Forum, WHO, National Archives and NHS England were searched using the participant–concept–context framework from 2015 to August 2020. Primary studies that recruited individuals with physical disabilities and guidance documents aimed at providers to implement movement-related telerehabilitation were included.Results23 articles (11 primary research studies, 3 systematic reviews and 9 guidance documents) were included out of 7857 that were identified from the literature search. Two main issues were found: (1) telerehabilitation guidance (from both research studies and guidance documents) was not specific to movement-related assessment and (2) most primary research studies provided neither guidance nor training of movement-specific assessment to practitioners. Of the COVID-19 related guidance, two articles reported COVID-19 management that only referred to identifying COVID-19 status without references to specific movement-related guidance.ConclusionsTelerehabilitation guidance and training have existed pre-COVID-19, yet the lack of specific movement-related information and provider support is surprising. This gap must be addressed to optimise effective implementation of remote assessments for those with physical disabilities.Review registrationOpen Science Framework: osf.io/vm6sp.

Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, mechanism-based therapeutic approaches. We have previously compared high vs low anxiety mice and identified changes in mitochondrial pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondrial pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no reported side effects in mice and humans.

The role of hydrogen peroxide (H 2 O 2 ) in mitochondrial oxidative damage and redox signaling is poorly understood, because it is difficult to measure H 2 O 2 in vivo . Here we describe a method for assessing changes in H 2 O 2 within the mitochondrial matrix of living Drosophila . We use a ratiometric mass spectrometry probe, MitoB ((3-hydroxybenzyl)triphenylphosphonium bromide), which contains a triphenylphosphonium cation component that drives its accumulation within mitochondria. The arylboronic moiety of MitoB reacts with H 2 O 2 to form a phenol product, MitoP. On injection into the fly, MitoB is rapidly taken up by mitochondria and the extent of its conversion to MitoP enables the quantification of H 2 O 2 . To assess MitoB conversion to MitoP, the compounds are extracted and the MitoP/MitoB ratio is quantified by liquid chromatography–tandem mass spectrometry relative to deuterated internal standards. This method facilitates the investigation of mitochondrial H 2 O 2 in fly models of pathology and metabolic alteration, and it can also be extended to assess mitochondrial H 2 O 2 production in mouse and cell culture studies.

Mitochondrial complex I, the primary entry point for electrons into the mitochondrial respiratory chain, is both critical for aerobic respiration and a major source of reactive oxygen species. In the heart, chronic dysfunction driving cardiomyopathy is frequently associated with decreased complex I activity, from both genetic and environmental causes. To examine the functional relationship between complex I disruption and cardiac dysfunction we used an established mouse model of mild and chronic complex I inhibition through heart-specific Ndufs4 gene ablation. Heart-specific Ndufs4-null mice had a decrease of ∼ 50% in complex I activity within the heart, and developed severe hypertrophic cardiomyopathy as assessed by magnetic resonance imaging. The decrease in complex I activity, and associated cardiac dysfunction, occurred absent an increase in mitochondrial hydrogen peroxide levels in vivo, accumulation of markers of oxidative damage, induction of apoptosis, or tissue fibrosis. Taken together, these results indicate that diminished complex I activity in the heart alone is sufficient to drive hypertrophic cardiomyopathy independently of alterations in levels of mitochondrial hydrogen peroxide or oxidative damage.

Background Early mobilisation (> 24 h post-stroke) is recommended for people with stroke. However, there is a paucity of evidence about how to implement early mobilisation for people who have had a severe stroke. Prolonged standing and task-specific training (sit-to-stand repetitions) have separately been evaluated in the literature; however, these functionally linked tasks have not been evaluated in combination for people with severe sub-acute stroke. Methods The objective was to determine the feasibility of conducting a randomised controlled trial (RCT) of a functional standing frame programme compared with usual physiotherapy for people with severe sub-acute stroke. An assessor-blinded feasibility RCT with nested qualitative component (interviews and focus group) and process evaluation was adopted. Participants were aged ≥ 18 years with new diagnosis of severe sub-acute stroke (modified Rankin Scale (mRS) 4/5) from four Stroke Rehabilitation Units across South West England. Participants were randomised to receive either: (1) functional standing frame programme (30 min. standing plus sit-to-stand repetitions) plus 15 min of usual physiotherapy daily (intervention); (2) usual physiotherapy (45 min) daily (control). Both programmes were protocolised to be undertaken a minimum of five sessions per week for 3 weeks. Feasibility indicators included process, resource, management, and safety. Adherence, fidelity, and acceptability of the trial and intervention were evaluated using data recorded by therapists, observation of intervention and control sessions, interviews and one focus group. Patient measures of motor impairment, activities/participation, and quality of life were carried out by blinded assessors at baseline, 3, 15, 29, and 55 weeks post-randomisation. Results Forty-five participants (51–96 years; 42% male, mRS 4 = 80% 5 = 20%) were randomised ( n = 22 to intervention). Twenty-seven (60%) participants were followed-up at all time points. Twelve participants (27%) died during the trial; no deaths were related to the trial. Adherence to the minimum number of sessions was low: none of the participants completed all 21 sessions, and only 8 participants (18%) across both groups completed ≥ 15 sessions, over the 3 weeks; 39% intervention; 51% control sessions were completed; mean session duration 39 min (SD 19) control, 37 min intervention (SD 11). Intervention group: mean standing time 13 min (SD 9); mean sit-to-stand repetitions/session 5 (SD 4). Interviews were conducted with 10 participants, four relatives and six physiotherapists. Five physiotherapists attended a focus group. Conclusions The majority of progression criteria for this feasibility trial were met. However, adherence to the interventions was unacceptably low. This aspect of the trial design needs to be addressed prior to moving to a definitive RCT of this standing frame intervention in people with severe sub-acute stroke. Solutions have been identified to address these concerns. Trial registration International Standard Randomised Controlled Trial Number ISRCTN15412695 . Registration 19 December 2016.

We appreciated the opportunity to co-edit papers submitted from the Nonprofit Academic Centers Council (NACC) 2017 Biennial Conference, July 31–August 2, 2017, in Indianapolis, Indiana, hosted by Indiana University Lilly Family School of Philanthropy.