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Increasing prevalence of native lowlanders sojourning to high altitudes (>2,500 m) for recreational, occupational, military, and competitive reasons has generated increased interest in physiological responses to multistressor environments. Exposure to hypoxia poses recognized physiological challenges that are amplified during exercise and further complicated by environments that might include combinations of heat, cold, and high altitude. There is a sparsity of data examining integrated responses in varied combinations of environmental conditions, with even less known about potential sex differences. How this translates into performance, occupational, and health outcomes requires further investigation. Acute hypoxic exposure decreases arterial oxygen saturation, resulting in a reflex hypoxic ventilatory response and sympathoexcitation causing an increase in heart rate, myocardial contractility, and arterial blood pressure, to compensate for the decreased arterial oxygen saturation. Acute altitude exposure impairs exercise performance, for example, reduced time to exhaustion and slower time trials, largely owing to impairments in pulmonary gas exchange and peripheral delivery resulting in reduced V̇o2max. This exacerbates with increasing altitude, as does the risk of developing acute mountain sickness and more serious altitude-related illnesses, but modulation of those risks with additional stressors is unclear. This review aims to summarize and evaluate current literature regarding cardiovascular, autonomic, and thermoregulatory responses to acute hypoxia, and how these may be affected by simultaneous thermal environmental challenges. There is minimal available information regarding sex as a biological variable in integrative responses to hypoxia or multistressor environments; we highlight these areas as current knowledge gaps and the need for future research.

Centrosomes are microtubule-organizing centers comprised of a pair of centrioles and the surrounding pericentriolar material. Abnormalities in centriole number are associated with cell division errors and can contribute to diseases such as cancer. Centriole duplication is limited to once per cell cycle and is controlled by the dosage-sensitive Polo-like kinase 4 (PLK4). Here, we show that PLK4 abundance is translationally controlled through conserved upstream open reading frames (uORFs) in the 5′ UTR of the mRNA. Plk4 uORFs suppress Plk4 translation and prevent excess protein synthesis. Mice with homozygous knockout of Plk4 uORFs (Plk4Δu/Δu) are viable but display dramatically reduced fertility because of a significant depletion of primordial germ cells (PGCs). The remaining PGCs in Plk4Δu/Δu mice contain extra centrioles and display evidence of increased mitotic errors. PGCs undergo hypertranscription and have substantially more Plk4 mRNA than somatic cells. Reducing Plk4 mRNA levels in mice lacking Plk4 uORFs restored PGC numbers and fully rescued fertility. Together, our data uncover a specific requirement for uORF-dependent control of PLK4 translation in counterbalancing the increased Plk4 transcription in PGCs. Thus, uORF-mediated translational suppression of PLK4 has a critical role in preventing centriole amplification and preserving the genomic integrity of future gametes.

Michael Wang,1,* Claude Negrier,2,* Frank Driessler,3,* Clifford Goodman,4,* Mark W Skinner5,6,* 1University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2National Reference Center for Haemophilia, Louis Pradel Cardiology Hospital, University of Lyon, Lyon, France; 3Bayer, Basel, Switzerland; 4The Lewin Group, Falls Church, VA, USA; 5Institute for Policy Advancement Ltd, Washington, DC, USA; 6McMaster University, Hamilton, ON, Canada*These authors contributed equally to this workCorrespondence: Frank Driessler, Bayer AG, Peter Merian Straße 84, Basel, CH-4052, Switzerland, Tel +41 79 422 32 18, Email frank.driessler@bayer.comPurpose: The anticipated emergence of hemophilia gene therapy will present people with hemophilia (PWH) and treating clinicians with increasingly complex treatment options. It will be critical that PWH and their families be empowered to participate fully in decision-making through transparent communication and the development of targeted educational resources.Methods: The Council of Hemophilia Community (CHC) convened across a series of roundtable meetings to define the patient journey for hemophilia gene therapy, and to develop a question-and-answer style resource to guide discussion between healthcare professionals (HCPs) and their patients. Patient groups were also consulted during the development of this tool.Results: The CHC defined 5 key stages in the hemophilia gene therapy patient journey: pre-gene therapy (information-seeking and decision-making), treatment initiation, short- and long-term post-gene therapy follow-up. PWH will have different questions and concerns at each stage of their journey, which should be discussed with their HCP to aid decision-making. The resulting patient journey infographic and Q&A resource (see Supplementary Materials) has been developed for HCPs and PWH to provide a novel and practical roadmap of key issues and considerations throughout all stages.Conclusion: These resources support a collaborative, patient-centric, shared decision-making approach to inform treatment decision discussions between HCPs and PWH. The value of such discussions will be influenced by the language adopted; health literacy is a particularly important consideration, and these discussions should be accessible and tailored to PWH. HCPs and PWH can benefit from awareness of the common questions and uncertainties as they progress together along the patient journey. While the contents of this article are specific to hemophilia gene therapy, the concepts developed here could be adapted to aid patients in other disease states.Keywords: hemophilia, patients, HCP guidance, health literacy, disease awareness, treatment landscape

Emergence of new therapies are anticipated to improve clinical outcomes and quality of life of persons with haemophilia. Challenges in conducting randomized clinical trials in rare diseases have resulted in a lack of direct head-to-head comparisons to support value-based decision-making between different treatments.We conducted a literature review for new and emerging haemophilia A and B therapies (extended half-life [EHL] replacement factor, non-replacement therapies [NRT], and gene therapies [GT]) to identify differentiating patient-centred outcomes defined previously in a haemophilia value framework. Since the literature included all publication types (e.g., surveys, modelling studies, commentaries/reviews), collected data were assigned level of evidence scores.Across different classes of therapies, bleeding was determined as the most frequently reported differentiating outcome, with EHL, NRT, and GT each demonstrating an advantage over comparator replacement therapies. EHL therapies for haemophilia A and B and NRT for haemophilia A showed good representation across Tier 1 outcomes (health status achieved/retained), while more publications were identified with Tier 2 (process of recovery) outcomes for NRT than EHL or GT. In Tier 3 (sustainability of health), frequency of breakthrough bleeds represented a differentiating outcome for EHL (both haemophilia A and B), NRT (haemophilia A only), and GT (haemophilia B only), whereas sustained good health was differentiating for most comparisons.We demonstrate the utility of the haemophilia value framework as a common core outcome set for effectively comparing therapies. Application of this framework will serve as a useful decision-making tool for patients, clinicians, and within health technology assessments.With the emergence of high-cost, paradigm changing treatments across multiple areas of medicine, we, the haemophilia community, need to be equipped to meet the growing demands for more rigorous evidence-based value assessments using the tools expected by assessors. The traditional access toolbox needs to evolve to meet the paradigm shift in treatment options. Value can no longer be defined by annualized bleed rates alone. To realize the full impact of new therapies, we need to utilize tools, such as a value framework, to organize evidence, identify data gaps, and assess patient-defined, meaningful outcomes across a multi-faceted dimension. The haemophilia value framework is an effective tool for organizing the available evidence and identifying gaps in the evidence. This can be used for assessing the value of emerging therapies in haemophilia utilizing data generated through randomized clinical trials and real world evidence generation. This is a call for incorporating the Value Framework into official submissions to authorities, as it captures a broader range of outcomes, including patient meaningful outcomes, in ways that better assess the potential benefits of new therapies.

Refereed/Peer-reviewed Recently, coal fly ash has become a potential candidate as a secondary resource of rare earth elements (REE). In this investigation, we studied the recovery of REE from fly ash from a commercial power plant. The specific aim was to assess the technical feasibility of recovering REE from the coal fly ash using conventional preconcentration methods, including gravity separation, magnetic separation, and froth flotation. The experimental results revealed that flotation achieved major gains in REE recovery and upgrading. However, during gravity and wet magnetic separation tests, the bulk of REE reported to the tailings. The results showed significant variations in the performance of the various beneficiation methods investigated. This study has confirmed that existing physical separation methods could be used to recover REE from coal fly ash prior to hydrometallurgical and pyrometallurgical processing, although some challenges persist. © 2022 South African Institute of Mining and Metallurgy.

Objectives To evaluate (1) the feasibility of an audit-feedback intervention to facilitate sports science journal policy change, (2) the reliability of the Transparency of Research Underpinning Social Intervention Tiers (TRUST) policy evaluation form, and (3) the extent to which policies of sports science journals support transparent and open research practices. Methods We conducted a cross-sectional, audit-feedback, feasibility study of transparency and openness standards of the top 38 sports science journals by impact factor. The TRUST form was used to evaluate journal policies support for transparent and open research practices. Feedback was provided to journal editors in the format of a tailored letter. Inter-rater reliability and agreement of the TRUST form was assessed using intraclass correlation coefficients and the standard error of measurement, respectively. Time-based criteria, fidelity of intervention delivery and qualitative feedback were used to determine feasibility. Results The audit-feedback intervention was feasible based on the time taken to rate journals and provide tailored feedback. The mean (SD) score on the TRUST form (range 0–27) was 2.05 (1.99), reflecting low engagement with transparent and open practices. Inter-rater reliability of the overall score of the TRUST form was moderate [ICC (2,1) = 0.68 (95% CI 0.55–0.79)], with standard error of measurement of 1.17. However, some individual items had poor reliability. Conclusion Policies of the top 38 sports science journals have potential for improved support for transparent and open research practices. The feasible audit-feedback intervention developed here warrants large-scale evaluation as a means to facilitate change in journal policies. Registration: OSF (https://osf.io/d2t4s/).

Rural fire services increasingly rely on older volunteers, providing an opportunity to examine the challenges of the ageing volunteer base that is underway in rural communities. To advance knowledge on the phenomena of ‘older voluntarism’, a case study of a rural volunteer fire department in Ontario, Canada was undertaken, drawing on semi-structured interviews with 24 fire service members. Findings from an iterative collaborative qualitative analysis demonstrate that the dynamics and intergenerational challenges of ageing volunteers and rural interconnectedness and cohesion combine to influence the experiences and sustainability of older volunteers, volunteer-based services and ageing rural places. The discussion advances a framework for understanding personal, program and community sustainability of rural ageing, and highlights emergent questions for research, policy and practice to guide further research into the sustainability of older voluntarism in ageing rural communities.

Recent advancements in gene-targeted therapies have highlighted the critical role data sharing plays in successful translational drug development for people with rare diseases. To scale these efforts, we need to systematize these sharing principles, creating opportunities for more rapid, efficient, and scalable drug discovery/testing including long-term and transparent assessment of clinical safety and efficacy. A number of challenges will need to be addressed, including the logistical difficulties of studying rare diseases affecting individuals who may be scattered across the globe, scientific, technical, regulatory, and ethical complexities of data collection, and harmonization and integration across multiple platforms and contexts. The NCATS/NIH Gene-Targeted Therapies: Early Diagnosis and Equitable Delivery meeting series held during June 2021 included data sharing models that address these issues and framed discussions of areas that require improvement. This article describes these discussions and provides a series of considerations for future data sharing.

Rare, chronic diseases such as hemophilia and other congenital coagulation disorders require coordinated delivery of services for optimal outcomes. Hemophilia Treatment Centers (HTCs) are specialized, multidisciplinary health-care centers providing team-based care to meet the physical, psychosocial, and emotional needs of people with hemophilia (PWH) and may serve as a model for other rare coagulation disorders. Health-care purchasers, as well as the general medical community, may not appreciate the breadth and quality of services provided by HTCs. They exemplify the acculturalization and actualization of integrated care by providing comprehensive diagnostic and treatment services that reduce morbidity, mortality, avoidable emergency room visits, hospitalizations, and overall costs, while promoting a longer lifespan and improved patient functioning and outcomes. This is accomplished by a team-based approach relying upon a shared decision-making model to effectively prevent complications and manage symptoms in PWH, who are dependent on high-cost treatments. This article provides a concise yet comprehensive description of the core components of an HTC and the regional and national networks in the United States, which together achieve their incomparable value for all stakeholders., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/_Nx_76pDKLw

Background Knowledge about sexual health, difficulty with sexual activity and intimacy (sexual difficulty), in people with hemophilia is little understood. Objectives The objectives were to determine the prevalence of sexual difficulty in people living with hemophilia (PWH) compared to people with no bleeding disorders (PWNoBD), and to determine factors associated with it. Methods This was an analysis of the PROBE study. We recruited individuals who had hemophilia A or B (PWH) and PWNoBD who were 18 years old or older. We calculated proportions of participants with sexual difficulty and odds ratios (ORs) adjusted for sex and age with 95% confidence intervals. Results There were 2007 PWH and 1972 PWNoBD. Mean (standard deviation) age was 41 (15) years in PWH and 42 (13) years in PWNoBD. Sexual difficulty was reported in 302 (15.1%) PWH and 79 (4.0%) PWNoBD. The odds of sexual difficulty were significantly higher in PWH (OR 3.82, 95% CI 2.85, 5.11). Among PWH, older age, experiencing acute or chronic pain in the past 12 months, bleeds within the past two weeks, ≥3 spontaneous joint bleeds (past six months), limitation of range of motion of any joints, and any life- or limb-threatening bleeds in the past 12 months were associated with sexual difficulty. Conclusions Sexual difficulty is more prevalent in people living with hemophilia and associated with markers of disease severity. Sexual health issues should be incorporated in comprehensive hemophilia care, future research, and hemophilia related health policy.

During large-scale crises such as the COVID-19 pandemic, the precarity of older people and older volunteers can become exacerbated, especially in under-serviced rural regions and small towns. To understand how the pandemic has affected “older voluntarism”, this article presents a case study of three volunteer-based programs in rural Ontario, Canada. Interviews with 34 volunteers and administrators reveal both challenging and growth-oriented experiences of volunteers and the programs during the first wave of COVID-19. The findings demonstrate the vulnerability and resiliency of older volunteers and the adaptability and uncertainty of programs that rely on older voluntarism, as the community and its older residents navigate pandemic-related changes. The article advances a framework for understanding the pandemic’s impacts on older voluntarism in relation to personal, program, and community dimensions of sustainable rural aging. Further, it explores ways that older volunteers, organizations that depend on them, and communities experiencing population aging can persevere post-pandemic.

People with non-severe haemophilia appear to be under-treated in many countries, and this may lead to joint damage and worsen quality of life.To review literature for clotting factor replacement prophylaxis in people with non-severe haemophilia A and B (HA/HB) in relation to long-term outcomes to support clinical decision-making.A targeted literature search was performed to identify studies published between 2000 and 2021 that included prophylaxis in people with non-severe HA/HB and long-term outcomes, including annualized bleeding rates, joint health and quality of life.Although eligible articles included 2737 and 2272 people with mild or moderate HA, respectively, only 22% (n = 609) and 29% (n = 668) reported treatment regimens. A total of 549 people with moderate HA were treated with factor replacement prophylaxis and were from high-income countries. On the contrary, nearly all people with mild HA received desmopressin (n = 599). Details of treatment regimens for women with haemophilia and people with HB were sparse. Three studies provided long-term outcomes for people with moderate haemophilia who received prophylaxis with factor concentrate, supporting early prophylaxis in people with a frequent bleeding phenotype regardless of their endogenous clotting factor level to preserve joint health.There remain large knowledge gaps when considering how to provide optimal treatment for people with non-severe haemophilia. Nonetheless, there is a strong rationale that prophylaxis should be considered early in life according to similar strategies as for severe haemophilia for those with a frequent severe bleeding phenotype.

Chromosome movements and licensing of synapsis must be tightly regulated during early meiosis to ensure accurate chromosome segregation and avoid aneuploidy, although how these steps are coordinated is not fully understood. Here we show that GRAS-1, the worm homolog of mammalian GRASP/Tamalin and CYTIP, coordinates early meiotic events with cytoskeletal forces outside the nucleus. GRAS-1 localizes close to the nuclear envelope (NE) in early prophase I and interacts with NE and cytoskeleton proteins. Delayed homologous chromosome pairing, synaptonemal complex (SC) assembly, and DNA double-strand break repair progression are partially rescued by the expression of human CYTIP in gras-1 mutants, supporting functional conservation. However, Tamalin, Cytip double knockout mice do not exhibit obvious fertility or meiotic defects, suggesting evolutionary differences between mammals. gras-1 mutants show accelerated chromosome movement during early prophase I, implicating GRAS-1 in regulating chromosome dynamics. GRAS-1-mediated regulation of chromosome movement is DHC-1-dependent, placing it acting within the LINC-controlled pathway, and depends on GRAS-1 phosphorylation at a C-terminal S/T cluster. We propose that GRAS-1 serves as a scaffold for a multi-protein complex coordinating the early steps of homology search and licensing of SC assembly by regulating the pace of chromosome movement in early prophase I.

Thionocarbamate, specifically modified Isopropyl Ethyl Thionocarbamate (IPETC) is selective in the separation of pyrite from arsenopyrite, following copper activation. In this work, the flotation response of a refractory gold (Au) ore containing arsenic (As) mainly in the form of arsenian pyrite is investigated to reject gold-barren sulphidic phases. The recovery of Au increased with an increase in CuSO4 concentration to 0.3 kg/t, beyond which further increase in concentration yielded no significant recovery. Variations of IPETC concentration between 0.2 and 1.5 kg /t of ore influenced both gold and arsenic recovery. It was surmised that the high collector dosage may have resulted from competitive adsorption between arsenian pyrite and other gangue minerals in the ore. 0.3 kg/t CuSO4 and 1.2 kg/t IPETC concentration at pH 11 gave the best results of 86% Au and 83% As recovery at an Au and As grade of 8.14 g/t and 2436 ppm respectively. LA-ICP-MS analysis of the concentrate showed a positive correlation between gold and arsenic. The technique also revealed arsenic-rich zones in pyrite which was further confirmed by SEM/BSD imaging to be rims of arsenian pyrite encapsulating Au-barren pyrite. MLA mineral maps of concentrates obtained at different times also showed that there is no relationship between the arsenic content of pyrite and the flotation rate. The deportment of arsenic in the rims of pyrite presents a complex mineralogical association which results in a decrease in concentrate grade. Refereed/Peer-reviewed

Question Does feeling reassured after a consultation reduce future disability or healthcare use in people with acute low back pain (LBP)? Design Mediation analysis of a randomised, sham-controlled trial. Participants Two hundred and two people with acute LBP at above average risk (high risk) of developing chronic LBP. Intervention All participants received guideline-based care from their usual clinician. Participants received two additional 1-hour sessions of patient education focused on emphasising the benign nature of LBP or sham patient education that included active listening only. Outcome measures The two primary outcomes for this study were self-reported disability and healthcare use. The mediator was feeling reassured that LBP was not caused by serious illness. Results Data from 194 (96%) participants and 178 (88%) participants were included in the analysis for disability and healthcare use outcome models, respectively. Feeling reassured did not mediate the effect of the intervention on disability (indirect effect −0.23, 95% CI −0.71 to 0.18) or healthcare use (indirect effect 0.00, 95% CI −0.04 to 0.04). Patient education intervention increased feeling reassured (1.14 points, 95% CI 0.43 to 1.85) compared with sham patient education. However, the mediator (ie, feeling reassured) did not reduce disability (−0.20 points, 95% CI −0.58 to 0.19) or healthcare use (OR 1.09, 95% CI 0.98 to 1.21). Conclusion Feeling reassured after a consultation did not lead to improvements in disability and healthcare use for people with acute LBP. Clinicians should reflect on the time that they allocate to reassuring their patients and consider reallocating time to other aspects of the consultation that could reduce disability and future healthcare use. Trial registration ACTRN12612001180808, study protocol https://osf.io/4tfaz/ .

Objectives This pilot study assessed whether frontal lobe transcranial direct current stimulation (tDCS) combined with complex walking rehabilitation is feasible, safe, and shows preliminary efficacy for improving walking and executive function. Materials and methods Participants were randomized to one of the following 18-session interventions: active tDCS and rehabilitation with complex walking tasks (Active/Complex); sham tDCS and rehabilitation with complex walking tasks (Sham/Complex); or sham tDCS and rehabilitation with typical walking (Sham/Typical). Active tDCS was delivered over F3 (cathode) and F4 (anode) scalp locations for 20 min at 2 mA intensity. Outcome measures included tests of walking function, executive function, and prefrontal activity measured by functional near infrared spectroscopy. Results Ninety percent of participants completed the intervention protocol successfully. tDCS side effects of tingling or burning sensations were low (average rating less than two out of 10). All groups demonstrated gains in walking performance based on within-group effect sizes (d ≥ 0.50) for one or more assessments. The Sham/Typical group showed the greatest gains for walking based on between-group effect sizes. For executive function, the Active/Complex group showed the greatest gains based on moderate to large between-group effect sizes (d = 0.52-1.11). Functional near-infrared spectroscopy (fNIRS) findings suggest improved prefrontal cortical activity during walking. Conclusions Eighteen sessions of walking rehabilitation combined with tDCS is a feasible and safe intervention for older adults. Preliminary effects size data indicate a potential improvement in executive function by adding frontal tDCS to walking rehabilitation. This study justifies future larger clinical trials to better understand the benefits of combining tDCS with walking rehabilitation.

Introduction Severe haemophilia A (HA) has a major impact on health‐related quality of life (HRQoL). Aim Assess the impact of emicizumab on HRQoL in persons with severe HA (PwHA) without factor VIII (FVIII) inhibitors in the phase 3 HAVEN 3 and 4 studies. Methods This pooled analysis examines the HRQoL of PwHA aged ≥ 18 years treated with emicizumab prophylaxis via Haemophilia‐Specific Quality of Life Questionnaire for Adults (Haem‐A‐QoL) and EuroQoL 5‐Dimensions 5‐levels (EQ‐5D‐5L). In particular, changes from baseline in Haem‐A‐QoL ‘Physical Health’ (PH) domain and ‘Total Score’ (TS) are evaluated. Results Among 176 evaluable participants, 96 (55%) had received prior episodic treatment and 80 (45%) prophylaxis; 70% had ≥ 1 target joint and 51% had experienced ≥ 9 bleeds in the previous 24 weeks. Mean Haem‐A‐QoL PH and TS improved after emicizumab initiation. Mean (standard deviation) –12.0 (21.26)‐ and –8.6 (12.57)‐point improvements were observed in PH and TS from baseline to Week 73; Week 73 scores were 27.9 (24.54) and 22.0 (14.38), respectively. Fifty‐four percent of participants reported a clinically meaningful improvement in PH scores (≥ 10 points) by Week 73. Subgroups with poorer HRQoL prior to starting emicizumab (i.e. receiving episodic treatment, ≥ 9 bleeds, target joints) had the greatest improvements in PH scores, and corresponding reductions in missed workdays; change was not detected among those previously taking prophylaxis. No change over time was detected by the EQ‐5D‐5L questionnaire. Conclusions Emicizumab prophylaxis in PwHA without FVIII inhibitors resulted in persistent and meaningful improvements in Haem‐A‐QoL PH and less work disruption than previous treatment.

As encouraged by Toxicity Testing in the 21st Century, researchers increasingly apply high-throughput in vitro approaches to identify and characterize nanoparticle hazards, including conventional aqueous cell culture systems to assess respiratory hazards. Translating nanoparticle dose from conventional toxicity testing systems to relevant human exposures remains a major challenge for assessing occupational risk of nanoparticle exposures. Here, we explored existing computational tools and data available to translate nanoparticle dose metrics from cellular test systems to inhalation exposures of silver nanoparticles in humans. We used the Multiple-Path Particle Dosimetry (MPPD) Model to predict nanoparticle deposition of humans exposed to 20 and 110 nm silver nanoparticles at 0.9 μg/m(3) over an 8 h period, the proposed National Institute of Occupational Safety and Health (NIOSH) recommended exposure limit (REL). MPPD predicts 8.1 and 3.7 μg of silver deposited in an 8 h period for 20 and 110 nm nanoparticles, respectively, with 20 nm particles displaying nearly 11-fold higher total surface area deposited. Peak deposited nanoparticle concentrations occurred more proximal in the pulmonary tract compared to mass deposition patterns (generation 4 vs. generations 20–21, respectively) due to regional differences in lung lining fluid volumes. Assuming 0.4% nanoparticle dissolution by mass measured in previous studies predicted peak concentrations of silver ions in cells of 1.06 and 0.89 μg/mL for 20 and 110 nm particles, respectively. Both predicted concentrations are below the measured toxic threshold of 1.7 μg/mL of silver ions in cells from in vitro assessments. Assuming 4% dissolution by mass predicted 10-fold higher silver concentrations in tissues, peaking at 10.6 and 8.9 μg/mL, for 20 and 110 nm nanoparticles respectively, exceeding the observed in vitro toxic threshold and highlighting the importance and sensitivity of dissolution rates. Overall, this approach offers a framework for extrapolating nanotoxicity results from in vitro cell culture systems to human exposures. Aligning appropriate dose metrics from in vitro and in vivo hazard characterizations and human pulmonary doses from occupational exposures are critical components for successful nanoparticle risk assessment and worker protection providing guidance for designing future in vitro studies aimed at relevant human exposures.

Objective: To assess changes in walking function and walking-related prefrontal cortical activity following two post-stroke rehabilitation interventions: an accurate adaptability (ACC) walking intervention and a steady state (SS) walking intervention. Design: Randomized, single blind, parallel group clinical trial. Setting: Hospital research setting. Subjects: Adults with chronic post-stroke hemiparesis and walking deficits. Interventions: ACC emphasized stepping accuracy and walking adaptability, while SS emphasized steady state, symmetrical stepping. Both included 36 sessions led by a licensed physical therapist. ACC walking tasks recruit cortical regions that increase corticospinal tract activation, while SS walking activates the corticospinal tract less intensely. Main measures: The primary functional outcome measure was preferred steady state walking speed. Prefrontal brain activity during walking was measured with functional near infrared spectroscopy to assess executive control demands. Assessments were conducted at baseline, post-intervention (three months), and follow-up (six months). Results: Thirty-eight participants were randomized to the study interventions (mean age 59.6 ± 9.1 years; mean months post-stroke 18.0 ± 10.5). Preferred walking speed increased from baseline to post-intervention by 0.13 ± 0.11 m/s in the ACC group and by 0.14 ± 0.13 m/s in the SS group. The Time × Group interaction was not statistically significant ( P = 0.86). Prefrontal fNIRS during walking decreased from baseline to post-intervention, with a marginally larger effect in the ACC group ( P = 0.05). Conclusions: The ACC and SS interventions produced similar changes in walking function. fNIRS suggested a potential benefit of ACC training for reducing demand on prefrontal (executive) resources during walking.

Notwithstanding a few exceptions, the global age-friendly literature remains mostly silent on the problem of the longer-term, sustainable implementation of age-friendly initiatives. This paper seeks to address this gap by presenting rural insights from a multi-site case study in Ontario, Canada, that considers the influence of unique, rural community contexts that may differentially impact parameters of success and longer-term sustainability among rural age-friendly programs. Findings from interviews with 46 age-friendly leaders across five rural communities demonstrate that contextual community factors directly affected rural age-friendly sustainability. Specifically, the presence of social connectivity (sense of community) created an opportunity for age-friendly sustainability, whereas a lack of geographic connectivity (jurisdictional fragmentation) presented a challenge. These contextual insights demonstrate an additional pathway to rural age-friendly sustainability – considering the social and jurisdictional level of age-friendly implementation prior to initial development, a pathway which reinforces the need for a specifically rural age-friendly agenda that supports rural older adults.