The effect of attentional cues on mechanical efficiency and movement smoothness in running gait: An interdisciplinary investigation.

The aim was to examine the effect of focus of attention cues on foot angle for retraining movement purposes. Twenty (females: 8) rearfoot-striking recreational runners (mass: 72.5 ± 11.8 kg; height: 1.73 ± 0.09 m; age: 32.9 ± 11.3 years) were randomly assigned to an internal focus (IF) (n = 10) or external focus (EF) (n = 10) verbal cue group. Participants performed 5 × 6 minute blocks of treadmill running (control run, 3 × cued running, retention run) at a self-selected running velocity (9.4 ± 1.1 km∙h-1) during a single laboratory visit. Touchdown foot angle, mechanical efficiency, internal and external work were calculated and, centre of mass (COM) and foot movement smoothness was quantified. Linear-mixed effect models showed an interaction for foot angle (p < 0.001, ηp2 = 0.35) and mechanical efficiency (p < 0.001, ηp2 = 0.40) when comparing the control to the cued running. Only the IF group reduced foot angle and mechanical efficiency during cued running, but not during the retention run. The IF group produced less external work during the 1st cued run than the control run. COM and foot smoothness were unaffected by cueing. Only an IF produced desired technique changes but at the cost of reduced mechanical efficiency. Movement smoothness was unaffected by cue provision. Changes to foot angle can be achieved within 6 minutes of gait retraining.

Impact of COVID-19-related restricted family presence policies on Canadian pediatric intensive care unit clinicians: a qualitative study.

PURPOSE: Pediatric intensive care units (PICUs) worldwide restricted family presence in response to the COVID-19 pandemic. We aimed to explore the experiences and impact of restricted family presence policies on Canadian PICU clinicians. METHODS: We conducted a qualitative study that followed an interpretive phenomenological design. Participants were PICU clinicians providing direct patient care in Canada during periods of COVID-19-related restricted family presence. We purposively sampled for maximum variation among survey participants who consented to be contacted for further research on the same topic. In-depth interviews were conducted remotely via telephone or video-call, audio-recorded, and transcribed. Interviews were inductively coded and underwent thematic analysis. Proposed themes were member-checked by interviewees. RESULTS: Sixteen PICU clinicians completed interviews. Interviewees practiced across Canada, represented a range of disciplines (eight nurses, two physicians, two respiratory therapists, two child life specialists, two social workers) and years in profession (0-34 years). We identified four themes representing the most meaningful aspects of restricted family presence for participants: 1) balancing infection control and family presence; 2) feeling disempowered by hospital and policy-making hierarchies; 3) empathizing with family trauma; and 4) navigating threats to the therapeutic relationship. CONCLUSION: Pediatric intensive care unit clinicians were impacted by restricted family presence policies during the COVID-19 pandemic. These policies contributed to feelings of disempowerment and challenged clinicians' perceived ability to provide the best family-centred care possible. Frontline expertise should be incorporated into the design and implementation of policies to best support family-centred care in any context and minimize risks of moral distress for PICU clinicians.

RéSUMé: OBJECTIF: Les unités de soins intensifs pédiatriques (USIP) du monde entier ont restreint la présence des familles en réponse à la la pandémie de COVID-19. Notre objectif était d'explorer les expériences et l'impact des politiques de restriction de la présence familiale sur les clinicien·nes des USIP canadiennes. MéTHODE: Nous avons mené une étude qualitative qui a suivi un plan phénoménologique interprétatif. Les participant·es étaient des clinicien·nes des USIP qui dispensaient des soins directs aux patient·es au Canada pendant les périodes de présence restreinte des familles en raison de la COVID-19. Nous avons délibérément échantillonné pour obtenir une variation maximale parmi les participant·es à l'enquête qui ont accepté d'être contacté·es pour d'autres recherches sur le même sujet. Des entretiens approfondis ont été menés à distance par téléphone ou par appel vidéo, enregistrés et transcrits. Les entretiens ont été codés de manière inductive et ont fait l'objet d'une analyse thématique. Les thèmes proposés ont été contrôlés par membre par les personnes interrogées. RéSULTATS: Seize cliniciennes et cliniciens des USIP ont passé des entrevues. Les personnes interrogées exerçaient partout au Canada, représentaient un éventail de disciplines (huit infirmiers et infirmières, deux médecins, deux inhalothérapeutes, deux spécialistes du milieu de l'enfant, deux travailleuses et travailleurs sociaux) et d'années d'expérience professionnelle (de 0 à 34 ans). Nous avons identifié quatre thèmes représentant les aspects les plus significatifs de la présence restreinte de la famille pour les participant·es : 1) l'équilibre entre la prévention des infections et la présence de la famille; 2) le sentiment d'être dépossédé·e par les hiérarchies de l'hôpital et de ne pas pouvoir participer à l'élaboration des politiques; 3) le sentiment d'empathie à l'égard des traumatismes familiaux; et 4) la réponse aux menaces qui ont pesé sur la relation thérapeutique. CONCLUSION: Les cliniciens et cliniciennes des unités de soins intensifs pédiatriques ont été touché·es par les politiques de restriction de la présence familiale pendant la pandémie de COVID-19. Ces politiques ont contribué à un sentiment d'impuissance et ont remis en question la capacité perçue des équipes à fournir les meilleurs soins possibles axés sur la famille. L'expertise de première ligne devrait être intégrée à la conception et à la mise en œuvre des politiques afin de mieux soutenir les soins axés sur la famille dans n'importe quel contexte et de minimiser les risques de détresse morale pour les cliniciennes et cliniciens des USIP.

AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich's ataxia.

Friedreich's ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progresses to heart failure and death. The potential to reverse or prevent progression of the cardiac phenotype of FRDA was investigated in a mouse model of FRDA, using an adeno-associated viral vector (AAV8) containing the coding sequence of the FXN gene. The Fxnflox/null::MCK-Cre conditional knockout mouse (FXN-MCK) has an FXN gene ablation that prevents FXN expression in cardiac and skeletal muscle, leading to cardiac insufficiency, weight loss, and morbidity. FXN-MCK mice received a single intravenous injection of an AAV8 vector containing human (hFXN) or mouse (mFXN) FXN genes under the control of a phosphoglycerate kinase promoter. Compared to vehicle-treated FXN-MCK control mice, AAV-treated FXN-MCK mice displayed increases in body weight, reversal of cardiac deficits, and increases in survival without apparent toxicity in the heart or liver for up to 12 weeks postdose. FXN protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy.

Using wearable technology data to explain recreational running injury: A prospective longitudinal feasibility study.

OBJECTIVES: Investigate 1) if collecting and analysing wristwatch inertial measurement unit (IMU) and global positioning system (GPS) data using a commercially-available training platform was feasible in recreational runners and 2) which variables were associated with subsequent injury. DESIGN: Prospective longitudinal cohort. PARTICIPANTS: Healthy recreational runners. MAIN OUTCOME MEASURES: We set a priori feasibility thresholds for recruitment (maximum six-months), acceptance (minimum 80%), adherence (minimum 70%), and data collection (minimum 80%). Participants completed three patient-reported outcome measures (PROMS) detailing their psychological health, sleep quality, and intrinsic motivation to run. We extracted baseline anthropometric, biomechanical, metabolic, and training load data from their IMU/GPS wristwatch for analysis. Participants completed a weekly injury status surveillance questionnaire over the next 12-weeks. Feasibility outcomes were analysed descriptively and injured versus non-injured group differences with 95% confidence intervals were calculated for PROM/IMU/GPS data. RESULTS: 149 participants consented; 86 participants completed (55 men, 31 women); 21 developed an injury (0.46 injuries/1000km). Feasibility outcomes were satisfied (recruitment = 47 days; acceptance = 133/149 [89%]; adherence = 93/133 [70%]; data collection = 86/93 [92%]). Acute load by calculated effort was associated with subsequent injury (mean difference -562.14, 95% CI -1019.42, -21.53). CONCLUSION: Collecting and analysing wristwatch IMU/GPS data using a commercially-available training platform was feasible in recreational runners.

A survey of pediatric intensive care unit clinician experience with restricted family presence during COVID-19.

PURPOSE: Limiting family presence runs counter to the family-centred values of Canadian pediatric intensive care units (PICUs). This study explores how implementing and enforcing COVID-19-related restricted family presence (RFP) policies impacted PICU clinicians nationally. METHODS: We conducted a cross-sectional, online, self-administered survey of Canadian PICU clinicians to assess experience and opinions of restrictions, moral distress (Moral Distress Thermometer, range 0-10), and mental health impacts (Impact of Event Scale [IES], range 0-75 and attributable stress [five-point Likert scale]). For analysis, we used descriptive statistics, multivariate regression modelling, and a general inductive approach for free text. RESULTS: Representing 17/19 Canadian PICUs, 368 of 388 respondents (94%) experienced RFP policies and were predominantly female (333/368, 91%), English speaking (338/368, 92%), and nurses (240/368, 65%). The mean (standard deviation [SD]) reported moral distress score was 4.5 (2.4) and was associated with perceived differential impact on families. The mean (SD) total IES score was 29.7 (10.5), suggesting moderate traumatic stress with 56% (176/317) reporting increased/significantly increased stress from restrictions related to separating families, denying access, and concern for family impacts. Incongruence between RFP policies/practices and PICU values was perceived by 66% of respondents (217/330). Most respondents (235/330, 71%) felt their opinions were not valued when implementing policies. Though respondents perceived that restrictions were implemented for the benefit of clinicians (252/332, 76%) and to protect families (236/315, 75%), 57% (188/332) disagreed that their RFP experience was mainly positive. CONCLUSION: Pediatric intensive care unit-based RFP rules, largely designed and implemented without bedside clinician input, caused increased psychological burden for clinicians, characterized as moderate moral distress and trauma triggered by perceived impacts on families.

RéSUMé: OBJECTIF: Limiter la présence de la famille va à l'encontre des valeurs centrées sur la famille des unités de soins intensifs pédiatriques (USIP) canadiennes. Cette étude explore comment la mise en œuvre et l'application des politiques de restriction de la présence familiale liées à la COVID-19 ont eu une incidence sur les cliniciennes et cliniciens des USIP à l'échelle nationale. MéTHODE: Nous avons mené un sondage transversal, en ligne et auto-administré auprès des cliniciens et cliniciennes des USIP canadiennes afin d'évaluer leur expérience et opinions sur les restrictions, la détresse morale (thermomètre de détresse morale, intervalle de 0 à 10) et les impacts sur la santé mentale (échelle d'impact des événements [EIE], intervalle de 0 à 75, et le stress qui peut y être attribué [échelle de Likert à cinq points]). Pour l'analyse, nous avons utilisé des statistiques descriptives, une modélisation de régression multivariée et une analyse inductive générale pour le texte libre. RéSULTATS: Représentant 17/19 USIP canadiennes, 368 des 388 personnes répondantes (94 %) ont vécu des politiques de restriction de la présence familiale et étaient principalement des femmes (333/368, 91 %), anglophones (338/368, 92 %) et infirmières (240/368, 65 %). Le score moyen (écart type [ET]) rapporté de détresse morale était de 4,5 (2,4) et était associé à l'impact différentiel perçu sur les familles. Le score moyen (ET) total de l'EIE était de 29,7 (10,5), ce qui suggère un stress traumatique modéré, 56 % (176/317) des personnes répondantes déclarant une augmentation ou une augmentation significative du stress associé aux restrictions liées à la séparation des familles, au refus d'accès et à la préoccupation pour les impacts familiaux. L'incongruité entre les politiques et les pratiques de restriction des visites familiales et les valeurs des USIP était perçue par 66 % des personnes répondantes (217/330). La plupart (235/330, 71 %) estimaient que leurs opinions n'étaient pas prises en compte lors de la mise en œuvre de politiques. Bien que les répondant·es aient perçu que les restrictions avaient été mises en œuvre dans l'intérêt des cliniciens et cliniciennes (252/332, 76 %) et pour protéger les familles (236/315, 75 %), 57 % (188/332) n'étaient pas d'accord pour dire que leur expérience de la restriction des visites familiales était principalement positive. CONCLUSION: Les règles de restriction de la présence familiale dans les unités de soins intensifs pédiatriques, en grande partie conçues et mises en œuvre sans l'avis du personnel clinique au chevet des patient·es, ont entraîné une augmentation du fardeau psychologique pour le personnel clinique, caractérisée par une détresse morale modérée et un traumatisme déclenché par des répercussions perçues sur les familles.

"Live a normal life": Constructions of resilience among people in mixed HIV status relationships in Canada.

Positive Plus One is a mixed-methods study of long-term mixed HIV-serostatus relationships in Canada (2016-19). Qualitative interviews with 51 participants (10 women, 41 men, including 27 HIV-positive and 24 HIV-negative partners) were analyzed using inductive thematic analysis to examine notions of relationship resilience in the context of emerging HIV social campaigns. Relationship resilience meant finding ways to build and enact life as a normal couple, that is, a couple not noticeably affected by HIV, linked to the partner with HIV maintaining viral suppression and achieving "undetectable = untransmittable" (U = U). Regardless of serostatus, participants with material resources, social networks, and specialized care were better able to construct resilience for HIV-related challenges within their relationships. Compared to heterosexual couples and those facing socioeconomic adversity, gay and bisexual couples were easier able to disclose, and access capital, networks and resources supporting resilience. We conclude that important pathways of constructing, shaping, and maintaining resilience were influenced by the timing of HIV diagnosis in the relationship, access to HIV-related information and services, disclosure, stigma and social acceptance.

"I want to be there. I have to be there.": Parents' perceived barriers and facilitators to bedside presence in the pediatric intensive care unit.

Introduction: Parental presence at the bedside during a stressful pediatric intensive care unit (PICU) admission may improve child comfort, reduce parental anxiety, and enable family engagement. We performed this study to identify factors that parents perceive impact their capability, opportunity, and motivation to be at the bedside in PICU. Methods: We conducted a qualitative descriptive study using semi-structured interviews based on the Theoretical Domains Framework (TDF). We included parents of children admitted to the PICU for at least 24 h at IWK Health in Nova Scotia, Canada. Interviews were coded independently by two researchers using a directed content approach based on the TDF. We generated themes and subthemes, with the subthemes identified as factors impacting parental presence, and assigned TDF domains to each of the subthemes. Results: Fourteen primary caregivers (8 mother figures, 6 father figures) participated in 11 interviews. The factors associated with parental presence were captured by 6 themes: Understanding the Medicalized Child; Maintaining the Parent Role; Life Beyond the Hospital; Parental Intrinsic Responses and Coping; Support Structures; and The PICU Environment. Fifty-two barriers and enablers were identified within 13 TDF domains; 10 TDF domains were determined to be relevant to parental presence, which may be used to guide design of future interventions. Participants emphasized the importance of self-care to enable them to remain physically at their child's bedside and to be engaged in their care. Conclusions: Parents perceive multiple factors within 6 themes act as barriers or enablers to presence with their critically ill child in the PICU. Guided by relevant TDF domains, interventions may be designed to optimize presence, particularly engaged presence, which may improve health-related outcomes of children and their parents.

"We Aren't Meant to Go Through the Hardest Parts of Our Lives Alone": Family Experience With Restricted PICU Presence During the COVID-19 Pandemic.

CONTEXT: PICUs across Canada restricted family presence (RFP) in response to the COVID-19 pandemic from allowing two or more family members to often only one family member at the bedside. The objective of this study was to describe the experiences and impact of RFP on families of critically ill children to inform future policy and practice. HYPOTHESIS: RFP policies negatively impacted families of PICU patients and caused moral distress. METHODS AND MODELS: National, cross-sectional, online, self-administered survey. Family members of children admitted to a Canadian PICU between March 2020 and February 2021 were invited to complete the survey. RFP-attributable distress was measured with a modified distress thermometer (0-10). Closed-ended questions were reported with descriptive statistics and multivariable linear regression assessed factors associated with RFP-attributable distress. Open-ended questions were analyzed using inductive content analysis. RESULTS: Of 250 respondents who experienced RFP, 124 (49.6%) were restricted to one family member at the bedside. The median amount of distress that families attributed to RFP policies was 6 (range: 0-10). Families described isolation, removal of supports, and perception of trauma related to RFP. Most families (183, 73.2%) felt that policies were enforced in a way that made them feel valued by PICU clinicians, which was associated with less RFP-attributable distress. Differential impact was seen where families with lower household income indicated higher RFP-attributable distress score (2.35; 95% CI, 0.53-4.17; p = 0.03). Most respondents suggested that future policies should allow at least two family members at the bedside. INTERPRETATIONS AND CONCLUSIONS: Families of children admitted to PICUs during the COVID-19 pandemic described increased distress, trauma, and removal of supports due to RFP policies. Vulnerable families showed an increased odds of higher distress. Healthcare professionals played an important role in mitigating distress. Allowance of at least two family members at the bedside should be considered for future policy.

Outcomes associated with family presence at the bedside of critically ill children in the pediatric intensive care unit: a scoping review protocol.

OBJECTIVE: The objective of this review is to identify the outcomes of family presence at the bedside of critically ill children in pediatric intensive care units (PICUs) that have been reported in the literature. INTRODUCTION: PICU admission is traumatic for critically ill children and their family members, and family presence may alleviate negative outcomes. Family presence may change with family member, patient, health care provider, and institutional circumstances. Prior to designing studies to assess the outcomes of family presence at the bedside, or to conducting a systematic review of the literature, a scoping review is needed to systematically identify and map the outcomes for stakeholders. INCLUSION CRITERIA: This review will include literature addressing outcomes of family presence at the bedside in the PICU on the patient, family members, and health care providers. Emotional, social, psychological, and physiological outcomes will be considered, including outcomes on the provision of PICU care. METHODS: A systematic search will be undertaken across four databases and several sources of gray literature. The review will not be restricted by language, and will be limited to sources published after 1960. The search strategy was designed using text words from titles and abstracts of relevant studies. Title and abstract screening, followed by full text assessment of sources against inclusion criteria, will be completed in duplicate. Data will be extracted by two independent reviewers using a data extraction tool developed by the study team. Data will be presented in tabular format to address findings related to the review objectives.

Family presence in Canadian PICUs during the COVID-19 pandemic: a mixed-methods environmental scan of policy and practice.

BACKGROUND: Despite their broad commitment to family-centred care, children's hospitals and associated pediatric intensive care units (PICUs) restricted family presence during the COVID-19 pandemic. This study aimed to describe family presence policies and practices in Canadian PICUs from March to May 2020, and their evolution by August to December 2020. METHODS: We conducted an environmental scan of family presence policies and restrictions in all 19 Canadian PICUs using 2 methods. We conducted a literature review of public-facing visitation policy documents in June 2020 using a standardized data extraction form. We also administered a cross-sectional survey of PICU leadership (managers and physician chiefs) between August and December 2020 by telephone or videoconferencing. We used inductive content analysis to code qualitative data, generating summative count data. We analyzed quantitative data descriptively. RESULTS: As part of the literature search, we collected 2 (12%) PICU-specific, 14 (82%) pediatric-specific and 1 (6%) hospital-wide visitation policy documents from the early pandemic. One policy document provided guidance on all of the policy elements sought; the number of enabled caregivers was not included in the documents for 7 of 19 units (37%). All 19 Canadian PICUs were represented among the 24 survey respondents (15 physician chiefs and 9 operations or clinical managers). Before the COVID-19 pandemic, all units allowed the presence of 2 or more family members. Early in the pandemic, reported practices limited the number of adult caregivers for patients without SARS-CoV-2 infection to 1 (n = 21/24, 88%) or 2 (n = 3/24, 12%); all units prohibited siblings. Some centres restricted caregivers from switching bedside presence with one another (patients without SARS-CoV-2 infection: n = 16/23, 70%; patients with confirmed or suspected SARS-CoV-2 infection: n = 20/23, 87%); leaving their child's PICU room (patients without SARS-CoV-2 infection: n = 1/24, 4%; patients with confirmed or suspected SARS-CoV-2 infection: n = 16/24, 67%); and joining in-person rounds (patients without SARS-CoV-2 infection: n = 9/22, 41%; patients with confirmed or suspected SARS-CoV-2 infection: n = 17/22, 77%). All respondents endorsed policy exceptions during end-of-life care. Some reported policies and practices were adapted over the study period. INTERPRETATION: Early COVID-19-related family presence policies in Canadian PICUs varied among centres. Although some centres adapted policies and practices, this study revealed ongoing potential threats to family centred care at the mid-pandemic stage.

Dual pharmaceutical citizenship: Exploring biomedicalization in the daily lives of mixed HIV-serostatus couples in Canada.

Positive Plus One is the first large-scale mixed methods study of mixed HIV serostatus couples in Canada. We aimed to understand how biomedicalization i.e., a social process of commodification and expansion of the jurisdiction of medicine over health, influenced the everyday relationships of these couples. We completed 51 semi-structured interviews among a purposive sample of HIV-positive (n = 27) and HIV-negative (n = 24) partners in current or past mixed-serostatus relationships. Participants were recruited after completing an online survey where they consented to be re-contacted for qualitative interviews. Participants represented a diversity of sexual orientations, gender identities, and other sociodemographic characteristics. Drawing on inductive thematic analysis to identify patterns within couples, across serostatus and sexual orientations, we argue that everyday lives of mixed-serostatus couples were shaped by biomedical knowledge and enacted through routine adherence to obtain and maintain viral load undetectability. Our findings illustrated the importance of learning biomedical knowledge for mixed-serostatus couples in this study, the empowering influence of undetectable = untransmittable (UU) discourse, and its role in rendering HIV mundane through routine ART adherence. We introduce the concept of 'dual pharmaceutical citizenship' to underscore a process by which particular biopolitical and biomedical expectations are fulfilled in mixed-serostatus relationships. These findings have implications for people who do not readily accept or have access to biomedical knowledge, particularly when treatment-as-prevention frames a "right" and "wrong" approach to HIV management. Future studies should focus on couples where at least one partner does not readily accept or have access to biomedical knowledge.

Evidence of enhanced reproductive performance and lack-of-fitness costs among soybean aphids, Aphis glycines, with varying levels of pyrethroid resistance.

BACKGROUND: Foliar application of insecticides is the main strategy to manage soybean aphid, Aphis glycines (Hemiptera: Aphididae), in the northcentral United States. Subpopulations of A. glycines have multiple nonsynonymous mutations in the voltage-gated sodium channel (vgsc) genes that are associated with pyrethroid resistance. We explored if fitness costs are associated with phenotypes conferred by vgsc mutations using life table analyses. We predicted that there would be significant differences between pyrethroid susceptibility and field-collected, parthenogenetic isofemale clones with differing, nonsynonymous mutations in vgsc genes. RESULTS: Estimated resistance ratios for the pyrethroid-resistant clones ranged from 3.1 to 37.58 and 5.6 to 53.91 for lambda-cyhalothrin and bifenthrin, respectively. Although life table analyses revealed some biological and demographic parameters to be significantly different among the clonal lines, there was no association between levels of pyrethroid resistance and a decline in fitness. By contrast, one of the most resistant clonal lines (SBA-MN1-2017) had a significantly higher finite rate of increase, intrinsic rate of increase and greater overall fitness compared to the susceptible control and other pyrethroid-resistant clonal lines. CONCLUSIONS: Our life history analysis suggests that there are no negative pleotropic effects associated with the pyrethroid resistance in the clonal A. glycines lines used in this study. We discuss the potential impact of these results on efficacies of insecticide resistance management (IRM) and integrated pest management (IPM) plans directed at delaying the spread of pyrethroid-resistant A. glycines.

Movement strategy correspondence across jumping and cutting tasks after anterior cruciate ligament reconstruction.

There are currently a multitude of tests used to assess readiness to return to sport (RTS) following anterior cruciate ligament reconstruction (ACLR). The aim of this study was to establish the extent to which movement strategies transfer between three common assessment tasks to help improve design of athlete testing batteries following ACLR. A cohort of 127 male patients 8-10 months post-ACLR and 45 non-injured controls took part in the study. Three movement tasks were completed (unilateral and bilateral drop jump, and 90° pre-planned cut), while ground reaction forces and three-dimensional kinematics (250 Hz) were recorded. Compared to the bilateral drop jump and cut, the unilateral drop jump had a higher proportion of work done at the ankle (d = 0.29, p < 0.001 and d = -1.87, p < 0.001, respectively), and a lower proportion of work done at the knee during the braking phase of the task (d = 0.447, p < 0.001 and d = 1.56, p < 0.001, respectively). The ACLR group had higher peak hip moments than the non-injured controls, although the proportion of work done at the ankle, knee and hip joints were similar. Movement strategies were moderately and positively related at the ankle (rs  = 0.728, p < 0.001), knee (rs  = 0.638, p < 0.001) and hip (rs  = 0.593, p < 0.001) between the unilateral and bilateral drop jump, but there was no relationship at the ankle (rs  = 0.10, p = 0.104), knee (rs  = 0.106, p = 0.166) and hip (rs  = -0.019, p = 0.808) between the unilateral drop jump and the cut. Clinicians could therefore consider omitting one of the drop jumps from assessment batteries but should include both jumping and cutting tasks.

Ruxolitinib Inhibits IFNγ Licensing of Human Bone Marrow Derived Mesenchymal Stromal Cells.

Ruxolitinib is a JAK2/JAK1 inhibitor that blocks the inflammatory JAK-STAT signaling pathway. Ruxolitinib has been demonstrated to be effective in the treatment of steroid-resistant acute graft-versus-host disease (GVHD). Ruxolitinib's effect on inflammatory cells of hematopoietic origin is known. However, its effect on nonhematopoietic cell types with immune-modulating and antigen-presenting cell competency plausibly involved in pathogenesis of GVHD has not been explored. Mesenchymal stromal cells (MSCs) are CD45- nonhematopoietic cells of the bone marrow with immune modulatory functions in vivo. MSCs' immunobiology largely depends on their responsiveness to IFNγ. We aimed to define the effect of ruxolitinib on the immunobiology of MSCs that are modulated by IFNγ. Human bone marrow derived MSCs, peripheral blood mononuclear cells (PBMCs), and primary bone marrow aspirates were analyzed for their sensitivity to ruxolitinib-mediated blocking of IFNγ-induced STAT-1 phosphorylation and downstream effector molecules, utilizing Western blot, flow cytometry, secretome analysis, and phosflow techniques. IFNγ-induced cytostatic effects on MSCs are reversed by ruxolitinib. Ruxolitinib inhibits IFNγ and secretome of activated peripheral PBMC-induced STAT-1 phosphorylation on human bone marrow derived MSCs. In addition, ruxolitinib inhibits IFNγ-induced pro-GVHD pathways on MSCs, which includes HLAABC(MHCI), HLADR(MHCII), CX3CL1, and CCL2. IFNγ-induced immunosuppressive molecules IDO and PDL-1 were also inhibited by ruxolitinib on MSCs. Comparative analysis with PBMCs has demonstrated that MSCs are as equal as to HLADR+ PBMC populations in responding to ruxolitinib-mediated inhibition of IFNγ-induced STAT-1 phosphorylation. Ex vivo analysis of human marrow aspirates has demonstrated that ruxolitinib blocks IFNγ-induced STAT-1 phosphorylation in CD45+/-HLADR+/- populations at different levels, which is depending on their sensitivity to IFNγ responsiveness. These results inform the hypothesis that ruxolitinib's immune-modulatory effects in vivo may pharmacologically involve marrow and tissue-resident MSCs. Ruxolitinib affects the immunobiology of MSCs equivalent to professional HLADR+ antigen presenting cells, which collectively mitigate GVHD.

Assessment of the Welfare of Experimental Cattle and Pigs Using the Animal Welfare Assessment Grid.

The Animal Welfare Assessment Grid (AWAG) is a method for assessing quality of life, originally designed for experimental primates. This study adapts the AWAG for use in cattle and pigs, by adapting the factors included for these species and including data which had been collected previously as the standard approach to monitoring these species in research. The intention is that the results presented here will allow the future data collected for experimental cattle and pigs to be optimised for inclusion in an AWAG. Data were collected from two vaccine assessment studies at the Pirbright Institute. Factors were scored for every recorded event using retrospective data and CCTV clips. There was a lack of behavioural data recorded in both studies, which limited the accuracy of assessing each animal's welfare. This paper emphasises the importance of including behavioural information when assessing welfare and not simply relying on assessment of physical condition. Scores peaked following an exponential rise as animals reached set humane end points. This demonstrated the potential of using the AWAG to aid the decision-making of when euthanasia should be performed. Our study shows the AWAG to be a useful tool for assessing welfare, which can be used in harm:benefit assessment.

VE-1902-A direct thrombin inhibitor with reversible covalent mechanism of action shows efficacy with reduced bleeding in rodent models of thrombosis.

INTRODUCTION: High incidence of bleeding events remains a key risk for patients taking anticoagulants, especially those in need of long-term combination therapy with antiplatelet agents. As a consequence, patients may not receive clinically indicated combination antithrombotic therapy. Here, we report on VE-1902, a member of a novel class of precision oral anticoagulants (PROACs) that combines effective anticoagulation with reduced bleeding in preclinical testing. METHODS AND RESULTS: Acting through covalent, reversible active-site modification of thrombin similar to a previously described molecule [1], VE-1902 shows potency and selectivity for thrombin inhibition in human plasma comparable to clinically relevant direct thrombin inhibitors (DTI) such as argatroban and dabigatran (thrombin generation assay ETP EC50 = 1.3 µM compared to 0.36 µM and 0.31 µM for argatroban and dabigatran; >100-fold selectivity against related serine proteases). Unlike the current anticoagulants, VE-1902 does not significantly inhibit thrombin-mediated platelet activation in in vivo models of thrombosis. In the thrombin generation assay, the compound inhibits thrombin formation without significantly delaying the initiation phase of the clotting cascade. These features are possibly responsible for the observed reduced bleeding in tail bleeding and saphenous vein bleeding models. Consistent with this novel pharmacological profile, VE-1902 shows efficacious anticoagulation in several fibrin-driven animal models of thrombosis (arteriovenous shunt, venous stasis thrombosis, and thrombin-induced thromboembolism models), whereas it does not significantly prevent arterial occlusion in the platelet dependent FeCl3 model. CONCLUSIONS: By leaving platelet activation following vascular injury mostly unaffected, VE-1902, and the PROACs more generally, represent a new generation of precision anticoagulants with reduced bleeding risk.

Technologies of trust in epidemic response: openness, reflexivity and accountability during the 2014-2016 Ebola outbreak in West Africa.

Trust is an essential component of successful cooperative endeavours. The global health response to the 2014-2016 West Africa Ebola outbreak confronted historically tenuous regional relationships of trust. Challenging sociopolitical contexts and initially inappropriate communication strategies impeded trustworthy relationships between communities and responders during the epidemic. Social scientists affiliated with the Ebola 100-Institut Pasteur project interviewed approximately 160 local, national and international responders holding a wide variety of roles during the epidemic. Focusing on responder's experiences of communities' trust during the epidemic, this qualitative study identifies and explores social techniques for effective emergency response. The response required individuals with diverse knowledges and experiences. Responders' included on-the-ground social mobilisers, health workers and clinicians, government officials, ambulance drivers, contact tracers and many more. We find that trust was fostered through open, transparent and reflexive communication that was adaptive and accountable to community-led response efforts and to real-time priorities. We expand on these findings to identify 'technologies of trust' that can be used to promote actively legitimate trustworthy relationships. Responders engaged the social technologies of openness (a willingness and genuine effort to incorporate multiple perspectives), reflexivity (flexibly responsive to context and ongoing dialogue) and accountability (taking responsibility for local contexts and consequences) to facilitate relations of trust. Technologies of trust contribute to the development of a framework of practical techniques to improve the acceptance and effectiveness of future emergency response strategies.

The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT.

FGFR1 has been implicated in numerous cancer types including squamous cell lung cancer, a subset of non-small cell lung cancer with a dismal 5-year survival rate. Small-molecule inhibitors targeting FGFR1 are currently in clinical trials, with AZD4547 being one of the furthest along; however, the development of drug resistance is a major challenge for targeted therapies. A prevalent mechanism of drug resistance in kinases occurs through mutation of the gatekeeper residue, V561M in FGFR1; however, mechanisms underlying V561M resistance to AZD4547 are not fully understood. Here, the cellular consequences of the V561M gatekeeper mutation were characterized, and it was found that although AZD4547 maintains nanomolar affinity for V561M FGFR1, based on in vitro binding assays, cells expressing V561M demonstrate dramatic resistance to AZD4547 driven by increased STAT3 activation downstream of V561M FGFR1. The data reveal that the V561M mutation biases cells toward a more mesenchymal phenotype, including increased levels of proliferation, migration, invasion, and anchorage-independent growth, which was confirmed using CyTOF, a novel single-cell analysis tool. Using shRNA knockdown, loss of STAT3 restored sensitivity of cancer cells expressing V561M FGFR1 to AZD4547. Thus, the data demonstrate that combination therapies including FGFR and STAT3 may overcome V561M FGFR1-driven drug resistance in the clinic. IMPLICATIONS: The V561M FGFR1 gatekeeper mutation leads to devastating drug resistance through activation of STAT3 and the epithelial-mesenchymal transition; this study demonstrates that FGFR1 inhibitor sensitivity can be restored upon STAT3 knockdown.

Humans Optimize Ground Contact Time and Leg Stiffness to Minimize the Metabolic Cost of Running.

Trained endurance runners appear to fine-tune running mechanics to minimize metabolic cost. Referred to as self-optimization, the support for this concept has primarily been collated from only a few gait (e.g., stride frequency, length) and physiological (e.g., oxygen consumption, heart rate) characteristics. To extend our understanding, the aim of this study was to examine the effect of manipulating ground contact time on the metabolic cost of running in trained endurance runners. Additionally, the relationships between metabolic cost, and leg stiffness and perceived effort were examined. Ten participants completed 5 × 6-min treadmill running conditions. Self-selected ground contact time and step frequency were determined during habitual running, which was followed by ground contact times being increased or decreased in four subsequent conditions whilst maintaining step frequency (2.67 ± 0.15 Hz). The same self-selected running velocity was used across all conditions for each participant (12.7 ± 1.6 km · h-1). Oxygen consumption was used to compute the metabolic cost of running and ratings of perceived exertion (RPE) were recorded for each run. Ground contact time and step frequency were used to estimate leg stiffness. Identifiable minimums and a curvilinear relationship between ground contact time and metabolic cost was found for all runners (r 2 = 0.84). A similar relationship was observed between leg stiffness and metabolic cost (r 2 = 0.83). Most (90%) runners self-selected a ground contact time and leg stiffness that produced metabolic costs within 5% of their mathematical optimal. The majority (n = 6) of self-selected ground contact times were shorter than mathematical optimals, whilst the majority (n = 7) of self-selected leg stiffness' were higher than mathematical optimals. Metabolic cost and RPE were moderately associated (r s = 0.358 p = 0.011), but controlling for condition (habitual/manipulated) weakened this relationship (r s = 0.302, p = 0.035). Both ground contact time and leg stiffness appear to be self-optimized characteristics, as trained runners were operating at or close to their mathematical optimal. The majority of runners favored a self-selected gait that may rely on elastic energy storage and release due to shorter ground contact times and higher leg stiffness's than optimal. Using RPE as a surrogate measure of metabolic cost during manipulated running gait is not recommended.

Establishing Teams: How Does It Change Practice Configuration, Size, and Composition?

Little is known about how practices reorganize when transitioning from traditional practice organization to team-based care. We compared practice-level (1) configuration as well as practice- and team-level (2) size and (3) composition, before and after establishing teams. We employed a pre-/poststudy using personnel lists of 1571 to 1711 staff (eg, job licenses, titles, and team assignment) and practice manager surveys. All personnel (physician and nonphysician) worked within 18 Massachusetts academic primary care practices participating in a 2-year learning collaborative aimed at establishing team-based care. We found that establishing team-based care can involve changing practice configurations and composition without substantially changing practice size.