Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity

Utilising electrodermal activity sensor signals to quantify nociceptive response during movement activities

ObjectiveWith an increasingly ageing population and osteoarthritis prevalence, the quantification of nociceptive signals responsible for painful movements and individual responses could lead to better treatment and monitoring solutions. Changes in electrodermal activity (EDA) can be detected via changes in skin conductance (SC) and measured using finger electrodes on a wearable sensor, providing objective information for increased physiological stress response.ResultsTo provide EDA response preliminary data, this was recorded with healthy volunteers on an array of activities while receiving a noxious stimulus. This provides a defined scenario that can be utilised as protocol feasibility testing. Raw signal extraction, processing and statistical analysis was performed using mean SC values on all participant data. Extra exploratory analysis on a case study was incorporated using various decomposition tools. The application of the stimuli resulted in a 35% average increase in mean SC with considerable gender differences in SC and self-reported pain scores. Though EDA parameters are a promising tool for nociceptive response indicators, limitations including motion artifact sensitivities and lack of previous movement-based EDA published data result in restricted analysis understanding. Refined processing pipelines with signal decomposition tools will be necessary to incorporate into a protocol that quantifies nociceptive response clinically meaningfully

Utilising electrodermal activity sensor signals to quantify nociceptive response during movement activities

ObjectiveWith an increasingly ageing population and osteoarthritis prevalence, the quantification of nociceptive signals responsible for painful movements and individual responses could lead to better treatment and monitoring solutions. Changes in electrodermal activity (EDA) can be detected via changes in skin conductance (SC) and measured using finger electrodes on a wearable sensor, providing objective information for increased physiological stress response.ResultsTo provide EDA response preliminary data, this was recorded with healthy volunteers on an array of activities while receiving a noxious stimulus. This provides a defined scenario that can be utilised as protocol feasibility testing. Raw signal extraction, processing and statistical analysis was performed using mean SC values on all participant data. Extra exploratory analysis on a case study was incorporated using various decomposition tools. The application of the stimuli resulted in a 35% average increase in mean SC with considerable gender differences in SC and self-reported pain scores. Though EDA parameters are a promising tool for nociceptive response indicators, limitations including motion artifact sensitivities and lack of previous movement-based EDA published data result in restricted analysis understanding. Refined processing pipelines with signal decomposition tools will be necessary to incorporate into a protocol that quantifies nociceptive response clinically meaningfully

Experiencing event management during the coronavirus pandemic: a public sector perspective

Events have played a significant role in the way in which the Coronavirus pandemic has been experienced and known around the world. Little is known though about how the pandemic has impacted on supporting, managing and governing events in municipal (i.e., local) authorities as key stakeholders, nor how events have featured in the opening-up of localities. This paper reports on empirical research with senior events officers for local authorities in the UK on these key knowledge gaps. Specifically, it examines events officers' unfolding experiences of the pandemic. The paper points to unpreparedness for a crisis of this scale and magnitude, and the roles of innovation, adaptation and co-production in the emergent response. It highlights the transformative nature of the pandemic through reconsiderations of the purpose of public sector involvement in events and, from a policy perspective, how relatively smaller-scale, more agile and lower-risk arts events and performances can figure in local recovery. Finally, while the effects on, and response of, the body corporate (the local authority) to crises is an obvious focus, it is important to recognise those of the individuals who manage the response and drive change

Refinement of an Educational Toolkit to Promote Cervical Cancer Screening among Hispanic Farmworker Women in Southeast Georgia

Cervical cancer incidence and mortality continue to affect Hispanic women in the U.S. disproportionately. Our project sought to refine a cervical cancer intervention designed for use by community health workers, or promotoras, in rural southern Georgia. We collaborated with Hispanicpromotoras to refine a Spanish language educational flipchart featuring cervical cancer topic areas for use in screening promotion

Arguments for the biological and predictive relevance of the proportional recovery rule

The proportional recovery rule (PRR) posits that most stroke survivors can expect to reduce a fixed proportion of their motor impairment. As a statistical model, the PRR explicitly relates change scores to baseline values - an approach that arises in many scientific domains but has the potential to introduce artifacts and flawed conclusions. We describe approaches that can assess associations between baseline and changes from baseline while avoiding artifacts due either to mathematical coupling or to regression to the mean. We also describe methods that can compare different biological models of recovery. Across several real datasets in stroke recovery, we find evidence for non-artifactual associations between baseline and change, and support for the PRR compared to alternative models. We also introduce a statistical perspective that can be used to assess future models. We conclude that the PRR remains a biologically relevant model of stroke recovery

W-DARE: a three-year program of participatory action research to improve the sexual and reproductive health of women with disabilities in the Philippines

BACKGROUND: In many contexts, women with disability have less access to sexual and reproductive health information, screening, prevention, and care services than women without disability. Women with disability are also known to be more likely to experience physical and sexual violence than women without disability. In the Philippines, health service providers often have little awareness of the sexual and reproductive experiences of women with disability and limited capacity to provide services in response to their needs. Very limited data are available to inform development of disability-inclusive sexual and reproductive health, and violence prevention and response, services in the country. This paper presents the protocol for W-DARE (Women with Disability taking Action on REproductive and sexual health), a three-year program of participatory action research that aims to improve the sexual and reproductive health of women with disability in the Philippines. DESIGN: W-DARE is a disability-inclusive program that will use mixed methods to 1) increase understanding of factors influencing the sexual and reproductive health of women with disability, and 2) develop, implement and evaluate local interventions to increase supply of and demand for services. W-DARE will generate data on the prevalence of disability in two districts; the wellbeing and community participation of people with and without disability, and identify barriers to community; and describe the sexual and reproductive health needs and experiences, and service-related experiences of women with disability. These data will inform the development and evaluation of interventions aiming to improve access to sexual and reproductive health services, and violence prevention and response services, for women with disability. Local women with disabilities, their representative organisations, and SRH service providers will be involved as members of the research team across all stages of the research. DISCUSSION: This three-year study will provide evidence about factors undermining the sexual and reproductive health of women with disability in a lower-middle income country, and provide new insights about what may be effective in increasing access to services in settings of limited resources. Findings will be relevant across Asia and the Pacific. Analysis of the program will also provide evidence about disability-inclusion in participatory action research approaches

Timing of antibiotics, volume, and vasoactive infusions in children with sepsis admitted to intensive care

Introduction: Early administration of antibiotics for sepsis, and of fluid boluses and vasoactive agents for septic shock, is recommended. Evidence for this in children is limited. Methods: The Alberta Sepsis Network prospectively enrolled eligible children admitted to the Pediatric Intensive Care Unit (PICU) with sepsis from 04/2012-10/2014. Demographics, severity of illness, and outcomes variables were prospectively entered into the ASN database after deferred consent. Timing of interventions were determined by retrospective chart review using a study manual and case-report-form. We aimed to determine the association of intervention timing and outcome in children with sepsis. Univariate (t-test and Fisher's Exact) and multiple linear regression statistics evaluated predictors of outcomes of PICU length of stay (LOS) and ventilation days. Results: Seventy-nine children, age median 60 (IQR 22-133) months, 40 (51 %) female, 39 (49 %) with severe underlying co-morbidity, 44 (56 %) with septic shock, and median PRISM-III 10.5 [IQR 6.0-17.0] were enrolled. Most patients presented in an ED: 36 (46 %) at an outlying hospital ED, and 21 (27 %) at the Children's Hospital ED. Most infections were pneumonia with/without empyema (42, 53 %), meningitis (11, 14 %), or bacteremia (10, 13 %). The time from presentation to acceptable antibiotic administration was a median of 115.0 [IQR 59.0-323.0] minutes; 20 (25 %) of patients received their antibiotics in the first hour from presentation. Independent predictors of PICU LOS were PRISM-III, and severe underlying co-morbidity, but not time to antibiotics. In the septic shock subgroup, the volume of fluid boluses given in the first 2 hours was independently associated with longer PICU LOS (effect size 0.22 days; 95 % CI 0.5, 0.38; per ml/kg). Independent predictors of ventilator days were PRISM-III score and severe underlying co-morbidity. In the septic shock subgroup, volume of fluid boluses in the first 2 hours was independently associated with more ventilator days (effect size 0.09 days; 95 % CI 0.02, 0.15; per ml/kg). Conclusion: Higher volume of early fluid boluses in children with sepsis and septic shock was independently associated with longer PICU LOS and ventilator days. More study on the benefits and harms of fluid bolus therapy in children are needed

Utilising electrodermal activity sensor signals to quantify nociceptive response during movement activities

Objective: With an increasingly ageing population and osteoarthritis prevalence, the quantification of nociceptive signals responsible for painful movements and individual responses could lead to better treatment and monitoring solutions. Changes in electrodermal activity (EDA) can be detected via changes in skin conductance (SC) and measured using finger electrodes on a wearable sensor, providing objective information for increased physiological stress response. Results: To provide EDA response preliminary data, this was recorded with healthy volunteers on an array of activities while receiving a noxious stimulus. This provides a defined scenario that can be utilised as protocol feasibility testing. Raw signal extraction, processing and statistical analysis was performed using mean SC values on all participant data. The application of the stimuli resulted in a significant average increase (p < 0.05) in mean SC in four out of five activities with significant gender differences (p < 0.05) in SC and self-reported pain scores and large effect sizes. Though EDA parameters are a promising tool for nociceptive response indicators, limitations including motion artifact sensitivities and lack of previous movement-based EDA published data result in restricted analysis understanding. Refined processing pipelines with signal decomposition tools could be utilised in a protocol that quantifies nociceptive response clinically meaningfully