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Osteoarthritis (OA) is a debilitating condition affecting an individual’s quality of life in multiple ways. However, little is known about about the experiences of täne (men) Māori living with OA in Aotearoa New Zealand. We aimed to explore the lived experiences of ngā tāne Māori with OA. This qualitative study was guided by tikanga and kaupapa Māori philosophies. Interviews were conducted in a semi-structured method, with seven tāne Māori living with OA. Key themes were identified and developed from the data through thematic analysis, and were informed by Tā Mason Durie’s Māori health frameworks, Te Whare Tapa Whā and Te Pae Māhutonga. Four themes developed from the data and were named: (1) The interface of masculine embodiment and mana, (2) Taha whānau and connection as central to ngā tāne Māori wellbeing, (3) The benefits of taha wairua (spiritual wellbeing), and (4) Te urutau kia uru ki te punaha tiaki hauora: Adapting to access the health-care system. OA places a significant burden on ngā tāne Māori and their whānau, impacting on all aspects of hauora (health). The unique lived experiences and impact on wider whānau of Māori living with OA indicates the need to consider te ao Māori (Māori world view) when developing clinical services and a Model of Care for OA.

Physiotherapists’ and general practitioners’ (GPs) treatment knowledge affects the management of people with knee osteoarthritis (OA), but little is known about the OA referral decisions and treatment knowledge of these clinicians in New Zealand. Data were collected from New Zealand registered physiotherapists and GPs (n = 272) using an online vignette-based questionnaire. Approximately two-thirds (63%, n = 172) of participants stated they would likely refer the hypothetical patient with knee OA to another profession. Participants indicated they would refer the woman between the two professions (73%, n = 57 GPs would refer to a physiotherapist; 47%, n = 92 physiotherapists would refer to a GP). However, few participants indicated they would refer the woman to other health professionals (such as 19%, n = 52 would refer to a dietitian). The majority of participants reported they would recommend education (98%, n = 267), therapeutic exercises (92%, n = 251) and weight-loss advice (87%, n = 237) as treatments for knee OA. These results indicate that first-line knee OA treatment knowledge of New Zealand GPs and physiotherapists are generally in keeping within international guidelines. However, promoting interprofessional collaboration with other health professions, such as dietetics, and providing education regarding treatments not recommended for OA is needed to meet all first-line treatment recommendations.

Osteoarthritis (OA) is a prevalent and costly condition. Evidence-based clinical guidelines recommend three core treatments for OA: education, exercise, and weight loss (as appropriate). However, the translation of evidence into practice is limited. Clinical guidelines do not provide information on how to implement recommendations in local care settings. In New Zealand, management of people with OA in primary care is inconsistent and fragmented. Clinicians and researchers have made a call for a New Zealand OA model of care to close this evidence-practice gap and optimise primary care OA management nationwide. A model of care is a condition specific implementation strategy that outlines what care should be funded and delivered, who should provide it, and where and how care should be addressed. Various models of care for OA have been implemented with promising results in Australia, the United Kingdom (UK) and Europe. One programme that is translating guidelines into practice is the Model OsteoArthritis Consultation (MOAC). Empirical evaluations of the MOAC in the UK and Europe have demonstrated greater delivery of core treatments, better service quality, and improved patient outcomes. This article makes a case for piloting the MOAC in New Zealand as an implementation strategy to optimise primary care management of OA.

BACKGROUND AND PURPOSE Prostacyclin mimetics express potent vsoactive effects via prostanoid receptors which are not defined unequivocally, as to date no study has considered sex as a factor. The aim of this study was to determine the contribution of IP and EP3 prostanoid receptors to prostacyclin mimetic Iloprost mediated responses, whether KV 7.1-5 channels represent downstream targets of selective prostacyclin-IP-receptor agonist MRE-269 and the impact of the oestrus cycle on vascular reactivity. EXPERIMENTAL APPROACH Within 2nd order mesenteric arteries (MAs) from male and female Wistar rats, we determined; 1.) relative mRNA transcripts for EP1-4 (Ptger1-4 ), IP (Ptgi) and TXA2 (Tbxa) prostanoid receptors via RT-qPCR; 2.) The effect of Iloprost, MRE-269, isoprenaline and ML277 on pre-contracted arterial tone in the presence of inhibitors of prostanoid receptors, potassium channels and molecular interreference of KV 7.1 via wire-myograph; 3.) Oestrus cycle stage via histological changes in cervical cell preparations. KEY RESULTS Iloprost evoked a bi-phasic response in male MAs, at concentrations ≤100nmol-L-1 relaxing, then contracting the vessel at concentration ≥300nmol-L-1 in a process attributed to IP and EP3 receptors respectively. Secondary contraction was absent in the females, which was associated with a reduction in Ptger3. Pharmacological inhibition and molecular interference of KV 7.1 significantly attenuated relaxations produced by the selective IP-receptor agonist MRE-269 in male and female Wistar in Diestrus /Metoestrous, but not Pro-oestrus/Oestrus. CONCLUSIONS AND IMPLICATIONS Stark sexual dimorphisms in Iloprost mediated vasoactive responses are present within MAs. KV 7.1 is implicated in IP-receptor mediated vasorelaxation and is impaired by the Oestrus cycle.

Sex hormones and the reproductive cycle (estrus in rodents and menstrual in humans) have a known impact on arterial function. In spite of this, sex hormones and the estrus/menstrual cycle are often neglected experimental factors in vascular basic preclinical scientific research. Recent research by our own laboratory indicates that cyclical changes in serum concentrations of sex -hormones across the rat estrus cycle, primary estradiol, have significant consequences for the subcellular trafficking and function of KV. Vascular potassium channels, including KV, are essential components of vascular reactivity. Our study represents a small part of a growing field of literature aimed at determining the role of sex hormones in regulating arterial ion channel function. This review covers key findings describing the current understanding of sex hormone regulation of vascular potassium channels, with a focus on KV channels. Further, we highlight areas of research where the estrus cycle should be considered in future studies to determine the consequences of physiological oscillations in concentrations of sex hormones on vascular potassium channel function.

Background and purposeKcnq-encoded KV7 channels (termed KV7.1-5) regulate vascular smooth muscle cell (VSMC) contractility at rest and as downstream targets of receptor mediated responses. However, the current literature focuses predominantly on males. Considering the known impact of sex, the oestrus cycle and sex-hormones on vascular reactivity, the aim of this investigation was to characterise the molecular and functional properties of KV7 within renal and mesenteric arteries from female Wistar rats separated into Di-oestrus and Met-oestrus (F-D/M) and Pro-oestrus and Oestrus (F-P/E).Experimental approachRT-qPCR, immunocytochemistry, proximity-ligation assay and wire myography were performed in renal and mesenteric arteries. Circulating sex-hormone concentrations was determined by liquid chromatography tandem mass-spectrometry. Whole-cell electrophysiology undertaken on cells expressing KV7.4 in association with G-protein coupled Oestrogen receptor 1 (GPER1).Key resultsThe KV7.2-5 activators S-1/ML213 and the pan-KV7 inhibitor Linopirdine were more effective in arteries from F-D/M compared to F-P/E animals. In VSMCs isolated from F-P/E rats, the membrane abundance of KV7.4 but not KV7.1, KV7.5 and Kcne4 was reduced compared to F-D/M cells. Plasma oestradiol was significantly higher in F-P/E compared to F-D/M and progesterone showed the converse pattern. Oestradiol/GPER1 agonist G-1 diminished KV7.4 currents in heterologous expression system and reduced KV7.4 membrane abundance, ML213 relaxations, and interaction between KV7.4 and the molecular chaperone protein, heat shock protein 90 (HSP90), in arteries from F-D/M but not F-P/E.Conclusions and implicationsGPER1 signalling decreases KV7.4 membrane abundance in conjunction with diminished interaction with HSP90, giving rise to a ‘pro-contractile state.’

INTRODUCTION/AIMS We explored correlates of night-time and exercise-associated lower limb cramps in participants of the 1000 Norms Project. METHODS A volunteer community sample of healthy people aged ≥18 y underwent assessment of motor function and physical performance, and were questioned about muscle cramps in the previous 3 mo. RESULTS Of 491 (221 female) participants age 18-101 y (mean: 59.12; SD: 18.03), about 1 in 3 experienced night-time lower limb cramps, and about 1 in 4 experienced exercise-associated lower limb cramps. For night-cramps, a one unit increase in Beighton score (greater whole-body flexibility) was associated with a 31% reduced odds of cramps (odds ratio [OR] = 0.69, 95% confidence interval [CI]:0.45, 0.99) and passing all three lesser-toe strength tests was associated with 50% reduced odds of cramps (OR = 0.50, 95% CI: 0.32, 0.78). For exercise-associated cramps, participants in the fourth (lowest arch) quartile of Foot Posture Index were 2.1 times (95% CI: 1.11, 3.95) more likely to experience cramps than participants in the first (highest arch) quartile. Odds of experiencing both types of cramps versus no cramps were lower with passing all three lesser-toe strength tests (OR = 0.40, 95% CI: 0.19, 0.85) and better performance in the six-minute walk test (OR = 0.997, 95% CI: 0.996, 0.998). DISCUSSION People who experienced both exercise-associated and night-time cramps were less functional. The association between night-time cramps with less whole-body flexibility and reduced lesser-toe flexor strength should be explored to determine causation. Planovalgus (low-arched) foot type was independently associated with exercise-associated cramps. The effectiveness of foot orthoses for secondary prevention of exercise-associated cramps in people with low-arched feet should be explored.

Kcnq-encoded KRT-qPCR, immunocytochemistry, proximity ligation assay and wire myography were performed in renal and mesenteric arteries. Circulating sex hormone concentrations were determined by liquid chromatography-tandem mass spectrometry. Whole-cell electrophysiology was undertaken on cells expressing KThe KGPER1 signalling decreased K

Background The relationship between diet quality and health care costs is unclear. Objective The aim of this study was to investigate the relationship between baseline diet quality and change in diet quality over time, with 15-year cumulative health care claims/costs. Design Data from a longitudinal cohort study were analyzed. Participants/setting Data for survey 3 (2001) (n = 7,868) and survey 7 (2013) (n = 6,349 both time points) from the 1946-1951 cohort of the Australian Longitudinal Study on Women’s Health were analyzed. Main outcome measures Diet quality was assessed using the Australian Recommended Food Score (ARFS). Fifteen-year cumulative Medicare Benefits Schedule (Australia’s universal health care coverage) data were reported by baseline ARFS quintile and category of diet quality change (“diet quality worsened” [ARFS change ≤ –4 points], “remained stable” [–3 ≤ change in ARFS ≤3 points], or “improved” [ARFS change ≥4 points]). Statistical analyses Linear regression analyses were conducted adjusting for area of residence, socioeconomic status, lifestyle factors, and private health insurance status. Results Consuming a greater variety of vegetables at baseline but fewer fruit and dairy products was associated with lower health care costs. For every 1-point increment in the ARFS vegetable subscale, women made 3.3 (95% CI, 1.6-5.0) fewer claims and incurred AU$227 (95% CI, AU$104-350 [US$158; 95% CI, US$72-243]) less in costs. Women whose diet quality worsened over time made more claims (median, 251 claims; quintile 1, quintile 3 [Q1; Q3], 168; 368 claims) and incurred higher costs (AU$15,519; Q1; Q3, AU$9,226; AU$24,847 [US$10,793; Q1; Q3, US$6,417; US$17,281]) compared with those whose diet quality remained stable (median, 236 claims [Q1; Q3, 158; 346 claims], AU$14,515; Q1; Q3, AU$8,539; AU$23,378 [US$10,095; Q1; Q3, US$5,939; US$16,259]). Conclusions Greater vegetable variety was associated with fewer health care claims and costs; however, this trend was not consistent across other subscales. Worsening diet quality over 12 years was linked with higher health care claims and costs.

Introduction: The Living Donor Navigator (LDN) program is one of several initiatives designed to help transplant candidates identify living donors with the help of a friend or family member advocate to speak on their behalf. More than half of advocates in the LDN program were the spouse or parent of the candidate and served in a caregiving role. Caregivers for patients awaiting transplantation have reported poorer quality of life than the general population, suggesting more support is needed for this vulnerable group. The purpose of this study was to understand whether the LDN program met the needs of advocates who were also caregivers for the transplant candidate. Methods: We performed a supplementary secondary qualitative analysis of a parent study conducted December 2017-January 2018 with 9 advocates who participated in the LDN program. Transcripts were reanalyzed from focus group discussions, concentrating on comments about caregiving or made by caregivers. Using manual coding and reflexive thematic analysis, we identified broad codes and major themes. Findings: Our re-analysis revealed one theme overlapping with our previous analysis (Support) and 2 new themes specific to caregiver advocates: Quality of Life and Fear. Caregivers agreed that the LDN program equipped them with tools to address these areas and best serve their simultaneous caregiver/advocate roles. Discussion: These analyses demonstrated that those who served as advocate and caregiver derived a benefit from the LDN program but had distinct needs from other advocates. These findings can inform continued refinement of the program and expansion to support needs of caregiver

Longitudinal fibular deficiency (LFD) is the most common congenital long bone deficiency. This study aimed to objectively assess the physical performance of children and adolescents with LFD compared with unaffected peers, and to examine trends over age for subgroups of the LFD population.Differences between children with LFD and unaffected peers were examined with hand-held dynamometry for lower-limb muscle strength, Six-Minute Walk Test, Timed up and down stairs test, Star Excursion Balance Test, and Standing long jump.Thirty-nine children with LFD and 284 unaffected peers participated. Children with LFD performed at a lower level than their unaffected peers, on all measures of physical performance (mean 2.1Children with LFD performed at a significantly lower level than unaffected peers on all measures of physical performance other than jumping. The largest differences were in older children. This paper provides baseline functional data for future interventions in LFD.Cross-sectional study.Implications for RehabilitationThis paper provides the first baseline functional data using validated objective measures on a consecutive cohort of children and adolescents with longitudinal fibular deficiency.Children with LFD performed significantly worse than their unaffected peers on all measures of physical performance other than jumping, with children falling further behind their peers as they age.Children who undergo an amputation typically have the most severe anatomical presentation and yet perform at an equivalent functional level.This paper identifies multiple modifiable impairments that represent potential opportunities for rehabilitation professionals to target with conservative treatment options to improve functional performance.

The aim of this study was to establish reference values for rate of torque development (RTD) and muscle torque steadiness (MTS) of knee extensors across the lifespan, and evaluate if these measures are independently associated with Osteoarthritis Research Society International (OARSI)-recommended performance-based measures (6-minute walk test, 30-second chair stand test, stair climb test) and other clinical variables.In this cross-sectional observational study, knee extensor strength of 764 participants (12-89 years) from the 1000 Norms Project was assessed via fixed dynamometry. Age- and sex-stratified normative RTD (Nms-1 kg-1) and MTS (Nm kg-1) values were presented as means and 95% confidence intervals. Correlations and multiple regression analyses were calculated to identify factors (age, sex, height, weight, OARSI-recommended performance-based measures, Knee Injury and Osteoarthritis Outcome Score, vertical jump, long jump, grip strength, basic gait-related knee biomechanics) independently associated with RTD or MTS.Age- and sex-stratified normative RTD and MTS reference values were generated. Male subjects exhibited higher RTD but poorer MTS (less steady) than female subjects across all age groups. Better performance in OARSI-recommended performance-based measures, vertical jump, long jump, and grip strength were associated with greater RTD but poorer MTS. Thirty-second chair stand test, stair climb test, vertical jump, long jump, and grip strength were independent determinants of RTD and MTS.The RTD and MTS demonstrated associations with clinical variables relevant to knee osteoarthritis. The normative reference values generated may help identify the presence and extent of impairments in RTD and MTS associated with knee osteoarthritis and assist in developing responsive outcome measures for therapeutic trials.

ObjectivesTo establish normative reference values for work ability in healthy Australian adults using the Work Ability Score and investigate the association of physical performance factors.MethodsThe Work Ability Score was collected from 720 participants aged 18–101 years from the 1000 Norms Project. Physical performance was evaluated by assessing isometric strength of 13 muscle groups; flexibility of six joints; and 11 functional measures categorised as gross motor, fine motor and balance tasks. Correlations and multiple regression analyses were performed to identify physical performance factors independently associated with work ability.ResultsAge-stratified reference values were generated for work ability. Work ability increased during young adulthood (18–44 years) and declined from middle adulthood (45–64 years) into older adulthood (≥65 years), with no sex differences. Greater gross motor function and balance correlated with work ability (r=−0.498 to −0.285; p2=0.333, pConclusionsReference data can be used to identify individuals with low work ability. This study has identified physical factors associated with work ability that can potentially be targeted to maintain longevity in work. Physical tests such as the timed up and down stairs test may assist in the development of objective job-specific screening tools to assess work ability, supplementing subjective evaluation.

Background Pedobarography software calculates the centre-of-pressure trajectory in relation to the foot to quantify foot contact patterns. This study presents two new pedobarography measures using the centre-of-pressure trajectory to assess heel rocker. Methods To validate these pedobarography measures against 3D gait analysis, emed®-x and Vicon Nexus gait analysis data were captured from 25 children aged 8–16 years (11 male) with unilateral (n = 18) and bilateral (n = 7) cerebral palsy or acquired brain injury. 3D gait analysis identified whether heel rocker was intact (n = 22 feet) or absent (n = 28 feet) based on centre-of-pressure at initial contact and the ankle kinematic curve between 0 and 2% of the gait cycle. Pedobarography measures calculated from the initial centre-of-pressure point were the distance to the heel (point of initial contact) and to the most posterior point of the trajectory (rollback), reported as a percentage of foot length. Findings The median point of initial contact in limbs with an intact heel rocker was 9% (range 7–12%) and median rollback was 0% (range 0–0.2%), whereas the median point of initial contact in limbs with an absent heel rocker was 58% (range 8–78%) and rollback was 18% (range 0–40%). Point of initial contact is the more accurate method for predicting heel rocker, with a threshold of 14% of foot length identifying the correct heel rocker status in 94% of cases. Interpretation Point of initial contact can assess heel rocker with high accuracy. Both point of initial contact and rollback provide sensitive information on foot strike pattern, enhancing the utility of pedobarography.

RATIONALE: Clinically relevant pain is associated with functional impairment and behavioral depression, including depression of social behavior. Moreover, recovery of function is a major goal in pain treatment. We used a recently developed model of operant responding for social interaction in rats to evaluate the vulnerability of social behavior to an experimental pain manipulation and the sensitivity of pain-depressed social behavior to treatment with clinically effective analgesics. METHODS: Sprague-Dawley male and female rats were trained to lever press for social access to another rat, and responding was evaluated after treatment with (a) intraperitoneal injection of dilute lactic acid (IP acid; 0.18–5.6%) administered alone as a visceral noxious stimulus, (b) the mu-opioid receptor (MOR) agonist morphine (0.32–10 mg/kg) or nonsteroidal anti-inflammatory drug (NSAID) ketoprofen (10 mg/kg) administered alone, or (c) morphine or ketoprofen administered before IP acid. For comparison, the same treatments were evaluated in separate rats trained to lever press for food delivery. RESULTS: Both IP acid alone and morphine alone more potently decreased responding maintained by social interaction than by food, whereas ketoprofen did not affect responding for either reinforcer. In general, analgesics were most effective to rescue operant responding when relatively low IP acid concentrations produced significant but submaximal behavioral depression; however, morphine was not effective to rescue responding for social interaction. CONCLUSIONS: Operant responding maintained by social interaction was more sensitive to pain-related disruption and less responsive to opioid analgesic rescue than food-maintained operant responding. Social behavior may be especially vulnerable to depression by pain states.

Background and ObjectivesThis study examined the association between body mass index (BMI) and disability in children with Charcot-Marie-Tooth disease (CMT).MethodsWe conducted a cross-sectional analysis of 477 patients with CMT who were 3 to 20 years of age from the Inherited Neuropathy Consortium and 316 age- and sex-matched healthy children from the 1,000 Norms Project. BMI was categorized according to the International Obesity Task Force (IOTF) criteria, and BMI categorization was compared with healthy children. IOTF categories (adult equivalent BMI cut points) were severely underweight (BMI 2), underweight (BMI ≥17–2), healthy weight (BMI ≥18.5–2), overweight (BMI ≥25–2), and obese (BMI ≥30 kg/m2). Scores on the 0 to 44–point CMT Pediatric Scale (CMTPedS), a well-validated measure of disability, were examined in relation to BMI.ResultsThere was a higher proportion of children with CMT categorized as severely underweight (5.7% vs 0.3%), underweight (10.3% vs 5.1%), and obese (7.3% vs 3.8%) (p< 0.05). Fewer children with CMT were categorized as healthy weight (61.8% vs 74.4%) (p< 0.05), and the proportion of overweight (14.9% vs 16.5%) between groups was similar. CMTPedS scores (mean ± SD) for weight categories were as follows: severely underweight 27 ± 9, underweight 20 ± 8, healthy weight 17 ± 9, overweight 17 ± 9, and obese 22 ± 10. Compared to children with a healthy weight with CMT, being severely underweight was associated with being more disabled (p< 0.001), as was being obese (p= 0.015).DiscussionThe proportion of children with CMT who are underweight or obese is higher compared to age- and sex-matched healthy children. In children with CMT, being underweight or obese is associated with greater disability, when compared to children with CMT of healthy weight.

Prostacyclin mimetics express potent vasoactive effects via prostanoid receptors that are not unequivocally defined, as to date no study has considered sex as a factor. The aim of this study was to determine the contribution of IP and EPWithin second-order mesenteric arteries from male and female Wistar rats, we determined (1) relative mRNA transcripts for EPIloprost evoked a biphasic response in male mesenteric arteries, at concentrations ≤100 nmol·LStark sexual dimorphisms in iloprost-mediated vasoactive responses are present within mesenteric arteries. K

Hypertension is a major cause of cardiovascular morbidity and mortality, despite the availability of antihypertensive drugs with different targets and mechanisms of action. Here, we provide evidence that pharmacological inhibition of TMEM16A (ANO1), a calcium-activated chloride channel expressed in vascular smooth muscle cells, blocks calcium-activated chloride currents and contraction in vascular smooth muscle invitro and decreases blood pressure in spontaneously hypertensive rats. The acylaminocycloalkylthiophene TMinh-23 fully inhibited calcium-activated TMEM16A chloride current with nanomolar potency in Fischer rat thyroid cells expressing TMEM16A, and in primary cultures of rat vascular smooth muscle cells. TMinh-23 reduced vasoconstriction caused by the thromboxane mimetic U46619 in mesenteric resistance arteries of wild-type and spontaneously hypertensive rats, with a greater inhibition in spontaneously hypertensive rats. Blood pressure measurements by tail-cuff and telemetry showed up to a 45-mmHg reduction in systolic blood pressure lasting for four-six hours in spontaneously hypertensive rats after a single dose of TMinh-23. A minimal effect on blood pressure was seen in wild-type rats or mice treated with TMinh-23. Five-day twice daily treatment of spontaneously hypertensive rats with TMinh-23 produced sustained reductions of 20-25 mmHg in daily mean systolic and diastolic blood pressure. TMinh-23 action was reversible, with blood pressure returning to baseline in spontaneously hypertensive rats by three days after treatment discontinuation. Thus, our studies provide validation for TMEM16A as a target for antihypertensive therapy and demonstrate the efficacy of TMinh-23 as an antihypertensive with a novel mechanism of action.

To investigate associations between eating behavior constructs (social eating, perceived competence, habit automaticity, self-determined motivation) and diet quality among young adults.Cross-sectional analysis.Young adults (n = 1,005; mean age, 21.7 ± 2.0 years; 85% female) enrolled in the Advice, Ideas, and Motivation for My Eating (Aim4Me) study.Four eating behavior measures collected via online surveys: Social Eating Scale, Perceived Competence in Healthy Eating Scale, Self-Report Behavioral Automaticity Index, and Regulation of Eating Behaviors scales. Diet quality was assessed using the Australian Recommended Food Score (ARFS) and percentage energy from energy-dense, nutrient-poor (EDNP) foods.Multivariate linear regression investigating associations between eating behavior measures (independent variables) and ARFS and EDNP foods (dependent variables), adjusting for sociodemographic and lifestyle confounders.Greater perceived competence in healthy eating and behavioral automaticity for consuming healthy foods, limiting EDNP food intake, and higher intrinsic motivation, integrated regulation, and identified regulation of eating behaviors were associated with higher ARFS and lower percentage energy EDNP foods (P0.001). Greater self-reported social influence on eating behaviors was associated with higher ARFS (P = 0.01). Higher amotivation was associated with greater % energy from EDNP foods (P0.001).Perceived competence, habit automaticity, and self-determined motivation are determinants of diet quality in young adults. These findings support the development of interventions that promote healthy eating habits by focusing on eating behavior constructs and evaluating their use in improving diet quality.

Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L-carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L-carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12-week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naive to L-carnitine. Primary outcomes were safety (self-reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6-minute-walk test [6MWT]), and parent-reported questionnaires (PedsQL™, CBCL/6-18). Six children completed the trial with no self-reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89-60.75; p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99-134.1; p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97-16.03; p = 0.01) and 6MWT distance (95% CI 5.88-75.45; p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z-score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of individuals remaining on L-carnitine after the study. Twelve weeks of L-carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment.

INTRODUCTION/AIMS: We aim to describe 12-month functional and motor outcome performance in a cohort of participants with congenital myotonic dystrophy (CDM). METHODS: CDM participants performed the Six Minute Walk Test (6MWT), 10 Meter Run, 4 Stair Climb, Grip Strength and Lip Force at baseline and 12 month visits. Parents completed the Vineland Adaptive Behavior Scale. RESULTS: Forty-seven participants, aged 0 to 13 years old, with CDM were enrolled. 6MWT, 10 Meter Run and 4 Stair Climb were completed in >85% of eligible participants. The only significant difference between mean baseline and 12-month performance was an improvement in 6MWT in children 3–6 years old (p=0.008). This age group also had the largest mean % improvement in performance in all other timed functional testing. In children >7 years, the slope of change on timed functional tests decreased or plateaued, with further reductions in performance in children ≥10 years. Participants with CTG repeat lengths 1000. DISCUSSION: 6MWT, 10 Meter Run and 4 Stair Climb were the most feasible measures. Our findings are consistent with the clinical profile and prior cross-sectional data, helping to establish reasonable expectations of functional trajectories in this population as well as identifying points in which therapeutic interventions may be best studied. Further study of outcomes in children >10 years old and

Background and Purpose: Arterial diameter is dictated by the contractile state of the vascular smooth muscle cells (VSMCs), which is modulated by direct and indirect inputs from endothelial cells (ECs). Modulators of KCNQ-encoded kV7 channels have considerable impact on arterial diameter and these channels are known to be expressed in VSMCs but not yet defined in ECs. However, expression of kV7 channels in ECs would add an extra level of vascular control. This study aims to characterize the expression and function of KV7 channels within rat mesenteric artery ECs.Experimental Approach: In rat mesenteric artery, KCNQ transcript and KV7 channel protein expression were determined via RT-qPCR, immunocytochemistry, immunohistochemistry and immunoelectron microscopy. Wire myography was used to determine vascular reactivity.Key Results: KCNQ transcript was identified in isolated ECs and VSMCs. KV7.1, KV7.4 and KV7.5 protein expression was determined in both isolated EC and VSMC and in whole vessels. Removal of ECs attenuated vasorelaxation to two structurally different KV7.2-5 activators S-1 and ML213. KIR2 blockers ML133, and BaCl2 also attenuated S-1 or ML213-mediated vasorelaxation in an endothelium-dependent process. KV7 inhibition attenuated receptor-dependent nitric oxide (NO)-mediated vasorelaxation to carbachol, but had no impact on relaxation to the NO donor, SNP.Conclusion and Implications: In rat mesenteric artery ECs, KV7.4 and KV7.5 channels are expressed, functionally interact with endothelial KIR2.x channels and contribute to endogenous eNOS-mediated relaxation. This study identifies KV7 channels as novel functional channels within rat mesenteric ECs and suggests that these channels are involved in NO release from the endothelium of these vessels.

To discuss and understand urban teaching and Black girls’ pedagogies, the fundamental premise is that Black girls are not monolithic, but complex and nonhomogenous. Black girlhood studies recognize that, because of their intersectional race, class, and gender status, Black girls have different experiences than Black boys and White girls. Core themes in Black girlhood include self-identity and socialization; beauty and self-expression; popular culture, hip hop, and stereotypes; violence; systemic discipline in schools; and resiliency and survival. Responding to the unique experiences of Black girls, Black women educators developed and adopted a pedagogy that focuses on and centers Black girls and Black girlhood in all their complexity. Using a strengths-based approach, Black girls’ pedagogy is built on a Black feminist and womanist framework that recognizes the need for culturally informed curriculum and classroom experiences, more Black women educators, and a commitment to an ethics of care.

Hypertension is a major cause of cardiovascular morbidity and mortality, despite the availability of antihypertensive drugs with different targets and mechanisms of action. There is an unmet need for antihypertensive drugs with novel mechanisms of action to better control hypertension and reduce cardiovascular morbidity and mortality. Here, we provide evidence that pharmacological inhibition of TMEM16A (transmembrane member 16A or anoctamin-1), a Ca 2+ -activated Cl - channel expressed in vascular smooth muscle cells, reduces in vitro vascular smooth muscle contraction and decreases blood pressure in spontaneously hypertensive rats (SHR). We recently identified by high-throughput screening and subsequent medicinal chemistry, small molecule TMEM16A inhibitor TM inh -23 (2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid o-tolylamide) that inhibits TMEM16A current fully, with IC 50 ~ 30 nM. TM inh -23 pretreatment blocked maximum in vitro vascular smooth muscle contractions induced by a thromboxane mimetic (U46619) in rat mesenteric arteries by 90%. Intraperitoneal (ip) administration of TM inh -23 to rodents at 10 mg/kg produced sustained serum concentrations of >10 μM for >4 hours. BP measurements by tail-cuff and telemetry showed a maximum ~45 mmHg reduction in SBP in spontaneously hypertensive rats (SHR) after a single dose (10 mg/kg, ip) TM inh -23 administration compared to vehicle treatment, with BP gradually returning to baseline values within 6-8 hours after TM inh -23 treatment. Minimal effect on BP (less than 10 mmHg decrease in SBP) was seen in wild-type rats and mice with TM inh -23 treatment (10 mg/kg, ip). Chronic 5-day treatment of SHR with TM inh -23 (10 mg/kg, ip, twice daily) caused sustained decreases (~20-25 mmHg) in daily average SBP, DBP and MAP during the treatment period. TM inh -23 action was reversible, with BP returning to baseline (~170/115 mmHg) by 3 days after discontinuation of treatment. These studies provide validation for TMEM16A as a target for antihypertensive therapy, and demonstrate the proof-of-concept for efficacy of TM inh -23 as an antihypertensive with a novel mechanism of action.

Background and Purpose: Arterial diameter is dictated by the contractile state of the vascular smooth muscle cells (VSMCs), which is modulated by direct and indirect inputs from endothelial cells (ECs). Modulators of KCNQ-encoded kV7 channels have considerable impact on arterial diameter and these channels are known to be expressed in VSMCs but not yet defined in ECs. However, expression of kV7 channels in ECs would add an extra level of vascular control. This study aims to characterize the expression and function of KV7 channels within rat mesenteric artery ECs. Experimental Approach: In rat mesenteric artery, KCNQ transcript and KV7 channel protein expression were determined via RT-qPCR, immunocytochemistry, immunohistochemistry and immunoelectron microscopy. Wire myography was used to determine vascular reactivity. Key Results: KCNQ transcript was identified in isolated ECs and VSMCs. KV7.1, KV7.4 and KV7.5 protein expression was determined in both isolated EC and VSMC and in whole vessels. Removal of ECs attenuated vasorelaxation to two structurally different KV7.2-5 activators S-1 and ML213. KIR2 blockers ML133, and BaCl2 also attenuated S-1 or ML213-mediated vasorelaxation in an endothelium-dependent process. KV7 inhibition attenuated receptor-dependent nitric oxide (NO)-mediated vasorelaxation to carbachol, but had no impact on relaxation to the NO donor, SNP. Conclusion and Implications: In rat mesenteric artery ECs, KV7.4 and KV7.5 channels are expressed, functionally interact with endothelial KIR2.x channels and contribute to endogenous eNOS-mediated relaxation. This study identifies KV7 channels as novel functional channels within rat mesenteric ECs and suggests that these channels are involved in NO release from the endothelium of these vessels.