Canadian Institutes For Health Research Research Articles

Contrasting Reflex Neural Modulation of Muscle Sympathetic Nerve Activity at Rest and During One‐leg Dynamic Exercise in Subjects with and without Heart Failure

We previously showed that muscle sympathetic nerve activity (MSNA) is augmented at rest in patients with heart failure due to reduced ejection fraction (HFrEF), and rises further during mild and moderate dynamic 1‐leg exercise in stark contrast to the drop observed in healthy controls at similar exercise intensities. The reflex mechanisms responsible for this unique response are unknown. We hypothesized that MSNA may be reduced at rest and during exercise in HFrEF by either: 1) stimulating the sympatho‐inhibitory cardiopulmonary baroreceptors by exercising supine rather than upright; or 2) inhibiting the sympatho‐excitatory peripheral chemoreceptors by breathing 32% oxygen (O2). We studied 6 stable, non‐diabetic, medicated HFrEF men ( mean age 58 ± 3 SE [range 46 to 65] years; mean left ventricular ejection fraction 29 ± 4% [range 15–38]); of either ischemic (n=5) or non‐ischemic (n=1) etiology; plus 6 healthy, age matched, medication‐free volunteers (3 women; mean age 58 ± 3 [range 49 to 72]). We assessed peak oxygen uptake (VO2peak ) by open‐circuit spirometry. On a separate day, fibular MSNA (microneurography) was measured at rest and during upright 1‐leg cycling (2 min each unloaded and at 50% of VO2peak). The identical cycling protocol was then repeated during supine exercise (n=5 HFrEF) and again during upright cycling while breathing 32% O2 (n=4 HFrEF). Heart rate and diastolic blood pressure were similar across interventions in both groups but systolic blood pressure was significantly lower in HFrEF vs controls (main effect P=0.01). MSNA was reduced at rest only while supine in control subjects (main effect P=0.01; P=0.01 vs upright). Whereas in HFrEF, both supine posture and supplemental O2 attenuated MSNA burst frequency at rest (main effect P=0.01; P=0.02 vs upright). During exercise, MSNA burst frequency progressively decreased in healthy controls particularly during unloaded cycling (main effect of time P<0.001), and tended to be lower throughout supine cycling (P=0.06 vs upright). By contrast, in HFrEF patients, there was no significant change in MSNA burst frequency during exercise while supine nor with supplemental oxygen (main effect of intervention P=0.51; time P=0.34). Thus, both at rest and during mild cycling exercise, supine posture augments the sympathoinhibitory response in control subjects. However in HFrEF patients, sympathoexcitation at rest can be reduced to a similar extent by either triggering the inhibitory cardiopulmonary baroreflex or abolishing arterial chemoreceptor activation with no further effect during exercise.Support or Funding InformationSupported by Heart and Stroke Foundation of Ontario and Canadian Institutes for Health Research

Changes in gene expression caused by genetic elimination of high molecular weight FGF2 are associated with prevention of stress‐induced cardiac systolic dysfunction

Fibroblast growth factor 2 (FGF2) is produced as high (>20 kDa, Hi‐) and low molecular weight (18 kDa, Lo) isoforms in the heart. While administered Lo‐FGF2 has been established as a cardioprotective agent in multiple models of cardiac injury, there is limited information about the role of Hi‐FGF2 in the heart. To investigate the effect of endogenous Hi‐FGF2 we compared cardiac transcriptome (35240 targets, GeneChip™ Mouse Gene 2.0 ST Array (Affymetrix, 902119)) and systolic function between Hi‐FGF2 knock‐out mice, FGF2(Lo), expressing only Lo‐FGF2, and wild type mice, FGF2(WT), expressing both Hi‐FGF2 and Lo‐FGF2, under ‘normal’ (sham‐operated) and “stress” (pressure overload) conditions. Transaortic constriction surgery (TAC) was used to induce pressure overload. Echocardiography was done at baseline and at 4–8 weeks post‐surgery. Microarray analysis showed that under normal conditions, the absence of Hi‐FGF2 promoted changes in relative levels of 118 transcripts, including those associated with circadian rhythm regulation and heat shock protein (HSP70)‐associated apoptosis regulation. Comparative analysis of TAC surgery‐induced gene expression changes showed that 275 transcripts were differentially affected by the presence or absence of Hi‐FGF2 expression, most prominently the orphan nuclear receptor NR1D1 which is linked to regulation of circadian rhythm and metabolism. Under non‐stress conditions, systolic function was unaffected by endogenous Hi‐FGF2 expression. Pressure overload stress caused a decline in systolic function in the presence of endogenous Hi‐FGF2, at 4–8 weeks post‐TAC surgery, accompanied by increases in markers of myocardial stress/damage including B‐type natriuretic peptide (BNP) and the pro‐cell death protein BCL2/adenovirus E1B 19 kDa protein‐interacting protein‐3, Bnip3. In the absence of endogenous Hi‐FGF2, mice were protected from stress‐induced loss of systolic function and increases in BNP and Bnip3. TAC surgery induced Hi‐FGF2‐independent increases in: cardiac mass (heart weight/tibia length); cardiac fibrosis; transcripts linked to exracellular matrix remodeling. Increased cardiomyocyte size, however, was only observed in FGF2(WT) but not FGF2(Lo) hearts post‐TAC. It is suggested that elimination of endogenous Hi‐FGF2 elicits cardioprotection by increasing cardiac HSP70 (pre‐TAC surgery); and NR1D1, after TAC surgery.Support or Funding InformationFunding (EK, PAC, DJ) was provided by the Canadian Institutes for Health Research (FRN‐74733) and the Molson Women’s Heart Health Foundation (EK). MPC was supported by a CIHR Open Operating Grant (MOP136862). NK and RSN were the recipients of a Bank of Montreal studentship award via the St. Boniface Hospital Albrechtsen Research Centre and University of Manitoba funding to PAC.

Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial

Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

Caring Near and Far by Connecting Community-Based Clients and Family Member/Friend Caregivers Using Passive Remote Monitoring: Protocol for a Pragmatic Randomized Controlled Trial.

BackgroundSignificant chronic disease challenges exist among older adults. However, most older adults want to remain at home even if their health conditions challenge their ability to live independently. Yet publicly funded home care resources are scarce, private home care is expensive, and family/friend caregivers have limited capacity. Many older adults with chronic illness would require institutional care without the support from family member/friend caregivers. This role raises the risk of physical health problems, stress, burnout, and depression. Passive remote monitoring (RM), the use of sensors that do not require any action by the individual for the system to work, may increase the older adult’s ability to live independently while also providing support and peace of mind to both the client and the family member/friend caregiver.ObjectiveThis paper presents the protocol of a study conducted in two provinces in Canada to investigate the impact of RM along with usual home care (the intervention) versus usual home care alone (control) on older adults with complex care. The primary outcome for this study is the occurrence of and time to events such as trips to emergency, short-term admission to the hospital, terminal admission to the hospital awaiting admission to long-term care, and direct admission to long-term care. The secondary outcomes for this study are (1) health care costs, (2) client functional status and quality of life in the home, (3) family/friend caregiver stress, and (4) family/friend caregiver functional health status.MethodsThe design for this study is an unblinded pragmatic randomized controlled trial (PRCT) with two parallel arms in two geographic strata (Ontario and Nova Scotia). Quantitative and qualitative methodologies will be used to address the study objectives. This PRCT is conceptually informed by the principles of client-centered care and viewing the family as the client and aims at providing supported self-management.ResultsThis study is supported by the Canadian Institutes for Health Research. A primary completion date is anticipated in fall 2022.ConclusionsFindings from this real-world rigorous randomized trial will support Canadian decision-makers, providers, and clients and their caregivers in assessing the health, well-being, and economic benefits and the social and technological challenges of integrating RM technologies to support older adults to stay in their home, including evaluating the impact on the burden of care experienced by family/friend caregivers. With an aging population, this technology may reduce institutionalization and promote safe and independent living for the elderly as long as possible.Trial RegistrationInternational Standard Randomised Controlled Trial Number (ISRCTN) 79884651; http://www.isrctn.com/ISRCTN79884651International Registered Report Identifier (IRRID)DERR1-10.2196/15027

Oral Micronized Progesterone for Perimenopausal Night Sweats and Hot Flushes: A 12-Week Randomized Phase III Canada-Wide Clinical Trial

Background: Oral micronized progesterone (progesterone) has been shown superior to placebo for vasomotor symptoms (VMS, night sweats and/or hot flushes) in menopausal women (>1 year after final flow). A VMS Score difference ≥3 was clinically important. VMS begin in perimenopause; however, all but two VMS randomized placebo-controlled trials (RCT) were in menopausal women. No well-performed RCT has proven any therapy to be effective for perimenopausal VMS. Methods: To test progesterone for perimenopausal VMS, we ran a quadruple masked, randomized (1:1), placebo-controlled trial (2012-2016) with 28-day run-in and 84 days’ experimental phases. Our academic medical centre recruited locally/nationally for women ages 35-58 with cycle irregularity but menstruation within 12 months plus untreated, problematic VMS. Our primary, intent-to-treat outcome was participant-recorded daily VMS Score ([# night sweats x intensity]+[#daytime hot flushes x intensity]) days 56-84, adjusted for run-in VMS Score. Our secondary outcome was Women’s Perceived VMS Change (-5 to +5) on day 84. Findings: We randomized 189 women of mean (SD) age 49·9 (4·6) years to progesterone, 300 mg/bedtime [n=93], vs placebo [n=96]. The mean run-in VMS Score (n=189) was 12·2 (11·3). VMS Scores days 56-84 were not different by progesterone vs placebo (Rate Ratio [RR] 0·79 [95% CI 0·54, 1·15]; Rate Difference [RD] -1·51 [95% CI -3·97, 0·95]; P=0·222). RD 95% CI included -3, thus did not exclude a clinically important effect. Perceived VMS Change indicated progesterone significantly improved night sweats over placebo (-3 vs -2, P=0·023). No serious adverse events occurred. Interpretation: Progesterone-treated perimenopausal women perceived significantly improved night sweats. These results show trends toward clinically important VMS benefits from perimenopausal progesterone. Given the previously undocumented high perimenopausal VMS variability, a larger RCT of progesterone for perimenopause VMS is still needed. Trial Registered: ClinicalTrials.gov NCT0146469. Funding Statement: Funded by a grant from the Canadian Institutes for Health Research (#MOP106644). Extended enrollment was funded by an arms-length unrestricted grant to the Centre for Menstrual Cycle and Ovulation Research of the University of British Columbia from Besins Healthcare International. Declaration of Interests: None of the investigators, co-investigators or collaborators in this RCT has a financial or other conflict of interest with these data or other ethical conflicts. Ethics Approval Statement: The University of British Columbia Clinical Research Ethics Board approved this protocol and its amendments.

Explaining the variability in cardiovascular risk factors among First Nations communities in Canada: a population-based study

Historical, colonial, and racist policies continue to influence the health of Indigenous people, and they continue to have higher rates of chronic diseases and reduced life expectancy compared with non-Indigenous people. We determined factors accounting for variations in cardiovascular risk factors among First Nations communities in Canada. Men and women (n=1302) aged 18 years or older from eight First Nations communities participated in a population-based study. Questionnaires, physical measures, blood samples, MRI of preclinical vascular disease, and community audits were collected. In this cross-sectional analysis, the main outcome was the INTERHEART risk score, a measure of cardiovascular risk factor burden. A multivariable model was developed to explain the variations in INTERHEART risk score among communities. The secondary outcome was MRI-detected carotid wall volume, a measure of subclinical atherosclerosis. The mean INTERHEART risk score of all communities was 17·2 (SE 0·2), and more than 85% of individuals had a risk score in the moderate to high risk range. Subclinical atherosclerosis increased significantly across risk score categories (p<0·0001). Socioeconomic advantage (-1·4 score, 95% CI -2·5 to -0·3; p=0·01), trust between neighbours (-0·7, -1·2 to -0·3; p=0·003), higher education level (-1·9, -2·9 to -0·8, p<0·001), and higher social support (-1·1, -2·0 to -0·2; p=0·02) were independently associated with a lower INTERHEART risk score; difficulty accessing routine health care (2·2, 0·3 to 4·1, p=0·02), taking prescription medication (3·5, 2·8 to 4·3; p<0·001), and inability to afford prescription medications (1·5, 0·5 to 2·6; p=0·003) were associated with a higher INTERHEART risk score. Collectively, these factors explained 28% variation in the cardiac risk score among communities. Communities with higher socioeconomic advantage and greater trust, and individuals with higher education and social support, had a lower INTERHEART risk score. Communities with difficulty accessing health care, and individuals taking or unable to afford prescription medications, had a higher INTERHEART risk score. Cardiac risk factors are lower in communities with high socioeconomic advantage, greater trust, social support and educational opportunities, and higher where it is difficult to access health care or afford prescription medications. Strategies to optimise the protective factors and reduce barriers to health care in First Nations communities might contribute to improved health and wellbeing. Heart and Stroke Foundation of Canada, Canadian Partnership Against Cancer, Canadian Institutes for Health Research.

External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial

Whole breast irradiation delivered once per day over 3-5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5-8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035. Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3-9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9-4·0) in the APBI group and 2·8% (1·8-3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84-1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5-15·0), 5 years (16·5%, 12·5-20·4), and 7 years (17·7%, 12·9-22·3). External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

Heart failure treatment and the art of medical decision making.

Heart failure treatment and the art of medical decision making.

Cardiovascular Morbidity and Mortality Among People Diagnosed with Tuberculosis: A Systematic Review and Meta-Analysis

Background: Emerging evidence of increased disease risk among people diagnosed with appears to indicate risk assessment among people diagnosed with TB; however, no synthesis of the epidemiological evidence of disease among people diagnosed with TB exists. We hypothesized elevated risk of morbidity and mortality among people diagnosed with active or latent tuberculosis. Methods: We conducted a systematic review and meta-analysis. EMBASE, MEDLINE, and Cochrane databases were searched (inception to June 2018) for terms related to tuberculosis and cardiovascular diseases. Inclusion criteria: trial, cohort, or case-control study design; patient population that includes people diagnosed with TB infection or disease; relative risk (RR) estimate and confidence interval reported for morbidity or mortality compared to suitable controls. Exclusions: TB definition not provided; outcome definition not provided; duplicate study; no English abstract; non-human participants. Two reviewers screened studies, applied ROBINS-I tool to assess risk of bias, and extracted data independently. Random effects meta-analysis estimated a pooled RR of morbidity and mortality. PROSPERO (CRD42018100498). Findings: 5,628 articles were identified, 211 full texts were reviewed, and 15 included. We estimated a per-protocol meta-analysis pooled RR of 2·06 (95% CI 1·58-2·68) for morbidity and mortality among those diagnosed with TB (p<0.0001). A 'Serious' pooled risk of bias was found across studies. High between-study heterogeneity was found (I2 = 95%). Interpretation: Systematic risk assessment among patients may be warranted. Prospective studies are needed to understand the relationship between and disease. Clinical Registration Number: The study was prospectively registered in PROSPERO (CRD42018100498). Funding: JCJ is funded by a Michael Smith Foundation Scholar Award and the Canadian Institutes for Health Research. Declaration of Interests: The authors declare that they have no conflicts. Ethical Approval Statement: Not required.

A new era in research on the epididymis

After meetings in Hong Kong, Robertson (Australia), Charlottesville (Virginia), Chatel-Guyon (France), Sao Palo (Brazil), and Shanghai (China), the 7th International Conference on the Epididymis was held in Montreal (Canada) from September 20 to 23, 2018. One hundred scientists from 11 countries gathered to present their most recent findings on this critically important tissue in male reproduction, one that has received far less attention than it deserves. Special presentations were made to honor two of the founding ‘parents’ of our modern understanding of the epididymis (Fig. 1). The Plenary lecture, named after Dr. Marie-Claire Orgebin-Crist, was delivered by Dr. Louis Hermo. Dr. Patricia Cuasnicu presented the remarkable achievements of Dr. Michael Bedford, who passed away earlier in 2018. We are fortunate to have a picture of these two pioneers that was taken at the previous Conference on the Epididymis. The outstanding suggestions from members of the Program Committee (Avellar MC—Brazil, Breton S—USA, Cornwall G—USA, Cuasnicu P—Argentina, Drevet J—France, Hinton BT—USA, Robaire B—Canada, and Zhang Y—China) allowed us to bring together leaders researching every facet of ‘the tissue’. The main themes of the meeting were as follows: development of the Wolffian duct and the epididymis; physiology of the epididymis; epididymal sperm maturation and contraception; non-coding RNAs in the epididymis; infections of and defense by the epididymis; immune system and the epididymis; toxicants and epididymal function; the human epididymis; and clinical aspects of epididymal dysfunction. Excellent presentations were provided by 22 invited speakers and in 51 posters, covering a remarkably rich variety of novel and exciting developments regarding our understanding of how this tissue functions and is regulated. A PDF of the program and of abstracts may be found at: http://www.medicine.mcgill.ca/pharma/robairelab/Documents/Epididymis7_FinalProgram.pdf This issue of Andrology contains 19 articles, representing nearly 90% of the presentations delivered by invited speakers. Each of these peer-reviewed articles contributes new dimensions to our understanding of the complexity of this remarkably long tube that creates and provides continuously changing environments for spermatozoa as they mature and are then stored. The dynamic interactions with the immune system, the interface between the epithelial cells and spermatozoa via epididymosomes, our evolving understanding of the roles of non-coding RNAs and other small molecules, are all opening new avenues that are likely to provide new opportunities for the development of male contraceptives and the treatment of male infertility. The success of this meeting would not have been possible without the untiring efforts of Ms. Elise Boivin-Ford and Dr. Anais Noblanc and the financial contributions from the Male Contraceptive Initiative, Canadian Institutes for Health Research, Society for the Study of Reproduction, American Society of Andrology, International Society of Andrology, Reseau Quebecois en Reproduction, McGill University, McGill University Health Centre, Centre for Research in Reproduction and Development, Université de Montréal, Université Laval, Institut National de Recherche en Santé, and Fluxion.

Association between premorbid neuropsychological conditions and pediatric mild traumatic brain injury/concussion recovery time and symptom severity: a systematic review.

The objective of this review was to identify associations between premorbid neuropsychological conditions and pediatric mild traumatic brain injury/concussion recovery time and symptom severity. There is a lack of evidence-based clinical guidelines for the care of children with a premorbid neuropsychological condition who have sustained a mild traumatic brain injury, also known as concussion. This necessitates inquiry for any associations that may exist, which may contribute to an enhanced understanding of injury recovery patterns. Participants included children ages six through 18 years with any diagnosed or self-reported premorbid neuropsychological condition(s) and mild traumatic brain injury/concussion. Participants with concomitant intracranial or extra-axial head injury found on diagnostic imaging were excluded. Outcomes for this review included recovery time or symptom(s) severity post-concussion. Studies considered for review were analytical observational studies, including retrospective, prospective, cross-sectional or longitudinal cohort studies or case-control studies, as well as descriptive observational study designs, including case series, individual case reports and descriptive cross-sectional studies. A comprehensive search was undertaken in January 2018 for both published and unpublished studies utilizing an a priori protocol. Major databases searched included CINAHL, Embase, PubMed, Psychology and Behavioral Sciences Collection and PsycINFO. Other sources searched for unpublished and gray literature included the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Google Scholar, ProQuest Dissertations and Theses Global: Sciences and Engineering Collection and MedNar. Additional searches of government websites and reports targeting healthcare or sports-related concussions included Australian Sports Commission, Canadian Institutes for Health Research, the National Health Service of the United Kingdom, the U.S. Department of Health and Human Services: Agency for Healthcare Research and Quality, and the U.S. Department of Health and Human Services: Centers for Disease Control and Prevention. Critical appraisal and data extraction were completed by two independent reviewers. Validation of methodologic quality was performed utilizing standardized tools from the Joanna Briggs Institute, and any disputes were resolved through discussion. Due to significant heterogeneity among studies, a meta-analysis could not be conducted. Therefore, extracted data are reported in a narrative synthesis. A total of 12 studies (one analytical cross-sectional, two case-control and nine cohort) with 2,973 participants met inclusion criteria. Results of the findings among premorbid conditions varied. However, statistically significant associations with prolonged recovery or increased symptom severity were identified in children with pre-concussion histories of learning disabilities or poor academic achievement; anxiety, depression, mood disorders or other psychiatric illnesses; prior head injuries; somatization (in females); sleep disorders (in males); and the presence of multiple neuropsychological conditions. Due to heterogeneity among studies and limitations of the review, findings suggest that clinicians providing post-concussive care may consider the presence of premorbid neuropsychological conditions, specifically learning disabilities or poor academic achievement; anxiety, depression, mood disorders or other psychiatric illnesses; prior head injuries; somatization; sleep disorders; or the presence of multiple neuropsychological conditions as potential contributors to prolonged recovery times or increased symptom severity in children and adolescents with mild traumatic brain injuries.

Exercise intervention in the management of urinary incontinence in older women in villages in Bangladesh: a cluster randomised trial

Group exercise-based programmes for urinary incontinence appear to be promising low-cost interventions for women in developing countries, but no evidence exists to support whether they could be implemented or effective in such populations. We aimed to evaluate whether a group intervention that comprised pelvic floor muscle training, mobility exercises, and bladder education would be more effective than education alone, and report changes between villages (ie, clusters) rather than between individual participants. In this cluster randomised trial, we recruited women from 16 pairs of villages in Bangladesh, with each pair comprising similar villages from the same sub-district. Women aged 60-75 years were interviewed to establish eligibility. Women were eligible if they had current urinary incontinence, and were excluded if they had a third degree or higher uterine prolapse, if they were unable to walk or stand without help, or if they had insufficient intellectual capacity to understand questions and follow instructions. The villages were randomly assigned within each pair to either exercise plus education or education-only intervention by use of a random number generator from a fixed seed. Women were excluded after consenting if they lived too far from the centre of the village. The exercise intervention was a physiotherapist-led group exercise class that was held twice weekly for 12 weeks, with home exercises between classes and to 24 weeks. Both groups received bladder-health education. Participants were followed up for 24 weeks. A 3-day continence record was collected at recruitment and every 4 weeks up until 24 weeks. This record involved the participant tying a knot in ribbons worn under the clothing each time they had an episode of urinary leakage. The primary outcome was change in number of knots (recorded leakage episodes) from recruitment to 24 weeks. Safety was assessed in all participants in the exercise intervention group. The trial is registered at ClinicalTrials.gov, number NCT02453100. Between Aug 22, 2015, and July 2, 2018, of 3577 women aged 60-75 years identified, 1003 were eligible, of whom 625 consented to participate (n=335 exercise plus education villages, and n=290 in education-only villages). Of these consenting women, 46 were excluded (n=37 exercise plus education, n=9 education only) because they lived too far from the centre of the village. At week 24, 283 (95%) of 298 in the exercise plus education group and 274 (98%) of 281 in the education-only group completed a 3-day continence record. The estimate of change in number of leakage episodes between baseline and 24 weeks was -7·7 (95% CI -10·6 to -4·8) at the village level in an unadjusted model, and -6·64 (-7·95 to -5·33) in a random-effects model accounting for cluster randomisation. No adverse events were reported. A structured group-exercise intervention has the potential to manage urinary incontinence in older women in communities largely outside the reach of pharmaceutical or surgical interventions. Canadian Institutes for Health Research.

Application of the Indicator Amino Acid Oxidation Method for the Determination of the Metabolic Availability of Lysine from Indian Sorghum Protein in Young Adult Men (P08-069-19)

ObjectivesTo measure the protein quality of cooked sorghum by determining the metabolic availability (MA) of lysine; the first limiting indispensable amino acid. Additionally, we aimed to assess the effect of complementation by combining lentils and sorghum in a mixed meal format. MethodsIn a repeated measures design, the MA of lysine in sorghum was studied using the indicator amino acid oxidation (IAAO) method with L-[1–13C] phenylalanine as the indicator at four levels of lysine: 5, 8, 12, 15 mg. kg−1. d−1 in five healthy adult men. These intakes represent 13, 21, 32 and 40%, respectively, of the lysine requirement (37 mg. kg−1. d−1) for adult men. Each subject participated in 8 experimental diets: 4 lysine intakes as L-lysine from crystalline amino acid, 3 intakes of lysine from sorghum prepared by moist cooking and 1 experiment to discern the effects of complementation with lentils. The principles of slope-ratio were applied to calculate the MA of lysine in sorghum by comparing the IAAO response to varying intakes of lysine in cooked sorghum relative to the IAAO response to free crystalline lysine in the reference protein which was modelled after egg protein. ResultsThe MA of lysine from cooked sorghum was found to be 94%. Upon complementation with lentils, there was a decline in the oxidation of L-[1–13C] phenylalanine, reflecting an increased uptake of lysine for the synthesis of protein. ConclusionsThe findings demonstrate that most of the lysine in cooked sorghum, the fifth most commonly consumed cereal grain, is available for protein synthesis despite being of limiting concentration. Upon complementation with lentils, there was a decrease in oxidation which highlights the effectiveness of complementation. A combination of sorghum and lentil protein in a 2:1 ratio is a viable strategy to improve the protein quality for individuals consuming a plant-based sorghum and lentil diet. Funding SourcesSupported by the Canadian Institutes for Health Research. Pfizer Consumer Healthcare (Mississauga, Ontario) donated the multivitamins. Mead Johnson Nutritionals donated the protein-free powder for experimental diets.

Type II Diabetes Mellitus in the Goto‐Kakizaki Rat Impairs Microvascular Function and Contributes to Premature Skeletal Muscle Fatigue

Despite extensive investigation into the impact of metabolic disease on vascular function and, by extension, tissue perfusion and organ function, interpreting results for specific risk factors can be complicated by the additional risks present in most models. To specifically determine the impact of type II diabetes without obesity on skeletal muscle microvascular structure/function, and on active hyperemia with elevated metabolic demand, we used 17‐week old Goto‐Kakizaki rats (GK) to study microvascular function at multiple levels of resolution. Gracilis muscle arterioles demonstrated blunted dilation to acetylcholine (both ex vivo proximal and in situ distal arterioles) and elevated shear (distal arterioles only). All other alterations to reactivity appeared to reflect compromised endothelial function associated with increased TxA2 production and oxidant stress/inflammation rather than alterations to vascular smooth muscle function. Structural changes to the microcirculation of GK were confined to reduced microvessel density of ~12%, with no evidence for altered vascular wall mechanics. Active hyperemia with either field stimulation of in situ cremaster muscle or electrical stimulation via the sciatic nerve for in situ gastrocnemius muscle was blunted in GK; primarily due to blunted functional dilation of skeletal muscle arterioles. The blunted active hyperemia was associated with impaired oxygen uptake (VO2) across the muscle and an accelerated muscle fatigue. Acute interventions to reduce oxidant stress (TEMPOL) and TxA2 action (SQ‐29548) or production (dazmegrel) improved muscle perfusion, VO2, and muscle performance. These results suggest that T2DM in GK impairs skeletal muscle arteriolar function apparently early in the progression of the disease and potentially via an increased ROS/inflammation‐induced TxA2 production/action on network function as a major contributing mechanism.Support or Funding InformationAmerican Heart Association and National Institutes of Health (USA); Canadian Institutes for Health Research and Natural Sciences and Engineering Research Council (Canada)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impaired Dilator Reactivity of Middle Cerebral Arteries in Goto‐Kakizaki Rats with Type II Diabetes Mellitus

Type II diabetes mellitus (T2DM) is a highly prevalent disease and is associated with the development of cerebrovascular disease. The objective of the study was to determine whether alterations to the regulation of cerebral vascular tone exist in a non‐obese model of T2DM and to determine the mechanistic contributors to changes in this response. Middle cerebral arteries (MCA) from 17–18‐wk‐old male Wistar Kyoto (WKY) and Goto‐Kakizaki (GK) were isolated and cannulated with glass micropipettes. Vascular reactivity was assessed in response to challenge with acetylcholine (ACh), sodium nitroprusside (SNP), reductions in Po2, 5‐HT, and increased intraluminal pressure. Vessels were treated with the competitive nitric oxide synthase (NOS) inhibitor L‐NAME, the cyclooxygenase inhibitor indomethacin, and the cell‐permeable superoxide dismutase (SOD) mimetic TEMPOL to support interpretation of mechanistic contributors to changes in vessel reactivity. Similar measurements of vascular reactivity to methacholine (MCh), phenylephrine, SNP, and reductions in PO2 were measured in aortic ring preparations, along with measurements of vascular NO production and metabolites of arachidonic acid. There was an impairment of vessel dilation within the MCA and aorta of GK in response to ACh/MCh and hypoxia but not SNP. Decreased vascular NO release and ratio of PGI2/TxA2 were measured within the aorta in response to hypoxia, and increasing MCh concentration. No change was seen in the constrictor response to either 5‐HT or phenylephrine within the MCA or aorta respectively or in the myogenic activation of the MCA. Treatment with L‐NAME severely blunted the dilator reactivity of both the MCA and aorta, while TEMPOL showed mild improvements in GK, and indomethacin yielded improved dilator reactivity to MCh in GK but blunted it in WKY. These results suggest that the vasodilator reactivity of the MCA and aorta of GK in response to endothelium‐dependent dilator stimuli is impaired vs. WKY. This may be due to decreased NO bioavailability and altered arachidonic acid metabolism as a result of a pro‐oxidant pro‐inflammatory condition present in T2DM. The lack of change to the constrictor response of MCA and aorta in GK suggests a lack of structural remodeling as a result of T2DM at this age.Support or Funding InformationAmerican Heart Association and National Institutes of Health (USA); Canadian Institutes for Health Research and Natural Sciences and Engineering Research Council (Canada)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Epigenetics and chronic pain

The emerging field of pain epigenetics will be introduced and the potential implications of this new field will be reviewed. Long‐term programming of gene expression is dynamically regulated by chemical modifications to the DNA and histones collectively referred to as epigenetic modifications. Epigenetic changes are responsive to the environment and have long‐lasting biological consequences. For example, early life neglect results in altered DNA methylation in the brain that are associated with maladaptive behavioural patterns in the adult. Evidence of epigenetic dysregulation in pre‐clinical pain models and in individuals with low back pain will be highlighted. Finally, the potential for epigenetics to understand biological mechanisms, to unmask new therapeutic targets and as biomarkers for chronic pain will be discussed.Support or Funding InformationSupported by The Canadian Institutes for Health Research, The Quebec Pain Research Network and the Louise and Alan Edwards Foundation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

APP21 transgenic rats develop age‐dependent cognitive impairment and microglia accumulation within white matter tracts

BackgroundMost of the animal models commonly used for preclinical research into Alzheimer's disease (AD) largely fail to address the pathophysiology, including the impact of known risk factors, of the widely diagnosed sporadic form of the disease. Here, we use a transgenic rat (APP21) that does not develop AD‐like pathology spontaneously with age, but does develop pathology following vascular stress. To further the potential of this novel rat model as a much‐needed pre‐clinical animal model of sporadic AD, we characterize APP21 transgenic rats behaviorally and histologically up to 19 months of age.MethodsThe open field test was used as a measure of activity; and the Morris water maze was used to assess learning, memory, and strategy shift. Neuronal loss and microglia activation were also assessed throughout the brain.ResultsAPP21 transgenic rats showed deficits in working memory from an early age, yet memory recall performance after 24 and 72 h was equal to that of wildtype rats and did not deteriorate with age. A deficit in strategy shift was observed at 19 months of age in APP21 transgenic rats compared to Fischer wildtype rats. Histologically, APP21 transgenic rats demonstrated accelerated white matter inflammation compared to wildtype rats, but interestingly no differences in neuron loss were observed.ConclusionsThe combined presence of white matter pathology and executive function deficits mirrored what is often found in patients with mild cognitive impairment or early dementia, and suggests that this rat model will be useful for translationally meaningful studies into the development and prevention of sporadic AD. The presence of widespread white matter inflammation as the only observed pathological correlate for cognitive deficits raises new questions as to the role of neuroinflammation in cognitive decline.Support or Funding InformationWe appreciate funding support from the Ontario Mental Health Foundation, and funding from the Canadian Institutes for Health Research, Canadian Consortium on Neurodegeneration in Aging and Canadian Foundation of Innovation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hand-to-genital and genital-to-genital transmission of human papillomaviruses between male and female sexual partners (HITCH): a prospective cohort study

Hand-to-genital contact is hypothesised to be a transmission mode of human papillomavirus (HPV) of the Alphapapillomavirus genus. We compared the relative importance of hand-to-genital and genital-to-genital HPV transmission between sexual partners. In this prospective cohort study, we recruited and followed up female university students aged 18-24 years and their male sexual partners in Montreal, QC, Canada (2005-11). Participants were eligible if they had initiated sexual activity within the past 6 months. Women were examined at clinic visits at baseline and every 4-6 months for up to 24 months. Men had a baseline visit and a single follow-up visit approximately 4 months later. Partners provided hand and genital swab samples, which we tested for DNA of 36 HPV types using PCR. We assessed predictors of incident type-specific HPV detections using Cox proportional hazards models. Participants were recruited between June 5, 2006, and April 4, 2013. 264 women and 291 men had valid hand samples. The hazard ratio (HR) of incident detection of HPV in genital samples from women was 5·0 (95% CI 1·5-16·4) when her partner was positive for the same HPV type on his hand versus negative, but adjustment for his genital HPV status reduced the HR to 0·5 (0·1-1·8). Similarly, the HR of incident detection of HPV on men's genitals was 17·4 (95% CI 7·9-38·5) when his partner was positive for the same HPV type on her hand versus negative, but adjustment for her genital HPV status reduced the HR to 2·3 (0·9-6·2). Conversely, the HR of type-specific incident detection of HPV in genital samples associated with partner genital HPV positivity was 19·3 (95% CI 11·8-31·8) for women and 28·4 (15·4-52·1) for men after adjustment for their hand HPV status. Clinicians can reassure their patients that HPV transmission is unlikely to occur through hand-to-genital contact. The majority of genital HPV infections are likely to be caused by genital-to-genital sexual transmission. Canadian Institutes for Health Research, National Institutes of Health, Fonds de la Recherche en Santé du Québec, and Merck & Co.

Live attenuated varicella-zoster virus vaccine does not induce HIV target cell activation

Varicella-zoster virus (VZV) is under consideration as a promising recombinant viral vector to deliver foreign antigens including HIV. However, new vectors have come under increased scrutiny, since trials with adenovirus serotype 5-vectored (Ad5-vectored) HIV vaccine demonstrated increased HIV risk in individuals with pre-immunity to the vector that was thought to be associated with mucosal immune activation (IA). Therefore, given the prospect of developing an HIV/VZV chimeric vaccine, it is particularly important to define the impact of VZV vaccination on IA. Healthy VZV-seropositive Kenyan women (n = 44) were immunized with high-dose live attenuated VZV vaccine, and we assessed the expression on CD4+ T cells isolated from blood, cervix, and rectum of IA markers including CD38 and HLA-DR and of markers of cell migration and tissue retention, as well as the concentration of genital and intestinal cytokines. A delayed-start group (n = 22) was used to control for natural variations in these parameters. Although immunogenic, VZV vaccination did not result in significant difference in the frequency of cervical activated (HLA-DR+CD38+) CD4+ T cells (median 1.61%, IQR 0.93%-2.76%) at 12 weeks after vaccination when compared with baseline (median 1.58%, IQR 0.75%-3.04%), the primary outcome for this study. VZV vaccination also had no measurable effect on any of the IA parameters at 4, 8, and 12 weeks after vaccination. This study provides the first evidence to our knowledge about the effects of VZV vaccination on human mucosal IA status and supports further evaluation of VZV as a potential vector for an HIV vaccine. ClinicalTrials.gov NCT02514018. Primary support from the Canadian Institutes for Health Research (CIHR). For other sources, see Acknowledgments.

Dabigatran Treatment of Acute Non-Cardioembolic Ischaemic Stroke: A Randomised Controlled Trial

Background: Transient ischaemic attack (TIA) and minor ischaemic stroke patients are at high risk for recurrent events. Anticoagulants are associated with reduced recurrent ischemic stroke rates, but also increased risk of haemorrhagic transformation (HT). Dabigatran, a novel oral anticoagulant associated with reduced risk of intracranial bleeding compared with warfarin in atrial fibrillation patients, has not been assessed in acute brain ischemia. We hypothesised that HT rates are not increased by dabigatran relative to aspirin after acute ischaemic stroke/TIA. Methods: DAbigatran Treatment of Acute Stroke II (DATAS II) was a prospective, randomised open label, blinded endpoint trial of dabigatran versus aspirin in acute stroke/TIA (clinicatrials.gov NCT02295826). Non-cardio-embolic stroke/TIA patients (NIHSS score ≤9, infarct volume < 25 ml) who did not receive thrombolytic therapy or thrombectomy were randomised 1:1 to dabigatran 150 mg BID (110 mg BID in patients ≥80 or if CrCl <50 ml/min) or aspirin (81 mg OD). Magnetic resonance imaging was performed prior to randomisation and was repeated at day 30, with clinical assessments at 30 and 90 days. Imaging endpoints were ascertained centrally by readers blinded to treatment. The primary endpoint was symptomatic HT within 37 days of randomisation. Secondary endpoints included asymptomatic HT and recurrent cerebral infarcts. Findings: A total of 305 patients, mean age 66±13.21 years, were randomised to dabigatran or aspirin a mean of 40.10±19.44 hours after symptom onset. The qualifying event was a TIA in 21%, and ischaemic stroke in79% of patients. Median NIHSS (IQR) was 1 (0-2), and mean infarct volume 3.2±6.5 ml. No symptomatic HT occurred. Asymptomatic petechial HT developed in 11/142 (7.8%) of dabigatran-assigned patients and 5/142 (3.5%) of aspirin-assigned patients (RR=2.32, 95% CI 0.78, 6.85). Baseline infarct volume predicted incident HT (OR 1.07; 95% CI 1.03-1.12, p=0.0026). Incident covert infarcts on day 30 imaging occurred in 9/142 (6.3%) of dabigatran and 14/142 (9.8%) of aspirin patients (RR=0.62, 95% CI 0.26, 1.48). There were no major bleeding events with either treatment. Interpretation: Dabigatran given to patients with acute minor non-cardioembolic ischaemic stroke/TIA was safe and was associated with a risk of HT similar to aspirin. Trial Registration Number: clinicatrials.gov NCT02295826 Funding Statement: DATAS II was funded by the Canadian Institutes for Health Research (G327075). Declaration of Interests: Dr. Butcher has served as an advisory board consultant and received speaker’s fees and investigatorinitiated grant support from Boehringer-Ingelheim, Bayer, BMS-Pfizer and Servier. Dr. Sharma has served as an advisory board consultant and or received speaker’s fees and investigator-initiated grant support from Boehringer-Ingelheim, Bayer, BMS-Pfizer, Daiichi Sankyo and Servier. Dr. Benavente has served as an advisory board consultant and or received speaker’s fees from Boehringer-Ingelheim, Bayer, BMS-Pfizer and Servier. Dr. Field has served as an advisory board consultant and received speaker’s fees from BoehringerIngelheim, Bayer, BMS-Pfizer and Servier and investigator-initiated grant support from BoehringerIngelheim and Bayer (study medication). Dr. Hill has served as a consultant for Boehringer-Ingelheim. He has received grants to the University of Calgary from Medtronic, Stryker, Boehringer-Ingelheim Canada, Bayer Canada. Dr. Gioia has received speaker honoraria from Bayer, and BMS Pfizer and has served as an advisory board consultant for Bayer, and Servier Inc. Dr. Coutts has served as an advisory board consultant for BMS-Pfizer. Boehringer-Ingelheim is providing study drug for an investigator-initiated study led by Dr. Coutts. Ethics Approval Statement: The trial was approved by research ethics review boards at each institution.