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An improved understanding of diagnostic and treatment practices for patients with rare primary mitochondrial disorders can support benchmarking against guidelines and establish priorities for evaluative research. We aimed to describe physician care for patients with mitochondrial diseases in Canada, including variation in care.
We conducted a cross-sectional survey of Canadian physicians involved in the diagnosis and/or ongoing care of patients with mitochondrial diseases. We used snowball sampling to identify potentially eligible participants, who were contacted by mail up to five times and invited to complete a questionnaire by mail or internet. The questionnaire addressed: personal experience in providing care for mitochondrial disorders; diagnostic and treatment practices; challenges in accessing tests or treatments; and views regarding research priorities.
We received 58 survey responses (52% response rate). Most respondents (83%) reported spending 20% or less of their clinical practice time caring for patients with mitochondrial disorders. We identified important variation in diagnostic care, although assessments frequently reported as diagnostically helpful (e.g., brain magnetic resonance imaging, MRI/MR spectroscopy) were also recommended in published guidelines. Approximately half (49%) of participants would recommend “mitochondrial cocktails” for all or most patients, but we identified variation in responses regarding specific vitamins and cofactors. A majority of physicians recommended studies on the development of effective therapies as the top research priority.
While Canadian physicians’ views about diagnostic care and disease management are aligned with published recommendations, important variations in care reflect persistent areas of uncertainty and a need for empirical evidence to support and update standard protocols.
We apply two methods to estimate the 21-cm bispectrum from data taken within the Epoch of Reionisation (EoR) project of the Murchison Widefield Array (MWA). Using data acquired with the Phase II compact array allows a direct bispectrum estimate to be undertaken on the multiple redundantly spaced triangles of antenna tiles, as well as an estimate based on data gridded to the uv-plane. The direct and gridded bispectrum estimators are applied to 21 h of high-band (167–197 MHz; z = 6.2–7.5) data from the 2016 and 2017 observing seasons. Analytic predictions for the bispectrum bias and variance for point-source foregrounds are derived. We compare the output of these approaches, the foreground contribution to the signal, and future prospects for measuring the bispectra with redundant and non-redundant arrays. We find that some triangle configurations yield bispectrum estimates that are consistent with the expected noise level after 10 h, while equilateral configurations are strongly foreground-dominated. Careful choice of triangle configurations may be made to reduce foreground bias that hinders power spectrum estimators, and the 21-cm bispectrum may be accessible in less time than the 21-cm power spectrum for some wave modes, with detections in hundreds of hours.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterised by the progressive degeneration of dopaminergic (DA) neurons. The cause of degeneration is not well understood; however, both genetics and environmental factors, such as nutrition, have been implicated in the disease process. Deficiencies in one-carbon metabolism in particular have been associated with increased risk for PD onset and progression, though the precise relationship is unclear. The aim of the present review is to determine the role of one-carbon metabolism and elevated levels of homocysteine in PD onset and pathology and to identify potential mechanisms involved. A search of PubMed, Google Scholar and Web of Science was undertaken to identify relevant human and animal studies. Case–control, prospective cohort studies, meta-analyses and non-randomised trials were included in the present review. The results from human studies indicate that polymorphisms in one-carbon metabolism may increase risk for PD development. There is an unclear role for dietary B-vitamin intake on PD onset and progression. However, dietary supplementation with B-vitamins may be beneficial for PD-affected individuals, particularly those on l-DOPA (levodopa or l-3,4-dihydroxyphenylalanine) treatment. Additionally, one-carbon metabolism generates methyl groups, and methylation capacity in PD-affected individuals is reduced. This reduced capacity has an impact on expression of disease-specific genes that may be involved in PD progression. During B-vitamin deficiency, animal studies report increased vulnerability of DA cells through increased oxidative stress and altered methylation. Nutrition, especially folates and related B-vitamins, may contribute to the onset and progression of PD by making the brain more vulnerable to damage; however, further investigation is required.
People with severe neuromuscular trunk impairment cannot maintain or control upright posture of the upper body in sitting while reaching. Passive orthoses are clinically available to provide support and promote the use of upper extremities in this population. However, these orthoses only position the torso passively without any degree of trunk movement.
We introduce for the first time a novel active-assistive torso brace called Wheelchair Robot for Active Postural Support (WRAPS). It consists of two rings over the hips and chest connected by a 2RPS-2UPS parallel robotic device. WRAPS can modulate the displacement of the upper ring and/or the forces applied on the torso through the ring in four degrees-of-freedom (DOF), including rotations and translation in the sagittal and frontal planes.
In the present study, we evaluate the design of WRAPS and its functions. Moreover, we discuss the potential effectiveness of WRAPS as a therapeutic robotic tool in people with severe trunk control deficits. The performance of WRAPS was evaluated in seated healthy subjects. Kinematics and surface electromyography (sEMG) were collected when the participants performed selective trunk movements. First, the torso range of motion (tROM) was calculated with WRAPS in transparent mode—zero-force control mode—which was compared with free-guided tROM (no WRAPS) with motion capture system. Second, a position control mode was configured to mobilize the torso along the trajectories obtained with the transparent mode.
Our results show that the design of WRAPS suited well the subject’s anthropometrics while supporting the weight of the torso. Importantly, WRAPS can be programmed to replicate the subject’s tROM, without the full activation of torso muscles. This can be critical in individuals with no trunk control. Altogether, these preliminary results indicate the potential applicability of WRAPS to promote active-assistive trunk mobility in people who cannot sit independently because of trunk dysfunction.
Introduction: Individualizing risk for stroke following a transient ischemic attack (TIA) is a topic of intense research, as existing scores are context-dependent or have not been well validated. The Canadian TIA Score stratifies risk of subsequent stroke into low, moderate and high risk. Our objective was to prospectively validate the Canadian TIA Score in a new cohort of emergency department (ED) patients. Methods: We conducted a prospective cohort study in 14 Canadian EDs over 4 years. We enrolled consecutive adult patients with an ED visit for TIA or nondisabling stroke. Treating physicians recorded standardized clinical variables onto data collection forms. Given the ability of prompt emergency carotid endarterectomy (CEA) to prevent stroke (NNT = 3) in high risk patients, our primary outcome was the composite of subsequent stroke or CEA ≤7 days. We conducted telephone follow-up using the validated Questionnaire for Verifying Stroke Free Status at 7 and 90 days. Outcomes were adjudicated by panels of 3 local stroke experts, blinded to the index ED data collection form. Based on prior work, we estimated a sample size of 5,004 patients including 93 subsequent strokes, would yield 95% confidence bands of +/− 10% for sensitivity and likelihood ratio (LR). Our analyses assessed interval LRs (iLR) with 95% CIs. Results: We prospectively enrolled 7,569 patients with mean 68.4 +/−14.7 years and 52.4% female, of whom 107 (1.4%) had a subsequent stroke and 74 (1.0%) CEA ≤7 days (total outcomes = 181). We enrolled 81.2% of eligible patients; missed patients were similar to enrolled. The Canadian TIA Score stratified the stroke/CEA ≤7days risk as: Low (probability <0.2%, iLR 0.20 [95%CI 0.091-0.44]; Moderate (probability 1.3%, iLR 0.79 [0.68-0.92]; High (probability 2.6%, iLR 2.2 [1.9-2.6]. Sensitivity analysis for just stroke ≤7 days yielded similar results: Low iLR 0.17 [95%CI 0.056-0.52], Medium iLR 0.89 [0.75-1.1], High iLR 2.0 [1.6-2.4]. Conclusion: The Canadian TIA Score accurately identifies TIA patients risk for stroke/CEA ≤7 days. Patients classified as low risk can be safely discharged following a careful ED assessment with elective follow-up. Patients at moderate risk can undergo additional testing in the ED, have antithrombotic therapy optimized, and be offered early stroke specialist follow-up. Patients at high risk should in most cases be fully investigated and managed ideally in consultation with a stroke specialist during their index ED visit.
The use of transdiagnostic mental health treatments in low resource settings has been proposed as a possible aid in scaling up mental health services. Modular, multi-problem transdiagnostic treatments can be used to treat a range of mental health problems and are designed to handle comorbidity. Two randomized controlled trials have been completed on one treatment – the Common Elements Treatment Approach, or CETA – delivered by lay counsellors in Iraq and Thailand. This paper utilizes data from two clinical trials to explore the delivery of CETA by lay providers, examining fidelity and flexibility of element use. Data were collected at every therapy session. Clients completed a short symptom assessment and providers described the clinical elements delivered during sessions. Analyses included descriptive statistics of delivery including selection and sequencing of treatment elements, and the variance in element dose, clustering at the counsellor level, using multi-level models. Results indicate that lay providers in low resource settings (with supervision) demonstrated fidelity to the recommended CETA elements, order and dose, and occasionally added in elements and flexed dosage based on client presentation (i.e. flexibility). This modular approach did not result in significantly longer treatment duration. Our analysis suggests that lay providers were able to learn decision-making processes of CETA based on client presentation and adjust treatment as needed with supervision. As modular multi-problem transdiagnostic treatments continue to be explored in low resource settings, research should continue to focus on ‘unpacking’ lay counsellor delivery of these interventions, decision-making processes, and the level of supervision required.
Psychoses, especially schizophrenia, are often preceded by cognitive deficits and psychosis risk states. Altered metabolic profiles have been found in schizophrenia. However, the associations between metabolic profiles and poorer cognitive performance and psychosis risk in the population remain to be determined.
Detailed molecular profiles were measured for up to 8976 individuals from two general population-based prospective birth cohorts: the Northern Finland Birth Cohort 1986 (NFBC 1986) and the Avon Longitudinal Study of Parents and Children (ALSPAC). A high-throughput nuclear magnetic resonance spectroscopy platform was used to quantify 70 metabolic measures at age 15–16 years in the NFBC 1986 and at ages 15 and 17 years in ALSPAC. Psychosis risk was assessed using the PROD-screen questionnaire at age 15–16 years in the NFBC 1986 or the psychotic-like symptoms assessment at age 17 years in ALSPAC. Cognitive measures included academic performance at age 16 years in both cohorts and general intelligence and executive function in ALSPAC. Logistic regression measured cross-sectional and longitudinal associations between metabolic measures and psychosis risk and cognitive performance, controlling for important covariates.
Seven metabolic measures, primarily fatty acid (FA) measures, showed cross-sectional associations with general cognitive performance, four across both cohorts (low density lipoprotein diameter, monounsaturated FA ratio, omega-3 ratio and docosahexaenoic acid ratio), even after controlling for important mental and physical health covariates. Psychosis risk showed minimal metabolic associations.
FA ratios may be important in marking risk for cognitive deficits in adolescence. Further research is needed to clarify whether these biomarkers could be causal and thereby possible targets for intervention.
This paper reports on: (1) an evaluation of a common elements treatment approach (CETA) developed for comorbid presentations of depression, anxiety, traumatic stress, and/or externalizing symptoms among children in three Somali refugee camps on the Ethiopian/Somali border, and (2) an evaluation of implementation factors from the perspective of staff, lay providers, and families who engaged in the intervention.
This project was conducted in three refugee camps and utilized locally validated mental health instruments for internalizing, externalizing, and posttraumatic stress (PTS) symptoms. Participants were recruited from either a validity study or from referrals from social workers within International Rescue Committee Programs. Lay providers delivered CETA to youth (CETA-Youth) and families, and symptoms were re-assessed post-treatment. Providers and families responded to a semi-structured interview to assess implementation factors.
Children who participated in the CETA-Youth open trial reported significant decreases in symptoms of internalizing (d = 1.37), externalizing (d = 0.85), and posttraumatic stress (d = 1.71), and improvements in well-being (d = 0.75). Caregivers also reported significant decreases in child symptoms. Qualitative results were positive toward the acceptability and appropriateness of treatment, and its feasibility.
This project is the first to examine a common elements approach (CETA: defined as flexible delivery of elements, order, and dosing) with children and caregivers in a low-resource setting with delivery by lay providers. CETA-Youth may offer an effective treatment that is easier to implement and scale-up versus multiple focal interventions. A fullscale randomized clinical trial is warranted.
The aim of this paper is to examine Canadian key informants’ perceptions of intrapersonal (within an individual) and interpersonal (among individuals) factors that influence successful primary care and public health collaboration.
Primary health care systems can be strengthened by building stronger collaborations between primary care and public health. Although there is literature that explores interpersonal factors that can influence successful inter-organizational collaborations, a few of them have specifically explored primary care and public health collaboration. Furthermore, no papers were found that considered factors at the intrapersonal level. This paper aims to explore these gaps in a Canadian context.
This interpretative descriptive study involved key informants (service providers, managers, directors, and policy makers) who participated in one h telephone interviews to explore their perceptions of influences on successful primary care and public health collaboration. Transcripts were analyzed using NVivo 9.
A total of 74 participants [from the provinces of British Columbia (n=20); Ontario (n=19); Nova Scotia (n=21), and representatives from other provinces or national organizations (n=14)] participated. Five interpersonal factors were found that influenced public health and primary care collaborations including: (1) trusting and inclusive relationships; (2) shared values, beliefs and attitudes; (3) role clarity; (4) effective communication; and (5) decision processes. There were two influencing factors found at the intrapersonal level: (1) personal qualities, skills and knowledge; and (2) personal values, beliefs, and attitudes. A few differences were found across the three core provinces involved. There were several complex interactions identified among all inter and intra personal influencing factors: One key factor – effective communication – interacted with all of them. Results support and extend our understanding of what influences successful primary care and public health collaboration at these levels and are important considerations in building and sustaining primary care and public health collaborations.
The association between cannabis use and the risk of psychosis has been studied extensively but the temporal order still remains controversial.
To examine the association between cannabis use in adolescence and the risk of psychosis after adjustment for prodromal symptoms and other potential confounders.
The sample (n = 6534) was composed of the prospective general population-based Northern Finland Birth Cohort of 1986. Information on prodromal symptoms of psychosis and cannabis use was collected using questionnaires at age 15–16 years. Participants were followed up for ICD-10 psychotic disorders until age 30 years using nationwide registers.
The risk of psychosis was elevated in individuals who had tried cannabis five times or more (hazard ratio, (HR) = 6.5, 95% CI 3.0–13.9). The association remained statistically significant even when adjusted for prodromal symptoms, other substance use and parental psychosis (HR = 3.0, 95% CI 1.1–8.0).
Adolescent cannabis use is associated with increased risk of psychosis even after adjustment for baseline prodromal symptoms, parental psychosis and other substance use.
In the proceedings of this, and of several recent close binary conferences, there have been several contributions describing smoothed particle hydrodynamics simulations of accretion disks. It is opposite therefore to review the numerical scheme itself with emphasis on its advantages for disk modelling, and the methods used for modelling viscous processes.
Enteric pathogens are commonly known to be transmitted through food or water; however, contact with animals is another important transmission route. This study estimated the annual burden of illness attributable to animal contact for eight enteric pathogens in Canada. Using data from a Canadian expert elicitation on transmission routes, the proportion of enteric illnesses attributable to animal contact was estimated for each pathogen to estimate the annual number of illnesses, hospitalizations and deaths in Canada. For each estimate, a mean and probability intervals were generated. Of all illnesses caused by these eight pathogens, 16% were estimated attributable to animal contact. This estimate translates to 86 000 (31 000–166 000) illnesses, 488 (186–890) hospitalizations and 12 (2–28) deaths annually for the eight pathogens combined. Campylobacter spp. is the leading cause of illnesses annually, with an estimated 38 000 (14 000–71 000) illnesses occurring each year, followed by non-typhoidal Salmonella spp. (17 000, 6000–32 000). The majority of hospitalizations were attributable to non-typhoidal Salmonella spp. (36%) and Campylobacter spp. (31%). Non-typhoidal Salmonella spp. (28%) and Listeria monocytogenes (31%) were responsible for the majority of the estimated deaths. These results identify farm animal and pet/pet food exposure as key pathways of transmission for several pathogens. The estimated burden of illness associated with animal contact is substantial.
A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related.
This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes.
The P300 amplitude and latency were not associated (regression coef. −0.06, 95% CI −0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10–0.28, p < 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (all p > 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships.
The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.
Investigations of drinking behavior across military deployment cycles are scarce, and few prospective studies have examined risk factors for post-deployment alcohol misuse.
Prevalence of alcohol misuse was estimated among 4645 US Army soldiers who participated in a longitudinal survey. Assessment occurred 1–2 months before soldiers deployed to Afghanistan in 2012 (T0), upon their return to the USA (T1), 3 months later (T2), and 9 months later (T3). Weights-adjusted logistic regression was used to evaluate associations of hypothesized risk factors with post-deployment incidence and persistence of heavy drinking (HD) (consuming 5 + alcoholic drinks at least 1–2×/week) and alcohol or substance use disorder (AUD/SUD).
Prevalence of past-month HD at T0, T2, and T3 was 23.3% (s.e. = 0.7%), 26.1% (s.e. = 0.8%), and 22.3% (s.e. = 0.7%); corresponding estimates for any binge drinking (BD) were 52.5% (s.e. = 1.0%), 52.5% (s.e. = 1.0%), and 41.3% (s.e. = 0.9%). Greater personal life stress during deployment (e.g., relationship, family, or financial problems) – but not combat stress – was associated with new onset of HD at T2 [per standard score increase: adjusted odds ratio (AOR) = 1.20, 95% CI 1.06–1.35, p = 0.003]; incidence of AUD/SUD at T2 (AOR = 1.54, 95% CI 1.25–1.89, p < 0.0005); and persistence of AUD/SUD at T2 and T3 (AOR = 1.30, 95% CI 1.08–1.56, p = 0.005). Any BD pre-deployment was associated with post-deployment onset of HD (AOR = 3.21, 95% CI 2.57–4.02, p < 0.0005) and AUD/SUD (AOR = 1.85, 95% CI 1.27–2.70, p = 0.001).
Alcohol misuse is common during the months preceding and following deployment. Timely intervention aimed at alleviating/managing personal stressors or curbing risky drinking might reduce risk of alcohol-related problems post-deployment.
Violence against women and girls (VAWG) is an urgent global health problem. Root causes for VAWG include the individual- and family-level factors of alcohol abuse, mental health problems, violence exposure, and related adverse experiences. Few studies in low- and middle-income countries (LMIC) have assessed the effectiveness of psychological interventions for reducing VAWG. This randomized controlled trial, part of the What Works to Prevent Violence Against Women and Girls consortium, examines the effectiveness of a common elements treatment approach (CETA) for reducing VAWG and comorbid alcohol abuse among families in Zambia.
Study participants are families consisting of three persons: an adult woman, her male husband or partner, and one of her children aged 8–17 (if available). Eligibility criteria include experience of moderate-to-severe intimate partner violence by the woman and hazardous alcohol use by her male partner. Family units are randomized to receive CETA or treatment as usual. The primary outcome is VAWG as measured by the Severity of Violence Against Women Scale, assessed along with secondary outcomes at 24 months post-baseline. Interim assessments are also conducted at 4–5 months (following CETA completion) and 12 months post-baseline.
This ongoing trial is one of the first in sub-Saharan Africa to evaluate the use of an evidence-based common elements approach for reducing VAWG by targeting a range of individual- and family-level factors, including alcohol abuse. Results of this trial will inform policy on what interventions work to prevent VAWG in LMIC with local perspectives on scale up and wider implementation.