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ABSTRACT Background: Though multidisciplinary pain treatment (MPT) is considered the gold standard for managing chronic pain, it is unclear which patients benefit most from this high-cost treatment approach. Aims: The goals were to identify subgroups of patients sharing similar pain severity trajectories over time and predictors of MPT responsiveness. Methods: Participants were 1894 patients (mean age = 53.18 years [SD = 14.0]; female = 60.3%) enrolled in the Quebec Pain Registry with moderate to severe baseline pain severity. Patients completed validated questionnaires on pain and related constructs before initiating treatment and 6, 12, and 24 months later. Results: Trajectory analyses of pain severity (intensity and interference) showed that a three-class model best fit the data. Two of the trajectories, which included 24.5% of patients, showed significant improvement in pain severity levels over time (improvers). Compared to patients in the nonimproving trajectory (non-improvers), improvers were younger and more likely to suffer from neuropathic pain and had pain of shorter duration, lower worst pain intensity, lower sleep disturbances and depression scores at baseline, a lower tendency to catastrophize, and better physical health–related quality of life (QOL). This predictive model had a specificity of 96.2% and a sensitivity of 23.6%. Conclusions: Only a minority of patients exhibited an improvement in their pain severity with MPT. Several patients’ characteristics were significantly associated with pain trajectory membership. Early identification of nonimprovers, through examination of baseline characteristics and rates of change in pain scores, can provide valuable information about prognosis and open the doors for evaluation of different cost-effective treatment approaches. Abbreviations: CP = chronic pain; MPT = multidisciplinary pain treatment; QPR = Quebec Pain Registry; QOL = quality of life.

From 1967 until 2020, [Community] has had 85 million litres of pulp and paper mill effluent dumped every day into an estuary that borders the community. Despite long-term concerns about cancer in the community, a federal government appointed Joint Environmental Health Monitoring Committee, mandated to oversee the health of the community, has never addressed [Community] concerns. In this study we accessed the 2013 Canadian Cancer Registry microfile data, and using the standard geographical classification code, accessed the cancer data for [Community], and provided comparable data for all Nova Scotia First Nations, as well as the county, provincial, and national population level data. We determined that digestive organ cancers, respiratory organ cancers, male genital organ cancers, and urinary tract cancers are higher in [Community] than at all comparable levels. Female breast and genital organ cancers are lowest in [Community] than at all other comparable levels. We note the limitation of this study as not being able to capture cancer data for off-reserve members at the time of diagnosis and the lapse in availability of up-to-date CCR data. This study demonstrates that cancer data can be compiled for First Nation communities using the standard geographic code, and although not a comprehensive count of all diagnoses for the registered members of [Community], it is the first study to provide data for those who lived in [Community] at the time of diagnosis. Moreover, it highlights the lack of capacity (or will) by Joint Environmental Health Monitoring Committee to uphold their fiduciary duty.

Abstract Objective Performance measurement and reporting is proliferating in all sectors of the healthcare system, including primary care, despite a dearth of evidence on how the public uses reports on primary care performance. We explored how the public might use this information, to guide the development of effective reporting systems for primary care. Methods We conducted six full‐day deliberative dialogue sessions with a purposive sample of 56 citizen‐patients across three Canadian provinces (British Columbia, Ontario and Nova Scotia). Participants identified how they would use publicly reported performance data. We conducted a thematic analysis of the data by region. Results Common uses for primary care performance information emerged across all sessions. Participants most often discussed the utility of this information for community advocacy and participation in health system decision making. Similar barriers for using performance information to choose a primary care provider were identified in each region including the perceived lack of choice of providers and the high value placed on relationships with current providers. Finally, the value of public performance reporting in enhancing trust that people would receive good care was also a common theme. Conclusions Citizen‐patient perspectives highlight that public reporting on primary care performance could promote the health system's responsiveness by enabling public engagement in decision making at the community level. The role of public reporting in promoting trust rather than empowering patient choice may reflect unique elements of the Canadian health system's context.

Radiographic contrast agents cause acute kidney injury (AKI), yet the underlying pathogenesis is poorly understood. Nod-like receptor pyrin containing 3-deficient (Nlrp3-deficient) mice displayed reduced epithelial cell injury and inflammation in the kidney in a model of contrast-induced AKI (CI-AKI). Unexpectedly, contrast agents directly induced tubular epithelial cell death in vitro that was not dependent on Nlrp3. Rather, contrast agents activated the canonical Nlrp3 inflammasome in macrophages. Intravital microscopy revealed diatrizoate (DTA) uptake within minutes in perivascular CX3CR1+ resident phagocytes in the kidney. Following rapid filtration into the tubular luminal space, DTA was reabsorbed and concentrated in tubular epithelial cells via the brush border enzyme dipeptidase-1 in volume-depleted but not euvolemic mice. LysM-GFP+ macrophages recruited to the kidney interstitial space ingested contrast material transported from the urine via direct interactions with tubules. CI-AKI was dependent on resident renal phagocytes, IL-1, leukocyte recruitment, and dipeptidase-1. Levels of the inflammasome-related urinary biomarkers IL-18 and caspase-1 were increased immediately following contrast administration in patients undergoing coronary angiography, consistent with the acute renal effects observed in mice. Taken together, these data show that CI-AKI is a multistep process that involves immune surveillance by resident and infiltrating renal phagocytes, Nlrp3-dependent inflammation, and the tubular reabsorption of contrast via dipeptidase-1.

Sleep serves crucial learning and memory functions in both nervous and immune systems. Microglia are brain immune cells that actively maintain health through their crucial physiological roles exerted across the lifespan, including phagocytosis of cellular debris and orchestration of neuroinflammation. The past decade has witnessed an explosive growth of microglial research. Considering the recent developments in the field of microglia and sleep, we examine their possible impact on various pathological conditions associated with a gain, disruption, or loss of sleep in this focused mini-review. While there are extensive studies of microglial implication in a variety of neuropsychiatric and neurodegenerative diseases, less is known regarding their roles in sleep disorders. It is timely to stimulate new research in this emergent and rapidly growing field of investigation.

Background: A better understanding of the neural mechanisms that underlie the development of fear of falling (FoF) in seniors may help to detect potential treatable factors and reduce future falls. We therefore investigate the neural correlates of FoF in older adults using 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET). Methods: This cohort study included 117 community-dwelling older adults. At baseline, participants were assessed for FoF, psychiatric symptoms, walking speed, global cognition and cerebral glucose metabolism with FDG-PET. The incidence of FoF in the participants who did not report FoF (N-FoF) at baseline was again ascertained 2 years later. FDG uptake was compared between the FoF and non-FoF groups. Logistic regression analyses to examine the predictors of newly developed FoF (D-FoF) using normalized regional FDG uptake were then performed. Results: At baseline, 50.4% (n = 59) of participants had FoF. The FoF group had significantly decreased glucose metabolism in the left superior frontal gyrus (supplementary motor area, SMA; BA6) compared to the non-FoF group. After 2 years, 19 out of the 58 participants in the non-FoF group developed FoF. Logistic regression analysis revealed that decreased cerebral glucose metabolism in the left SMA at the baseline was a significant predictor of the future development of FoF, independently of psychiatric symptoms and walking speed. Conclusion: In healthy older adults, hypometabolism in the left SMA, which is involved in motor planning and motor coordination, contributes to the development of FoF. Our result might help elucidate underlying mechanism of the association between deficits in motor control and FoF.

The dietary phenol tyrosol has been reported to be endogenously transformed into hydroxytyrosol, a potent antioxidant with multiple health benefits. In this work, we evaluated whether tyrosine hydroxylase (TH) and cytochrome P450s (CYPs) catalyzed this process. To assess TH involvement, Wistar rats were treated with α-methyl-L-tyrosine and tyrosol. Tyrosol was converted into hydroxytyrosol whilst α-methyl-L-tyrosine did not inhibit the biotransformation. The role of CYP was assessed in human liver microsomes (HLM) and tyrosol-to-hydroxytyrosol conversion was observed. Screening with selective enzymatic CYP inhibitors identified CYP2A6 as the major isoform involved in this process. Studies with baculosomes further demonstrated that CYP2D6 and CYP3A4 could transform tyrosol into hydroxytyrosol. Experiments using human genotyped livers showed an interindividual variability in hydroxytyrosol formation and supported findings that CYP2D6 and CYP2A6 mediated this reaction. The dietary health benefits of tyrosol-containing foods remain to be evaluated in light of CYP pharmacogenetics. This work was supported by grants from Instituto de Salud Carlos III FEDER, (PI14/00072), the CICYT-FEDER (AGL2009-13517- C03-01 and AGL2012-40144-C03-01), grants from DIUE of the Generalitat de Catalunya (2014 SGR 680). CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of the Instituto de Salud Carlos III, Madrid, Spain. JRM was supported by a FI-DGR2012 predoctoral fellowship from the Generalitat de Catalunya and CPM was supported by a Juan Rodés fellowship (ISCIII, JR, 15/00005). The authors acknowledge the support received from National Institutes of Health grant DA U01 020830, Canadian Institutes of Health Research grant MOP86471, the Endowed Chair in Addiction for the Department of Psychiatry University of Toronto (RFT), and funds from the Centre for Addiction and Mental Health (CAMH) and the CAMH Foundation (RFT)

BackgroundIn 2017, a provincial health-system released a Rehabilitation Model of Care (RMoC) to promote patient-centred care, provincial standardisation and data-driven innovation. Eighteen early-adopter community-rehabilitation teams implemented the RMoC using a 1.5-year-long Innovation Learning Collaborative (in-person learning sessions; balanced scorecards). More research is required on developing, implementing and evaluating models of care. We aimed to explore experiences of early-adopter providers and provincial consultants involved in the community-rehabilitation RMoC implementation in Alberta, Canada.MethodsUsing focused ethnography, we used focus groups (or interviews for feasibility/confidentiality) and aggregate, site-level data analysis of RMoC standardised metrics. Purposive sampling ensured representation across geography, service types and patient populations. Team-specific focus groups were onsite and led by a researcher-moderator and cofacilitator. A semistructured question guide promoted discussions on interesting/challenging occurrences; perceptions of RMoC impact and perceptions of successful implementation. Focus groups and interviews were audio-recorded and transcribed alongside field notes. Data collection and analysis were concurrent to saturation. Transcripts coding involves collapsing similar ideas into themes, with intertheme relationships identified. Rigour tactics included negative case analysis, thick description and audit trail.ResultsWe completed 11 focus groups and seven interviews (03/2018 to 01/2019) (n=45). Participants were 89.6% women, mostly Canadian trained and represented diverse rehabilitation professions. The implementation experience involved navigating emotions, operating among dynamics and integrating the RMoC details. Confident, satisfied early-adopter teams demonstrated traits including strong coping strategies; management support and being opportunistic and candid about failure. Teams faced common challenges (eg, emotions of change; delayed data access and lack of efficient, memorable communication across team and site). Implementation success targeted patient, team and system levels.ConclusionsWe recommend training priorities for future teams including evaluation training for novice teams; timelines for stepwise implementation; on-site, in-person time with a facilitator and full-team present and prolonged facilitated introductions between similar teams for long-term mentorship.

ABSTRACT Human fungal pathogens cause over 2 million infections per year and are major drivers of morbidity and mortality. Cryptococcus neoformans and Candida albicans are two of the most common fungal pathogens of humans, together accounting for a staggering 1.4 million infections annually, with very high mortality rates. Patients with dysfunctional immune systems, such as individuals with HIV/AIDS, are particularly susceptible to fungal infections. Unfortunately, relatively few antifungal drugs are currently available and fungi frequently develop resistance, further complicating treatment approaches. In this study, we screened the Pathogen Box chemical library (Medicines for Malaria Venture, Switzerland) in an effort to identify novel antifungal compounds. This approach led to the discovery of a novel, highly potent antifungal agent with activity against both C. neoformans and C. albicans. Our initial study of the mechanism of action suggested that this novel compound prevents fungal proliferation by targeting the ability of C. neoformans to withstand stress at the plasma membrane and cell wall. Because this compound had previously been shown to have low toxicity for mammalian cells, we propose that it represents an attractive lead compound for further antifungal drug development. IMPORTANCE Cryptococcus neoformans and Candida albicans are two major human fungal pathogens and together account for over 1.4 million infections annually, with very high mortality rates. These fungi often infect immunocompromised individuals, such as HIV/AIDS patients. In an effort to identify novel drugs with antifungal activity, we have screened the Pathogen Box for compounds with anticryptococcal and anticandidal activities. This approach led to the discovery of a promising lead compound (MMV688271) with strong antifungal potency under nutrient-limited conditions. Cryptococcus neoformans and Candida albicans are two major human fungal pathogens and together account for over 1.4 million infections annually, with very high mortality rates. These fungi often infect immunocompromised individuals, such as HIV/AIDS patients. In an effort to identify novel drugs with antifungal activity, we have screened the Pathogen Box for compounds with anticryptococcal and anticandidal activities. This approach led to the discovery of a promising lead compound (MMV688271) with strong antifungal potency under nutrient-limited conditions.

BackgroundAdherence to nutritional guidelines for chronic disease prevention and management remains a challenge in clinical practice. Innovative strategies are needed to help optimise dietary behaviour change.ObjectiveThe objective of this study was to determine if a nutrigenomics-guided lifestyle intervention programme could be used to motivate greater dietary adherence and change in dietary intake short-term, moderate-term and long-term compared to the gold-standard population-based weight management intervention (Group Lifestyle Balance (GLB)/Diabetes Prevention Programme (DPP)).DesignThe Nutrigenomics, Overweight/Obesity, and Weight Management (NOW) randomised controlled trial is a pragmatic, parallel-group, superiority clinical trial (n=140), which was conducted at the East Elgin Family Health Team (EEFHT). GLB weight management groups were prerandomised 1:1 to receive either the standard GLB programme or a modified GLB+nutrigenomics (GLB+NGx) programme. Three 24-hour recalls were collected at baseline, 3, 6 and 12 months using the validated multiple pass method. Research assistants collecting the three 24-hour recalls were blinded to the participants’ group assignments. Statistical analyses included split plot analyses of variance (ANOVAs), two-way ANOVAs, binary logistic regression, χ2 and Fisher’s exact tests. Using the Theory of Planned Behaviour as guidance, key confounding factors of behaviour change were considered in the analyses. This study was registered with clinicaltrials.gov (NCT03015012).ResultsOnly the GLB+NGx group significantly reduced their total fat intake from baseline to 12-month follow-up (from 36.0%±4.8% kcal to 30.2%±8.7% kcal, p=0.02). Long-term dietary adherence to total fat and saturated fat guidelines was also significantly (p<0.05) greater in the GLB+NGx group compared to the standard GLB group.ConclusionsWeight management interventions guided by nutrigenomics can motivate long-term improvements in dietary fat intake above and beyond gold-standard population-based interventions.