ABSTRACT BACKGROUND Understanding the complex interaction of risk factors that increase the likelihood of developing common diseases is challenging. The Canadian Partnership for Tomorrow Project ...(CPTP) is a prospective cohort study created as a population-health research platform for assessing the effect of genetics, behaviour, family health history and environment (among other factors) on chronic diseases. METHODS Volunteer participants were recruited from the general Canadian population for a confederation of 5 regional cohorts. Participants were enrolled in the study and core information obtained using 2 approaches: attendance at a study assessment centre for all study measures (questionnaire, venous blood sample and physical measurements) or completion of the core questionnaire (online or paper), with later collection of other study measures where possible. Physical measurements included height, weight, percentage body fat and blood pressure. Participants consented to passive follow-up through linkage with administrative health databases and active follow-up through recontact. All participant data across the 5 regional cohorts were harmonized. RESULTS A total of 307 017 participants aged 30–74 from 8 provinces were recruited. More than half provided a venous blood sample and/or other biological sample, and 33% completed physical measurements. A total of 709 harmonized variables were created; almost 25% are available for all participants and 60% for at least 220 000 participants. INTERPRETATION Primary recruitment for the CPTP is complete, and data and biosamples are available to Canadian and international researchers through a data-access process. The CPTP will support research into how modifiable risk factors, genetics and the environment interact to affect the development of cancer and other chronic diseases, ultimately contributing evidence to reduce the global burden of chronic disease.
The aim of this work was to compare a high-resolution diffusion-weighted imaging (HR-DWI) acquisition (voxel size = 4.8 mm(3)) to a standard diffusion-weighted imaging (STD-DWI) acquisition (voxel ...size = 29.3 mm(3)) for monitoring neoadjuvant therapy-induced changes in breast tumors.
Nine women with locally advanced breast cancer were imaged with both HR-DWI and STD-DWI before and after 3 weeks (early treatment) of neoadjuvant taxane-based treatment. Tumor apparent diffusion coefficient (ADC) metrics (mean and histogram percentiles) from both DWI methods were calculated, and their relationship to tumor volume change after 12 weeks of treatment (posttreatment) measured by dynamic contrast enhanced magnetic resonance imaging was evaluated with a Spearman's rank correlation.
The HR-DWI pretreatment 15th percentile tumor ADC (P = .03) and early treatment 15th, 25th, and 50th percentile tumor ADCs (P = .008, .010, .04, respectively) were significantly lower than the corresponding STD-DWI percentile ADCs. The mean tumor HR-ADC was significantly lower than STD-ADC at the early treatment time point (P = .02), but not at the pretreatment time point (P = .07). A significant early treatment increase in tumor ADC was found with both methods (P < .05). Correlations between HR-DWI tumor ADC and posttreatment tumor volume change were higher than the STD-DWI correlations at both time points and the lower percentile ADCs had the strongest correlations.
These initial results suggest that the HR-DWI technique has potential for improving characterization of low tumor ADC values over STD-DWI and that HR-DWI may be of value in evaluating tumor change with treatment.
Background Few studies have evaluated both the overall effect of ICU telemedicine programs and the effect of individual components of the intervention on clinical outcomes. Methods The effects of ...nonrandomized ICU telemedicine interventions on crude and adjusted mortality and length of stay (LOS) were measured. Additionally, individual intervention components related to process and setting of care were evaluated for their association with mortality and LOS. Results Overall, 118,990 adult patients (11,558 control subjects, 107,432 intervention group patients) from 56 ICUs in 32 hospitals from 19 US health-care systems were included. After statistical adjustment, hospital (hazard ratio HR = 0.84; 95% CI, 0.78-0.89; P < .001) and ICU (HR = 0.74; 95% CI, 0.68-0.79; P < .001) mortality in the ICU telemedicine intervention group was significantly better than that of control subjects. Moreover, adjusted hospital LOS was reduced, on average, by 0.5 (95% CI, 0.4-0.5), 1.0 (95% CI, 0.7-1.3), and 3.6 (95% CI, 2.3-4.8) days, and adjusted ICU LOS was reduced by 1.1 (95% CI, 0.8-1.4), 2.5 (95% CI, 1.6-3.4), and 4.5 (95% CI, 1.5-7.2) days among those who stayed in the ICU for ≥ 7, ≥ 14, and ≥ 30 days, respectively. Individual components of the interventions that were associated with lower mortality, reduced LOS, or both included (1) intensivist case review within 1 h of admission, (2) timely use of performance data, (3) adherence to ICU best practices, and (4) quicker alert response times. Conclusions ICU telemedicine interventions, specifically interventions that increase early intensivist case involvement, improve adherence to ICU best practices, reduce response times to alarms, and encourage the use of performance data, were associated with lower mortality and LOS.
Human study participants Willison, Donald, ScD; Ondrusek, Nancy, PhD; McLaughlin, John, PhD
Canadian Medical Association journal (CMAJ),
04/2015, Volume:
187, Issue:
7
Journal Article
Peer reviewed
Open access
Fletcher points to streamlined ethics review processes introduced in New Zealand and the United Kingdom. There is also a Canadian solution. Public Health Ontario has developed a process wherein all ...studies involving human participants receive an initial risk screening to determine the required level of ethical scrutiny.2 Similar to the New Zealand protocol with 24 questions,3 the Public Health Ontario process involves a 20-item risk-screening tool, which sorts projects into one of four review levels: full ethics board review, a conventional delegated review process, an expedited delegated review process or no further review with periodic audit (manuscript currently under review).
Summary Background Several of the known risk factors for ovarian cancer are thought to act through their effects on ovulation and the menstrual cycle, such as parity, breastfeeding, and use of oral ...contraceptives. We aimed to assess the effect of these three risk factors, and of tubal ligation, on the risk of ovarian cancer in women who carry a mutation in the BRCA1 or BRCA2 genes. Methods We did a matched case-control study in women who were found to carry a pathogenetic mutation in BRCA1 or BRCA2 . Participants were derived from a population-based study of ovarian cancer in Ontario, Canada, and from an international registry of mutation carriers based in Toronto, ON, Canada. All participants completed a written questionnaire that detailed their reproductive history. Women with invasive ovarian cancer and controls were matched on year of birth, country of residence, mutation ( BRCA1 or BRCA2 ), and history of breast cancer. The odds ratios and 95% CI for ovarian cancer were estimated with respect to use of oral contraceptives, parity, breastfeeding, and tubal ligation. Findings Questionnaires were completed by 799 women with a history of invasive ovarian cancer (670 with BRCA1 mutations, 128 with BRCA2 mutations, and one with a mutation in both genes), and controls were 2424 women without ovarian cancer (2043 with BRCA1 mutations, 380 with BRCA2 mutations, and one with a mutation in both genes). Use of oral contraceptives reduced the risk of ovarian cancer in carriers of BRCA1 mutations (odds ratio 0·56 95% CI 0·45–0·71; p<0·0001) and carriers of BRCA2 mutations (0·39 0·23–0·66; p=0·0004). Parity was associated with a reduced risk for carriers of BRCA1 mutations (0·67 0·46–0·96; p=0·03), but with an increased risk for those with BRCA2 mutations (2·74 1·18–6·41; p=0·02). Breastfeeding was associated with a reduced risk for carriers of BRCA1 mutations (0·74 0·56–0·97; p=0·03). An effect of similar magnitude was seen for carriers of BRCA2 mutations (0·72 0·41–1·29; p=0·27), but this was not statistically significant. The association with tubal ligation was not significant for carriers of BRCA1 mutations (0·80 0·59–1·08; p=0·15), or for carriers of BRCA2 mutations (0·63 0·34–1·15; p=0·13). Interpretation Oral contraceptives could be used as a means to prevent ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The possible adverse effect of parity on ovarian-cancer risk in women with a BRCA2 mutation needs further study.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Extracorporeal membrane oxygenation (ECMO) is a complex rescue therapy utilised to provide circulatory and/or respiratory support to critically ill patients who have failed maximal conventional ...therapy. The use of ECMO in adult cardiac surgery is not routine, occurring in a minority of critically ill patients, typically postoperatively. Presented here are three cases of post-infarct ventricular septal defect with cardiogenic shock managed preoperatively with ECMO support as a bridge to definitive surgical closure. We present a review of ECMO in the adult cardiac surgical population and highlight the potential role of preoperative ECMO for cardiogenic shock in the setting of post-infarct ventricular septal defect (PI VSD) as a bridge to definitive closure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Clenbuterol, a beta(2)-agonist with potent anabolic properties, has been shown to improve skeletal muscle function in healthy subjects, and in high doses, promotes cardiac recovery in patients with ...left ventricular assist devices. In a small, randomized controlled study, we investigated the effect of clenbuterol on skeletal muscle function, cardiac function, and exercise capacity in patients with chronic heart failure. Clenbuterol was well tolerated and led to a significant increase in both lean mass and the lean/fat ratio. Maximal strength increased significantly with both clenbuterol (27%) and placebo (14%); however, endurance and exercise duration decreased after clenbuterol. Prior data support combining exercise training with clenbuterol to maximize performance, and on-going studies will evaluate this approach.
Background Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and ...metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD. Study Design Cross-sectional and longitudinal observational analysis. Setting & Participants Adults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. Predictor Quartiles of plasma CX3CL1 levels at baseline. Outcomes Baseline estimated glomerular filtration rate from a creatinine and cystatin C–based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A1c level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality. Results Among 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P = 0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P < 0.001) in adjusted models. During a mean follow-up of 6 years, there were 352 deaths, 176 myocardial infarctions, and 484 composite outcomes. In fully adjusted models, 1-SD higher CX3CL1 level increased the hazard for all-cause mortality (1.11; 95% CI, 1.00-1.22; P = 0.02) and the composite outcome (1.09; 95% CI, 1.00-1.19; P = 0.04). Limitations Study design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect. Conclusions Circulating CX3CL1 level may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX3CL1 affects the pathogenesis of atherosclerosis and diabetes.
Objective To characterize the population pharmacokinetics (PK) of oral baclofen and assess impact of patient-specific covariates in children with cerebral palsy (CP) in order to support its clinical ...use. Subjects design Children (2-17 years of age) with CP received a dose of titrated oral baclofen from 2.5 mg 3 times a day to a maximum tolerated dose of up to 20 mg 4 times a day. PK sampling followed titration of 10-12 weeks. Serial R- and S-baclofen plasma concentrations were measured for up to 16 hours in 49 subjects. Population PK modeling was performed using NONMEM 7.1 (ICON PLC; Ellicott City, Maryland). Results R- and S-baclofen showed identical concentration-time profiles. Both baclofen enantiomers exhibited linear and dose/kg-proportional PK, and no sex differences were observed. Average baclofen terminal half-life was 4.5 hours. A 2-compartment PK model with linear elimination and transit absorption steps adequately described concentration-time profiles of both baclofen enantiomers. The mean population estimate of apparent clearance/F was 0.273 L/h/kg with 33.4% inter-individual variability (IIV), and the apparent volume of distribution (Vss /F) was 1.16 L/kg with 43.9% IIV. Delayed absorption was expressed by a mean transit time of 0.389 hours with 83.7% IIV. Body weight, a possible genetic factor, and age were determinants of apparent clearance in these children. Conclusion The PK of oral baclofen exhibited dose-proportionality and were adequately described by a 2-compartment model. Our population PK findings suggest that baclofen dosage can be based on body weight (2 mg/kg per day) and the current baclofen dose escalation strategy is appropriate in the treatment of children with CP older than 2 years of age.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Bjornson KF, Belza B, Kartin D, Logsdon RG, McLaughlin J. Self-reported health status and quality of life in youth with cerebral palsy and typically developing youth. Objective To describe ...self-reported health status and quality of life (QOL) of ambulatory youths with cerebral palsy (CP) compared with sex- and age-matched typically developing youth (TDY). Design Prospective cross-sectional cohort comparison. Setting Community-based. Participants A convenience sample of 81 youth with CP (age range, 10−13y) with Gross Motor Function Classification System (GMFCS) levels I through III and 30 TDY participated. They were recruited from 2 regional children’s hospitals and 1 regional military medical center. Interventions Not applicable. Main Outcome Measures Participants completed the Child Health Questionnaire−Child Form (CHQ-CF87) for health status and the Youth Quality of Life for QOL. Results Youth with CP reported significantly lower health status than age- and sex-matched TDY in the following CHQ-CF87 subscales: role/social behavioral physical, bodily pain, physical function, and general health (CP mean rank, 46.8−55.2; TDY mean rank, 62.2−80.9). There were significant differences across GMFCS levels. There were no significant differences in self-reported QOL. Conclusions Self-reported health status, but not QOL, appears sensitive to the functional health issues experienced by ambulatory youth with CP. Pain management and psychosocial support may be indicated for them.
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