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.
Diabetes confers a two times excess risk of cardiovascular disease, yet predicting individual risk remains challenging. The effect of total microvascular disease burden on cardiovascular disease risk ...among individuals with diabetes is unknown.
A population-based cohort of patients with type 2 diabetes from the UK Clinical Practice Research Datalink was studied (n=49 027). We used multivariable Cox models to estimate hazard ratios (HRs) for the primary outcome (the time to first major cardiovascular event, which was a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal ischaemic stroke) associated with cumulative burden of retinopathy, nephropathy, and peripheral neuropathy among individuals with no history of cardiovascular disease at baseline.
During a median follow-up of 5·5 years, 2822 (5·8%) individuals experienced a primary outcome. After adjustment for established risk factors, significant associations were observed for the primary outcome individually for retinopathy (HR 1·39, 95% CI 1·09-1·76), peripheral neuropathy (1·40, 1·19-1·66), and nephropathy (1·35, 1·15-1·58). For individuals with one, two, or three microvascular disease states versus none, the multivariable-adjusted HRs for the primary outcome were 1·32 (95% CI 1·16-1·50), 1·62 (1·42-1·85), and 1·99 (1·70-2·34), respectively. For the primary outcome, measures of risk discrimination showed significant improvement when microvascular disease burden was added to models. In the overall cohort, the net reclassification index for USA and UK guideline risk strata were 0·036 (95% CI 0·017-0·055, p<0·0001) and 0·038 (0·013-0·060, p<0·0001), respectively.
The cumulative burden of microvascular disease significantly affects the risk of future cardiovascular disease among individuals with type 2 diabetes. Given the prevalence of diabetes globally, further work to understand the mechanisms behind this association and strategies to mitigate this excess risk are warranted.
Circulation Foundation.
The Cobb angle,3 determined from vertical excavation photos, was 75° from the upper border of T6 to the lower border of T11. Since this was measured supine, whereas clinical angles are taken ...standing, we estimate the Cobb angle to have been in the range 70-90° during life. Determining the cause of Richard's scoliosis allows us to estimate the age at which it developed, and how it may have affected him. Since the spinal ligaments are some of the last to decompose after death, and in this case had partly ossified, the position of the vertebrae should show only minimum change from the time of burial, having been surrounded by soil.
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Hyperphosphatemia is strongly associated with cardiovascular morbidity and mortality in patients with chronic kidney disease. Phosphate in beverages is readily absorbed and could have a significant ...impact on serum phosphate levels. Patients are routinely warned about the phosphoric acid in colas, but information on the phosphate content of other beverages is difficult to find. We have shown that the phosphomolybdate method, which is used in the vast majority of hospital laboratories for measuring phosphate in urine, can give an accurate measurement of the phosphate content of beer, cider, wine, and soft drinks. No change to the standard assay protocol is required. There was considerable variation between different types of wine and beer, probably due to the methods of production. The information the assay provides could enable staff providing dietary advice to compare locally available beverages and help patients to avoid or limit their intake of those with high phosphate content.
Prognostication following ICU admission can often be determined based on known risk factors, including demographics and illness severity; however, little is known about outcomes of patients deemed to ...be "low-risk" at the time of hospital admission who subsequently are admitted to the ICU.
The objectives of this study were to determine the characteristics, outcomes, and costs for patients requiring ICU admission despite having lower predicted mortality when they were admitted to the hospital.
In this historical cohort study, we used a prospectively maintained ICU registry that included all ICU admissions to The Ottawa Hospital for patients 18 years or older from January 2011 to December 2016. We classified patients as low-risk using the Hospital-patient 1-year Mortality Risk at admission score, a hospital admission score validated to predict 1-year mortality.
The primary outcome was inhospital mortality. Secondary outcomes included adverse events, resource utilization, and costs.
Of the 17,173 total ICU patients, 3,445 (20.1%) were classified as low-risk at hospital admission. Low-risk patients were younger (48.7 vs 67.5 yr;
< 0.001) and had a lower Multiple Organ Dysfunction Score (2.37 vs 4.14;
< 0.001). Mortality for low-risk patients was significantly lower than for non-low-risk patients (4.1% vs 25.4%;
< 0.001). For low-risk patients, multivariable logistic regression showed mortality was independently associated with older age (odds ratio, 1.02 per 1 yr; 95% CI, 1.00-1.03 per 1 yr), Multiple Organ Dysfunction Score (odds ratio, 1.42 per 1 point; 95% CI, 1.31-1.54 per 1 point), fluid management adverse events (odds ratio, 2.84; 95% CI, 1.29-6.25), hospital-acquired infections (odds ratio, 1.60; 95% CI, 1.02-2.51), and mechanical ventilation (odds ratio, 1.98; 95% CI, 1.20-3.26).
Despite their robust premorbid status, low-risk patients admitted to the ICU had significant inhospital mortality. Fluid management adverse events, hospital-associated infections, multiple organ dysfunction, and mechanical ventilation are important prognostic factors for low-risk patients.
Summary Background Obesity is a major health problem that is determined by interactions between lifestyle and environmental and genetic factors. Although associations between several genetic variants ...and body-mass index (BMI) have been identified, little is known about epigenetic changes related to BMI. We undertook a genome-wide analysis of methylation at CpG sites in relation to BMI. Methods 479 individuals of European origin recruited by the Cardiogenics Consortium formed our discovery cohort. We typed their whole-blood DNA with the Infinium HumanMethylation450 array. After quality control, methylation levels were tested for association with BMI. Methylation sites showing an association with BMI at a false discovery rate q value of 0·05 or less were taken forward for replication in a cohort of 339 unrelated white patients of northern European origin from the MARTHA cohort. Sites that remained significant in this primary replication cohort were tested in a second replication cohort of 1789 white patients of European origin from the KORA cohort. We examined whether methylation levels at identified sites also showed an association with BMI in DNA from adipose tissue (n=635) and skin (n=395) obtained from white female individuals participating in the MuTHER study. Finally, we examined the association of methylation at BMI-associated sites with genetic variants and with gene expression. Findings 20 individuals from the discovery cohort were excluded from analyses after quality-control checks, leaving 459 participants. After adjustment for covariates, we identified an association (q value ≤0·05) between methylation at five probes across three different genes and BMI. The associations with three of these probes—cg22891070, cg27146050, and cg16672562, all of which are in intron 1 of HIF3A —were confirmed in both the primary and second replication cohorts. For every 0·1 increase in methylation β value at cg22891070, BMI was 3·6% (95% CI 2·4–4·9) higher in the discovery cohort, 2·7% (1·2–4·2) higher in the primary replication cohort, and 0·8% (0·2–1·4) higher in the second replication cohort. For the MuTHER cohort, methylation at cg22891070 was associated with BMI in adipose tissue (p=1·72 × 10−5 ) but not in skin (p=0·882). We observed a significant inverse correlation (p=0·005) between methylation at cg22891070 and expression of one HIF3A gene-expression probe in adipose tissue. Two single nucleotide polymorphisms—rs8102595 and rs3826795—had independent associations with methylation at cg22891070 in all cohorts. However, these single nucleotide polymorphisms were not significantly associated with BMI. Interpretation Increased BMI in adults of European origin is associated with increased methylation at the HIF3A locus in blood cells and in adipose tissue. Our findings suggest that perturbation of hypoxia inducible transcription factor pathways could have an important role in the response to increased weight in people. Funding The European Commission, National Institute for Health Research, British Heart Foundation, and Wellcome Trust.
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Background In the context of clinical research, investigators have historically selected the outcomes that they consider to be important, but these are often discordant with patients’ priorities. ...Efforts to define and report patient-centered outcomes are gaining momentum, though little work has been done in nephrology. We aimed to identify patient and caregiver priorities for outcomes in hemodialysis. Study Design Nominal group technique. Setting & Participants Patients on hemodialysis therapy and their caregivers were purposively sampled from 4 dialysis units in Australia (Sydney and Melbourne) and 7 dialysis units in Canada (Calgary). Methodology Identification and ranking of outcomes. Analytical Approach Mean rank score (of 10) for top 10 outcomes and thematic analysis. Results 82 participants (58 patients, 24 caregivers) aged 24 to 87 (mean, 58.4) years in 12 nominal groups identified 68 outcomes. The 10 top-ranked outcomes were fatigue/energy (mean rank score, 4.5), survival (defined by patients as resilience and coping; 3.7), ability to travel (3.6), dialysis-free time (3.3), impact on family (3.2), ability to work (2.5), sleep (2.3), anxiety/stress (2.1), decrease in blood pressure (2.0), and lack of appetite/taste (1.9). Mortality ranked only 14th and was not regarded as the complement of survival. Caregivers ranked mortality, anxiety, and depression higher than patients, whereas patients ranked ability to work higher. Four themes underpinned their rankings: living well, ability to control outcomes, tangible and experiential relevance, and severity and intrusiveness. Limitations Only English-speaking participants were eligible. Conclusions Although trials in hemodialysis have typically focused on outcomes such as death, adverse events, and biological markers, patients tend to prioritize outcomes that are more relevant to their daily living and well-being. Researchers need to consider interventions that are likely to improve these outcomes and measure and report patient-relevant outcomes in trials, and clinicians may become more patient-orientated by using these outcomes in their clinical encounters.
Summary Background Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare ...gefitinib with placebo in previously treated advanced oesophageal cancer. Methods For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0–2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179. Findings Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3·73 months, 95% CI 3·23–4·50, for gefitinib vs 3·67 months, 95% CI 2·97–4·37, for placebo; hazard ratio HR 0·90, 95% CI 0·74–1·09, p=0·29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference −8·61, 95% CI −14·49 to −2·73; n=227; p=0·004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2·69, 95% CI −2·33 to 7·72, n=231, p=0·293), dysphagia (−3·18, 95% CI −8·36 to 2·00, n=231, p=0·228), and eating (−4·11, 95% CI −9·96 to 1·75, n=229, p=0·168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1·57 months, 95% CI 1·23–1·90 in the gefitinib group vs 1·17 months, 95% CI 1·07–1·37 in the placebo group; HR 0·80, 95% CI 0·66–0·96, p=0·020). The most common toxicities were diarrhoea (36 16% of 224 patients on gefitinib vs six 3% of 225 on placebo) and skin toxicity (46 21% vs two 1%), both mostly grade 2. The commonest grade 3–4 toxicities were fatigue (24 11% vs 13 6% patients) and diarrhoea (13 6% vs two 1%). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0·023). Interpretation The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients. Funding Cancer Research UK.
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Summary Background In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different ...AEs have been reported than in blinded trials. Methods In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40–79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest—muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment—and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. Results The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 50% in the atorvastatin group and 5079 50% in the placebo group), with a median follow-up of 3·3 years (IQR 2·7–3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 65% atorvastatin users and 3490 35% non-users), with a median follow-up of 2·3 years (2·2–2·4). During the blinded phase, muscle-related AEs (298 2·03% per annum vs 283 2·00% per annum; hazard ratio 1·03 95% CI 0·88–1·21; p=0·72) and erectile dysfunction (272 1·86% per annum vs 302 2·14% per annum; 0·88 0·75–1·04; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 1·00% per annum vs 210 1·46% per annum; 0·69 0·56–0·85; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 0·20% per annum vs 32 0·22% per annum; 0·94 0·57–1·54; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 1·87% per annum vs 392 1·51% per annum; 1·23 1·08–1·41; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 1·26% per annum vs 124 1·00% per annum; 1·41 1·10–1·79; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 8·69% per annum vs 831 7·45% per annum; 1·17 1·06–1·29; p=0·001) and blood and lymphatic system disorders (114 0·88% per annum vs 80 0·64% per annum; 1·40 1·04–1·88; p=0·03), which were reported more commonly by statin users than by non-users. Interpretation These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. these results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. Funding Pfizer, Servier Research Group, and Leo Laboratories.
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