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Background Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. Methods We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary efficacy period (weeks 24–36). Results Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups (hazard ratio 1.10; 95% CI 0.62, 1.93). In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was −0.10 g/dL (95% CI −0.33, 0.12) in the primary efficacy period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. Conclusions In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.

RLGS fragments and their corresponding chromosome loci

Supplementary Table S2

Purpose: Newfoundland has one of the highest rates of colorectal cancer in North America. The most common hereditary form of colorectal cancer is hereditary nonpolyposis colorectal cancer caused by mutations in genes involved in mismatch repair. Our purpose was to determine the proportion of hereditary colorectal cancer and to determine the genetic basis of disease in both population and clinically referred cohorts from Newfoundland.Experimental Design: Seventy-eight colorectal cancer patients were accrued over a 2-year period from the Avalon Peninsula of Newfoundland. We also examined 31 hereditary nonpolyposis colorectal cancer–like families, which had been referred to the Provincial Medical Genetics Program. Tumors from probands were tested by immunohistochemistry for deficiencies in MLH1, MSH2, and MSH6 proteins and tested for DNA microsatellite instability. Mutation analyses of MLH1, MSH2, and MSH6 were undertaken by direct sequencing and an assay to detect deletions, amplifications, and rearrangements in MSH2 and MLH1.Results: We identified eight population-based families that fulfill the Amsterdam I or II criteria, 4 (50%) of which seem to have hereditary cancer not attributable to the most commonly mutated mismatch repair genes. In addition, in 16 of 21 (76%) referred families fulfilling Amsterdam I or II criteria, no mutations were found in the three most commonly altered mismatch repair genes, and tumor analyses corroborated these findings.Conclusions: It seems that strong and novel genetic causes of hereditary colorectal cancer are responsible for a high proportion of colorectal cancer in this population. Conditions are suitable for the identification of these genes by linkage studies of large Newfoundland cancer families.

Supplementary Tables 1-3 from High Frequency of Hereditary Colorectal Cancer in Newfoundland Likely Involves Novel Susceptibility Genes

Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65–1.04)] but not BRAF-wildtype tumors [1.09 (0.97–1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case–control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (Ptrend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported.Significance:These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.

Introduction: Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production. Methods: To comprehensively analyze the safety profile of vadadustat in patients with dialysis-dependent and non-dialysis-dependent CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n = 7,373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm. Results: In patients randomized to vadadustat versus darbepoetin alfa, rates of TEAEs (88.9% vs. 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs. 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events. Discussion/Conclusion: Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa.

Paradoxically epidemiological data illustrate a negative relationship between dietary folate intake and colorectal cancer (CRC) risk. The occurrence and progression of CRC may be influenced by variants in some key enzyme coding genes in the folate metabolic pathway. We investigated the correlation between genetic variants in methionine synthase reductase (This study used data collected from the Newfoundland Familial Colorectal Cancer Study. A total of 532 patients diagnosed with CRC for the first time from 1999 to 2003 were enrolled, and their mortality were tracked until April 2010. DNA samples were genotyped by Illumina's integrated quantum 1 million chip. Cox models were established to assess 33 tag single-nucleotide polymorphisms inThePolymorphic variants in

Vitamin D, Ca and dairy products are negatively associated with colorectal cancer (CRC) incidence, but little is known of their influence on CRC survival. To investigate prediagnostic intakes of vitamin D, Ca and dairy products for their relevance to CRC prognosis, we analysed 504 CRC patients enrolled in the Newfoundland Colorectal Cancer Registry Cohort Study who were diagnosed for the first time with CRC between 1999 and 2003. Follow-up for mortality and cancer recurrence was through April 2010. Data on diet and lifestyle factors were gathered via a validated, semi-quantitative FFQ and a Personal History Questionnaire. Multivariate Cox models estimated hazard ratios (HR) and 95 % CI for the relationship of prediagnostic intakes of vitamin D, Ca and dairy products with all-cause mortality (overall survival, OS) and disease-free survival (DFS) among CRC patients. We found that prediagnostic Ca intake from foods, but not total Ca intake, was negatively associated with all-cause mortality (HR for Q2 v. Q1, 0·44; 95 % CI, 0·26, 0·75). An inverse relationship was also seen in a dose–response fashion for prediagnostic cheese intake (HR for Q4 v. Q1, 0·57, 95 % CI, 0·34, 0·95, Ptrend = 0·029). No evidence for modification by sex, physical activity, alcohol drinking and cigarette smoking was observed. In summary, high prediagnostic intakes of cheese and Ca from foods may be associated with increased survival among CRC patients. By manipulating diet, this study may contribute to the development of novel therapies that add to the armamentarium against CRC. Replication studies are required before any nutritional interventions are made available.

Background Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. Meth...

Objective: The use of antipsychotics to treat seniors in long-term care facilities (LTCFs) has raised concern because of health consequences (i.e., increased risk of falls, stroke, death) in this vulnerable population. This study measured geographic patterns of antipsychotic utilization among seniors living in LTCFs in Newfoundland and Labrador (NL) and assessed potential inappropriateness. Method: We analyzed prescription records among adults 66 years and older with provincial prescription drug coverage admitted to LTCFs in NL between April 1, 2011, and March 31, 2014. Patterns of use were analyzed across the 4 regional health authorities (RHAs) in NL and LTCFs. Logistic, Poisson and linear regression models were used to test variations in prevalence, rate and volume of antipsychotic utilization. To assess potential inappropriateness of antipsychotic use, we analyzed data from Resident Assessment Instrument–Minimum Data Set (RAI-MDS) 2.0 forms from NL LTCFs between January 1, 2016, and December 31, 2018. Pearson chi-squared analysis was performed at the RHA and LTCF levels to determine changes in percentage of total prescriptions or antipsychotic prescriptions without psychosis. Results: Between 2011 and 2014, 2843 seniors were admitted to LTCFs across NL; of these, 1323 residents were prescribed 1 or more antipsychotics. Within the 3-year period, the percentage of antipsychotic use across facilities ranged from 35% to 78%. Using data from 27,260 RAI-MDS 2.0 assessments between 2016 and 2018, 71% (6995/9851) of antipsychotic prescriptions were potentially inappropriate. Discussion: There is substantial variation across NL regions concerning the utilization of antipsychotics for senior in LTCFs. Facility size and management styles may be reasons for this. Conclusion: With nearly three-quarters of antipsychotic prescriptions shown to be potentially inappropriate, systematic interventions to assess indications for antipsychotic use are warranted. Can Pharm J (Ott) 2021;154:xx-xx.

Introduction Several jurisdictions have adopted a more conservative approach to anemia in patients receiving dialysis amid safety concerns from target hemoglobin studies. It is largely unknown if this has contributed to a change in clinical outcomes. Methods A national registry was used to identify 35,945 adult patients who initiated and were maintained on dialysis for ≥90 days in Canada from January 2007 to December 2015. Outcomes were ascertained until March 2017 via linkage with hospital discharge diagnoses. Cox proportional hazards models were used to investigate the association between the era of dialysis initiation and the primary composite outcome (acute myocardial infarction [AMI], stroke, or mortality). Results The mean hemoglobin at dialysis initiation decreased from 102.9 g/l in 2007 to 95.5 g/l in 2015, corresponding with a higher prevalence of hemoglobin, Graphical abstract

We examined dietary fiber intake for its relevance to Colorectal cancer (CRC) survival in a cohort of CRC patients and a meta-analysis including results from four prospective cohort studies. We analyzed 504 CRC patients enrolled in the Newfoundland Familial Colorectal Cancer Study (NFCCS) who were newly diagnosed with CRC between 1999 and 2003. Follow-up for deaths was through April 2010. All participants completed a self-administered food frequency questionnaire to evaluate their dietary intakes one year before diagnosis. Multivariable Cox proportional hazard models were used to explore the associations of dietary fiber intake with all-cause mortality and CRC-specific mortality. In the meta-analysis, we identified prospective cohort studies published between January 1991 and December 2021 by searching PubMed, EMBASE, and Cochrane Library. Fixed-effects or random-effects models were used to combine the study-specific hazard ratio (HR) from our original analysis and three other cohorts. In the NFCCS, we found that CRC patients with the second quartile of dietary fiber intake had a 42% lower risk of all-cause mortality (HR: 0.58, 95% CI: 0.35–0.98) and 58% lower risk of CRC-specific mortality (HR: 0.42, 95% CI: 0.21–0.87) compared with those with the lowest quartile. In the meta-analysis, a similar inverse association between dietary fiber and total mortality was detected among CRC patients; each 10 g/day increase in dietary fiber intake was associated with a 16% decreased risk of total mortality. The dose–response meta-analysis showed a linear relationship between dietary fiber intake and all-cause mortality, with no sign of a plateau. For CRC-specific mortality, intriguingly, the benefit associated with increasing dietary fiber intake achieved its maximum at approximately 22 g/day, and no further reduction in CRC-specific mortality was observed beyond this intake level. Our results suggest that high dietary fiber intake may be associated with prolonged survival among CRC patients. Our findings add to the sparse literature on the role of dietary fiber in CRC survival.

Background CT Imaging is often requested for patients with low back pain (LBP) by their general practitioners. It is currently unknown what reasons are common for these referrals and if CT images are ordered according to guidelines in one province in Canada, which has high rates of CT imaging. The objective of this study is to categorise lumbar spine CT referrals into serious spinal pathology, radicular syndrome, and non-specific LBP and evaluate the appropriateness of CT imaging referrals from general practitioners for patients with LBP. Methods A retrospective medical record review of electronic health records was performed in one health region in Newfoundland and Labrador, Canada. Inclusion criteria were lumbar spine CT referrals ordered by general practitioners for adults ≥18 years, and performed between January 1st-December 31st, 2016. Each CT referral was identified from linked databases (Meditech and PACS). To the study authors’ knowledge, guidelines regarding when to refer patients with low back pain for CT imaging had not been actively disseminated to general practitioners or implemented at clinics/hospitals during this time period. Data were manually extracted and categorised into three groups: red flag conditions (judged to be an appropriate referral), radicular syndrome (judged be unclear appropriateness), or nonspecific LBP (determined to be inappropriate). Results Three thousand six hundred nine lumbar spine CTs were included from 2016. The mean age of participants was 54.7 (SD 14 years), with females comprising 54.6% of referrals. 1.9% of lumbar CT referrals were missing/unclear, 6.5% of CTs were ordered on a red-flag suspicion, 75.6% for radicular syndromes, and 16.0% for non-specific LBP; only 6.5% of referrals were clearly appropriate. Key information including patient history and clinical exams performed at appointment were often missing from referrals. Conclusion This audit found high proportions of inappropriate or questionable referrals for lumbar spine CT and many were missing information needed to categorise. Further research to understand the drivers of inappropriate imaging and cost to the healthcare system would be beneficial.

Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65–1.04)] but not BRAF-wildtype tumors [1.09 (0.97–1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case–control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (Ptrend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. Significance: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.

High-level exercise has been associated with a malignant phenotype in desmosomal and genotype-negative forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). This is the first study to examine this issue with ARVC secondary to the TMEM43 p.S358L mutation.The purpose of this study was to evaluate the impact of exercise on arrhythmic risk and cardiac death in TMEM43 p.S358L ARVC.Individuals with the TMEM43 p.S358L mutation enrolled in a prospective registry who had received a primary prevention implantable cardioverter-defibrillator (ICD) were invited to complete the modified Paffenbarger Physical Activity Questionnaire to assess their physical activity in the year before their ICD implantation. Time-to-event analyses using unadjusted and adjusted Cox proportional hazards models evaluated associations between physical activity and first appropriate ICD discharge secondary to malignant ventricular arrhythmia or cardiac death.In 80 subjects with the TMEM43 p.S358L mutation, exercise ≥9.0 metabolic equivalent of task (MET)-hours/day (high level) in the year before ICD implantation was associated with an adjusted 9.1-fold increased hazard of first appropriate ICD discharge (there were no deaths) relative to physical activity9.0 MET-hours/day (moderate level) (95% confidence interval [CI] 3.3-24.6 MET-hours/day; P.001). The median age from birth to first appropriate ICD discharge was 58.5 years (95% CI 56.5-60.5 years) vs 35.8 years (95% CI 28.2-43.4 years) (P.001) in subjects in moderate- and high-level exercise groups, respectively.Exercise ≥9.0 MET-hours/day is associated with an increased risk of malignant ventricular arrhythmias in the TMEM43 p.S358L subtype of ARVC. Extrapolating these data, we suggest molecular testing be offered in early childhood to inform exercise choices reflective of the genotype.

Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.

The prevalence of anemia increases as chronic kidney disease (CKD) progresses. Ultimately, anemia occurs in most patients who undergo dialysis, as well as in many patients with CKD who do not under...

Background Reducing computed tomography (CT) examinations of the lumbar spine is one of Choosing Wisely Canada's initial top 10 recommendations. This study's objective was to report the age- and-sex standardized rates of lumbar spine CT ordered by family physicians in 1 health region in Newfoundland and Labrador. Methods We conducted a retrospective study using local health data from Meditech, an electronic health record system, from 2013 to 2016 for the Eastern Health Region of Newfoundland and Labrador, the largest health region in the province. Records were included if the referral was for an adult aged 20 years or more, and CT was ordered by a family physician. Lumbar spine CT rates were contextualized with age- and sex-stratified estimates. Population estimates were provided by the Newfoundland and Labrador Centre for Health Information to calculate age- and sex-standardized rates per 100 000 people. We calculated rate ratios to test for statistical significance in differences in rates between years. Results A total of 14 370 records were examined. The age- and sex-standardized rates of lumbar spine CT per 100 000 were 1225 in 2013, 1393 in 2014, 1556 in 2015 and 1395 in 2016. The rate ratio was 1.137 (95% confidence interval [CI] 1.084-1.194) for the comparison between 2014 and 2013, 1.117 (95% CI 1.067-1.169) between 2015 and 2014, and 0.896 (95% CI 0.857-0.938) between 2016 and 2015. Interpretation The age- and sex-standardized rates suggest that there was a steady rate of lumbar spine CT examinations being ordered by family physicians in Newfoundland and Labrador in 2013-2016. Although all rate ratios were statistically significant, the magnitude of the difference between years is likely not clinically relevant. These rates are important because they serve as a benchmark for future initiatives to reduce unnecessary referrals for lumbar spine CT.

Highlights •CKD is associated with very high risk of CAD. CAD management is complicated in CKD patients, due to comorbid conditions and potential side effects during interventions. •There are few trials related to CAD with focus on CKD patients, particularly in those with advanced CKD. •Additional prospective studies focusing on diagnosis, prevention, and treatment of CAD are needed in CKD.

Joint models for recurrent and terminal events have not been yet developed for clustered data. The goals of our study are to develop a statistical framework for modelling clustered recurrent and terminal events and to perform dynamic predictions of the terminal event in family studies. We propose a joint nested frailty model for colonoscopy screening visits and colorectal cancer onset in Lynch Syndrome families. The screening and disease processes could each depend on individuals' screening history and other measured covariates and be correlated within families; our approach allows for familial correlations to affect both the visit process and the terminal event and the dependence between the two processes is specified through frailty distributions. We provide dynamic predictions of colorectal cancer risk for an individual conditional on his/her own screening history, his/her family history of screening and disease and other important clinical covariates. We apply our model to 18 Lynch Syndrome families from Newfoundland for individualized dynamic predictions of colorectal cancer risks. We demonstrate that the screening visits are non-ignorable for estimating the disease risks, and the joint nested frailty model improves dynamic prediction accuracies compared to existing joint frailty models after accounting for familial and individual screening and cancer histories.

Background Colorectal cancer is the third most common cancer in the world. In this study, we assessed the long-term survival characteristics and prognostic associations and potential time-varying effects of clinico-demographic variables and two molecular markers (microsatellite instability (MSI) and BRAF Val600Glu mutation) in a population-based patient cohort followed up to ~ 19 years. Methods The patient cohort included 738 incident cases diagnosed between 1999 and 2003. Cox models were used to analyze the association between the variables and a set of survival outcome measures (overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), metastasis-free survival (MFS), recurrence/metastasis-free survival (RMFS), and event-free survival (EFS)). Cox proportional hazard (PH) assumption was tested for all variables, and Cox models with time-varying effects were used if any departure from the PH assumption was detected. Results During the follow-up, ~ 61% patients died from any cause, ~ 26% died from colorectal cancer, and ~ 10% and ~ 20% experienced recurrences and distant metastases, respectively. Stage IV disease and post-diagnostic recurrence or metastasis were strongly linked to risk of death from colorectal cancer. If a patient had survived the first 6 years without any disease-related event (i.e., recurrence, metastasis, or death from colorectal cancer), their risks became very minimal after this time period. Distinct sets of markers were associated with different outcome measures. In some cases, the effects by variables were constant throughout the follow-up. For example, MSI-high tumor phenotype and older age at diagnosis predicted longer MFS times consistently over the follow-up. However, in some other cases, the effects of the variables varied with time. For example, adjuvant radiotherapy treatment was associated with increased risk of metastasis in patients who received this treatment after 5.5 years post-diagnosis, but not before that. Conclusions This study describes the long-term survival characteristics of a prospective cohort of colorectal cancer patients, relationships between baseline variables and a detailed set of patient outcomes over a long time, and time-varying effects of a group of variables. The results presented advance our understanding of the long-term prognostic characteristics in colorectal cancer and are expected to inspire future studies and clinical care strategies. Electronic supplementary material The online version of this article (10.1186/s12916-019-1379-5) contains supplementary material, which is available to authorized users.

Background: Paradoxically epidemiological data illustrate a negative relationship between dietary folate intake and colorectal cancer (CRC) risk. The occurrence and progression of CRC may be influenced by variants in some key enzyme coding genes in the folate metabolic pathway. We investigated the correlation between genetic variants in methionine synthase reductase (MTRR) and methylenetetrahydrofolate reductase (MTHFR) and CRC survival. Methods: This study used data collected from the Newfoundland Familial Colorectal Cancer Study. A total of 532 patients diagnosed with CRC for the first time from 1999 to 2003 were enrolled, and their mortality were tracked until April 2010. DNA samples were genotyped by Illumina’s integrated quantum 1 million chip. Cox models were established to assess 33 tag single-nucleotide polymorphisms in MTRR and MTHFR in relation to overall survival (OS), disease-free survival (DFS) and CRC-specific survival. Results: The MTRR and MTHFR genes were associated with DFS and CRC-specific survival in CRC patients at the gene level. After multiple comparison adjustment, MTRR rs1801394 A (vs. G) allele was associated with increased DFS (p = 0.024), while MTHRT rs3737966 (G vs. A), rs4846049 (T vs. G), rs1476413 (A vs. G), rs1801131 (C vs. A), rs12121543 (A vs. C), rs1801133 (C vs. T), rs4846052 (T vs. C), rs2066471 (A vs. G) and rs7533315 (T vs. C) were related to worse CRC-specific survival. Additionally, significant interactions were seen among pre-diagnostic alcohol consumption with MTRR rs1801394, rs3776467, rs326124, rs162040, and rs3776455, with superior OS associated with those protective variant alleles limited to patients with alcohol consumption under the median. The MTHFR rs3737966 (G vs. A) allele seemed to be detrimental to CRC survival only among subjects with fruit intake below the median. Conclusions: Polymorphic variants in MTRR and MTHFR genes that code for key enzymes for folate metabolism may be associated with survival in patients with CRC. The gene-CRC outcome association seems modulated by alcohol drinking and fruit intake.

Background Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite. Methods Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite. Results Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27; P = .04). Conclusion In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease.

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production.We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter).A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively.Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO

The quantity of health spending does not equate directly to the quality of healthcare. Social spending and nonmedical determinants of health impact on health outcomes. The value of health spending in the United States is limited by the high cost of goods and labor, and administrative costs, high use of low-level care, and lack of basic healthcare coverage in a substantial minority of the population. There are additional reasons for differences in the value of health spending as revealed by a comparison of Canada and Australia, where similar spending per capita results in better health system performance in Australia than in Canada. Within Canada, there are large differences between provinces in the value of health spending. Overutilization of health resources occurs when an intervention is not indicated, or of low value, or is provided at the wrong time. The Choosing Wisely Initiative is a solution for overutilization of low-value care. Recognition of the reality that effective treatments are often applied inconsistently and inappropriately has spurred the development of a science concerned with improvement of quality of care.

When analyzing the results of a trial, the primary outcome variable must be kept in clear focus. In the analysis plan, consideration must be given to comparing the characteristics of the subjects, taking account of differences in these characteristics, intention-to-treat analysis, interim analyses and stopping rules, mortality comparisons, composite outcomes, research design including run-in periods, factorial, stratified and crossover designs, number needed to treat, power issues, multivariate modeling, subgroup analysis, competing risks, and hypothesis-generating analyses.

Statistical models are used to study the relationship between exposure and disease while accounting for the potential role of other factors' impact upon outcomes. This adjustment is useful to obtain unbiased estimates of true effects or to predict future outcomes. Statistical models include a systematic and an error component. The systematic component explains the variability of the response variable as a function of the predictors and is summarized in the effect estimates (model coefficients). The error element of the model represents the variability in the data unexplained by the model and is used to build measures of precisions around the point estimates (Confidence Intervals).

In longitudinal studies, the relationship between exposure and disease can be measured once or multiple times while participants are monitored over time. Traditional regression techniques are used to model outcome data when each epidemiological unit is observed once. These models include generalized linear models for quantitative continuous, discrete, or qualitative outcome responses, and models for time-to-event data. When data come from the same subjects or group of subjects, observations are not independent and the underlying correlation needs to be addressed in the analysis. In these circumstances, extended models are necessary to handle complexities related to clustered data, and repeated measurements of time-varying predictors and/or outcomes.

The intention-to-treat analysis is the gold standard for evaluating the efficacy in a randomized controlled trial. However, when non-adherence to randomized treatments is high the actual treatment effect may be underestimated. The impact of drop-out from the intervention group or drop-in to the control group may be controlled by trial design, increasing the sample size, effective study execution, and a pre-specified analytical plan to take contamination into account.These analyses may include censoring at the time of co-interventions associated with stopping treatment, lag censoring which allows an additional period after discontinuation of study treatment to account for residual treatment effects, inverse probability of censoring weights (IPCW), accelerated failure time models, and contamination adjusted intent-to-treat analysis . These methods are particularly useful in assessing the "prescribed efficacy" of the study treatment, which can aid clinical decision-making .

Knowledge translation (KT) is critical to realizing real-world impacts from health research by reducing the amount of time it takes for evidence to inform practice. One way this is achieved is by engaging with knowledge users throughout the process to ensure that research responds to their needs. It is also important to share the study results in a way that is useful, accessible, and relevant to knowledge user groups. KT planning involves multiple categories described in templates that are available online and referenced in the text. Common knowledge translation challenges and suggested solutions, as well as real-world KT examples, are also provided.

Knowledge translation (KT) is critical to realizing real-world impacts from health research by reducing the amount of time it takes for evidence to inform practice. One way this is achieved is by engaging with knowledge users throughout the process to ensure that research responds to their needs. It is also important to share the study results in a way that is useful, accessible, and relevant to knowledge user groups. KT planning involves multiple categories described in templates that are available online and referenced in the text. Common knowledge translation challenges and suggested solutions, as well as real-world KT examples, are also provided.

Quality-of-life (QoL) outcomes are important elements of randomized controlled trials. The instruments for measurement of QoL vary but usually multiple comparisons are possible, a concern that can be offset by prespecifying the outcomes of interest. Missing data may threaten the validity of QoL assessments in trials. Therefore, familiarity with the strategies used to account for missing data is necessary. Measures that incorporate both survival and QoL are helpful for treatment decisions. The definition of minimal clinically important differences in QoL scores is important and often derived using inadequate methods.

ObjectiveAn understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for sporadic CRC differs by anatomical subsite of the primary tumor has not been examined.DesignTo identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48,214 CRC cases and 64,159 controls of European ancestry. We characterized effect heterogeneity at CRC risk loci using multinomial modeling.ResultsWe identified 13 loci that reached genome-wide significance (P−8) and that were not reported by previous GWAS for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.ConclusionGenetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumor.Significance of this studyWhat is already known about this subject?Heterogeneity among colorectal cancer (CRC) tumors originating at different locations of the colorectum has been revealed in somatic genomes, epigenomes, and transcriptomes, and in some established environmental risk factors for CRC.Genome-wide association studies (GWAS) have identified over 100 genetic variants for overall CRC risk; however, a comprehensive analysis of the extent to which genetic risk factors differ by the anatomical sublocation of the primary tumor is lacking.What are the new findings?In this large consortium-based study, we analyzed clinical and genome-wide genotype data of 112,373 CRC cases and controls of European ancestry to comprehensively examine whether CRC case subgroups defined by anatomical sublocation have distinct germline genetic etiologies.We discovered 13 new loci at genome-wide significance (P−8) that were specific to certain anatomical sublocations and that were not reported by previous GWAS for overall CRC risk; multiple lines of evidence support strong candidate target genes at several of these loci, including PTGER3, LCT, MLH1, CDX1, KLF14, PYGL, BCL11B, and BMP7.Systematic heterogeneity analysis of genetic risk variants for CRC identified thus far, revealed that the genetic architectures of proximal and distal CRC are partly distinct.Taken together, our results further support the idea that tumors arising in different anatomical sublocations of the colorectum may have distinct etiologies.How might it impact on clinical practice in the foreseeable future?Our results provide an informative resource for understanding the differential role that genes and pathways may play in the mechanisms of proximal and distal CRC carcinogenesis.The new insights into the etiologies of proximal and distal CRC may inform the development of new precision prevention strategies, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention.Our findings suggest that future studies of etiological risk factors for CRC and molecular mechanisms of carcinogenesis should take into consideration the anatomical sublocation of the colorectal tumor.

The intention-to-treat analysis is the gold standard for evaluating the efficacy in a randomized controlled trial. However, when non-adherence to randomized treatments is high the actual treatment effect may be underestimated. The impact of drop-out from the intervention group or drop-in to the control group may be controlled by trial design, increasing the sample size, effective study execution, and a pre-specified analytical plan to take contamination into account.These analyses may include censoring at the time of co-interventions associated with stopping treatment, lag censoring which allows an additional period after discontinuation of study treatment to account for residual treatment effects, inverse probability of censoring weights (IPCW), accelerated failure time models, and contamination adjusted intent-to-treat analysis . These methods are particularly useful in assessing the "prescribed efficacy" of the study treatment, which can aid clinical decision-making .

The quantity of health spending does not equate directly to the quality of healthcare. Social spending and nonmedical determinants of health impact on health outcomes. The value of health spending in the United States is limited by the high cost of goods and labor, and administrative costs, high use of low-level care, and lack of basic healthcare coverage in a substantial minority of the population. There are additional reasons for differences in the value of health spending as revealed by a comparison of Canada and Australia, where similar spending per capita results in better health system performance in Australia than in Canada. Within Canada, there are large differences between provinces in the value of health spending. Overutilization of health resources occurs when an intervention is not indicated, or of low value, or is provided at the wrong time. The Choosing Wisely Initiative is a solution for overutilization of low-value care. Recognition of the reality that effective treatments are often applied inconsistently and inappropriately has spurred the development of a science concerned with improvement of quality of care.

In longitudinal studies, the relationship between exposure and disease can be measured once or multiple times while participants are monitored over time. Traditional regression techniques are used to model outcome data when each epidemiological unit is observed once. These models include generalized linear models for quantitative continuous, discrete, or qualitative outcome responses, and models for time-to-event data. When data come from the same subjects or group of subjects, observations are not independent and the underlying correlation needs to be addressed in the analysis. In these circumstances, extended models are necessary to handle complexities related to clustered data, and repeated measurements of time-varying predictors and/or outcomes.

Clinical epidemiological research entails assessing the burden and etiology of disease, the diagnosis and prognosis of disease, the efficacy of preventive measures or treatments, the analysis of the risks and benefits of diagnostic and therapeutic maneuvers, and the evaluation of health care services. In all areas, the main focus is to describe the relationship between exposure and outcome and to determine one of the following: prevalence, incidence, cause, prognosis, or effect of treatment. The accuracy of these conclusions is determined by the validity of the study. Validity is determined by addressing potential biases and possible confounders that may be responsible for the observed association. Therefore, it is important to understand the types of bias that exist and also to be able to assess their impact on the magnitude and direction of the observed effect. The following chapter reviews the epidemiological concepts of selection bias, information bias, intervention bias, and confounding and discusses ways in which these sources of bias can be minimized.

In March 2016, an Enhanced Recovery After Surgery (ERAS) initiative was implemented for all elective colorectal resections at an urban hospital in St. John's, Newfoundland and Labrador, Canada. An ERAS coordinator supervised and enforced guideline compliance for 6 months. The aim of this study was to evaluate the sustainability of the ERAS program after supervision of guideline compliance was eliminated.Patient outcomes and guideline compliance were compared between surgeries performed under standard practice (April 2014 to March 2015) and those performed during and after the implementation of the ERAS initiative (March 2016 to August 2016 was the implementation phase and September 2016 to February 2017 was the sustainability phase).Hospital length of stay decreased from 7.26 days at baseline to 5.44 days during the implementation phase of the ERAS program (p0.001). There was no significant difference between length of stay at baseline and during the 6-month sustainability phase of the ERAS program (7.10 d). There were no significant differences in rates of readmission or mortality during and after implementation. Rate of ileus decreased significantly from 13.8% during the implementation phase to 4.6% during the sustainability phase (p = 0.036). Total guideline compliance increased from 52.2% at baseline to 80.7% during the implementation phase (p0.001), and decreased to 74.7% during the sustainability phase (p0.001). Adherence to postoperative guidelines regressed: 79.2% in the implementation phase and 68.6% in the sustainability phase (p0.001).La durée des séjours à l’hôpital a diminué après l’adoption du programme de RAAC, lorsque le coordonnateur du programme était présent. Les méthodes de maintien des lignes directrices après leur adoption seront cruciales au succès de programmes similaires à l’avenir.En mars 2016, une initiative de récupération améliorée après la chirurgie (RAAC) a été mise en place pour toutes les résections colorectales électives effectuées dans un hôpital urbain de St. John’s, à Terre-Neuve-et-Labrador, au Canada. Un coordonnateur du projet de RAAC a supervisé l’application des directives pendant 6 mois. Cette étude visait à évaluer la viabilité du programme une fois que l’application des directives n’était plus surveillée.Nous avons comparé les issues pour les patients et le respect des directives pour les chirurgies réalisées selon les pratiques habituelles (avril 2014 à mars 2015) et pour celles réalisées pendant et après l’adoption du programme de RAAC (mars 2016 à août 2016 — mise en oeuvre — et septembre 2016 à février 2017 — évaluation de la viabilité).La durée du séjour à l’hôpital est passée de 7,26 jours à 5,44 jours pendant la phase de mise en oeuvre du programme (p0,001). Il n’y avait pas de différence significative entre la durée du séjour au début du programme et pendant les 6 mois de la phase d’évaluation de la viabilité (7,10 jours). Les taux de réadmission et de mortalité avant et après la mise en place du programme n’ont pas changé de manière significative. Le taux d’iléus a connu une baisse significative, passant de 13,8 % pendant la phase de mise en oeuvre à 4,6 % pendant l’évaluation de la viabilité (p = 0,036). Le respect des directives est passé de 52,2 % au début de la mise en oeuvre à 80,7 % pendant cette même phase (p0,001), pour ensuite descendre à 74,7 % pendant la phase suivante (p0,001). Le respect de lignes directrices postopératoires a régressé : il était de 79,2 % pendant la phase de mise en oeuvre et de 68,6 % pendant la phase d’évaluation de la viabilité (p0,001).La durée des séjours à l’hôpital a augmenté après l’adoption du programme de RAAC, lorsque le coordonnateur du programme était présent. Les méthodes de maintien des lignes directrices après leur adoption seront cruciales au succès de programmes similaires à l’avenir.

Current clinical practice guidelines for anemia management in non–dialysis-dependent chronic kidney disease (NDD-CKD) recommend the use of erythropoiesis-stimulating agents (ESAs) as standard of care. Vadadustat, an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor, stimulates endogenous erythropoietin production. The PRO2TECT program comprises 2 global, Phase 3, randomized, open-label, active-controlled, sponsor-blind clinical trials to evaluate safety and efficacy of vadadustat vs darbepoetin alfa in adult patients with anemia associated with NDD-CKD. Patients recruited into the ESA-untreated NDD-CKD trial (N = 1751) had hemoglobin

Background Erythropoiesis-stimulating agents (ESAs) are currently the mainstay of treatment for anaemia of chronic kidney disease (CKD). Vadadustat is an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates endogenous erythropoietin formation. The INNO2VATE programme comprises two studies designed to evaluate the safety and efficacy of vadadustat versus the ESA darbepoetin alfa in ameliorating anaemia in patients with dialysis-dependent CKD (DD-CKD). Here we describe the trial design along with patient demographics and baseline characteristics. Methods Two Phase 3, open-label, sponsor-blind, active-controlled trials enrolled adults with anaemia of CKD who recently initiated dialysis and had limited ESA exposure (incident DD-CKD trial) or were receiving maintenance dialysis with ESA treatment (prevalent DD-CKD trial). Study periods include correction/conversion (Weeks 0–23), maintenance (Weeks 24–52), long-term treatment (Weeks 53 to end of treatment) and safety follow-up. The primary safety endpoint is the time to the first major adverse cardiovascular event and the primary efficacy endpoint is the change in haemoglobin (baseline to Weeks 24–36). Results A total of 369 and 3554 patients were randomized in the incident DD-CKD and prevalent DD-CKD trials, respectively. Demographics and baseline characteristics were similar among patients in both trials and comparable to those typically observed in DD-CKD. Conclusions The two INNO2VATE trials will provide important information on the safety and efficacy of a novel approach for anaemia management in a diverse DD-CKD population. Demographics and baseline characteristics of enrolled patients suggest that study results will be representative for a large proportion of the DD-CKD population.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P, Reporting Summary. Further information on experimental design is available in the Life Sciences Reporting Summary linked to this article.