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To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy ( ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1-2 decades. The most prevalent electrocardiogram ( ECG) manifestation was poor R wave progression ( PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre-symptomatic diagnosis has the greatest clinical utility. [ABSTRACT FROM AUTHOR]

Lifetime risk of developing endometrial cancer in Lynch syndrome carriers is very high and females are also at an increased risk of developing ovarian cancer. The aim of the study was to determine the impact of gynecological screening in MSH2 mutation carriers. Gynecological cancer incidence and overall survival was compared in female mutation carriers who received gynecological screening (cases) and in matched controls. Controls were randomly selected from non-screened mutation carriers who were alive and disease-free at the age the case entered the screening program. Median age to diagnosis of gynecological cancer was 54 years in the screened group compared to 56 years in controls (p = 0.50). Stage I or II cancer was diagnosed in 92% of screened patients compared to 71% in the control group (p = 0.17). Two of three deaths in the screened group were the result of ovarian cancer. Mean survival in the screened group was 79 years compared to 69 years in the control group (p = 0.11), likely associated with concomitant colonoscopy screening. Gynecological screening did not result in earlier gynecologic cancer detection and despite screening two young women died from ovarian cancer suggesting that prophylactic hysterectomy with bilateral salpingo-oophorectomy be considered in female mutation carriers who have completed childbearing. [ABSTRACT FROM AUTHOR]

Stuckless S, Green JS, Morgenstern M, Kennedy C, Green RC, Woods MO, Fitzgerald W, Cox J, Parfrey PS. Impact of colonoscopic screening in male and female Lynch syndrome carriers with an MSH2 Mutation. The lifetime risk of developing colorectal cancer (CRC) in Lynch syndrome (LS) carriers is very high. To determine the impact of colonoscopic screening in 54 male and 98 female MSH2 mutation carriers, outcomes were compared with 94 males and 76 females who were not screened. CRC incidence and survival in the screened group were compared to that expected, derived from the non-screened group. To correct for survivor bias, controls were matched for age at entry into screening and also for gender. In males, median age to CRC was 58 years, whereas expected was 47 years (p = 0.000), and median survival was 66 years vs 62 years (p = 0.034). In screened females, median age to CRC was 79 years compared to 57 years in the non-screened group (p = 0.000), and median survival was 80 years compared with expected of 63 years (p = 0.001). Twenty percent of males and 7% of females developed an interval CRC within 2 years of previous colonoscopy. Although colonoscopic screening was associated with decreased CRC risk and better survival, CRCs continued to occur. CRC development may be further reduced by decreasing the screening interval to 1 year and improving quality of colonoscopy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Limited research has focused on the predictive nature of organizational culture and trust on registered nurses' perceived health care quality in reformed health care systems. PURPOSES: The purpose of this article was to investigate nurses' perceptions of organizational culture factors, trust in employer, and perceived health care quality during and 5 years after major organizational reform in the acute care setting and to test a model linking culture to perceived health care quality. METHODOLOGY: Survey data collected from two samples of nurses (N = 222,343) during and 5 years after major organizational reform in the acute care setting of one Canadian province were analyzed, and an exploratory model linking aspects of culture, trust, and quality was tested. FINDINGS: For both periods, most variable scores were in the low range and depicted moderately positive intercorrelations with each other. Support for the proposed model was mixed. Select culture variables predicted health care quality at both periods, but trust emerged as a significant predictor in 2000 only. The findings support the negative impact of system transformation on nurses and the link between culture and health care quality. PRACTICE IMPLICATIONS: The study findings suggest that managers and policy makers must develop and implement supportive and nurturing strategies that will enhance the organizational culture (emotional climate, collaborative relations), which should result in more positive perceptions of health care quality. However, further research is required to gain a better understanding of the relationships among trust, organizational culture, and perceptions of health care quality and what implications this may or may not have for nursing practice. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To evaluate whether the participating controls represented the underlying population in a colorectal cancer case-control study in a geographically isolated North American population. METHODS: The characteristics of the study controls recruited through Random-digit-dialing (RDD) were compared with those in the corresponding target population estimates. RESULTS: Participating controls were more likely to have higher levels of education and income and were less likely to be smokers. CONCLUSION: Study controls recruited through RDD tend to have higher socioeconomic status, which may lead to overestimation of a number of risk factors in this study. [ABSTRACT FROM AUTHOR]

The neuronal ceroid lipofuscinoses (NCLs) are the commonest neurodegenerative disorders of children. The aims of this study were to determine the incidence of NCL in Newfoundland, identify the causative genes, and analyze the relationship between phenotype and genotype. Patients with NCL diagnosed between 1960 and 2005 were ascertained through the provincial genetics and pediatric neurology clinics. Fifty-two patients from 34 families were identified. DNA was obtained from 28/34 (82%) families; 18 families had mutations in the CLN2 gene, comprising five different mutations of which two were novel. One family had a CLN3 mutation, another had a novel mutation in CLN5, and five families shared the same mutation in CLN6. One family was misdiagnosed, and in two, molecular testing was inconclusive. Disease from CLN2 mutations had an earlier presentation (p = 0.003) and seizure onset (p < 0.001) compared with CLN6 mutation. There was a slower clinical course for those with CLN5 mutation compared with CLN2 mutation. NCL in Newfoundland has a high incidence, 1 in 7353 live births, and shows extensive genetic heterogeneity. The incidence of late infantile NCL, 9.0 per 100,000 (or 1 in 11,161) live births, is the highest reported in the world. [ABSTRACT FROM AUTHOR]

Bardet-Biedl Syndrome (BBS) is an autosomal recessive, multisystem, genetically heterogeneous, ciliopathic condition caused by mutations in multiple genes. Here we sought to determine if inheritance of a single BBS mutation increased the risks of frequent disorders of this syndrome such as obesity, hypertension, and diabetes. Various metabolic and renal diseases in a cohort of 46 patients with BBS, prospectively followed for up to 28 years, were compared to recent assessments of these factors in 96 relatives with a heterozygote mutation (carriers) and 37 relatives without a contributing mutation (non-carriers). Ten mutations in 6 genes causing this syndrome were identified in 21 families from whom DNA was obtained. The body mass index or the incidences of hypertension, diabetes, or stage 3 chronic kidney diseases were found to be similar between carriers and non-carriers but were all significantly less than those of family members with BBS. Similarly, the median age of onset of hypertension or diagnosis of stage 3 kidney disease, or the diagnosis of diabetes by age 70 were all significantly lower in those with BBS than in gene carriers or non-carriers. While our study shows that metabolic and renal events occurred frequently and at an early age in BBS, the heterozygous inheritance of any of the 10 described BBS mutations did not predispose family members to obesity, diabetes, hypertension, or renal impairment. [ABSTRACT FROM AUTHOR]

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 evaluation 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% confidence interval (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 evaluation 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Objective: Leptin (LEP) is an obesity-associated adipokine associated with tumor cell growth. We examined the relevance of genetic variants of LEP and leptin receptor ( LEPR ) to colorectal cancer (CRC) survival by using data from the Newfoundland Familial Colorectal Cancer Study., Methods: A total of 532 patients newly diagnosed with CRC between 1997 and 2003 were followed up until April 2010. Data on their demographics and lifestyles were collected via questionnaires. Genotyping of blood samples was performed with the Illumina Human Omni-Quad Bead chip. Multivariable Cox models were used to assess the relationships of 35 tag single-nucleotide polymorphisms (SNPs) in LEP and LEPR with overall survival (OS), disease-free survival (DFS), and CRC-specific survival., Results: At the gene level, LEP was associated with DFS ( P = 0.017), and LEPR was associated with both DFS ( P = 0.021) and CRC-specific survival ( P = 0.013) in patients with CRC. In single-SNP analysis, LEP rs11763517, LEPR rs9436301, and LEPR rs7602 were associated with DFS after adjustment for multiple testing. The LEPR haplotypes G-C-T (rs7534511-rs9436301-rs1887285) and A-A-G (rs7602-rs970467-rs9436748) were associated with prolonged OS among patients with CRC overall (G-C-T: HR, 0.63; 95% CI, 0.43-0.93; A-A-G: HR, 0.59; 95% CI, 0.38-0.91) and those diagnosed with colon cancer (G-C-T: HR, 0.54; 95% CI, 0.34-0.86; A-A-G: HR, 0.49; 95% CI, 0.29-0.83). Similar results were observed for DFS. Moreover, significant interactions were found among LEPR rs7602 (A vs. G), LEPR rs1171278 (T vs . C), red meat intake, and BMI status: the associations between these variants and prolonged DFS were limited to patients with below-median red meat consumption and body mass index (BMI) < 25 kg/m 2 ., Conclusions: Polymorphic variations in the LEP and LEPR genes were associated with survival of patients after CRC diagnosis. The LEP / LEPR -CRC survival association was modified by participants' red meat intake and BMI., Competing Interests: No potential conflicts of interest are disclosed., (Copyright © 2023 Cancer Biology & Medicine.)

Rationale & Objective: In the PRO 2 TECT trials, vadadustat was found to be noninferior to darbepoetin alfa in hematologic efficacy but not for major adverse cardiovascular events (MACE; all-cause death or nonfatal myocardial infarction or stroke) in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). We investigated the regional differences in MACE in the PRO 2 TECT trials., Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial., Setting & Participants: A total of 1,725 erythropoiesis-stimulating agent (ESA)-treated patients with anemia and NDD-CKD., Intervention: 1:1 randomization to receive vadadustat or darbepoetin alfa., Outcomes: The primary safety end point was the time to first MACE., Results: At baseline, patients in Europe (n=444) were primarily treated with darbepoetin alfa, showed higher proportions on low ESA doses (<90 U/kg/wk epoetin alfa equivalents) with a hemoglobin concentration of ≥10 g/dL compared with patients in the US (n=665) and non-US/non-Europe (n=614) regions. The MACE rates per 100 person-years in the 3 vadadustat groups across regions were 14.5 in the US, 11.6 in Europe, and 10.0 in the non-US/non-Europe groups, whereas event rates in the darbepoetin alfa group were considerably lower in Europe than in the US and non-US/non-Europe groups (6.7 vs 13.3 and 10.5, respectively). The overall hazard ratio for MACE for vadadustat vs darbepoetin alpha was 1.16; 95% CI, 0.93-1.45, but varied by geographical region, with a greater hazard ratio seen in Europe (US, 1.07; 95% CI, 0.78-1.46; Europe, 2.05; 95% CI, 1.24-3.39; non-US/non-Europe, 0.91; 95% CI, 0.60-1.37); interaction between study treatment and geographical region, P  = 0.07). In Europe, ESA rescue was associated with a higher risk of MACE in both groups., Limitations: Several analyses are exploratory., Conclusions: In this trial, there was a low risk of MACE in the darbepoetin alfa group in Europe. Patients in Europe were generally on low doses of ESA, with hemoglobin already within target range. The low risk of MACE may have been related to a limited need to switch and titrate darbepoetin alfa compared with the non-US/non-Europe group., Funding: Akebia Therapeutics, Inc., Trial Registration: ClinicalTrials.gov identifier: NCT02680574., (© 2023 The Authors.)

Rationale & Objective: Prespecified analyses of the PRO 2 TECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PRO 2 TECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents., Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial., Setting and Participants: Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD., Intervention: Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa., Outcomes: The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis)., Results: In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of ≤10 mL/min/1.73 m 2 in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of ≤10 mL/min/1.73 m 2 and who may not have had access to dialysis., Limitations: Different regional treatment patterns of patients with NDD-CKD., Conclusions: The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths., (© 2023 The Authors.)

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.

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., (© 2022 Akebia Therapeutics Inc and The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

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: The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants., Methods: Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve., Results: Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores., Conclusions: Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Objective: An 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 CRC differs by anatomical subsite of the primary tumor has not been examined., Design: To 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 characterised effect heterogeneity at CRC risk loci using multinomial modelling., Results: We identified 13 loci that reached genome-wide significance (p<5×10 -8 ) and that were not reported by previous GWASs 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., Conclusion: Genetic 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 tumour., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© The Author(s) 2021. Published by Oxford University Press.)

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 PRO 2 TECT 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 <10 g/dL and had not received an ESA within 8 weeks prior to inclusion in the study. Patients recruited into the ESA-treated NDD-CKD trial (N = 1725) had hemoglobin between 8 and 11 g/dL (US) or 9 and 12 g/dL (non-US) and were actively treated with an ESA for anemia associated with CKD. Trial periods in both trials include (1) correction/conversion (weeks 0-23); (2) maintenance (weeks 24-52); (3) long-term treatment (week 53 to end of treatment); and (4) safety follow-up (end-of-treatment to 4 weeks later). The primary safety endpoint is time to first adjudicated major adverse cardiovascular event, defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke, pooled across both trials. The primary efficacy endpoint in each trial is change in hemoglobin from baseline to primary evaluation period (weeks 24-36), comparing vadadustat vs darbepoetin alfa treatment groups. Demographics and baseline characteristics are similar among patients in both trials and broadly representative of the NDD-CKD population. These trials will help to evaluate the safety and efficacy of vadadustat for management of anemia associated with NDD-CKD., Competing Interests: Disclosures GMC reports grants from NIDDK and Amgen and personal fees from Akebia Therapeutics, Inc., Satellite Healthcare, Ardelyx, AstraZeneca, Baxter, Cricket, DiaMedica, Gilead, Reata, Sanifit, Vertex, Angion, Bayer, and ReCor. PEP reports personal fees from Akebia Therapeutics, Inc., Astra-Zeneca, Bayer, Reata, Gilead, Corvidia, FibroGen, Tricida, and Ardelyx. PEP's institution, Renal Associates (PA), has received support from multiple pharmaceutical companies, including Akebia Therapeutics, Inc. RA reports personal fees from Akebia Therapeutics, Inc., Relypsa Inc., a Vifor Pharma Group Company, AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Sandoz, ZS Pharma, Takeda, Sanofi, Reata, Ironwood Pharmaceuticals, Otsuka, OPKO Health, and Bird Rock Bio. RA has also served as associate editor of the American Journal of Nephrology and Nephrology, Dialysis, Transplantation and has received research grants from the US Veterans Administration and the National Institutes of Health. GAB reports grants, personal fees, and nonfinancial support from Akebia Therapeutics, Inc., Keryx Biopharmaceuticals, Inc., Astra-Zeneca, Kirin, and Ardelyx, Inc., as well as personal fees from U.S. Renal Care. YMKF reports personal fees and other from Akebia Therapeutics, Inc. AGJ has nothing to disclose. MJK reports personal fees from Akebia Therapeutics, Inc., FibroGen, Inc., and Micelle BioPharma, Inc. WL was an employee of Akebia Therapeutics, Inc., during the conduct of this study. ZK was an employee of Akebia Therapeutics, Inc., during the conduct of this study. EFL reports grants from Akebia Therapeutics, Inc. KM reports grants from NIH and personal fees from Akebia Therapeutics, Inc.; KM also reports grants and personal fees from Kyowa Kirin and Fukuda Denshi. PAM reports personal fees from Akebia Therapeutics, Inc. PSP reports personal fees from Akebia Therapeutics, Inc.; PSP was also a member of an advisory committee for Vifor Pharma and was a member of the data monitoring committee for the CREDANCE trial for Janssen. JW and KAW are employees of Statistics Collaborative, Inc., which received fees from Akebia Therapeutics, Inc. for conduction of study analyses. CT and TL are employees of Firma Clinical Research, which received fees from Akebia Therapeutics, Inc. for data analyses. MJS was a member of the steering committee for Akebia Therapeutics, Inc.; MJS also reports personal fees from Bayer and Carurian. DLV is an employee of Akebia Therapeutics, Inc. WCW reports personal fees from Akebia Therapeutics, Inc., Amgen, and Relypsa. and personal fees and nonfinancial support from AstraZeneca, Bayer, Daiichi-Sankyo, Janssen, Merck, and Vifor Fresenius Medical Care Renal Pharma. KUE reports grants from Amgen, Astra Zeneca, Bayer, Fresenius, Genzyme, and Vifor and personal fees from Akebia Therapeutics, Inc., Bayer, and Boehringer Ingelheim., (Copyright © 2020. Published by Elsevier Inc.)

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., Methods: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52., Results: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter., Conclusions: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO 2 TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production., Methods: 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)., Results: 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., Conclusions: 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 2 VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.)., (Copyright © 2021 Massachusetts Medical Society.)

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., Competing Interests: Conflict of Interest Statement:The authors declare that they have no significant competing financial, professional or personal interests that might have influenced the performance or presentation of the work described in this article., (© The Author(s) 2021.)

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.

Clinical epidemiology is the science of human disease investigation with a focus on diagnosis, prognosis, and treatment. The generation of a reasonable question requires definition of patients, interventions, controls, and outcomes. The goal of research design is to minimize error, ensure adequate samples, measure input and output variables appropriately, consider external and internal validities, limit bias, and address clinical as well as statistical relevance. The hierarchy of evidence for clinical decision-making places randomized controlled trials (RCT) or systematic review of good-quality RCTs at the top of the evidence pyramid. Prognostic and etiologic questions are best addressed with longitudinal cohort studies.

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.

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.

Today's clinical practice relies on the application of well-designed clinical research, the gold standard test of an intervention being the randomized controlled trial. Principles of the randomized control trial include emphasis on the principal research question, randomization, blinding; definitions of outcome measures, of inclusion and exclusion criteria, and of co-morbid and confounding factors; enrolling an adequate sample size; planning data management and analysis; preventing challenges to trial integrity such as drop-out, drop-in, and bias. The application of pre-trial planning is stressed to ensure the proper application of epidemiological principles resulting in clinical studies that are feasible and generalizable. In addition, funding strategies and trial team composition are discussed.

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).

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 .

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.

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.

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.

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 ( P trend 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., (©2020 American Association for Cancer Research.)

Background: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex., Methods: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10 -8 ) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study., Results: The associations between circulating UCB levels and CRC risk differed by sex (P heterogeneity  = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P heterogeneity  ≥ 0.2)., Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

Objectives: Measuring blood urea at the same time as serum creatinine in stable ambulatory patients in family practice is largely unnecessary. The objective was to assess the relative impact of changing the laboratory requisition versus audit and feedback and academic detailing on the volume of orders for blood urea., Design and Methods: A natural experiment was observed over the period April 2015 to March 2018 in the Canadian province of Newfoundland where three health regions had different approaches to trying to reduce such urea testing. The Eastern and Western regions removed urea from the standard laboratory requisition but the test could still be ordered by writing it on the requisition. Central region requisitions continued to list urea. Audit and feedback was undertaken with family doctors in Eastern region after the requisition change and that was followed by academic detailing. A nephrologist gave presentations to groups of family doctors on one occasion in Central region., Results: The volume of serum creatinine testing was largely unchanged over time in each region. The volume of urea testing reduced by 73%, 48% and 28% in Eastern, Western and central regions. Interrupted time series analysis showed significant changes in test volume after requisition change in Eastern and Western regions as well as after audit and feedback in Eastern and the presentations in Central region. The incremental impact of academic detailing was not statistically significant., Conclusion: We conclude that removing urea from standard test order menus was the most effective in reducing test volumes, but combination with audit and feedback augmented the impact., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: 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., Objective: The purpose of this study was to evaluate the impact of exercise on arrhythmic risk and cardiac death in TMEM43 p.S358L ARVC., Methods: 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., Results: 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 activity <9.0 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., Conclusion: 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., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)