Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

Risk Stratification for Early-Onset Colorectal Cancer Using a Combination of Genetic and Environmental Risk Scores: An International Multi-Center Study.

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.

Nongenetic Determinants of Risk for Early-Onset Colorectal Cancer.

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.

Prescribing Patterns of Heart Failure-Exacerbating Medications Following a Heart Failure Hospitalization.

OBJECTIVES: This study sought to describe the patterns of heart failure (HF)-exacerbating medications used among older adults hospitalized for HF and to examine determinants of HF-exacerbating medication use. BACKGROUND: HF-exacerbating medications can potentially contribute to adverse outcomes and could represent an important target for future strategies to improve post-hospitalization outcomes. METHODS: Medicare beneficiaries ≥65 years of age with an adjudicated HF hospitalization between 2003 and 2014 were derived from the geographically diverse REGARDS (Reasons for Geographic and Racial Difference in Stroke) cohort study. Major HF-exacerbating medications, defined as those listed on the 2016 American Heart Association Scientific Statement listing medications that can precipitate or induce HF, were examined. Patterns of prescribing medications at hospital admission and at discharge were examined, as well as changes that occurred between admission and discharge; and a multivariable logistic regression analysis was conducted to identify determinants of harmful prescribing practices following HF hospitalization (defined as either the continuation of an HF-exacerbating medications or an increase in the number of HF-exacerbating medications between hospital admission and discharge). RESULTS: Among 558 unique individuals, 18% experienced a decrease in the number of HF-exacerbating medications between admission and discharge, 19% remained at the same number, and 12% experienced an increase. Multivariable logistic regression analysis revealed that diabetes (odds ratio [OR]: 1.80; 95% confidence interval [CI]: 1.18 to 2.75]) and small hospital size (OR: 1.93; 95% CI: 1.18 to 3.16) were the strongest, independently associated determinants of harmful prescribing practices. CONCLUSIONS: HF-exacerbating medication regimens are often continued or started following an HF hospitalization. These findings highlight an ongoing need to develop strategies to improve safe prescribing practices in this vulnerable population.

Polypharmacy in Older Adults Hospitalized for Heart Failure.

BACKGROUND: Despite potential harm that can result from polypharmacy, real-world data on polypharmacy in the setting of heart failure (HF) are limited. We sought to address this knowledge gap by studying older adults hospitalized for HF derived from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). METHODS: We examined 558 older adults aged ≥65 years with adjudicated HF hospitalizations from 380 hospitals across the United States. We collected and examined data from the REGARDS baseline assessment, medical charts from HF-adjudicated hospitalizations, the American Hospital Association annual survey database, and Medicare's Hospital Compare website. We counted the number of medications taken at hospital admission and discharge; and classified each medication as HF-related, non-HF cardiovascular-related, or noncardiovascular-related. RESULTS: The vast majority of participants (84% at admission and 95% at discharge) took ≥5 medications; and 42% at admission and 55% at discharge took ≥10 medications. The prevalence of taking ≥10 medications (polypharmacy) increased over the study period. As the number of total medications increased, the number of noncardiovascular medications increased more rapidly than the number of HF-related or non-HF cardiovascular medications. CONCLUSIONS: Defining polypharmacy as taking ≥10 medications might be more ideal in the HF population as most patients already take ≥5 medications. Polypharmacy is common both at admission and hospital discharge, and its prevalence is rising over time. The majority of medications taken by older adults with HF are noncardiovascular medications. There is a need to develop strategies that can mitigate the negative effects of polypharmacy among older adults with HF.

Indications for ß-Blocker Prescriptions in Heart Failure with Preserved Ejection Fraction.

OBJECTIVES: To better understand indications for ß-blocker (BB) prescriptions among older adults hospitalized with heart failure with preserved ejection fraction (HFpEF). DESIGN/SETTING: Retrospective observational study of hospitalizations derived from the geographically diverse Reasons for Geographic and Racial Differences in Stroke cohort. PARTICIPANTS: We examined Medicare beneficiaries aged 65 years or older with an expert-adjudicated hospitalization for HFpEF (left ventricular ejection fraction = 50% or greater). MEASUREMENTS: Discharge medications and indications for BBs were abstracted from medical records. RESULTS: Of 306 hospitalizations for HFpEF, BBs were prescribed at discharge in 68%. Among hospitalizations resulting in BB prescriptions, 60% had a compelling indication for BB-44% had arrhythmias, and 29% had myocardial infarction (MI) history. Among the 40% with neither indication, 57% had coronary artery disease (CAD) without MI and 38% had hypertension alone (without arrhythmia, MI, or CAD), both clinical scenarios with little supportive evidence of benefit of BBs. Among hospitalizations resulting in BB prescription at discharge, 69% had geriatric conditions (functional limitation, cognitive impairment, hypoalbuminemia, or history of falls). There were no significant differences in the prevalence of geriatric conditions between hospitalizations of individuals with compelling indications for BBs and hospitalizations of individuals with noncompelling indications. CONCLUSIONS: BBs are commonly prescribed following a hospitalization for HFpEF, even in the absence of compelling indications. This occurs even for hospitalizations of individuals with geriatric conditions, a subpopulation who may be at elevated risk for experiencing harm from BBs.

Immunomodulatory germline variation associated with the development of multiple primary melanoma (MPM).

Multiple primary melanoma (MPM) has been associated with a higher 10-year mortality risk compared to patients with single primary melanoma (SPM). Given that 3-8% of patients with SPM develop additional primary melanomas, new markers predictive of MPM risk are needed. Based on the evidence that the immune system may regulate melanoma progression, we explored whether germline genetic variants controlling the expression of 41 immunomodulatory genes modulate the risk of MPM compared to patients with SPM or healthy controls. By genotyping these 41 variants in 977 melanoma patients, we found that rs2071304, linked to the expression of SPI1, was strongly associated with MPM risk reduction (OR = 0.60; 95% CI = 0.45-0.81; p = 0.0007) when compared to patients with SPM. Furthermore, we showed that rs6695772, a variant affecting expression of BATF3, is also associated with MPM-specific survival (HR = 3.42; 95% CI = 1.57-7.42; p = 0.0019). These findings provide evidence that the genetic variation in immunomodulatory pathways may contribute to the development of secondary primary melanomas and also associates with MPM survival. The study suggests that inherited host immunity may play an important role in MPM development.

What to expect that you're not expecting: A pilot video education intervention to improve patient self-efficacy surrounding discharge medication barriers.

The objective of this study was to test the feasibility of video discharge education to improve self-efficacy in dealing with medication barriers around hospital discharge. We conducted a single-arm intervention feasibility trial to evaluate the use of video education in participants who were being discharged home from the hospital. The scores of pre- and post-intervention self-efficacy involving medication barriers were measured. We also assessed knowledge retention, patient and nursing feedback, follow-up barrier assessments, and hospital revisits. A total of 40 patients participated in this study. Self-efficacy scores ranged from 5 to 25. Median pre- and post-intervention scores were 21.5 and 23.5, respectively. We observed a median increase of 2.0 points from before to after the intervention (p = 0.046). In total, 95 percent of participants reported knowledge retention and 90 percent found the intervention to be helpful. Video discharge education improved patient self-efficacy surrounding discharge medication challenges among general medicine inpatients. Patients and nurses reported satisfaction with the video discharge education.

Impact of Hospitalist-Led Interdisciplinary Antimicrobial Stewardship Interventions at an Academic Medical Center.

BACKGROUND: Approximately 20%-50% of antimicrobial use in hospitals is inappropriate. Limited data exist on the effect of frontline provider engagement on antimicrobial stewardship outcomes. METHODS: A three-arm pre-post quality improvement study was conducted on three adult internal medicine teaching services at an urban academic hospital. Data from September through December 2016 were compared to historic data from corresponding months in 2015. Intervention arms were (1) Educational bundle (Ed-only); (2) Educational bundle plus antimicrobial stewardship rounds twice weekly with an infectious disease-trained clinical pharmacist (Ed+IDPharmDx2); and (3) Educational bundle plus internal medicine-trained clinical pharmacist embedded into daily attending rounds (Ed+IMPharmDx5). RESULTS: Total antibiotic use decreased by 16.8% (p < 0.001), 6.8% (p = 0.08), and 33.0% (p < 0.001) on Ed-only, Ed+IDPharmDx2, and Ed+IMPharmDx5 teams, respectively. Broad-spectrum antibiotic use decreased by 26.2% (p < 0.001), 7.8% (p = 0.09), and 32.4% (p < 0.001) on the Ed-only, Ed+IDPharmDx2, and Ed+IMPharmDx5 teams, respectively. Duration of inpatient antibiotic therapy decreased from 4 to 3 days on the Ed+IMPharmDx5 team (p = 0.01). Length of stay for patients who received any antibiotic decreased from 9 to 7 days on the Ed-only team (p < 0.001) and from 9 to 6 days on the Ed+IMPharmDx5 team (p < 0.001). There was no significant change in 30-day readmission to the same facility, transfer to ICU, or in-hospital mortality for any team. CONCLUSION: Multidisciplinary, frontline provider-driven approaches to antimicrobial stewardship may contribute to reduced antibiotic use and length of hospital stay.