Hospitalizations and Emergency Department Use in Mayo Clinic Biobank Participants Within the Employee and Community Health Medical Home

ObjectiveTo evaluate the participants in the Mayo Clinic Biobank for their representativeness to the entire Employee and Community Health program (ECH) primary care population with regard to hospital utilization.Patients and MethodsParticipants enrolled in the Mayo Clinic Biobank from April 1, 2009, to December 31, 2010, were linked to the ECH population. These individuals were categorized into risk tiers (0-4) on the basis of the number of health conditions present as of December 31, 2010. Outcomes were ascertained through December 31, 2011. Hazard ratios (HRs) and 95% CIs for risk of hospitalization, emergency department (ED) visits, and for risk of hospitalization and emergency department (ED) visits were estimated.ResultsThe 8927 Biobank participants were part of ECH (N=84,872). Compared with the entire ECH population, the Biobank-ECH participants were more likely to be female (64.3% vs 54.6%), older (median age, 58 years vs 47 years), and categorized to tier 0 (6.4% vs 24.0%). There were strong positive associations between tier (tier 4 vs combined tiers 0 and 1) and risk of hospitalization (HR, 5.8; 95% CI, 4.6-7.5) and ED visits (HR, 5.4; 95% CI, 4.2-6.8) among Biobank-ECH participants. Similar associations for risk of hospitalization (HR, 8.5; 95% CI, 7.8-9.3) and ED visits (HR, 6.9; 95% CI, 6.4-7.5) were observed for the entire ECH population.ConclusionAlthough the Biobank-ECH participants were older and had more chronic conditions compared with the overall ECH population, the associations of risk tier with utilization outcomes were similar, supporting the use of the Biobank participants to assess biomarkers for health care outcomes in the primary care setting.     

Chronic Obstructive Pulmonary Disease and Association With Mild Cognitive Impairment: The Mayo Clinic Study of Aging

ObjectiveTo investigate the association of chronic obstructive pulmonary disease (COPD) with mild cognitive impairment (MCI) and MCI subtype: amnestic MCI and nonamnestic MCI, in a population-based study of elderly patients.Patients and MethodsParticipants included 1927 individuals aged 70 to 89 years enrolled in the population-based Mayo Clinic Study of Aging. Participants were evaluated by using a nurse assessment, neurological evaluation, and neuropsychological testing, and the diagnosis of MCI was made by a consensus panel according to the standardized criteria. Chronic obstructive pulmonary disease was identified by the review of medical records. The study was conducted from October 1, 2004, through July 31, 2007. The associations of COPD and disease duration with MCI and its subtypes were evaluated by using logistic regression models adjusted for potential covariates.ResultsOf 1927 participants, 288 had COPD (men vs women: 18% vs 12%; P<.001). As compared with patients without COPD, patients with COPD had a higher prevalence of MCI (27% vs 15%; P<.001). The odds ratio (OR) for MCI was almost 2 times higher in patients with COPD than in those without (OR, 1.87; 95% CI, 1.34-2.61), with a similar effect in men and women. The OR for MCI increased from 1.60 (95% CI, 0.97-2.57) in patients with a COPD duration of 5 years or less to 2.10 (95% CI, 1.38-3.14) in patients with a COPD duration of more than 5 years.ConclusionThis population-based study suggests that COPD is associated with increased odds of having MCI and its subtypes. There was a dose-response relationship with the duration of COPD after controlling for the potential covariates.     

A DPYD Variant (Y186C) Specific to Individuals of African Descent in a Patient With Life-Threatening 5-FU Toxic Effects: Potential for an Individualized Medicine Approach

5-Fluorouracil (5-FU) is commonly administered as a therapeutic agent for the treatment of various aggressive cancers. Severe toxic reactions to 5-FU have been associated with decreased levels of dihydropyrimidine dehydrogenase (DPD) enzyme activity. Manifestations of 5-FU toxicity typically include cytopenia, diarrhea, stomatitis, mucositis, neurotoxicity, and, in extreme cases, death. A variety of genetic variations in DPYD, the gene encoding DPD, are known to result in decreased DPD enzyme activity and to contribute to 5-FU toxic effects. Recently, it was reported that healthy African American individuals carrying the Y186C DPYD variant (rs115232898) had significantly reduced DPD enzyme activity compared with noncarriers of Y186C. Herein, we describe for the first time, to our knowledge, an African American patient with cancer with the Y186C variant who had severe toxic effects after administration of the standard dose of 5-FU chemotherapy. The patient lacked any additional toxic effect–associated variations in the DPYD gene or the thymidylate synthase (TYMS) promoter. This case suggests that Y186C may have contributed to 5-FU toxicity in this patient and supports the use of Y186C as a predictive marker for 5-FU toxic effects in individuals of African ancestry.     

Prostate Cancer Ki-67 (MIB-1) Expression,Perineural Invasion,and Gleason Score as Biopsy-Based Predictors of Prostate Cancer Mortality: The Mayo Model

ObjectiveTo determine the role of cellular proliferation and other biopsy-based features in the prediction of prostate cancer mortality.Patients and MethodsBetween 1993 and 2012, our institution has performed quantitation of prostate cancer DNA ploidy and Ki-67 (MIB-1) on most prostate cancer needle biopsy specimens. The outcomes of 451 consecutive patients with biopsy-proven cancer treated by radical prostatectomy between January 24, 1995, and December 29, 1998, without neoadjuvant hormonal therapy were assessed. Clinical and biopsy information obtained before radical prostatectomy was placed in multivariate Cox proportional hazards regression models to predict local or systemic progression and cancer-specific death. Predictive ability was evaluated using a concordance index.ResultsWith a median follow-up of 12.9 years, 46 patients experienced local or systemic progression, and 18 patients died of prostate cancer. On multivariate analysis, the biopsy features of Ki-67 expression, perineural invasion, and Gleason score were associated with local or systemic progression. Ki-67 expression, perineural invasion, and Gleason score were associated with cancer-specific death with a concordance index of 0.892. After adjusting for perineural invasion and Gleason score, each 1% increase in Ki-67 expression was associated with a 12% increased risk of cancer-specific death (P<.001). Ki-67 expression alone was a strong predictor of cancer-specific outcomes and improved the predictive ability of currently used algorithms.ConclusionThis study documents that long-term prostate cancer outcomes are best estimated with a combination of Gleason score, perineural invasion, and Ki-67 expression. Given its low cost, rapid assessment, and strong predictive power, we believe that adding Ki-67 expression to perineural invasion and Gleason score at biopsy should be considered a standard by which all new biomarkers are compared before introducing them into clinical practice.     

The Necessity for Clinical Reasoning in the Era of Evidence-Based Medicine

Clinical decisions are increasingly driven by evidence-based recommendations of guideline groups, which aim to be based on the highest quality knowledge—randomized clinical trials (RCTs) and meta-analyses. Although RCTs provide the best assessment of the overall value of a therapy, high-quality evidence from RCTs is often incomplete, contradictory, or absent even in areas that have been most exhaustively studied. Moreover, the likelihood of the success or failure of a therapy is not identical in all the individuals treated in any trial because therapy is not the only determinant of outcome. Therefore, the overall results of a trial cannot be assumed to apply to any particular individual, not even someone who corresponds to all the entry criteria for the trial. In addition, the potential for bias due to financial conflicts remains in many guideline groups. Guidelines are key sources of knowledge. Nevertheless, limitations in the extent, quality, generalizability, and transferability of evidence mean that we clinicians must still reason through the best choices for an individual because even in the absence of full and secure knowledge, clinical decisions must still be made. Clinical reasoning is the pragmatic, tried-and-true process of expert clinical problem solving that does value mechanistic reasoning and clinical experience as well as RCTs and observational studies. Clinicians must continue to value clinical reasoning if our aim is the best clinical care for all the individuals we treat.     

Biobank Participants' Preferences for Disclosure of Genetic Research Results: Perspectives From the OurGenes,OurHealth, OurCommunity Project

ObjectiveTo assess biobank participants' preferences for disclosure of genetic research results.Patients and MethodsWe conducted a cross-sectional survey of participants in the OurGenes, OurHealth, OurCommunity biobank. Respondents were surveyed about preferences for disclosure, importance of disclosure, communication of results with practitioners, and sharing of results after respondents' death. Multivariate regression analysis was used to assess independent sociodemographic and clinical predictors of disclosure preferences. Data collection occurred from June 6, 2011, to June 25, 2012.ResultsAmong 1154 biobank participants, 555 (48%) responded. Most thought that research result disclosure was important (90%). Preference for disclosure varied, depending on availability of disease treatment (90% vs 64%, P<.001), high vs low disease risk (79% vs 66%, P<.001), and serious vs mild disease (83% vs 68%, P<.001). More than half of respondents (57%) preferred disclosure even when there is uncertainty about the results' meaning, and 87% preferred disclosure if the disease is highly heritable. Older age was positively associated with interest in disclosure, whereas female sex, nonwhite race, diabetes mellitus, and depression and/or anxiety were negatively associated with disclosure. More than half of respondents (52%) would want their results returned to their nearest biological relative after death.ConclusionsOurGenes biobank participants report strong preferences for disclosure of research results, and most would designate a relative to receive results after death. Participant preferences for serious vs mild disease, high vs low disease risk, and availability of disease treatment differed significantly. Future research should consider family members' preferences for receiving research results from enrolled research participants.     

The Increasing Incidence of Young-Onset Colorectal Cancer: A Call to Action

In the United States, colorectal cancer (CRC) is the third most common and second most lethal cancer. More than one-tenth of CRC cases (11% of colon cancers and 18% of rectal cancers) have a young onset (ie, occurring in individuals younger than 50 years). The CRC incidence and mortality rates are decreasing among all age groups older than 50 years, yet increasing in younger individuals for whom screening use is limited and key symptoms may go unrecognized. Familial syndromes account for approximately 20% of young-onset CRCs, and the remainder are typically microsatellite stable cancers, which are more commonly diploid than similar tumors in older individuals. Young-onset CRCs are more likely to occur in the distal colon or rectum, be poorly differentiated, have mucinous and signet ring features, and present at advanced stages. Yet, stage-specific survival in patients with young-onset CRC is comparable to that of patients with later-onset cancer. Primary care physicians have an important opportunity to identify high-risk young individuals for screening and to promptly evaluate CRC symptoms. Risk modification, targeted screening, and prophylactic surgery may benefit individuals with a predisposing hereditary syndrome or condition (eg, inflammatory bowel disease) or a family history of CRC or advanced adenomatous polyps. When apparently average-risk young adults present with CRC-like symptoms (eg, unexplained persistent rectal bleeding, anemia, and abdominal pain), endoscopic work-ups can expedite diagnosis. Early screening in high-risk individuals and thorough diagnostic work-ups in symptomatic young adults may improve young-onset CRC trends.     

Isometric Exercise Training for Blood Pressure Management: A Systematic Review and Meta-analysis

ObjectiveTo conduct a systematic review and meta-analysis quantifying the effects of isometric resistance training on the change in systolic blood pressure(SBP), diastolic blood pressure (DBP), and mean arterial pressure in subclinical populations and to examine whether the magnitude of change in SBP and DBP was different with respect to blood pressure classification.Patients and MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials lasting 4 or more weeks that investigated the effects of isometric exercise on blood pressure in healthy adults (aged ≥18 years) and were published in a peer-reviewed journal. PubMed, CINAHL, and the Cochrane Central Register of Controlled Trials were searched for trials reported between January 1, 1966, and July 31, 2013. We included 9 randomized trials, 6 of which studied normotensive participants and 3 that studied hypertensive patients, that included a total of 223 participants (127 who underwent exercise training and 96 controls).ResultsThe following reductions were observed after isometric exercise training: SBP—mean difference (MD), −6.77 mm Hg (95% CI, −7.93 to −5.62 mm Hg; P<.001); DBP—MD, −3.96 mm Hg (95% CI, −4.80 to −3.12 mm Hg; P<.001); and mean arterial pressure—MD, −3.94 mm Hg (95% CI, −4.73 to −3.16 mm Hg; P<.001). A slight reduction in resting heart rate was also observed (MD, −0.79 beats/min; 95% CI, −1.23 to −0.36 beats/min; P=.003).ConclusionIsometric resistance training lowers SBP, DBP, and mean arterial pressure. The magnitude of effect is larger than that previously reported in dynamic aerobic or resistance training. Our data suggest that this form of training has the potential to produce significant and clinically meaningful blood pressure reductions and could serve as an adjunctive exercise modality.     

Influence of Early Surgical Treatment on the Prognosis of Left-Sided Infective Endocarditis: A Multicenter Cohort Study

ObjectiveTo analyze the influence of early valve operation on mortality in patients with left-sided infective endocarditis (IE).Patients and MethodsA multicenter cohort study was carried out between 1990 and 2010. Data from consecutive patients with definite IE and possible left-sided IE were collected. Propensity score matching and adjustment for survivor bias were used to control for confounders. The primary outcome was in-hospital mortality.ResultsA total of 1019 patients with a mean age of 61 years (interquartile range, 47-71 years) were included. Early surgical treatment was performed in 417 episodes (40.9%). By propensity score, we matched 316 episodes: 158 who underwent early surgical treatment and 158 who did not (medical treatment group). In-hospital mortality and late mortality were lower in the surgically treated group (26.6% vs 41.8%; absolute risk reduction [ARR], −15.2%; P=.004 and 29.7% vs 46.2%; ARR, −16.5%; P=.002, respectively). Operation was independently associated with a lower risk of in-hospital mortality (odds ratio, 0.42; 95% CI, 0.22-0.79; P=.007). Operation was associated with reduced mortality in patients with paravalvular complications (ARR, −40.5%), severe heart failure (ARR, −32%), and native valve endocarditis (ARR, −17.8%).ConclusionThis study supports the benefit of surgical treatment in patients with left-sided IE carried out during the initial phase of hospitalization, especially in patients with moderate or severe heart failure and paravalvular extension of infection.     

Prognostic Value of Exercise Capacity in Patients With Coronary Artery Disease: The FIT (Henry Ford ExercIse Testing) Project

ObjectiveTo examine the prognostic value of exercise capacity in patients with nonrevascularized and revascularized coronary artery disease (CAD) seen in routine clinical practice.Patients and MethodsWe analyzed 9852 adults with known CAD (mean ± SD age, 61±12 years; 69% men [n=6836], 31% black race [n=3005]) from The Henry Ford ExercIse Testing (FIT) Project, a retrospective cohort study of patients who underwent physician-referred stress testing at a single health care system between January 1, 1991, and May 31, 2009. Patients were categorized by revascularization status (nonrevascularized, percutaneous coronary intervention [PCI], or coronary artery bypass graft [CABG] surgery) and by metabolic equivalents (METs) achieved on stress testing. Using Cox regression models, hazard ratios for mortality, myocardial infarction (MI), and downstream revascularizations were calculated after adjusting for potential confounders, including cardiac risk factors, pertinent medications, and stress testing indication.ResultsThere were 3824 all-cause deaths during median follow-up of 11.5 years. In addition, 1880 MIs, and 1930 revascularizations were ascertained. Each 1-MET increment in exercise capacity was associated with a hazard ratio (95% CI) of 0.87 (0.85-0.89), 0.87 (0.85-0.90), and 0.86 (0.84-0.89) for mortality; 0.98 (0.96-1.01), 0.88 (0.84-0.92), and 0.93 (0.90-0.97) for MI; and 0.94 (0.92-0.96), 0.91 (0.88-0.95), and 0.96 (0.92-0.99) for downstream revascularizations in the nonrevascularized, PCI, and CABG groups, respectively. In each MET category, the nonrevascularized group had similar mortality risk as and higher MI and downstream revascularization risk than the PCI and CABG surgery groups (P<.05).ConclusionExercise capacity was a strong predictor of mortality, MI, and downstream revascularizations in this cohort. Furthermore, patients with similar exercise capacities had an equivalent mortality risk, irrespective of baseline revascularization status.     

Breast Density and Breast Cancer Risk: A Practical Review

New legislation in several states requiring breast density notification in all mammogram reports has increased awareness of breast density. Estimates indicate that up to 50% of women undergoing mammography will have high breast density; thus, with increased attention and high prevalence of increased breast density, it is crucial that primary care clinicians understand the implications of dense breasts and are able to provide appropriate counseling. This review provides an overview of breast density, specifically by defining breast density, exploring the association between breast density and breast cancer risk, both from masking and as an independent risk factor, and reviewing supplemental screening options as part of a larger framework for counseling patients with dense breasts.     

Hemoglobin A1c in Nondiabetic Patients: An Independent Predictor of Coronary Artery Disease and Its Severity

ObjectiveTo examine the association between hemoglobin A_1c (HbA_1c) and the presence, severity, and complexity of angiographically proven coronary artery disease (CAD) in nondiabetic patients.Patients and MethodsWe performed a single-center, observational, cross-sectional study of 1141 consecutive nondiabetic patients who underwent coronary angiography from January 1, 2011, through December 31, 2011. The study population was divided into 4 interquartiles according to HbA_1c levels (<5.5%, 5.5%-5.7%, 5.8%-6.1%, and >6.1%).ResultsPatients with higher HbA_1c levels tended to be older, overweight, and hypertensive, had higher blood glucose levels, and had lower glomerular filtration rates. Higher HbA_1c levels were associated in a graded fashion with the presence of CAD, disease severity (higher number of diseased vessels and presence of left main and/or triple vessel disease), and disease complexity (higher SYNTAX score, higher number of patients in intermediate or high SYNTAX tertiles, coronary calcium, and chronic total occlusions). After adjustment for major conventional cardiovascular risk factors, compared with patients with HbA_1c levels less than 5.5%, the odds ratios of occurrence of CAD in the HbA_1c quartiles of 5.5% to 5.7%, 5.8% to 6.1%, and greater than 6.1% were 1.8 (95% CI, 1.2-2.7), 3.5 (95% CI, 2.3-5.3), and 4.9 (95% CI, 3.0-8.1), respectively.ConclusionThe HbA_1c level has a linear incremental association with CAD in nondiabetic individuals. The HbA_1c level is also independently correlated with disease severity and higher SYNTAX scores. Thus, HbA_1c measurement could be used to improve cardiovascular risk assessment in nondiabetic individuals.     

Extraintestinal Clostridium difficile Infections: A Single-Center Experience

ObjectivesTo evaluate the clinical burden of extraintestinal Clostridium difficile infection (CDI) seen at a single institution and to characterize the management and outcomes of these rare infections.Patients and MethodsA retrospective medical record review was conducted to identify patients with isolation of C difficile from extraintestinal sites from January 1, 2004, through December 31, 2013. Medical records were reviewed and data, including demographic characteristics, microbiology, clinical associations, management, and infection outcomes, were abstracted.ResultsOverall, 40 patients with extraintestinal CDI were identified: 25 had abdominopelvic infections, 11 had bloodstream infections, 3 had wound infections, and 1 had pulmonary infection. C difficile was isolated with other organisms in 63% of cases. A total of 85% of infections were nosocomial. Factors associated with extraintestinal CDI included surgical manipulation of the gastrointestinal tract (88%), recent antibiotic exposure (88%), malignant tumors (50%), and proton pump inhibitor use (50%). Diarrhea was present in 18 patients (45%), 12 of whom had C difficile polymerase chain reaction (PCR)–positive stool samples. All isolates tested were susceptible to metronidazole and piperacillin-tazobactam. Management included both antimicrobial therapy and guided drainage or surgical intervention in all but one patient. The infection-associated mortality rate was 25%, with death a median of 16 days (range, 1-61 days) after isolation of C difficile.ConclusionExtraintestinal CDI is uncommon and often occurs in patients with surgical manipulation of the gastrointestinal tract and well-recognized risk factors for intestinal CDI. Management of extraintestinal CDI includes both antimicrobial and surgical therapies. Extraintestinal CDI is characterized by poor outcome with high mortality.     

Incidence of Leukocytoclastic Vasculitis, 1996 to 2010: A Population-Based Study in Olmsted County,Minnesota

ObjectiveTo determine the population-based incidence of leukocytoclastic vasculitis (LCV).Patients and MethodsThis is a retrospective population-based study of all Olmsted County, Minnesota, residents with a skin biopsy–proven diagnosis of LCV from January 1, 1996, through December 31, 2010.ResultsA total of 84 patients (mean age at diagnosis, 48.3 years) with newly diagnosed skin biopsy–proven LCV (43 women and 41 men) were identified. The incidence rate (age and sex adjusted to the 2000 US white population) was 4.5 per 100,000 person-years (95% CI, 3.5-5.4). The incidence of LCV increased significantly with age at diagnosis (P<.001) and did not differ between female and male patients. Subtypes of LCV were cutaneous small-vessel vasculitis (CSVV), 38 patients (45%); IgA vasculitis, 25 (30%); urticarial vasculitis, 10 (12%); cryoglobulinemic vasculitis, 3 (4%); and antineutrophil cytoplasmic antibody–associated vasculitis, 8 (10%). LCV was idiopathic in 29 of 38 patients with CSVV (76%) and 24 of 25 patients with IgA vasculitis (96%). Thirty-nine of 84 patients (46%) had systemic involvement, with the renal system most commonly involved (17 of 39 [44%]). Twenty-four of 80 patients (30%) with follow-up data available had recurrent disease. Compared with the Minnesota white population, observed survival in the incident LCV cohort was significantly poorer than expected (P<.001), including the subset of patients with idiopathic CSVV (P=.03).ConclusionThe incidence of LCV was higher than that reported in previously published studies. Idiopathic LCV was more common in our population-based cohort than that described previously. Overall survival was significantly poorer (P<.001) and should be explored further in future studies.     

Epidemiology of Emergency Department Visits for Opioid Overdose: A Population-Based Study

ObjectivesTo evaluate the rate of emergency department (ED) visits for opioid overdose and to examine whether frequent ED visits for opioid overdose are associated with more hospitalizations, near-fatal events, and health care spending.Patients and MethodsRetrospective cohort study of adults with at least 1 ED visit for opioid overdose between January 1, 2010, and December 31, 2011, derived from population-based data of State Emergency Department Databases and State Inpatient Databases for 2 large and diverse states: California and Florida. Main outcome measures were hospitalizations for opioid overdose, near-fatal events (overdose involving mechanical ventilation), and hospital charges during the year after the first ED visit.ResultsThe analytic cohort comprised 19,831 unique patients with 21,609 ED visits for opioid overdose. During a 1-year period, 7% (95% CI, 7%-7%; n=1389 patients) of the patients had frequent (2 or more) ED visits, accounting for 15% (95% CI, 14%-15%; n=3167) of all opioid overdose ED visits. Middle age, male sex, public insurance, lower household income, and comorbidities (such as chronic pulmonary disease and neurological diseases) were associated with frequent ED visits (all P<.01). Overall, 53% (95% CI, 52%-54%; n=11,412) of the ED visits for opioid overdose resulted in hospitalizations; patients with frequent ED visits for opioid overdose had a higher likelihood of hospitalization (adjusted odds ratio, 3.98; 95% CI, 3.38-4.69). In addition, 10.0% (95% CI, 10%-10%; n=2161) of the ED visits led to near-fatal events; patients with frequent ED visits had a higher likelihood of a near-fatal event (adjusted odds ratio, 2.27; 95% CI, 1.96-2.66). Total charges in Florida were $208 million (95% CI, $200-$219 million).ConclusionIn this population-based cohort, we found that frequent ED visits for opioid overdose were associated with a higher likelihood of future hospitalizations and near-fatal events.