Background

Elevated low-density lipoprotein cholesterol (LDL-C) levels are a major cardiovascular disease risk factor. Genetic factors are an important determinant of LDL-C levels.

Methods

To identify single nucleotide polymorphisms associated with LDL-C and subclinical coronary atherosclerosis, we performed a genome-wide association study of LDL-C in 841 asymptomatic Amish individuals aged 20 to 80 years, with replication in a second sample of 663 Amish individuals. We also performed scanning for coronary artery calcification (CAC) in 1018 of these individuals.

Results

From the initial genome-wide association study, a cluster of single nucleotide polymorphisms in the region of the apolipoprotein B-100 gene (APOB) was strongly associated with LDL-C levels (P < 10−68). Additional genotyping revealed the presence of R3500Q, the mutation responsible for familial defective apolipoprotein B-100, which was also strongly associated with LDL-C in the replication sample (P < 10−36). The R3500Q carrier frequency, previously reported to be 0.1% to 0.4% in white European individuals, was 12% in the combined sample of 1504 Amish participants, consistent with a founder effect. The mutation was also strongly associated with CAC in both samples (P < 10−6 in both) and accounted for 26% and 7% of the variation in LDL-C levels and CAC, respectively. Compared with noncarriers, R3500Q carriers on average had LDL-C levels 58 mg/dL higher, a 4.41-fold higher odds (95% confidence interval, 2.69–7.21) of having detectable CAC, and a 9.28-fold higher odds (2.93–29.35) of having extensive CAC (CAC score ≥400).

Conclusion

The R3500Q mutation in APOB is a major determinant of LDL-C levels and CAC in the Amish.

Background

Fractures have been associated with subsequent increases in mortality, but it is unknown how long that increase persists.

Methods

5580 women from a large community-based multicenter US prospective cohort of 9704 (Study of Osteoporotic Fractures) were followed prospectively for almost 20 years. We age-matched 1116 hip fracture cases with four controls (n=4464). To examine the effect of health status, we examined a healthy older subset (n=960) aged 80+ who attended the 10-year follow-up examination, and reported good/excellent health. Incident hip fractures were adjudicated from radiology reports by study physicians. Death was confirmed by death certificates.

Results

Hip fracture cases had two-fold increased mortality in the year after fracture compared to controls [16.9% vs. 8.4%; Odds Ratio (OR)=2.4; 95% Confidence Interval (CI) 1.9, 3.1]. When examined by age and health status, short-term mortality was increased in those aged 65 to 70 (16.3% vs 3.7%; OR=5.0; 2.6, 9.5), aged 70 to 79 (16.5% vs 8.9%; OR=2.4; 1.8, 3.3), and only in aged 80+ with good/excellent health (15.1% vs. 7.2%; OR=2.8; 1.5, 5.2). After the first year, survival of hip fracture cases and controls was similar except in those aged 65 to 70 who continued to have increased mortality.

Conclusions

Short-term mortality is increased after hip fracture in women aged 65 to 79 and in exceptionally healthy women 80 or older. Women 70 and older return to previous risk levels after a year. Interventions are needed to decrease mortality in the year after hip fracture, when mortality risk is highest.

Context

Physician referrals play a central role in ambulatory care in the US, yet little is known about national trends in physician referrals over time.

Objective

To assess changes in the rate of referrals to other physicians from physician office visits in the US, 1999 to 2009.

Design, Setting and Participants

We analyzed nationally representative cross-sections of ambulatory patient visits in the US using a sample of 845,243 visits from the National Ambulatory Medical Care Surveys 1993–2009, focusing on the decade from 1999 to 2009.

Main Outcome Measures

Survey-weighted estimates of the total number and percentage of visits resulting in a referral to another physician across several patient and physician characteristics.

Results

From 1999 to 2009, the probability that an ambulatory visit to a physician resulted in a referral to another physician increased from 4.83% to 9.29% (p<0.001), a 92% increase. The absolute number of visits resulting in a physician referral increased 159% nationally over this time, from 40.6 million to 105 million. This trend was consistent across all subgroups examined, except for slower growth among physicians with ownership stakes in their practice (p=0.016) or with the majority of income from managed care contracts (p=0.007). Changes in referral rates varied according to the principal symptoms accounting for patients’ visits, with significant increases noted for visits to PCPs with cardiovascular, gastrointestinal, and ear/nose/throat complaints.

Conclusion

The percentage and absolute number of ambulatory visits resulting in a referral in the US grew substantially from 1999 to 2009. More research is necessary to understand the contribution of rising referral rates to costs of care.

Background

Family history is a risk factor for colon cancer and guidelines recommend initiating colonoscopy screening at age 40 in individuals with affected relatives. Racial differences exist in colon cancer incidence and mortality which could be related to variations in screening of increased risk individuals.

Methods

Baseline data from 41830 participants in the Southern Community Cohort Study were analyzed to determine the proportion of colonoscopy procedures in individuals with strong family histories of colon cancer, and whether differences existed based on race.

Results

In participants with multiple affected first degree relatives (FDR) or relatives diagnosed before age 50, 27.3% (95% confidence interval [CI] 23.5%–31.1%) of African-Americans reported a colonoscopy within the past 5 years compared to 43.1% (37.0%–49.2%) of white participants (p-value < 0.0001). In these individuals, African-Americans had an odds ratio of 0.51 (0.38–0.68) of having undergone recommended screening procedures compared to white participants after adjusting for age, gender, education, income, insurance status, total number of FDR, and time since last medical visit. African-Americans reporting multiple affected first degree relatives or relatives diagnosed before age 50, who had ever undergone endoscopy were less likely to report a personal history of colon polyps (OR = 0.29; 0.20–0.42) when compared to whites with similar family histories.

Conclusions

African-Americans with first-degree relatives affected with colon cancer are less likely to undergo colonoscopy screening compared to whites with affected relatives. Increased efforts need to be directed at identifying and managing underserved populations who might be at increased risk for colon cancer based on their family history.

Background

The risk of sudden cardiac death and the assessment of risk factors in prediction models have not been assessed in women with coronary artery disease (CAD). We sought to evaluate sudden cardiac death (SCD) incidence, risk factors and their predictive accuracy among a population of women with CAD.

Methods

The Hormone and Estrogen Replacement Study (HERS) evaluated the effects of hormone replacement therapy on cardiovascular events among 2,763 postmenopausal women with CAD. SCD was defined as death from cardiac origin that occurred within 1 hour of symptom onset. The associations between candidate predictor variables and SCD were evaluated in a Cox proportional hazards model. The C-index was used to compare the predictive value of the clinical risk factors with left ventricular ejection fraction alone and in combination. The net reclassification improvement (NRI) was also computed.

Results

Over a mean follow-up of 6.8 years, SCD comprised 136 of the 254 cardiac deaths. The annual SCD event rate was 0.79% (95% CI, 0.67–0.94%). The following variables were independently associated with SCD in the multivariate model: myocardial infarction, heart failure, estimated glomerular filtration rate (eGFR) <40ml/min/1.73m2, atrial fibrillation, physical inactivity and diabetes. The incidences of SCD among women with 0 (n=683), 1 (n=1224), 2 (n=610), and 3 plus (n=246) risk factors at baseline were 0.3, 0.5, 1.2 and 2.9% per year, respectively. The combination of clinical risk factors and LVEF (C-index 0.681) were better predictors of SCD than LVEF alone (C-index 0.600) and resulted in a NRI of 0.20 (p<0.001).

Conclusions

SCD comprised the majority of cardiac deaths among postmenopausal women with CAD. Independent predictors of SCD including myocardial infarction, heart failure, eGFR <40ml/min/1.73m2, atrial fibrillation, physical inactivity and diabetes improved SCD prediction when used in addition to LVEF.

Background

Hyperkalemia is a potential threat to patient safety in chronic kidney disease (CKD). This study determined the incidence of hyperkalemia in CKD and whether it is associated with excess mortality.

Methods

This retrospective analysis of a national cohort comprised of 2,103,422 records from 245,808 veterans with at least one hospitalization and at least one inpatient or outpatient serum potassium record during fiscal year 2005. CKD and treatment with ACE-I and/or ARBs (RAAS blockers) were the key predictors of hyperkalemia. Death within one day of a hyperkalemic event was the principal outcome.

Results

Of the 66,529 hyperkalemic events (3.2% of records), more occurred inpatient (34937 (52.7%)) versus outpatient (31322 (47.3%)). The adjusted rate of hyperkalemia was higher in patients with CKD than without CKD among individuals treated with RAAS blockers (7.67 vs. 2.30 per 100 patient months, p<0.0001) and those without RAAS blocker treatment (8.22 vs. 1.77 per 100 patient months, p<0.0001). The adjusted odds (OR) of death with a moderate (K+≥ 5.5 and < 6.0mg/dl) and severe (K+≥ 6.0 mg/dl) hyperkalemic event was highest with no CKD (OR: 10.32, 31.64, respectively), versus Stage 3 (5.35, 19.52), Stage 4 (OR: 5.73, 11.56), or Stage 5 CKD (OR: 2.31, 8.02) with all p<0.0001 versus normokalemia and no CKD.

Conclusion

The risk of hyperkalemia is increased with CKD, and its occurrence increases the odds of mortality within one day of the event. These findings underscore the importance of this metabolic disturbance as a threat to patient safety in CKD.

Background

Accurate estimation of favorable neurological survival after in-hospital cardiac arrest could provide critical information for physicians, patients, and families.

Methods

Within the Get With The Guidelines-Resuscitation registry, we identified 42,957 patients from 551 hospitals admitted between January 2000 and October 2009 who were successfully resuscitated from an in-hospital cardiac arrest. A simple prediction tool for favorable neurological survival in patients successfully resuscitated from an in-hospital cardiac arrest was developed using multivariable logistic regression, with two-thirds of the sample randomly selected as the derivation cohort and one-third as the validation cohort. Favorable neurological status was defined as the absence of severe neurological deficits (Cerebral Performance Category score of ≤2).

Results

Rates of favorable neurological survival were similar in the derivation (n=7052; 24.6%) and validation cohorts (n=3510; 24.5%). Eleven variables were associated with favorable neurological survival: younger age, initial cardiac arrest rhythm of ventricular fibrillation or pulseless ventricular tachycardia with a defibrillation time of ≤2 minutes, baseline neurological status without disability, arrest location in a monitored unit, shorter duration of resuscitation, and absence of mechanical ventilation, renal insufficiency, hepatic insufficiency, sepsis, malignancy, and hypotension prior to the arrest. The model had excellent discrimination (C statistic of 0.80 for both the derivation and validation cohorts) and calibration. The prediction tool demonstrated the ability to identify patients across a wide range of rates of favorable neurological survival: patients in the top decile had a 70.7% probability of this outcome while patients in the bottom decile had a 2.8% probability.

Conclusion

Among successfully resuscitated patients with an in-hospital cardiac arrest, a simple, bedside prediction tool provides robust estimates of the probability of favorable neurological survival. This tool permits accurate prognostication after cardiac arrest for physicians, patients, and families.

Background

Childhood cancer survivors are at increased risk of morbidity and mortality. To further characterize this risk, this study aimed to compare the prevalence of diabetes mellitus (DM) in childhood cancer survivors and their siblings.

Methods

Participants included 8599 survivors in the Childhood Cancer Survivor Study (CCSS), a retrospectively ascertained North American cohort of long-term survivors who were diagnosed 1970–1986, and 2936 randomly selected siblings of CCSS survivors. The main outcome was self-reported DM.

Results

Survivors and siblings had mean ages of 31.5 years (range, 17.0–54.1) and 33.4 years (range, 9.6–58.4), respectively. DM was reported in 2.5% of survivors and 1.7% of siblings. Adjusting for body mass index (BMI), age, sex, race/ethnicity, household income, and insurance, survivors were 1.8 times more likely to report DM (95% confidence interval [CI], 1.3–2.5; P<0.001) than siblings, with survivors who received total body irradiation (odds ratio [OR], 12.6; 95% CI, 6.2–25.3; P<0.001), abdominal irradiation (OR, 3.4; 95% CI, 2.3–5.0; P<0.001) and cranial irradiation (OR, 1.6; 95% CI 1.0–2.3; P=0.03) at increased risk. In adjusted models, increased risk of DM was associated with: total body irradiation (OR 7.2; 95% CI, 3.4–15.0; P<0.001); abdominal irradiation (OR 2.7; 95% CI, 1.9–3.8; P<0.001); alkylating agents (OR 1.7; 95% CI, 1.2–2.3; P<0.01); and younger age at diagnosis (0–4 years; OR 2.4; 95% CI 1.3–4.6; P<0.01).

Conclusions

Childhood cancer survivors treated with total body or abdominal irradiation have an increased risk of diabetes that appears unrelated to BMI or physical inactivity.

Background

Chronic low back pain is a common problem lacking highly effective treatment options. Small trials suggest that yoga may have benefits for this condition. This trial was designed to determine whether yoga is more effective than conventional stretching exercises or a self-care book for primary care patients with chronic low back pain.

Methods

228 adults with chronic low back pain were randomized to 12 weekly classes of yoga (n=92) or conventional stretching exercises (n=91) or a self-care book (n=45). Back-related functional status (modified Roland Disability Questionnaire, 23-point scale) and bothersomeness of pain (11-point numerical scale) at 12 weeks were the primary outcomes. Outcomes were assessed at baseline, 6, 12 and 26 weeks by interviewers unaware of treatment group.

Results

After adjustment for baseline values, 12-week outcomes for the yoga group were superior to those for the self-care group (mean difference for function = −2.5 [95% CI= −3.7 to −1.3; P<0.001]; mean difference for symptoms = −1.1 [95% CI= −1.7 to −0.4; P<0.001]). At 26 weeks, function for the yoga group remained superior (mean difference = −1.8 [95% CI= − 3.1 to −0.5; P<0.0001]). Yoga was not superior to conventional stretching exercises at any time point.

Conclusions

Yoga classes were more effective than a self-care book, but not stretching classes, in improving function and reducing symptoms due to chronic low back pain, with benefits lasting at least several months.

Background

Although maintaining near normal glycemia delays onset and slows progression of diabetes complications, many diabetes patients and their physicians struggle to achieve glycemic targets. Best methods to support patients as they follow diabetes prescriptions and recommendations are unclear.

Methods

To test the efficacy of a behavioral diabetes intervention in improving glycemia in long-duration, poorly-controlled diabetes, we randomized 222 adults with diabetes (49% type 1, 53±12 years old, 18±12 years duration, hemoglobin A1c=9.0±1.1%) to attend 1) a 5-session manual-based, educator-led structured group intervention with cognitive behavioral strategies (structured behavioral arm), 2) educator-led attention-control group education program (group attention control), or 3) unlimited individual nurse and dietitian education sessions for 6 months (individual control). Outcomes were baseline, and 3, 6, and 12-month post-intervention hemoglobin A1c levels (primary), frequency of diabetes self-care, 3-day pedometer readings, 24-hour diet recalls, average number of glucose checks, physical fitness, depression, coping style, self-efficacy, and quality of life (secondary).

Results

Linear mixed modeling found that all groups improved hemoglobin A1c (p<0.001). However, the structured behavioral arm improved more than group and individual control arms (3-month HbA1c change: −0.8% versus −0.4% and −0.4%; groupXtime interaction p-value=0.04). Further, type 2 participants improved more than type 1 participants (type of diabetesXtime interaction p-value=0.04). Quality of life, glucose monitoring, and frequency of diabetes self-care did not differ by intervention over time.

Conclusions

A structured, cognitive behavioral program is more effective than two control interventions in improving glycemia in adults with long-duration diabetes. Educators can successfully utilize modified psychological and behavioral strategies.

(ClinicalTrail.gov registration number: NCT000142922)

Background

Dietary fiber has been hypothesized to lower risk of coronary heart disease, diabetes, and some cancers. However, little is known of the effect of dietary fiber on total death and cause-specific deaths.

Methods

We examined dietary fiber intake in relation to total mortality and death from specific causes in the NIH-AARP Diet and Health Study, a prospective cohort study. Diet was assessed using a food frequency questionnaire at baseline. Cause of death was identified using the National Death Index Plus. Cox proportional hazard models were used to estimate relative risks (RRs) and two-sided 95% confidence intervals (CI).

Results

During an average of 9 years of follow-up, we identified 20,126 deaths in men and 11,330 deaths in women. Dietary fiber intake was associated with significantly lowered risk of total death in both men and women (multivariate RR comparing the highest vs. the lowest quintile =0.78, 95% CI:0.73–0.82, p-trend, <0.001 in men; 0.78. 95% CI:0.73–0.85, p-trend, <0.001 in women). Dietary fiber intake also lowered risk of death from cardiovascular, infectious, and respiratory diseases by 24%–56% in men and 34%–59% in women. Inverse association between dietary fiber intake and cancer death was observed in men, but not in women. Dietary fiber from grains, but not from other sources, was significantly inversely related to total and cause-specific death in both men and women.

Conclusions

Dietary fiber may reduce the risk of death from cardiovascular, infectious and respiratory diseases. Making fiber-rich food choices more often may provide significant health benefits.