Kerrie P. Nelson

Incidence of Second Malignancies Among Patients Treated With Proton Versus Photon Radiation

PURPOSE Proton radiation, when compared with photon radiation, allows delivery of increased radiation dose to the tumor while decreasing dose to adjacent critical structures. Given the recent expansion of proton facilities in the United States, the long-term sequelae of proton therapy should be carefully assessed. The objective of this study was to compare the incidence of second cancers in patients treated with proton radiation with a population-based cohort of matched patients treated with photon radiation. METHODS AND MATERIALS We performed a retrospective cohort study of 558 patients treated with proton radiation from 1973 to 2001 at the Harvard Cyclotron in Cambridge, MA and 558 matched patients treated with photon therapy in the Surveillance, Epidemiology, and End Results (SEER) Program cancer registry. Patients were matched by age at radiation treatment, sex, year of treatment, cancer histology, and site. The main outcome measure was the incidence of second malignancies after radiation. RESULTS We matched 558 proton patients with 558 photon patients from the Surveillance, Epidemiology, and End Results registry. The median duration of follow-up was 6.7 years (interquartile range, 7.4) and 6.0 years (interquartile range, 9.3) in the proton and photon cohorts, respectively. The median age at treatment was 59 years in each cohort. Second malignancies occurred in 29 proton patients (5.2%) and 42 photon patients (7.5%). After we adjusted for sex, age at treatment, primary site, and year of diagnosis, proton therapy was not associated with an increased risk of second malignancy (adjusted hazard ratio, 0.52 [95% confidence interval, 0.32-0.85]; P=.009). CONCLUSIONS The use of proton radiation therapy was not associated with a significantly increased risk of secondary malignancies compared with photon therapy. Longer follow-up of these patients is needed to determine if there is a significant decrease in second malignancies. Given the limitations of the study, these results should be viewed as hypothesis generating.

A randomized controlled trial of an automated exercise coach for older adults.

To compare the efficacy of a computer‐based physical activity program (Embodied Conversational Agent—ECA) with that of a pedometer control condition in sedentary older adults.

Clinician Impression Versus Prescription Drug Monitoring Program Criteria in the Assessment of Drug-Seeking Behavior in the Emergency Department

STUDY OBJECTIVE We compare emergency provider impression of drug-seeking behavior with objective criteria from a state prescription drug monitoring program, assess change in opioid pain reliever prescribing after prescription drug monitoring program review, and examine clinical factors associated with suspected drug-seeking behavior. METHODS This was a prospective observational study of emergency providers assessing a convenience sample of patients aged 18 to 64 years who presented to either of 2 academic medical centers with chief complaint of back pain, dental pain, or headache. Drug-seeking behavior was objectively defined as present when a patient had greater than or equal to 4 opioid prescriptions by greater than or equal to 4 providers in the 12 months before emergency department evaluation. Emergency providers completed data forms recording their impression of the likelihood of drug-seeking behavior, patient characteristics, and plan for prescribing pre- and post-prescription drug monitoring program review. Descriptive statistics were generated. We calculated agreement between emergency provider impression of drug-seeking behavior and prescription drug monitoring program definition, and sensitivity, specificity, and positive predictive value of emergency provider impression, using prescription drug monitoring program criteria as the criterion standard. A multivariate logistic regression analysis was conducted to determine clinical factors associated with drug-seeking behavior. RESULTS Thirty-eight emergency providers with prescription drug monitoring program access participated. There were 544 patient visits entered into the study from June 2011 to January 2013. There was fair agreement between emergency provider impression of drug-seeking behavior and prescription drug monitoring program (κ=0.30). Emergency providers had sensitivity 63.2% (95% confidence interval [CI] 54.8% to 71.7%), specificity 72.7% (95% CI 68.4% to 77.0%), and positive predictive value 41.2% (95% CI 34.4% to 48.2%) for identifying drug-seeking behavior. After exposure to prescription drug monitoring program data, emergency providers changed plans to prescribe opioids at discharge in 9.5% of cases (95% CI 7.3% to 12.2%), with 6.5% of patients (n=35) receiving opioids not previously planned and 3.0% (n=16) no longer receiving opioids. Predictors for drug-seeking behavior by prescription drug monitoring program criteria were patient requests opioid medications by name (odds ratio [OR] 1.91; 95% CI 1.13 to 3.23), multiple visits for same complaint (OR 2.5; 95% CI 1.49 to 4.18), suspicious history (OR 1.88; 95% CI 1.1 to 3.19), symptoms out of proportion to examination (OR 1.83; 95% CI 1.1 to 3.03), and hospital site (OR 3.1; 95% CI 1.76 to 5.44). CONCLUSION Emergency providers had fair agreement with objective criteria from the prescription drug monitoring program in suspecting drug-seeking behavior. Program review changed management plans in a small number of cases. Multiple clinical factors were predictive of drug-seeking behavior.

Electrocardiographic PR Interval and Adverse Outcomes in Older Adults The Health, Aging, and Body Composition Study

Background— The electrocardiographic PR interval increases with aging, differs by race, and is associated with atrial fibrillation (AF), pacemaker implantation, and all-cause mortality. We sought to determine the associations between PR interval and heart failure, AF, and mortality in a biracial cohort of older adults. Methods and Results— The Health, Aging, and Body Composition (Health ABC) Study is a prospective, biracial cohort. We used multivariable Cox proportional hazards models to examine PR interval (hazard ratios expressed per SD increase) and 10-year risks of heart failure, AF, and all-cause mortality. Multivariable models included demographic, anthropometric, and clinical variables in addition to established cardiovascular risk factors. We examined 2722 Health ABC participants (aged 74±3 years, 51.9% women, and 41% black). We did not identify significant effect modification by race for the outcomes studied. After multivariable adjustment, every SD increase (29 ms) in PR interval was associated with a 13% greater 10-year risk of heart failure (95% confidence interval, 1.02–1.25) and a 13% increased risk of incident AF (95% confidence interval, 1.04–1.23). PR interval >200 ms was associated with a 46% increased risk of incident heart failure (95% confidence interval, 1.11–1.93). PR interval was not associated with increased all-cause mortality. Conclusions— We identified significant relationships of PR interval to heart failure and AF in older adults. Our findings extend prior investigations by examining PR interval and associations with adverse outcomes in a biracial cohort of older men and women.Background—The electrocardiographic PR interval increases with aging, differs by race, and is associated with atrial fibrillation (AF), pacemaker implantation, and all-cause mortality. We sought to determine the associations between PR interval and heart failure, AF, and mortality in a biracial cohort of older adults. Methods and Results—The Health, Aging, and Body Composition (Health ABC) Study is a prospective, biracial cohort. We used multivariable Cox proportional hazards models to examine PR interval (hazard ratios expressed per SD increase) and 10-year risks of heart failure, AF, and all-cause mortality. Multivariable models included demographic, anthropometric, and clinical variables in addition to established cardiovascular risk factors. We examined 2722 Health ABC participants (aged 74±3 years, 51.9% women, and 41% black). We did not identify significant effect modification by race for the outcomes studied. After multivariable adjustment, every SD increase (29 ms) in PR interval was associated with a 13% greater 10-year risk of heart failure (95% confidence interval, 1.02–1.25) and a 13% increased risk of incident AF (95% confidence interval, 1.04–1.23). PR interval >200 ms was associated with a 46% increased risk of incident heart failure (95% confidence interval, 1.11–1.93). PR interval was not associated with increased all-cause mortality. Conclusions—We identified significant relationships of PR interval to heart failure and AF in older adults. Our findings extend prior investigations by examining PR interval and associations with adverse outcomes in a biracial cohort of older men and women.

Consuming a hypocaloric high fat low carbohydrate diet for 12 weeks lowers C-reactive protein, and raises serum adiponectin and high density lipoprotein-cholesterol in obese subjects

OBJECTIVE High fat, low carbohydrate (HFLC) diets have become popular tools for weight management. We sought to determine the effects of a HFLC diet compared to a low fat high carbohydrate (LFHC) diet on the change in weight loss, cardiovascular risk factors and inflammation in subjects with obesity. METHODS Obese subjects (29.0-44.6 kg/m2) recruited from Boston Medical Center were randomized to a hypocaloric LFHC (n=26) or HFLC (n=29) diet for 12 weeks. RESULTS The age range of subjects was 21-62 years. As a percentage of daily calories, the HFLC group consumed 33.5% protein, 56.0% fat and 9.6% carbohydrate and the LFHC group consumed 22.0% protein, 25.0% fat and 55.7% carbohydrate. The change in percent body weight, lean and fat mass, blood pressure, flow mediated dilation, hip:waist ratio, hemoglobin A1C, fasting insulin and glucose, and glucose and insulin response to a 2h oral glucose tolerance test did not differ (P>0.05) between diets after 12 weeks. The HFLC group had greater mean decreases in serum triglyceride (P=0.07), and hs-CRP (P=0.03), and greater mean increases in HDL cholesterol (P=0.004), and total adiponectin (P=0.045) relative to the LFHC. Secreted adipose tissue adiponectin or TNF-α did not differ after weight loss for either diet. CONCLUSIONS Relative to the LFHC group, the HFLC group had greater improvements in blood lipids and systemic inflammation with similar changes in body weight and composition. This small-scale study suggests that HFLC diets may be more beneficial to cardiovascular health and inflammation in free-living obese adults compared to LFHC diets.

Use of the Probability Integral Transformation to Fit Nonlinear Mixed-Effects Models With Nonnormal Random Effects

This article describes a simple computational method for obtaining the maximum likelihood estimates (MLE) in nonlinear mixed-effects models when the random effects are assumed to have a nonnormal distribution. Many computer programs for fitting nonlinear mixed-effects models, such as PROC NLMIXED in SAS, require that the random effects have a normal distribution. However, there is often interest in either fitting models with nonnormal random effects or assessing the sensitivity of inferences to departures from the normality assumption for the random effects. When the random effects are assumed to have a nonnormal distribution, we show how the probability integral transform can be used, in conjunction with standard statistical software for fitting nonlinear mixed-effects models (e.g., PROC NLMIXED in SAS), to obtain the MLEs. Specifically, the probability integral transform is used to transform a normal random effect to a nonnormal random effect. The method is illustrated using a gamma frailty model for clustered survival data and a beta-binomial model for clustered binary data. Finally, the results of a simulation study, examining the impact of misspecification of the distribution of the random effects, are presented.

Opioid education and nasal naloxone rescue kits in the emergency department.

Introduction Emergency departments (EDs) may be high-yield venues to address opioid deaths with education on both overdose prevention and appropriate actions in a witnessed overdose. In addition, the ED has the potential to equip patients with nasal naloxone kits as part of this effort. We evaluated the feasibility of an ED-based overdose prevention program and described the overdose risk knowledge, opioid use, overdoses, and overdose responses among participants who received overdose education and naloxone rescue kits (OEN) and participants who received overdose education only (OE). Methods Program participants were surveyed by telephone after their ED visit about their substance use, overdose risk knowledge, history of witnessed and personal overdoses, and actions in a witnessed overdose including use of naloxone. Results A total of 415 ED patients received OE or OEN between January 1, 2011 and February 28, 2012. Among those, 51 (12%) completed the survey; 37 (73%) of those received a naloxone kit, and 14 (27%) received OE only. Past 30-day opioid use was reported by 35% OEN and 36% OE, and an overdose was reported by 19% OEN and 29% OE. Among 53% (27/51) of participants who witnessed another individual experiencing an overdose, 95% OEN and 88% OE stayed with victim, 74% OEN and 38% OE called 911, 26% OEN and 25% OE performed rescue breathing, and 32% OEN (n=6) used a naloxone kit to reverse the overdose. We did not detect statistically significant differences between OEN and OE-only groups in opioid use, overdose or response to a witnessed overdose. Conclusion This is the first study to demonstrate the feasibility of ED-based opioid overdose prevention education and naloxone distribution to trained laypersons, patients and their social network. The program reached a high-risk population that commonly witnessed overdoses and that called for help and used naloxone, when available, to rescue people. While the study was retrospective with a low response rate, it provides preliminary data for larger, prospective studies of ED-based overdose prevention programs.

Age of Natural Menopause and Atrial Fibrillation: the Framingham Heart Study

BACKGROUND Early menopausal age is associated with risk of cardiovascular events including myocardial infraction, stroke, and increased mortality. Relations between menopausal age and atrial fibrillation (AF) have not been investigated. We examined the association between menopausal age and AF. METHODS Framingham Heart Study women ≥ 60 years old without prevalent AF and natural menopause were followed up for 10 years or until incident AF. Menopausal age was modeled as a continuous variable and by categories (<45, 45-53, and >53 years). We used Cox proportional hazards regression to determine associations between menopausal age and AF risk. RESULTS In 1,809 Framingham women (2,662 person-examinations, mean baseline age 71.4 ± 7.6 years, menopausal age 49.8 ± 3.6 years), there were 273 unique participants with incident AF. We did not identify a significant association between the SD of menopausal age (3.6 years) and AF (hazard ratio [HR] per SD 0.94, 95% CI 0.83-1.06; P = .29). In a multivariable model with established risk factors for AF, menopausal age was not associated with incident AF (HR per SD 0.97, 95% CI 0.86-1.09; P = .60). Examining categorical menopausal age, earlier menopausal age (<45 years) was not significantly associated with increased AF risk compared with older menopausal age >53 years (HR 1.20, 95% CI 0.74-1.94; P = .52) or menopausal age 45 to 53 years (HR 1.38, 95% CI 0.93-2.04; P = .11). CONCLUSION In our moderate-sized, community-based sample, we did not identify menopausal age as significantly increasing AF risk. However, future larger studies will need to examine whether there is a small effect of menopausal age on AF risk.

Effects of caffeinated vs. non-caffeinated alcoholic beverage on next-day hangover incidence and severity, perceived sleep quality, and alertness

AIMS Beliefs about the effects of mixing caffeine and alcohol on hangover or sleep may play a role in motivation to consume these mixtures; therefore, information is needed about actual effects. We investigated whether intoxication with caffeinated vs. non-caffeinated beer differentially affected perceived sleep quality, sleepiness, and hangover incidence and severity the next morning. METHODS University students (89%) and recent graduate drinkers were randomized to receive: (1) beer with the equivalent of 69mg caffeine/12oz glass of regular beer (n=28) or (2) beer without caffeine (n=36), in sufficient quantity to attain a BrAC of 0.12g%. After an 8-h supervised sleep period, participants completed measures of hangover, sleep quality, sleep latency and time asleep, and sleepiness. RESULTS While caffeinated beer improved perceived sleep quality, effect sizes were greater for morning alertness than for quality while sleeping, with no effect on sleep latency or total sleep time. No effects were seen on hangover incidence or severity. CONCLUSIONS Mixing caffeine and alcohol does not significantly impair amount of sleep or sleep latency, hangover, or sleepiness the morning after drinking to intoxication in this population.

The Association Between Benzodiazepine Prescription and Aberrant Drug-related Behaviors in Primary Care Patients Receiving Opioids for Chronic Pain

ABSTRACT Background: Benzodiazepine use has been associated with addiction-related risks, but little is known about its association with aberrant drug-related behaviors in patients receiving opioids for chronic pain. The authors examined the association between receipt of a benzodiazepine prescription and 2 aberrant drug-related behaviors, early opioid refills and illicit drug (cocaine) use in patients receiving opioids for noncancer chronic pain. Methods: This was a retrospective cohort study of 847 patients with ≥1 visit to either a hospital-based primary care clinic or one of two community health centers between September 1, 2011, and August 31, 2012. All patients received ≥3 opioid prescriptions written at least 21 days apart within 6 months, and ≥1 urine drug screen during the study period. A Cox proportional hazards model estimated the hazard of a second early opioid refill, defined as an opioid prescription written 7–25 days after the previous prescription for the same drug, as a function of time-varying benzodiazepine prescription. A logistic regression model examined the relationship between benzodiazepine prescription and a positive urine test for cocaine. Models were adjusted for demographics and mental/substance use disorder diagnoses. Results: Twenty-three percent (n = 196) of patients received ≥1 benzodiazepine prescription during the study period. Twenty-two percent (n = 183) of patients had ≥2 early opioid refills, and 11% (n = 93) had ≥1 positive urine drug tests for cocaine. Receipt of benzodiazepine prescription was associated with an increased hazard of having a second early opioid refill, adjusted hazard ratio = 1.54 (95% confidence interval [CI]: 1.09–2.18), but not associated with a positive cocaine test, adjusted odds ratio = 1.07 (95% CI: 0.55–2.23). Conclusions: Among primary care patients receiving chronic opioid therapy, benzodiazepine prescription was associated with early opioid refills but not with cocaine use. Further research should better elucidate the risks and benefits of prescribing benzodiazepines to patients receiving opioids for chronic pain.