Multi-Criteria Decision Analysis Model for Assessing the Risk from Multi-Ingredient Dietary Supplements (MIDS).

Military personnel use dietary supplements (DS) for performance enhancement, bodybuilding, weight loss, and to maintain health. Adverse events, including cardiovascular (CV) effects, have been reported in military personnel taking supplements. Previous research determined that ingestion of multi-ingredient dietary supplements (MIDS), can lead to signals of safety concerns. Therefore, to assess the safety of MIDS, the Department of Defense via a contractor explored the development of a model-based risk assessment tool. We present a strategy and preliminary novel multi-criteria decision analysis (MCDA)-based tool for assessing the risk of adverse CV effects from MIDS. The tool integrates toxicology and other relevant data available on MIDS; likelihood of exposure, and biologic plausibility that could contribute to specific aspects of risk.Inputs for the model are values of four measures assigned based on the available evidence supplemented with the opinion of experts in toxicology, modeling, risk assessment etc. Measures were weighted based on the experts' assessment of measures' relative importance. Finally, all data for the four measures were integrated to provide a risk potential of 0 (low risk) to 100 (high risk) that defines the relative risk of a MIDS to cause adverse reactions.We conclude that the best available evidence must be supplemented with the opinion of experts in medicine, toxicology and pharmacology. Model-based approaches are useful to inform risk assessment in the absence of data. This MCDA model provides a foundation for refinement and validation of accuracy of the model predictions as new evidence becomes available.

Real-world assessment of concomitant opioid utilization and associated trends in patients with migraine.

Migraine is a debilitating condition that affects approximately 16% of adults and is the fifth leading cause of emergency department visits in the United States. There are several treatment options for migraines; opioids are frequently prescribed. Results from a recent study showed that more than half of the patients with chronic migraine and a third of the patients with episodic migraine received an opioid prescription in the past year. The American Headache Society recognizes the magnitude of this issue and is working to educate providers on the danger of prescribing opioids in the migraine population The objective of this article is to assess the utilization trends of prescription opioid products and evaluate the impact of opioid utilization on healthcare costs in this patient population. This retrospective claims database analysis used real-world medical claims from multiple health plans. The study period was from January 1, 2009, to September 30, 2017. Patients were included if they were 18 years or older and continuously enrolled in the study period for at least 3 years. Patients were included in the migraine cohort if they had any diagnosis of migraine headache during the study period, while patients without a headache related diagnosis were included in the control cohort. Control patients were propensity matched 1:1 to migraine patients. Discrete (count) data are represented by frequencies and percentages. Continuous results are presented as means, medians, and standard deviations. In the study, 107,216 patients met the inclusion criteria, with 53,608 assigned to each cohort. In the migraine and control cohorts, respectively, 28% and 11% were prescribed opioids. In both cohorts, a majority of the patients were female (81.8%). In both cohorts, opioid use was associated with higher total costs compared with patients who were not prescribed opioids: $82,007 for 200 morphine milligram equivalents (MME)/day or more versus $19,792 for no opioid in patients with migraine; and $54,200 for 200 MME/day or more versus $12,060 for no opioid use in control patients; P <.0001. Patients with more than 2 comorbidities who were prescribed opioids had higher costs than patients with more than 2 comorbidities who were not prescribed opioids and patients with less than 2 comorbidities who were prescribed opioids ($65,980, $32,152, and $35,964, respectively, for patients with migraine, and $52,883, $24,641, and $35,748, respectively, for control patients; P <.0001). Patients with migraine have more than twice the healthcare costs as patients without migraines. The additional increase in healthcare costs in patients with migraine who use opioids for treatment and/or have 2 or more comorbidities is significant. Control of the pain associated with migraine, specifically among those with multiple comorbid conditions, may contribute to substantial reductions in healthcare costs.

Concomitant medical conditions and total cost of care in patients with migraine: a real-world claims analysis.

This study evaluates the impact of concomitant medical conditions on patients with and without migraine, assessing healthcare utilization, and total cost of care. Medical and pharmacy claims from multiple health plans, both nationally and internationally, were examined to evaluate overall real-world trends in commercially insured patients diagnosed with migraine. A total of 53,608 patients with diagnosis codes for migraine met the study criteria and were matched 1:1 with controls (81.8% female; mean age, 42 years; mean Charlson Comorbidity Index score, 0.34). During the 3-year measurement period, mean medical costs per patient in the migraine cohort were about 1.7 times that of the control group ($22,429 vs $13,166). Unique encounters and cost per patient by medical service type for the migraine cohort compared with the control group were as follows: emergency department, 4.13 ($4000) versus 2.94 ($2639); hospital inpatient, 3.15 ($17,748) versus 2.67 ($16,010); hospital outpatient, 5.14 ($365) versus 4.85 ($396); physician office, 36.78 ($6803) versus 21.39 ($4069); laboratory, 10.12 ($1433) versus 7.71 ($1057); radiology, 7.64 ($2609) versus 5.94 ($1733). Mean pharmacy costs per patient were approximately 1.8 times higher in the migraine cohort compared with the control cohort ($8441 vs $4588, respectively; P <.0001). These results suggest that patients with migraine have more comorbidities compared with those without migraine. These patients also utilize healthcare resources at a significantly higher rate compared with similar patients without a migraine diagnosis. An unmet need exists for new treatment modalities in this patient population. More effective interventions and proper management may lead to improved patient outcomes and healthcare costs for patients with migraine.

Patient experience with non-invasive vagus nerve stimulator: gammaCore patient registry.

gammaCore is cleared by the FDA for acute and preventive treatment of cluster headache and the acute treatment of migraine in adults. Previously, only 2 treatments were approved for acute treatment of cluster headache while none were approved for preventive treatment. Following the initial FDA clearance, based on the ACT-1 and ACT-2 studies, a gammaCore Patient Registry (GPR) was designed to provide insights on the use of gammaCore and prescription patterns in the real-world setting and to characterize respective benefits and challenges during the acute treatment of episodic cluster headache. GPR was a prospective observational registry in which patients with episodic cluster headache (3rd edition of the International Classification of Headache Disorders criteria) who were prescribed gammaCore were invited to voluntarily enroll and provide information on their experiences between July 2017 and June 2018. Participants provided baseline information and were trained to self-administer treatment with gammaCore for cluster pain. Participants were also requested to record information for each cluster attack. Of the 182 patients who provided baseline demographic and cluster headache characteristics, 152 provided health index baseline data using EuroQol Health Index tool, 5-level format (EQ5D-5L) and 17 patients provided attack data on a total of 192 cluster headache attacks. The mean age was 49 years; 65% were male and 82% were white; the mean number of months of known diagnosis of cluster headache was 57; the mean number of attacks per cluster headache 4-week period was 14; and the mean pain score was 3.7 (0-4 scale) with a mean attack duration of 74 minutes. Sixty-seven percent of patients had used preventive treatments and 83% had used abortive treatments for cluster headaches; 25% of participants reported at least 1 comorbidity. The mean EQ5D-5L score (scale 0-1) was 0.83. Of the 192 cluster headache attacks reported, gammaCore was used in 116 (60%) attacks. Within this group, the mean pain score at the start of the attacks was 2.7, the mean number of stimulations used was 3.6, and the pain score after 30 minutes was 1.3. At 30 minutes, the pain of 81 (70%) attacks was reduced to none (27%) or mild (43%) (a pain score of 0 or 1) and in 94 (81%) attacks, patients experienced a reduction of at least 1 point in the pain score. This real-world observational evidence suggests that gammaCore adds clinically meaningful value to patients with episodic cluster headache by providing rapid pain relief and confirms that there is significant interest among prescribers in providing this new treatment and technology. This evidence further supports the need to redefine gammaCore as no longer investigational or experimental during considerations for reimbursement.

Effect of Access to Prescribed PCSK9 Inhibitors on Cardiovascular Outcomes.

BACKGROUND: Atherosclerotic cardiovascular disease remains a major cause of death and disability, especially for high-risk familial hypercholesterolemia individuals. PCSK9i (proprotein convertase subtilisin kexin type 9 inhibitors) reduce low-density lipoprotein cholesterol levels and cardiovascular event rates. However, PCSK9i prescriptions are rejected at high rates by payers, and use is often delayed or eventually abandoned as a treatment option. We tested the hypothesis that acute coronary syndromes, coronary interventions, stroke, and cardiac arrest are more prevalent in patients with rejected or abandoned PCSK9i prescriptions than for those with paid PCSK9i prescriptions. METHODS AND RESULTS: We identified 139 036 individuals aged ≥18 years who met the following 3 criteria: prescribed PCSK9i between August 2015 and December 2017, had claims history, and had an established date of exposure for paid, rejected, or abandoned status. To compare the effects of rejected versus paid and abandoned versus paid status, propensity score matching was performed to minimize confounding because of baseline differences in patient groups. Cox regression analyses and incidence density rates for cardiovascular events were estimated on the propensity score-matched cohorts. Patients who received 168 or more days of paid PCSK9i medication within a 12-month period were defined as paid. The hazard ratios for composite cardiovascular events outcome in propensity score-matched analyses were 1.10 (95% CI, 1.01-1.19; P=0.02) for rejected versus paid and 1.12 (95% CI, 1.01-1.24; P=0.03) for abandoned versus paid. In a stricter analysis where paid patients were defined by receiving 338 or more days of therapy within 12-months, hazard ratio was 1.16 (95% CI, 1.02-1.30; P=0.04) for rejected versus paid and 1.21 (95% CI, 1.04-1.38; P=0.03) for the abandoned versus paid status. Higher PCSK9i rejection rates were observed with women, racial minorities, and lower-income groups. CONCLUSIONS: Individuals in the rejected and abandoned cohorts had significantly increased risk of cardiovascular events compared with those in the paid cohort. Rejection, abandonment, and disparities related to PCSK9i prescriptions are related to higher cardiovascular outcome rates.

Review of evidence on noninvasive vagus nerve stimulation for treatment of migraine: efficacy, safety, and implications.

GammaCore was cleared by the FDA for the acute treatment of episodic migraine and episodic cluster headache and has 5 Conformité Européenne marks. Data indicate that gammaCore treatment is both safe and effective as an acute treatment for migraine. Current reimbursement policies need to be updated based on the growing body of evidence to reflect the established status of gammaCore that is no longer experimental. GammaCore provides substantial value to patients and to payers for consideration for pay-for-performance health coverage strategies and policies.

Noninvasive vagus nerve stimulation in a primary care setting: effects on quality of life and utilization measures in multimorbidity patients with or without primary headache.

A patient audit was conducted in the UK to evaluate the impact of gammaCore use in multimorbidity patients on quality of life and healthcare resources utilization measures. A total of 233 patients were enrolled and their data was examined over a 1-year period after their gammaCore prescription. Of these patients, 132 (56%) had primary headache disorders while 101 (44%) were patients without a headache disorder (nonheadache patients). The mean age was 49 years, 169 (72%) were female, the mean number of comorbid conditions was 3.1, and the mean baseline EQ-5D score was 0.581. The mean paired difference in EQ-5D index for persistent gammaCore users (ie patients who used gammaCore for at least 40 weeks) was +0.156 at week 40. The mean percentage reductions in number of general practice consults (doctor's office appointments) was -28.5% from baseline mean of 7.31 and, 40.0% from baseline mean of 3.52 for medical codes used. This evidence demonstrates that a significant proportion of these multimorbidity patients on gammaCore remained compliant with the prescribed treatment regimen for an extended period. GammaCore use in multimorbidity patients may be associated with lower costs of care and provide opportunities for pay-for-performance coverage policies.

Cost-effectiveness of noninvasive vagus nerve stimulation for acute treatment of episodic migraine and role in treatment sequence strategies.

Migraine affects 15% of the population in the United States and is associated with comorbidities, with an estimated economic burden of $78 billion annually. GammaCore is used adjunctively with current standard of care and abortive medications and has shown to be superior in acute treatment of episodic migraine compared to sham. However, the economic impact has not been characterized for this indication. We conducted a cost-effectiveness analyses for 2 hypothetical scenarios: a primary model for treatment options gammaCore plus standard of care compared to standard of care alone for acute treatment of migraine; and a secondary model for treatment sequence strategies where acute treatment with gammaCore or standard of care each prior to erenumab prevention compared to initiating erenumab prevention with no prerequisite. The time horizon for the model is 1 year, using a payer perspective. GammaCore plus standard of care arm was dominant over standard of care alone in the primary model. The mean costs for gammaCore plus standard of care arm and standard of care individually were $9678 and $10,010, respectively. The mean quality of life-years for gammaCore plus standard of care arm and standard of care alone were 0.67, and 0.63, respectively. For the secondary model, the mean costs for gammaCore followed by erenumab, standard of care followed by erenumab and initiating with erenumab with no prior gammaCore or standard of care treatment were $10,678, $11,583, and $13,766. The corresponding mean for quality of life-years were 0.70, 0.67, and 0.65, respectively. For gammaCore dominance, ie, in this scenario, patients were more satisfied on gammaCore, to not need erenumab for preventative therapy lower mean costs and represents savings for payers. This was driven by efficacy, improvement in quality of life, and reduction in costs of care associated with successful treatment of migraine attacks. These findings provide new economic evidence to support value forcoverage for gammaCore.

Review of non-invasive vagus nerve stimulation (gammaCore): efficacy, safety, potential impact on comorbidities, and economic burden for episodic and chronic cluster headache.

The FDA has cleared gammaCore (non-invasive vagus nerve stimulator [nVNS]) for the treatment of episodic cluster headache (eCH). With the exception of subcutaneous sumatriptan, all other treatments are used off label and have many limitations. The FDA approval process for devices differs from that of drugs. We performed a review of the literature to evaluate new evidence on various aspects of gammaCore treatment and impact. The ACute Treatment of Cluster Headache Studies (ACT1 and ACT2), both double-blind sham-controlled randomized trials, did not meet the primary endpoints of the trials but each demonstrated significant superiority of gammaCore among patients with eCH. In ACT1, gammaCore resulted in a higher response rate (RR) (RR, 3.2; 95% CI, 1.6-8.2; P = .014), higher pain-free rate for >50% of attacks (RR, 2.3; 95% CI, 1.1-5.2; P = .045), and shorter duration of attacks (mean difference [MD], -30 minutes; P <.01) compared with the sham group. In ACT2, gammaCore resulted in higher odds of achieving pain-free attacks in 15 minutes (OR, 9.8; 95% CI, 2.2-44.1; P = .01), lower pain intensity in 15 minutes (MD, -1.1; P <.01), and higher rate of achieving responder status at 15 minutes for ≥50% of treated attacks (RR, 2.8; 95% CI, 1.0-8.1; P = .058) compared with the sham group. The PREVention and Acute Treatment of Chronic Cluster Headache (PREVA) study also demonstrated that gammaCore plus standard of care (SOC) was superior to SOC alone in patients with chronic cluster headache (CH). Medical costs, pharmacy refills, and pharmacy costs were higher in patients coded for CH in claims data compared with controls with nonheadache codes. gammaCore is easy to use, practical, and safe; delivery cannot be wasted; and patients prefer using gammaCore compared with SOC. The treatment improves symptoms and reduces the need for CH rescue medications. Current US reimbursement policies, which predate nVNS and are based on expensive, surgically implanted, and permanent implanted vagus nerve stimulation (iVNS), need to be modified to distinguish nVNS from iVNS. gammaCore, cleared by the FDA in April 2017, provides substantial value to patients and also to payers. There is sufficient evidence to support the need to modify current reimbursement policies to include coverage for gammaCore (nVNS) for eCH.

Cost-effectiveness of gammaCore (non-invasive vagus nerve stimulation) for acute treatment of episodic cluster headache.

Cluster headache is a debilitating disease characterized by excruciatingly painful attacks that affects 0.15% to 0.4% of the US population. Episodic cluster headache manifests as circadian and circannual seasonal bouts of attacks, each lasting 15 to 180 minutes, with periods of remission. In chronic cluster headache, the attacks occur throughout the year with no periods of remission. While existing treatments are effective for some patients, many patients continue to suffer. There are only 2 FDA-approved medications for episodic cluster headache in the United States, while others, such as high-flow oxygen, are used off-label. Episodic cluster headache is associated with comorbidities and affects work, productivity, and daily functioning. The economic burden of episodic cluster headache is considerable, costing more than twice that of nonheadache patients. gammaCore adjunct to standard of care (SoC) was found to have superior efficacy in treatment of acute episodic cluster headaches compared with sham-gammaCore used with SoC in ACT1 and ACT2 trials. However, the economic impact has not been characterized for this indication. We conducted a cost-effectiveness analysis of gammaCore adjunct to SoC compared with SoC alone for the treatment of acute pain associated with episodic cluster headache attacks. The model structure was based on treatment of acute attacks with 3 outcomes: failures, nonresponders, and responders. The time horizon of the model is 1 year using a payer perspective with uncertainty incorporated. Parameter inputs were derived from primary data from the randomized controlled trials for gammaCore. The mean annual costs associated with the gammaCore-plus-SoC arm was $9510, and mean costs for the SoC-alone arm was $10,040. The mean quality-adjusted life years for gammaCore-plus-SoC arm were 0.83, and for the SoC-alone arm, they were 0.74. The gammaCore-plus-SoC arm was dominant over SoC alone. All 1-way and multiway sensitivity analyses were cost-effective using a threshold of $20,000. gammaCore dominance, representing savings, was driven by superior efficacy, improvement in quality of life (QoL), and reduction in costs associated with successful and consistent abortion of episodic attacks. These findings serve as additional economic evidence to support coverage for gammaCore. Additional real-world data are needed to characterize the long-term impact of gammaCore on comorbidities, utilization, QoL, daily functioning, productivity, and social engagement of these patients, and for other indications.

The association between hope and mortality in homebound elders.

OBJECTIVE: Despite high rates of mortality and depression, there is limited knowledge of how depressive symptoms, especially feeling of hopefulness, affect mortality in the homebound elderly. METHODS: We conducted a secondary analysis of data from a community sample of 1034 adults, age 60 years and older. The Center for Epidemiologic Studies Depression Scale was used to evaluate the mood symptoms and feeling of hopefulness at baseline. The death data were collected within an 8-year follow-up period. Analysis of variance and Chi-square were used to compare the clinical conditions among the groups of individuals who feel hopeful always, sometimes, and rarely. Logistic regression was used to explore the association between the hopefulness about the future and mortality as an outcome. RESULTS: In the 8-year follow-up period, frequency of feeling hopeful, but not other individual depressive symptoms, was associated with mortality rate. The mortality rate among those who always, sometimes, and rarely felt hopeful were 21.6%, 26.4%, and 35.7%, respectively (P = 0.002). Logistic regression also confirmed that individuals who rarely feel hopeful had higher odds of decease within the 8-year follow-up period than those who always felt hopeful (OR = 1.74, CI = 1.14-2.65) after adjusting for age and medical conditions. CONCLUSIONS: Baseline hopefulness predicts mortality outcome among the homebound elderly in the community. Identifying individuals who are depressed with hopelessness in the elderly and providing early intervention may improve the mortality rate. Copyright © 2017 John Wiley & Sons, Ltd.

Different associations of premorbid intelligence vs. current cognition with BMI, insulin and diabetes in the homebound elderly.

Premorbid intelligence does not decline through life even at the early stages of Alzheimer's disease (AD). However, other cognitive measures such as Mini Mental State Examination (MMSE) decline with aging and severely with dementia. In this study, we examine the associations of premorbid intelligence vs. current cognition with body mass index (BMI), insulin and diabetes in elderly adults. Using a cross-sectional, population-based study, we assessed BMI, plasma insulin and the evidence of diabetes in homebound elders. The North American Adult Reading Test (NAART) and MMSE were conducted. Associations were assessed by T-test, linear correlation and multivariate regression analysis. Subjects were divided into four subgroups: 1) BMI <25; 2) 25 < BMI <30; 3) 30 < BMI <35 and 4) BMI >35. Lower verbal IQ, assessed by NAART, was associated with higher BMI (ß=-0.28; P<0.01), elevated insulin (ß= -0.02, P=0.02), and diabetes (ß=- 3.18, P<0.01). Multivariate regression analyses showed that all three clinical conditions - obesity, hyperinsulinaemia and diabetes - were associated with lower premorbid intelligence assessed by verbal IQ, but only diabetes was associated with current cognitive impairment assessed by MMSE. These relationships persisted after adjustment for education. Premorbid intelligence is associated with diabetes precursors - obesity and high insulin - and diabetes itself, but cognitive impairment is related to diabetes only. Understanding the mechanisms that link verbal IQ to diabetes precursors might suggest targeted interventions for the prevention of diabetes and cognitive decline caused by diabetes.

Systematic literature review of treatments for management of complications of ischemic central retinal vein occlusion.

BACKGROUND: To understand the clinical and economic outcomes of treatments for managing complications of ischemic central retinal vein occlusion (iCRVO). METHODS: We conducted a systematic literature review by searching multiple databases and ophthalmology conferences from 2004 to 2015. Studies published in English language and populations of age ≥45 years were included. For clinical endpoints, we defined eligibility criteria as randomized controlled trials, prospective before-and-after study designs, and non-randomized studies reporting on treatments in patients with iCRVO. For economic endpoints, all types of study design except cost-of-illness studies were included. We evaluated the definitions of ischemia, clinical and economic endpoints, and rate of development of complications. Risk of bias was assessed for clinical studies using the Cochrane risk-of-bias tool. RESULTS: A total of 20 studies (1338 patients) were included. Treatments included anti-vascular endothelial growth factors (anti-VEGFs), steroids, and procedures primarily targeting macular edema and neovascularization. Ischemia was not defined consistently in the included studies. The level of evidence was mostly low. Most treatments did not improve visual acuity significantly. Development of treatment complications ranged from 11 to 57 %. Incremental cost-effectiveness ratios reported for anti-VEGFs and steroids were below the accepted threshold of GB£30,000, but considering such treatments only ameliorate disease symptoms they seem relatively expensive. CONCLUSIONS: There is a lack of evidence for any intervention being effective in iCRVO, especially in the prevention of neovascularisation. iCRVO poses a significant clinical and economic burden. There is a need to standardize the definition of ischemia, and for innovative treatments which can significantly improve visual outcomes and prevent neovascular complications.

Disease-related mortality exceeds treatment-related mortality in patients with chronic myeloid leukemia on second-line or later therapy.

Treatment of newly-diagnosed patients with chronic-phase chronic myeloid leukemia (CP-CML) with tyrosine kinase inhibitors (TKIs) results in near-normal life expectancy. However, CP-CML patients resistant to initial TKIs face a poorer prognosis and significantly higher CML-related mortality. We conducted a systematic literature review to evaluate the specific causes of deaths (diseases progression versus drug-related) in CP-CML patients receiving second- or third-line therapy. We identified eight studies based on our criteria that reported causes of death. Overall, 5% of second-line and 10% of third-line patients died during the study follow-up period. For second-line, (7 studies, n=1926), mortality was attributed to disease progression for 41% of deaths, 2% to treatment-related causes, 3% were treatment-unrelated, and 50% were unspecified adverse events (AEs), not likely related to study drug. In third-line, (2 studies, n=144), 71% deaths were attributed to disease progression, 7% treatment-related AEs, 14% treatment-unrelated and 7% unspecified AEs. Annual death rates for second- and third-line therapy were significantly higher than for general population in similar age group. Our findings suggest death attributed to disease progression is approximately 10 times that due to treatment-related AEs in patients with CP-CML receiving second- or third-line therapy. Therefore, the potential benefits of effective treatment for these patients with the currently available TKIs outweigh the risks of treatment-induced AEs.

Amyloid-associated depression and ApoE4 allele: longitudinal follow-up for the development of Alzheimer's disease.

BACKGROUND: Amyloid-associated depression is associated with cognitive impairment cross sectionally. This follow-up study was to determine the relationship between amyloid-associated depression and the development of Alzheimer's disease (AD). METHODS: Two hundred and twenty three subjects who did not have dementia at baseline were given a repeat cognitive evaluation for incident AD. Depression was defined by having a Center for Epidemiological Studies Depression (CES-D) score ≥ 16, and non-amyloid vs. amyloid-associated depression by having a low vs. high plasma amyloid-ß peptide 40 (Aß40)/Aß42 ratio. Apolipoprotein E (ApoE) genotype was determined, and antidepressant usage was documented. RESULTS: Fifteen subjects developed AD (7%) after an average follow-up time of 6.2 years. While none of those with non-amyloid depression developed AD, 9% of those with amyloid-associated depression developed AD. Further, among those with amyloid-associated depression, ApoE4 carriers tended to have a higher risk of AD than ApoE4 non-carriers (40% vs. 4%, p = 0.06). In contrast, 8% of those who did not have depression at baseline developed AD, but ApoE4 carriers and non-carriers did not show a difference in the AD risk. After adjusting for age, the interaction between ApoE4 and amyloid-associated depression (ß = +0.113, SE = 0.047, P = 0.02) and the interaction between ApoE4 and antidepressant use (ß = +0.174, SE = 0.064, P = 0.007) were associated with the AD risk. CONCLUSIONS: Amyloid-associated depression may be prodromal depression of AD especially in the presence of ApoE4. Future studies with a larger cohort and a longer follow-up are warranted to further confirm this conclusion.

Age and its association with low insulin and high amyloid-ß peptides in blood.

Age is the major risk factor for developing Alzheimer's disease (AD), and modifying age-related factors may help to delay the onset of the disease. The goal of this study was to investigate the relationship between age and the metabolic factors related to the risk of developing AD. The concentrations of insulin, amylin, and amyloid-ß peptide (Aß) in plasma were measured. We further measured the activity of serum Aß degradation by using fluorescein- and biotin-labeled Aß40. Apolipoprotein E4 allele (ApoE4) and cognitive impairment were characterized. Subjects were divided into three age groups: 60-70, 70-80, and ≥80 years old. We found that the older the subjects, the lower the concentration of insulin (p = 0.001) and the higher the concentration of Aß1-40 (p = 0.004) in plasma. However, age was not associated with the concentration of another pancreatic peptide, amylin, and only marginally with Aß1-42. These relationships remained in the absence of diabetes, cardiovascular disease, and stroke, and regardless of the presence of ApoE4 and cognitive impairment. Both age and ApoE4 were inversely associated with, while insulin was positively associated with, the activities of Aß degradation in serum. Our study suggested that low concentration of insulin and high concentration of Aß40 are aging factors related to the risk of AD.

A Randomized Cross-over Air Filtration Intervention Trial for Reducing Cardiovascular Health Risks in Residents of Public Housing near a Highway.

Exposure to traffic-generated ultrafine particles (UFP; particles <100 nm) is likely a risk factor for cardiovascular disease. We conducted a trial of high-efficiency particulate arrestance (HEPA) filtration in public housing near a highway. Twenty residents in 19 apartments living <200 m from the highway participated in a randomized, double-blind crossover trial. A HEPA filter unit and a particle counter (measuring particle number concentration (PNC), a proxy for UFP) were installed in living rooms. Participants were exposed to filtered air for 21 days and unfiltered air for 21 days. Blood samples were collected and blood pressure measured at days 0, 21 and 42 after a 12-hour fasting period. Plasma was analyzed for high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor alpha-receptor II (TNF-RII) and fibrinogen. PNC reductions ranging from 21% to 68% were recorded in 15 of the apartments. We observed no significant differences in blood pressure or three of the four biomarkers (hsCRP, fibrinogen, and TNF-RII) measured in participants after 21-day exposure to HEPA-filtered air compared to measurements after 21-day exposure to sham-filtered air. In contrast, IL-6 concentrations were significantly higher following HEPA filtration (0.668 pg/mL; CI = 0.465-0.959) compared to sham filtration. Likewise, PNC adjusted for time activity were associated with increasing IL-6 in 14- and 21-day moving averages, and PNC was associated with decreasing blood pressure in Lags 0, 1 and 2, and in a 3-day moving average. These negative associations were unexpected and could be due to a combination of factors including exposure misclassification, unsuccessful randomization (i.e., IL-6 and use of anti-inflammatory medicines), or uncontrolled confounding. Studies with greater reduction in UFP levels and larger sample sizes are needed. There also needs to be more complete assessment of resident time activity and of outdoor vs. indoor source contributions to UFP exposure. HEPA filtration remains a promising, but not fully realized intervention.

Implementation and Operational Research: Correlates of Adherence and Treatment Failure Among Kenyan Patients on Long-term Highly Active Antiretroviral Therapy.

BACKGROUND: Universal access to highly active antiretroviral therapy (HAART) is still elusive in most developing nations. We asked whether peer support influenced adherence and treatment outcome and if a single viral load (VL) could define treatment failure in a resource-limited setting. METHODS: A multicenter longitudinal and cross-sectional survey of VL, CD4 T cells, and adherence in 546 patients receiving HAART for up to 228 months. VL and CD4 counts were determined using m2000 Abbott RealTime HIV-1 assay and FACS counters, respectively. Adherence was assessed based on pill count and on self-report. RESULTS: Of the patients, 55.8%, 22.2%, and 22% had good, fair, and poor adherence, respectively. Adherence, peer support, and regimen, but not HIV disclosure, age, or gender, independently correlated with VL and durability of treatment in a multivariate analysis (P < 0.001). Treatment failure was 35.9% using sequential VL but ranged between 27% and 35% using alternate single VL cross-sectional definitions. More patients failed stavudine (41.2%) than zidovudine (37.4%) or tenofovir (28.8%, P = 0.043) treatment arms. Peer support correlated positively with adherence (χ(2), P < 0.001), with nonadherence being highest in the stavudine arm. VL before the time of regimen switch was comparable between patients switching and not switching treatment. Moreover, 36% of those switching still failed the second-line regimen. CONCLUSION: Weak adherence support and inaccessible VL testing threaten to compromise the success of HAART scale-up in Kenya. To hasten antiretroviral therapy monitoring and decision making, we suggest strengthening patient-focused adherence programs, optimizing and aligning regimen to WHO standards, and a single point-of-care VL testing when multiple tests are unavailable.

Effect of time-activity adjustment on exposure assessment for traffic-related ultrafine particles.

Exposures to ultrafine particles (<100 nm, estimated as particle number concentration, PNC) differ from ambient concentrations because of the spatial and temporal variability of both PNC and people. Our goal was to evaluate the influence of time-activity adjustment on exposure assignment and associations with blood biomarkers for a near-highway population. A regression model based on mobile monitoring and spatial and temporal variables was used to generate hourly ambient residential PNC for a full year for a subset of participants (n=140) in the Community Assessment of Freeway Exposure and Health study. We modified the ambient estimates for each hour using personal estimates of hourly time spent in five micro-environments (inside home, outside home, at work, commuting, other) as well as particle infiltration. Time-activity adjusted (TAA)-PNC values differed from residential ambient annual average (RAA)-PNC, with lower exposures predicted for participants who spent more time away from home. Employment status and distance to highway had a differential effect on TAA-PNC. We found associations of RAA-PNC with high sensitivity C-reactive protein and Interleukin-6, although exposure-response functions were non-monotonic. TAA-PNC associations had larger effect estimates and linear exposure-response functions. Our findings suggest that time-activity adjustment improves exposure assessment for air pollutants that vary greatly in space and time.

Toxicity and clinical outcomes in patients with HIV on zidovudine and tenofovir based regimens: a retrospective cohort study.

BACKGROUND: Adverse drug reactions are a major concern with zidovudine/stavudine treatment regimens. The less toxic tenofovir regimen is an alternative, but is seldom considered due to the higher costs. This study compared adverse drug reactions and other clinical outcomes resulting from the use of these two treatment regimens in India. METHODS: Baseline, clinical characteristics and follow-up outcomes were collected by chart reviews of HIV-positive adults and compared using univariate/multivariate analysis, with and without propensity score adjustments. RESULTS: Data were collected from 129 and 92 patients on zidovudine (with lamivudine and nevirapine) and tenofovir (with emtricitabine and efavirenz) regimens, respectively. Compared to patients receiving the zidovudine regimen, patients receiving the tenofovir regimen had fewer adverse drug reactions (47%, 61/129 vs 11%, 10/92; p<0.01), requiring fewer regimen changes (36%, 47/129 vs 3%, 3/92; p0.01). With the propensity score, the zidovudine regimen had 8 times more adverse drug reactions (p<0.01). Opportunistic infections were similar between regimens without propensity score, while the zidovudine regimen had 1.2 times (p=0.63) more opportunistic infections with propensity score. Patients on the tenofovir regimen gained more weight. Increase in CD4 levels and treatment adherence (>95%) was similar across regimens. CONCLUSIONS: Patients on a tenofovir regimen have better clinical outcomes and improved general health than patients on the zidovudine regimen.