Enhanced perceptual selection of predicted stimulus orientations following statistical learning.

Perception is influenced by predictions about the sensory environment. These predictions are informed by past experience and can be shaped by exposure to recurring patterns of sensory stimulation. Predictions can enhance perception of a predicted stimulus, but they can also suppress it by favoring novel and unexpected sensory information that is inconsistent with the predictions. Here we employed statistical learning to assess the effects of exposure to consistent sequences of oriented gratings on subsequent visual perceptual selection, as measured with binocular rivalry. Following statistical learning, the first portion of a learned sequence of stimulus orientations was presented to both eyes, followed by simultaneous presentation of the next grating in the sequence to one eye and an orthogonal unexpected orientation to the other eye. We found that subjects were more likely to perceive the grating that matched the orientation that was consistent with the predictive context. That is, observers were more likely to see what they expected to see, compared to the likelihood of perceiving the unexpected stimulus. Some other studies in the literature have reported the opposite effect of prediction on visual perceptual selection, and we suggest that these inconsistencies may be due to differences across studies in the level of the visual processing hierarchy at which competing perceptual interpretations are resolved.

A phase II study of cabozantinib alone or in combination with trastuzumab in breast cancer patients with brain metastases.

PURPOSE: To analyze the efficacy and tolerability of cabozantinib-a small molecule inhibitor of MET and VEGFR2-alone or with trastuzumab in patients with breast cancer brain metastases (BCBM). METHODS: This single-arm phase II study enrolled patients with new or progressive measurable BCBM into 3 cohorts: Cohort 1 (HER2-positive), Cohort 2 (hormone receptor-positive/HER2-negative), and Cohort 3 (triple-negative). Patients received cabozantinib 60-mg daily on a 21-day cycle. Cohort 1 added trastuzumab every 3 weeks and had a primary objective of central nervous system (CNS) objective response rate (ORR) by RECIST 1.1. Secondary objectives for all cohorts were progression-free survival, overall survival, toxicity, and changes in vascular parameters and circulating biomarkers. Cohorts 2 and 3 also had CNS ORR as a secondary objective. RESULTS: Thirty-six BCBM patients enrolled (cohort 1, n = 21; cohort 2, n = 7; cohort 3, n = 8), with a median age of 50. Patients had a median of 3 prior lines for metastatic disease (range 1-9). Treatments prior to enrollment included craniotomy (n = 4), whole brain radiation (n = 24) and stereotactic radiosurgery (n = 11). CNS ORR was 5% in cohort 1, 14% in cohort 2, and 0% in cohort 3. Most common grade 3/4 adverse events included elevations in lipase (11%), AST (8%), ALT (6%), hyponatremia (8%), and hypertension (6%). Cabozantinib increased plasma concentrations of CA-IX, soluble (s)MET, PlGF, sTIE-2, VEGF, and VEGF-D, and decreased sVEGFR2 and TNF-α and total tumor blood volume. CONCLUSIONS: Cabozantinib had insufficient activity in heavily pretreated BCBM patients. Biomarker analysis showed that cabozantinib had antiangiogenic activity and increased tissue hypoxia. TRIAL REGISTRATION: Clinicaltrial.gov registration: NCT02260531.

Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.

PURPOSE: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. PATIENTS AND METHODS: Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders. RESULTS: Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. CONCLUSION: Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

Incidence of Adjacent Synchronous Invasive Carcinoma and/or Ductal Carcinoma In-situ in Patients with Lobular Neoplasia on Core Biopsy: Results from a Prospective Multi-Institutional Registry (TBCRC 020).

BACKGROUND: Lobular neoplasia (LN) represents a spectrum of atypical proliferative lesions, including atypical lobular hyperplasia and lobular carcinoma-in-situ. The need for excision for LN found on core biopsy (CB) is controversial. We conducted a prospective multi-institutional trial (TBCRC 20) to determine the rate of upgrade to cancer after excision for pure LN on CB. METHODS: Patients with a CB diagnosis of pure LN were prospectively identified and consented to excision. Cases with discordant imaging and those with additional lesions requiring excision were excluded. Upgrade rates to cancer were quantified on the basis of local and central pathology review. Confidence intervals and sample size were based on exact binomial calculations. RESULTS: A total of 77 of 79 registered patients underwent excision (median age 51 years, range 27-82 years). Two cases (3%; 95% confidence interval 0.3-9) were upgraded to cancer (one tubular carcinoma, one ductal carcinoma-in-situ) at excision per local pathology. Central pathology review of 76 cases confirmed pure LN in the CB in all but two cases. In one case, the tubular carcinoma identified at excision was also found in the CB specimen, and in the other, LN was not identified, yielding an upgrade rate of one case (1%; 95% CI 0.01-7) by central pathology review. CONCLUSIONS: In this prospective study of 77 patients with pure LN on CB, the upgrade rate was 3% by local pathology and 1% by central pathology review, demonstrating that routine excision is not indicated for patients with pure LN on CB and concordant imaging findings.

Weight gain on antipsychotic medication is associated with sustained use among veterans with schizophrenia.

OBJECTIVE: Continuous antipsychotic treatment is important in schizophrenia, and studies have shown that rates of discontinuation are high. Some studies suggest that weight gain may lead schizophrenic patients to discontinue treatment, whereas other studies show smaller effects of weight gain on medication discontinuation, and some find weight gain associated with symptom improvement. Our retrospective cohort study investigated the effect of weight change on the continued use for 1 year (persistence) of all antipsychotics, then among users of first-generation antipsychotics and second-generation antipsychotics (SGAs), and lastly subgroups of SGAs. METHODS: We identified 2130 patients with schizophrenia starting an antipsychotic that had not used 1 in the prior year. Using multivariable logistic regression adjusted for demographic and clinical variables, we determined the odds of remaining persistent on medication among patients who either gained weight or did not gain weight in the following year. RESULTS: For all antipsychotics combined, weight change was not associated with persistence. Among SGAs, weight gain was associated with a 23% increase in the adjusted odds ratio (OR) for persistence (OR, 1.23; 95% confidence interval [CI], 1.00-1.51), whereas there was a nonsignificant decrease in the adjusted odds of persistence among first-generation antipsychotic users (OR, 0.74; 95% CI, 0.43-1.28). When SGAs were divided into subgroups (clozapine/olanzapine, risperidone/quetiapine), both had increases in the likelihood of persistence, but only the association for clozapine/olanzapine was significant at a trend level (adjusted OR, 1.46; 95% CI, 0.99-2.16). CONCLUSIONS: These findings are supportive of other research that shows weight gain does not invariably lead to medication discontinuation and may be associated with clinical improvement.

Dementia Coding, Workup, and Treatment in the VA New England Healthcare System.

Growing evidence suggests that Alzheimer's disease and other types of dementia are underdiagnosed and poorly documented. In our study, we describe patterns of dementia coding and treatment in the Veteran's Administration New England Healthcare System. We conducted a retrospective cohort study with new outpatient ICD-9 codes for several types of dementia between 2002 and 2009. We examined healthcare utilization, medication use, initial dementia diagnoses, and changes in diagnoses over time by provider type. 8,999 veterans received new dementia diagnoses during the study period. Only 18.3% received a code for cognitive impairment other than dementia, most often "memory loss" (65.2%) prior to dementia diagnosis. Two-thirds of patients received their initial code from a PCP. The etiology of dementia was often never specified by ICD-9 code, even by specialists. Patients followed up exclusively by PCPs had lower rates of neuroimaging and were less likely to receive dementia medication. Emergency room visits and hospitalizations were frequent in all patients but highest in those seen by dementia specialists. Dementia medications are commonly used off-label. Our results suggest that, for the majority the patients, no prodrome of the dementia syndrome is documented with diagnostic code, and patients who do not see dementia specialists have less extensive diagnostic assessment and treatment.

Incident severe thrombocytopenia in veterans treated with pegylated interferon plus ribavirin for chronic hepatitis C infection.

PURPOSE: We sought to determine the incidence and risks for severe thrombocytopenia (platelets < 50,000/µL) in United States Veteran patients treated with pegylated interferon (PEG-IFN) plus ribavirin for hepatitis C virus-positive (HCV) chronic liver disease (CLD). METHODS: Using a retrospective, observational cohort study design to analyze databases from the New England Veterans Healthcare System, we identified 979 patients diagnosed with HCV-positive CLD treated solely with PEG-IFN plus ribavirin. The cohort was stratified by pre-treatment platelet counts of 50,000-100,000/µL (N = 90), >100,000-150,000/µL (N = 162), and >150,000µL (N = 727). The cumulative incidence of severe thrombocytopenia and major bleeding events were determined for each baseline platelet group for 48 weeks following treatment initiation. Multivariable Cox regression was used to identify risk factors for incident severe thrombocytopenia. RESULTS: Overall, severe thrombocytopenia occurred in 6.1% (N = 60), but in 41.1% of patients with pre-treatment platelet counts 50, 000-100,000/µL compared with 11.7% (p < 0.001) and 0.55% (p < 0.001) in the two higher pre-treatment platelet groups. Most episodes occurred within the first 12 weeks of treatment. Median nadir count for these 60 patients was 35,000/µL (inter-quartile range 28,000, 44,000). Baseline platelet counts of 50,000-100,000/µL [adjusted hazard ratio (HR) = 3.81; 95%CI = 2.07-7.00] and hemoglobin <10 g/dL (adjusted HR = 3.39; 95%CI = 1.45-7.960) associated with severe thrombocytopenia. Major bleeding events during the 48-week observation period were rare (N = 5, 0.51%). CONCLUSIONS: The incidence of severe thrombocytopenia in a large, observational cohort of veteran patients with HCV CLD treated with PEG-IFN plus ribavirin was 6.1%. Low pre-treatment platelet counts and hemoglobin levels associated with early, incident severe thrombocytopenia.

Prescription opioid analgesics increase the risk of depression.

BACKGROUND: Prescription opioid analgesic use has quintupled recently. Evidence linking opioid use with depression emanates from animal models and studies of persons with co-occurring substance use and major depression. Little is known about depressogenic effects of opioid use in other populations. OBJECTIVE: The purpose of this study was to determine whether prescription opioids are associated with increased risk of diagnosed depression. DESIGN: Retrospective cohort study, new user design. PATIENTS: Medical record data from 49,770 US Department of Veterans Affairs (VA) health care system patients with no recent (24-month) history of opioid use or a diagnosis of depression in 1999 and 2000. MAIN MEASURES: Propensity scores were used to control for bias by indication, and the data were weighted to balance the distribution of covariates by duration of incident opioid exposure. Cox proportional hazard models with adjustment for painful conditions were used to estimate the association between duration of prescription opioid use and the subsequent risk of development of depression between 2001 and 2007. KEY RESULTS: Of 49,770 patients who were prescribed an opioid analgesic, 91 % had a prescription for < 90 days, 4 % for 90-180 days, and 5 % for > 180 days. Compared to patients whose prescription was for < 90 days, the risk of depression increased significantly as the duration of opioid prescription increased (HR = 1.25; 95 % CI: 1.05-1.46 for 90-180 days, and HR = 1.51; 95 % CI:1.31-1.74 for > 180 days). CONCLUSIONS: In this sample of veterans with no recent (24-month) history of depression or opioid analgesic use, the risk of development of depression increased as the duration of opioid analgesic exposure increased. The potential for depressogenic effect should be considered in risk-benefit discussions, and patients initiating opioid treatment should be monitored for development of depression.

MRSA nasal carriage patterns and the subsequent risk of conversion between patterns, infection, and death.

BACKGROUND: Patterns of methicillin-resistant S. aureus (MRSA) nasal carriage over time and across the continuum of care settings are poorly characterized. Knowledge of prevalence rates and outcomes associated with MRSA nasal carriage patterns could help direct infection prevention strategies. The VA integrated health-care system and active surveillance program provides an opportunity to delineate nasal carriage patterns and associated outcomes of death, infection, and conversion in carriage. METHODS/FINDINGS: We conducted a retrospective cohort study including all patients admitted to 5 acute care VA hospitals between 2008-2010 who had nasal MRSA PCR testing within 48 hours of admission and repeat testing within 30 days. The PCR results were used to define a baseline nasal carriage pattern of never, intermittently, or always colonized at 30 days from admission. Follow-up was up to two years and included acute, long-term, and outpatient care visits. Among 18,038 patients, 91.1%, 4.4%, and 4.6% were never, intermittently, or always colonized at the 30-day baseline. Compared to non-colonized patients, those who were persistently colonized had an increased risk of death (HR 2.58; 95% CI 2.18;3.05) and MRSA infection (HR 10.89; 95% CI 8.6;13.7). Being in the non-colonized group at 30 days had a predictive value of 87% for being non-colonized at 1 year. Conversion to MRSA colonized at 6 months occurred in 11.8% of initially non-colonized patients. Age >70 years, long-term care, antibiotic exposure, and diabetes identified >95% of converters. CONCLUSIONS: The vast majority of patients are not nasally colonized with MRSA at 30 days from acute hospital admission. Conversion from non-carriage is infrequent and can be risk-stratified. A positive carriage pattern is strongly associated with infection and death. Active surveillance programs in the year following carriage pattern designation could be tailored to focus on non-colonized patients who are at high risk for conversion, reducing universal screening burden.

Thrombocytopenia and bleeding in veterans with non-hepatitis C-related chronic liver disease.

BACKGROUND: Thrombocytopenia in chronic liver disease (CLD) typically reflects disease severity and may indicate an increased risk for bleeding. AIMS: To describe the longitudinal course of thrombocytopenia and risks for bleeding in veteran patients with non-hepatitis C-related CLD. METHODS: We identified 2,349 patients with non-hepatitis C-related CLD from databases of the New England Veterans Healthcare System between 1999 and 2008. The cohort was stratified by baseline platelet counts of <50,000, 50-100,000, > 100,000-150,000, and >150,000/µl. Primary outcomes were the incidence and hazard rates for bleeding episodes requiring hospitalization and incident severe thrombocytopenia (<50,000/µl). RESULTS: Over a median follow-up of 3.3 years (IQR 1.2, 6.3), incident major bleeds, predominantly gastrointestinal, occurred in 254 patients (10.8 % of the cohort) and in 19.9 % of those with baseline platelets <50,000/µl. Incident severe thrombocytopenia occurred in 315 patients (13.4 % of cohort) and in 40.7 % of those with baseline platelet counts between 50,000 and 100,000/µl. Baseline platelet counts between 50,000 and 100,000/µl independently predicted bleeding [adjusted HR 2.89 (1.76, 4.73) p < 0.001] as did esophageal varices, hemoglobin ≤ 9.9 g %, and INR 1.4-2.0. Incident severe thrombocytopenia and minimum platelet counts <25,000/µl each associated with bleeding episodes, but the average of minimum platelet counts recorded for those who bled was 76,000/µl. CONCLUSIONS: Among veteran patients with non-hepatitis C-related CLD, baseline platelet counts of 50,000 to 100,000/µl increased subsequent risks for both incident severe thrombocytopenia and major bleeding events. Whereas associations between severe thrombocytopenia and bleeding most likely reflect CLD severity, liver-related coagulopathies, and co-morbid bleeding risks, interventions to enhance platelet production may be beneficial for such patients.

Sexual victimization and completed suicide among Danish female adults.

Although sexual victimization has been associated with suicidal behaviors, its association with completed suicide has not been examined. We investigated this association among Danish women using longitudinal data and a conservative definition of victimization. This population-based case-control study included 476 suicide cases and 12,010 matched controls. Seven cases (1.5%) and 5 controls (0.04%) experienced sexual victimization that was reported to the police and resulted in a conviction. Sexual victimization was associated with a 14-fold increased rate of suicide, controlling for confounders and matching (95% CI: [3.4, 59]). Completed suicide is an important potential outcome of sexual victimization, warranting further examination.

Prolonged clopidogrel use after bare metal and drug-eluting stent placement: the Veterans Administration drug-eluting stent study.

BACKGROUND: Current guidelines recommend combining clopidogrel with aspirin for up to 1 year after coronary stenting, but the value of clopidogrel beyond this time is uncertain. METHODS AND RESULTS: We evaluated all patients in the Veterans Administration healthcare system receiving either drug-eluting or bare metal stents from 2002 to 2006. The Veterans Administration National Patient Care and Pharmacy databases were used to extract patient characteristics, duration of clopidogrel use, and outcomes for up to 4 years after the index procedure. We used Cox proportional hazards to estimate hazard ratios for death, myocardial infarction, revascularization, and bleeding from a 12-month landmark after stenting that excluded patients with events within the first 12 months. Of 42,254 patients, 29,175 met the study inclusion criteria. Compared with ≤12 months of clopidogrel, prolonged clopidogrel (>12 months) was associated with a lower adjusted risk of death for both drug-eluting stents (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.61, 0.82; P<0.01) and bare metal stents (HR, 0.85; 95% CI, 0.76, 0.96; P=0.01) as well as for death and myocardial infarction but was unrelated to stroke or major bleeding. The effect of prolonged clopidogrel on death or myocardial infarction was significantly greater among patients receiving drug-eluting (HR, 0.70; 95% CI, 0.64, 0.84) compared with bare metal stents (HR, 0.88; 95% CI, 0.79, 0.98; interaction P=0.024). CONCLUSIONS: Patients receiving clopidogrel beyond 12 months had a lower risk of death or myocardial infarction compared patients receiving clopidogrel ≤12 months. The risk reduction was greater for drug-eluting stents. These data support longer durations of dual antiplatelet therapy for patients receiving a stent, particularly for those receiving a drug-eluting stent.

Underuse of diagnostic codes for specific dementias in the Veterans Affairs New England healthcare system.

OBJECTIVES: To examine the specificity of dementia coding in large populations. DESIGN: Retrospective cohort and chart review study of dementia diagnosis. SETTING: U.S. Department of Veterans Affairs (VA) New England healthcare system. PARTICIPANTS: Veterans aged 50 and older given outpatient visit codes for dementia between January 1, 2000, and December 31, 2009. MEASUREMENTS: The frequency of the code "dementia not otherwise specified (DNOS)" as a first and final diagnosis was determined. DNOS use was examined according to provider type and geographic location. The medical records of 100 individuals with unspecified dementia were reviewed to determine their underlying diagnoses and describe their examination. RESULTS: Twenty-two thousand fifty veterans diagnosed with dementia were identified over 10 years of follow-up. One-third of all cases had no specific dementia code (n = 6,659). DNOS was the most commonly used code as a first dementia diagnosis (42.5%) and was second only to Alzheimer's type dementia (35.8%) as a final diagnosis. Individuals who saw geriatricians and neurologists were most likely to have a specific dementia diagnosis, and DNOS use was lowest in centers with the most dementia specialists. Only 12% of primary care physicians performed cognitive testing the first time they used the DNOS code, compared with 98% of specialists. Nearly half of individuals with a persistent diagnosis of DNOS met criteria for a specific dementia. CONCLUSION: Substantial overuse was found of nonspecific dementia codes in the VA New England healthcare system, leading to an underestimation of the prevalence of Alzheimer's disease and other dementias. System-based changes in dementia coding and greater access to dementia specialists may help improve diagnostic specificity.

Veterans and suicide: a reexamination of the National Death Index-linked National Health Interview Survey.

OBJECTIVES: We assessed the risk of suicide among veterans compared with nonveterans. METHODS: Cox proportional hazards models estimated the relative risk of suicide, by self-reported veteran status, among 500,822 adult male participants in the National Death Index (NDI)-linked National Health Interview Survey (NHIS), a nationally representative cohort study. RESULTS: A total of 482 male veterans died by suicide during 1,837,886 person-years of follow-up (76% by firearm); 835 male nonveterans died by suicide during 4,438,515 person-years of follow-up (62% by firearm). Crude suicide rates for veterans and nonveterans were, respectively, 26.2 and 18.8 per 100,000 person-years. The risk of suicide was not significantly higher among veterans, compared with nonveterans, after adjustment for differences in age, race, and survey year (hazard ratio = 1.11; 95% confidence interval = 0.96, 1.29). CONCLUSIONS: Consistent with most studies of suicide risk among veterans of conflicts before Operation Iraqi Freedom/Operation Enduring Freedom, but in contrast to a previous study using the NDI-linked NHIS data, we found that male veterans responding to the NHIS were modestly, but not significantly, at higher risk for suicide compared with male nonveterans.

Structure-activity relationships of organofluorine inhibitors of ß-amyloid self-assembly.

A broad group of structurally diverse small organofluorine compounds were synthesized and evaluated as inhibitors of ß-amyloid (Aß) self-assembly. The main goal was to generate a diverse library of compounds with the same functional group and to observe general structural features that characterize inhibitors of Aß oligomer and fibril formation, ultimately identifying structures for further focused inhibitor design. The common structural motifs in these compounds are CF(3) -C-OH and CF(3) -C-NH groups that were proposed to be binding units in our previous studies. A broad range of potential small-molecule inhibitors were synthesized by combining various carbocyclic and heteroaromatic rings with an array of substituents, generating a total of 106 molecules. The compounds were tested by standard methods such as thioflavin-T fluorescence spectroscopy for monitoring fibril formation, biotinyl Aß(1-42) single-site streptavidin-based assays for observing oligomer formation, and atomic force microscopy for morphological studies. These assays revealed a number of structures that show significant inhibition against either Aß fibril or oligomer formation. A detailed analysis of the structure-activity relationship of anti-fibril and -oligomer properties is provided. These data present further experimental evidence for the distinct nature of fibril versus oligomer formation and indicate that the interaction of the Aß peptide with chiral small molecules is not stereospecific in nature.

Benefits associated with achieving optimal risk factor levels for the primary prevention of cardiovascular disease in older men.

BACKGROUND: Most incident cardiovascular disease (CVD) occurs after patients reach the age of 65. The additive benefits of aggressive risk factor management with advancing age are not well established. OBJECTIVE: To evaluate the relationship between control of four modifiable risk factors (smoking, non-high density lipoprotein cholesterol, blood pressure, and aspirin use) and risk of CVD in a primary prevention population of older men. MATERIALS AND METHODS: U.S. male physicians from the Physicians' Health Study (n = 4182; an epidemiologic follow-up of a randomized trial of aspirin and beta-carotene) who in 1997 were ≥ 65 years, free of CVD and diabetes, and had a blood sample on file were studied. Cox proportional hazard models were adjusted for age and competing causes of death. The first of any CVD event, defined as cardiovascular death, nonfatal myocardial infarction, angina, coronary revascularization, nonfatal stroke, transient ischemic attack, carotid artery surgery, and other peripheral vascular disease surgery, was measured. RESULTS: Mean follow-up was 9.3 years, mean age was 73 years, and 96% were nonsmokers. Compared with when 4 of 4 risk factors were controlled (6.0% of participants), control of 0 of 4 risk factors almost quadrupled the risk of CVD (0.4% of participants; event rate 41.2%; hazard ratio [HR] 3.83, 95% confidence interval [95% CI] 1.72-8.55); control of 1 of 4 risk factors more than doubled the risk (14.2% of participants; HR 2.53, 95% CI 1.80-3.57); control of 2 of 4 risk factors almost doubled the risk (43.8% of participants; HR 1.94, 95% CI 1.41-2.69), and those with control of 3 of 4 risk factors also were at increased risk (35.6% of participants; HR 1.80, 95% CI 1.30-2.50). Control of each additional risk factor was associated with greater cardiovascular protection (P for trend P = .002). Depending on the number of risk factors controlled, the number-needed to control to prevent one CVD event ranged from 5 to 22. CONCLUSION: Control of 4 treatable risk factors (nonsmoking, control of non-high density lipoprotein cholesterol and blood pressure, and aspirin use) was associated with substantial protection against incident cardiovascular events in older men even after adjustment for competing causes of mortality.

Florbetaben PET in the Early Diagnosis of Alzheimer's Disease: A Discrete Event Simulation to Explore Its Potential Value and Key Data Gaps.

The growing understanding of the use of biomarkers in Alzheimer's disease (AD) may enable physicians to make more accurate and timely diagnoses. Florbetaben, a beta-amyloid tracer used with positron emission tomography (PET), is one of these diagnostic biomarkers. This analysis was undertaken to explore the potential value of florbetaben PET in the diagnosis of AD among patients with suspected dementia and to identify key data that are needed to further substantiate its value. A discrete event simulation was developed to conduct exploratory analyses from both US payer and societal perspectives. The model simulates the lifetime course of disease progression for individuals, evaluating the impact of their patient management from initial diagnostic work-up to final diagnosis. Model inputs were obtained from specific analyses of a large longitudinal dataset from the New England Veterans Healthcare System and supplemented with data from public data sources and assumptions. The analyses indicate that florbetaben PET has the potential to improve patient outcomes and reduce costs under certain scenarios. Key data on the use of florbetaben PET, such as its influence on time to confirmation of final diagnosis, treatment uptake, and treatment persistency, are unavailable and would be required to confirm its value.

Risk of community-acquired pneumonia in veteran patients to whom proton pump inhibitors were dispensed.

BACKGROUND: Observational studies linking proton pump inhibitor (PPI) exposure with community-acquired pneumonia (CAP) have reported either modest or no associations. Accordingly, we studied PPI exposure and CAP in veteran patients, using a retrospective, nested case-control design. METHODS: From linked pharmacy and administrative databases of the New England Veterans Healthcare System, we identified 71985 outpatients newly prescribed PPIs between 1998 and 2007; 1544 patients met criteria for CAP subsequent to PPI initiation; 15440 controls were matched through risk-set sampling by age and time under observation. Crude and adjusted odds ratios comparing current with past PPI exposures, as well as tests for interactions, were conducted for the entire and stratified samples. RESULTS: Current PPI use associated with CAP (adjusted odds ratio [OR], 1.29 [95% confidence interval {CI}, 1.15-1.45]). Risks were not substantially altered by age or year of diagnosis. Dementia (n = 85; P = .062 for interaction) and sedative/tranquilizer use (n = 224; P = .049 for interaction) were likely effect modifiers increasing a PPI-CAP association; conversely, for some chronic medical conditions, PPI-associated CAP risks were reversed. PPI exposures between 1 and 15 days increased CAP risks, compared with longer exposures, but PPI initiation also frequently occurred shortly after CAP diagnoses. Prescribed PPI doses >1 dose/day also increased PPI-associated CAP risks. CONCLUSIONS: Among the veterans studied, current compared with past PPI exposures associated modestly with increased risks of CAP. However, our observations that recent treatment initiation and higher PPI doses were associated with greater risks, and the inconsistent PPI-CAP associations between patient subgroups, indicate that further inquiries are needed to separate out coincidental patterns of associations.

Statin pharmacogenomics: opportunities to improve patient outcomes and healthcare costs with genetic testing.

HMG-CoA reductase inhibitors, commonly known as statins, are some of the most widely prescribed medications worldwide and have been shown to be effective at lowering cholesterol in numerous long-term prospective trials, yet there are significant limitations to their use. First, patients receiving statin therapy have relatively low levels of medication adherence compared with other drug classes. Next, numerous statin formulations are available, each with its own unique safety and efficacy profile, and it may be unclear to prescribers which treatment is optimal for their patients. Finally, statins have class-wide side effects of myopathy and rhabdomyolysis that have resulted in a product recall and dosage limitations. Recent evidence suggests that two genomic markers, KIF6 and SLCO1B1, may inform the therapy choice of patients initiating statins. Given the prevalence of statin usage, their potential health advantages and their overall cost to the healthcare system, there could be significant clinical benefit from creating personalized treatment regimens. Ultimately, if this approach is effective it may encourage higher adoption of generic statins when appropriate, promote adherence, lower rates of myopathy, and overall achieve higher value cardiovascular care. This paper will review the evidence for personalized prescribing of statins via KIF6 and SLCO1B1 and consider some of the implications for testing these markers as part of routine clinical care.