Longitudinal hierarchical Bayesian models of covariate effects on airway and alveolar nitric oxide.

Biomarkers such as exhaled nitric oxide (FeNO), a marker of airway inflammation, have applications in the study of chronic respiratory disease where longitudinal studies of within-participant changes in the biomarker are particularly relevant. A cutting-edge approach to assessing FeNO, called multiple flow FeNO, repeatedly assesses FeNO across a range of expiratory flow rates at a single visit and combines these data with a deterministic model of lower respiratory tract NO to estimate parameters quantifying airway wall and alveolar NO sources. Previous methodological work for multiple flow FeNO has focused on methods for data from a single participant or from cross-sectional studies. Performance of existing ad hoc two-stage methods for longitudinal multiple flow FeNO in cohort or panel studies has not been evaluated. In this paper, we present a novel longitudinal extension to a unified hierarchical Bayesian (L_U_HB) model relating longitudinally assessed multiple flow FeNO to covariates. In several simulation study scenarios, we compare the L_U_HB method to other unified and two-stage frequentist methods. In general, L_U_HB produced unbiased estimates, had good power, and its performance was not sensitive to the magnitude of the association with a covariate and correlations between NO parameters. In an application relating height to longitudinal multiple flow FeNO in schoolchildren without asthma, unified analysis methods estimated positive, statistically significant associations of height with airway and alveolar NO concentrations and negative associations with airway wall diffusivity while estimates from two-stage methods were smaller in magnitude and sometimes non-significant.

Hierarchical Bayesian estimation of covariate effects on airway and alveolar nitric oxide.

Exhaled breath biomarkers are an important emerging field. The fractional concentration of exhaled nitric oxide (FeNO) is a marker of airway inflammation with clinical and epidemiological applications (e.g., air pollution health effects studies). Systems of differential equations describe FeNO-measured non-invasively at the mouth-as a function of exhalation flow rate and parameters representing airway and alveolar sources of NO in the airway. Traditionally, NO parameters have been estimated separately for each study participant (Stage I) and then related to covariates (Stage II). Statistical properties of these two-step approaches have not been investigated. In simulation studies, we evaluated finite sample properties of existing two-step methods as well as a novel Unified Hierarchical Bayesian (U-HB) model. The U-HB is a one-step estimation method developed with the goal of properly propagating uncertainty as well as increasing power and reducing type I error for estimating associations of covariates with NO parameters. We demonstrated the U-HB method in an analysis of data from the southern California Children's Health Study relating traffic-related air pollution exposure to airway and alveolar airway inflammation.

Patterns and determinants of exhaled nitric oxide trajectories in schoolchildren over a 7-year period.

Fractional exhaled nitric oxide (F ENO50 ), a marker of allergic airway inflammation, is used in respiratory research and asthma clinical care; however, its trajectory with increasing age during childhood has not been well characterised. We examined F ENO50 longitudinally during a period of important somatic growth to describe trajectories across childhood and adolescence in healthy participants and evaluate clinical factors as potential determinants of trajectories.F ENO50 was collected at six visits over 8 years in a population-based cohort of 1791 schoolchildren without asthma (median age at entry 8.4 years). Smooth sex-specific F ENO50 trajectories were estimated using generalised additive mixed models, with participant-level random effects. We evaluated whether sex-specific trajectories were influenced by race/ethnicity, body mass index (BMI) percentile, allergic rhinitis or puberty.Different F ENO50 patterns were observed by sex in later childhood and several factors were associated with either F ENO50 level or change in F ENO50 as participants aged. F ENO50 -age trajectories were similar by sex until age ∼11.5 years, after which males had greater F ENO50 change than females. This divergence in F ENO50 -age trajectories coincides with puberty. Males with higher starting BMI percentile had attenuated F ENO50 -age slopes. Among males, F ENO50 levels were lower in non-Hispanic white subjects. Among both sexes, participants with rhinitis had higher F ENO50 F ENO50 levels within individuals tracked over time; however, there was considerable variation in F ENO50 patterns across participants.F ENO50 trajectories from longitudinal data provide evidence of sex differences coinciding with puberty, suggesting potential hormone link. Improved understanding of determinants of F ENO50 trajectories is needed to realise the potential for using individualised predicted F ENO50 trajectories.

Impact of different fixed flow sampling protocols on flow-independent exhaled nitric oxide parameter estimates using the Bayesian dynamic two-compartment model.

Exhaled nitric oxide (FeNO) is an established respiratory biomarker with clinical applications in the diagnosis and management of asthma. Because FeNO depends strongly on the flow (exhalation) rate, early protocols specified that measurements should be taken when subjects exhaled at a fixed rate of 50 ml/s. Subsequently, multiple flow (or "extended") protocols were introduced which measure FeNO across a range of fixed flow rates, allowing estimation of parameters including Caw NO and CA NO which partition the physiological sources of NO into proximal airway wall tissue and distal alveolar regions (respectively). A recently developed dynamic model of FeNO uses flow-concentration data from the entire exhalation maneuver rather than plateau means, permitting estimation of Caw NO and CA NO from a wide variety of protocols. In this paper, we use a simulation study to compare Caw NO and CA NO estimation from a variety of fixed flow protocols, including: single maneuvers (30, 50,100, or 300 ml/s) and three established multiple maneuver protocols. We quantify the improved precision with multiple maneuvers and the importance of low flow maneuvers in estimating Caw NO. We conclude by applying the dynamic model to FeNO data from 100 participants of the Southern California Children's Health Study, establishing the feasibility of using the dynamic method to reanalyze archived online FeNO data and extract new information on Caw NO and CA NO in situations where these estimates would have been impossible to obtain using traditional steady-state two compartment model estimation methods.

Sex-specific associations of autism spectrum disorder with residential air pollution exposure in a large Southern California pregnancy cohort.

Autism spectrum disorder (ASD) affects more boys than girls. Recent animal studies found that early life exposure to ambient particles caused autism-like behaviors only in males. However, there has been little study of sex-specificity of effects on ASD in humans. We evaluated ASD risk associated with prenatal and first year of life exposures to particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5) by child sex. This retrospective cohort study included 246,420 singleton children born in Kaiser Permanente Southern California (KPSC) hospitals between 1999 and 2009. The cohort was followed from birth through age five to identify 2471 ASD cases from the electronic medical record. Ambient PM2.5 and other regional air pollution measurements (PM less than 10 µm, ozone, nitrogen dioxide) from regulatory air monitoring stations were interpolated to estimate exposure during each trimester and first year of life at each geocoded birth address. Hazard ratios (HRs) were estimated using Cox regression models to adjust for birth year, KPSC medical center service areas, and relevant maternal and child characteristics. Adjusted HRs per 6.5 µg/m3 PM2.5 were elevated during entire pregnancy [1.17 (95% confidence interval (CI), 1.04-1.33)]; first trimester [1.10 (95% CI, 1.02-1.19)]; third trimester [1.08 (1.00-1.18)]; and first year of life [1.21 (95% CI, 1.05-1.40)]. Only the first trimester association remained robust to adjustment for other exposure windows, and was specific to boys only (HR = 1.18; 95% CI, 1.08-1.27); there was no association in girls (HR = 0.90; 95% CI, 0.76-1.07; interaction p-value 0.03). There were no statistically significant associations with other pollutants. PM2.5-associated ASD risk was stronger in boys, consistent with findings from recent animal studies. Further studies are needed to better understand these sexually dimorphic neurodevelopmental associations.

Serum uric acid and subsequent cognitive performance in patients with pre-existing cardiovascular disease.

High serum uric acid (UA) levels are associated with numerous vascular risk factors, and vascular disease, that predispose patients to cognitive impairment, yet UA is also a major natural antioxidant and higher levels have been linked to slower progression of several neurodegenerative disease. In-order to test the association between UA and subsequent cognitive performance among patients that carry a high vascular burden, UA levels were determined by calorimetric enzymatic tests in a sub-cohort of patients with chronic cardiovascular disease who previously participating in a secondary prevention trial. After an average of 9.8±1.7 years, we assessed cognitive performance (Neurotrax Computerized Cognitive Battery) as well as cerebrovascular reactivity (CVR) and common carotid intima-media thickness (IMT). Among 446 men (mean age 62.3±6.4 yrs) mean UA levels were 5.8±1.1 mg/dL. Adjusted linear regression models revealed that low UA levels (bottom quintile) were associated with poorer cognitive performance. Adjusted differences between the bottom quintile and grouped top UA quintiles were (B coefficient±SE) -4.23±1.28 for global cognitive scores (p = 0.001), -4.69±1.81 for memory scores (p = 0.010), -3.32±1.43 for executive scores (p = 0.020) and -3.43±1.97 for visual spatial scores (p = 0.082). Significant difference was also found for attention scores (p = 0.015). Additional adjustment for impaired CVR and high common carotid IMT slightly attenuated the relationship. Stronger UA effect on cognitive performance was found for older (age>65) patients with significant age interaction for global cognitive score (p = 0.016) and for executive (p = 0.018) and attention domains (p<0.001). In conclusion, we demonstrate that low UA levels in patients with preexisting cardiovascular disease are associated with poorer cognitive function a decade later. These findings lend support to the hypothesis that oxidative stress may be involved in the pathogenesis of age-associated cognitive impairment.

Antithrombotic treatment at onset of stroke with atrial fibrillation, functional outcome, and fatality: a systematic review and meta-analysis.

BACKGROUND: In atrial fibrillation-associated stroke, conflicting data exist regarding association between therapeutic vitamin K-antagonist anticoagulation (International Normalized Ratio 2-3) and early death and functional outcome, and few data exist relating to late outcome in ischemic and haemorrhagic atrial fibrillation-stroke. AIM: We performed a systematic review and meta-analysis of oral anticoagulation at stroke onset, death and functional outcome. METHODS: We performed a systematic review, searching multiple sources. Studies were included if outcomes in atrial fibrillation-associated stroke were reported stratified by pre-stroke antithrombotic status, with documented International Normalized Ratio at onset. Outcomes were survival and good functional outcome (modified Rankin score 0-2) at discharge/30 days, and at one-year. RESULTS: Of eight studies (3552 patients) in ischemic stroke, International Normalized Ratio ≥ 2 compared with other treatments (International Normalized Ratio < 2, antiplatelet, or no antithrombotic) was associated with good outcome [pooled odds ratio 1·9 (95% confidence interval) 1·5-2·5, P < 0·001] and improved survival at 30 days discharge (pooled odds ratio for death 0·4, confidence interval 0·2-0·5, P < 0·001). The net benefit remained after inclusion of haemorrhagic stroke (odds ratio for good outcome 1·89, confidence interval 1·45-2·46, P < 0·001). At one-year, improved functional outcome for International Normalized Ratio ≥ 2 (pooled odds ratio 1·7, confidence interval 1·0-2·7, P = 0·04) and survival (odds ratio for death 0·5, confidence interval 0·4-0·8, P = 0·001) were also observed. CONCLUSIONS: Therapeutic International Normalized Ratio at stroke onset was associated with early and late improved survival and functional recovery suggesting sustained benefit for warfarin anticoagulation for stroke outcome in atrial fibrillation patients. Long-term outcome data following stroke in patients taking new oral anticoagulants is required.

Correlates of quality of sexual life in male and female patients with Parkinson disease and their partners.

INTRODUCTION: Patients with Parkinson disease (PD) and their partners may experience a worsening of their sexual life. AIM: To assess quality of sexual life (QoSL) in male and female PD patients and their partners. MATERIALS AND METHODS: Medical, demographic and clinical data was collected regarding consecutive PD patients, including depression, and motor symptom rating. Partners' data included the short form-12 health questionnaire (SF-12). All patients and partners filled the 5-item QoSL questionnaire. RESULTS: Data from 89 PD patients (66 men) and 69 spouses (52 women) was analyzed. Male patients rejected sex significantly less than female patients and their sexual desire was higher, but female patients reported higher sexual satisfaction. Patients and partners similarly perceived their relationship which was averagely good. Analysis within couples demonstrated that better QoSL of patients could be predicted by gender (male), better QoSL of their partners and, motor severity, but not the patient's depression, age or use of l-dopa. The partner's QoSL was explained by younger age, and better motor scores of their parkinsonian partner. Treatment of the PD patient with l-dopa or dopamine agonist was associated with worse partner's QoSL. CONCLUSION: Differences in QoSL of male and female PD patients and within couples were found. These findings suggest that focusing on partner's needs may improve QoSL of patients and partners troubled by PD.

Trends in antihypertensive treatment--lessons from the National Acute Stroke Israeli (NASIS) registry.

BACKGROUND: Recent guidelines recommended different approaches to hypertension therapy. Our aim was to evaluate trends in blood pressure (BP) management among patients admitted with acute stroke over the past decade. METHODS: The study population comprised 6279 consecutive patients, admitted with an acute stroke, and included in a national registry of three consecutive periods conducted during the years 2004-2010. We compared patients' characteristics and temporal trends of antihypertensive therapy utilization before hospital admission. RESULTS: Among 4727 hypertensive patients, 3940 (83%) patients have taken antihypertensive drug therapy - 1430 (30.2%) a single agent, 1500 (31.7%) two agents and 1010 (21.4%) three or more antihypertensive agents. The most common class used was renin-angiotensin system (RAS) blockers (n = 2575; 54%) followed by beta-blockers (n = 2033; 43%). The same pattern was observed in patients treated with monotherapy. The use of RAS blockers and beta-blockers has increased over the years (p < 0.001 for both), whereas the use of diuretics decreased and the use of calcium antagonists remained stable. Among those who were treated with a single agent, the use of diuretics and calcium antagonists decreased and the use of RAS blockers increased, whereas the use of beta-blockers remained unchanged. CONCLUSIONS: RAS blockers and beta-blockers are the most common antihypertensive agents used in Israel. Over time, the use of RAS blockers and beta-blockers has increased, whereas the use of diuretics decreased.

Recovery of self-rated health as a predictor of recurrent ischemic events after first myocardial infarction: a 13-year follow-up.

OBJECTIVE: Following the trajectory hypothesis for the validity of self-rated health (SRH), we tested whether subjective recovery of health, that is, return to the same or higher level of SRH after a major health event, independently predicts better long-term prognosis. METHODS: Participants were 640 patients (≤ 65 years) admitted to the eight medical centers in central Israel with incident MI in a 1-year period (mean age 54, 17% female). Baseline data were collected within days of the index MI. SRH in the preceding year was assessed at baseline, and current SRH was assessed 3-6 months later. Recurrent ischemic events (recurrent MI, hospitalization with unstable angina pectoris, or cardiac death) were recorded during a mean follow-up of 13 years. RESULTS: A reduced risk of recurrent events was associated with an upward change of one level (e.g., from 3 at T1 to 4 at T2) in SRH (HR = 0.76, 95%CI: 0.69-0.85), controlling for baseline retrospective SRH. Risk was still significantly lower for each unit of improvement after adjusting for sociodemographics, preevent comorbidity, cardiac risk factors, MI severity, and early post-MI events (HR = 0.85, 95% CI 0.75-0.95). CONCLUSIONS: Individuals who perceived themselves 3-6 months after a first MI to be healthier than they had been in the year preceding the MI were more likely to survive event-free throughout the next 13 years, controlling for baseline retrospective SRH and multiple cardiac risk factors. Failure to experience such subjective recovery of one's health is a serious risk factor, which indicates that SRH should be monitored regularly after a MI.

The LRRK2 G2019S mutation status does not affect the outcome of subthalamic stimulation in patients with Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapy for advanced Parkinson's disease (PD). The most common genetic mutation associated with PD identified to date is the G2019S mutation of the LRRK2 gene, which is highly prevalent in the Ashkenazi Jewish population. The effect of STN-DBS surgery in patients carrying this mutation has not been systematically studied. We therefore performed a case-control study to evaluate the impact of the G2019S mutation status on the outcomes of bilateral STN-DBS. METHODS: The study sample included 39 Jewish PD patients with bilateral STN-DBS. Thirteen patients (5 females) were G2019S mutation heterozygous. The control group consisted of 26 PD patients with bilateral STN-DBS, negative for the mutation, matched (2:1) for gender, age at PD onset, and disease duration at surgery. Clinical data including the Unified PD Rating Scale scores (UPDRS), levodopa equivalent daily dose (LEDD), and clinical global impression of change (CGIC) concerning both motor and neuropsychiatric outcome- were available at 3 time points (preoperative baseline, 6-12 months and 3 years postoperatively). RESULTS: Implementing a linear mixed model, a significant improvement (p < 0.05) was found for the whole group concerning reduction in motor UPRDS (off state) and LEDD pre- vs. postoperatively, as expected. No difference in clinical outcome was found between carriers and matched non-carriers at baseline or at postoperative follow-up (up to 3 years). CONCLUSIONS: In our study, STN-DBS outcomes were not influenced by the LRRK2 G2019S mutation, and thus knowledge of carrier status may not be relevant to the considerations of patient selection for surgery.

Quantitative detection of thrombin activity in an ischemic stroke model.

Thrombin, a central factor in thrombogenesis, affects cells in the brain through protease activated receptors. Low levels of thrombin activity are neuroprotective while higher levels are deleterious, and we have therefore developed a new method for its direct quantitative measurement in brain slices following stroke. Thrombin activity was measured by a fluorescent substrate on fresh coronal slices taken from the ipsilateral and contralateral hemispheres 24-72 h following permanent right middle cerebral artery occlusion. Prolyl endopeptidase and aminopeptidases were inhibited as a critical step to insure the specificity of the assay for thrombin detection. Infarct volume was assessed using TTC staining. Thrombin activity in the right ischemic hemisphere was significantly higher compared to the contralateral hemisphere (32 ± 6 and 27 ± 10 mU/ml, mean ± SE in the two most affected slices from the ischemic hemisphere vs. 21 ± 6 and 8 ± 2 mU/ml in corresponding contralateral slices; p < 0.05). Thrombin levels in the ischemic and contralateral hemispheres were significantly higher compared to healthy control mice and were above the range known to be protective to brain cells. A significant correlation was found between thrombin activity in the ischemic hemisphere and the infarct volume. Results of studies based on this method may translate into potential thrombin based therapies.

Is the evaluation and treatment of transient ischemic attack performed according to current knowledge? A nationwide Israeli registry.

BACKGROUND: Patients with transient ischemic attack (TIA) at a high risk of stroke can be identified and should be managed urgently. OBJECTIVES: To investigate whether recognized recommendations are being implemented in Israel. METHODS: An Israeli nationwide registry (NASIS) on patients admitted with stroke and TIA was conducted in all acute care hospitals within 2 successive months during 2004, 2007 and 2010. A revised ABCD2 score was applied retrospectively. Patients with TIA were divided into a low risk group (LRG, 0-3 points) and a high risk group (HRG, 4-6 points) and were compared to patients with minor ischemic strokes (MIS, NIHSS score < or = 5 points). RESULTS: A total of 3336 patients were included (1023 with TIA: LRG 484, HRG 539, and MIS 2313). LRG patients were younger and had lower rates of most traditional risk factors as compared with HRG and MIS patients. Brain imaging was performed in almost all the patients. Ancillary tests (vascular and cardiac) were overall underused, yet were performed more in LRG (53.2% and 26.9% respectively) than in HRG patients (41.6%, 18.9%). Between periods there was no change in usage of ancillary tests for the LRG and a modest increase in both HRG and MIS patients. For performance of vascular investigations overall, the odds ratio was 1.69 (95% confidence interval 1.42-2.00) comparing 2010 with 2004, but 0.7 (95% CI 0.5-0.9) comparing HRG with LRG. Between periods an increase in statin usage was observed in all groups (OR 2.69, 95% CI 2.25-3.21) but was more marked in MIS patients (OR 3.06, 95% CI 2.47-3.8). CONCLUSIONS: The approach to TIA risk stratification and management in Israeli hospitals does not follow standards set by current guidelines. Standardized protocols for TIA should be used to assure effective management.

Cumulative exposure to particulate matter air pollution and long-term post-myocardial infarction outcomes.

INTRODUCTION: Chronic environmental exposure to particulate matter <2.5µm in diameter (PM2.5) has been associated with cardiovascular disease; however, the effect of air pollution on myocardial infarction (MI) survivors is not clear. We studied the association of chronic exposure to PM2.5 with death and recurrent cardiovascular events in MI survivors. METHODS: Consecutive patients aged ≤65years admitted to all medical centers in central Israel after first-MI in 1992-1993 were followed through 2005 for cardiovascular events and 2011 for survival. Data on sociodemographic and prognostic factors were collected at baseline and during follow-up. Residential exposure to PM2.5 was estimated for each patient based on data recorded at air quality monitoring stations. Cox and Andersen-Gill proportional hazards models were used to study the pollution-outcome association. RESULTS: Among the 1120 patients, 469 (41.9%) died and 541 (48.3%) experienced one or more recurrent cardiovascular event. The adjusted hazard ratios associated with a 10µg/m(3) increase in PM2.5 exposure were 1.3 (95% CI 0.8-2.1) for death and 1.5 (95% CI 1.1-1.9) for multiple recurrences of cardiovascular events (MI, heart failure and stroke). CONCLUSION: When adjustment for socio-demographic factors is performed, cumulative chronic exposure to PM2.5 is positively associated with recurrence of cardiovascular events in patients after a first MI.

Neurological outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: early versus late diagnosis.

OBJECTIVE: To present the long-term neurological outcome of Jewish Israeli patients with cerebrotendinous xanthomatosis (CTX) after several years of chenodeoxycholic acid (CDCA) treatment. METHODS: A cross sectional observational study of all patients with a diagnosis of CTX followed in a referral outpatient clinic during the years 2003-2012. RESULTS: Eighteen patients (10 men) from 11 families were enrolled. Sixteen patients were included in the analysis (2 patients had low compliance for treatment). The mean ± SD age at last evaluation was 35.0 ± 9.2 years (range, 16-45 years). After their diagnosis, at age 22.6 ± 10.8 years, all patients were treated with CDCA. Patients who started treatment after the age of 25 years had worse outcome and were significantly more limited in ambulation (P = 0.004) and more cognitively impaired (P = 0.047). Five patients who started treatment after 25 years of age continued to deteriorate despite CDCA treatment. CONCLUSIONS: Beginning CDCA treatment as early as possible is crucial to preventing neurological damage and deterioration in CTX. After significant neurological pathology is established, the effect of treatment is limited and deterioration may continue.

Perceived hardships at midlife: prediction of long-term stroke mortality.

OBJECTIVES: The objective of this study is to examine the association between perceived hardships and long-term stroke mortality among a large cohort of middle-aged men. BACKGROUND: Unlike cardiovascular morbidity and mortality, much less is known about the relationship between psychosocial factors and risk of stroke. METHODS: A cohort of 10,059 men aged ≥ 40 years at study inclusion that were tenured civil servants or municipal employees were followed for mortality over a median of 28.1 years (IQR 18.9-34.3). During follow-up 6528 (64.9%) men died, 665 of stroke and 1769 of coronary heart disease (CHD). A composite score of perceived hardships was calculated based on a structured psychosocial questionnaire filled at baseline, assessing domains of work, family, and finance. Cox proportional hazard models were used adjusting for traditional risk factors and socio-economic status. RESULTS: At baseline, subjects with higher hardship scores were slightly older, smoked more cigarettes, had higher prevalence of CHD, lower systolic blood pressure, higher anxiety levels and lower socio-economic status. Compared with the bottom tertile, the middle (HR 1.26, 95% CI 1.04-1.53) and top tertiles of the hardship score (HR 1.33, 95% CI 1.07-1.64) exhibited higher risk of stroke mortality (P for trend=0.008), while no significant association was found with long-term mortality from CHD. The magnitude of the association was comparable to that of diabetes (HR 1.30, 95% CI 1.02-1.66). CONCLUSION: Perceived hardships measured at midlife in a large cohort of apparently healthy men independently predict stroke mortality over long-term follow-up.

The relatively good outcome of cerebellum-brainstem ischemic strokes.

BACKGROUND: Our clinical experience suggests that the outcome of cerebellum-brainstem ischemic strokes is better than that of hemispheric ischemic strokes. METHODS: Within the setting of 2 national Israeli prospective stroke surveys, we analyzed risk factors, etiology, severity at presentation, and prognosis of first ischemic cerebellum-brainstem stroke (259 patients), comparing with strokes within the anterior circulation (1,029 patients). RESULTS: Patients with cerebellum-brainstem strokes were younger and had less frequently atrial fibrillation and congestive heart failure. Cardioembolic etiology was significantly less prevalent (p < 0.001). Severity at presentation was milder (p < 0.001). At discharge, worsening of the modified Rankin Scale was present in a smaller number of patients (p < 0.001); more returned to their home (p < 0.001). Six-month and 1-year mortality were lower (p < 0.001 for both). Adjusted logistic regression models showed that patients with cerebellum-brainstem strokes had 50% smaller chances of dying (OR 0.55; 95% CI 0.31-0.98) and a smaller chance of worsening of the modified Rankin Scale at discharge (OR 0.61; 95% CI 0.46-0.82). CONCLUSIONS: Cerebellum-brainstem strokes are less frequently cardioembolic, have a less severe presentation, and carry a better immediate and long-term prognosis.

Low cholesterol, statins and outcomes in patients with first-ever acute ischemic stroke.

BACKGROUND: High cholesterol has been associated with better stroke outcomes. Conversely, a protective effect of prestroke statin use in the acute phase of stroke has been reported. The effect of low cholesterol on outcome in patients with and without prestroke statin treatment has not been studied. We assessed the association between low cholesterol and ischemic stroke short- and long-term outcomes and studied potential interactions with statin treatment in patients with a first-ever ischemic stroke in a prospective national registry. METHODS: Ischemic stroke patients in the National Acute Stroke Israeli (NASIS) registry with a first-ever stroke and no previous disability, dementia or cancer admitted in all hospitals nationwide during 2-month periods in 2004, 2007 and 2010 were included (n = 1,895). Cholesterol levels ≤155 mg/dl (1st quintile) were defined as low cholesterol and patients treated with statins for at least 7 days before stroke onset were categorized as prestroke statin treated. Severe stroke (NIHSS ≥11), total anterior circulation infarction, poor functional outcome (defined as discharged to a nursing facility or modified Rankin Scale >3 or death), and mortality at discharge and at 3 years were the study outcomes. Associations between low cholesterol and outcomes at discharge were assessed separately in patients with and without prestroke statin treatment using multiple logistic regression analyses. Mortality at 3 years was assessed in a subset of 681 patients with Cox proportional hazard models. RESULTS: Patients were 67.4 ± 13.5 years old on average; 43.1% were women. Low cholesterol was associated with higher rates of stroke risk factors. Controlling for age, sex, hypertension, diabetes, current smoking, ischemic heart disease, congestive heart failure and atrial fibrillation, low cholesterol was significantly associated with severe stroke, total anterior circulation infarction and poor functional outcome in patients with and without statin treatment. There were no interactions between low cholesterol and prestroke statin therapy in association with outcomes. Short- and long-term mortality rates were increased for patients with low cholesterol (5.2% at discharge and 35% at 3-years) compared with higher levels (2.5% at discharge and 20.5% at 3 years). Adjusted mortality risks were increased for patients with low cholesterol; however, this finding was statistically significant only for patients not on statins before the stroke. CONCLUSIONS: Low cholesterol is associated with increased stroke severity and poorer functional outcome in patients with and without prestroke statin use. Low-cholesterol statin-naive patients show increased risks of mortality. 'Reverse epidemiology' in the association between cholesterol and outcome is possible in patients with ischemic stroke.

The frontal assessment battery as a tool for evaluation of frontal lobe dysfunction in patients with Parkinson disease.

BACKGROUND: Frontal-type cognitive deficits are common in patients with Parkinson disease (PD). The Frontal Assessment Battery (FAB) was developed to assess frontal lobe functions. However, many studies found that it also correlated with a variety of other general neuropsychological tests. OBJECTIVES: To evaluate whether the FAB has an added value over the Mini-Mental State Examination (MMSE) and other bedside neuropsychological tests in reflecting cognitive deficits in patients with PD. METHODS: Seventy-two consecutive patients with PD underwent cognitive assessment including the FAB, the MMSE, and a variety of other neuropsychological tests. Correlations were examined using the Spearman's r. RESULTS: Highly significant correlations were found between the total FAB score and tests of attention, executive functions, and memory. To evaluate the contribution of the FAB beyond that of the MMSE, partial correlation was used. Analyses revealed that the FAB still correlated with most of the tests. Dividing the patients according to the median MMSE score revealed that the high correlation between the FAB and the MMSE was preserved in the low MMSE group, while in the high MMSE group the correlation was relatively low. In the high MMSE group, the FAB correlated with 11 tests compared to the MMSE that correlated with one (P < .001), while in the low MMSE group the number of correlations was 13 versus 7, respectively (P = .05). CONCLUSIONS: In our sample of patients with PD, the FAB correlated with dysfunction in a variety of cognitive domains including attention, memory, and executive functions. The FAB has an added value over the MMSE, particularly among nondemented patients, an advantage that can be used in clinical practice.