Cerebrovascular Reactivity in Patients With Small Vessel Disease: A Cross-Sectional Study.

BACKGROUND: Cerebrovascular reactivity (CVR) is inversely related to white matter hyperintensity severity, a marker of cerebral small vessel disease (SVD). Less is known about the relationship between CVR and other SVD imaging features or cognition. We aimed to investigate these cross-sectional relationships. METHODS: Between 2018 and 2021 in Edinburgh, we recruited patients presenting with lacunar or cortical ischemic stroke, whom we characterized for SVD features. We measured CVR in subcortical gray matter, normal-appearing white matter, and white matter hyperintensity using 3T magnetic resonance imaging. We assessed cognition using Montreal Cognitive Assessment. Statistical analyses included linear regression models with CVR as outcome, adjusted for age, sex, and vascular risk factors. We reported regression coefficients with 95% CIs. RESULTS: Of 208 patients, 182 had processable CVR data sets (median age, 68.2 years; 68% men). Although the strength of association depended on tissue type, lower CVR in normal-appearing tissues and white matter hyperintensity was associated with larger white matter hyperintensity volume (BNAWM=-0.0073 [95% CI, -0.0133 to -0.0014] %/mm Hg per 10-fold increase in percentage intracranial volume), more lacunes (BNAWM=-0.00129 [95% CI, -0.00215 to -0.00043] %/mm Hg per lacune), more microbleeds (BNAWM=-0.00083 [95% CI, -0.00130 to -0.00036] %/mm Hg per microbleed), higher deep atrophy score (BNAWM=-0.00218 [95% CI, -0.00417 to -0.00020] %/mm Hg per score point increase), higher perivascular space score (BNAWM=-0.0034 [95% CI, -0.0066 to -0.0002] %/mm Hg per score point increase in basal ganglia), and higher SVD score (BNAWM=-0.0048 [95% CI, -0.0075 to -0.0021] %/mm Hg per score point increase). Lower CVR in normal-appearing tissues was related to lower Montreal Cognitive Assessment without reaching convention statistical significance (BNAWM=0.00065 [95% CI, -0.00007 to 0.00137] %/mm Hg per score point increase). CONCLUSIONS: Lower CVR in patients with SVD was related to more severe SVD burden and worse cognition in this cross-sectional analysis. Longitudinal analysis will help determine whether lower CVR predicts worsening SVD severity or vice versa. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN12113543.

Factors influencing cardiometabolic risk profile in patients with psoriasis.

BACKGROUND: Psoriasis has been associated with metabolic syndrome and with an increased cardiovascular risk especially in patients with severe disease. The goal of this study was to estimate the prevalence of metabolic syndrome and other cardiovascular risk factors and its association with the psoriasis severity, sex and age. METHODS: Consecutive patients with psoriasis were enrolled in a prospective study over a 1-year period. Blood samples were collected. Psoriasis area and severity index (PASI) and body surface area scores and two dermatology quality of life (DQOL) questionnaires were used to evaluate psoriasis severity and the impact of the disease. RESULTS: Altogether 178 patients were included, of whom 44% had moderate-severe psoriasis. The overall prevalence of metabolic syndrome was 30% (men 34%, women 26%) without significant differences between patients with severe and mild disease. Age and menopause appeared to increase the risk for metabolic syndrome. Patients with severe psoriasis smoked more heavily, were more likely to have diabetes or insulin resistance and had higher homocysteine and lower high density lipoprotein cholesterol (HDL-C) levels than patients with mild psoriasis (P < 0.05). In women, a higher waist circumference was observed. Women had higher HDL-C levels and lower smoking and alcohol consumption rates. In accordance with the systematic coronary risk evaluation system, 18% of the patients had a high 10-year risk of fatal cardiovascular disease. CONCLUSIONS: Psoriasis severity was associated with diabetes, insulin-resistance, smoking habit and higher cardiovascular risk. Metabolic syndrome was related to age and menopause but not to psoriasis severity.

A pragmatic, randomized, controlled study evaluating the impact of access to smoking cessation pharmacotherapy coverage on the proportion of successful quitters in a Canadian population of smokers motivated to quit (ACCESSATION).

BACKGROUND: Many smokers find the cost of smoking cessation medications a barrier. Financial coverage for these medications increases utilization of pharmacotherapies. This study assesses whether financial coverage increases the proportion of successful quitters. METHODS: A pragmatic, open-label, randomized, controlled trial was conducted in 58 Canadian sites between March 2009 and September 2010. Smokers (≥10 cigarettes/day) without insurance coverage who were motivated to quit within 14 days were randomized (1:1) in a blinded manner to receive either full coverage eligibility for 26 weeks or no coverage. Pharmacotherapies covered were varenicline, bupropion, or nicotine patches/gum. Investigators/subjects were unblinded to study group assignment after randomization and prior to choosing a smoking cessation method(s). All subjects received brief smoking cessation counseling. The primary outcome measure was self-reported 7-day point prevalence of abstinence (PPA) at week 26. RESULTS: Of the 1380 randomized subjects (coverage, 696; no coverage, 684), 682 (98.0%) and 435 (63.6%), respectively, were dispensed at least one smoking cessation medication dose. The 7-day PPA at week 26 was higher in the full coverage versus no coverage group: 20.8% (n = 145) and 13.9% (n = 95), respectively; odds ratio (OR) = 1.64, 95% confidence interval (CI) 1.23-2.18; p = 0.001. Urine cotinine-confirmed 7-day PPA at week 26 was 15.7% (n = 109) and 10.1% (n = 69), respectively; OR = 1.68, 95% CI 1.21-2.33; p = 0.002. After pharmacotherapy, coverage eligibility was withdrawn from the full coverage group, continuous abstinence between weeks 26 and 52 was 6.6% (n = 46) and 5.6% (n = 38), in the full coverage and no coverage groups, respectively; OR = 1.19, 95% CI 0.76-1.87; p = 0.439. CONCLUSIONS: In this study, the adoption of a smoking cessation medication coverage drug policy was an effective intervention to improve 26-week quit rates in Canada. The advantages were lost once coverage was discontinued. Further study is required on the duration of coverage to prevent relapse to smoking. (clinicaltrials.gov identifier: NCT00818207; the study was sponsored by Pfizer Inc.).

Magnetic Resonance Imaging Tissue Signatures Associated With White Matter Changes Due to Sporadic Cerebral Small Vessel Disease Indicate That White Matter Hyperintensities Can Regress.

BACKGROUND: White matter hyperintensities (WMHs) might regress and progress contemporaneously, but we know little about underlying mechanisms. We examined WMH change and underlying quantitative magnetic resonance imaging tissue measures over 1 year in patients with minor ischemic stroke with sporadic cerebral small vessel disease. METHODS AND RESULTS: We defined areas of stable normal-appearing white matter, stable WMHs, progressing and regressing WMHs based on baseline and 1-year brain magnetic resonance imaging. In these areas we assessed tissue characteristics with quantitative T1, fractional anisotropy (FA), mean diffusivity (MD), and neurite orientation dispersion and density imaging (baseline only). We compared tissue signatures cross-sectionally between areas, and longitudinally within each area. WMH change masks were available for N=197. Participants' mean age was 65.61 years (SD, 11.10), 59% had a lacunar infarct, and 68% were men. FA and MD were available for N=195, quantitative T1 for N=182, and neurite orientation dispersion and density imaging for N=174. Cross-sectionally, all 4 tissue classes differed for FA, MD, T1, and Neurite Density Index. Longitudinally, in regressing WMHs, FA increased with little change in MD and T1 (difference estimate, 0.011 [95% CI, 0.006-0.017]; -0.002 [95% CI, -0.008 to 0.003] and -0.003 [95% CI, -0.009 to 0.004]); in progressing and stable WMHs, FA decreased (-0.022 [95% CI, -0.027 to -0.017] and -0.009 [95% CI, -0.011 to -0.006]), whereas MD and T1 increased (progressing WMHs, 0.057 [95% CI, 0.050-0.063], 0.058 [95% CI, 0.050 -0.066]; stable WMHs, 0.054 [95% CI, 0.045-0.063], 0.049 [95% CI, 0.039-0.058]); and in stable normal-appearing white matter, MD increased (0.004 [95% CI, 0.003-0.005]), whereas FA and T1 slightly decreased and increased (-0.002 [95% CI, -0.004 to -0.000] and 0.005 [95% CI, 0.001-0.009]). CONCLUSIONS: Quantitative magnetic resonance imaging shows that WMHs that regress have less abnormal microstructure at baseline than stable WMHs and follow trajectories indicating tissue improvement compared with stable and progressing WMHs.

Impact of long-term white matter hyperintensity changes on mobility and dexterity.

White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, are related to worse clinical outcomes after stroke. We assessed the impact of white matter hyperintensity changes over 1 year after minor stroke on change in mobility and dexterity, including differences between the dominant and non-dominant hands and objective in-person assessment versus patient-reported experience. We recruited participants with lacunar or minor cortical ischaemic stroke, performed medical and cognitive assessments and brain MRI at presentation and at 1 year. At both time points, we used the timed-up and go test and the 9-hole peg test to assess mobility and dexterity. At 1 year, participants completed the Stroke Impact Scale. We ran two linear mixed models to assess change in timed-up and go and 9-hole peg test, adjusted for age, sex, stroke severity (National Institutes of Health Stroke Scale), dependency (modified Rankin Score), vascular risk factor score, white matter hyperintensity volume (as % intracranial volume) and additionally for 9-hole peg test: Montreal cognitive assessment, hand (dominant/non-dominant), National Adult Reading Test (premorbid IQ), index lesion side. We performed ordinal logistic regression, corrected for age and sex, to assess relations between timed-up and go and Stroke Impact Scale mobility, and 9-hole peg test and Stroke Impact Scale hand function. We included 229 participants, mean age 65.9 (standard deviation = 11.13); 66% male. 215/229 attended 1-year follow-up. Over 1 year, timed-up and go time increased with aging (standardized ß [standardized 95% Confidence Interval]: 0.124[0.011, 0.238]), increasing National Institutes of Health Stroke Scale (0.106[0.032, 0.180]), increasing modified Rankin Score (0.152[0.073, 0.231]) and increasing white matter hyperintensity volume (0.176[0.061, 0.291]). Men were faster than women (-0.306[0.011, 0.238]). Over 1 year, slower 9-hole peg test was related to use of non-dominant hand (0.290[0.155, 0.424]), aging (0.102[0.012, 0.192]), male sex (0.182[0.008, 0.356]), increasing National Institutes of Health Stroke Scale (0.160 [0.094, 0.226]), increasing modified Rankin Score (0.100[0.032, 0.169]), decreasing Montreal cognitive assessment score (-0.090[-0.167, -0.014]) and increasing white matter hyperintensity volume (0.104[0.015, 0.193]). One year post-stroke, Stroke Impact Scale mobility worsened per second increase on timed-up and go, odds ratio 0.67 [95% confidence interval 0.60, 0.75]. Stroke Impact Scale hand function worsened per second increase on the 9-hole peg test for the dominant hand (odds ratio 0.79 [0.71, 0.86]) and for the non-dominant hand (odds ratio 0.88 [0.83, 0.93]). Decline in mobility and dexterity is associated with white matter hyperintensity volume increase, independently of stroke severity. Mobility and dexterity declined more gradually for stable and regressing white matter hyperintensity volume. Dominant and non-dominant hands might be affected differently. In-person measures of dexterity and mobility are associated with self-reported experience 1-year post-stroke.

Cardiovascular safety of varenicline: patient-level meta-analysis of randomized, blinded, placebo-controlled trials.

Smoking is a major modifiable risk factor for cardiovascular (CV) disease. Varenicline is a pharmacological aid for smoking cessation. To explore the CV safety of varenicline, we investigated the incidence of CV events in varenicline-treated subjects across all phase 2-4 randomized placebo-controlled clinical trials of ≥12-week treatment duration conducted in smokers aged ≥18 years and sponsored by the drug manufacturer. This manuscript reports a subject-level meta-analysis of time to major adverse cardiovascular events (MACE; defined as CV-related death, nonfatal myocardial infarction, nonfatal stroke) and time to MACE+ (defined as MACE plus worsening or any procedure for peripheral vascular disease, hospitalization for angina, or performance of coronary revascularization). All events were adjudicated by an independent adjudication committee, blind to treatment assignment. Events were assessed during treatment and up to 30 days after the last treatment dose. The primary analytical method was a stratified logrank time-to-event analysis; secondary analyses were meta-analyses of incidence rate ratios and rate differences. Overall, 7002 subjects were included (varenicline: 4190; placebo: 2812) from 15 studies. MACE were reported by 13 varenicline subjects (0.31%) and 6 placebo subjects (0.21%) [hazard ratio, 1.95; 95% confidence interval (CI): 0.79-4.82; P = 0.15; risk difference, 0.006 events per subject-year; 95% CI: -0.003, 0.015, P = 0.19]. MACE+ were reported by 26 varenicline subjects (0.62%) and 12 placebo subjects (0.43%) (hazard ratio, 1.74; 95% CI: 0.91-3.34, P = 0.10; risk difference, 0.010; 95% CI: -0.002, 0.022, P = 0.11). This subject-level meta-analysis of MACE or MACE+ up to 30 days posttreatment in placebo-controlled clinical trials of varenicline found a trend toward increased incidence of these events in varenicline-treated patients that did not reach statistical significance. The overall number of events was low and the absolute risk of CV events with varenicline was small.

Retinal capillary microvessel morphology changes are associated with vascular damage and dysfunction in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is a cause of stroke and dementia. Retinal capillary microvessels revealed by optical coherence tomography angiography (OCTA) are developmentally related to brain microvessels. We quantified retinal vessel density (VD) and branching complexity, investigating relationships with SVD lesions, white matter integrity on diffusion tensor imaging (DTI) and cerebrovascular reactivity (CVR) to CO2 in patients with minor stroke. We enrolled 123 patients (mean age 68.1 ± SD 9.9 years), 115 contributed retinal data. Right (R) and left (L) eyes are reported. After adjusting for age, eye disease, diabetes, blood pressure and image quality, lower VD remained associated with higher mean diffusivity (MD) (standardized ß; R -0.16 [95%CI -0.32 to -0.01]) and lower CVR (L 0.17 [0.03 to 0.31] and R 0.19 [0.02 to 0.36]) in normal appearing white matter (NAWM). Sparser branching remained associated with sub-visible white matter damage shown by higher MD (R -0.24 [-0.08 to -0.40]), lower fractional anisotropy (FA) (L 0.17 [0.01 to 0.33]), and lower CVR (R 0.20 [0.02 to 0.38]) in NAWM. OCTA-derived metrics provide evidence of microvessel abnormalities that may underpin SVD lesions in the brain.

A randomized placebo-controlled trial of varenicline for smoking cessation allowing flexible quit dates.

INTRODUCTION: Current smoking cessation guidelines recommend setting a quit date prior to starting pharmacotherapy. However, providing flexibility in the date of quitting may be more acceptable to some smokers. The objective of this study was to compare varenicline 1 mg twice daily (b.i.d.) with placebo in subjects using a flexible quit date paradigm after starting medication. METHODS: In this double-blind, randomized, placebo-controlled international study, smokers of ≥10 cigarettes/day, aged 18-75 years, and who were motivated to quit were randomized (3:1) to receive varenicline 1 mg b.i.d. or placebo for 12 weeks. Subjects were followed up through Week 24. Subjects were instructed to quit between Days 8 and 35 after starting medication. The primary endpoint was carbon monoxide-confirmed continuous abstinence during Weeks 9-12, and a key secondary endpoint was continuous abstinence during Weeks 9-24. RESULTS: Overall, 493 subjects were randomized to varenicline and 166 to placebo. Continuous abstinence was higher for varenicline than for placebo subjects at the end of treatment (Weeks 9-12: 53.1% vs. 19.3%; odds ratio [OR] 5.9; 95% CI, 3.7-9.4; p < .0001) and through 24 weeks follow-up (Weeks 9-24: 34.7% vs. 12.7%; OR 4.4; 95% CI, 2.6-7.5; p < .0001). Serious adverse events occurred in 1.2% varenicline (none were psychiatric) and 0.6% placebo subjects. Fewer varenicline than placebo subjects reported depression-related adverse events (2.3% vs. 6.7%, respectively). CONCLUSIONS: Varenicline 1 mg b.i.d. using a flexible quit date paradigm had similar efficacy and safety compared with previous fixed quit date studies.

Longitudinal Changes of White Matter Hyperintensities in Sporadic Small Vessel Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: White matter hyperintensities (WMHs) are frequent imaging features of small vessel disease (SVD) and related to poor clinical outcomes. WMH progression over time is well described, but regression was also noted recently, although the frequency and associated factors are unknown. This systematic review and meta-analysis aims to assess longitudinal intraindividual WMH volume changes in sporadic SVD. METHODS: We searched EMBASE and MEDLINE for articles up to 28 January 2022 on WMH volume changes using MRI on ≥2 time points in adults with sporadic SVD. We classified populations (healthy/community-dwelling, stroke, cognitive, other vascular risk factors, and depression) based on study characteristics. We performed random-effects meta-analyses with Knapp-Hartung adjustment to determine mean WMH volume change (change in milliliters, percentage of intracranial volume [%ICV], or milliliters per year), 95% CI, and prediction intervals (PIs, limits of increase and decrease) using unadjusted data. Risk of bias assessment tool for nonrandomized studies was used to assess risk of bias. We followed Preferred Reporting in Systematic Review and Meta-Analysis guidelines. RESULTS: Forty-one articles, 12,284 participants, met the inclusion criteria. Thirteen articles had low risk of bias across all domains. Mean WMH volume increased over time by 1.74 mL (95% CI 1.23-2.26; PI -1.24 to 4.73 mL; 27 articles, N = 7,411, mean time interval 2.7 years, SD = 1.65); 0.25 %ICV (95% CI 0.14-0.36; PI -0.06 to 0.56; 6 articles, N = 1,071, mean time interval 3.5 years, SD = 1.54); or 0.58 mL/y (95% CI 0.35-0.81; PI -0.26 to 1.41; 8 articles, N = 3,802). In addition, 13 articles specifically mentioned and/or provided data on WMH regression, which occurred in asymptomatic, stroke, and cognitive disorders related to SVD. DISCUSSION: Net mean WMH volume increases over time mask wide-ranging change (e.g., mean increase of 1.75 mL ranging from 1.25 mL decrease to 4.75 mL increase), with regression documented explicitly in up to one-third of participants. More knowledge on underlying mechanisms, associated factors, and clinical correlates is needed, as WMH regression could be an important intervention target.

Associations of Peak-Width Skeletonized Mean Diffusivity and Post-Stroke Cognition.

Post-stroke cognitive impairment is common and can have major impact on life after stroke. Peak-width of Skeletonized Mean Diffusivity (PSMD) is a diffusion imaging marker of white matter microstructure and is also associated with cognition. Here, we examined associations between PSMD and post-stroke global cognition in an ongoing study of mild ischemic stroke patients. We studied cross-sectional associations between PSMD and cognition at both 3-months (N = 229) and 1-year (N = 173) post-stroke, adjusted for premorbid IQ, sex, age, stroke severity and disability, as well as the association between baseline PSMD and 1-year cognition. At baseline, (mean age = 65.9 years (SD = 11.1); 34% female), lower Montreal Cognitive Assessment (MoCA) scores were associated with older age, lower premorbid IQ and higher stroke severity, but not with PSMD (ßstandardized = −0.116, 95% CI −0.241, 0.009; p = 0.069). At 1-year, premorbid IQ, older age, higher stroke severity and higher PSMD (ßstandardized = −0.301, 95% CI −0.434, −0.168; p < 0.001) were associated with lower MoCA. Higher baseline PSMD was associated with lower 1-year MoCA (ßstandardized = −0.182, 95% CI −0.308, −0.056; p = 0.005). PSMD becomes more associated with global cognition at 1-year post-stroke, possibly once acute effects have settled. Additionally, PSMD in the subacute phase after a mild stroke could help predict long-term cognitive impairment.

Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial.

BACKGROUND: Smoking cessation is a key component of secondary cardiovascular disease prevention. Varenicline, a partial alpha4beta2 nicotinic acetylcholine receptor agonist, is effective for smoking cessation in healthy smokers, but its efficacy and safety in smokers with cardiovascular disease are unknown. METHODS AND RESULTS: A multicenter, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of varenicline with placebo for smoking cessation in 714 smokers with stable cardiovascular disease. Participants received varenicline (1 mg twice daily) or placebo, along with smoking-cessation counseling, for 12 weeks. Follow-up lasted 52 weeks. The primary end point was carbon monoxide-confirmed continuous abstinence rate for weeks 9 through 12 (last 4 weeks of treatment). The continuous abstinence rate was higher for varenicline than placebo during weeks 9 through 12 (47.0% versus 13.9%; odds ratio, 6.11; 95% confidence interval [CI], 4.18 to 8.93) and weeks 9 through 52 (19.2% versus 7.2%; odds ratio, 3.14; 95% CI, 1.93 to 5.11). The varenicline and placebo groups did not differ significantly in cardiovascular mortality (0.3% versus 0.6%; difference, -0.3%; 95% CI, -1.3 to 0.7), all-cause mortality (0.6% versus 1.4%; difference, -0.8%; 95% CI, -2.3 to 0.6), cardiovascular events (7.1% versus 5.7%; difference, 1.4%; 95% CI, -2.3 to 5.0), or serious adverse events (6.5% and 6.0%; difference, 0.5%; 95% CI, -3.1 to 4.1). As a result of adverse events, 9.6% of varenicline and 4.3% of placebo participants discontinued study drug. CONCLUSIONS: Varenicline is effective for smoking cessation in smokers with cardiovascular disease. It was well tolerated and did not increase cardiovascular events or mortality; however, trial size and duration limit definitive conclusions about safety. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov/ct2/show/NCT00282984. Unique identifier: NCT00282984.

Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3.

BACKGROUND: Cerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood-brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease.Patients and Methods: The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood-brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543. SUMMARY: Factors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy.

Clinical management of cerebral small vessel disease: a call for a holistic approach.

ABSTRACT: Cerebral small vessel disease (SVD) is a common global brain disease that causes cognitive impairment, ischemic or hemorrhagic stroke, problems with mobility, and neuropsychiatric symptoms. The brain damage, seen as focal white and deep grey matter lesions on brain magnetic resonance imaging (MRI) or computed tomography (CT), typically accumulates "covertly" and may reach an advanced state before being detected incidentally on brain scanning or causing symptoms. Patients have typically presented to different clinical services or been recruited into research focused on one clinical manifestation, perhaps explaining a lack of awareness, until recently, of the full range and complexity of SVD.In this review, we discuss the varied clinical presentations, established and emerging risk factors, relationship to SVD features on MRI or CT, and the current state of knowledge on the effectiveness of a wide range of pharmacological and lifestyle interventions. The core message is that effective assessment and clinical management of patients with SVD, as well as future advances in diagnosis, care, and treatment, will require a more "joined-up"' approach. This approach should integrate clinical expertise in stroke neurology, cognitive, and physical dysfunctions. It requires more clinical trials in order to improve pharmacological interventions, lifestyle and dietary modifications. A deeper understanding of the pathophysiology of SVD is required to steer the identification of novel interventions. An essential prerequisite to accelerating clinical trials is to improve the consistency, and standardization of clinical, cognitive and neuroimaging endpoints.

The role of left atrial enlargement and age in the prediction of recurrence in embolic strokes of undetermined source.

Objectives: Left atrial disease is an independent risk factor for ischemic stroke and can be used to predict atrial fibrillation (AF). We examine whether left atrial enlargement (LAE) could predict stroke recurrence in patients with embolic stroke of undetermined source (ESUS). Materials and methods: Sixty-four patients with a confirmed diagnosis of ESUS were followed for a median of 22 months. Clinical data and echocardiogram findings were recorded. The echocardiogram interpretation was performed centrally and blindly. The Brown ESUS - AF score was used to categorize patients into high (human resource planning [HRP]: score > 2) and low-risk patients (non-HRP score 0-1). Stroke recurrence was the primary outcome. Results: The median age was 62 years (range: 22-85 years); and 33 (51.6%) were men. The median initial NIHSS score was three points (range: 0-27). Twelve (18.8%) patients were categorized as HRP. We found a significant tendency toward recurrence among HRP versus non-HRP patients. Three (25%) HRP versus 2 (3.8%) non-HRP experienced recurrence (OR: 8.3 95% CI 1.2-57; p=0.042); this association was related to severe atrial dilatation (OR: 14.5 95% CI 0.78-277, p = 0.02) and age > 75 years (OR: 12.7 95% CI 1.7-92.2, p = 0.03). We found no differences in recurrence in a univariate analysis. Conclusions: Patients with severe LAE who are 75 years old or older have a significant tendency to experience stroke recurrence.

Objetivos: La patología atrial izquierda es factor de riesgo independiente para infarto cerebral y puede utilizarse para predecir fibrilación auricular. Examinamos si el crecimiento aurícular izquierdo puede predecir recurrencia en pacientes con infarto embolico de origen indeterminado (ESUS). Materiales y métodos: Sesenta y cuatro pacientes con diagnóstico confirmado de ESUS fueron seguidos por una mediana de seguimiento de 22 meses. Registramos los datos clínicos y ecocardiográficos. La interpretación ecocardiográfica fue centralizada y cegada. La escala de Brown ESUS ­ AF fue utilizada para categorizar a los pacientes en riesgo alto (HRP puntaje > 2) y bajo riesgo (no-HRP: puntaje 0-1). El descenlace primario fue recurrencia de infarto cerebral. Resultados: Mediana de edad fue de 62 años (rango: 22-85 años); 33 (51.6%) fueron hombres. La mediana inicial de la escala de NIHSS fue de 3 putnos (rango de 0 a 27). 12 (18.8%) pacientes fueron de alto riesgo (HRP) y 52 (81.3%) de bajo riesgo (non- HRP). El grupo HRP mostró tendencia significatica hacia mayor recurrencia. Tres (25%) HRP versus 2 (3.8%) no-HRP experimentaron recurrencia (OR: 8.3 IC 95% 1.2-57; p = 0.042); esta asociación se relacionó con dilatación auricular severa (OR: 14.5 IC 95% 0.78-277, p = 0.02) y edad > 75 años (OR: 12.7 IC 95% 1.7-92.2, p = 0.03). En el análisis multivarioado, no encontramos significativas. Conclusiones: El crecimiento auricular izquierdo severo y la edad mayor de 75 años mostraron tendencia significativa a recurrencia de infarto cerebral.

Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients.

The efficacy of voriconazole in 107 patients with scedosporiosis was analyzed. Principal infection sites were the lungs/sinuses (24%), central nervous system (CNS) (20%), and bone (18%), while 21% of patients had disseminated infection. Solid organ transplantation (22%), hematological malignancy (21%), and surgery/trauma (15%) were the predominant underlying conditions. A successful therapeutic response was achieved in 57% of patients (median, 103 therapy days), with > 98% of those responding receiving > or = 28 days of therapy. Patients receiving primary therapy showed a 61% response versus 56% for the others. The best therapeutic responses were seen for skin/subcutaneous (91%) or bone (79%) infections, and the lowest for CNS infections (43%). Patients without major immune suppression (72%) or those with solid organ transplantation (63%) or various hematological conditions (60%) showed the best responses by underlying condition. Median known survival time was 133 days (therapy successes, 252 days; failures, 21 days). In all, 43 (40%) patients died, 73% due to scedosporiosis. Patients with Scedosporium prolificans infection had significantly reduced survival times (P = 0.0259) and were more likely to die from fungal infection (P = 0.002) than were Scedosporium apiospermum-infected patients. In a subset of 43 patients where voriconazole baseline MICs were available, response to voriconazole was higher for S. apiospermum-infected patients (54% response; MIC(50), 0.25 microg/ml) than for S. prolificans-infected patients (40% response; MIC(50), 4.0 microg/ml). Voriconazole demonstrated clinically useful activity in the treatment of both S. apiospermum and S. prolificans infections and was well tolerated.

The role of left atrial enlargement and age in the prediction of recurrence in embolic strokes of undetermined source / El papel del crecimiento auricular izquierdo y la edad como predictores de recurrencia en infarto cerebral embólicos de origen indeterminado

Abstract Objectives: Left atrial disease is an independent risk factor for ischemic stroke and can be used to predict atrial fibrillation (AF). We examine whether left atrial enlargement (LAE) could predict stroke recurrence in patients with embolic stroke of undetermined source (ESUS). Materials and methods: Sixty-four patients with a confirmed diagnosis of ESUS were followed for a median of 22 months. Clinical data and echocardiogram findings were recorded. The echocardiogram interpretation was performed centrally and blindly. The Brown ESUS – AF score was used to categorize patients into high (human resource planning [HRP]: score > 2) and low-risk patients (non-HRP score 0-1). Stroke recurrence was the primary outcome. Results: The median age was 62 years (range: 22-85 years); and 33 (51.6%) were men. The median initial NIHSS score was three points (range: 0-27). Twelve (18.8%) patients were categorized as HRP. We found a significant tendency toward recurrence among HRP versus non-HRP patients. Three (25%) HRP versus 2 (3.8%) non-HRP experienced recurrence (OR: 8.3 95% CI 1.2-57; p=0.042); this association was related to severe atrial dilatation (OR: 14.5 95% CI 0.78-277, p = 0.02) and age > 75 years (OR: 12.7 95% CI 1.7-92.2, p = 0.03). We found no differences in recurrence in a univariate analysis. Conclusions: Patients with severe LAE who are 75 years old or older have a significant tendency to experience stroke recurrence.

Resumen Objetivos: La patología atrial izquierda es factor de riesgo independiente para infarto cerebral y puede utilizarse para predecir fibrilación auricular. Examinamos si el crecimiento aurícular izquierdo puede predecir recurrencia en pacientes con infarto embolico de origen indeterminado (ESUS). Materiales y métodos: Sesenta y cuatro pacientes con diagnóstico confirmado de ESUS fueron seguidos por una mediana de seguimiento de 22 meses. Registramos los datos clínicos y ecocardiográficos. La interpretación ecocardiográfica fue centralizada y cegada. La escala de Brown ESUS – AF fue utilizada para categorizar a los pacientes en riesgo alto (HRP puntaje > 2) y bajo riesgo (no-HRP: puntaje 0-1). El descenlace primario fue recurrencia de infarto cerebral. Resultados: Mediana de edad fue de 62 años (rango: 22-85 años); 33 (51.6%) fueron hombres. La mediana inicial de la escala de NIHSS fue de 3 putnos (rango de 0 a 27). 12 (18.8%) pacientes fueron de alto riesgo (HRP) y 52 (81.3%) de bajo riesgo (non- HRP). El grupo HRP mostró tendencia significatica hacia mayor recurrencia. Tres (25%) HRP versus 2 (3.8%) no-HRP experimentaron recurrencia (OR: 8.3 IC 95% 1.2-57; p = 0.042); esta asociación se relacionó con dilatación auricular severa (OR: 14.5 IC 95% 0.78-277, p = 0.02) y edad > 75 años (OR: 12.7 IC 95% 1.7-92.2, p = 0.03). En el análisis multivarioado, no encontramos significativas. Conclusiones: El crecimiento auricular izquierdo severo y la edad mayor de 75 años mostraron tendencia significativa a recurrencia de infarto cerebral.

Predictors of lapse and relapse to smoking in successful quitters in a varenicline post hoc analysis in Japanese smokers.

BACKGROUND: The efficacy of the smoking-cessation agent varenicline has been reported in Asian smokers; however, few studies have investigated factors that contribute to lapse and relapse. OBJECTIVE: This post hoc analysis aimed to identify predictors of smoking lapse and relapse. METHODS: This was a post-hoc analysis based on a double-blind, placebo-controlled, randomized, parallel-group study in which Japanese smokers (aged 20-75 years) who smoked ≥ 10 cigarettes/day and were motivated to quit were randomized to receive varenicline (0.25 mg twice daily [BID], 0.5 mg BID, 1 mg BID) or placebo for 12 weeks followed by a 40-week non-treatment follow-up. For inclusion in this analysis, participants must have been nicotine dependent (Tobacco Dependence Screener score ≥ 5) and must have successfully quit smoking continuously for 4 weeks (weeks 9-12). Lapse was defined by answering yes to ≥ 1 question in the Nicotine Use Inventory. Relapse was defined by participants having smoked for ≥ 7 days during follow-up measured by the Nicotine Use Inventory. RESULTS: Of the 619 randomized individuals, 515 had a Tobacco Dependence Screener score of ≥ 5, and 277 quit smoking continuously from weeks 9 to 12. Approximately 75% were male, with a mean (SD) BMI of 23.0 (3.0) kg/m(2). Maximum length of continuous abstinence (CA) during treatment and age (both P < 0.0001) were significant predictors of lapse. Maximum CA (P < 0.0001), age (P = 0.0002), Minnesota Nicotine Withdrawal Scale (MNWS) score for urge to smoke (P = 0.0019), and having made ≥ 1 serious quit attempt (P = 0.0063) were significant predictors of relapse. For participants with a maximum CA of 4 to 6 weeks versus those with a maximum CA of 10 to 11 weeks, the ORs for lapse and relapse were 4.649 (95% CI, 2.071-10.434) and 3.337 (95% CI, 1.538-7.239), respectively. In participants aged 21-34 years versus those aged 47-72 years, the ORs for lapse and relapse were 3.453 (95% CI 1.851, 6.441) and 3.442 (95% CI 1.795, 6.597), respectively. Participants with a MNWS urge to smoke score of 2 to 4 versus 0 had an OR for relapse of 3.175 (95% CI, 1.166-8.644). Participants having made ≥ 1 versus no serious quit attempts had an OR for relapse of 2.108 (95% CI, 1.168-3.805). CONCLUSION: Shorter maximum CA and younger age at quit attempt were associated with increased risk of lapse and relapse. Higher MNWS urge to smoke score and having made ≥ 1 serious quit attempt were associated with increased relapse risk. ClinicalTrials.gov identifier: NCT00139750.

Determinantes sociodemográficos y clínicos asociados a mortalidad fetal intrauterina en el municipio de Pasto, 2010-2012 / Demographic and clinical determinants associated with intrauterine fetal mortality in the municipality of Pasto, 2010-2012

Resumen Introducción: La mortalidad fetal intrauterina (MFIU) es un problema de salud pública por sus elevadas tasas a nivel mundial y en poblaciones de ingresos medios y bajos. Sin embargo, es un evento poco estudiado y carece de visibilidad en las políticas, planes y programas de salud pública. Objetivo: Analizar los determinantes sociodemográficos y clínicos asociados a la MFIU en Pasto-Colombia. Materiales y métodos: Estudio analítico observacional con 88 muertes fetales como casos y 88 nacidos vivos como controles, ocurridas en hospitales de tercer nivel en el municipio de Pasto-Colombia durante 2010-2012, para determinar la relación entre mortalidad fetal, condiciones clínicas (complicaciones del embarazo, edad gestacional, peso al nacer, controles prenatales, antecedentes obstétricos, tóxicos o aborto) y sociodemográficas (edad, etnia, ocupación, estado civil, estrato, zona de residencia, escolaridad, paridad, condición de desplazamiento, embarazo planeado). Resultados: Se identificó que el riesgo de mortalidad fetal es significativamente menor con el incremento de la edad gestacional (OR ajustado=0,76 IC95% 0,62; 0,93) y el peso al nacer (OR ajustado=0,99 IC95% 0,98; 0,99). Otras variables clínicas y sociodemográficas no se asociaron. Conclusión: Los resultados proveen evidencia para la planificación de planes de intervención que prioricen a mujeres cuyo feto tenga un peso inferior al normal y un riesgo de nacimiento prematuro.

Abstract Introduction: Intrauterine fetal mortality (IUFM) is a public health problem because of its high rates worldwide and in low-and middle-income populations. However, it is a little-studied event and lacks visibility in public health policies, plans and programs. Objective: To analyze the sociodemographic and clinical determinants associated with IUFM in Pasto-Colombia. Materials and methods: A study, that includes 88 fetal deaths as cases and 88 live births as controls occurred in third level hospitals in Pasto-Colombia during 2010 and 2012, was carried out to determine the relationship between fetal mortality, clinical conditions (complications of pregnancy, gestational age, birth weight, prenatal controls, pathological and toxic medical history, or abortion) and sociodemographic conditions (age, ethnicity, occupation, marital status, stratum, area of residence , schooling, parity, displacement condition, planned pregnancy). Results: It was identified that the risk of fetal mortality is significantly lower with the increase in gestational age (OR ajustado = 0.76 IC95% 0.62; 0.93) and birth weight (OR ajustado = 0.99 IC95% 0.98; 0.99). Other clinical and sociodemographic variables were not associated. Conclusion: The results provide evidence for planning intervention plans that prioritize women whose fetus has a lower-than-normal weight and a risk of premature birth.

Efficacy of a flexible quit date versus an a priori quit date approach to smoking cessation: a cross-study analysis.

Most treatment guidelines recommend that smokers should set a target quit date (TQD) at treatment onset because making a public commitment to quit on a given date should increase motivation. On the other hand, allowing smokers the flexibility to choose when to stop after starting treatment might allow smokers to better tailor their quit date and might improve the acceptability of treatment among smokers not willing to set a TQD. In a recent placebo-controlled study, we found varenicline effective when smokers were not required to set a quit date a priori; i.e., with a "flexible quit date" (FQD) approach. The current analysis compares the effect sizes and quit rates in this FQD study with those of nine prior varenicline randomized controlled trials (RCTs) that used a TQD approach. The odds ratio for varenicline versus placebo in the FQD study was the 4th highest of the 10 trials and the incidence of continuous abstinence for varenicline was 5th highest. These results suggest that a FQD approach can produce quit rates similar to a TQD approach. Cross-study comparisons can have hidden bias; thus, a RCT of fixed versus flexible quit dates would provide a more valid test. Also, a study of whether different subpopulations of smokers may be more interested in or especially benefit from, one or the other approach to quitting is indicated.

Predictors of post-treatment relapse to smoking in successful quitters: pooled data from two phase III varenicline trials.

BACKGROUND: Identifying predictors of smoking relapse helps to elucidate the challenges of long-term smoking cessation and provides direction for improved treatment development. METHODS: In this post hoc data analysis, we examined predictors of relapse from end-of-treatment (week 13) through 1-year follow-up (week 52) for treatment-responding participants who achieved the primary efficacy endpoint of 4-week continuous abstinence (weeks 9-12), during two phase III varenicline trials. RESULTS: Of 626 smokers classified as treatment responders for all treatment groups across both trials, 301 (48%) relapsed during follow-up (weeks 13-52). The odds of relapsing were almost 5 times greater (odds ratio [OR]=4.92, 95% confidence interval [CI]: 2.77-8.97; p<.001) for treatment responders who did not initiate continuous abstinence until the final 4 weeks of the treatment period compared with those who initiated continuous abstinence by their quit date. Participants who reported >30 days of abstinence during the year prior to study entry were significantly more likely to relapse than those who reported 0 days of abstinence (OR=2.38, 95% CI: 1.17-5.04; p=.013). CONCLUSION: Results of these analyses suggest that the ability to quit smoking on the initial quit date and maintain abstinence throughout the treatment period is a good prognostic indicator for long-term abstinence. The relationship between post-treatment relapse and longer pretreatment periods of abstinence is counterintuitive, yet not without precedence in the literature.