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We evaluated the relationship between baseline CSF p-tau181 and the rate of tau PET change in the temporal meta-ROI and entorhinal cortex (ERC) and how it varied by amyloid level (CSF Aβ42 or amyloid PET) among 143 individuals from the Mayo Clinic Study of Aging and Mayo Alzheimer Disease Research Center. Higher CSF p-tau181, lower CSF Aβ42, and higher amyloid PET levels were associated with faster rates of tau PET change in both the temporal meta-ROI and ERC. In the temporal meta-ROI, longitudinal tau PET accumulation occurred primarily in participants with abnormal biomarker levels and a diagnosis of dementia, which supports the hypothesis that tau aggregation begins later in the disease process. Compared to the temporal meta-ROI, the ERC showed greater change in tau PET in non-demented participants but less change in later disease stages, supporting ERC as a more sensitive marker of early tau PET changes but with less dynamic range over the disease spectrum. We found both amyloid and CSF p-tau181 were associated with rates of tau PET change but there were some differences in associations by region, amyloid biomarker, and disease stage. [ABSTRACT FROM AUTHOR]

To determine the degree to which dimensional psychopathology predicts length of stay in an emergency department (ED) and need for hospital admission among children with psychiatric complaints. Electronic health records of children age 4–17 years who presented to the ED of a large academic medical center were analyzed using a natural language processing tool to estimate Research Domain Criteria (RDoC) symptom scores. These scores' association with length of stay and probability of admission versus discharge to home were evaluated. We identified 3061 children and adolescents who presented to the ED and were evaluated by the psychiatry service between November 2008 and March 2015. Median length of stay was 7.8 h (interquartile range 5.2–14.3 h) and 1696 (55.4%) were admitted to the hospital. Higher estimated RDoC arousal, cognitive, positive, and social domain scores were associated with increased length of stay in multiple regression models, adjusted for age, sex, race, private insurance, voluntary admission, and diagnostic categories. In similarly adjusted models, odds of hospital admission were increased by higher RDoC arousal and cognitive domain scores and decreased by higher negative domain scores. A natural language processing tool to characterize dimensional psychopathology identified features associated with differential outcomes in children in the psychiatric ED, most notably symptoms reflecting arousal and cognitive function. Methodologically, this in silico approach to risk stratification should facilitate precision psychiatry in children within the emergency setting. [ABSTRACT FROM AUTHOR]

Background: A new classification for biomarkers in Alzheimer's disease and cognitive ageing research is based on grouping the markers into three categories: amyloid deposition (A), tauopathy (T), and neurodegeneration or neuronal injury (N). Dichotomising these biomarkers as normal or abnormal results in eight possible profiles. We determined the clinical characteristics and prevalence of each ATN profile in cognitively unimpaired individuals aged 50 years and older.Methods: All participants were in the Mayo Clinic Study of Aging, a population-based study that uses a medical records linkage system to enumerate all individuals aged 50-89 years in Olmsted County, MN, USA. Potential participants are randomly selected, stratified by age and sex, and invited to participate in cognitive assessments; individuals without medical contraindications are invited to participate in brain imaging studies. Participants who were judged clinically as having no cognitive impairment and underwent multimodality imaging between Oct 11, 2006, and Oct 5, 2016, were included in the current study. Participants were classified as having normal (A-) or abnormal (A+) amyloid using amyloid PET, normal (T-) or abnormal (T+) tau using tau PET, and normal (N-) or abnormal (N+) neurodegeneration or neuronal injury using cortical thickness assessed by MRI. We used the cutoff points of standard uptake value ratio (SUVR) 1·42 (centiloid 19) for amyloid PET, 1·23 SUVR for tau PET, and 2·67 mm for MRI cortical thickness. Age-specific and sex-specific prevalences of the eight groups were determined using multinomial models combining data from 435 individuals with amyloid PET, tau PET, and MRI assessments, and 1113 individuals who underwent amyloid PET and MRI, but not tau PET imaging.Findings: The numbers of participants in each profile group were 165 A-T-N-, 35 A-T+N-, 63 A-T-N+, 19 A-T+N+, 44 A+T-N-, 25 A+T+N-, 35 A+T-N+, and 49 A+T+N+. Age differed by ATN group (p<0·0001), ranging from a median 58 years (IQR 55-64) in A-T-N- and 57 years (54-64) in A-T+N- to a median 80 years (75-84) in A+T-N+ and 79 years (73-87) in A+T+N+. The number of APOE ε4 carriers differed by ATN group (p=0·04), with carriers roughly twice as frequent in each A+ group versus the corresponding A- group. White matter hyperintensity volume (p<0·0001) and cognitive performance (p<0·0001) also differed by ATN group. Tau PET and neurodegeneration biomarkers were discordant in most individuals who would be categorised as stage 2 or 3 preclinical Alzheimer's disease (A+T+N-, A+T-N+, and A+T+N+; 86% at age 65 years and 51% at age 80 years) or with suspected non-Alzheimer's pathophysiology (A-T+N-, A-T-N+, and A-T+N+; 92% at age 65 years and 78% at age 80 years). From age 50 years, A-T-N- prevalence declined and A+T+N+ and A-T+N+ prevalence increased. In both men and women, A-T-N- was the most prevalent until age late 70s. After about age 80 years, A+T+N+ was most prevalent. By age 85 years, more than 90% of men and women had one or more biomarker abnormalities.Interpretation: Biomarkers of fibrillar tau deposition can be included with those of β-amyloidosis and neurodegeneration or neuronal injury to more fully characterise the heterogeneous pathological profiles in the population. Both amyloid- dependent and amyloid-independent pathological profiles can be identified in the cognitively unimpaired population. The prevalence of each ATN group changed substantially with age, with progression towards more biomarker abnormalities among individuals who remained cognitively unimpaired.Funding: National Institute on Aging (part of the US National Institutes of Health), the Alexander Family Professorship of Alzheimer's Disease Research, the Mayo Clinic, and the GHR Foundation. [ABSTRACT FROM AUTHOR]

Background Sleep disordered breathing may be a risk factor for high altitude illness. Past Antarctic sleep studies suggest that rapid transport from sea level (SL) to the Amundsen Scott South Pole Station (SP, 2835 m) increases risk of Acute Mountain Sickness (AMS). We analyzed sleep studies in 38 healthy polar workers to explore the association between sleep disordered breathing and AMS after rapid transport to the South Pole. Methods Subjects completed a baseline questionnaire, performed basic physiology tests, and were evaluated for AMS and medication use using an extended Lake Louise Questionnaire (LLQ) during their first week at the South Pole. Participants were included in this study if they took no medications and underwent polysomnography on their first nights at Sea Level and the South Pole using the Vivometrics LifeShirt ® . Within group changes were assessed with Wilcoxon signed rank tests and between group differences were assessed with Kruskal–Wallis rank sum tests. Results Overall, 21/38 subjects met criteria for AMS at some time on or prior to the third morning at the South Pole. Subjective poor sleep quality was reported by both AMS (65%) and no AMS (41%) groups. The Apnea Hypopnea Index (AHI) increased significantly in both the AMS and no AMS groups, but the difference in the increase between the two groups was not statistically significant. Increased AHI was not associated with increased AMS symptoms. Previous altitude illness ( p = 0.06) and residence at low altitudes ( p = 0.02) were risk factors for AMS. Conclusion AMS was not significantly associated with sleep architecture changes or increased AHI. However, AHI sharply increased at South Pole (19/38 participants) primarily due to central apneas. Those developing AMS were more likely to have experienced previous problems at altitude and reported living at lowland altitudes within the 3 months prior to rapid transport to the South Pole than those without AMS. [ABSTRACT FROM AUTHOR]

Background and purpose First-degree atrioventricular (AV) block in relation to the outcome of cardiac resynchronization therapy (CRT) has not been well examined. Methods Patients who received a CRT defibrillator or pacemaker between January 2002 and September 2010 at Mayo Clinic were classified into 2 groups: normal PR interval and prolonged PR interval. Standard sensed (100 milliseconds) and paced (130 milliseconds) AV delay was programmed after CRT. Clinical presentations and echocardiography were assessed before CRT and at a median of 6 months after CRT. Results The normal PR interval group (n = 199) had greater improvements in heart failure functional class (mean [SD], 0.7 [0.8] vs 0.5 [0.9]; P = .03) and left ventricular ejection fraction (9.4% [12.4%] vs 5.9% [9.5%]; P = .007) than the prolonged PR group (n = 204). Conclusion Compared with prolonged PR interval, the presence of normal PR interval was associated with a greater improvement in heart failure. [ABSTRACT FROM AUTHOR]

Background: As preclinical Alzheimer's disease becomes a target for therapeutic intervention, the overlap between imaging abnormalities associated with typical ageing and those associated with Alzheimer's disease needs to be recognised. We aimed to characterise how typical ageing and preclinical Alzheimer's disease overlap in terms of β-amyloidosis and neurodegeneration.Methods: We measured age-specific frequencies of amyloidosis and neurodegeneration in individuals with normal cognitive function aged 50-89 years. Potential participants were randomly selected from the Olmsted County (MN, USA) population-based study of cognitive ageing and invited to participate in cognitive and imaging assessments. To be eligible for inclusion, individuals must have been judged clinically to have no cognitive impairment and have undergone amyloid PET, (18)F-fluorodeoxyglucose ((18)F-FDG) PET, and MRI. Imaging results were obtained from March 28, 2006, to Dec 3, 2013. Amyloid status (positive [A(+)] or negative [A(-)]) was determined by amyloid PET with (11)C Pittsburgh compound B. Neurodegeneration status (positive [N(+)] or negative [N(-)]) was determined by an Alzheimer's disease signature (18)F-FDG PET or hippocampal volume on MRI. We determined age-specific frequencies of the four groups (amyloid negative and neurodegeneration negative [A(-)N(-)], amyloid positive and neurodegeneration negative [A(+)N(-)], amyloid negative and neurodegeneration positive [A(-)N(+)], or amyloid positive and neurodegeneration positive [A(+)N(+)]) cross-sectionally using multinomial regression models. We also investigated associations of group frequencies with APOE ɛ4 status (assessed with DNA extracted from blood) and sex by including these covariates in the multinomial models.Findings: The study population consisted of 985 eligible participants. The population frequency of A(-)N(-) was 100% (n=985) at age 50 years and fell to 17% (95% CI 11-24) by age 89 years. The frequency of A(+)N(-) increased to 28% (24-32) at age 74 years, then decreased to 17% (11-25) by age 89 years. The frequency of A(-)N(+) increased from age 60 years, reaching 24% (16-34) by age 89 years. The frequency of A(+)N(+) increased from age 65 years, reaching 42% (31-52) by age 89 years. The results from our multinomial models suggest that A(+)N(-) and A(+)N(+) were more frequent in APOE ɛ4 carriers than in non-carriers and that A(+)N(+) was more, and A(+)N(-) less frequent in men than in women.Interpretation: Accumulation of amyloid and neurodegeneration are nearly inevitable by old age, but many people are able to maintain normal cognitive function despite these imaging abnormalities. Changes in the frequency of amyloidosis and neurodegeneration with age, which seem to be modified by APOE ɛ4 and sex, suggest that pathophysiological sequences might differ between individuals.Funding: US National Institute on Aging and Alexander Family Professorship of Alzheimer's Disease Research. [ABSTRACT FROM AUTHOR]

Background As preclinical Alzheimer's disease becomes a target for therapeutic intervention, the overlap between imaging abnormalities associated with typical ageing and those associated with Alzheimer's disease needs to be recognised. We aimed to characterise how typical ageing and preclinical Alzheimer's disease overlap in terms of β-amyloidosis and neurodegeneration. Methods We measured age-specific frequencies of amyloidosis and neurodegeneration in individuals with normal cognitive function aged 50–89 years. Potential participants were randomly selected from the Olmsted County (MN, USA) population-based study of cognitive ageing and invited to participate in cognitive and imaging assessments. To be eligible for inclusion, individuals must have been judged clinically to have no cognitive impairment and have undergone amyloid PET, 18 F-fluorodeoxyglucose ( 18 F-FDG) PET, and MRI. Imaging results were obtained from March 28, 2006, to Dec 3, 2013. Amyloid status (positive [A + ] or negative [A – ]) was determined by amyloid PET with 11 C Pittsburgh compound B. Neurodegeneration status (positive [N + ] or negative [N – ]) was determined by an Alzheimer's disease signature 18 F-FDG PET or hippocampal volume on MRI. We determined age-specific frequencies of the four groups (amyloid negative and neurodegeneration negative [A – N – ], amyloid positive and neurodegeneration negative [A + N – ], amyloid negative and neurodegeneration positive [A – N + ], or amyloid positive and neurodegeneration positive [A + N + ]) cross-sectionally using multinomial regression models. We also investigated associations of group frequencies with APOE ɛ4 status (assessed with DNA extracted from blood) and sex by including these covariates in the multinomial models. Findings The study population consisted of 985 eligible participants. The population frequency of A – N – was 100% (n=985) at age 50 years and fell to 17% (95% CI 11–24) by age 89 years. The frequency of A + N – increased to 28% (24–32) at age 74 years, then decreased to 17% (11–25) by age 89 years. The frequency of A – N + increased from age 60 years, reaching 24% (16–34) by age 89 years. The frequency of A + N + increased from age 65 years, reaching 42% (31–52) by age 89 years. The results from our multinomial models suggest that A + N – and A + N + were more frequent in APOE ɛ4 carriers than in non-carriers and that A + N + was more, and A + N – less frequent in men than in women. Interpretation Accumulation of amyloid and neurodegeneration are nearly inevitable by old age, but many people are able to maintain normal cognitive function despite these imaging abnormalities. Changes in the frequency of amyloidosis and neurodegeneration with age, which seem to be modified by APOE ɛ4 and sex, suggest that pathophysiological sequences might differ between individuals. Funding US National Institute on Aging and Alexander Family Professorship of Alzheimer's Disease Research. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cardiac resynchronization therapy (CRT) has been shown to improve heart failure (HF) symptoms and survival. We hypothesized that a greater improvement in left-ventricular ejection fraction (LVEF) after CRT is associated with greater survival benefit. METHODS AND RESULTS: In 693 patients across 2 international centers, the improvement in LVEF after CRT was determined. Patients were grouped as non-/modest-, moderate-, or super-responders to CRT, defined as an absolute change in LVEF of <=5%, 6-15%, and >15%, respectively. Changes in New York Heart Association (NYHA) functional class and left ventricular end-diastolic dimension (LVEDD) were assessed for each group. There were 395 non-/modest-, 186 moderate-, and 112 super-responders. Super-responders were more likely to be female and to have nonischemic cardiomyopathy, lower creatinine, and lower pulmonary artery systolic pressure than non-/modest- and moderate-responders. Super-responders were also more likely to have lower LVEF than non-/modest-responders. There was no difference in NYHA functional class, mitral regurgitation grade, or tricuspid regurgitation grade between groups. Improvement in NYHA functional class (-0.9 ± 0.9 vs -0.4 ± 0.8 [P < .001] and -0.6 ± 0.8 [P = .02]) and LVEDD (-8.7 ± 9.9 mm vs -0.5 ± 5.0 and -2.4 ± 5.8 mm [P < .001 for both]) was greatest in super-responders. Kaplan-Meier survival analysis revealed that super-responders achieved better survival compared with non-/modest- (P < .001) and moderate-responders (P = .049). CONCLUSIONS: Improvement in HF symptoms and survival after CRT is proportionate to the degree of improvement in LV systolic function. Super-response is more likely in women, those with nonischemic substrate, and those with lower pulmonary artery systolic pressure. [ABSTRACT FROM AUTHOR]

Background: Up to one-third of the patients who undergo cardiac resynchronization therapy (CRT) are not responders. Objective: To demonstrate that delayed lateral left ventricular activation time determined through time to intrinsicoid deflection onset (ID) predicts response after CRT. Methods: The ID in leads I, aVL, V1 and V2, and V5 and V6 were measured in 135 patients who underwent CRT. A CRT response was defined as a decrease in left ventricular end-systolic volume (LVESV) exceeding 15% at 6 months. Results: In patients with left bundle branch block or nonspecific intraventricular conduction delay, response was predicted by longer ID in lead I (odds ratio [OR] 3.23; 95% confidence interval (CI) 1.4–7.4; per 20-ms increase), in lead aVL (OR 3.0; 95% CI 1.2–7.3; per 20-ms increase), and in lead I minus lead V1 (OR 2.4; 95% CI 1.2–4.7) adjusting for baseline QRS duration and LVESV. Results were similar after adjusting for postimplant or change in QRS duration. The ID parameters were better predictors of response than QRS duration parameters. ID in lead I/QRS duration ratio (OR 3.1; 95% CI 1.6–5.9) also increased the odds of response after adjusting for baseline LVESV. Cutoff values for ID in leads—I, 110 ms; aVL, 130 ms; I minus V1, 90 ms—and ID in lead I/QRS duration ratio of 0.69 yielded a sensitivity and a specificity as high as 83% and 81%. Conclusions: Measurement of ID on surface electrocardiography permits a preimplant, noninvasive means of determining left ventricle activation delay; is a good predictor of CRT response; and represents a promising alternative to QRS duration parameters. [Copyright &y& Elsevier]

Background: Cardiac resynchronization therapy (CRT) is a therapy of proven benefit in patients with advanced heart failure. Identifying potential responders remains challenging, and whether the etiology of the heart failure is related to the potential hemodynamic benefit and long-term outcome of CRT is unclear. Objective: The purpose of this study was to evaluate whether heart failure etiology (ischemic cardiomyopathy [ICM] vs nonischemic dilated cardiomyopathy [DCM]) was associated with CRT outcome and implantable cardioverter-defibrillator (ICD) shocks. Methods: The study included 503 CRT recipients (CRT-D 90%) in a longitudinal CRT database: ICM (n = 312) and DCM (n = 191). Clinical variables and echocardiographic measures preimplant and postimplant were collected. Actuarial survival and ICD therapy data were assessed with Kaplan-Meier curve and log rank tests. Results: Pre-CRT, ICM patients were older and had higher creatinine levels (P <.001). At median follow-up of 7.1 months, the DCM group experienced greater improvement in left ventricular ejection fraction (8.3% ± 10% vs 6.2% ± 10%, P = .05) and left ventricular end-diastolic volumes than did those with ICM (−28%.4 ± 53 mL vs −15.3 ± 46 mL, P = .024). Survival estimates at 4 years were 55% for ICM and 77% for DCM groups (P <.001), respectively, whereas no significant difference in the incidence of appropriate/inappropriate ICD shocks was observed. The ICM group remained at higher risk for death compared to the DCM group after controlling for preimplant variables (hazard ratio 1.6, 95% confidence interval 1.1–2.3, P = .008). Conclusion: In response to CRT and in contrast to ICM, DCM patients experienced greater improvement in left ventricular systolic function and reverse remodeling while also sustaining a greater survival benefit. [ABSTRACT FROM AUTHOR]

Background: Cardiac resynchronization therapy (CRT) benefits patients with advanced heart failure. The role of atrioventricular nodal (AVN) ablation in improving CRT outcomes, including survival benefit in CRT recipients with atrial fibrillation, is uncertain. Objective: The purpose of this study was to assess the impact of AVN ablation on clinical and survival outcomes in a large atrial fibrillation and heart failure population that met the current indication for CRT and to determine whether AVN ablation is an independent predictor of survival in CRT recipients. Methods: Of 154 patients with atrial fibrillation who received CRT-D, 45 (29%) underwent AVN ablation (+AVN-ABL group), whereas 109 (71%) received drug therapy for rate control during CRT (−AVN-ABL group). New York Heart Association (NYHA) class, electrocardiogram, and echocardiogram were assessed before and after CRT. Survival data were obtained from the national death and location database (Accurint). Results: CRT comparably improved left ventricular ejection fraction (8.1% ± 10.7% vs 6.8% ± 9.6%, P = .49) and left ventricular end-diastolic diameter (−2.1 ± 5.9 mm vs −2.1 ± 6.7 mm, P = .74) in both +AVN-ABL and −AVN-ABL groups. Improvement in NYHA class was significantly greater in the +AVN-ABL group than in −AVN-ABL group (−0.7 ± 0.8 vs −0.4 ± 0.8, P = .04). Survival estimates at 2 years were 96.0% (95% confidence interval [CI] 88.6%–100%) for +AVN-ABL group and 76.5% (95% CI 68.1%–85.8%) for–AVN-ABL group (P = .008). AVN ablation was independently associated with survival benefit from death (hazard ratio [HR] 0.13, 95% CI 0.03–0.58, P = .007) and from combined death, heart transplant, and left ventricular assist device (HR 0.19, 95% CI 0.06–0.62, P = .006) after CRT. Conclusion: Among patients with atrial fibrillation and heart failure receiving CRT, AVN ablation for definitive biventricular pacing provides greater improvement in NYHA class and survival benefit. Larger-scale randomized trials are needed to assess the clinical and survival outcomes of this therapy. [Copyright &y& Elsevier]

Background: Cardiac resynchronization therapy (CRT) improves outcomes in patients with left bundle branch block (LBBB), but the benefits of CRT in patients with other QRS morphologies or previous pacing are uncertain. Objective: The purpose of this study was to describe outcomes in patients with prior right ventricular pacing and non-LBBB morphologies. Methods: We studied 505 patients who underwent de novo CRT (n = 338) or CRT upgrade (n = 167). De novo patients were categorized by underlying QRS morphology: LBBB (67%), right bundle branch block (RBBB; 11%), intraventricular conduction delay (IVCD; 13%), and QRS <120 ms (9%). Upgrade patients were categorized by the percentage of previous ventricular pacing. Results: Patients were followed for death over a median of 2.6 years (interquartile range 1.6–4.0). New York Heart Association (NYHA) functional class and echocardiographic improvements were similar in de novo and upgrade patients. However, within the de novo group, NYHA improvements were less in patients with RBBB (0.3 ± 0.8; P = .014) or IVCD (0.2 ± 0.7; P = .001) than in those with LBBB (0.7 ± 0.8). These patients had less left ventricular functional improvement as well. Survival was comparable after de novo versus upgrade CRT (61% vs 63% at 4 years; P = .906). No clinical or survival differences were noted in upgrade patients based on the percentage of previous pacing. However, survival in de novo CRT recipients with RBBB (32%) was lower than in those with LBBB (66%; P <.001), and RBBB independently predicted death (hazard ratio 3.5, confidence interval 1.9–6.5; P <.001). Conclusion: RBBB and IVCD result in less clinical improvement or worsened survival after CRT. Additional selection criteria may be beneficial in identifying potential responders with RBBB, IVCD, or narrow QRS. [Copyright &y& Elsevier]

Abstract: C-reactive protein (CRP) is a predictor of adverse cardiovascular outcomes. The effect of antihypertensive therapy on CRP levels is largely unknown. We undertook a cross-sectional study of CRP levels among participants with primary hypertension on single-agent antihypertensive therapy in the community-based biracial Genetic Epidemiology Network of Arteriopathy cohort. Linear regression models were used to assess the association of antihypertensive medication class with log-transformed CRP after adjustment for age, gender, ethnicity, body mass index, smoking, diabetes, hydroxymethylglutaryl CoA reductase inhibitor use, achieved blood pressure control (<140/90mm Hg), serum creatinine and urine albumin-to-creatinine ratios. There were 662 participants in the cohort taking single-agent therapy for hypertension. Median CRP levels differed across participants: 0.40mg/dL for those on diuretics, 0.34mg/dL on calcium-channel blockers, 0.25mg/dL on beta-blockers and 0.27mg/dL on renin-angiotensin-aldosterone system (RAAS) inhibitors (P < .001). With multivariable adjustment, the group on RAAS inhibitors had a 20% lower mean CRP on average than the group on diuretics (P =.044), differences between other medication classes were not apparent. Heart rate had a strong association with CRP (P < .001). Antihypertensive medication class may influence inflammation, particularly in patients on RAAS inhibitors. [Copyright &y& Elsevier]

BACKGROUND: To determine whether treatment guidelines for patients with lower-extremity venous thrombosis (DVT) could be applied to patients with renal vein thrombosis (RVT). The rates of recurrent venous thrombosis and survival for patients with these 2 diseases were compared. STUDY DESIGN: Inception cohort of individuals was identified with their first lifetime incident of RVT. Recurrent thrombosis and survival were compared with those for patients with DVT in a case-control fashion. SETTING & PARTICIPANTS: All patients with a diagnosis of RVT at Mayo Clinic from 1980 to 2000. OUTCOMES & MEASURES: Survival and recurrent venous thrombosis rates were compared with those for patients with DVT. Survival rates were also compared with those for US white residents. RESULTS: 218 patients (mean age, 55 +/- 19 years) were included (35% women). Malignancy (66%) and nephrotic syndrome (20%) were the most common underlying causes. Warfarin was prescribed for 74 patients (46% with lifelong therapy). During a mean follow-up of 42 +/- 57 months (768 patient-years), there were 8 recurrent venous thrombotic events (1.0/100 patient-years). This recurrence rate was less than that for patients with DVT (P < 0.001). Survival was lower compared with patients with DVT or age- and sex-matched US white residents (P < 0.001). Active malignancy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2 to 4.7) and infection (HR, 2.4; 95% CI, 1.4 to 4.0) were associated with poor survival. Survival was influenced positively by warfarin therapy (HR, 0.53; 95% CI, 0.31 to 0.90). LIMITATIONS: Retrospective nonrandomized study. CONCLUSIONS: RVT represents a distinct clinical entity with unique recurrence and survival rates. The finding of RVT should prompt a thorough evaluation for an underlying renal malignancy. Oral anticoagulation therapy may be associated with a survival advantage. Copyright © 2008 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Mutations in the voltage-gated sodium channel gene SCN1A are a major cause of severe myoclonic epilepsy of infancy (Dravet syndrome) and generalized epilepsy with febrile seizures plus. This study reports the identification of six de novo SCN1A mutations in patients with severe myoclonic epilepsy of infancy, including a tetranucleotide deletion in exon 26. The same deletion was previously observed in two unrelated patients and appears to result from slipped-strand mispairing of a direct repeat during deoxyribonucleic acid replication. Review of the literature indicates that recurrent mutations account for 25% of SCN1A mutations in severe myoclonic epilepsy of infancy, including six sites of deamination at CpG dinucleotides. [Copyright &y& Elsevier]

Abstract: We assessed the attitudes, knowledge, and perceptions of Chinese doctors who worked with drug abusers to provide direction for planned drug and alcohol education and training. A 34-item questionnaire was developed; 523 copies were distributed and 446 (84.5%) validated copies were collected. Half of the respondents (50.0%) had no formal training before they started treating drug abusers. Among them, only 16.6% were psychiatrists. Less than half of the respondents agreed that drug abuse (addiction) is a brain disorder. Male and female doctors and doctors from different facilities tended to have different opinions on reasons for relapse, efficacy of treatments, and awareness of treatment modalities, among others. Doctors from involuntary facilities were more likely to disagree with the idea that drug addiction is a brain disorder and favored compulsory treatment. Doctors involved in drug abuse treatment in China are not well prepared or experienced in drug abuse treatment and have negative attitudes toward drug abuse and abusers. [Copyright &y& Elsevier]

Do MRI-based metrics of a CSF-dynamics disorder, disproportionately enlarged subarachnoid-space hydrocephalus (DESH), correlate with discordant amyloid biomarkers (low CSF β-amyloid 1–42, normal Aβ-PET scan)? Individuals ≥50 years from the Mayo Clinic Study of Aging, with MRI, 11C-Pittsburgh compound B (Aβ) PET scans, and CSF phosphorylated-tau protein and Aβ42, were categorized into 4 groups: normal and/or abnormal by CSF β-amyloid 1–42 and Aβ amyloid PET. Within groups, we noted MRI patterns of CSF-dynamics disorders and Aβ-PET accumulation-change rate. One-hundred participants (21%) in the abnormal-CSF and/or normal-PET group had highest DESH-pattern scores and lowest CSF-phosphorylated-tau levels. Among normal amyloid-PET individuals, a 1-unit DESH-pattern score increase correlated with 30%-greater odds of abnormal amyloid CSF after age, and sex adjustment. Mean rate over time of amyloid-PET accumulation in abnormal-CSF and/or normal-PET individuals approximated individuals with normal amyloid values. Adjusting for phosphorylated-tau, abnormal CSF-amyloid and/or normal amyloid-PET individuals had higher mean amyloid-PET accumulation rates than normal individuals. CSF dynamics disorders confound β-amyloid and phosphorylated-tau CSF-biomarker interpretation. [ABSTRACT FROM AUTHOR]

Objective: Hyperhomocysteinemia is associated with an elevated cardiovascular disease risk. We examined whether women with a history of hypertension in pregnancy are more likely to have a high level of serum homocysteine decades after pregnancy. Study Design: Serum homocysteine was measured at a mean age of 60 years in nulliparous women (n = 216), and women with a history of normotensive (n = 1825) or hypertensive (n = 401) pregnancies who participated in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Relationships between homocysteine and pregnancy history were examined by linear and logistic regression, controlling for multiple covariates including personal and family history of hypertension, diabetes, obesity, tobacco use, and demographics. Results: A history of hypertension in pregnancy, when compared with normotensive pregnancy, was associated with a 4.5% higher serum homocysteine level (P = .015) and 1.60-fold increased odds of having an elevated homocysteine (95% confidence interval, 1.15–2.21; P = .005) after adjusting for potentially confounding covariates. In contrast, a history of normotensive pregnancy, as compared with nulliparity, was associated with a 6.1% lower serum homocysteine level (P = .005) and a 0.49-fold reduced odds of elevated homocysteine levels (95% confidence interval, 0.32–0.74; P < .001). Conclusion: Homocysteine levels decades after pregnancy are higher in women with a history of pregnancy hypertension, even after controlling for potential confounders. Thus, pregnancy history may prompt homocysteine assessment and risk modification in an attempt at primary prevention of cardiovascular disease. [Copyright &y& Elsevier]

Background: In a 2014 cross-sectional analysis, we showed that amyloid and neurodegeneration biomarker states in participants with no clinical impairment varied greatly with age, suggesting dynamic within-person processes. In this longitudinal study, we aimed to estimate rates of transition from a less to a more abnormal biomarker state by age in individuals without dementia, as well as to assess rates of transition to dementia from an abnormal state.Methods: Participants from the Mayo Clinic Study of Aging (Olmsted County, MN, USA) without dementia at baseline were included in this study, a subset of whom agreed to multimodality imaging. Amyloid PET (with (11)C-Pittsburgh compound B) was used to classify individuals as amyloid positive (A(+)) or negative (A(-)). (18)F-fluorodeoxyglucose ((18)F-FDG)-PET and MRI were used to classify individuals as neurodegeneration positive (N(+)) or negative (N(-)). We used all observations, including those from participants who did not have imaging results, to construct a multistate Markov model to estimate four different age-specific biomarker state transition rates: A(-)N(-) to A(+)N(-); A(-)N(-) to A(-)N(+) (suspected non-Alzheimer's pathology); A(+)N(-) to A(+)N(+); and A(-)N(+) to A(+)N(+). We also estimated two age-specific rates to dementia: A(+)N(+) to dementia and A(-)N(+) to dementia. Using these state-to-state transition rates, we estimated biomarker state frequencies by age.Findings: At baseline (between Nov 29, 2004, to March 7, 2015), 4049 participants did not have dementia (3512 [87%] were clinically normal and 537 [13%] had mild cognitive impairment). 1541 individuals underwent imaging between March 28, 2006, to April 30, 2015. Transition rates were low at age 50 years and, with one exception, exponentially increased with age. At age 85 years compared with age 65 years, the rate was nearly 11-times higher (17.2 vs 1.6 per 100 person-years) for the transition from A(-)N(-) to A(-)N(+), three-times higher (20.8 vs 6.1) for A(+)N(-) to A(+)N(+), and five-times higher (13.2 vs 2.6) for A(-)N(+) to A(+)N(+). The rate of transition was also increased at age 85 years compared with age 65 years for A(+)N(+) to dementia (7.0 vs 0.8) and for A(-)N(+) to dementia (1.7 vs 0.6). The one exception to an exponential increase with age was the transition rate from A(-)N(-) to A(+)N(-), which increased from 4.0 transitions per 100 person-years at age 65 years to 6.9 transitions per 100 person-years at age 75 and then plateaued beyond that age. Estimated biomarker frequencies by age from the multistate model were similar to cross-sectional biomarker frequencies.Interpretation: Our transition rates suggest that brain ageing is a nearly inevitable acceleration toward worse biomarker and clinical states. The one exception is the transition to amyloidosis without neurodegeneration, which is most dynamic from age 60 years to 70 years and then plateaus beyond that age. We found that simple transition rates can explain complex, highly interdependent biomarker state frequencies in our population.Funding: National Institute on Aging, Alexander Family Professorship of Alzheimer's Disease Research, the GHR Foundation. [ABSTRACT FROM AUTHOR]

Abstract: Our objective was to examine associations between glucose metabolism, as measured by 18F-fluorodeoxyglucose positron emission tomography (FDG PET), and age and to evaluate the impact of carriage of an apolipoprotein E (APOE) ε4 allele on glucose metabolism and on the associations between glucose metabolism and age. We studied 806 cognitively normal (CN) and 70 amyloid-imaging-positive cognitively impaired participants (35 with mild cognitive impairment and 35 with Alzheimer's disease [AD] dementia) from the Mayo Clinic Study of Aging, Mayo Alzheimer's Disease Research Center and an ancillary study who had undergone structural MRI, FDG PET, and 11C-Pittsburgh compound B (PiB) PET. Using partial volume corrected and uncorrected FDG PET glucose uptake ratios, we evaluated associations of regional FDG ratios with age and carriage of an APOE ε4 allele in CN participants between the ages of 30 and 95 years, and compared those findings with the cognitively impaired participants. In region-of-interest (ROI) analyses, we found modest but statistically significant declines in FDG ratio in most cortical and subcortical regions as a function of age. We also found a main effect of APOE ε4 genotype on FDG ratio, with greater uptake in ε4 noncarriers compared with carriers but only in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature meta-ROI. The latter consisted of voxels from posterior cingulate and/or precuneus, lateral parietal, and inferior temporal. In age- and sex-matched CN participants the magnitude of the difference in partial volume corrected FDG ratio in the AD-signature meta-ROI for APOE ε4 carriers compared with noncarriers was about 4 times smaller than the magnitude of the difference between age- and sex-matched elderly APOE ε4 carrier CN compared with AD dementia participants. In an analysis in participants older than 70 years (31.3% of whom had elevated PiB), there was no interaction between PiB status and APOE ε4 genotype with respect to glucose metabolism. Glucose metabolism declines with age in many brain regions. Carriage of an APOE ε4 allele was associated with reductions in FDG ratio in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature ROIs, and there was no interaction between age and APOE ε4 status. The posterior cingulate and/or precuneus and lateral parietal regions have a unique vulnerability to reductions in glucose metabolic rate as a function both of age and carriage of an APOE ε4 allele. [Copyright &y& Elsevier]

Cardiac resynchronization therapy (CRT) has a symptomatic and survival benefit for patients with heart failure (HF), but the percentage of nonresponders remains relatively high. The aims of this study were to assess the clinical significance of baseline tricuspid regurgitation (TR) or worsening TR after implantation of a CRT device on the response to therapy. This is a multicenter retrospective analysis of prospectively collected databases that includes 689 consecutive patients who underwent implantation of CRT. The patients were divided into groups according to baseline TR grade and according to worsening TR within 15 months after device implantation. Outcome was assessed by clinical and echocardiographic response within 15 months and by estimated survival for a median interquartile range follow-up time of 3.3 years (1.6, 4.6). TR worsening after CRT implantation was documented in 104 patients (15%). These patients had worse clinical and echocardiographic response to CRT, but worsening of TR was not a significant predictor of mortality (p = 0.17). According to baseline echocardiogram, 620 patients (90%) had some degree of TR before CRT implant. Baseline TR was an independent predictor of worse survival (p <0.001), although these patients had significantly better clinical and echocardiographic response compared with patients without TR. In conclusion, worsening of TR after CRT implantation is a predictor of worse clinical and echocardiographic response but was not significantly associated with increased mortality. Baseline TR is associated with reduced survival despite better clinical and echocardiographic response after CRT implantation. [ABSTRACT FROM AUTHOR]

Abstract: Background: An ankle-brachial index (ABI) (the ratio of ankle to brachial artery systolic blood pressure) value ≤0.9 identifies patients with peripheral arterial disease (PAD) and elevated cardiovascular event risk. This study examined whether women with a history of hypertension in pregnancy are more likely to have an ABI ≤0.9 decades after pregnancy. Methods and results: ABI was measured in nulliparous women (n = 144), and women with a history of normotensive (n = 1272) or hypertensive (n = 281) pregnancies who participated in the Genetic Epidemiology Network of Arteriopathy (GENOA) study [non-Hispanic white (39%) and black (61%) women, 60 (mean) ± 10 (SD) years of age]. Relationships between PAD and pregnancy history were examined by logistic regression. Compared to women with a history of normotensive pregnancy, women with a history of hypertensive pregnancy had greater odds of PAD (1.61 (odds ratio); 1.04–2.49 (95% confidence interval), p = 0.03, adjusted for age, race, height and heart rate). Additional adjustment for ever smoking, hypertension, diabetes, dyslipidemia, a family history of hypertension or coronary heart disease, body mass index and education did not attenuate this relationship (1.63; 1.02–2.62, p = 0.04). PAD risk did not differ between women with a history of normotensive pregnancy and nulliparous women (1.06; 0.52–2.14, p = 0.87). Conclusions: Hypertension in pregnancy is an independent risk factor for PAD decades after pregnancy after adjusting for race, age, height, heart rate, ever smoking, hypertension, diabetes, dyslipidemia, a family history of hypertension or coronary heart disease, body mass index and education. [Copyright &y& Elsevier]

Summary: In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer''s disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy. [Copyright &y& Elsevier]

Long-term outcomes of unselected patients with angina pectoris and bundle branch block (BBB) on initial electrocardiogram are not well established. The Olmsted County Chest Pain Study is a community-based cohort of 2,271 consecutive patients presenting to 3 Olmsted County emergency departments with angina from 1985 through 1992. Patients were followed for major adverse cardiovascular events (MACEs) including death, myocardial infarction, stroke, and revascularization at 30 days and over a median follow-up period of 7.3 years and for mortality only through a median of 16.6 years. Cox models were used to estimate associations between BBB and cardiovascular outcomes. Mean age of the cohort on presentation was 63 years, and 58% were men. MACEs at 30 days occurred in 11% with right BBB (RBBB), 8.8% with left BBB (LBBB), and 6.4% in patients without BBB (p = 0.17). Over a median follow-up of 7.3 years, patients with BBB were at higher risk for MACEs (RBBB, hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.44 to 2.38, p <0.001; LBBB, HR 2.04, 95% CI 1.62 to 2.56, p <0.001) compared to those without BBB. Over a median of 16.6 years, the 2 BBB groups had lower survival rates than patients without BBB (RBBB, HR 2.19, 95% CI 1.73 to 2.78, p <0.001; LBBB, HR 3.32, 95% CI 2.67 to 4.13, p ≤0.001), but after adjustment for multiple risk factors an increased risk of mortality for LBBB remained significant. In conclusion, appearance of LBBB or RBBB in patients presenting with angina predicts adverse long-term cardiovascular outcomes compared to patients without BBB. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine short- and long-term cardiovascular outcomes in unselected patients with diabetes mellitus (DM) with acute ischemic chest pain (AICP). In patients with DM presenting to the emergency department with AICP, short-term cardiovascular outcomes remain discordant between trials and registries, whereas long-term outcomes are not well-described. A consecutive cohort of all residents of Olmsted County, Minnesota, presenting with AICP from January 1, 1985, to December 31, 1992, was followed for a median duration of 16.6 years. The primary outcome was long-term all-cause mortality. Other outcomes included a composite of death, myocardial infarction, stroke, and revascularization (major adverse cardiovascular and cerebrovascular events [MACCEs]) as well as heart failure (HF) events at 30 days and at a median of 7.3 years, respectively. Of the 2,271 eligible patients, 336 (14.8%) were classified with DM. The crude 30-day MACCE rate was 10.1% in patients with DM and 6.1% in those without DM (p = 0.007). HF events were more common in patients with DM at 30 days (9.8% vs 3.1%, p <0.001). At 7.3 years, patients with DM were more likely to experience MACCEs and HF events than those without DM (71.2% vs 45.1%, unadjusted hazard ratio 2.15%, 95% confidence interval 1.87 to 2.48, p <0.001, and 45.1% vs 18.2%, p <0.001, respectively). Over the follow-up period, 272 patients with DM (81.9%) died, compared with 936 (49.2%) without DM (p <0.001). In conclusion, DM is associated with a higher short-term risk for MACCEs and HF and a higher long-term risk for mortality in unselected patients with AICP. DM should be included as a high-risk variable in national acute coronary syndrome guidelines. [Copyright &y& Elsevier]

Objectives: The purpose of this study was to characterize the prognosis of minimally symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM). Background: Recent data have suggested that obstruction may be present in the majority of HCM patients, irrespective of cardiac symptoms. The prognosis of minimally symptomatic obstructive HCM remains poorly defined. Methods: We examined 544 consecutive adult patients (age 59 ± 16 years; 55% men) with obstructive HCM documented by Doppler echocardiography who were free of severe cardiac symptoms, and we performed clinical follow-up (median 9.3 years). Results: There was only a slight excess mortality of the cohort in comparison to the expected survival of a similar U.S. general population (10-year observed vs. expected survival, 69.3% vs. 71.9%; p = 0.04) and 46% of the deaths were attributable to noncardiac causes. However, there was a clear relation between increasing severity of the left ventricular outflow tract (LVOT) gradient and outcome. For patients with high resting gradients (Doppler peak velocity >4 m/s), survival was significantly impaired (53% at 10 years; p = 0.001 vs. expected), and death or severe symptoms occurred in 68% of these patients within 10 years after the initial evaluation. Conversely, there was no impairment of long-term survival for patients with less-severe resting obstruction. Independent predictors of mortality in the entire cohort were age, prior stroke, and LVOT gradient severity. Conclusions: Patients with obstructive HCM and mild or no symptoms have only slight excess mortality. However, patients with markedly elevated resting LVOT gradients are at a high risk of heart failure and death. These findings may have important implications for therapy, including the timing of septal reduction therapy. [Copyright &y& Elsevier]

Objectives: The aim of our study was to examine the trends in procedural success, in-hospital, and long-term outcomes after percutaneous coronary intervention (PCI) for chronic total occlusions (CTO) over the last 25 years from a single PCI registry and to examine the impact of drug-eluting stents. Background: The percutaneous treatment of CTO remains a major challenge. Past studies have used variable definitions of CTO, and there are limited data available from contemporary practice. Methods: We evaluated the outcomes of 1,262 patients from the Mayo Clinic registry who required PCI for a CTO. The patients were divided into 4 groups according to the time of their intervention: group 1 (percutaneous transluminal coronary angioplasty era), group 2 (early stent era), group 3 (bare-metal stent era), and group 4 (drug-eluting stent era). Results: Procedural success rates were 51%, 72%, 73%, and 70% (p < 0.001), respectively, in the 4 groups. In-hospital mortality (2%, 1%, 0.4%, and 0%, p = 0.009), emergency coronary artery bypass grafting (15%, 3%, 2%, and 0.7%, p < 0.001), and rates of major adverse cardiac events (8%, 5%, 3%, and 4%, p = 0.052) decreased over time. During follow-up, the combined end point of death, myocardial infarction, or target lesion revascularization, was significantly lower in the 2 most recent cohorts compared with those patients treated before (p = 0.001 for trend). Technical failure to treat the CTO was not an independent predictor of long-term mortality (hazard ratio 1.16 [95% confidence interval 0.90 to 1.5], p = 0.25). Conclusions: Procedural success rates for CTO have not improved over time in the stent era, highlighting the need to develop new techniques and devices. Compared with the prestent era, in-hospital major adverse cardiac events and 1-year target vessel revascularization rates have declined by approximately 50%. [Copyright &y& Elsevier]

Abstract: Purpose: To examine the possibility that structural damage to the brain may play a role in the pathogenesis of schizophrenia by measuring the level of plasma S-100B, a calcium-binding protein found predominantly in the cytosol of glial cells. Method: Fifty-seven Chinese psychiatric inpatients who met DSM-IV diagnosis of schizophrenia and 60 healthy controls were enrolled in the study. Patients were assessed with the Positive and Negative Symptoms Scale (PANSS) at admission and at 12 weeks after treatment. Plasma samples were collected from patients and controls and S-100B protein was assayed using ELISA. Results: (1) 29 of 57 patients (50.9%) showed increased S-100B level compared to the mean level of 60 healthy controls (p <0.005) vs. only 1 of 60 (1.67%) controls. The S-100B levels of unmedicated (0.119±0.059μg/L) and medicated patients (0.117±.0.057μg/L) were significantly higher than controls (0.067±0.022μg/L, both p <0.001), and S-100B levels of unmedicated patients were higher than those of medicated patients (p =0.024); (2) at admission, S-100B level was positively correlated with total score of PANSS (r =0.269, p =0.043), especially with negative subscore of PANSS (r =0.306, p =0.021), but the correlation was no longer present after patients were treated by anti-psychotic agents. Conclusion: The S-100B levels of patients with schizophrenia are significantly higher than that of healthy controls, and the S-100B level is associated with severity of psychopathology, particularly negative symptoms, indicating that patients with schizophrenia may suffer structural damage to central nervous system. The concentration of S-100B may also be associated with treatment progress. [Copyright &y& Elsevier]