Association of the ATN Research Framework With Clinical Profile, Ccognitive Decline, and Mortality in Patients With Dementia With Lewy Bodies

Background and Objectives: The ATN framework has been developed to categorize biological processes within the Alzheimer’s disease (AD) continuum. Since AD pathology often coincides with dementia with Lewy Bodies (DLB), we aimed to investigate the distribution of ATN profiles in DLB and associate ATN-profiles in DLB to prognosis. / Methods: We included 202 DLB patients from the Amsterdam Dementia Cohort (68±7yrs, 19%F, MMSE: 24±3, DAT-SPECT abnormal: 105/119). Patients were classified into eight profiles according to the ATN framework, using CSF Aβ42 (A), CSF p-tau (T) and medial temporal atrophy scores (N). We compared presence of clinical symptoms in ATN profiles and used linear mixed models to analyze decline on cognitive tests (follow-up 3±2yrs for n=139). Mortality risk was assessed using Cox proportional hazards analysis. Analyses were performed on both the eight profiles, as well as three clustered categories (normal AD biomarkers, non-AD pathologic change, AD continuum). / Results: Fifty (25%) DLB patients had normal AD biomarkers (A-T-N-), 37 (18%) had non-AD pathologic change (A-T+N-: 10%/A-T-N+: 6%/A-T+N+: 3%) and 115 (57%) were classified within the AD continuum (A+T-N-: 20%/A+T+N-: 16%/A+T-N+: 10%/A+T+N+: 9%). A+T+N+ patients were older and least often had RBD symptoms. Parkinsonism was more often present in A+T-, compared to A-T+ (independent of N). Compared to patients with normal AD biomarkers, patients in A+ categories showed steeper decline on memory tests and higher mortality risk. Cognitive decline and mortality did not differ between non-AD pathologic change and normal AD biomarkers. / Discussion: In our DLB cohort, we found clinically relevant associations between ATN categories and disease manifestation. Patients within the AD continuum had steeper cognitive decline and shorter survival. Implementing the ATN framework within DLB patients aids in subtyping patients based on underlying biological processes and could provide targets for future treatment strategies, e.g. AD modifying treatment. Expanding the framework by incorporating markers for alpha-synucleinopathy would improve the use of the framework to characterize dementia patients with mixed pathology, which could enhance proper stratification of patients for therapeutic trials

Intramyocardial hemorrhage and microvascular obstruction after primary percutaneous coronary intervention

Reperfusion may cause intramyocardial hemorrhage (IMH) by extravasation of erythrocytes through severely damaged endothelial walls. The purpose of the study was to evaluate the clinical significance of IMH in relation to infarct size, microvascular obstruction (MVO) and function in patients after primary percutaneous intervention. Forty-five patients underwent cardiovascular MR imaging (CMR) 1 week and 4 months after primary stenting for a first acute myocardial infarction. T2-weighted spin-echo imaging (T2W) was used to assess infarct related edema and IMH, and delayed enhancement (DE) was used to assess infarct size and MVO. Cine CMR was used to assess left ventricular volumes and function at baseline and at 4 months follow-up. In 22 (49%) patients, IMH was detected as areas of attenuated signal in the core of the high signal intensity region on T2W images. Patients with IMH had larger infarcts, higher left ventricular volumes and lower ejection fraction. Contrast-to-noise ratio (CNR) between hyperintense periphery and the hypo-intense core of the T2W ischemic area correlated to peak CKMB, total infarct size and MVO size. Using univariable analysis, CNR predicted ejection fraction at baseline (β = −0.62, P = 0.003) and follow-up (β = −0.84, P < 0.001). However, after multivariable analysis, baseline ejection fraction and presence of MVO were the only parameters that predicted functional changes at follow-up. IMH was found in the majority of patients with MVO after reperfused myocardial infarction. It was closely related to markers of infarct size, MVO and function, but did not have prognostic significance beyond MVO

Increased aortic stiffness and blood pressure in non-classic Pompe disease

Vascular abnormalities and glycogen accumulation in vascular smooth muscle fibres have been described in Pompe disease. Using carotid-femoral pulse wave velocity (cfPWV), the gold standard methodology for determining aortic stiffness, we studied whether aortic stiffness is increased in patients with Pompe disease. Eighty-four adult Pompe patients and 179 age- and gender-matched volunteers participated in this cross-sectional case-controlled study. Intima media thickness and the distensibility of the right common carotid artery were measured using a Duplex scanner. Aortic augmentation index, central pulse pressure, aortic reflexion time and cfPWV were assessed using the SphygmoCor® system. CfPWV was higher in patients than in volunteers (8.8 versus 7.4 m/s, p < 0.001). This difference was still present after adjustment for age, gender, mean arterial blood pressure (MAP), heart rate and diabetes mellitus (p = 0.001), and was shown by subgroup analysis to apply to the 40-59 years age group (p = 0.004) and 60+ years age group (p = 0.01), but not to younger age groups (p = 0.99). Except for a shorter aortic reflexion time (p = 0.02), indirect indicators of arterial stiffness did not differ between patients and volunteers. Relative to volunteers (20 %), more Pompe patients had a history of hypertension (36 %, p = 0.005), and the MAP was higher than in volunteers (100 versus 92 mmHg, p < 0.001). This study shows that patients with non-classic Pompe disease have increased aortic stiffness and blood pressure. Whether this is due to glycogen accumulation requires further investigation. To reduce the potential risk of cardiovascular diseases, we recommend that blood pressure and other common cardiovascular risk factors are monitored regularly

Economic Evaluations of Occupational Health Interventions from a Company’s Perspective: A Systematic Review of Methods to Estimate the Cost of Health-Related Productivity Loss

Objectives: To investigate the methods used to estimate the indirect costs of health-related productivity in economic evaluations from a company’s perspective. Methods: The primary literature search was conducted in Medline and Embase. Supplemental searches were conducted in the Cochrane NHS Economic Evaluation Database, the National Institute for Occupational Safety and Health database, the Ryerson International Labour, Occupational Safety and Health Index database, scans of reference lists and researcher’s own literature database. Article selection was conducted independently by two researchers based on title, keywords, and abstract, and if needed, full text. Differences were resolved by a consensus procedure. Articles were selected based on seven criteria addressing study population, type of intervention, comparative intervention, outcome, costs, language and perspective, respectively. Characteristics of the measurement and valuation of health-related productivity were extracted and analyzed descriptively. Results: A total of 34 studies were included. Costs of health-related productivity were estimated using (a combination of) data related to sick leave, compensated sick leave, light or modified duty or work presenteeism. Data were collected from different sources (e.g. administrative databases, worker self-report, supervisors) and by different methods (e.g. questionnaires, interviews). Valuation varied in terms of reported time units, composition and source of the corresponding price weights, and whether additional elements, such as replacement costs, were included. Conclusions: Methods for measuring and valuing health-related productivity vary widely, hindering comparability of results and decision-making. We provide suggestions for improvement

Effect of additional treatment with EXenatide in patients with an Acute Myocardial Infarction (EXAMI): study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Myocardial infarction causes irreversible loss of cardiomyocytes and may lead to loss of ventricular function, morbidity and mortality. Infarct size is a major prognostic factor and reduction of infarct size has therefore been an important objective of strategies to improve outcomes. In experimental studies, glucagon-like peptide 1 and exenatide, a long acting glucagon-like peptide 1 receptor agonist, a novel drug introduced for the treatment of type 2 diabetes, reduced infarct size after myocardial infarction by activating pro-survival pathways and by increasing metabolic efficiency.</p> <p>Methods</p> <p>The EXAMI trial is a multi-center, prospective, randomized, placebo controlled trial, designed to evaluate clinical outcome of exenatide infusion on top of standard treatment, in patients with an acute myocardial infarction, successfully treated with primary percutaneous coronary intervention. A total of 108 patients will be randomized to exenatide (5 μg bolus in 30 minutes followed by continuous infusion of 20 μg/24 h for 72 h) or placebo treatment. The primary end point of the study is myocardial infarct size (measured using magnetic resonance imaging with delayed enhancement at 4 months) as a percentage of the area at risk (measured using T2 weighted images at 3-7 days).</p> <p>Discussion</p> <p>If the current study demonstrates cardioprotective effects, exenatide may constitute a novel therapeutic option to reduce infarct size and preserve cardiac function in adjunction to reperfusion therapy in patients with acute myocardial infarction.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01254123">NCT01254123</a></p

Morphological and Pathological Evolution of the Brain Microcirculation in Aging and Alzheimer’s Disease

Key pathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular “dysfunction” compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD

Early postural blood pressure response and cause-specific mortality among middle-aged adults

Orthostatic hypotension (OH) is associated with increased total mortality but contribution of specific death causes has not been thoroughly explored. In this prospective study, authors followed up 32,068 individuals without baseline history of cancer or cardiovascular disease (69% men; mean age, 46 years; range, 26–61 years) over a period of 24 years. Hazard ratios (HRs) for total and cause-specific mortality associated with presence of OH and by quartiles of postural systolic blood pressure response (∆SBP) were assessed using multivariate adjusted Cox regression model. A total of 7,145 deaths (22.3%, 9.4 deaths/1,000 person-years) occurred during follow-up. Those with OH (n = 1,943) had higher risk of death due to injury (HR, 1.88; 1.37–2.57) and neurological disease (HR, 2.21; 1.39–3.51). Analogically, risk of death caused by injury and neurological disease increased across the quartiles of ∆SBP from hyper- (Q1SBP, +8.5 ± 4.7 mmHg) to hypotensive response (Q4SBP, −13.7 ± 5.7 mmHg; HR, 1.32; 1.00–1.72, and 1.84; 1.20–2.82, respectively) as did also risk of death due to respiratory disease (Q4SBP vs. Q1SBP: HR, 1.53; 1.14–2.04). In contrast, risk curve for cerebrovascular death was U-shaped with nadir in the mildly hypotensive 3rd quartile of ∆SBP (−5.0 ± 0.1 mmHg, Q3SBP vs. Q1SBP: HR, 0.75; 0.54–1.03; P for linear trend = 0.021). Additionally, cardiovascular mortality was increased among 5,805 rescreened participants (mean age, 53 years; 9.8% OH positive: HR, 1.54; 1.24–1.89, and Q4SBP vs. Q1SBP: 1.27; 1.02–1.57, respectively). In summary, increased mortality predicted by blood pressure fall on standing is associated with injuries, neurodegenerative, and respiratory diseases, as well as with cardiovascular disease in older adults. Moreover, both increase and pronounced decrease of SBP during early orthostasis indicate higher risk of cerebrovascular death

The impact of a cancer Survivorship Care Plan on gynecological cancer patient and health care provider reported outcomes (ROGY Care): study protocol for a pragmatic cluster randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>There is a need for improvement of information provision and post-treatment care for cancer survivors. A Survivorship Care Plan (SCP) is recommended by the American Institute of Medicine and the Dutch Health Council, which is a summary of patients' course of treatment as a formal document, and includes recommendations for subsequent cancer surveillance, management of late effects, and strategies for health promotion. Until now, evidence on the effects of implementing the SCP in clinical practice is lacking. The rationale and study design of a pragmatic cluster randomized trial, aiming to assess the impact of SCP care in routine clinical practice, is presented.</p> <p>Methods/Design</p> <p>A web-based patient registration system 'Registrationsystem Oncological GYnecology' (ROGY) is used by gynecologists in the South of the Netherlands since 2006. A personalized SCP can automatically be generated out of ROGY. In this pragmatic cluster randomized controlled trial, 12 hospitals are randomized to either 'usual care' or 'SCP care'. In patients with 'usual care', the gynecologist provides care as usual. In patients with 'SCP care', information about the tumor stage and treatment is personally discussed with the patient and a document is handed to the patient. Prospectively, all patients diagnosed with endometrial or ovarian cancer in the participating hospitals will be approached for study participation. Patients will complete questionnaires after surgery, and before additional treatment, and after 6, 12, 18 and 24 months. In addition, health care providers will be asked their opinion about implementation of SCP care. Primary outcome is defined as patient satisfaction with information provision and care. Secondary outcomes are illness perception, health-related quality of life, health care use, prevalence, course and referral rate of survivors with psychosocial distress, and health care providers' evaluation of SCP care.</p> <p>Discussion</p> <p>The ROGY Care trial will help to gain insight into the impact of SCP care on patient reported outcomes, and on the evaluation of cancer survivors and health care providers of the different elements of the SCP. Therefore, results will contribute to efforts to improve quality of care for cancer survivors.</p> <p>Trial registration</p> <p>Trial Registration: <url>http://www.ClinicalTrials.gov</url>. Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01185626">NCT01185626</a></p> <p>Medical Research Ethics Committee Reference Number: NL33429.008.10 Grant Reference Number: UVT2010-4743</p

BMI Development of Normal Weight and Overweight Children in the PIAMA Study

Background: There is evidence that rapid weight gain during the first year of life is associated with overweight later in life. However, results from studies exploring other critical periods for the development of overweight are inconsistent. Objective: The objective was to investigate BMI development to assess at what ages essential differences between normal weight and overweight children occur, and to assess which age intervals the most strongly influence the risk of overweight at 8 years of age. Methods: Longitudinal weight and height data

Co-morbidity and drug treatment in Alzheimer's disease. A cross sectional study of participants in the Dementia Study in Northern Norway

Inappropriate medical treatment of co-morbidities in Alzheimer’s disease (AD) is an increasing concern in geriatric medicine. The objective of this study was to compare current drug use related to co-morbidity between individuals with a recent diagnosis of AD and a cognitively healthy control group in a population based clinical trial in Northern Norway. Setting: Nine rural municipalities with 70 000 inhabitants in Northern Norway. Participants: Participants with and without AD recruited in general practice and by population based screening. 187 participants with a recent diagnosis of AD were recruited among community dwellers. Of 791 respondents without cognitive symptoms, 500 were randomly selected and invited to further clinical and cognitive testing. The final control group consisted of 200 cognitively healthy individuals from the same municipalities. Demographic characteristics, data on medical history and current medication were included, and a physical and cognitive examination was performed. The statistical analyses were carried out by independent sample t-test, chi-square, ANCOVA and logistic regression. A co-morbidity score was significantly higher in AD participants compared to controls. The mean number of drugs was higher for AD participants compared to controls (5.1 ± 3.6 and 2.9 ± 2.4 respectively, p < 0.001 age and gender adjusted), also when adjusted for co-morbidity. AD participants used significantly more anticholinergic, sedative and antidepressant drugs. For nursing home residents with AD the mean number of drugs was significantly higher compared to AD participants living at home (6.9 ± 3.9 and 4.5 ± 3.3, respectively, p < 0.001). AD participants were treated with a significantly higher number of drugs as compared to cognitively healthy controls, even after adjustment for co-morbidity. An inappropriate use of anticholinergic and sedative drugs was identified, especially among nursing home residents with AD. The drug burden and the increased risk of adverse reactions among individuals suffering from AD need more attention from prescribing doctors