The Effects of HB1519 Funding on Early Childhood Programs

Includes bibliographical reference.In 1998, the Missouri Legislature created the Early Childhood Care and Education Fund (HB1519). The Department of Elementary and Secondary Education and the Department of Social Services funded a three-year study that evaluated the development and care of children participating in programs across the state that were supported by HB1519 funds compared to children participating in programs that did not receive funding. Program quality was evaluated using the Infant-Toddler Environmental Rating Scale, the Family Daycare Environmental Rating Scale and the Early Childhood Environmental Rating Scale-Revised. Furthermore, the intellectual abilities of children who attended high quality programs were compared to the abilities of children who attended programs of lower quality using the Peabody Picture Vocabulary Test and the Woodcock-Johnson Test of Cognitive Abilities.Funded by the Missouri Department of Social Services and the Missouri Department of Elementary and Secondary Education

Clinical phenotypes among patients with normal cardiac perfusion using unsupervised learning:a retrospective observational study

BACKGROUND: Myocardial perfusion imaging (MPI) is one of the most common cardiac scans and is used for diagnosis of coronary artery disease and assessment of cardiovascular risk. However, the large majority of MPI patients have normal results. We evaluated whether unsupervised machine learning could identify unique phenotypes among patients with normal scans and whether those phenotypes were associated with risk of death or myocardial infarction.METHODS: Patients from a large international multicenter MPI registry (10 sites) with normal perfusion by expert visual interpretation were included in this cohort analysis. The training population included 9849 patients, and external testing population 12,528 patients. Unsupervised cluster analysis was performed, with separate training and external testing cohorts, to identify clusters, with four distinct phenotypes. We evaluated the clinical and imaging features of clusters and their associations with death or myocardial infarction.FINDINGS: Patients in Clusters 1 and 2 almost exclusively underwent exercise stress, while patients in Clusters 3 and 4 mostly required pharmacologic stress. In external testing, the risk for Cluster 4 patients (20.2% of population, unadjusted hazard ratio [HR] 6.17, 95% confidence interval [CI] 4.64-8.20) was higher than the risk associated with pharmacologic stress (HR 3.03, 95% CI 2.53-3.63), or previous myocardial infarction (HR 1.82, 95% CI 1.40-2.36).INTERPRETATION: Unsupervised learning identified four distinct phenotypes of patients with normal perfusion scans, with a significant proportion of patients at very high risk of myocardial infarction or death. Our results suggest a potential role for patient phenotyping to improve risk stratification of patients with normal imaging results.FUNDING: This work was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health [R35HL161195 to PS]. The REFINE SPECT database was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health [R01HL089765 to PS]. MCW was supported by the British Heart Foundation [FS/ICRF/20/26002].</p

Multimodal analysis of drug transporter expression in gastrointestinal tissue

Objectives: Drug transporters affect antiretroviral therapy (ART) tissue disposition, but quantitative measures of drug transporter protein expression across preclinical species are not available. Our objective was to use proteomics to obtain absolute transporter concentrations and assess agreement with corresponding gene and immunometric protein data. Design: In order to make interspecies comparisons, two humanized mouse [hu-HSC-Rag (n = 41); bone marrow-liver-thymus (n = 13)] and one primate [rhesus macaque (nonhuman primate, n = 12)] models were dosed to steady state with combination ART. Ileum and rectum were collected at necropsy and snap frozen for analysis. Methods: Tissues were analyzed for gene (quantitative PCR) and protein [liquid chromatography-mass spectrometry (LC-MS) proteomics and western blot] expression and localization (immunohistochemistry) of ART efflux and uptake transporters. Drug concentrations were measured by LC-MS/MS. Multivariable regression was used to determine the ability of transporter data to predict tissue ART penetration. Results: Analytical methods did not agree, with different trends observed for gene and protein expression. For example, quantitative PCR analysis showed a two-fold increase in permeability glycoprotein expression in nonhuman primates versus mice; however, proteomics showed a 200-fold difference in the opposite direction. Proteomics results were supported by immunohistochemistry staining showing extensive efflux transporter localization on the luminal surface of these tissues. ART tissue concentration was variable between species, and multivariable regression showed poor predictive power of transporter data. Conclusion: Lack of agreement between analytical techniques suggests that resources should be focused on generating downstream measures of protein expression to predict drug exposure. Taken together, these data inform the use of preclinical models for studying ART distribution and the design of targeted therapies for HIV eradication

Developing cancer warning statements for alcoholic beverages

Background: There is growing evidence of the increased cancer risk associated with alcohol consumption, but this is not well understood by the general public. This study investigated the acceptability among drinkers of cancer warning statements for alcoholic beverages. Methods: Six focus groups were conducted with Australian drinkers to develop a series of cancer-related warning statements for alcohol products. Eleven cancer warning statements and one general health warning statement were subsequently tested on 2,168 drinkers via an online survey. The statements varied by message frame (positive vs negative), cancer reference (general vs specific), and the way causality was communicated (‘increases risk of cancer’ vs ‘can cause cancer’). Results: Overall, responses to the cancer statements were neutral to favorable, indicating that they are unlikely to encounter high levels of negative reaction from the community if introduced on alcoholic beverages. Females, younger respondents, and those with higher levels of education generally found the statements to be more believable, convincing, and personally relevant. Positively framed messages, those referring to specific forms of cancer, and those using ‘increases risk of cancer’ performed better than negatively framed messages, those referring to cancer in general, and those using the term ‘can cause cancer’. Conclusion: Cancer warning statements on alcoholic beverages constitute a potential means of increasing awareness about the relationship between alcohol consumption and cancer risk

Interpersonal violence: an important risk factor for disease and injury in South Africa

<p>Abstract</p> <p>Background</p> <p>Burden of disease estimates for South Africa have highlighted the particularly high rates of injuries related to interpersonal violence compared with other regions of the world, but these figures tell only part of the story. In addition to direct physical injury, violence survivors are at an increased risk of a wide range of psychological and behavioral problems. This study aimed to comprehensively quantify the excess disease burden attributable to exposure to interpersonal violence as a risk factor for disease and injury in South Africa.</p> <p>Methods</p> <p>The World Health Organization framework of interpersonal violence was adapted. Physical injury mortality and disability were categorically attributed to interpersonal violence. In addition, exposure to child sexual abuse and intimate partner violence, subcategories of interpersonal violence, were treated as risk factors for disease and injury using counterfactual estimation and comparative risk assessment methods. Adjustments were made to account for the combined exposure state of having experienced both child sexual abuse and intimate partner violence.</p> <p>Results</p> <p>Of the 17 risk factors included in the South African Comparative Risk Assessment study, interpersonal violence was the second leading cause of healthy years of life lost, after unsafe sex, accounting for 1.7 million disability-adjusted life years (DALYs) or 10.5% of all DALYs (95% uncertainty interval: 8.5%-12.5%) in 2000. In women, intimate partner violence accounted for 50% and child sexual abuse for 32% of the total attributable DALYs.</p> <p>Conclusions</p> <p>The implications of our findings are that estimates that include only the direct injury burden seriously underrepresent the full health impact of interpersonal violence. Violence is an important direct and indirect cause of health loss and should be recognized as a priority health problem as well as a human rights and social issue. This study highlights the difficulties in measuring the disease burden from interpersonal violence as a risk factor and the need to improve the epidemiological data on the prevalence and risks for the different forms of interpersonal violence to complete the picture. Given the extent of the burden, it is essential that innovative research be supported to identify social policy and other interventions that address both the individual and societal aspects of violence.</p

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Quantitative 18F-AV1451 Brain Tau PET Imaging in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer's Disease Patients

Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results:18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p &lt; 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p &gt; 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification