Interpreting Posterior Relative Risk Estimates in Disease-Mapping Studies

There is currently much interest in conducting spatial analyses of health outcomes at the small-area scale. This requires sophisticated statistical techniques, usually involving Bayesian models, to smooth the underlying risk estimates because the data are typically sparse. However, questions have been raised about the performance of these models for recovering the “true” risk surface, about the influence of the prior structure specified, and about the amount of smoothing of the risks that is actually performed. We describe a comprehensive simulation study designed to address these questions. Our results show that Bayesian disease-mapping models are essentially conservative, with high specificity even in situations with very sparse data but low sensitivity if the raised-risk areas have only a moderate (< 2-fold) excess or are not based on substantial expected counts (> 50 per area). Semiparametric spatial mixture models typically produce less smoothing than their conditional autoregressive counterpart when there is sufficient information in the data (moderate-size expected count and/or high true excess risk). Sensitivity may be improved by exploiting the whole posterior distribution to try to detect true raised-risk areas rather than just reporting and mapping the mean posterior relative risk. For the widely used conditional autoregressive model, we show that a decision rule based on computing the probability that the relative risk is above 1 with a cutoff between 70 and 80% gives a specific rule with reasonable sensitivity for a range of scenarios having moderate expected counts (~ 20) and excess risks (~1.5- to 2-fold). Larger (3-fold) excess risks are detected almost certainly using this rule, even when based on small expected counts, although the mean of the posterior distribution is typically smoothed to about half the true value

Cognitive Composite Score Association With Alzheimer\u27S Disease Plaque And Tangle Pathology

Background: Cognitive composite scores are used as the primary outcome measures for Alzheimer\u27s disease (AD) prevention trials; however, the extent to which these composite measures correlate with AD pathology has not been fully investigated. Since many on-going AD prevention studies are testing therapies that target either amyloid or tau, we sought to establish an association between a cognitive composite score and the underlying pathology of AD. Methods: Data from 192 older deceased and autopsied persons from the Rush Religious Order Study were used in this study. All participants were classified at their initial evaluations with a clinical diagnosis of no cognitive impairment (NCI). Of these individuals, 105 remained NCI at the time of their death while the remaining 87 progressed to mild cognitive impairment (MCI) or AD. A cognitive composite score composed of eight cognitive tests was used as the outcome measure. Individuals were classified into groups based on Consortium to Establish a Registry for Alzheimer\u27s Disease (CERAD) neuropathological diagnosis and Braak stage. Results: The rate of annualized composite score decline was significantly greater for the high CERAD (p \u3c 0.001, d = 0.56) and Braak (p \u3c 0.001, d = 0.55) groups compared with the low CERAD and Braak groups, respectively. Mixed-model repeated measure (MMRM) analyses revealed a significantly greater difference in composite score change from baseline for the high CERAD group relative to the low CERAD group after 5 years (Δ = -2.74, 95% confidence interval (CI) -5.01 to -0.47; p = 0.02). A similar analysis between low and high Braak stage groups found no significant difference in change from baseline (Δ = -0.69, 95% CI -3.03 to 1.66; p = 0.56). Conclusions: These data provide evidence that decreased cognitive composite scores were significantly associated with increased AD pathology and provide support for the use of cognitive composite scores in AD prevention trials

Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer's disease

Intravenous immunoglobulin (IVIG) has shown limited promise so far in human clinical studies on Alzheimer's disease (AD), yet overwhelmingly positive preclinical work in animals and human brain cultures support the notion that the therapy remains potentially efficacious. Here, we elaborate on IVIG neuropreservation by demonstrating that IVIG protects human primary neurons against oxidative stress in vitro and that IVIG preserves antioxidant defense mechanisms in vivo. Based on these results, we propose the following translational impact: If the dosage and treatment conditions are adequately optimized, then IVIG treatment could play a significant role in preventing and/or delaying the progression of neurodegenerative diseases, such as AD. We suggest that IVIG warrants further investigation to fully exploit its potential as an anti-oxidant, neuroprotective and synapto-protecting agent

Staging of Alzheimer's Pathology in Triple Transgenic Mice: A Light and Electron Microscopic Analysis

The age-related pathological cascade underlying intraneuronal tau formation in 3xTg-AD mice, which harbor the human APPSwe, PS1M126V , and TauP301L gene mutations, remains unclear. At 3 weeks of age, AT180, Alz50, MC1, AT8, and PHF-1 intraneuronal immunoreactivity appeared in the amygdala and hippocampus and at later ages in the cortex of 3xTg-AD mice. AT8 and PHF-1 staining was fixation dependent in young mutant mice. 6E10 staining was seen at all ages. Fluorescent immunomicroscopy revealed CA1 neurons dual stained for 6E10 and Alz50 and single Alz50 immunoreactive neurons in the subiculum at 3 weeks and continuing to 20 months. Although electron microscopy confirmed intraneuronal cytoplasmic Alz50, AT8, and 6E10 reaction product in younger 3xTg-AD mice, straight filaments appeared at 23 months of age in female mice. The present data suggest that other age-related biochemical mechanisms in addition to early intraneuronal accumulation of 6E10 and tau underlie the formation of tau filaments in 3xTg-AD mice

Quiet Time for Mechanically Ventilated Patients in The Medical Intensive Care Unit

Objective: Sleep disruption occurs frequently in critically ill patients. The primary aim of this study was to examine the effect of quiet time (QT) on patient sedation frequency, sedation and delirium scores; and to determine if consecutive QTs influenced physiologic measures (heart rate, mean arterial blood pressure and respiratory rate). Method: A prospective study of a quiet time protocol was conducted with 72 adult patients on mechanical ventilation. Setting: A Medical Intensive Care Unit (MICU) in the Midwest region of the United States. Results: Sedation was given less frequently after QT (p = 0.045). Those who were agitated prior to QT were more likely to be at goal sedation after QT (p \u3c 0.001). Although not statistically significant, the majority of patients who were negative on the Confusion Assessment Method (CAM-ICU) prior to QT remained delirium free after QT. Repeated measures analysis of variance (ANOVA) for three consecutive QTs showed a significant difference for respiratory rate (p = 0.035). Conclusion: QT may influence sedation administration and promote patient rest. Future studies are required to further understand the influence of QT on mechanically ventilated patients in the intensive care unit

Nerve Growth Factor Pathobiology During The Progression Of Alzheimer\u27s Disease

The current review summarizes the pathobiology of nerve growth factor (NGF) and its cognate receptors during the progression of Alzheimer’s disease (AD). Both transcript and protein data indicate that cholinotrophic neuronal dysfunction is related to an imbalance between TrkA-mediated survival signaling and the NGF precursor (proNGF)/p75NTR-mediated pro-apoptotic signaling, which may be related to alteration in the metabolism of NGF. Data indicate a spatiotemporal pattern of degeneration related to the evolution of tau pathology within cholinotrophic neuronal subgroups located within the nucleus basalis of Meynert (nbM). Despite these degenerative events the cholinotrophic system is capable of cellular resilience and/or plasticity during the prodromal and later stages of the disease. In addition to neurotrophin dysfunction, studies indicate alterations in epigenetically regulated proteins occur within cholinotrophic nbM neurons during the progression of AD, suggesting a mechanism that may underlie changes in transcript expression. Findings that increased cerebrospinal fluid levels of proNGF mark the onset of MCI and the transition to AD suggests that this proneurotrophin is a potential disease biomarker. Novel therapeutics to treat NGF dysfunction include NGF gene therapy and the development of small molecule agonists for the cognate prosurvival NGF receptor TrkA and antagonists against the pan-neurotrophin p75NTR death receptor for the treatment of AD

Data collection on trafficking in human beings in the EU:Final report

Trafficking in human beings is the buying and selling of women, girls, men, and boys. It has hugely deleterious consequences for individuals, society, and the economy. This is the fourth report published by the European Commission that presents a compilation of statistics at the EU Member State level on trafficking in human beings. This data collection exercise approached all 28-Member States and covers the years 2015 and 2016and updates the 2014 data collection as relevant

Infectious disease surveillance needs for the United States: lessons from Covid-19

The COVID-19 pandemic has highlighted the need to upgrade systems for infectious disease surveillance and forecasting and modeling of the spread of infection, both of which inform evidence-based public health guidance and policies. Here, we discuss requirements for an effective surveillance system to support decision making during a pandemic, drawing on the lessons of COVID-19 in the U.S., while looking to jurisdictions in the U.S. and beyond to learn lessons about the value of specific data types. In this report, we define the range of decisions for which surveillance data are required, the data elements needed to inform these decisions and to calibrate inputs and outputs of transmission-dynamic models, and the types of data needed to inform decisions by state, territorial, local, and tribal health authorities. We define actions needed to ensure that such data will be available and consider the contribution of such efforts to improving health equity