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The linear mixed effects model based on a full likelihood is one of the few methods available to model longitudinal data subject to left censoring. However, a full likelihood approach is complicated algebraically because of the large dimension of the numeric computations, and maximum likelihood estimation can be computationally prohibitive when the data are heavily censored. Moreover, for mixed models, the complexity of the computation increases as the dimension of the random effects in the model increases. We propose a method based on pseudo likelihood that simplifies the computational complexities, allows a wide class of multivariate models, and that can be used for many different data structures including settings where the level of censoring is high. The motivation for this work comes from the need for a joint model to assess the joint effect of pro-inflammatory and anti-inflammatory biomarker data on 30-day mortality status while simultaneously accounting for longitudinal left censoring and correlation between markers in the analysis of Genetic and Inflammatory Markers for Sepsis study conducted at the University of Pittsburgh. Two markers, interleukin-6 and interleukin-10, which naturally are correlated because of a shared similar biological pathways and are left-censored because of the limited sensitivity of the assays, are considered to determine if higher levels of these markers is associated with an increased risk of death after accounting for the left censoring and their assumed correlation. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We propose a latent variable model for informative missingness in longitudinal studies which is an extension of latent dropout class model. In our model, the value of the latent variable is affected by the missingness pattern and it is also used as a covariate in modeling the longitudinal response. So the latent variable links the longitudinal response and the missingness process. In our model, the latent variable is continuous instead of categorical and we assume that it is from a normal distribution. The EM algorithm is used to obtain the estimates of the parameter we are interested in and Gauss–Hermite quadrature is used to approximate the integration of the latent variable. The standard errors of the parameter estimates can be obtained from the bootstrap method or from the inverse of the Fisher information matrix of the final marginal likelihood. Comparisons are made to the mixed model and complete-case analysis in terms of a clinical trial dataset, which is Weight Gain Prevention among Women (WGPW) study. We use the generalized Pearson residuals to assess the fit of the proposed latent variable model. [ABSTRACT FROM AUTHOR]

The Genetic Markers of Inflammation Study (GenIMS) was conceived to investigate the role of severe sepsis, which is typically defined as system-wide multi-organ failure, on survival. One major hypothesis for this systemic collapse, and reduction in survival, is a cascade of pro-inflammatory and anti-inflammatory cytokines. In this paper, we devised a novel joint modeling strategy to evaluate the joint effect of longitudinal anti-inflammatory marker IL-6 and pro-inflammatory marker IL-10 on 90-day survival. We found that, on average, patients with high initial values of both IL-6 and IL-10, that tend to increase over time, are associated with a reduction in survival expectancy and that accounting for their assumed correlation was justified. [ABSTRACT FROM PUBLISHER]

Dimension reduction techniques, such as partial least squares, are useful for computing summary measures and examining relationships in complex settings. Partial least squares requires an estimate of the covariance matrix as a first step in the analysis, making this estimate critical to the results. In addition, the covariance matrix also forms the basis for other techniques in multivariate analysis, such as principal component analysis and independent component analysis. This paper has been motivated by an example from an imaging study in Alzheimer's disease where there is complete separation between Alzheimer's and control subjects for one of the imaging modalities. This separation occurs in one block of variables and does not occur with the second block of variables resulting in inaccurate estimates of the covariance. We propose the use of a copula to obtain estimates of the covariance in this setting, where one set of variables comes from a mixture distribution. Simulation studies show that the proposed estimator is an improvement over the standard estimators of covariance. We illustrate the methods from the motivating example from a study in the area of Alzheimer's disease. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Censoring of a longitudinal outcome often occurs when data are collected in a biomedical study and where the interest is in the survival and or longitudinal experiences of a study population. In the setting considered herein, we encountered upper and lower censored data as the result of restrictions imposed on measurements from a kinetic model producing “biologically implausible” kidney clearances. The goal of this paper is to outline the use of a joint model to determine the association between a censored longitudinal outcome and a time to event endpoint. This paper extends Guo and Carlin's [6] paper to accommodate censored longitudinal data, in a commercially available software platform, by linking a mixed effects Tobit model to a suitable parametric survival distribution. Our simulation results showed that our joint Tobit model outperforms a joint model made up of the more naïve or “fill-in” method for the longitudinal component. In this case, the upper and/or lower limits of censoring are replaced by the limit of detection. We illustrated the use of this approach with example data from the hemodialysis (HEMO) study [3] and examined the association between doubly censored kidney clearance values and survival. [ABSTRACT FROM AUTHOR]

In a longitudinal study with response data collected during a hospital stay, observations may be missing because of the subject's discharge from the hospital prior to completion of the study or the death of the subject, resulting in non-ignorable missing data. In addition to non-ignorable missingness, there is left-censoring in the response measurements because of the inherent limit of detection. For analyzing non-ignorable missing and left-censored longitudinal data, we have proposed to extend the theory of random effects tobit regression model to weighted random effects tobit regression model. The weights are computed on the basis of inverse probability weighted augmented methodology. An extensive simulation study was performed to compare the performance of the proposed model with a number of competitive models. The simulation study shows that the estimates are consistent and that the root mean square errors of the estimates are minimal for the use of augmented inverse probability weights in the random effects tobit model. The proposed method is also applied to the non-ignorable missing and left-censored interleukin-6 biomarker data obtained from the Genetic and Inflammatory Markers of Sepsis study. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: A major challenge in positron emission tomography (PET) amyloid imaging studies of Alzheimer''s disease (AD) is the reliable detection of early amyloid deposition in human brain. Manual region-of-interest (ROI) delineation on structural magnetic resonance (MR) images is generally the reference standard for the extraction of count-rate data from PET images, as compared to automated MR-template(s) methods that utilize spatial normalization and a single set of ROIs. The goal of this work was to assess the inter-rater reliability of manual ROI delineation for PiB PET amyloid retention measures and the impact of CSF dilution correction (CSF) on this reliability for data acquired in elderly control (n=5) and AD (n=5) subjects. The intraclass correlation coefficient (ICC) was used to measure reliability. As a secondary goal, ICC scores were also computed for PiB outcome measures obtained by an automated MR-template ROI method and one manual rater; to assess the level of reliability that could be achieved using different processing methods. Fourteen ROIs were evaluated that included anterior cingulate (ACG), precuneus (PRC) and cerebellum (CER). The PiB outcome measures were the volume of distribution (VT), summed tissue uptake (SUV), and corresponding ratios that were computed using CER as reference (DVR and SUVR). Substantial reliability (ICC≥0.932) was obtained across 3 manual raters for VT and SUV measures when CSF correction was applied across all outcomes and regions and was similar in the absence of CSF correction. The secondary analysis revealed substantial reliability in primary cortical areas between the automated and manual SUV [ICC≥0.979 (ACG/PRC)] and SUVR [ICC≥0.977/0.952 (ACG/PRC)] outcomes. The current study indicates the following rank order among the various reliability results in primary cortical areas and cerebellum (high to low): 1) VT or SUV manual delineation, with or without CSF correction; 2) DVR or SUVR manual delineation, with or without CSF correction; 3) SUV automated delineation, with CSF correction; and 4) SUVR automated delineation, with or without CSF correction. The high inter-rater reliability of PiB outcome measures in primary cortical areas (ACG/PRC) is important as reliable methodology is needed for the detection of low levels of amyloid deposition on a cross-sectional basis and small changes in amyloid deposition on a longitudinal basis. [Copyright &y& Elsevier]

Medical studies frequently collect biological markers in which many subjects have values below the detectable limits of the assay, resulting in heavily censored data. We develop a modification of the Rigobon and Stoker index method for application to a Cox regression model with censored covariates. The index approach is compared with a complete case method and various fill-in methods. Our simulation results demonstrated that the index approach is an improvement over the other methods. We illustrated the usefulness of this approach with an example for the GenIMS study examining the relationship between two inflammatory markers and survival. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This paper addresses the modelling of missing covariate data with the logistic regression model. The aim of this paper is to evaluate the properties of an efficient score for logistic regression in a two-phase design. Simulation studies show that the efficient score is more efficient than two other pseudo-likelihood methods when the correlation between the missing covariate and its surrogate is high or the sampling proportion is small. These methods are illustrated with data from the National Wilms Tumor Study Group. Results from the example confirm the simulation study findings with the exception that the pseudo-likelihood approach produces more reliable estimates than the weighted pseudo-likelihood approach. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Deposition of amyloid plaques is believed to be a central event in the development of Alzheimer''s disease (AD). The present study was undertaken to evaluate statistical methods for the assessment of group differences in retention of an amyloid imaging agent, PIB, throughout the brain and to compare these results to FDG studies of glucose metabolism performed in the same subjects on the same day. PET studies were performed in 10 mild to moderate AD and 11 control subjects. Parametric images of PIB retention (over 90 min post-injection) were generated using the Logan graphical analysis with cerebellar (CER, reference region) data as input. FDG parametric images were created by summing the uptake over 40–60 min post-injection and normalizing that to the CER to give a standardized uptake value ratio. Data were compared using parametric (SPM) and non-parametric (SnPM) statistical methods with familywise error (FWE) and false discovery rate (FDR) corrections. PIB results were consistent with previous regional results as AD subjects showed highly significant retention in frontal, parietal, temporal, and posterior cingulate cortices (FDR-corrected p <1.4e−10). FDG results showed regions of marginally significant decreases in uptake in AD subjects (frontal, parietal, temporal, posterior cingulate cortices: FDR-corrected p <0.1) consistent with previous studies. Relative to FDG, the PIB analyses were of greater statistical significance and larger spatial extent. Additionally, the PIB analyses retained significance after both FWE and FDR corrections. These results indicate that voxel-based methods will be useful for future larger longitudinal studies of amyloid deposition that could improve AD diagnosis and anti-amyloid therapy assessment. [Copyright &y& Elsevier]

A normal copula-based selection model is proposed for continuous longitudinal data with a non-ignorable non-monotone missing-data process. The normal copula is used to combine the distribution of the outcome of interest and that of the missing-data indicators given the covariates. Parameters in the model are estimated by a pseudo-likelihood method. We first use the GEE with a logistic link to estimate the parameters associated with the marginal distribution of the missing-data indicator given the covariates, assuming that covariates are always observed. Then we estimate other parameters by inserting the estimates from the first step into the full likelihood function. A simulation study is conducted to assess the robustness of the assumed model under different missing-data processes. The proposed method is then applied to one example from a community cohort study to demonstrate its capability to reduce bias. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

As part of the National Surgical Adjuvant Breast and Bowel Project, a controlled clinical trial known as the Breast Cancer Prevention Trial (BCPT)was conducted to assess the effectiveness of tamoxifen as a preventive agent for breast cancer. In addition to the incidence of breast cancer, data were collected on several other, possibly adverse, outcomes, such as invasive endometrial cancer, ischemic heart disease, transient ischemic attack, deep vein thrombosis and/or pulmonary embolism. In this article, we present results from an illustrative analysis of the BCPT data, based on a new modeling technique, to assess the e .ectiveness of the drug tamoxifen as a preventive agent for breast cancer. We extended the .exible model of Gray (1994, Spline-based test in survival analysis, Biometrics 50,640-652) to allow inference on multiple time-to-event outcomes in the style of the marginal modeling setup of Wei, Lin, and Weissfeld (1989, Regression analysis of multivariate incomplete failure time data by modeling marginal distributions, Journal of the American Statistical Association 84,1065-1073). This proposed model makes inference ossible for multiple time-to-event data while allowing for greater flexibility in modeling the effects of prognostic factors with nonlinear exposure-response relationships. Results from simulation studies on the small-sample properties of the asymptotic tests will also be presented. [ABSTRACT FROM AUTHOR]

Describes basic concepts of sample size and power estimation for planning nursing intervention trials and interpreting their results. Goal of a clinical trial; Sample size computation for trials with a continuous outcome measure; Sample size computation for trials with a dichotomous outcome measure.

Objective: The natural history of Friedreich ataxia is being investigated in a multi‐center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity‐matched comparison of data from the open‐label MOXIe extension (omaveloxolone) to that from FACOMS. Methods: MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis. Results: Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = −3.6; nominal p value = 0.0001). Interpretation: These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity‐matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations. [ABSTRACT FROM AUTHOR]

Background: Plasma‐derived medicinal products (PDMPs) are essential, life‐saving medicines manufactured from plasma donated by healthy human volunteers. PDMPs are used to treat a range of rare, serious, and chronic conditions, often genetic in origin. Approximately 70% of the Source Plasma (SP) used for PDMP manufacturing comes from United States (US). The hypothesis of the study is that US donation frequency does not impair donor self‐reported functional health and well‐being. Study Design and Methods: A total of 5608 SP donors from 14 US SP centers were enrolled in a cross‐sectional study to assess self‐reported health related quality of life (HRQoL) and well‐being. By sex, donors were assigned to one of four groups, according to their frequency of SP donation in the 12 months before enrollment. The SF‐36v2® Health Survey (SF‐36v2) and a survey assessing the frequency of various health conditions that may be associated with impaired immune function over different time periods were used. Results: There were no statistically significant differences in SF‐36v2 scores between any of the donor frequency groups, compared with new donors after controlling for potential confounding and accounting for multiple comparisons among males and females. Cough, cold, occasional fatigue, and sore throat were the most reported health conditions or symptoms, but there was no clear difference among sex or frequency groups. Discussion: The self‐reported data in this study support the hypothesis that compensated donations at US FDA permitted frequencies and volumes are consistent with maintaining donor health. Compared with the general population, SP donors have comparable or better health than the general population. [ABSTRACT FROM AUTHOR]

Background: The Procalcitonin Antibiotic Consensus Trial (ProACT) found provision of a procalcitonin antibiotic prescribing guideline to hospital-based clinicians did not reduce antibiotic use. Possible reasons include clinician reluctance to follow the guideline, with an observed 64.8% adherence rate. In this study we sought to determine the threshold adherence rate for reduction in antibiotic use, and to explore opportunities to increase adherence. Methods: This study is a retrospective analysis of ProACT data. ProACT randomized 1656 patients presenting to 14 U.S. hospitals with suspected lower respiratory tract infection to usual care or provision of procalcitonin assay results and an antibiotic prescribing guideline to the treating clinicians. We simulated varying adherence to guideline recommendations for low procalcitonin levels and determined which threshold adherence rate could have resulted in rejection of the null hypothesis of no difference between groups at alpha = 0.05. We also performed sensitivity analyses within specific clinical settings and grouped patients initially prescribed antibiotics despite low procalcitonin into low, medium, and high risk of illness severity or bacterial infection. Results: Our primary outcome was number of antibiotic-days by day 30 using an intention-to-treat approach and a null hypothesis of no difference in antibiotic use. We determined that an 84% adherence rate in the hospital setting (emergency department and inpatient) for low procalcitonin could have allowed rejection of the null hypothesis (3.7 vs 4.3 antibiotic-days, p = 0.048). The threshold adherence rate was 76% for continued guideline adherence after discharge. Even 100% adherence in the emergency department alone failed to reduce antibiotic-days. Of the 218 patients prescribed antibiotics in the emergency department despite low procalcitonin, 153 (70.2%) were categorized as low or medium risk. Conclusions: High adherence in the hospital setting to a procalcitonin antibiotic prescribing guideline is necessary to reduce antibiotic use in suspected lower respiratory tract infection. Continued guideline adherence after discharge and withholding of antibiotics in low and medium risk patients with low procalcitonin may offer impactful potential opportunities for antibiotic reduction. Trial registration Procalcitonin Antibiotic Consensus Trial (ProACT), ClinicalTrials.gov Identifier: NCT02130986. First posted May 6, 2014. [ABSTRACT FROM AUTHOR]

Importance: The risk of cardiovascular disease (CVD) after infection is poorly understood. Objective: To determine whether hospitalization for pneumonia is associated with an increased short-term and long-term risk of CVD. Design, Settings, and Participants: We examined 2 community-based cohorts: the Cardiovascular Health Study (CHS, n = 5888; enrollment age, ≥65 years; enrollment period, 1989–1994) and the Atherosclerosis Risk in Communities study (ARIC, n = 15 792; enrollment age, 45-64 years; enrollment period, 1987–1989). Participants were followed up through December 31, 2010. We matched each participant hospitalized with pneumonia to 2 controls. Pneumonia cases and controls were followed for occurrence of CVD over 10 years after matching. We estimated hazard ratios (HRs) for CVD at different time intervals, adjusting for demographics, CVD risk factors, subclinical CVD, comorbidities, and functional status. Exposures: Hospitalization for pneumonia. Main Outcomes and Measures: Incident CVD (myocardial infarction, stroke, and fatal coronary heart disease). Results: Of 591 pneumonia cases in CHS, 206 had CVD events over 10 years after pneumonia hospitalization. Compared with controls, CVD risk among pneumonia cases was highest during the first year after hospitalization and remained significantly higher than among controls through 10 years. In ARIC, o f 680 pneumonia cases, 112 had CVD events over 10 years after hospitalization. After the second year, CVD risk among pneumonia cases was not significantly higher than among controls. Conclusions and Relevance: Hospitalization for pneumonia was associated with increased short-term and long-term risk of CVD, suggesting that pneumonia may be a risk factor for CVD. [ABSTRACT FROM AUTHOR]

Background: Interleukin-1 receptor antagonists can reduce mortality in septic shock patients with hepatobiliary dysfunction and disseminated intravascular coagulation (HBD + DIC), an organ failure pattern with inflammatory features consistent with macrophage activation. Identification of clinical phenotypes in sepsis may allow for improved care. We aim to describe the occurrence of HBD + DIC in a contemporary cohort of patients with sepsis and determine the association of this phenotype with known macrophage activation syndrome (MAS) biomarkers and mortality. We performed a retrospective nested case–control study in adult septic shock patients with concurrent HBD + DIC and an equal number of age-matched controls, with comparative analyses of all-cause mortality and circulating biomarkers between the groups. Multiple logistic regression explored the effect of HBD + DIC on mortality and the discriminatory power of the measured biomarkers for HBD + DIC and mortality. Results: Six percent of septic shock patients (n = 82/1341) had HBD + DIC, which was an independent risk factor for 90-day mortality (OR = 3.1, 95% CI 1.4–7.5, p = 0.008). Relative to sepsis controls, the HBD + DIC cohort had increased levels of 21 of the 26 biomarkers related to macrophage activation (p < 0.05). This panel was predictive of both HBD + DIC (sensitivity = 82%, specificity = 84%) and mortality (sensitivity = 92%, specificity = 90%). Conclusion: The HBD + DIC phenotype identified patients with high mortality and a molecular signature resembling that of MAS. These observations suggest trials of MAS-directed therapies are warranted. [ABSTRACT FROM AUTHOR]

Abstract: An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Aβ) deposition. Use of amyloid PET for this purpose, requires a reproducible method for defining a cutoff that separates individuals with no significant Aβ deposition from those in which Aβ deposition has begun. We previously reported the iterative outlier approach (IO) for the analysis of Pittsburgh Compound-B (PiB) PET data. Developments in amyloid imaging since the initial report of IO have led us to re-examine the generalizability of this method. IO was developed using full-dynamic atrophy-corrected PiB PET data obtained from a group of control subjects with a fairly distinct separation between PiB-positive [PiB(+)] and PiB-negative [PiB(−)] subjects. Methods: We tested the performance of IO using late-summed tissue ratio data with atrophy correction or with an automated template method without atrophy correction and tested the robustness of the method when applied to a cohort of older subjects in which separation between PiB(+) and PiB(−) subjects was not so distinct. Results: The IO method did not perform consistently across analyses and performed particularly poorly when separation was less clear. We found that a sparse k-means (SKM) cluster analysis approach performed significantly better; performing more consistently across methods and subject cohorts. We also compared SKM to a consensus visual read approach and found very good correspondence. Conclusion: The visual read and SKM methods, applied together, may optimize the identification of early Aβ deposition. These methods have the potential to provide a standard approach to the detection of PiB-positivity that is generalizable across centers. [Copyright &y& Elsevier]

The article discusses a study which examined the factors associated with lower levels of confidence among family members to function as surrogates. Study authors found that family members without prior experience as a surrogate and those who had not engaged in advanced discussions with the patient about treatment preferences were at higher risk in relation to the quality of clinician-family communication and the timing of decisions to forego life support.

Biomarkers, increasingly used in biomedical studies for the diagnosis and prognosis of acute and chronic diseases, provide insight into the effectiveness of treatments and potential pathways that can be used to guide future treatment targets. The measurement of these markers is often limited by the sensitivity of the given assay, resulting in data that are censored either at the lower or at the upper limit of detection. For the Genetic and Inflammatory Markers of Sepsis (GenIMS) study, many different biomarkers were measured to examine the effect of different pathways on the development of sepsis. In this study, the left-censoring of several important inflammatory markers has led to the need for statistical methods that can incorporate this censoring into any analysis of the biomarker data. This paper focuses on the development of multiple imputation methods for the inclusion of multiple left-censored biomarkers in a logistic regression analysis. We assume a multivariate normal distribution to account for the correlations between biomarkers and use the Gibbs sampler for the estimation of the distributional parameters and the imputation of the censored markers. We evaluate and compare the proposed methods with some simple imputation methods through simulation. We use a data set of inflammatory and coagulation markers from the GenIMS study for illustration. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article examines whether there is a volume-outcome relationship among patients in intensive care units who receive renal support therapy in two different healthcare systems, France and the U.S. Results show that there is variation in annual renal support therapy volume in both French and U.S. intensive care units, but there was no association found between higher volumes and improved outcomes. Higher renal support therapy volume was associated with shorter length of stay in CUB-Réa.

Background: The pulmonary artery catheter (PAC) remains widely used in acute lung injury (ALI) despite known complications and little evidence of improved short-term mortality. Concurrent with NHLBI ARDS Clinical Trials Network Fluid and Catheters Treatment Trial (FACTT), we conducted a prospectively-defined comparison of healthcare costs and long-term outcomes for care with a PAC vs. central venous catheter (CVC). We explored if use of the PAC in ALI is justified by a beneficial cost-effectiveness profile. Methods: We obtained detailed bills for the initial hospitalization. We interviewed survivors using the Health Utilities Index Mark 2 questionnaire at 2, 6, 9 and 12 m to determine quality of life (QOL) and post-discharge resource use. Outcomes beyond 12 m were estimated from federal databases. Incremental costs and outcomes were generated using MonteCarlo simulation. Results: Of 1001 subjects enrolled in FACTT, 774 (86%) were eligible for long-term follow-up and 655 (85%) consented. Hospital costs were similar for the PAC and CVC groups ($96.8k vs. $89.2k, p = 0.38). Post-discharge to 12 m costs were higher for PAC subjects ($61.1k vs. 45.4k, p = 0.03). One-year mortality and QOL among survivors were similar in PAC and CVC groups (mortality: 35.6% vs. 31.9%, p = 0.33; QOL [scale: 0-1]: 0.61 vs. 0.66, p = 0.49). MonteCarlo simulation showed PAC use had a 75.2% probability of being more expensive and less effective (mean cost increase of $14.4k and mean loss of 0.3 quality-adjusted life years (QALYs)) and a 94.2% probability of being higher than the $100k/QALY willingness-to-pay threshold. Conclusion: PAC use increased costs with no patient benefit and thus appears unjustified for routine use in ALI. Trial Registration: www.clinicaltrials.gov NCT00234767 [ABSTRACT FROM AUTHOR]

Inverse correlations between amyloid-β (Aβ) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [18F]fluoro-2-deoxy-D-glucose (FDG) in Alzheimer's disease (AD) patients, suggest local Aβ-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of Aβ deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloid-positive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that Aβ deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Aβ deposition or increasing the level of Aβ necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Aβ deposition has been present for longer periods of time does Aβ become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices. [ABSTRACT FROM AUTHOR]

Abstract: Spatial normalization is the process of standardizing images of different subjects into the same anatomical space. The goal of this work was to assess standard and unified methods in SPM5 for the normalization of structural magnetic resonance imaging (MRI) data acquired in mid-life/elderly subjects with diabetes. In this work, we examined the impact of different parameters (i.e. nonlinear frequency cutoff, nonlinear regularization and nonlinear iterations) on the normalization, in terms of the residual variability. Total entropy was used to assess the residual anatomical variability after spatial normalization in a sample of 14 healthy mid-life/elderly control subjects and 24 mid-life/elderly subjects with type 2 diabetes. Spatial normalization was performed using default settings and by varying a single parameter or a combination of parameters. Descriptive statistics and nonparametric tests were used to examine differences in total entropy. Statistical parametric mapping analyses were performed to evaluate the influence of parameter settings on the spatial normalization. Total entropy results and SPM analyses suggest that the best parameters for the spatial normalization of mid-life/elderly image data to the MNI template, when applying the standard approach, correspond to the default cutoff (25 mm), heavy regularization, and the default number of nonlinear iterations (16). On the other hand, when applying the unified approach, the default parameters were the best for spatial normalization of mid-life/elderly image data to the MNI priors. These findings are relevant for studies of structural brain alterations that may occur in normal aging, chronic medical conditions, neuropsychiatric disorders, and neurodegenerative disorders. [Copyright &y& Elsevier]

Objective. To determine if racial and ethnic variations exist in intensive care (ICU) use during terminal hospitalizations, and, if variations do exist, to determine whether they can be explained by systematic differences in hospital utilization by race/ethnicity. Data Source. 1999 hospital discharge data from all nonfederal hospitals in Florida, Massachusetts, New Jersey, New York, and Virginia. Design. We identified all terminal admissions ( N=192,705) among adults. We calculated crude rates of ICU use among non-Hispanic whites, blacks, Hispanics, and those with “other” race/ethnicity. We performed multivariable logistic regression on ICU use, with and without adjustment for clustering of patients within hospitals, to calculate adjusted differences in ICU use and by race/ethnicity. We explored both a random-effects (RE) and fixed-effect (FE) specification to adjust for hospital-level clustering. Data Collection. The data were collected by each state. Principal Findings. ICU use during the terminal hospitalization was highest among nonwhites, varying from 64.4 percent among Hispanics to 57.5 percent among whites. Compared to white women, the risk-adjusted odds of ICU use was higher for white men and for nonwhites of both sexes (odds ratios [ORs] and 95 percent confidence intervals: white men =1.16 (1.14–1.19), black men =1.35 (1.17–1.56), Hispanic men =1.52 (1.27–1.82), black women =1.31 (1.25–1.37), Hispanic women =1.53 (1.43–1.63)). Additional adjustment for within-hospital clustering of patients using the RE model did not change the estimate for white men, but markedly attenuated observed differences for blacks (OR for men =1.12 (0.96–1.31), women =1.10 (1.03–1.17)) and Hispanics (OR for men =1.19 (1.00–1.42), women =1.18 (1.09–1.27)). Results from the FE model were similar to the RE model (OR for black men =1.10 (0.95–1.28), black women =1.07 (1.02–1.13) Hispanic men =1.17 (0.96–1.42), and Hispanic women =1.14 (1.06–1.24)) Conclusions. The majority of observed differences in terminal ICU use among blacks and Hispanics were attributable to their use of hospitals with higher ICU use rather than to racial differences in ICU use within the same hospital. [ABSTRACT FROM AUTHOR]

He, Jing, Amit Varma, Lisa A. Weissfeld, and Sherin U. Devaskar. Postnatal glucocorticoid exposure alters the adult phenotype. Am J Physiol Regul lntegr Comp Physiol 287: R198-R208, 2004. First published March 4, 2004; 10.1152/ajpregu.00349.2003.--We examined the effect of six doses of dexamethasone (Dex) administered daily (2–7 days of age) to postnatal rats on body weight gain, food and water intake, peripheral hormonal/metabolic milieu, and hypothalamic neuropeptides that regulate food intake. We observed a Dex-induced acute (3 days of age) suppression of endogenous corticosterone and an increase in circulating leptin concentrations that were associated with a decrease in body weight in males and females. Followup during the suckling, postsuckling, and adult stages (7–120 days of age) revealed hypoleptinemia in males and females, and hypoinsulinemia, a relative increase in the glucose-to-insulin ratio, and a larger increase in skeletal muscle glucose transporter (GLUT 4) concentrations predominantly in the males, reflective of a catabolic state associated with a persistent decrease in body weight gain. The increase in the glucose-to-insulin ratio and hyperglycemia was associated with an increase in water intake. In addition, the changes in the hormonal/metabolic milieu were associated with an increase in hypothalamic neuropeptide Y content in males and females during the suckling phase, which persisted only in the 120-day-old female with a transient postnatal decline in α-melanocyte-stimulating hormone and corticotropin-releasing factor. This increase in neuropeptide Y (NPY) during the suckling phase in males and females was associated with a subsequent increase in adult food intake that outweighed the demands of body weight gain. In contrast to the adult hypothalamic findings, cerebral ventricular dilatation was more prominent in adult males. We conclude that postnatal Dex treatment causes permanent sex-specific changes in the adult phenotype, setting the stage for future development of diabetes (increased glucose:insulin ratio), obesity (increased NPY and food intake), and neurological impairment (loss of cerebral volume). development; food intake; neuropeptide Y; glucose transporters [ABSTRACT FROM AUTHOR]

We investigated the effect of repetitive postnatal (2-7 days) intracerebroventricular administration of neuropeptide Y (NPY) on food intake and body weight gain in the 3- to 120-day-old Sprague-Dawley rats. NPY caused a 32% transient increase in body weight gain with elevated circulating insulin concentrations within 24 h. This early intervention led to the persistence of hyperinsulinemia and relative hyperleptinemia with euglycemia in the 120-day-old female alone. This perturbation was associated with 50% suppression in adult female hypothalamic NPY concentrations and a 50-85% decline in NPY immunoreactivity in the paraventricular and arcuate nuclei. This change was paralleled by a -20% decline in food intake and body weight gain at 60 and 120 days. However, when exogenous NPY was stereotaxically reinjected into the paraventricular nucleus of the ∼120-day-old adult females who were pretreated with NPY postnatally, an increase in food intake and body weight gain was noted, attesting to no disruption in the NPY end-organ responsivity. We conclude that postnatal intracerebroventricular NPY has long-lasting effects that predetermine the resultant adult phenotype in a sex-specific manner. [ABSTRACT FROM AUTHOR]

Objectives: Optimistic expectations about prognosis by surrogate decision-makers in ICUs are common, but there are few data about the causes and clinical consequences. Our objective was to determine the causes of optimistic expectations about prognosis among surrogates and whether it is associated with more use of life support at the end of life.Design: Prospective, multicenter cohort study from 2009 to 2012.Setting: Twelve ICUs from multiple regions of the United States.Subjects: The surrogates and physicians of 275 incapacitated ICU patients at high risk of death.Interventions: None.Measurements and Main Results: Surrogates and physicians completed a validated instrument assessing their prognostic expectations for hospital survival. We determined the proportion of surrogates with optimistic expectations, defined as a prognostic estimate that was at least 20% more optimistic than the physician's, then determined how frequently this arose from surrogates miscomprehending the physicians' prognosis versus holding more hopeful beliefs compared with the physician. We used multivariable regression to examine whether optimistic expectations were associated with length of stay, stratified by survival status, and time to withdrawal of life support among nonsurvivors. Overall, 45% of surrogates (95% CI, 38-51%) held optimistic expectations about prognosis, which arose from a combination of misunderstanding the physician's prognostic expectations and from holding more hopeful beliefs compared with the physician. Optimistic expectations by surrogates were associated with significantly longer duration of ICU treatment among nonsurvivors before death (β coefficient = 0.44; 95% CI, 0.05-0.83; p = 0.027), corresponding to a 56% longer ICU stay. This difference was associated with a significantly longer time to withdrawal of life support among dying patients whose surrogates had optimistic prognostic expectations compared with those who did not (β coefficient = 0.61; 95% CI, 0.16-1.07; p = 0.009).Conclusions: The prevalent optimism about prognosis among surrogates in ICUs arises both from surrogates' miscomprehension of physicians' prognostications and from surrogates holding more hopeful beliefs. This optimism is associated with longer duration of life support at the end of life. [ABSTRACT FROM AUTHOR]

Background: Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD.Methods: In this open-label, dose-escalation phase 1-2a study, we gave monthly intrathecal HPβCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPβCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range.Findings: Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPβCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPβCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPβCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423).Interpretation: Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPβCD.Funding: National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson. [ABSTRACT FROM AUTHOR]

Background: Overuse of antibiotics is a major public health problem, contributing to growing antibiotic resistance. Procalcitonin has been reported to be commonly elevated in bacterial, but not viral infection. Multiple European trials found procalcitonin-guided care reduced antibiotic use in lower respiratory tract infection, with no apparent harm. However, applicability to US practice is limited due to trial design features impractical in the US, between-country differences, and residual safety concerns.Methods: The Procalcitonin Antibiotic Consensus Trial (ProACT) is a multicenter randomized trial to determine the impact of a procalcitonin antibiotic prescribing guideline, implemented with basic reproducible strategies, in US patients with lower respiratory tract infection.Discussion: We describe the trial methods using the Consolidated Standards of Reporting Trials (CONSORT) framework, and the rationale for key design decisions, including choice of eligibility criteria, choice of control arm, and approach to guideline implementation.Trial Registration: ClinicalTrials.gov NCT02130986 . Registered May 1, 2014. [ABSTRACT FROM AUTHOR]

Importance: Misperceptions about prognosis by individuals making decisions for incapacitated critically ill patients (surrogates) are common and often attributed to poor comprehension of medical information.Objective: To determine the prevalence of and factors related to physician-surrogate discordance about prognosis in intensive care units (ICUs).Design, Setting, and Participants: Mixed-methods study comprising quantitative surveys and qualitative interviews conducted in 4 ICUs at a major US medical center involving surrogate decision makers and physicians caring for patients at high risk of death from January 4, 2005, to July 10, 2009.Main Outcomes and Measures: Discordance about prognosis, defined as a difference between a physician's and a surrogate's prognostic estimates of at least 20%; misunderstandings by surrogates (defined as any difference between a physician's prognostic estimate and a surrogate's best guess of that estimate); differences in belief (any difference between a surrogate's actual estimate and their best guess of the physician's estimate).Results: Two hundred twenty-nine surrogate decision makers (median age, 47 [interquartile range {IQR}, 35-56] years; 68% women) and 99 physicians were involved in the care of 174 critically ill patients (median age, 60 [IQR, 47-74] years; 44% women). Physician-surrogate discordance about prognosis occurred in 122 of 229 instances (53%; 95% CI, 46.8%-59.7%). In 65 instances (28%), discordance was related to both misunderstandings by surrogates and differences in belief about the patient's prognosis; 38 (17%) were related to misunderstandings by surrogates only; 7 (3%) were related to differences in belief only; and data were missing for 12. Seventy-five patients (43%) died. Surrogates' prognostic estimates were much more accurate than chance alone, but physicians' prognostic estimates were statistically significantly more accurate than surrogates' (C statistic, 0.83 vs 0.74; absolute difference, 0.094; 95% CI, 0.024-0.163; P = .008). Among 71 surrogates interviewed who had beliefs about the prognosis that were more optimistic than that of the physician, the most common reasons for optimism were a need to maintain hope to benefit the patient (n = 34), a belief that the patient had unique strengths unknown to the physician (n = 24), and religious belief (n = 19).Conclusions and Relevance: Among critically ill patients, discordant expectations about prognosis were common between patients' physicians and surrogate decision makers and were related to misunderstandings by surrogates about physicians' assessments of patients' prognoses and differences in beliefs about patients' prognoses. [ABSTRACT FROM AUTHOR]

Background: Long-term acute care hospitals (LTACs) provide specialized treatment for patients with chronic critical illness. Increasingly LTACs are co-located within traditional short-stay hospitals rather than operated as free-standing facilities, which may affect LTAC utilization patterns and outcomes. Methods: We compared free-standing and co-located LTACs using 2005 data from the United States Centers for Medicare & Medicaid Services. We used bivariate analyses to examine patient characteristics and timing of LTAC transfer, and used propensity matching and multivariable regression to examine mortality, readmissions, and costs after transfer. Results: Of 379 LTACs in our sample, 192 (50.7%) were free-standing and 187 (49.3%) were co-located in a short-stay hospital. Co-located LTACs were smaller (median bed size: 34 vs. 66, p <0.001) and more likely to be for-profit (72.2% v. 68.8%, p = 0.001) than freestanding LTACs. Co-located LTACs admitted patients later in their hospital course (average time prior to transfer: 15.5 days vs. 14.0 days) and were more likely to admit patients for ventilator weaning (15.9% vs. 12.4%). In the multivariate propensity-matched analysis, patients in co-located LTACs experienced higher 180-day mortality (adjusted relative risk: 1.05, 95% CI: 1.00–1.11, p = 0.04) but lower readmission rates (adjusted relative risk: 0.86, 95% CI: 0.75–0.98, p = 0.02). Costs were similar between the two hospital types (mean difference in costs within 180 days of transfer: -$3,580, 95% CI: -$8,720 –$1,550, p = 0.17). Conclusions: Compared to patients in free-standing LTACs, patients in co-located LTACs experience slightly higher mortality but lower readmission rates, with no change in overall resource use as measured by 180 day costs. [ABSTRACT FROM AUTHOR]

Background: The biomarker model of Alzheimer's disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimer's disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed.Methods: For this prospective cohort study, carriers of autosomal dominant Alzheimer's disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2, or APP were assessed at the University of Pittsburgh Alzheimer's Disease Research Center every 1-2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid β (Aβ) load using (11)C-Pittsburgh Compound-B PET, posterior cortical metabolism with (18)F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimer's Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65-89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls).Findings: 16 people with mutations in PSEN1, PSEN2, or APP, aged 28-56 years, completed between two and eight assessments (a total of 83 assessments) over 2-11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6-11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline.Interpretation: Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimer's disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimer's disease-active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline-indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimer's disease.Funding: National Institutes of Health and Howard Hughes Medical Institute. [ABSTRACT FROM AUTHOR]

Summary Background The biomarker model of Alzheimer's disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimer's disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed. Methods For this prospective cohort study, carriers of autosomal dominant Alzheimer's disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2 , or APP were assessed at the University of Pittsburgh Alzheimer's Disease Research Center every 1–2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid β (Aβ) load using 11 C-Pittsburgh Compound-B PET, posterior cortical metabolism with 18 F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimer's Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65–89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls). Findings 16 people with mutations in PSEN1, PSEN2 , or APP , aged 28–56 years, completed between two and eight assessments (a total of 83 assessments) over 2–11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6–11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline. Interpretation Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimer's disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimer's disease—active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline—indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimer's disease. Funding National Institutes of Health and Howard Hughes Medical Institute. [ABSTRACT FROM AUTHOR]

Background: The bulk of randomized trial evidence for the expanding use of High Flux (HF) hemodialysis worldwide comes from two randomized controlled trials, one of which (HEMODIALYSIS, HEMO) allowed, while the other (Membrane Outcomes Permeability, MPO) excluded, the reuse of membranes. It is not known whether dialyzer reuse has a differential impact on outcomes with HF vs low flyx (LF) dialyzers. Methods: Proportional Hazards Models and Joint Models for longitudinal measures and survival outcomes were used in HEMO to analyze the relationship between β2-microglobulin (β2M) concentration, flux, and reuse. Meta-analysis and regression techniques were used to synthesize the evidence for HF dialysis from HEMO and MPO. Findings: In HEMO, minimally reused (< 6 times) HF dialyzers were associated with a hazard ratio (HR) of 0.67 (95% confidence interval, 95%CI: 0.48–0.92, p = 0.015), 0.64 (95%CI: 0.44 – 0.95, p = 0.03), 0.61 (95%CI: 0.41 – 0.90, p = 0.012), 0.53 (95%CI: 0.28 – 1.02, p = 0.057) relative to minimally reused LF ones for all cause, cardiovascular, cardiac and infectious mortality respectively. These relationships reversed for extensively reused membranes (p for interaction between reuse and flux < 0.001, p = 0.005) for death from all cause and cardiovascular causes, while similar trends were noted for cardiac and infectious mortality (p of interaction between reuse and flux of 0.10 and 0.08 respectively). Reduction of β2M explained only 1/3 of the effect of minimally reused HF dialyzers on all cause mortality, while non-β2M related factors explained the apparent attenuation of the benefit with more extensively reused dialyzers. Meta-regression of HEMO and MPO estimated an adjusted HR of 0.63 (95% CI: 0.51–0.78) for non-reused HF dialyzers compared with non-reused LF membranes. Conclusions: This secondary analysis and synthesis of two large hemodialysis trials supports the widespread use of HF dialyzers in clinical hemodialysis over the last decade. A mechanistic understanding of the effects of HF dialysis and the reuse process on dialyzers may suggest novel biomarkers for uremic toxicity and may accelerate membrane technology innovations that will improve patient outcomes. [ABSTRACT FROM AUTHOR]

Objectives Bipolar disorder ( BD) is associated with cognitive dysfunction and structural brain abnormalities. In human and non-human studies, lithium has been related to neuroprotective and neurotrophic effects. We explored whether lithium treatment is related to better brain integrity and cognitive function in older adults with BD. Methods We examined cognitive and neuroimaging data in 58 individuals with BD [mean (standard deviation) age = 64.5 (9.8) years] and 21 mentally healthy comparators (controls) of similar age and education. Subjects received comprehensive neurocognitive assessment and structural brain imaging, examining total gray matter volume, overall white matter integrity (fractional anisotropy), and total white matter hyperintensity burden. Results In comparison to controls, subjects with BD had worse overall cognitive performance, lower total gray matter volume, and lower white matter integrity. Among subjects with BD, longer duration of lithium treatment was related to higher white matter integrity after controlling for age and vascular disease burden, but not with better cognitive performance. Conclusions Lithium treatment appears to be related to better brain integrity in older individuals with BD, in particular, in those who take lithium long-term. While intriguing, these findings need to be confirmed in a larger sample. [ABSTRACT FROM AUTHOR]

For policy and medical issues, it is important to know if the proportion of an event changes after an intervention is administered. When the later proportion can only be calculated in a portion of the sample used to compute the previous proportion, the two proportions are nested. The motivating example for this work comes from the need to test whether admission rates in emergency departments are different between the first and a return visit. Here, subjects who contribute to the admission rate at the return visit must be included in the first rate and also return, but not vice versa. This conditionality means that existing methods, including the basic test of equality of two proportions, longitudinal data analysis methods, and recurrent event approaches are not directly applicable. Currently, researchers can only explore this question by the use of descriptive statistics. We propose a likelihood ratio test to compare two nested proportions by using the product of conditional probabilities. This test accommodates the conditionality, subject dependencies, and cluster effects and can be implemented in SAS PROC NLMIXED allowing for the proposed method to be readily used in an applied setting. Simulation studies showed that our approach provides unbiased estimates and reasonable power. Moreover, it generally outperforms the two-sample proportion z-test, in the presence of heterogeneity, and the Cochran-Mantel-Haenszel test. An example based on readmission rates through an emergency department is used to illustrate the proposed method. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

See Toga and Thompson (doi:10.1093/brain/awu276) for a scientific commentary on this article.Hyun Kook Lim et al. investigate the relationship between amyloid burden and intrinsic functional connectivity in cognitively normal older adults. Individuals with amyloid deposition show aberrant functional connectivity in the default mode and central executive networks compared to those without detectable amyloid. Changes may reflect early deleterious effects of amyloid deposition.Although previous studies demonstrated decreased functional connectivity in the default mode network in the cognitively normal older adults with amyloid burden, effects of amyloid burden in the other large-scale intrinsic connectivity networks are not yet clear. The aim of this study was to investigate the distinctive association pattern of amyloid-β deposition on the three large-scale intrinsic connectivity networks (the default mode network, salience network and central executive network) in older adults with normal cognition. Fifty-six older adults with normal cognition underwent functional magnetic resonance imaging and were dichotomized using 11C-labelled Pittsburgh compound B positron emission tomography imaging into subjects with (PiB+; n = 27) and without (PiB−; n = 29) detectable amyloid burden. We found that the functional connectivities of (i) the default mode network were greater; (ii) the salience network were not different; and (iii) the central executive network were lower in the Pittsburgh compound B positive group, compared with the Pittsburgh compound B negative group. Anterior cingulate cortex Pittsburgh compound B retention was negatively correlated with the functional connectivities of the posterior default mode network, and positively correlated with fronto-parietal functional connectivity (within the central executive network) in the Pittsburgh compound B positive group. The anti-correlation strength between the default mode network and the central executive network was negatively correlated with the anterior cingulate cortex Pittsburgh compound B levels. Additionally, significant group × episodic memory interactions with functional connectivities in the posterior default mode network, and the frontal default mode network were observed. Our results of aberrant default mode network functional connectivity and distinctive correlation patterns between the Pittsburgh compound B retention in the anterior cingulate cortex and functional connectivities in the default mode network and central executive network in the Pittsburgh compound B positive group might reflect a detrimental effect of amyloid retention on functional changes in the course of Alzheimer’s disease progression. [ABSTRACT FROM AUTHOR]

Objectives: Severe infections, often requiring ICU admission, have been associated with persistent cognitive dysfunction. Less severe infections are more common and whether they are associated with an increased risk of dementia is unclear. We determined the association of pneumonia hospitalization with risk of dementia in well-functioning older adults. Design: Secondary analysis of a randomized multicenter trial to determine the effect of Gingko biloba on incident dementia. Setting: Five academic medical centers in the United States. Subjects: Healthy community volunteers (n = 3,069) with a median follow-up of 6.1 years. Interventions: None. Measurement and Main Results: We identified pneumonia hospitalizations using International Classification of Diseases, 9th Edition-Coding Manual codes and validated them in a subset. Less than 3% of pneumonia cases necessitated ICU admission, mechanical ventilation, or vasopressor support. Dementia was adjudicated based on neuropsychological evaluation, neurological examination, and MRI. Two hundred twenty-one participants (7.2%) incurred at least one hospitalization with pneumonia (mean time to pneumonia = 3.5 yr). Of these, dementia was developed in 38 (17%) after pneumonia, with half of these cases occurring 2 years after the pneumonia hospitalization. Hospitalization with pneumonia was associated with increased risk of time to dementia diagnosis (unadjusted hazard ratio = 2.3; CI, 1.6-3.2; p < 0.0001). The association remained significant when adjusted for age, sex, race, study site, education, and baseline mini-mental status examination (hazard ratio = 1.9; CI, 1.4-2.8; p < 0.0001). Results were unchanged when additionally adjusted for smoking, hypertension, diabetes, heart disease, and preinfection functional status. Results were similar using propensity analysis where participants with pneumonia were matched to those without pneumonia based on age, probability of developing pneumonia, and similar trajectories of cognitive and physical function prior to pneumonia (adjusted prevalence rates, 91.7 vs 65 cases per 1,000 person-years; adjusted prevalence rate ratio = 1.6; CI, 1.06-2.7; p = 0.03). Sensitivity analyses showed that the higher risk also occurred among those hospitalized with other infections. Conclusion: Hospitalization with pneumonia is associated with increased risk of dementia. [ABSTRACT FROM AUTHOR]

Purpose: To describe and compare the design of three independent but collaborating multicenter trials of early goal-directed resuscitation for severe sepsis and septic shock.Methods: We reviewed the three current trials, one each in the USA (ProCESS: protocolized care for early septic shock), Australasia (ARISE: Australasian resuscitation in sepsis evaluation), and the UK (ProMISe: protocolised management in sepsis). We used the 2010 CONSORT (consolidated standards of reporting trials) statement and the 2008 CONSORT extension for trials assessing non-pharmacologic treatments to describe and compare the underlying rationale, commonalities, and differences.Results: All three trials conform to CONSORT guidelines, address the same fundamental questions, and share key design elements. Each trial is a patient-level, equal-randomized, parallel-group superiority trial that seeks to enroll emergency department patients with inclusion criteria that are consistent with the original early goal-directed therapy (EGDT) trial (suspected or confirmed infection, two or more systemic inflammatory response syndrome criteria, and refractory hypotension or elevated lactate), is powered to detect a 6–8 % absolute mortality reduction (hospital or 90-day), and uses trained teams to deliver EGDT. Design differences appear to primarily be driven by between-country variation in health care context. The main difference between the trials is the inclusion of a third, alternative resuscitation strategy arm in ProCESS.Conclusions: Harmonization of study design and methods between severe sepsis trials is feasible and may facilitate pooling of data on completion of the trials. [ABSTRACT FROM AUTHOR]

Abstract: Substantial individual differences exist in the magnitude of the cognitive decline associated with normal aging. Potential contributors to this intersubject variability include white matter hyperintensities (WMH) and preclinical Alzheimer′s disease, evident as increased brain amyloid. This study examined whether older individuals with minimal evidence of WMH and/or brain amyloid-beta (seen on positron emission tomography with the Pittsburgh compound B radiotracer—PiB) still showed significant cognitive decrements compared to the young. Older individuals, conservatively screened for normal range performance on an extensive neuropsychological battery, underwent structural magnetic resonance imaging (MRI) and PiB scans and performed tests of information processing speed, working memory and inhibitory function. The elderly were divided into PiB(+) and PiB(−) groups based on radiotracer retention. There were no significant differences in cognitive performance between PiB(+) and PiB(−) elderly. However, both PiB groups performed significantly worse than did the young on cognitive testing. WMH burden in the same individuals was quantified by consensus ratings using a 10 point scale with a median split defining two groups, WMH(+) and WMH(−). There were no differences in cognitive performance between WMH(+) and WMH(−) individuals, but both WMH groups performed significantly worse than did the young. Older participants who were both PiB(−) and WMH(−) also performed significantly worse than did the young in all three cognitive domains. The present results suggest that normal-elderly individuals whose brain scans show minimal evidence of amyloid deposition or WMH, still demonstrate a major decrement in comparison to younger persons on measures of processing resources and inhibitory efficiency. [Copyright &y& Elsevier]

Background: Preventing pneumonia requires better understanding of incidence, mortality, and long-term clinical and biologic risk factors, particularly in younger individuals.Methods: This was a cohort study in three population-based cohorts of community-dwelling individuals. A derivation cohort (n = 16,260) was used to determine incidence and survival and develop a risk prediction model. The prediction model was validated in two cohorts (n = 8,495). The primary outcome was 10-year risk of pneumonia hospitalization.Results: The crude and age-adjusted incidences of pneumonia were 6.71 and 9.43 cases/1,000 person-years (10-year risk was 6.15%). The 30-day and 1-year mortality were 16.5% and 31.5%. Although age was the most important risk factor (range of crude incidence rates, 1.69-39.13 cases/1,000 person-years for each 5-year increment from 45-85 years), 38% of pneumonia cases occurred in adults < 65 years of age. The 30-day and 1-year mortality were 12.5% and 25.7% in those < 65 years of age. Although most comorbidities were associated with higher risk of pneumonia, reduced lung function was the most important risk factor (relative risk = 6.61 for severe reduction based on FEV1 by spirometry). A clinical risk prediction model based on age, smoking, and lung function predicted 10-year risk (area under curve [AUC] = 0.77 and Hosmer-Lemeshow [HL] C statistic = 0.12). Model discrimination and calibration were similar in the internal validation cohort (AUC = 0.77; HL C statistic, 0.65) but lower in the external validation cohort (AUC = 0.62; HL C statistic, 0.45). The model also calibrated well in blacks and younger adults. C-reactive protein and IL-6 were associated with higher pneumonia risk but did not improve model performance.Conclusions: Pneumonia hospitalization is common and associated with high mortality, even in younger healthy adults. Long-term risk of pneumonia can be predicted in community-dwelling adults with a simple clinical risk prediction model. [ABSTRACT FROM AUTHOR]

The article presents an analysis of three cohort studies on the incidence, mortality, and long-term clinical and biologic risk factors of pneumonia in community-dwelling Americans. The results of the analysis show that hospitalization for pneumonia is common and is linked to high mortality even for younger healthy adult patients. The authors conclude that a simple clinical risk prediction model can be used to predict long-term risk of pneumonia in community-dwelling adults.

Purpose: To determine the global metabolomic profile as measured in circulating plasma from surviving and non-surviving patients with community-acquired pneumonia (CAP) and sepsis. Methods: Random, outcome-stratified case-control sample from a prospective study of 1,895 patients hospitalized with CAP and sepsis. Cases ( n = 15) were adults who died before 90 days, and controls ( n = 15) were adults who survived, matched on demographics, infection type, and procalcitonin. We determined the global metabolomic profile in the first emergency department blood sample using non-targeted mass-spectrometry. We derived metabolite-based prognostic models for 90-day mortality. We determined if metabolites stimulated cytokine production by differentiated Thp1 monocytes in vitro, and validated metabolite profiles in mouse liver and kidney homogenates at 8 h in cecal ligation and puncture (CLP) sepsis. Results: We identified 423 small molecules, of which the relative levels of 70 (17 %) were different between survivors and non-survivors ( p ≤ 0.05). Broad differences were present in pathways of oxidative stress, bile acid metabolism, and stress response. Metabolite-based prognostic models for 90-day survival performed modestly (AUC = 0.67, 95 % CI 0.48, 0.81). Five nucleic acid metabolites were greater in non-survivors ( p ≤ 0.05). Of these, pseudouridine increased monocyte expression of TNFα and IL1β versus control ( p < 0.05). Pseudouridine was also increased in liver and kidney homogenates from CLP mice versus sham ( p < 0.05 for both). Conclusions: Although replication is required, we show the global metabolomic profile in plasma broadly differs between survivors and non-survivors of CAP and sepsis. Metabolite-based prognostic models had modest performance, though metabolites of oxidative stress may act as putative damage-associated molecular patterns. [ABSTRACT FROM AUTHOR]

Objective: This study examined amyloid-β (Aβ) deposition in 190 nondemented subjects aged ≥82 years to determine the proportion of Aβ-positive scans and associations with cognition, apolipoprotein E (APOE) status, brain volume, and Ginkgo biloba (Gb) treatment.Methods: Subjects who agreed to participate had a brain magnetic resonance imaging and positron emission tomography scan with (11) C-labeled Pittsburgh compound B (PiB) following completion of a Gb treatment clinical trial. The youngest subject in this imaging study was 82 years, and the mean age of the subjects was 85.5 years at the time of the scans; 152 (80%) were cognitively normal, and 38 (20%) were diagnosed with mild cognitive impairment (MCI) at the time of the PiB study.Results: A high proportion of the cognitively normal subjects (51%) and MCI subjects (68%) were PiB-positive. The APOE*4 allele was more prevalent in PiB-positive than in PiB-negative subjects (30% vs 6%). Measures of memory, language, and attentional functions were worse in PiB-positive than in PiB-negative subjects, when both normal and MCI cases were analyzed together; however, no significant associations were observed within either normal or MCI subject groups alone. There was no relationship between Gb treatment and Aβ deposition as determined by PiB.Interpretation: The data revealed a 55% prevalence of PiB positivity in nondemented subjects age >80 years and 85% PiB positivity in the APOE*4 nondemented elderly subjects. The findings also showed that long-term exposure to Gb did not affect the prevalence of cerebral Aβ deposition. [ABSTRACT FROM AUTHOR]

Objective This study examined amyloid-β (Aβ) deposition in 190 nondemented subjects aged ≥82 years to determine the proportion of Aβ-positive scans and associations with cognition, apolipoprotein E (APOE) status, brain volume, and Ginkgo biloba (Gb) treatment. Methods Subjects who agreed to participate had a brain magnetic resonance imaging and positron emission tomography scan with 11C-labeled Pittsburgh compound B (PiB) following completion of a Gb treatment clinical trial. The youngest subject in this imaging study was 82 years, and the mean age of the subjects was 85.5 years at the time of the scans; 152 (80%) were cognitively normal, and 38 (20%) were diagnosed with mild cognitive impairment (MCI) at the time of the PiB study. Results A high proportion of the cognitively normal subjects (51%) and MCI subjects (68%) were PiB-positive. The APOE*4 allele was more prevalent in PiB-positive than in PiB-negative subjects (30% vs 6%). Measures of memory, language, and attentional functions were worse in PiB-positive than in PiB-negative subjects, when both normal and MCI cases were analyzed together; however, no significant associations were observed within either normal or MCI subject groups alone. There was no relationship between Gb treatment and Aβ deposition as determined by PiB. Interpretation The data revealed a 55% prevalence of PiB positivity in nondemented subjects age >80 years and 85% PiB positivity in the APOE*4 nondemented elderly subjects. The findings also showed that long-term exposure to Gb did not affect the prevalence of cerebral Aβ deposition. ANN NEUROL 2013;73:751-761 [ABSTRACT FROM AUTHOR]