Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data.

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.

Effects of donation frequency on U.S. source plasma donor health.

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).

A Multicenter Study of the Causes and Consequences of Optimistic Expectations About Prognosis by Surrogate Decision-Makers in ICUs.

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.

A Randomized Trial of a Family-Support Intervention in Intensive Care Units.

Background: Surrogate decision makers for incapacitated, critically ill patients often struggle with decisions related to goals of care. Such decisions cause psychological distress in surrogates and may lead to treatment that does not align with patients' preferences.

Methods: We conducted a stepped-wedge, cluster-randomized trial involving patients with a high risk of death and their surrogates in five intensive care units (ICUs) to compare a multicomponent family-support intervention delivered by the interprofessional ICU team with usual care.

Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection.

Background: The effect of procalcitonin-guided use of antibiotics on treatment for suspected lower respiratory tract infection is unclear.

Methods: In 14 U.S.

Design and rationale of the Procalcitonin Antibiotic Consensus Trial (ProACT), a multicenter randomized trial of procalcitonin antibiotic guidance in lower respiratory tract infection.

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.

Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.

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.

Amyloid-Beta Deposition is Associated with Increased Medial Temporal Lobe Activation during Memory Encoding in the Cognitively Normal Elderly.

Background: Much is unknown about changes that occur in the brain in the years preceding the cognitive and functional impairment associated with Alzheimer disease (AD). This period before mild cognitive impairment is present has been referred to as preclinical AD, and is thought to begin with amyloid-beta deposition and then progress to neurodegeneration and functional brain circuit alterations. Prior studies have shown that there is increased medial temporal lobe activation on functional magnetic resonance imaging (fMRI) early in the course of mild cognitive impairment.

Pseudo maximum likelihood approach for the analysis of multivariate left-censored longitudinal data.

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.

Prevalence of and Factors Related to Discordance About Prognosis Between Physicians and Surrogate Decision Makers of Critically Ill Patients.

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.

A Comparison of Free-Standing versus Co-Located Long-Term Acute Care Hospitals.

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.

Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort study.

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.

Dialyzer Reuse and Outcomes of High Flux Dialysis.

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.

Subjective Cognitive Complaints, Personality and Brain Amyloid-beta in Cognitively Normal Older Adults.

Objective: Subjective cognitive complaints in otherwise normal aging are common but may be associated with preclinical Alzheimer disease in some individuals. Little is known about who is mostly likely to show associations between cognitive complaints and preclinical Alzheimer pathology. We sought to demonstrate associations between subjective complaints and brain amyloid-β in cognitively normal older adults; and to explore personality factors as potential moderators of this association.

Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease.

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).

A likelihood ratio test for nested proportions.

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.

Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old.

Objective: To examine the association between brain structural changes and β-amyloid deposition, and incident dementia in 183 elderly subjects without dementia (mean age 85.5 years) 2 years later.

Methods: Subjects had a brain structural MRI scan and a PET scan with (11)C-labeled Pittsburgh compound B (PiB) in 2009, and were evaluated clinically in 2011.

Regional amyloid burden and intrinsic connectivity networks in cognitively normal elderly subjects.

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.

Longer lithium exposure is associated with better white matter integrity in older adults with bipolar disorder.

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.

A randomized trial of protocol-based care for early septic shock.

Background: In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.

Methods: In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care.

A variant of sparse partial least squares for variable selection and data exploration.

When data are sparse and/or predictors multicollinear, current implementation of sparse partial least squares (SPLS) does not give estimates for non-selected predictors nor provide a measure of inference. In response, an approach termed "all-possible" SPLS is proposed, which fits a SPLS model for all tuning parameter values across a set grid. Noted is the percentage of time a given predictor is chosen, as well as the average non-zero parameter estimate.

Risk of cardiovascular events in survivors of severe sepsis.

Rationale: The risk of cardiovascular events after severe sepsis is not known, and these events may explain increased long-term mortality in survivors of severe sepsis.

Objectives: To determine whether survivors of severe sepsis hospitalization have high long-term risk of cardiovascular events. We examined whether higher risk is due to severe sepsis hospitalization or poor prehospitalization health status, and if the higher risk is also observed in patients hospitalized for infectious and noninfectious reasons, and in other critically ill patients.

Intensive care unit readmission during childhood after preterm birth with respiratory failure.

Objective: To determine the incidence and risk factors for readmission to the intensive care unit (ICU) among preterm infants who required mechanical ventilation at birth.

Study Design: We studied preterm newborns (birth weight 500-1250 g) who required mechanical ventilation at birth and were enrolled in a multicenter trial of inhaled nitric oxide therapy. Patients were assessed up to 4.

Infection hospitalization increases risk of dementia in the elderly.

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.