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. hospitals with high adherence to quality measures for the treatment of pneumonia, we provided guidance for clinicians about national clinical practice recommendations for the treatment of lower respiratory tract infections and the interpretation of procalcitonin assays. We then randomly assigned patients who presented to the emergency department with a suspected lower respiratory tract infection and for whom the treating physician was uncertain whether antibiotic therapy was indicated to one of two groups: the procalcitonin group, in which the treating clinicians were provided with real-time initial (and serial, if the patient was hospitalized) procalcitonin assay results and an antibiotic use guideline with graded recommendations based on four tiers of procalcitonin levels, or the usual-care group. We hypothesized that within 30 days after enrollment the total antibiotic-days would be lower - and the percentage of patients with adverse outcomes would not be more than 4.5 percentage points higher - in the procalcitonin group than in the usual-care group. RESULTS: A total of 1656 patients were included in the final analysis cohort (826 randomly assigned to the procalcitonin group and 830 to the usual-care group), of whom 782 (47.2%) were hospitalized and 984 (59.4%) received antibiotics within 30 days. The treating clinician received procalcitonin assay results for 792 of 826 patients (95.9%) in the procalcitonin group (median time from sample collection to assay result, 77 minutes) and for 18 of 830 patients (2.2%) in the usual-care group. In both groups, the procalcitonin-level tier was associated with the decision to prescribe antibiotics in the emergency department. There was no significant difference between the procalcitonin group and the usual-care group in antibiotic-days (mean, 4.2 and 4.3 days, respectively; difference, -0.05 day; 95% confidence interval [CI], -0.6 to 0.5; P=0.87) or the proportion of patients with adverse outcomes (11.7% [96 patients] and 13.1% [109 patients]; difference, -1.5 percentage points; 95% CI, -4.6 to 1.7; P<0.001 for noninferiority) within 30 days. CONCLUSIONS: The provision of procalcitonin assay results, along with instructions on their interpretation, to emergency department and hospital-based clinicians did not result in less use of antibiotics than did usual care among patients with suspected lower respiratory tract infection. (Funded by the National Institute of General Medical Sciences; ProACT ClinicalTrials.gov number, NCT02130986 .).

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. 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.

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. 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.

Incidental Cerebral Microbleeds and Cerebral Blood Flow in Elderly Individuals.

IMPORTANCE: Cerebral microbleeds (CMBs) are collections of blood breakdown products that are a common incidental finding in magnetic resonance imaging of elderly individuals. Cerebral microbleeds are associated with cognitive deficits, but the mechanism is unclear. Studies show that individuals with CMBs related to symptomatic cerebral amyloid angiopathy have abnormal vascular reactivity and cerebral blood flow (CBF), but, to our knowledge, abnormalities in cerebral blood flow have not been reported for healthy individuals with incidental CMBs. OBJECTIVE: To evaluate the association of incidental CMBs with resting-state CBF, cerebral metabolism, cerebrovascular disease, ß-amyloid (Aß), and cognition. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study of 55 cognitively normal individuals with a mean (SD) age of 86.8 (2.7) years was conducted from May 1, 2010, to May 1, 2013, in an academic medical center in Pittsburgh; data analysis was performed between June 10, 2013, and April 9, 2015. INTERVENTIONS: 3-Tesla magnetic resonance imaging was performed with susceptibility-weighted imaging or gradient-recalled echo to assess CMBs, arterial spin labeling for CBF, and T1- and T2-weighted imaging for atrophy, white matter hyperintensities, and infarcts. Positron emission tomography was conducted with fluorodeoxyglucose to measure cerebral metabolism and Pittsburgh compound B for fibrillar Aß. Neuropsychological evaluation, including the Clinical Dementia Rating scale, was performed. MAIN OUTCOMES AND MEASURES: Magnetic resonance images were rated for the presence and location of CMBs. Lobar CMBs were subclassified as cortical or subcortical. Measurements of CBF, metabolism, and Aß were compared with the presence and number of CMBs with voxelwise and region-of-interest analyses. RESULTS: The presence of cortical CMBs was associated with significantly reduced CBF in multiple regions on voxelwise and region-of-interest analyses (percentage difference in global CBF, -25.3%; P = .0003), with the largest reductions in the parietal cortex (-37.6%; P < .0001) and precuneus (-31.8%; P = .0006). Participants with any CMBs showed a nonsignificant trend toward reduced CBF. Participants with cortical CMBs had a significant association with greater prevalence of infarcts (24% vs 6%; P = .047) and demonstrated a trend to greater prevalence of deficits demonstrated on the Clinical Dementia Rating scale (45% vs 19%; P = .12). There was no difference in cortical amyloid (measured by Pittsburgh compound B positron emission tomography) between participants with and without CMBs (P = .60). CONCLUSIONS AND RELEVANCE: In cognitively normal elderly individuals, incidental CMBs in cortical locations are associated with widespread reductions in resting-state CBF. Chronic hypoperfusion may put these people at risk for neuronal injury and neurodegeneration. Our results suggest that resting-state CBF is a marker of CMB-related small-vessel disease.

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-ß in cognitively normal older adults; and to explore personality factors as potential moderators of this association. DESIGN: Cross-sectional observational study. SETTING: Clinical neuroimaging research center. PARTICIPANTS: Community volunteer sample of 92 healthy older adults, screened for normal cognition with comprehensive neuropsychological evaluation. MEASUREMENTS: Subjective cognitive self-report measures included the Memory Functioning Questionnaire (MFQ), Cognitive Failures Questionnaire, and the Subjective Cognitive Complaint Scale. Personality was measured with the NEO Five Factor Inventory. Brain amyloid-ß deposition was assessed with Pittsburgh compound B (PiB)-PET imaging. RESULTS: One of three cognitive complaint measures, the MFQ, was associated with global PiB retention (standardized beta = -0.230, p = 0.046, adjusting for age, sex and depressive symptoms). Neuroticism moderated this association such that only high neuroticism individuals showed the predicted pattern of high complaint-high amyloid-ß association. CONCLUSION: Evidence for association between subjective cognition and brain amyloid-ß deposition in healthy older adults is demonstrable but measure-specific. Neuroticism may moderate the MFQ-amyloid-ß association such that it is observed in the context of higher trait neuroticism. Subjective cognitive complaints and neuroticism may reflect a common susceptibility toward psychological distress and negative affect, which are in turn risk factors for cognitive decline in aging and incident Alzheimer disease.

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). 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. CVD risk after pneumonia was highest in the first year. CVD occurred in 54 cases and 6 controls in the first 30 days (HR, 4.07; 95% CI, 2.86-5.27); 11 cases and 9 controls between 31 and 90 days (HR, 2.94; 95% CI, 2.18-3.70); and 22 cases and 55 controls between 91 days and 1 year (HR, 2.10; 95% CI, 1.59-2.60). Additional CVD risk remained elevated into the tenth year, when 4 cases and 12 controls developed CVD (HR, 1.86; 95% CI, 1.18-2.55). In ARIC, of 680 pneumonia cases, 112 had CVD over 10 years after hospitalization. CVD occurred in 4 cases and 3 controls in the first 30 days (HR, 2.38; 95% CI, 1.12-3.63); 4 cases and 0 controls between 31 and 90 days (HR, 2.40; 95% CI, 1.23-3.47); 11 cases and 8 controls between 91 days and 1 year (HR, 2.19; 95% CI, 1.20-3.19); and 8 cases and 7 controls during the second year (HR, 1.88; 95% CI, 1.10-2.66). After the second year, the HRs were no longer statistically significant. 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.

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. 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.

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. 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.

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. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support. RESULTS: We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P=0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P=0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support. CONCLUSIONS: In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes. (Funded by the National Institute of General Medical Sciences; ProCESS ClinicalTrials.gov number, NCT00510835.).

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. METHODS: Unmatched and matched-cohort analyses of Medicare beneficiaries. For unmatched analysis, we compared patients with severe sepsis admitted to the intensive care unit (ICU) and survived hospitalization (n = 4,179) to unmatched population control subjects (n = 819,283). For matched analysis, we propensity-score-matched each patient with severe sepsis to four control subjects (population, hospitalized, non-severe sepsis ICU control subjects, and infection hospitalization). Primary outcome was 1-year incidence rate of hospitalization for cardiovascular events. MEASUREMENTS AND MAIN RESULTS: Cardiovascular events were common among patients discharged alive after severe sepsis hospitalization (29.5%; 498.2 events/1,000 person-years). Survivors of severe sepsis had a 13-fold higher risk of cardiovascular events compared with unmatched control subjects (498.2 vs. 36 events/1,000 person-years; P < 0.0001), and a 1.9-fold higher risk compared with matched-population control subjects (P < 0.0001). Survivors of severe sepsis had 1.1-fold higher risk compared with matched hospitalized patients and infection hospitalizations (P = 0.002 and 0.001) and similar risk compared with matched-ICU control subjects. CONCLUSIONS: Survivors of severe sepsis have high risk of cardiovascular events. The higher risk is mainly due to poor prehospitalization health status, and is also seen in a broader population of acutely ill patients.

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. 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.

Protocolized Care for Early Septic Shock (ProCESS) statistical analysis plan.

BACKGROUND: The Protocolized Care for Early Septic Shock study is a randomised, multicentre, prospective, three-arm, parallel-group trial of alternative resuscitation strategies for early septic shock. OBJECTIVE: To state our analysis plan for trial data. METHODS: Our plan is to guide data collection and analysis using pre-existing definitions and testing, with local consensus-based efforts where needed. We examine protocolised care (two experimental approaches) and compare this to usual "wild type" care. RESULTS: Our plan is to address three aims (clinical efficacy, biology of illness and recovery, and costs and cost-effectiveness) and four hypotheses, and we specify rules for handling data and determining outcomes. CONCLUSION: By using measures to maintain study conduct and analysis rigour, we hope to improve understanding of early septic shock resuscitation and care of patients.

Cognitive aging in persons with minimal amyloid-ß and white matter hyperintensities.

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.

Harmonizing international trials of early goal-directed resuscitation for severe sepsis and septic shock: methodology of ProCESS, ARISE, and ProMISe.

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 6­8 % 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.

Epidemiology and long-term clinical and biologic risk factors for pneumonia in community-dwelling older Americans: analysis of three cohorts.

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.

In vivo assessment of amyloid-ß deposition in nondemented very elderly subjects.

OBJECTIVE: This study examined amyloid-ß (Aß) deposition in 190 nondemented subjects aged ≥82 years to determine the proportion of Aß-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 Aß 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 Aß deposition.

Cognitive trajectories associated with ß-amyloid deposition in the oldest-old without dementia.

OBJECTIVE: To determine whether a high prevalence (55%) of Aß deposition in a cohort of individuals remaining dementia-free into their 9th and 10th decades is associated with cognitive decline prior to imaging. METHODS: A total of 194 participants (mean age 85.5 years, range 82-95) who completed the Ginkgo Evaluation of Memory Study (GEMS) and remained dementia-free subsequently completed Pittsburgh compound B-PET imaging. We examined cross-sectional associations between Aß status and performance on a broad neuropsychological test battery completed at GEMS entry 7-9 years prior to neuroimaging. We also longitudinally examined cognition over annual evaluations using linear mixed models. RESULTS: At GEMS screening (2000-2002), participants who were Aß-positive in 2009 had lower performance on the Stroop test (p < 0.01) and Raven's Progressive Matrices (p = 0.05), with trend level difference for Block Design (p = 0.07). Longitudinal analyses showed significant slope differences for immediate and delayed recall of the Rey-Osterrieth figure, semantic fluency, and Trail-Making Test parts A and B, indicating greater performance decline prior to neuroimaging for Aß-positive relative to Aß-negative participants (ps < 0.05). CONCLUSIONS: Highly prevalent Aß deposition in oldest-older adults is associated with cognitive decline in visual memory, semantic fluency, and psychomotor speed beginning 7-9 years prior to neuroimaging. Mean differences in nonmemory domains, primarily executive functions, between Aß-status groups may be detectable 7-9 years before neuroimaging.

Classification of amyloid-positivity in controls: comparison of visual read and quantitative approaches.

UNLABELLED: An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Aß) deposition. Use of amyloid PET for this purpose, requires a reproducible method for defining a cutoff that separates individuals with no significant Aß deposition from those in which Aß 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 Aß deposition. These methods have the potential to provide a standard approach to the detection of PiB-positivity that is generalizable across centers.

Application of copulas to improve covariance estimation for partial least squares.

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.

Light and the outcome of the critically ill: an observational cohort study.

INTRODUCTION: Light before and during acute illness has been associated with both benefit and harm in animal models and small human studies. Our objective was to determine the associations of light duration (photoperiod) and intensity (insolation) before and during critical illness with hospital mortality in ICU patients. Based on the 'winter immunoenhancement' theory, we tested the hypothesis that a shorter photoperiod before critical illness is associated with improved survival. METHODS: We analyzed data from 11,439 patients admitted to 8 ICUs at the University of Pittsburgh Medical Center between June 30, 1999 and July 31, 2004. Daily photoperiod and insolation prior to and after ICU admission were estimated for each patient by using data provided by the United States Naval Observatory and National Aeronautics and Space Administration and direct measurement of light gradient from outside to bedside for each ICU room. Our primary outcome was hospital mortality. The association between light and risk of death was analyzed using multivariate analyses, adjusting for potential confounders, including severity of illness, case mix, and ICU type. RESULTS: The cohort had an average APACHE III of 52.9 and a hospital mortality of 10.7%. In total, 128 ICU beds were analyzed; 108 (84%) had windows. Pre-illness photoperiod ranged from 259 to 421 hours in the prior month. A shorter photoperiod was associated with a reduced risk of death: for each 1-hour decrease, the adjusted OR was 0.997 (0.994 to 0.999, p = 0.03). In the ICU, there was near complete (99.6%) degradation of natural light from outside to the ICU bed. Thus, light exposure once in the ICU approached zero; the 24-hour insolation was 0.005 ± 0.003 kWh/m² with little diurnal variation. There was no association between ICU photoperiod or insolation and mortality. CONCLUSIONS: Consistent with the winter immunoenhancement theory, a shorter photoperiod in the month before critical illness is associated with a reduced risk of death. Once in the ICU, patients are exposed to near negligible natural light despite the presence of windows. Further studies are warranted to determine the underlying mechanisms and whether manipulating light exposure, before or during ICU admission, can enhance survival.