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Abstract 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.

In a cluster-randomized trial conducted in five ICUs, a nurse-led family-support intervention did not affect surrogates’ scores for anxiety and depression 6 months after the patients’ hospitalization, but it improved surrogates’ ratings of the patient-centeredness of care.

In septic shock, the first few hours of care are critical for survival. In this study, two protocols for the care of patients with septic shock were compared with usual care with respect to 60-day mortality and other outcomes. There were no significant differences in outcome. There are more than 750,000 cases of severe sepsis and septic shock in the United States each year. 1 Most patients who present with sepsis receive initial care in the emergency department, and the short-term mortality is 20% or more. 2 , 3 In 2001, Rivers et al. reported that among patients with severe sepsis or septic shock in a single urban emergency department, mortality was significantly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT) than among those who were given standard therapy (30.5% vs. 46.5%). 4 On the basis of the premise that usual care . . .

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. 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. 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. 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. ► Limitations of the iterative outlier method for Aβ-positive cutoffs ► Use of sparse k-means as a method for identification of Aβ-positive cutoffs ► Comparison of the above objective methods to visual reads shows good agreement. ► A combination of methods may be the best approach to identify early Aβ.

Differentiating acute bacterial infection from other causes of lower respiratory tract illness is challenging. In this trial, procalcitonin was investigated as a point-of-care test to aid in determining whether antibiotics were needed in the treatment of these illnesses.

Abstract Rationale Survivors of hospitalization for community-acquired pneumonia (CAP) are at increased risk of cardiovascular events, repeat infections, and death in the following months but the cause is unknown. Objectives To investigate whether persistent inflammation, defined as elevating circulating inflammatory markers at hospital discharge, is associated with subsequent outcomes. Methods Prospective cohort study at 28 sites. Measurements and Main Results We used standard criteria to define CAP and the National Death Index to determine all-cause and cause-specific 1-year mortality. At hospital discharge, 1,799 subjects (77.5%) were alive and vital signs had returned to normal in 1,512 (87%) subjects. The geometric means (±SD) for circulating IL-6 and IL-10 concentrations were 6.9 (±1) pg/ml and 1.2 (±1.1) pg/ml. At 1 year, 307 (17.1%) subjects had died. Higher IL-6 and IL-10 concentrations at hospital discharge were associated with an increased risk of death, which gradually fell over time. Using Gray's survival model, the associations were independent of demographics, comorbidities, and severity of illness (for each log-unit increase, the range of adjusted hazard ratios [HRs] for IL-6 were 1.02–1.46, P < 0.0001, and for IL-10 were 1.17–1.44, P = 0.01). The ranges of HRs for each log-unit increase in IL-6 and IL-10 concentrations among subjects who did and did not develop severe sepsis were 0.95–1.27 and 1.07–1.55, respectively. High IL-6 concentrations were associated with death due to cardiovascular disease, cancer, infections, and renal failure (P = 0.008). Conclusions Despite clinical recovery, many patients with CAP leave hospital with ongoing subclinical inflammation, which is associated with an increased risk of death.

Objective Safety culture may influence patient outcomes, but evidence is limited. We sought to determine if intensive care unit (ICU) safety culture is independently associated with outcomes. Design Cohort study combining safety culture survey data with the Project IMPACT Critical Care Medicine (PICCM) clinical database. Setting Thirty ICUs participating in the PICCM database. Participants A total of 65 978 patients admitted January 2001–March 2005. Interventions None. Main outcome measures Hospital mortality and length of stay (LOS). Methods From December 2003 to April 2004, we surveyed study ICUs using the Safety Attitudes Questionnaire-ICU version, a validated instrument that assesses safety culture across six factors. We calculated factor mean and percent-positive scores (% respondents with mean score ≥75 on a 0–100 scale) for each ICU, and generated case-mix adjusted, patient-level, ICU-clustered regression analyses to determine the independent association of safety culture and outcome. Results We achieved a 47.9% response (2103 of 4373 ICU personnel). Culture scores were mostly low to moderate and varied across ICUs (range: 13–88, percent-positive scores). After adjustment for patient, hospital and ICU characteristics, for every 10% decrease in ICU perceptions of management percent-positive score, the odds ratio for hospital mortality was 1.24 (95% CI: 1.07–1.44; P = 0.005). For every 10% decrease in ICU safety climate percent-positive score, LOS increased 15% (95% CI: 1−30%; P = 0.03). Sensitivity analyses for non-response bias consistently associated safety climate with outcome, but also yielded some counterintuitive results. Conclusion In a multicenter study conducted in the USA, perceptions of management and safety climate were moderately associated with outcomes. Future work should further develop methods of assessing safety culture and association with outcomes.

Abstract Rationale Despite ongoing ethical debate concerning who should control decisions to discontinue life support for incapacitated, critically ill patients, the perspectives of surrogate decision makers are poorly understood. Objectives To determine (1) what degree of decisional authority surrogates prefer for value-sensitive life support decisions compared with more technical biomedical decisions, and (2) what predicts surrogates' preferences for more control over life support decisions. Methods This was a prospective study of 230 surrogate decision makers for incapacitated, mechanically ventilated patients at high risk of death. Surrogates reported their preferred degree of decisional authority using the Degner Control Preferences Scale for two types of decisions: a value-sensitive decision about whether to discontinue life support and a decision regarding which antibiotic to prescribe for an infection. Measurements and Main Results The majority of surrogates (55%, 127/230; 95% confidence interval, 49–62%) preferred to have final control over the value-sensitive life support decision; 40% (91/230) wished to share control equally with the physician; 5% (12/230) of surrogates wanted the physician to make the decision. Surrogates preferred significantly more control over the value-sensitive life support decision compared with the technical decision about choice of antibiotics (P < 0.0001). Factors independently associated with surrogates' preference for more control over the life support decision were: less trust in the intensive care unit physician, male sex, and non-Catholic religious affiliation. Conclusions Surrogates vary in their desire for decisional authority for value-sensitive life support decisions, but prefer substantially more authority for this type of decision compared with technical, medical judgments. Low trust in physicians is associated with surrogates preferring more control of life support decisions.

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.

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. 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. 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). 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.