IMPORTANCE Sepsis is a heterogeneous syndrome. Identification of distinct clinical phenotypes may allow more precise therapy and improve care. OBJECTIVE To derive sepsis phenotypes from clinical data, determine their reproducibility and correlation with host-response biomarkers and clinical outcomes, and assess the potential causal relationship with results from randomized clinical trials (RCTs). DESIGN, SETTINGS, AND PARTICIPANTS Retrospective analysis of data sets using statistical, machine learning, and simulation tools. Phenotypes were derived among 20 189 total patients (16 552 unique patients) who met Sepsis-3 criteria within 6 hours of hospital presentation at 12 Pennsylvania hospitals (2010-2012) using consensus k means clustering applied to 29 variables. Reproducibility and correlation with biological parameters and clinical outcomes were assessed in a second database (2013-2014; n = 43 086 total patients and n = 31 160 unique patients), in a prospective cohort study of sepsis due to pneumonia (n = 583), and in 3 sepsis RCTs (n = 4737). EXPOSURES All clinical and laboratory variables in the electronic health record. MAIN OUTCOMES AND MEASURES Derived phenotype (α, β, γ, and δ) frequency, host-response biomarkers, 28-day and 365-day mortality, and RCT simulation outputs. RESULTS The derivation cohort included 20 189 patients with sepsis (mean age, 64 [SD, 17] years; 10 022 [50%] male; mean maximum 24-hour Sequential Organ Failure Assessment [SOFA] score, 3.9 [SD, 2.4]). The validation cohort included 43 086 patients (mean age, 67 [SD, 17] years; 21 993 [51%] male; mean maximum 24-hour SOFA score, 3.6 [SD, 2.0]). Of the 4 derived phenotypes, the α phenotype was the most common (n = 6625; 33%) and included patients with the lowest administration of a vasopressor; in the β phenotype (n = 5512; 27%), patients were older and had more chronic illness and renal dysfunction; in the γ phenotype (n = 5385; 27%), patients had more inflammation and pulmonary dysfunction; and in the δ phenotype (n = 2667; 13%), patients had more liver dysfunction and septic shock. Phenotype distributions were similar in the validation cohort. There were consistent differences in biomarker patterns by phenotype. In the derivation cohort, cumulative 28-day mortality was 287 deaths of 5691 unique patients (5%) for the α phenotype; 561 of 4420 (13%) for the β phenotype; 1031 of 4318 (24%) for the γ phenotype; and 897 of 2223 (40%) for the δ phenotype. Across all cohorts and trials, 28-day and 365-day mortality were highest among the δ phenotype vs the other 3 phenotypes (P < .001). In simulation models, the proportion of RCTs reporting benefit, harm, or no effect changed considerably (eg, varying the phenotype frequencies within an RCT of early goal-directed therapy changed the results from >33% chance of benefit to >60% chance of harm). CONCLUSIONS AND RELEVANCE In this retrospective analysis of data sets from patients with sepsis, 4 clinical phenotypes were identified that correlated with host-response patterns and clinical outcomes, an...

Among critically ill patients and their surrogates, a family-support intervention delivered by the interprofessional ICU team did not significantly affect the surrogates' burden of psychological symptoms, but the surrogates' ratings of the quality of communication and the patient- and family-centeredness of care were better and the length of stay in the ICU was shorter with the intervention than with usual care. (Funded by the UPMC Health System and the Greenwall Foundation; PARTNER ClinicalTrials.gov number, NCT01844492 .).

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 .).

Background Whether human immunodeficiency virus (HIV) infection is a risk factor for heart failure (HF) is not clear. The presence of coronary heart disease and alcohol consumption in this population may confound this association. Methods To determine whether HIV infection is a risk factor for incident HF, we conducted a population-based, retrospective cohort study of HIV-infected and HIV-uninfected veterans enrolled in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC) and the 1999 Large Health Study of Veteran Enrollees (LHS) from January 1, 2000, to July 31, 2007. Results There were 8486 participants (28.2% HIV-infected) enrolled in the VACS-VC who also participated in the 1999 LHS. During the median 7.3 years of follow-up, 286 incident HF events occurred. Age- and race/ethnicity–adjusted HF rates among HIV-infected and HIV-uninfected veterans were 7.12 (95% confidence interval [CI],6.90-7.34) and 4.82 (95% CI, 4.72-4.91) per 1000 person-years, respectively. Compared with HIV-uninfected veterans, those who were HIV infected had an increased risk ofHF (adjusted hazard ratio [HR], 1.81; 95% CI, 1.39-2.36). This association persisted among veterans who did not have a coronary heart disease event or a diagnosis related to alcohol abuse or dependence before the incident HF event (adjusted HR, 1.96; 95% CI, 1.29-2.98). Compared with HIV-uninfected veterans, those who were HIV infected with a baseline Human immunodeficiency virus 1 (HIV-1) RNA level of 500 or more copies/mL had a higher risk of HF (adjusted HR, 2.28; 95% CI, 1.57-3.32), while those with baseline and a recent HIV-1 RNA level less than 500 copies/mL did not (adjusted HR, 1.10; 95% CI, 0.64-1.89; P< .001 for comparison between high and low HIV-1 RNA groups). Conclusions Our data suggest that HIV infection is a risk factor for HF. Ongoing viral replication is associated with a higher risk of developing HF.

Rationale: Studies demonstrating an association between chronic obstructive pulmonary disease and low bone mineral density (BMD) implicate factors distinct from treatments and severity of lung disease in the pathogenesis of osteoporosis. Whereas emphysema has been independently associated with vascular disease and other comorbidities, its association with BMD has not been well studied. Objectives: We explored the associations of BMD with computed tomography (CT) measures of emphysema and other risk factors in current and former smokers. Methods: One hundred ninety subjects completed a CT scan, pulmonary function testing, questionnaires, and dual x-ray absorptiometry measurements of hip and lumbar spine BMD. Subjects were classified as having normal BMD, osteopenia, or osteoporosis. Demographic, physiologic, and radiographic characteristics were compared and the association of BMD with radiographic emphysema, airflow obstruction, and osteoporosis risk factors was assessed. Measurements and Main Results: No difference existed in age, tobacco exposure, oral steroid use, or physical activity across BMD categories. Both osteopenia and osteoporosis were associated with the presence of airflow obstruction, inhaled corticosteroid use, and female sex, and demonstrated a significant relationship with the presence of visual emphysema (P 5 0.0003). Quantitative emphysema, but not CTmeasured indices of airway wall thickness, was inversely associated with BMD. Visual emphysema alone was a significant predictor of osteopenia/osteoporosis (odds ratio 5 2.55; 95% confidence interval, 1.24-5.25) in a model including obstruction severity, age, sex, and inhaled and oral steroid use. Conclusions: Radiographic emphysema is a strong, independent predictor of low BMD in current and former smokers. This relationship suggests a common mechanistic link between emphysema and osteopenia/osteoporosis.

Objectives To estimate and compare the frequency and prevalence of mild cognitive impairment (MCI) and related entities using different classification approaches at the population level. Design Cross-sectional epidemiologic study of population-based cohort recruited by age-stratified random sampling from electoral rolls. Setting Small-town communities in western Pennsylvania, USA Participants Of 2036 individuals aged 65 years and older, 1982 participants with normal or mildly impaired cognition (age-education-corrected Mini-Mental State scores ≥ 21). Measurements Demographics, neuropsychological assessment expressed as cognitive domains, functional ability, subjective reports of cognitive difficulties; based on these measurements, operational criteria for the Clinical Dementia Rating (CDR) scale, the 1999 criteria for Amnestic MCI, the 2004 Expanded criteria for MCI, and new, purely cognitive criteria for MCI. Results A CDR rating of 0.5 (questionable dementia) was obtained by 27.6% of participants, while 1.2% had CDR ≥ 1 (mild or moderate dementia). Among those with CDR <1, 2.27% had Amnestic MCI and 17.61% had Expanded MCI, while 34.6 % had MCI by purely cognitive classification. Isolated executive function impairment was the least common, while impairment in multiple domains including executive function was the most common. Prevalence estimates weighted against the US Census are also provided. Conclusions The manner in which criteria for MCI are operationalized determines the proportion of individuals who are thus classified, and the degree of overlap with other criteria. Prospective followup is needed to determine progression from MCI to dementia, and thus empirically develop improved MCI criteria with good predictive value.

Objectives-Performance on cognitive tests can be affected by age, education, and also selection bias. We examined the distribution of scores on a several cognitive screening tests by age and educational levels in a population-based cohort.Method-An age-stratified random sample of individuals aged 65+ years was drawn from the electoral rolls of an urban U.S. community. Those obtaining age and education-corrected scores ≥ 21/30 on the Mini-Mental State Examination were designated as cognitively normal or only mildly impaired, and underwent a full assessment including a battery of neuropsychological tests. Participants were also rated on the Clinical Dementia Rating scale. The distribution of neuropsychological test scores within demographic strata, among those receiving a CDR of 0 (no dementia), are reported here as cognitive test norms. After combining individual test scores into cognitive domain composite scores, multiple linear regression models were used to examine associations of cognitive test performance with age, and education.Results-In this cognitively normal sample of older adults, younger age and higher education were associated with better performance in all cognitive domains. Age and education together explained 22% of the variation of memory, and less of executive function, language, attention, and visuospatial function.Conclusion-Older age and lesser education are differentially associated with worse neuropsychological test performance in cognitively normal older adults representative of the community at large. The distribution of scores in these participants can serve as population-based norms for these tests, and be especially useful to clinicians and researchers assessing older adults outside specialty clinic settings.

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