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BACKGROUND: There is uncertainty surrounding the use of direct oral anticoagulants (DOACs) in patients with kidney dysfunction. METHODS: Using the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database (data from RE-LY [Randomized Evaluation of Long-term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48]), we performed an individual patient-level network meta-analysis to evaluate the safety and efficacy of DOACs versus warfarin across continuous creatinine clearance (CrCl). A multivariable Cox model including treatment-by-CrCl interaction with random effects was fitted to estimate hazard ratios for paired treatment strategies (standard-dose DOAC, lower-dose DOAC, and warfarin). Outcomes included stroke and systemic embolism (S/SE), major bleeding, intracranial hemorrhage (ICH), and death. RESULTS: Among 71 683 patients (mean age, 70.6±9.4 years; 37.3% female; median follow-up, 23.1 months), the mean CrCl was 75.5±30.5 mL/min. The incidence of S/SE, major bleeding, ICH, and death increased significantly with worsening kidney function. Across continuous CrCl values down to 25 mL/min, the hazard of major bleeding did not change for patients randomized to standard-dose DOACs compared with those randomized to warfarin ( P interaction =0.61). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of ICH at CrCl values P interaction =0.08). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of S/SE with CrCl P interaction =0.01). The hazard of death was significantly lower with standard-dose DOACs for patients with CrCl P interaction =0.08). Use of lower-dose rather than standard-dose DOACs was not associated with a significant difference in incident bleeding or ICH in patients with reduced kidney function but was associated with a higher incidence4 of death and S/SE. CONCLUSIONS: Standard-dose DOACs are safer and more effective than warfarin down to a CrCl of at least 25 mL/min. Lower-dose DOACs do not significantly lower the incidence of bleeding or ICH compared with standard-dose DOACs but are associated with a higher incidence of S/SE and death. These findings support the use of standard-dose DOACs over warfarin in patients with kidney dysfunction.

BackgroundCandidemia is one of the most common nosocomial bloodstream infections in the United States, causing significant morbidity and mortality in hospitalized patients, but the breadth of the host response toCandidainfections in human patients remains poorly defined.MethodsIn order to better define the host response toCandidainfection at the transcriptional level, we performed RNA sequencing on serial peripheral blood samples from 48 hospitalized patients with blood cultures positive forCandidaspecies and compared them to patients with other acute viral, bacterial, and non-infectious illnesses. Regularized multinomial regression was utilized to develop pathogen class-specific gene expression classifiers.ResultsCandidemia triggers a unique, robust, and conserved transcriptomic response in human hosts with 1641 genes differentially upregulated compared to healthy controls. Many of these genes corresponded to components of the immune response to fungal infection, heavily weighted toward neutrophil activation, heme biosynthesis, and T cell signaling. We developed pathogen class-specific classifiers from these unique signals capable of identifying and differentiating candidemia, viral, or bacterial infection across a variety of hosts with a high degree of accuracy (auROC 0.98 for candidemia, 0.99 for viral and bacterial infection). This classifier was validated on two separate human cohorts (auROC 0.88 for viral infection and 0.87 for bacterial infection in one cohort; auROC 0.97 in another cohort) and an in vitro model (auROC 0.94 for fungal infection, 0.96 for bacterial, and 0.90 for viral infection).ConclusionsTranscriptional analysis of circulating leukocytes in patients with acuteCandidainfections defines novel aspects of the breadth of the human immune response during candidemia and suggests promising diagnostic approaches for simultaneously differentiating multiple types of clinical illnesses in at-risk, acutely ill patients.

Background. Functional decline in conjunction with low levels of physical activity has implications for health risks in older adults. Previous studies have examined the associations between accelerometry-derived activity and physical function, but most of these studies reduced these data into average means of total daily physical activity (e.g., daily step counts). A new method of analysis “functional data analysis” provides more in-depth capability using minute-level accelerometer data. Methods. A secondary analysis of community-dwelling adults ages 30 to 90+ residing in southwest region of North Carolina from the Physical Performance across the Lifespan (PALS) study. PALS assessments were completed in-person at baseline and one-week of accelerometry. Final analysis includes 669 observations at baseline with minute-level accelerometer data from 7:00 to 23:00, after removing non-wear time. A novel scalar-on-function regression analysis was used to explore the associations between baseline physical activity features (minute-by-minute vector magnitude generated from accelerometer) and baseline physical function (gait speed, single leg stance, chair stands, and 6-minute walk test) with control for baseline age, sex, race and body mass index. Results. The functional regressions were significant for specific times of day indicating increased physical activity associated with increased physical function around 8:00, 9:30 and 15:30-17:00 for rapid gait speed; 9:00-10:30 and 15:00-16:30 for normal gait speed; 9:00-10:30 for single leg stance; 9:30-11:30 and 15:00-18:00 for chair stands; 9:00-11:30 and 15:00-18:30 for 6-minute walk. Conclusion. This method of functional data analysis provides news insights into the relationship between minute-by-minute daily activity and health.

Background Candidemia is one of the most common nosocomial bloodstream infections in the United States and causes significant morbidity and mortality in hospitalized patients. Improved rapid diagnostics capable of differentiating candidemia from other causes of febrile illness in the hospitalized patient are of paramount importance. Pathogen class-specific biomarker-based diagnostics such as those focusing on host gene expression patterns in circulating leukocytes may offer a promising alternative. Methods RNA sequencing was performed on peripheral blood samples from 27 hospitalized patients with blood culture positive invasive candidiasis. Samples from healthy controls as well as at-risk subjects with acute febrile illness and similar clinical backgrounds but other infectious or noninfectious etiologies were used as comparator phenotypes (35 subjects with culture-proven bacterial infection, 49 with confirmed viral infection, and 17 with acute noninfectious illness). Bayesian techniques were utilized to develop infection-specific classifiers and leave one out cross-validation was used to estimate the predictive probability of each pathogen class. Results Candidemia triggers a unique, robust and conserved transcriptomic response in human hosts with 1,170 genes differentially upregulated compared with healthy controls. Based on this strength of signal, we developed a transcriptomic classifier that was capable of identifying candidemia, viral, or bacterial infection with a high degree of accuracy (auROC for Candida 0.93, Bacterial 0.98, Viral 0.99). The Candida component of this classifier (29-genes) was able to diagnose candidemia with a sensitivity of 88% and specificity of 100%. Conclusion The host transcriptomic response during candidemia in hospitalized adults is highly conserved and unique from the genomic responses to acute viral and bacterial infection. This approach shows promise for the development of host response-based classifiers capable of differentiating multiple types of clinical illnesses at once in at-risk febrile patients. Disclosures Ephraim L. Tsalik, MD MHS PhD, Immunexpress: Consultant; Predigen, Inc.: Officer or Board Member, Research Grant.