Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

Acute bacterial skin and skin structure infections (ABSSSI): practice guidelines for management and care transitions in the emergency department and hospital.

BACKGROUND: Acute bacterial skin and skin structure infections (ABSSSI), formally referred to as complicated skin and soft tissue infections, include infections with resistance to previously effective antimicrobials. Increasing dramatically in incidence, they have become a challenging medical problem associated with high direct and indirect costs to both the medical system and society. OBJECTIVES: To describe the burden of ABSSSI and to explore multidisciplinary approaches to its management and new treatments that can be initiated in the emergency department. DISCUSSION: We offer a best practice model aimed at providing risk-stratified and convenient care for ABSSSI at the lowest possible cost, while minimizing complications, readmissions, and inappropriate antibiotic use. In doing so, we focus on the care provided by emergency physicians and hospitalists and the transition of management between them for inpatient care, as well as the facilitation of observation or direct-to-outpatient care for suitable patients. CONCLUSIONS: A standard, consistent, and multidisciplinary approach to ABSSSI can streamline care, reduce admissions, support antimicrobial stewardship, and improve clinical and resource consumption outcomes.

Investigation of nosocomial SARS-CoV-2 transmission from two patients to healthcare workers identifies close contact but not airborne transmission events.

OBJECTIVE: To describe the pattern of transmission of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) during 2 nosocomial outbreaks of coronavirus disease 2019 (COVID-19) with regard to the possibility of airborne transmission. DESIGN: Contact investigations with active case finding were used to assess the pattern of spread from 2 COVID-19 index patients. SETTING: A community hospital and university medical center in the United States, in February and March, 2020, early in the COVID-19 pandemic. PATIENTS: Two index patients and 421 exposed healthcare workers. METHODS: Exposed healthcare workers (HCWs) were identified by analyzing the electronic medical record (EMR) and conducting active case finding in combination with structured interviews. Healthcare coworkers (HCWs) were tested for COVID-19 by obtaining oropharyngeal/nasopharyngeal specimens, and RT-PCR testing was used to detect SARS-CoV-2. RESULTS: Two separate index patients were admitted in February and March 2020, without initial suspicion for COVID-19 and without contact or droplet precautions in place; both patients underwent several aerosol-generating procedures in this context. In total, 421 HCWs were exposed in total, and the results of the case contact investigations identified 8 secondary infections in HCWs. In all 8 cases, the HCWs had close contact with the index patients without sufficient personal protective equipment. Importantly, despite multiple aerosol-generating procedures, there was no evidence of airborne transmission. CONCLUSION: These observations suggest that, at least in a healthcare setting, most SARS-CoV-2 transmission is likely to take place during close contact with infected patients through respiratory droplets, rather than by long-distance airborne transmission.

Hospitalist to home: outpatient parenteral antimicrobial therapy at an academic center.

The cost of health care in the United States continues to increase as an aging population places increasing demands on institutions providing health care. Moreover, despite increases in the complexity and cost of health care, reimbursement for some services has been reduced or denied. Thus, the current challenge at many hospitals throughout the United States is to deliver high-quality health care while maximizing resource use and reducing costs without compromising clinical outcomes. We describe an answer to the challenge that combines 2 emerging treatment models in an academic setting: hospital-based physicians and outpatient parenteral antimicrobial therapy.

Nonmonotonic Pathway Gene Expression Analysis Reveals Oncogenic Role of p27/Kip1 at Intermediate Dose.

The mechanistic basis by which the level of p27Kip1 expression influences tumor aggressiveness and patient mortality remains unclear. To elucidate the competing tumor-suppressing and oncogenic effects of p27Kip1 on gene expression in tumors, we analyzed the transcriptomes of squamous cell papilloma derived from Cdkn1b nullizygous, heterozygous, and wild-type mice. We developed a novel functional pathway analysis method capable of testing directional and nonmonotonic dose response. This analysis can reveal potential causal relationships that might have been missed by other nondirectional pathway analysis methods. Applying this method to capture dose-response curves in papilloma gene expression data, we show that several known cancer pathways are dominated by low-high-low gene expression responses to increasing p27 gene doses. The oncogene cyclin D1, whose expression is elevated at an intermediate p27 dose, is the most responsive gene shared by these cancer pathways. Therefore, intermediate levels of p27 may promote cellular processes favoring tumorigenesis-strikingly consistent with the dominance of heterozygous mutations in CDKN1B seen in human cancers. Our findings shed new light on regulatory mechanisms for both pro- and anti-tumorigenic roles of p27Kip1. Functional pathway dose-response analysis provides a unique opportunity to uncover nonmonotonic patterns in biological systems.

Discerning mechanistically rewired biological pathways by cumulative interaction heterogeneity statistics.

Changes in response of a biological pathway could be a consequence of either pathway rewiring, changed input, or a combination of both. Most pathway analysis methods are not designed for mechanistic rewiring such as regulatory element variations. This limits our understanding of biological pathway evolution. Here we present a Q-method to discern whether changed pathway response is caused by mechanistic rewiring of pathways due to evolution. The main innovation is a cumulative pathway interaction heterogeneity statistic accounting for rewiring-specific effects on the rate of change of each molecular variable across conditions. The Q-method remarkably outperformed differential-correlation based approaches on data from diverse biological processes. Strikingly, it also worked well in differentiating rewired chaotic systems, whose dynamics are notoriously difficult to predict. Applying the Q-method on transcriptome data of four yeasts, we show that pathway interaction heterogeneity for known metabolic and signaling pathways is indeed a predictor of interspecies genetic rewiring due to unbalanced TATA box-containing genes among the yeasts. The demonstrated effectiveness of the Q-method paves the way to understanding network evolution at the resolution of functional biological pathways.

Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era.

IMPORTANCE: Clostridium difficile is a major cause of health care-associated infection, but disagreement between diagnostic tests is an ongoing barrier to clinical decision making and public health reporting. Molecular tests are increasingly used to diagnose C difficile infection (CDI), but many molecular test-positive patients lack toxins that historically defined disease, making it unclear if they need treatment. OBJECTIVE: To determine the natural history and need for treatment of patients who are toxin immunoassay negative and polymerase chain reaction (PCR) positive (Tox-/PCR+) for CDI. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational cohort study at a single academic medical center among 1416 hospitalized adults tested for C difficile toxins 72 hours or longer after admission between December 1, 2010, and October 20, 2012. The analysis was conducted in stages with revisions from April 27, 2013, to January 13, 2015. MAIN OUTCOMES AND MEASURES: Patients undergoing C difficile testing were grouped by US Food and Drug Administration-approved toxin and PCR tests as Tox+/PCR+, Tox-/PCR+, or Tox-/PCR-. Toxin results were reported clinically. Polymerase chain reaction results were not reported. The main study outcomes were duration of diarrhea during up to 14 days of treatment, rate of CDI-related complications (ie, colectomy, megacolon, or intensive care unit care) and CDI-related death within 30 days. RESULTS: Twenty-one percent (293 of 1416) of hospitalized adults tested for C difficile were positive by PCR, but 44.7% (131 of 293) had toxins detected by the clinical toxin test. At baseline, Tox-/PCR+ patients had lower C difficile bacterial load and less antibiotic exposure, fecal inflammation, and diarrhea than Tox+/PCR+ patients (P < .001 for all). The median duration of diarrhea was shorter in Tox-/PCR+ patients (2 days; interquartile range, 1-4 days) than in Tox+/PCR+ patients (3 days; interquartile range, 1-6 days) (P = .003) and was similar to that in Tox-/PCR- patients (2 days; interquartile range, 1-3 days), despite minimal empirical treatment of Tox-/PCR+ patients. No CDI-related complications occurred in Tox-/PCR+ patients vs 10 complications in Tox+/PCR+ patients (0% vs 7.6%, P < .001). One Tox-/PCR+ patient had recurrent CDI as a contributing factor to death within 30 days vs 11 CDI-related deaths in Tox+/PCR+ patients (0.6% vs 8.4%, P = .001). CONCLUSIONS AND RELEVANCE: Among hospitalized adults with suspected CDI, virtually all CDI-related complications and deaths occurred in patients with positive toxin immunoassay test results. Patients with a positive molecular test result and a negative toxin immunoassay test result had outcomes that were comparable to patients without C difficile by either method. Exclusive reliance on molecular tests for CDI diagnosis without tests for toxins or host response is likely to result in overdiagnosis, overtreatment, and increased health care costs.

Treatments for hepatitis B.

New optimism surrounds treatments for chronic hepatitis B (CHB). Interferon- alpha , lamivudine, and adefovir dipivoxil are currently approved by the United States Food and Drug Administration for the treatment of CHB. All 3 treatments possess unique characteristics with respect to their side effect profiles, potencies, and treatment niches within the spectrum of CHB. New agents, which are in various stages of clinical development, represent potential improvements within existing, as well as novel, classes of antiviral therapy, and they offer significant promise of a cure for the many patients with chronic and progressive hepatitis B. However, there remain many challenges in understanding the implications of drug resistance, the role of combination therapy, and how to define the response to therapy within subsets of patients with hepatitis B.

Managing an outpatient parenteral antibiotic therapy team: challenges and solutions.

Outpatient parenteral antimicrobial therapy (OPAT) programs should strive to deliver safe, cost effective, and high quality care. One of the keys to developing and sustaining a high quality OPAT program is to understand the common challenges or barriers to OPAT delivery. We review the most common challenges to starting and managing an OPAT program and give practical advice on addressing these issues.

Development and evaluation of a study design typology for human research.

A systematic classification of study designs would be useful for researchers, systematic reviewers, readers, and research administrators, among others. As part of the Human Studies Database Project, we developed the Study Design Typology to standardize the classification of study designs in human research. We then performed a multiple observer masked evaluation of active research protocols in four institutions according to a standardized protocol. Thirty-five protocols were classified by three reviewers each into one of nine high-level study designs for interventional and observational research (e.g., N-of-1, Parallel Group, Case Crossover). Rater classification agreement was moderately high for the 35 protocols (Fleiss' kappa = 0.442) and higher still for the 23 quantitative studies (Fleiss' kappa = 0.463). We conclude that our typology shows initial promise for reliably distinguishing study design types for quantitative human research.

Derivation and validation of a clinical prediction score for isolation of inpatients with suspected pulmonary tuberculosis.

BACKGROUND: The use of a clinical prediction score to improve the practice of instituting airborne-transmission precautions in patients with suspected tuberculosis holds promise for increasing appropriate isolation and decreasing unnecessary isolation. The objective of this study was to derive and validate a clinical prediction score for patients with suspected tuberculosis. METHODS: We used a case-control study design to evaluate differences between patients with a diagnosis of tuberculosis and those placed under airborne precautions who had negative culture results. We developed risk scores based on a multivariable analysis of independently significant factors associated with tuberculosis. Subsequently, we evaluated the sensitivity and specificity of the score in a separate (validation) cohort of patients. RESULTS: Within our population, we found 4 clinical factors associated with tuberculosis: chronic symptoms (odds ratio [OR], 10.2 [95% confidence interval {CI}, 2.95-35.4]), upper lobe disease on chest radiograph (OR, 5.27 [95% CI, 1.6-17.23]), foreign-born status (OR, 7.01 [95% CI, 2.1-23.8]), and immunocompromised state other than human immunodeficiency virus infection (OR, 8.14 [95% CI, 2.08-31.8]). Shortness of breath (OR, 0.13 [95% CI, 0.04-0.45]) was found to be associated with non-tuberculosis diagnoses and considered a negative predictor in the model. Using a cut-off point to maximize sensitivity, we applied the prediction rule to the validation cohort, resulting in a sensitivity of 97% and a specificity of 42%. CONCLUSION: The tuberculosis prediction rule derived from our patient population could improve utilization of airborne precautions. Clinical prediction rules continue to show their utility for improvement in isolation practices in different demographic areas.

Electronic medical records and their impact on resident and medical student education.

OBJECTIVE: Electronic medical records (EMRs) are becoming prevalent and integral tools for residents and medical students. EMRs can integrate point-of-service information delivery within the context of patient care. Though it may be an educational tool, little is known about how EMR technology is currently used for medical learners. METHOD: The authors reviewed the available published literature about the impact of EMRs on learners, including learners' attitudes about EMRs, educational uses of EMRs, and the potential effects of EMRs on learners' daily work. RESULTS: Research on EMRs for education is in its infancy. The authors found fewer than 50 articles with evidence on their use in medical education. The applications to education included point-of-care knowledge delivery, computerized clinical decision support systems, profiling of learner experiences, and daily workflow management. The evidence was mainly derived from single institution studies and occasionally across disciplines. CONCLUSIONS: EMRs have great potential as an educational tool, but thus far, strong data to support their use for this are lacking. As the usage of EMRs rises, educators must continue to study how best to use technology as an educational tool and as a tool to improve the daily work of residents and medical students.