Risk Factors for Adverse Events in Children Receiving Outpatient Parenteral Antibiotic Therapy.

BACKGROUND: Outpatient parenteral antibiotic therapy (OPAT) can decrease length of hospital stay but is associated with adverse events (AEs). The purpose of this study was to quantify and identify risk factors for OPAT-associated AEs in children. METHODS: Retrospective single-center study of children ≤21 years old discharged on OPAT from January 2016 to April 2019 with infectious diseases follow-up. Demographic and clinical factors and medication and central venous catheter (CVC)-associated AEs were assessed through chart review. Univariable and multivariable analyses were performed. RESULTS: Among 181 OPAT courses, an AE occurred in 70 (39%). Medication AEs occurred in 30 of 181 courses (16.6%). Children residing in an urban area had a 4.5 times higher risk of having a medication-related AE compared with those in a rural area (odds ratio: 4.51; 95% confidence interval: 1.60-12.77; P = .005). CVC AEs occurred in 47 of 181 courses (26%). Every additional day of OPAT increased the odds of having a CVC-related AE by 4% (odds ratio: 1.04; 95% confidence interval: 1.01-1.07; P = .003). Twenty (11.1%) courses resulted in readmission to the hospital because of an AE. CONCLUSIONS: In this cohort, 39% of children experienced an OPAT-associated AE, and CVC AEs were more common than medication AEs. Longer duration of intravenous therapy and urban residence were independently associated with OPAT-associated AEs, highlighting the importance of converting to oral antibiotic therapy as soon as feasible to reduce OPAT-associated AEs.

Upregulation of HLA-E by dengue and not Zika viruses.

INTRODUCTION: The most severe form of dengue virus (DENV) illness, dengue haemorrhagic fever, is characterised by plasma leakage and increased vascular permeability. OBJECTIVES: Given the critical role that endothelial cells play in the pathogenesis of DENV, we wanted to determine whether infection with DENV altered the expression of MHC class I related genes including HLA-E. RESULTS: In this study, we provide evidence that HLA-E but not MICA/B or HLA-G is upregulated by all four serotypes of DENV in an endothelial cell line human microvascular endothelial cells (HMEC)-1. In contrast, Zika virus (ZIKV), a related flavivirus, where plasma leakage is not a major manifestation of disease, did not upregulate HLA-E. We found modest levels of soluble HLA-E in supernatants from DENV but not ZIKV-infected cells. Coculture experiments found minimal activation of natural killer (NK) cells in the presence of both uninfected and infected HMEC-1 cells. HLA-E induced by DENV infection could not dampen the degranulation of activated NK cells by interacting with its ligand NKG2a. CONCLUSIONS: Our results suggest that while DENV infection induces HLA-E, the high MHC class I expression on uninfected and infected HMEC-1 cells may dominate the diverse signals generated between inhibitory and activating receptors on NK cells and ligands on target cells.

Short-term global health education programs abroad: disease patterns observed in Haitian migrant worker communities around La Romana, Dominican Republic.

The possibility of encountering rare tropical disease presentations is commonly described as a benefit derived by developed world medical trainees participating in clinical service-oriented short-term global health experiences in the developing world. This study describes the health status of a population served by a short-term experience conducted by a North American institute, and the results of a retrospective review are used to identify commonly encountered diseases and discuss their potential educational value. Descriptive analysis was conducted on 1,024 encounter records collected over four unique 1-week-long trips by a North American institution serving Haitian migrant workers in La Romana, Dominican Republic. The top five diagnoses seen in the clinic were gastroesophageal reflux disease (GERD), hypertension (HTN), upper respiratory infections, otitis media, and fungal skin infection. On occasion, diagnoses unique to an indigent tropical population were encountered (e.g., dehydration, malnutrition, parasites, and infections.). These findings suggest a similarity between frequently encountered diagnoses on a short-term clinical service trip in Dominican Republic and primary care presentations in developed world settings, which challenges the assumption that short-term service experiences provide exposure to rare tropical disease presentations. These findings also represent additional data that can be used to better understand the health and healthcare planning among this vulnerable population of Haitian migrant workers.

Elucidating the role of T cells in protection against and pathogenesis of dengue virus infections.

Dengue viruses (DENV) cause significantly more human disease than any other arbovirus, with hundreds of thousands of cases leading to severe disease in thousands annually. Antibodies and T cells induced by primary infection with DENV have the potential for both positive (protective) and negative (pathological) effects during subsequent DENV infections. In this review, we summarize studies that have examined T-cell responses in humans following natural infection and vaccination. We discuss studies that support a role for T cells in protection against and those that support a role for the involvement of T cells in the pathogenesis of severe disease. The mechanisms that lead to severe disease are complex, and T-cell responses are an important component that needs to be further evaluated for the development of safe and efficacious DENV vaccines.

Distinct activation phenotype of a highly conserved novel HLA-B57-restricted epitope during dengue virus infection.

Variation in the sequence of T-cell epitopes between dengue virus (DENV) serotypes is believed to alter memory T-cell responses during second heterologous infections. We identified a highly conserved, novel, HLA-B57-restricted epitope on the DENV NS1 protein. We predicted higher frequencies of B57-NS1(26-34) -specific CD8(+) T cells in peripheral blood mononuclear cells from individuals undergoing secondary rather than primary DENV infection. However, high tetramer-positive T-cell frequencies during acute infection were seen in only one of nine subjects with secondary infection. B57-NS1(26-34) -specific and other DENV epitope-specific CD8(+) T cells, as well as total CD8(+) T cells, expressed an activated phenotype (CD69(+) and/or CD38(+)) during acute infection. In contrast, expression of CD71 was largely limited to DENV epitope-specific CD8(+) T cells. In vitro stimulation of cell lines indicated that CD71 expression was differentially sensitive to stimulation by homologous and heterologous variant peptides. CD71 may represent a useful marker of antigen-specific T-cell activation.

Covert genetic selections to optimize phenotypes.

In many high complexity systems (cells, organisms, institutions, societies, economies, etc.), it is unclear which components should be regulated to affect overall performance. To identify and prioritize molecular targets which impact cellular phenotypes, we have developed a selection procedure ("SPI"-single promoting/inhibiting target identification) which monitors the abundance of ectopic cDNAs. We have used this approach to identify growth regulators. For this purpose, complex pools of S. cerevisiae cDNA transformants were established and we quantitated the evolution of the spectrum of cDNAs which was initially present. These data emphasized the importance of translation initiation and ER-Golgi traffic for growth. SPI provides functional insight into the stability of cellular phenotypes under circumstances in which established genetic approaches cannot be implemented. It provides a functional "synthetic genetic signature" for each state of the cell (i.e. genotype and environment) by surveying complex genetic libraries, and does not require specialized arrays of cDNAs/shRNAs, deletion strains, direct assessment of clonal growth or even a conditional phenotype. Moreover, it establishes a hierarchy of importance of those targets which can contribute, either positively or negatively, to modify the prevailing phenotype. Extensions of these proof-of-principle experiments to other cell types should provide a novel and powerful approach to analyze multiple aspects of the basic biology of yeast and animal cells as well as clinically-relevant issues.