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Item Acute kidney injury in hospitalized children with sickle cell anemia(BMC, 2022-03-18) Batte, Anthony; Menon, Sahit; Ssenkusu, John; Kiguli, Sarah; Kalyesubula, Robert; Lubega, Joseph; Mutebi, Edrisa Ibrahim; Opoka, Robert O.; John, Chandy C.; Starr, Michelle C.; Conroy, Andrea L.; Pediatrics, School of MedicineBackground: Children with sickle cell anemia (SCA) are at increased risk of acute kidney injury (AKI) that may lead to death or chronic kidney disease. This study evaluated AKI prevalence and risk factors in children with SCA hospitalized with a vaso-occlusive crisis (VOC) in a low-resource setting. Further, we evaluated whether modifications to the Kidney Disease: Improving Global Outcomes (KDIGO) definition would influence clinical outcomes of AKI in children with SCA hospitalized with a VOC. Methods: We prospectively enrolled 185 children from 2 - 18 years of age with SCA (Hemoglobin SS) hospitalized with a VOC at a tertiary hospital in Uganda. Kidney function was assessed on admission, 24-48 h of hospitalization, and day 7 or discharge. Creatinine was measured enzymatically using an isotype-dilution mass spectrometry traceable method. AKI was defined using the original-KDIGO definition as ≥ 1.5-fold change in creatinine within seven days or an absolute change of ≥ 0.3 mg/dl within 48 h. The SCA modified-KDIGO (sKDIGO) definition excluded children with a 1.5-fold change in creatinine from 0.2 mg/dL to 0.3 mg/dL. Results: Using KDIGO, 90/185 (48.7%) children had AKI with 61/185 (33.0%) AKI cases present on admission, and 29/124 (23.4%) cases of incident AKI. Overall, 23 children with AKI had a 1.5-fold increase in creatinine from 0.2 mg/dL to 0.3 m/dL. Using the sKDIGO-definition, 67/185 (36.2%) children had AKI with 43/185 (23.2%) cases on admission, and 24/142 (16.9%) cases of incident AKI. The sKDIGO definition, but not the original-KDIGO definition, was associated with increased mortality (0.9% vs. 7.5%, p = 0.024). Using logistic regression, AKI risk factors included age (aOR, 1.10, 95% CI 1.10, 1.20), hypovolemia (aOR, 2.98, 95% CI 1.08, 8.23), tender hepatomegaly (aOR, 2.46, 95% CI 1.05, 5.81), and infection (aOR, 2.63, 95% CI 1.19, 5.81) (p < 0.05). Conclusion: These results demonstrate that AKI is a common complication in children with SCA admitted with VOC. The sKDIGO definition of AKI in children with SCA was a better predictor of clinical outcomes in children. There is need for promotion of targeted interventions to ensure early identification and treatment of AKI in children with SCA.Item Autoantibody levels are associated with acute kidney injury, anemia and post-discharge morbidity and mortality in Ugandan children with severe malaria(Nature Research, 2019-10-17) Rivera-Correa, Juan; Conroy, Andrea L.; Opoka, Robert O.; Batte, Anthony; Namazzi, Ruth; Ouma, Benson; Bangirana, Paul; Idro, Richard; Schwaderer, Andrew L.; John, Chandy C.; Rodriguez, Ana; Pediatrics, School of MedicineAutoantibodies targeting host antigens contribute to autoimmune disorders, frequently occur during and after infections and have been proposed to contribute to malaria-induced anemia. We measured anti-phosphatidylserine (PS) and anti-DNA antibody levels in 382 Ugandan children prospectively recruited in a study of severe malaria (SM). High antibody levels were defined as antibody levels greater than the mean plus 3 standard deviations of community children (CC). We observed increases in median levels of anti-PS and anti-DNA antibodies in children with SM compared to CC (p < 0.0001 for both). Children with severe malarial anemia were more likely to have high anti-PS antibodies than children with cerebral malaria (16.4% vs. 7.4%), p = 0.02. Increases in anti-PS and anti-DNA antibodies were associated with decreased hemoglobin (p < 0.05). A one-unit increase in anti-DNA antibodies was associated with a 2.99 (95% CI, 1.68, 5.31) increase odds of acute kidney injury (AKI) (p < 0.0001). Elevated anti-PS and anti-DNA antibodies were associated with post-discharge mortality (p = 0.031 and p = 0.042, respectively). Children with high anti-PS antibodies were more likely to have multiple hospital readmissions compared to children with normal anti-PS antibody levels (p < 0.05). SM is associated with increased autoantibodies against PS and DNA. Autoantibodies were associated with anemia, AKI, post-discharge mortality, and hospital readmission.Item Both MisR (CpxR) and MisS (CpxA) Are Required for Neisseria gonorrhoeae Infection in a Murine Model of Lower Genital Tract Infection(American Society for Microbiology, 2017-08-18) Gangaiah, Dharanesh; Raterman, Erica L.; Wu, Hong; Fortney, Kate R.; Gao, Hongyu; Liu, Yunlong; Jerse, Ann E.; Spinola, Stanley M.; Microbiology and Immunology, School of MedicineDuring infection, Neisseria gonorrhoeae senses and responds to stress; such responses may be modulated by MisRS (NGO0177 and NGO0176), a two-component system that is a homolog of CpxRA. In Escherichia coli, CpxRA senses and responds to envelope stress; CpxA is a sensor kinase/phosphatase for CpxR, a response regulator. When a cpxA mutant is grown in medium containing glucose, CpxR is phosphorylated by acetyl phosphate but cannot be dephosphorylated, resulting in constitutive activation. Kandler and coworkers (J. L. Kandler, C. L. Holley, J. L. Reimche, V. Dhulipala, J. T. Balthazar, A. Muszyński, R. W. Carlson, and W. M. Shafer, Antimicrob Agents Chemother 60:4690-4700, 2016, https://doi.org/10.1128/AAC.00823-16) showed that MisR (CpxR) is required for the maintenance of membrane integrity and resistance to antimicrobial peptides, suggesting a role in gonococcal survival in vivo Here, we evaluated the contributions of MisR and MisS (CpxA) to gonococcal infection in a murine model of cervicovaginal colonization and identified MisR-regulated genes using RNA sequencing (RNA-Seq). The deletion of misR or misS severely reduced the capacity of N. gonorrhoeae to colonize mice or maintain infection over a 7-day period and reduced microbial fitness after exposure to heat shock. Compared to the wild type (WT), the inactivation of misR identified 157 differentially regulated genes, most of which encoded putative envelope proteins. The inactivation of misS identified 17 differentially regulated genes compared to the WT and 139 differentially regulated genes compared to the misR mutant, 111 of which overlapped those differentially expressed in the comparison of the WT versus the misR mutant. These data indicate that an intact MisRS system is required for gonococcal infection of mice. Provided the MisR is constitutively phosphorylated in the misS mutant, the data suggest that controlled but not constitutive activation is required for gonococcal infection in mice.Item Cerebrospinal fluid levels of extracellular heat shock protein 72: A potential biomarker for bacterial meningitis in children(Thieme, 2014-03) Standage, Stephen W.; Lahni, Patrick M.; Ma, William; Kernie, Steven G.; Wong, Hector R.; Wheeler, Derek S.; Pediatrics, School of MedicineExtracellular heat shock protein 72 (Hsp72) is an endogenous danger signal and potential biomarker for critical illness in children. We hypothesized that elevated levels of extracellular Hsp72 in the cerebrospinal fluid (CSF) of children with suspected meningitis could predict bacterial meningitis. We measured extracellular Hsp72 levels in the CSF of 31 critically ill children with suspected meningitis via a commercially available enzyme-linked immunosorbent assay. Fourteen had bacterial meningitis based on CSF pleocytosis and bacterial growth in either blood or CSF culture. Seventeen children with negative cultures comprised the control group. CSF Hsp72 was significantly elevated in children with bacterial meningitis compared to controls. Importantly, CSF Hsp72 levels did not correlate with the CSF white blood cell count. On receiver operator characteristic analysis, using a cut-off of 8.1 ng/mL, CSF Hsp72 has a sensitivity of 79% and a specificity of 94% for predicting bacterial meningitis. We therefore conclude that CSF extracellular Hsp72 levels are elevated in critically ill children with bacterial meningitis versus controls. Hsp72 potentially offers clinicians improved diagnostic information in distinguishing bacterial meningitis from other processes.Item The Cost of Complications Following Major Resection of Malignant Neoplasia(Springer Nature, 2018-11) Zogg, Cheryl K.; Ottesen, Taylor D.; Kebaish, Kareem; Galivanche, Anoop; Murthy, Shilpa; Changoor, Navin R.; Zogg, Donald L.; Pawlik, Timothy M.; Haider, Adil H.; Surgery, School of MedicineBACKGROUND: Rising healthcare costs have led to increased focus on the need to achieve a higher "value of care." As value-maximization efforts expand to include more complex surgical patients, evidence to support meaningful implementation of complication-based initiatives is lacking. The objective of this study was to compare incremental costs of complications following major gastrointestinal (GI) resections for organ-specific malignant neoplasia using nationally representative data. METHODS: National (Nationwide) Inpatient Sample data, 2001-2014, were queried for adult (≥ 18 years) patients undergoing major resections for malignant neoplasia. Based on system-based complications considered relevant to the long-term treatment of GI disease, stratified differences in risk-adjusted incremental hospital costs and complication probabilities were compared. Differences in surgical outcomes and costs over time were also assessed. RESULTS: A total of 293,967 patients were included, weighted to represent 1,408,117 patients nationwide. One fourth (26.1%; 95% CI, 25.7-26.4%) experienced ≥ 1 pre-discharge complication (range, 45.3% esophagectomy to 24.0% rectal resection). Resultant annual risk-adjusted incremental hospital costs totaled $540 million nationwide (19.5% of the overall cost of care and an average of $20,900 per patient). Costs varied substantially with both cancer/resection type and complication group, ranging from $76.7 million for colectomies with infectious complications to $0.2 million for rectal resections with urinary complications. For each resection type, infectious ($154.7 million), GI ($85.5 million), and pulmonary ($77.9 million) complications were among the most significant drivers of increased hospital cost. CONCLUSIONS: Quantifying and comparing the impact of complications on an indication-specific level in more complex patients offers an important step toward allowing providers/payers to meaningfully prioritize the design of novel and adaptation of existing value-maximization approaches.Item Effect of a point-of-care ultrasound (POCUS) curriculum on emergency department soft tissue management(Springer, 2022-10-21) Nti, Benjamin K.; Phillips, Whitney; Sarmiento, Elisa; Russell, Frances; Emergency Medicine, School of MedicineBackground: Pediatric emergency department (ED) visits for superficial skin and soft tissue infections (SSTI) have steadily been increasing and point-of-care ultrasound (POCUS) continues to be an effective modality to improve management and shorter ED length of stays (LOS). Objective: We sought to determine the impact of a soft tissue POCUS curriculum on POCUS utilization, ED LOS, and cost-effectiveness. Methods: This was a retrospective pre- and post-interventional study of pediatric patients aged 0 to 17 years. Patients presenting to ED with international classification of disease 9 or 10 code for abscess or cellulitis were included. Data were collected a year before and after curriculum implementation with a 1-year washout training period. Training included continuing medical education, greater than 25 quality assured examinations, and a post-test. We compared diagnostic imaging type, ED LOS, and mean charges in patients with SSTI. Results: We analyzed data on 119 total patients, 38 pre- and 81 post-intervention. We found a significant increase in the total number of POCUS examinations performed pre- to post-curriculum intervention, 26 vs. 59 (p = 0.0017). Mean total charges were significantly decreased from $3,762 (± 270) to $2,622 (± 158; p = 0.0009). There was a significant trend towards a decrease in average ED LOS 282 (standard error of mean [SEM] ± 19) vs 185 (± 13) minutes (p = 0.0001). Conclusions: Implementation of a soft tissue POCUS curriculum in a pediatric ED was associated with increased POCUS use, decreased LOS, and lower cost. These findings highlight the importance of POCUS education and implementation in the management of pediatric SSTI.Item Elucidating the interaction of Borrelia burgdorferi OspC with phagocytes in the establishment of lyme borreliosis(2015-03-20) Carrasco, Sebastian Eduardo; Yang, X. Frank; Serezani, C. Henrique; Blum, Janice Sherry, 1957-; Johnson, Raymond M.; Bauer, Margaret E.Lyme disease, the most prevalent vector-borne illness in the United States, is a multisystem inflammatory disorder caused by infection with the spirochete Borrelia burgdorferi (Bb). This spirochete is maintained in nature through an enzootic cycle involving ticks and small mammals. The Bb genome encodes a large number of surface lipoproteins, many of which are expressed during mammalian infection. One of these lipoproteins is the major outer surface protein C (OspC) whose production is induced during transmission as spirochetes transition from ticks to mammals. OspC is required for Bb to establish infection in mice and has been proposed to facilitate evasion of innate immunity. However, the exact biological function of OspC remains elusive. Our studies show the ospC-deficient spirochete could not establish infection in NOD-scid IL2rγnull mice that lack B cells, T cells, NK cells, and lytic complement, whereas the wild-type spirochete was fully infectious in these mice. The ospC mutant also could not establish infection in SCID and C3H mice that were transiently neutropenic during the first 48 h post-challenge. However, depletion of F4/80+ phagocytes at the skin-site of inoculation in SCID mice allowed the ospC mutant to establish infection in vivo. In phagocyte-depleted SCID mice, the ospC mutant was capable to colonize the joints and triggered neutrophilia during dissemination in a similar pattern as wild-type bacteria. We then constructed GFP-expressing Bb strains to evaluate the interaction of the ospC mutant with phagocytes. Using flow cytometry and fluorometric assay for phagocytosis, we found that phagocytosis of GFP-expressing ospC mutant spirochetes by murine peritoneal macrophages and human THP-1 cells was significantly higher than parental wild-type Bb strains, suggesting that OspC has an anti-phagocytic property. This enhancement in phagocytosis was not mediated by MARCO and CD36 scavenger receptors and was not associated with changes in mRNA levels of TNFα, IL-1β, and IL-10. Phagocytosis assays with HL60 neutrophil-like cells showed that uptake of Bb strains was independent to OspC. Together, our findings reveal that F4/80+ phagocytes are important for clearance of the ospC mutant, and suggest that OspC promotes spirochetes' evasion of macrophages in the skin of mice during early Lyme borreliosis.Item Exposure to Epstein Barr Virus and Cognitive Functioning in Individuals with Schizophrenia(Elsevier, 2021) Dickerson, Faith; Katsafanas, Emily; Origoni, Andrea; Squire, Amalia; Khushalani, Sunil; Newman, Theresa; Rowe, Kelly; Stallings, Cassie; Savage, Christina L. G.; Sweeney, Kevin; Nguyen, Tanya T.; Breier, Alan; Goff, Donald; Ford, Glen; Jones-Brando, Lorraine; Yolken, Robert; Psychiatry, School of MedicineCognitive deficits are a central feature of schizophrenia whose etiology is not fully understood. Epstein Barr Virus (EBV) is a potentially neurotropic infectious agent that can generate persistent infections with immunomodulatory effects. Previous studies have found an association between EBV antibodies and cognitive functioning in different populations, but there has been limited investigation in schizophrenia. In this study, 84 individuals with schizophrenia were administered a comprehensive neuropsychological battery, the MATRICS Consensus Cognitive Battery (MCCB). Participants also provided a blood sample, from which antibodies to the EBV whole virion and specific proteins were measured. Multivariate models were constructed to determine the association between these antibodies and cognitive performance on the MCCB overall and domain scores. Using these models, we found a significant association between the MCCB overall percent composite score and level of antibodies to the EBV Nuclear Antigen-1 (EBNA-1) protein, the Viral Capsid Antigen (VCA) protein, and the EBV whole virion. A significant association was also found for the MCCB social cognition domain with the level of antibodies to the EBV Nuclear Antigen-1 (EBNA-1) protein, the Viral Capsid Antigen (VCA) protein, and the EBV whole virion. In all cases, a higher level of antibodies was associated with a lower level cognitive performance. These findings suggest that exposure to EBV may contribute to cognitive deficits in schizophrenia, a finding which may have implications for new methods of prevention and treatment.Item Gastrointestinal Eosinophilic Granulomatosis with Polyangiitis following a Clostridium difficile Infecti(Karger, 2023-06-13) Mohideen, Haseeb; Weldemichael, Wegahta; Hussain, Hafsa; Dahiya, Dushyant Singh; Shin, Andrea; Medicine, School of MedicineEosinophilic granulomatosis with polyangiitis (EGPA), historically named Churg-Strauss syndrome, is a rare vasculitis affecting small- and medium-sized blood vessels. The disease has a predilection for numerous organs including the lungs, sinuses, kidneys, heart, nerves, and gastrointestinal tract but is prominently associated with asthma, rhinosinusitis, and eosinophilia. Gastrointestinal involvement is common; however, a gastrointestinal manifestation as the cardinal symptom following an infection is atypical. Here, we present a case of a 61-year-old male who presented with persistent diarrhea following a toxigenic Clostridium difficile infection despite multiple antibiotic courses. Repeat testing confirmed eradication of the infection, and further evaluation with colon biopsy revealed small and medium-sized vasculitis with eosinophilic infiltration and granulomas. Treatment with prednisone and cyclophosphamide resulted in rapid improvement of his diarrhea. Gastrointestinal symptoms in EGPA are associated with worse prognosis, so prompt identification and treatment of the disease is crucial. EGPA is rarely documented in histopathological samples from the gastrointestinal tract as endoscopic biopsies are typically too superficial to sample the submucosal layer containing the affected vessels. Additionally, the link between EGPA and infections as a potential trigger has not been clearly established, but gastrointestinal EGPA manifesting after a colonic infection raises concerns that this may have been a triggering event. Ultimately, further study is needed to understand, diagnose, and treat gastrointestinal and postinfection EGPA.Item Genes Differentially Expressed by Haemophilus ducreyi during Anaerobic Growth Significantly Overlap Those Differentially Expressed during Experimental Infection of Human Volunteers(American Society for Microbiology, 2022) Brothwell, Julie A.; Spinola, Stanley M.; Microbiology and Immunology, School of MedicineHaemophilus ducreyi causes cutaneous ulcers in children and the genital ulcer disease chancroid in adults. In humans, H. ducreyi is found in the anaerobic environment of an abscess; previous studies comparing bacterial gene expression levels in pustules with the inocula (∼4-h aerobic mid-log-phase cultures) identified several upregulated differentially expressed genes (DEGs) that are associated with anaerobic metabolism. To determine how H. ducreyi alters its gene expression in response to anaerobiosis, we performed RNA sequencing (RNA-seq) on both aerobic and anaerobic broth cultures harvested after 4, 8, and 18 h of growth. Principal-coordinate analysis (PCoA) plots showed that anaerobic growth resulted in distinct transcriptional profiles compared to aerobic growth. During anaerobic growth, early-time-point comparisons (4 versus 8 h) identified few DEGs at a 2-fold change in expression and a false discovery rate (FDR) of <0.01. By 18 h, we observed 18 upregulated and 16 downregulated DEGs. DEGs involved in purine metabolism, the uptake and use of alternative carbon sources, toxin production, nitrate reduction, glycine metabolism, and tetrahydrofolate synthesis were upregulated; DEGs involved in electron transport, thiamine biosynthesis, DNA recombination, peptidoglycan synthesis, and riboflavin synthesis or modification were downregulated. To examine whether transcriptional changes that occur during anaerobiosis overlap those that occur during infection of human volunteers, we compared the overlap of DEGs obtained from 4 h of aerobic growth to 18 h of anaerobic growth to those found between the inocula and pustules in previous studies; the DEGs significantly overlapped. Thus, a major component of H. ducreyi gene regulation in vivo involves adaptation to anaerobiosis. IMPORTANCE: In humans, H. ducreyi resides in the anaerobic environment of an abscess and appears to upregulate genes involved in anaerobic metabolism. How anaerobiosis alone affects gene transcription in H. ducreyi is unknown. Using RNA-seq, we investigated how anaerobiosis affects gene transcription over time compared to aerobic growth. Our results suggest that a substantial component of H. ducreyi gene regulation in vivo overlaps the organism's response to anaerobiosis in vitro. Our data identify potential therapeutic targets that could be inhibited during in vivo growth.