IU Indianapolis ScholarWorks :: Browsing by Author "Katz, Barry P."

Browsing by Author "Katz, Barry P."

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Aetiology and prevalence of mixed-infections and mono-infections in non-gonococcal urethritis in men: a case-control study
(BMJ, 2020-06) Jordan, Stephen J.; Toh, Evelyn; Williams, James A.; Fortenberry, Lora; LaPradd, Michelle L.; Katz, Barry P.; Batteiger, Byron E.; Nelson, David E.; Batteiger, Teresa A.; Medicine, School of Medicine
Objectives: Chlamydia trachomatis (CT) and Mycoplasma genitalium (MG) cause the majority of non-gonococcal urethritis (NGU). The role of Ureaplasma urealyticum (UU) in NGU is unclear. Prior case-control studies that examined the association of UU and NGU may have been confounded by mixed infections and less stringent criteria for controls. The objective of this case-control study was to determine the prevalence and aetiology of mixed infections in men and assess if UU monoinfection is associated with NGU. Methods: We identified 155 men with NGU and 103 controls. Behavioural and clinical information was obtained and men were tested for Neisseria gonorrhoeae and CT, MG, UU and Trichomonas vaginalis (TV). Men who were five-pathogen negative were classified as idiopathic urethritis (IU). Results: Twelve per cent of NGU cases in which a pathogen was identified had mixed infections, mostly UU coinfections with MG or CT; 27% had IU. In monoinfected NGU cases, 34% had CT, 17% had MG, 11% had UU and 2% had TV. In controls, pathogens were rarely identified, except for UU, which was present in 20%. Comparing cases and controls, NGU was associated with CT and MG monoinfections and mixed infections. UU monoinfection was not associated with NGU and was almost twice as prevalent in controls. Men in both the case and control groups who were younger and who reported no prior NGU diagnosis were more likely to have UU (OR 0.97 per year of age, 95% CI 0.94 to 0.998 and OR 6.3, 95% CI 1.4 to 28.5, respectively). Conclusions: Mixed infections are common in men with NGU and most of these are UU coinfections with other pathogens that are well-established causes of NGU. UU monoinfections are not associated with NGU and are common in younger men and men who have never previously had NGU. Almost half of NGU cases are idiopathic.
Age and Sex Divergence in Hematopoietic Radiosensitivity in Aged Mouse Models of the Hematopoietic Acute Radiation Syndrome
(BioOne, 2022) Patterson, Andrea M.; Vemula, Sasidhar; Plett, P. Artur; Sampson, Carol H.; Chua, Hui Lin; Fisher, Alexa; Wu, Tong; Sellamuthu, Rajendran; Feng, Hailin; Katz, Barry P.; DesRosiers, Colleen M.; Pelus, Louis M.; Cox, George N.; MacVittie, Thomas J.; Orschell, Christie M.; Medicine, School of Medicine
The hematopoietic system is highly sensitive to stress from both aging and radiation exposure, and the hematopoietic acute radiation syndrome (H-ARS) should be modeled in the geriatric context separately from young for development of age-appropriate medical countermeasures (MCMs). Here we developed aging murine H-ARS models, defining radiation dose response relationships (DRRs) in 12-month-old middle-aged and 24-month-old geriatric male and female C57BL/6J mice, and characterized diverse factors affecting geriatric MCM testing. Groups of approximately 20 mice were exposed to ∼10 different doses of radiation to establish radiation DRRs for estimation of the LD50/30. Radioresistance increased with age and diverged dramatically between sexes. The LD50/30 in young adult mice averaged 853 cGy and was similar between sexes, but increased in middle age to 1,005 cGy in males and 920 cGy in females, with further sex divergence in geriatric mice to 1,008 cGy in males but 842 cGy in females. Correspondingly, neutrophils, platelets, and functional hematopoietic progenitor cells were all increased with age and rebounded faster after irradiation. These effects were higher in aged males, and neutrophil dysfunction was observed in aged females. Upstream of blood production, hematopoietic stem cell (HSC) markers associated with age and myeloid bias (CD61 and CD150) were higher in geriatric males vs. females, and sex-divergent gene signatures were found in HSCs relating to cholesterol metabolism, interferon signaling, and GIMAP family members. Fluid intake per gram body weight decreased with age in males, and decreased after irradiation in all mice. Geriatric mice of substrain C57BL/6JN sourced from the National Institute on Aging were significantly more radiosensitive than C57BL/6J mice from Jackson Labs aged at our institution, indicating mouse source and substrain should be considered in geriatric radiation studies. This work highlights the importance of sex, vendor, and other considerations in studies relating to hematopoiesis and aging, identifies novel sex-specific functional and molecular changes in aging hematopoietic cells at steady state and after irradiation, and presents well-characterized aging mouse models poised for MCM efficacy testing for treatment of acute radiation effects in the elderly.
Association of Blood Biomarkers With Acute Sport-Related Concussion in Collegiate Athletes: Findings From the NCAA and Department of Defense CARE Consortium
(JAMA Network, 2020-01-03) McCrea, Michael; Broglio, Steven P.; McAllister, Thomas W.; Gill, Jessica; Giza, Christopher C.; Huber, Daniel L.; Harezlak, Jaroslaw; Cameron, Kenneth L.; Houston, Megan N.; McGinty, Gerald; Jackson, Jonathan C.; Guskiewicz, Kevin; Mihalik, Jason; Brooks, M. Alison; Duma, Stephan; Rowson, Steven; Nelson, Lindsay D.; Pasquina, Paul; Meier, Timothy B.; CARE Consortium Investigators; Foroud, Tatiana; Katz, Barry P.; Saykin, Andrew J.; Campbell, Darren E.; Svoboda, Steven J.; Goldman, Joshua; DiFiori, Jon; Psychiatry, School of Medicine
Importance: There is potential scientific and clinical value in validation of objective biomarkers for sport-related concussion (SRC). Objective: To investigate the association of acute-phase blood biomarker levels with SRC in collegiate athletes. Design, Setting, and Participants: This multicenter, prospective, case-control study was conducted by the National Collegiate Athletic Association (NCAA) and the US Department of Defense Concussion Assessment, Research, and Education (CARE) Consortium from February 20, 2015, to May 31, 2018, at 6 CARE Advanced Research Core sites. A total of 504 collegiate athletes with concussion, contact sport control athletes, and non-contact sport control athletes completed clinical testing and blood collection at preseason baseline, the acute postinjury period, 24 to 48 hours after injury, the point of reporting being asymptomatic, and 7 days after return to play. Data analysis was conducted from March 1 to November 30, 2019. Main Outcomes and Measures: Glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light chain, and tau were quantified using the Quanterix Simoa multiplex assay. Clinical outcome measures included the Sport Concussion Assessment Tool-Third Edition (SCAT-3) symptom evaluation, Standardized Assessment of Concussion, Balance Error Scoring System, and Brief Symptom Inventory 18. Results: A total of 264 athletes with concussion (mean [SD] age, 19.08 [1.24] years; 211 [79.9%] male), 138 contact sport controls (mean [SD] age, 19.03 [1.27] years; 107 [77.5%] male), and 102 non-contact sport controls (mean [SD] age, 19.39 [1.25] years; 82 [80.4%] male) were included in the study. Athletes with concussion had significant elevation in GFAP (mean difference, 0.430 pg/mL; 95% CI, 0.339-0.521 pg/mL; P < .001), UCH-L1 (mean difference, 0.449 pg/mL; 95% CI, 0.167-0.732 pg/mL; P < .001), and tau levels (mean difference, 0.221 pg/mL; 95% CI, 0.046-0.396 pg/mL; P = .004) at the acute postinjury time point compared with preseason baseline. Longitudinally, a significant interaction (group × visit) was found for GFAP (F7,1507.36 = 16.18, P < .001), UCH-L1 (F7,1153.09 = 5.71, P < .001), and tau (F7,1480.55 = 6.81, P < .001); the interaction for neurofilament light chain was not significant (F7,1506.90 = 1.33, P = .23). The area under the curve for the combination of GFAP and UCH-L1 in differentiating athletes with concussion from contact sport controls at the acute postinjury period was 0.71 (95% CI, 0.64-0.78; P < .001); the acute postinjury area under the curve for all 4 biomarkers combined was 0.72 (95% CI, 0.65-0.79; P < .001). Beyond SCAT-3 symptom score, GFAP at the acute postinjury time point was associated with the classification of athletes with concussion from contact controls (β = 12.298; 95% CI, 2.776-54.481; P = .001) and non-contact sport controls (β = 5.438; 95% CI, 1.676-17.645; P = .005). Athletes with concussion with loss of consciousness or posttraumatic amnesia had significantly higher levels of GFAP than athletes with concussion with neither loss of consciousness nor posttraumatic amnesia at the acute postinjury time point (mean difference, 0.583 pg/mL; 95% CI, 0.369-0.797 pg/mL; P < .001). Conclusions and Relevance: The results suggest that blood biomarkers can be used as research tools to inform the underlying pathophysiological mechanism of concussion and provide additional support for future studies to optimize and validate biomarkers for potential clinical use in SRC.
Baseline Performance of NCAA Athletes on a Concussion Assessment Battery: A Report from the CARE Consortium
(Springer, 2018-08) Katz, Barry P.; Kudela, Maria; Harezlak, Jaroslaw; McCrea, Michael; McAllister, Thomas; Broglio, Steven P.; Biostatistics, School of Public Health
Background Sport-related concussion and repetitive head impact exposure in contact sports continue to receive increased attention in public and medical spheres. The Concussion Assessment, Research and Education (CARE) Consortium, a multicenter cooperative, was established to study the natural history of concussion in National Collegiate Athletic Association (NCAA) collegiate student-athletes across 29 colleges and universities in the United States. The purpose of this investigation is to provide normative data from the CARE Consortium and evaluate for differences between sport categories. Methods NCAA student-athletes were evaluated annually for general demographics and sport-specific characteristics before the start of the competitive season. We collected demographic and medical history information and evaluated each student-athlete’s neurocognitive function, neurological status, postural stability, and self-reported symptoms. Sports were categorized by the amount of contact typically associated with the sport (i.e., contact, limited contact, non-contact). Comparisons between the three sport categories for the evaluated variables were made using linear or zero inflated negative binomial regression models adjusted for gender, concussion history, and household income. Results Over a 2-year period (August 2014–July 2016), 15,681 NCAA athletes completed preseason evaluations. Overall, 53% of the athletes were in the contact sport group, 31% were in the limited contact group and 17% were in the non-contact group. After adjusting for covariates, there were statistically significant differences found between athlete groups, although the differences and effect sizes were small and not clinically significant. The contact sport group had better scores on Immediate Post-Concussion Assessment Testing (ImPACT®) visual and verbal memory, Sport Concussion Assessment Tool (SCAT) symptom checklist, and Brief Symptom Inventory–18 (BSI-18), but slower ImPACT reaction time and worse scores on Standardized Assessment of Concussion (SAC). Further, the data indicate that some ImPACT score distributions were noticeably different from those presented in the technical manual. Conclusions In this large, racially and socio-economically diverse cohort of male and female college athletes, we found no evidence that student-athletes participating in contact sports have clinically meaningful deficits in pre-season cognitive and balance testing. They also did not report significantly more symptoms of psychological distress when compared with student-athletes in non-contact or limited contact sports. In addition, the data suggest potential limitations when using published ImPACT norms when evaluating injured athletes.
Challenges in Patient Enrollment and Retention in Clinical Studies for Alcoholic Hepatitis: Experience of the TREAT Consortium
(Wiley, 2017) Comerford, Megan; Lourens, Spencer; Liangpunsakul, Suthat; Chalasani, Naga P.; Sanyal, Arun J.; Shah, Vijay H.; Kamath, Patrick S.; Puri, Puneet; Katz, Barry P.; Radaeva, Svetlana; Crabb, David W.; Medicine, School of Medicine
The TREAT Consortium has carried out clinical studies on alcoholic hepatitis (AH) for over 4 years. We encountered problems with participant recruitment, retention, and eligibility for specific protocols. To improve our ability to carry out such trials, we reviewed recruitment screening logs, end of study logs, and surveyed study coordinators to learn the reasons for missing patients, why patients declined enrollment, and the number of patients eligible for treatment trials. Associations of the recruited subjects’ demographics with their adherence to follow-up appointments were examined. Three hundred eight-seven patients (AH and heavy drinking controls) were enrolled in the observational study, and 55 AH patients were recruited into treatment trials. About half of patients identified with AH could not be recruited; no specific reason could be determined for about two-thirds of these. Among the patients who gave a reason for not participating, the most common reasons were feeling too sick to participate, desire to concentrate on abstinence, and lack of interest in research. Approximately a quarter of the AH patients met eligibility criteria for treatment trials for moderate or severe AH and we were able to recruit half to two-thirds of those eligible. Approximately 35% of participants in the observational study returned for both 6- and 12-month follow-up visits. We did not identify biopsychosocial or demographic correlates of retention in the study. This analysis revealed that attempts at recruitment into trials for AH miss some subjects because of structural issues surrounding their hospital admission, and encounter a high rate of patient refusal to participate. Nonetheless, more than half of the patients who met the eligibility criteria for moderate or severe AH were entered into clinical trials. Retention rates for the observational study are relatively low. These findings need to be accounted for in clinical trial design and power analysis.
Characteristics and Outcomes of Athletes With Slow Recovery From Sports-Related Concussion: A CARE Consortium Study
(Wolters Kluwer, 2023) McAllister, Thomas W.; Broglio, Steven P.; Katz, Barry P.; Perkins, Susan M.; LaPradd, Michelle; Zhou, Wenxian; McCrea, Michael A.; Concussion Assessment, Research and Education (CARE) Consortium; Psychiatry, School of Medicine
Background and objectives: Some athletes experience a slow recovery after sport-related concussion (SRC). There is little agreement on what constitutes slow recovery, however, and minimal data on the prevalence, predictors, or prognosis for this group. The objectives of this study were to apply an operationalized definition of slow recovery and characterize predictors and long-term prognosis of these individuals. Methods: This is a prospective multisite observational study of collegiate athletes. Participants underwent multimodal assessments preseason and 5 additional time points after SRC. Time from injury to initiation of return to play progression (asymptomatic timepoint) and from injury to return to play (RTP) were the primary markers of recovery. Results: One thousand seven hundred fifty-one concussed male and female collegiate athletes were studied. Eighty percent of participants reached the asymptomatic and/or RTP time points by days 14 and 24, respectively. Slow recovery was thus defined as exceeding 1 or both of those intervals (n = 399). This group was statistically more likely to be female (41.1% vs 35.6%, p = 0.05), have higher initial postinjury SCAT symptom severity scores (mean [SD]: 36.6 [23.4] vs 25.4 [19.9], p < 0.001), lower postinjury Standardized Assessment of Concussion scores (mean [SD]:25.74 [2.98] vs 26.26 [2.85], p = 0.004), perform worse on the postinjury Balance Error Scoring System (mean [SD]: 17.8 [8.9] vs 15.9 [8.5], p < 0.01), have fewer assessments in the first 14 days after injury (mean [SD]: 48.8 [29.7] vs 67.9 [24.6], p < 0.01), and be injured in practice (70.7% vs 65.1%, p = 0.04). 77.6% of the slow recovery group returned to play within 60 days of injury, and 83.4% (n = 349) returned to play within 90 days of injury. Only 10.6% had not returned to play 6 months postinjury. Discussion: This study suggests an overall favorable prognosis for slowly recovering athletes and provides data for athletes and medical teams to consider in calibrating RTP expectations and making decisions about medical disqualification vs ongoing engagement in their sport.
A Class I Haemophilus ducreyi Strain Containing a Class II hgbA Allele Is Partially Attenuated in Humans: Implications for HgbA Vaccine Efficacy Trials
(American Society for Microbiology, 2019-07) Leduc, Isabelle; Fortney, Kate R.; Janowicz, Diane M.; Zwickl, Beth; Ellinger, Sheila; Katz, Barry P.; Lin, Huaiying; Dong, Qunfeng; Spinola, Stanley M.; Microbiology and Immunology, School of Medicine
Haemophilus ducreyi causes chancroid and is a major cause of cutaneous ulcers in children. Due to environmental reservoirs, both class I and class II H. ducreyi strains persist in cutaneous ulcer regions of endemicity following mass drug administration of azithromycin, suggesting the need for a vaccine. The hemoglobin receptor (HgbA) is a leading vaccine candidate, but its efficacy in animal models is class specific. Controlled human infection models can be used to evaluate vaccines, but only a class I strain (35000HP) has been characterized in this model. As a prelude to evaluating HgbA vaccines in the human model, we tested here whether a derivative of 35000HP containing a class II hgbA allele (FX548) is as virulent as 35000HP in humans. In eight volunteers infected at three sites with each strain, the papule formation rate was 95.8% for 35000HP versus 62.5% for FX548 (P = 0.021). Excluding doses of FX548 that were ≥2-fold higher than those of 35000HP, the pustule formation rate was 25% for 35000HP versus 11.7% for FX548 (P = 0.0053). By Western blot analysis, FX548 and 35000HP expressed equivalent amounts of HgbA in whole-cell lysates and outer membranes. The growth of FX548 and 35000HP was similar in media containing hemoglobin or hemin. By whole-genome sequencing and single-nucleotide polymorphism analysis, FX548 contained no mutations in open reading frames other than hgbA. We conclude that by an unknown mechanism, FX548 is partially attenuated in humans and is not a suitable strain for HgbA vaccine efficacy trials in the model.
Correction to: Test-Retest Reliability and Interpretation of Common Concussion Assessment Tools: Findings from the NCAA-DoD CARE Consortium
(Springer, 2018-07) Broglio, Steven P.; Katz, Barry P.; Zhao, Shi; McCrea, Michael; McAllister, Thomas; CARE Consortium Investigators; Biostatistics, School of Public Health
Corrigendum to: Human Challenge Studies Are Unlikely to Accelerate Coronavirus Vaccine Licensure due to Ethical and Practical Issues
(Oxford University Press, 2021-05-28) Spinola, Stanley M.; Zimet, Gregory D.; Ott, Mary A.; Katz, Barry P.; Microbiology and Immunology, School of Medicine
This corrects the article "Human Challenge Studies Are Unlikely to Accelerate Coronavirus Vaccine Licensure Due to Ethical and Practical Issues" in volume 222 on page 1572; https://doi.org/10.1093/infdis/jiaa457
CpxA Phosphatase Inhibitor Activates CpxRA and Is a Potential Treatment for Uropathogenic Escherichia coli in a Murine Model of Infection
(American Society for Microbiology, 2022-04-27) Fortney, Kate R.; Smith, Sara N.; van Rensburg, Julia J.; Brothwell, Julie A.; Gardner, Jessi J.; Katz, Barry P.; Ahsan, Nagib; Duerfeldt, Adam S.; Mobley, Harry L.T.; Spinola, Stanley M.; Microbiology and Immunology, School of Medicine
CpxRA is an envelope stress response system that is highly conserved in the Enterobacteriaceae. CpxA has kinase activity for CpxR and phosphatase activity for phospho-CpxR (CpxR-P), a transcription factor. In response to membrane stress, CpxR-P is produced and upregulates genes involved in membrane repair and downregulates genes that encode virulence factors that are trafficked across the cell membrane. Mutants that constitutively activate CpxRA in Salmonella enterica serovar Typhimurium and in uropathogenic Escherichia coli (UPEC) are attenuated in murine models. We hypothesized that pharmacologic activation of CpxR could serve as an antimicrobial/antivirulence strategy and recently showed that 2,3,4,9-tetrahydro-1H-carbazol-1-amines activate the CpxRA system by inhibiting CpxA phosphatase activity. Here, we tested the ability of a series of three CpxRA-activating compounds with increasing potency to clear UPEC stain CFT073 in a murine urinary tract infection model. We show that these compounds are well tolerated and achieve sufficient levels to activate CpxR in the kidneys, bladder, and urine. Although the first two compounds were ineffective in promoting clearance of CFT073 in the murine model, the most potent derivative, compound 26, significantly reduced bacterial recovery in the urine and trended toward reducing bacterial recovery in the bladder and kidneys, with efficacy similar to ciprofloxacin. Treatment of CFT073 cultured in human urine with compound 26 fostered accumulation of CpxR-P and decreased the expression of proteins involved in siderophore biosynthesis and binding, heme degradation, and flagellar movement. These studies suggest that chemical activation of CpxRA may present a viable strategy for treating infections due to UPEC. IMPORTANCE: The increasing prevalence of urinary tract infections (UTIs) due to antibiotic-resistant uropathogenic Escherichia coli (UPEC) is a major public health concern. Bacteria contain proteins that sense their environment and have no human homologs and, thus, are attractive drug targets. CpxRA is a conserved sensing system whose function is to reduce stress in the bacterial cell membrane; activation of CpxRA reduces the expression of virulence determinants, which must cross the cell membrane to reach the bacterial surface. We previously identified a class of compounds that activate CpxRA. We show in a mouse UTI model that our most potent compound significantly reduced recovery of UPEC in the urine, trended toward reducing bacterial recovery in the bladder and kidneys, did not kill UPEC, and downregulated multiple proteins involved in UPEC virulence. Since these compounds do not act by a killing mechanism, they have potential to treat UTIs caused by antibiotic-resistant bacteria.

Browsing by Author "Katz, Barry P."

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