Browsing by Author "Benjamin, Daniel K"
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Item Open Access A School-Based SARS-CoV-2 Testing Program: Testing Uptake and Quarantine Length After In-School Exposures.(Pediatrics, 2022-02) Boutzoukas, Angelique E; Zimmerman, Kanecia O; Mann, Tara K; Moorthy, Ganga S; Blakemore, Ashley; McGann, Kathleen A; Smith, Michael J; Nutting, Boen; Kerley, Karen; Brookhart, M Alan; Edwards, Laura; Rak, Zsolt; Benjamin, Daniel K; Kalu, Ibukunoluwa CObjectives
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related quarantines, which are required after close contact with infected individuals, have substantially disrupted in-person education for kindergarten through 12th grade (K-12) students. In recent recommendations, shortened durations of quarantine are allowed if a negative SARS-CoV-2 test result is obtained at 5 to 7 days postexposure, but access to testing remains limited. We hypothesized that providing access to in-school SARS-CoV-2 testing postexposure would increase testing and reduce missed school days.Methods
This prospective cohort study was conducted in one large public K-12 school district in North Carolina and included 2 periods: preimplementation (March 15, 2021, to April 21, 2021) and postimplementation (April 22, 2021, to June 4, 2021), defined around initiation of an in-school SARS-CoV-2 testing program in which on-site access to testing is provided. Number of quarantined students and staff, testing uptake, test results, and number of missed school days were analyzed and compared between the preimplementation and postimplementation periods.Results
Twenty-four schools, including 12 251 in-person learners, participated in the study. During preimplementation, 446 close contacts were quarantined for school-related exposures; 708 close contacts were quarantined postimplementation. Testing uptake after school-related exposures increased from 6% to 40% (95% confidence interval: 23% to 45%) after implementation, and 89% of tests were conducted in-school. After in-school testing implementation, close contacts missed ∼1.5 fewer days of school (95% confidence interval: -2 to -1).Conclusions
Providing access to in-school testing may be a worthwhile mechanism to increase testing uptake after in-school exposures and minimize missed days of in-person learning, thereby mitigating the pandemic's ongoing impact on children.Item Open Access Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.(JAMA, 2023-07) O'Halloran, Jane A; Ko, Emily R; Anstrom, Kevin J; Kedar, Eyal; McCarthy, Matthew W; Panettieri, Reynold A; Maillo, Martin; Nunez, Patricia Segura; Lachiewicz, Anne M; Gonzalez, Cynthia; Smith, P Brian; de Tai, Sabina Mendivil-Tuchia; Khan, Akram; Lora, Alfredo J Mena; Salathe, Matthias; Capo, Gerardo; Gonzalez, Daniel Rodríguez; Patterson, Thomas F; Palma, Christopher; Ariza, Horacio; Lima, Maria Patelli; Blamoun, John; Nannini, Esteban C; Sprinz, Eduardo; Mykietiuk, Analia; Alicic, Radica; Rauseo, Adriana M; Wolfe, Cameron R; Witting, Britta; Wang, Jennifer P; Parra-Rodriguez, Luis; Der, Tatyana; Willsey, Kate; Wen, Jun; Silverstein, Adam; O'Brien, Sean M; Al-Khalidi, Hussein R; Maldonado, Michael A; Melsheimer, Richard; Ferguson, William G; McNulty, Steven E; Zakroysky, Pearl; Halabi, Susan; Benjamin, Daniel K; Butler, Sandra; Atkinson, Jane C; Adam, Stacey J; Chang, Soju; LaVange, Lisa; Proschan, Michael; Bozzette, Samuel A; Powderly, William G; ACTIV-1 IM Study Group MembersImportance
Immune dysregulation contributes to poorer outcomes in COVID-19.Objective
To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia.Design, setting, and participants
Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021.Interventions
Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day).Main outcomes and measures
The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale.Results
Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies.Conclusions and relevance
Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo.Trial registration
ClinicalTrials.gov Identifier: NCT04593940.Item Open Access Analysis of the Impact of Early Surgery on In-Hospital Mortality of Native Valve Endocarditis(2010-03) Lalani, Tahaniyat; Cabell, Christopher H; Benjamin, Daniel K; Lasca, Ovidiu; Naber, Christoph; Fowler, Vance G; Corey, G Ralph; Chu, Vivian H; Fenely, Michael; Pachirat, Orathai; Tan, Ru-San; Watkin, Richard; Ionac, Adina; Moreno, Asuncion; Mestres, Carlos A; Casabé, José; Chipigina, Natalia; Eisen, Damon P; Spelman, Denis; Delahaye, Francois; Peterson, Gail; Olaison, Lars; Wang, Andrew; International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS) InvestigatorsBackground— The impact of early surgery on mortality in patients with native valve endocarditis (NVE) is unresolved. This study sought to evaluate valve surgery compared with medical therapy for NVE and to identify characteristics of patients who are most likely to benefit from early surgery. Methods and Results— Using a prospective, multinational cohort of patients with definite NVE, the effect of early surgery on in-hospital mortality was assessed by propensity-based matching adjustment for survivor bias and by instrumental variable analysis. Patients were stratified by propensity quintile, paravalvular complications, valve perforation, systemic embolization, stroke, Staphylococcus aureus infection, and congestive heart failure. Of the 1552 patients with NVE, 720 (46%) underwent early surgery and 832 (54%) were treated with medical therapy. Compared with medical therapy, early surgery was associated with a significant reduction in mortality in the overall cohort (12.1% [87/720] versus 20.7% [172/832]) and after propensity-based matching and adjustment for survivor bias (absolute risk reduction [ARR] −5.9%, P<0.001). With a combined instrument, the instrumental-variable–adjusted ARR in mortality associated with early surgery was −11.2% (P<0.001). In subgroup analysis, surgery was found to confer a survival benefit compared with medical therapy among patients with a higher propensity for surgery (ARR −10.9% for quintiles 4 and 5, P=0.002) and those with paravalvular complications (ARR −17.3%, P<0.001), systemic embolization (ARR −12.9%, P=0.002), S aureus NVE (ARR −20.1%, P<0.001), and stroke (ARR −13%, P=0.02) but not those with valve perforation or congestive heart failure. Conclusions— Early surgery for NVE is associated with an in-hospital mortality benefit compared with medical therapy alone.Item Open Access Approaches for enhancing the informativeness and quality of clinical trials: Innovations and principles for implementing multicenter trials from the Trial Innovation Network.(Journal of clinical and translational science, 2023-01) Lane, Karen; Palm, Marisha E; Marion, Eve; Kay, Marie T; Thompson, Dixie; Stroud, Mary; Boyle, Helen; Hillery, Shannon; Nanni, Angeline; Hildreth, Meghan; Nelson, Sarah; Burr, Jeri S; Edwards, Terri; Poole, Lori; Waddy, Salina P; Dunsmore, Sarah E; Harris, Paul; Wilkins, Consuelo; Bernard, Gordon R; Dean, J Michael; Dwyer, Jamie; Benjamin, Daniel K; Selker, Harry P; Hanley, Daniel F; Ford, Daniel EOne challenge for multisite clinical trials is ensuring that the conditions of an informative trial are incorporated into all aspects of trial planning and execution. The multicenter model can provide the potential for a more informative environment, but it can also place a trial at risk of becoming uninformative due to lack of rigor, quality control, or effective recruitment, resulting in premature discontinuation and/or non-publication. Key factors that support informativeness are having the right team and resources during study planning and implementation and adequate funding to support performance activities. This communication draws on the experience of the National Center for Advancing Translational Science (NCATS) Trial Innovation Network (TIN) to develop approaches for enhancing the informativeness of clinical trials. We distilled this information into three principles: (1) assemble a diverse team, (2) leverage existing processes and systems, and (3) carefully consider budgets and contracts. The TIN, comprised of NCATS, three Trial Innovation Centers, a Recruitment Innovation Center, and 60+ CTSA Program hubs, provides resources to investigators who are proposing multicenter collaborations. In addition to sharing principles that support the informativeness of clinical trials, we highlight TIN-developed resources relevant for multicenter trial initiation and conduct.Item Open Access Exposure-safety relationship for acyclovir in the treatment of neonatal herpes simplex virus disease.(Early human development, 2022-07) Ericson, Jessica E; Benjamin, Daniel K; Boakye-Agyeman, Felix; Balevic, Stephen J; Cotten, C Michael; Adler-Shohet, Felice; Laughon, Matthew; Poindexter, Brenda; Harper, Barrie; Payne, Elizabeth H; Kaneshige, Kim; Smith, P Brian; Best Pharmaceuticals for Children Act - Pediatric Trials NetworkBackground
Neonatal herpes simplex virus (HSV) disease has been treated with high-dose (20 mg/kg/dose) acyclovir since 1991.Aims
Determine the safety of acyclovir in infants with neonatal HSV treated with high-dose acyclovir; examine the association between acyclovir dose and exposure with adverse events (AEs).Study design
We obtained demographic information and acyclovir dosing via medical records. Acyclovir exposure was calculated using an established pharmacokinetic model.Subjects
Infants <120 days of age with neonatal HSV discharged from four academic children's hospitals.Outcome measures
We identified clinical and laboratory adverse events (AEs).Results and conclusions
We identified 49 infants with neonatal HSV treated with acyclovir; 42 infants had complete 21-day dosing information. Median mean daily dose was 59 mg/kg/day. Clinical AEs were common among all gestational and postnatal age groups. Rash was the most common clinical AE (37 %). Mild laboratory AEs occurred in 2-37 % of infants. The median maximum doses (mg/kg/day) were higher among infants with hypokalemia, elevated blood urea nitrogen, and thrombocytosis. For all other laboratory AEs, the median maximum doses for infants without events were higher or equal to the median maximum dose of infants with the AE. The odds of experiencing any clinical or laboratory AE did not differ by predicted acyclovir exposure for either area under the curve (AUC) or maximum concentration (Cmax) (odds ratio [OR] = 1.00 [0.98, 1.03] and OR = 1.01 [0.93, 1.12], respectively). Although AEs were common with high-dose acyclovir exposure, severe AEs were rare. Acyclovir exposure was not associated with AEs.Item Open Access Pediatric Antibacterial and Antifungal Trials From 2007 to 2017.(Pediatrics, 2018-09) Thaden, Joshua T; Chiswell, Karen; Jaffe, Ian; Bergin, Stephen P; Yang, William E; Romaine, Andrew; Roberts, Jamie; Nambiar, Sumathi; Farley, John; Benjamin, Daniel K; Smith, P Brian; Tsalik, Ephraim LBACKGROUND AND OBJECTIVES:The impact of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) on pediatric antibacterial or antifungal drug trials is unknown. Our objective was to identify and characterize trials conducted under the BPCA and/or the PREA. METHODS:Pediatric antibacterial and antifungal drug trials with industry or US federal funding registered in clinicaltrials.gov from 2007 to 2017 were identified. Those conducted under BPCA and/or PREA were identified through US Food and Drug Administration and National Institute of Child Health and Human Development databases. RESULTS:Of 17 495 pediatric trials registered on clinicaltrials.gov between October 2007 and September 2017, 122 systemic antibacterial or antifungal drug trials with industry or US federal funding were identified. Of these 122 trials, 98 (80%) involved antibacterials only, 23 (19%) antifungals only, and 1 (1%) both antibacterials and antifungals. These represented <1% (122 of 17 495) of pediatric trials. Neither pediatric antibacterial nor antifungal drug trials commonly enrolled neonates 0 to 30 days old (30% [30 of 99] vs 42% [10 of 24], respectively). Pediatric antibacterial and antifungal trials were commonly industry funded (79% [78 of 99] and 83% [20 of 24], respectively). In total, 65% (79 of 122) of pediatric antibacterial and/or antifungal drug trials were conducted under BPCA and/or PREA. Researchers in trials conducted under BPCA and/or PREA, relative to non-BPCA and/or PREA trials, more often collected pharmacokinetic data (70% [55 of 79] vs 26% [11 of 43]). CONCLUSIONS:Although the majority of pediatric antibacterial and/or antifungal drug trials were conducted under BPCA and/or PREA, the overall number was low. Greater effort is needed to stimulate such trials.Item Open Access Solithromycin in Children and Adolescents With Community-acquired Bacterial Pneumonia.(The Pediatric infectious disease journal, 2022-07) Lang, Jason E; Hornik, Christoph P; Elliott, Carrie; Silverstein, Adam; Hornik, Chi; Al-Uzri, Amira; Bosheva, Miroslava; Bradley, John S; Borja-Tabora, Charissa Fay Corazon; Di John, David; Mendez Echevarria, Ana; Ericson, Jessica E; Friedel, David; Gonczi, Ferenc; Isidro, Marie Grace Dawn; James, Laura P; Kalocsai, Krisztina; Koutroulis, Ioannis; Laki, Istvan; Ong-Lim, Anna Lisa T; Nad, Marta; Simon, Gabor; Syed, Salma; Szabo, Eva; Benjamin, Daniel K; Cohen-Wolkowiez, Michael; SOLI-PEDS ProgramBackground
Solithromycin is a new macrolide-ketolide antibiotic with potential effectiveness in pediatric community-acquired bacterial pneumonia (CABP). Our objective was to evaluate its safety and effectiveness in children with CABP.Methods
This phase 2/3, randomized, open-label, active-control, multicenter study randomly assigned solithromycin (capsules, suspension or intravenous) or an appropriate comparator antibiotic in a 3:1 ratio (planned n = 400) to children 2 months to 17 years of age with CABP. Primary safety endpoints included treatment-emergent adverse events (AEs) and AE-related drug discontinuations. Secondary effectiveness endpoints included clinical improvement following treatment without additional antimicrobial therapy.Results
Unrelated to safety, the sponsor stopped the trial prior to completion. Before discontinuation, 97 participants were randomly assigned to solithromycin (n = 73) or comparator (n = 24). There were 24 participants (34%, 95% CI, 23%-47%) with a treatment-emergent AE in the solithromycin group and 7 (29%, 95% CI, 13%-51%) in the comparator group. Infusion site pain and elevated liver enzymes were the most common related AEs with solithromycin. Study drug was discontinued due to AEs in 3 subjects (4.3%) in the solithromycin group and 1 (4.2%) in the comparator group. Forty participants (65%, 95% CI, 51%-76%) in the solithromycin group achieved clinical improvement on the last day of treatment versus 17 (81%, 95% CI, 58%-95%) in the comparator group. The proportion achieving clinical cure was 60% (95% CI, 47%-72%) and 68% (95% CI, 43%-87%) for the solithromycin and comparator groups, respectively.Conclusions
Intravenous and oral solithromycin were generally well-tolerated and associated with clinical improvement in the majority of participants treated for CABP.Item Open Access Test-to-Stay After Exposure to SARS-CoV-2 in K-12 Schools.(Pediatrics, 2022-05) Campbell, Melissa M; Benjamin, Daniel K; Mann, Tara; Fist, Alex; Kim, Hwasoon; Edwards, Laura; Rak, Zsolt; Brookhart, M Alan; Anstrom, Kevin; Moore, Zack; Tilson, Elizabeth Cuervo; Kalu, Ibukunoluwa C; Boutzoukas, Angelique E; Moorthy, Ganga S; Uthappa, Diya; Scott, Zeni; Weber, David J; Shane, Andi L; Bryant, Kristina A; Zimmerman, Kanecia O; ABC SCIENCE COLLABORATIVEObjectives
We evaluated the safety and efficacy of a test-to-stay program for unvaccinated students and staff who experienced an unmasked, in-school exposure to someone with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Serial testing instead of quarantine was offered to asymptomatic contacts. We measured secondary and tertiary transmission rates within participating schools and in-school days preserved for participants.Methods
Participating staff or students from universally masked districts in North Carolina underwent rapid antigen testing at set intervals up to 7 days after known exposure. Collected data included location or setting of exposure, participant symptoms, and school absences up to 14 days after enrollment. Outcomes included tertiary transmission, secondary transmission, and school days saved among test-to-stay participants. A prespecified interim safety analysis occurred after 1 month of enrollment.Results
We enrolled 367 participants and completed 14-day follow-up on all participants for this analysis. Nearly all (215 of 238, 90%) exposure encounters involved an unmasked index case and an unmasked close contact, with most (353 of 366, 96%) occurring indoors, during lunch (137 of 357, 39%) or athletics (45 of 357, 13%). Secondary attack rate was 1.7% (95% confidence interval: 0.6%-4.7%) based on 883 SARS-CoV-2 serial rapid antigen tests with results from 357 participants; no tertiary cases were identified, and 1628 (92%) school days were saved through test-to-stay program implementation out of 1764 days potentially missed.Conclusion
After unmasked in-school exposure to SARS-CoV-2, even in a mostly unvaccinated population, a test-to-stay strategy is a safe alternative to quarantine.Item Open Access Test-to-Stay After SARS-CoV-2 Exposure: A Mitigation Strategy for Optionally Masked K-12 Schools.(Pediatrics, 2022-11) Campbell, Melissa M; Benjamin, Daniel K; Mann, Tara K; Fist, Alex; Blakemore, Ashley; Diaz, Kylee S; Kim, Hwasoon; Edwards, Laura J; Rak, Zsolt; Brookhart, M Alan; Moore, Zack; Tilson, Elizabeth Cuervo; Kalu, Ibukun; Boutzoukas, Angelique E; Moorthy, Ganga S; Uthappa, Diya; Scott, Zeni; Weber, David J; Shane, Andi L; Bryant, Kristina A; Zimmerman, Kanecia OObjectives
We evaluated the impact of a test-to-stay (TTS) program on within-school transmission and missed school days in optionally masked kindergarten through 12th grade schools during a period of high community severe acute respiratory syndrome coronavirus 2 transmission.Methods
Close contacts of those with confirmed severe acute respiratory syndrome coronavirus 2 infection were eligible for enrollment in the TTS program if exposure to a nonhousehold contact occurred between November 11, 2021 and January 28, 2022. Consented participants avoided school exclusion if they remained asymptomatic and rapid antigen testing at prespecified intervals remained negative. Primary outcomes included within-school tertiary attack rate (test positivity among close contacts of positive TTS participants) and school days saved among TTS participants. We estimated the number of additional school-acquired cases resulting from TTS and eliminating school exclusion.Results
A total of 1675 participants tested positive or received at least 1 negative test between days 5 and 7 and completed follow-up; 92% were students and 91% were exposed to an unmasked primary case. We identified 201 positive cases. We observed a tertiary attack rate of 10% (95% confidence interval: 6%-19%), and 7272 (89%) of potentially missed days were saved through TTS implementation. We estimated 1 additional school-acquired case for every 21 TTS participants remaining in school buildings during the entire study period.Conclusions
Even in the setting of high community transmission, a TTS strategy resulted in substantial reduction in missed school days in optionally masked schools.Item Open Access Test-to-Stay in Kindergarten Through 12th Grade Schools After Household Exposure to Severe Acute Respiratory Syndrome Coronavirus 2.(The Journal of school health, 2023-05) Scott, Zeni; Uthappa, Diya M; Mann, Tara K; Kim, Hwasoon; Brookhart, MA; Edwards, Laura; Rak, Zsolt; Benjamin, Daniel K; Zimmerman, Kanecia O; ABC Science CollaborativeBackground
Test-to-stay (TTS) is a strategy to limit school exclusion following an exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the use of TTS within universally masked kindergarten through 12th grade (K-12) school settings following household SARS-CoV-2 exposure.Methods
Three hundred twenty-two participants were enrolled. Serial rapid antigen testing was performed up to 15 days post-exposure. Analysis-eligible participants completed the 15-day testing protocol, tested positive any time during the testing window, or received a negative test on or after day 9. Primary outcomes included within-school tertiary attack rate (TAR) (test positivity among close contacts of positive TTS participants), and school days saved among TTS participants.Results
Seventy-three of 265 analysis-eligible participants tested positive for SARS-CoV-2 (secondary attack rate of 28% [95% CI: 16-63%]). Among 77 within-school close contacts, 2 were positive (TAR = 3% [95% CI: 1-5%]). Participant absences were limited to 338 days, resulting in 82% of 1849 school days saved.Implications for school health policy, practice, and equity
TTS facilitates continued in-person learning and can greatly reduce the number of missed school days.Conclusions
Within universally masked K-12 schools, TTS is a safe alternative to school exclusion following household SARS-CoV-2 exposure.