Developing Wolbachia-based disease interventions for an extreme environment.

Aedes aegypti mosquitoes carrying self-spreading, virus-blocking Wolbachia bacteria are being deployed to suppress dengue transmission. However, there are challenges in applying this technology in extreme environments. We introduced two Wolbachia strains into Ae. aegypti from Saudi Arabia for a release program in the hot coastal city of Jeddah. Wolbachia reduced infection and dissemination of dengue virus (DENV2) in Saudi Arabian mosquitoes and showed complete maternal transmission and cytoplasmic incompatibility. Wolbachia reduced egg hatch under a range of environmental conditions, with the Wolbachia strains showing differential thermal stability. Wolbachia effects were similar across mosquito genetic backgrounds but we found evidence of local adaptation, with Saudi Arabian mosquitoes having lower egg viability but higher adult desiccation tolerance than Australian mosquitoes. Genetic background effects will influence Wolbachia invasion dynamics, reinforcing the need to use local genotypes for mosquito release programs, particularly in extreme environments like Jeddah. Our comprehensive characterization of Wolbachia strains provides a foundation for Wolbachia-based disease interventions in harsh climates.

Paediatric resident identification of cardiac emergencies.

OBJECTIVES: Critical CHD is associated with morbidity and mortality, worsened by delayed diagnosis. Paediatric residents are front-line clinicians, yet identification of congenital CHD remains challenging. Current exposure to cardiology is limited in paediatric resident education. We evaluated the impact of rapid cycle deliberate practice simulation on paediatric residents' skills, knowledge, and perceived competence to recognise and manage infants with congenital CHD. METHODS: We conducted a 6-month pilot study. Interns rotating in paediatric cardiology completed a case scenario assessment during weeks 1 and 4 and participated in paired simulations (traditional debrief and rapid cycle deliberate practice) in weeks 2-4. We assessed interns' skills during the simulation using a checklist of "cannot miss" tasks. In week 4, they completed a retrospective pre-post knowledge-based survey. We analysed the data using summary statistics and mixed effect linear regression. RESULTS: A total of 26 interns participated. There was a significant increase in case scenario assessment scores between weeks 1 and 4 (4, interquartile range 3-6 versus 8, interquartile range 6-10; p-value < 0.0001). The percentage of "cannot miss" tasks on the simulation checklist increased from weeks 2 to 3 (73% versus 83%, p-value 0.0263) and from weeks 2-4 (73% versus 92%, p-value 0.0025). The retrospective pre-post survey scores also increased (1.67, interquartile range 1.33-2.17 versus 3.83, interquartile range 3.17-4; p-value < 0.0001). CONCLUSION: Rapid cycle deliberate practice simulations resulted in improved recognition and initiation of treatment of simulated infants with congenital CHD among paediatric interns. Future studies will include full implementation of the curriculum and knowledge retention work.

Correction: Broad dengue neutralization in mosquitoes expressing an engineered antibody.

[This corrects the article DOI: 10.1371/journal.ppat.1008103.].

Broad dengue neutralization in mosquitoes expressing an engineered antibody.

With dengue virus (DENV) becoming endemic in tropical and subtropical regions worldwide, there is a pressing global demand for effective strategies to control the mosquitoes that spread this disease. Recent advances in genetic engineering technologies have made it possible to create mosquitoes with reduced vector competence, limiting their ability to acquire and transmit pathogens. Here we describe the development of Aedes aegypti mosquitoes synthetically engineered to impede vector competence to DENV. These mosquitoes express a gene encoding an engineered single-chain variable fragment derived from a broadly neutralizing DENV human monoclonal antibody and have significantly reduced viral infection, dissemination, and transmission rates for all four major antigenically distinct DENV serotypes. Importantly, this is the first engineered approach that targets all DENV serotypes, which is crucial for effective disease suppression. These results provide a compelling route for developing effective genetic-based DENV control strategies, which could be extended to curtail other arboviruses.

Social Disparities among Sudden Death victims with HIV.

Although cardiovascular death is a growing source of mortality for people living with human immunodeficiency virus (HIV), the risk factors and circumstances surrounding sudden death in this population are poorly understood. We compared 399 adult sudden death victims reported by Emergency Medical Services in North Carolina to 1,114 controls. Sudden death was more common among HIV-positive than HIV-negative individuals (OR: 2.59, 95% CI: 1.15-5.83). In a multivariable model of sudden death victims including Black race, BMI, and history of divorce, incarceration, substance abuse, and respiratory disease, HIV-positive individuals were more likely to be Black (adjusted OR [aOR]: 6.04, 95% CI: 1.08-33.7) or divorced (aOR: 4.71, 95% CI: 1.04-21.3), adjusted for all other variables in the model. Compared to controls with HIV, sudden death victims with HIV were more likely to have a history of incarceration, divorce, respiratory disease, alcohol abuse, or dyslipidemia. A qualitative assessment of victims suggested that many died in isolation, suffering from past and current substance abuse and depression. HIV infection appears to be an important risk factor for sudden death, and incarceration history, social isolation, and medical comorbidities contribute to sudden death risk for HIV-positive individuals.

Randomized Controlled Trial of Interactive Spaced Education to Support Constipation Management by Pediatric Primary Care Providers.

INTRODUCTION: Integrating continuing medical education and quality improvement (QI) initiatives is challenging. We aimed to compare one method, Interactive Spaced Education (ISE/QI), with standard (sTD/Qi) education embedded within a constipation management Qi initiative. METHODS: We conducted a randomized, controlled study to compare ISE/QI and STD/QI education. Pediatric primary care providers (PCPs) were recruited from a network of local private practices. The QI initiative was implemented with all providers before education interventions. ISE/QI participants received questions by email weekly, provided answers, received feedback, and repeated questions over a 4-month period. The STD/QI group received a Power Point with the same educational content. Pre- and post-surveys evaluated usability, self-assessed confidence, and practice changes while quizzes evaluated knowledge. Process control charts tracked subsequent visits to gastroenterology (GI). RESULTS: Of the 212 eligible PCPs, 101 (48%) enrolled, with 49 PCPs in the ISE/QI arm and 52 in STD/QI education arm. Quiz scores improved in the ISE/QI arm with a strong effect size (Cohen d 1.76). Mean increase in confidence managing difficult cases was higher in the ISE/QI group (1.84 vs 1.21, P  = 0.030). ISE/QI participants were more likely to rate the activity better than most online education (odds ratio [OR] 18.1, P < 0.0001) and incorporate practice changes (OR 3.35, P = 0.0152). Visits to GI decreased among the entire population, but the effect on GI visits within each education arm was mixed. CONCLUSIONS: ISE/QI improved knowledge and confidence managing difficult cases. ISE/QI participants reported higher likelihood to change practice, but no differences were seen in GI referrals.

An Immersive Virtual Reality Curriculum for Pediatric Hematology Clinicians on Shared Decision-making for Hydroxyurea in Sickle Cell Anemia.

Although hydroxyurea (HU) is an effective treatment for sickle cell anemia, uptake remains low. Shared decision-making (SDM) is a recommended strategy for HU initiation to elicit family preferences; however, clinicians lack SDM training. We implemented an immersive virtual reality (VR) curriculum at 8 pediatric institutions to train clinicians on SDM that included counseling virtual patients. Clinicians' self-reported confidence significantly improved following the VR simulations on all communication skills assessed, including asking open-ended questions, eliciting specific concerns, and confirming understanding (Ps≤0.01 for all). VR may be an effective method for educating clinicians to engage in SDM for HU.

Engineered resistance to Zika virus in transgenic Aedes aegypti expressing a polycistronic cluster of synthetic small RNAs.

Recent Zika virus (ZIKV) outbreaks have highlighted the necessity for development of novel vector control strategies to combat arboviral transmission, including genetic versions of the sterile insect technique, artificial infection with Wolbachia to reduce population size and/or vectoring competency, and gene drive-based methods. Here, we describe the development of mosquitoes synthetically engineered to impede vector competence to ZIKV. We demonstrate that a polycistronic cluster of engineered synthetic small RNAs targeting ZIKV is expressed and fully processed in Aedes aegypti, ensuring the formation of mature synthetic small RNAs in the midgut where ZIKV resides in the early stages of infection. Critically, we demonstrate that engineered Ae. aegypti mosquitoes harboring the anti-ZIKV transgene have significantly reduced viral infection, dissemination, and transmission rates of ZIKV. Taken together, these compelling results provide a promising path forward for development of effective genetic-based ZIKV control strategies, which could potentially be extended to curtail other arboviruses.

Development and evaluation of a pediatric hospital medicine board review course.

BACKGROUND: The American Board of Medical Specialties recognized Pediatric Hospital Medicine (PHM) for subspecialty certification in 2016, with the first certification exam in 2019. To address the need for exam preparatory materials, we designed and evaluated a novel PHM board review course that was offered both in-person and online. METHODS: Course content was based on the American Board of Pediatrics (ABP) PHM certifying exam outline. Course objectives were developed from published PHM core competencies and the 2012 ABP general pediatrics content objectives. National experts served as faculty, presenting didactic sessions, and contributing to a question bank for high-yield review. For program evaluation, we applied the Kirkpatrick Model, evaluating estimated exam pass rates (Level 4), participant learning (Level 2) via post-presentation practice questions, and participants' ratings of presenters (via five-point Likert scale) and satisfaction (Level 1). RESULTS: There were 112 in-person and 144 online participants with estimated pass rates of 89 and 93%, respectively. The mean correct response for the post-presentation knowledge questions was 84%. Faculty effectiveness ratings ranged from 3.81 to 4.96 (median score 4.60). Strengths included the pace of the course, question bank, and printed syllabus. Suggestions for improvement included question bank expansion, focus on "testable" points rather than general information, and challenges with long days of didactic presentations. CONCLUSIONS: This novel PHM board review course demonstrated effectiveness. Hospitalists preferred focused "testable" information, an active learning environment, and a robust question bank. Future preparatory courses should consider including more opportunities for practice questions, focused content review, and learner engagement.

School Health Service Provider Perceptions on Facilitated Interactive Role-Play Around HPV Vaccine Recommendation.

The purpose of this study was to evaluate a facilitated interactive role-playing activity on increasing human papillomavirus (HPV) vaccine recommendation skills for school nurses and school-based health center staff. A 1-day workshop was implemented for school-based clinicians focused on improving HPV vaccination rates in schools. The workshop included a facilitated interactive role-playing activity involving five scenarios related to recommending the HPV vaccine to parents. Participants completed a usability survey with open-ended questions assessing their experience. A general inductive approach was used to examine responses. Sixteen participants completed the usability survey. The major strength identified specific to the activity included opportunity to practice evidence-based recommendation skills (n = 10). Weaknesses of the activity identified included lack of diversity (n = 4) and complexity within the scenarios (n = 2). Results could shift current educational and clinical paradigms through the implementation of hands-on education strategies to effectively train school-based clinicians to strongly recommend the HPV vaccine.

Risk Factors for Maternal Chagas Disease and Vertical Transmission in a Bolivian Hospital.

BACKGROUND: Vertical transmission of Trypanosoma cruzi infection accounts for a growing proportion of new cases of Chagas disease. Better risk stratification is needed to predict which women are more likely to transmit the infection. METHODS: This study enrolled women and their infants at the Percy Boland Women's Hospital in Santa Cruz, Bolivia. Pregnant women were screened for Chagas disease by rapid test and received confirmatory serology. Infants of seropositive mothers underwent diagnostic testing with quantitative polymerase chain reaction (qPCR). RESULTS: Among 5828 enrolled women, 1271 (21.8%) screened positive for Chagas disease. Older maternal age, family history of Chagas disease, home conditions, lower educational level, and history of living in a rural area were significantly associated with higher adjusted odds of maternal infection. Of the 1325 infants of seropositive mothers, 65 infants (4.9%) were diagnosed with congenital Chagas disease. Protective factors against transmission included cesarean delivery (adjusted odds ratio [aOR]: .60; 95% confidence interval [CI]: .36-.99) and family history of Chagas disease (aOR: .58; 95% CI: .34-.99). Twins were significantly more likely to be congenitally infected than singleton births (OR: 3.32; 95% CI: 1.60-6.90). Among congenitally infected infants, 32.3% had low birth weight, and 30.8% required hospitalization after birth. CONCLUSIONS: Although improved access to screening and qPCR increased the number of infants diagnosed with congenital Chagas disease, many infants remain undiagnosed. A better understanding of risk factors and improved access to highly sensitive and specific diagnostic techniques for congenital Chagas disease may help improve regional initiatives to reduce disease burden.

Evaluation of HPV Vaccine: Same Way, Same DayTM: A Pilot Study.

Missed clinical opportunities and the lack of strong and consistent vaccine recommendations are key reasons for low HPV vaccination rates. The purpose of this study was to conduct a pilot evaluation of a web-based training's impact on knowledge, attitudes, and self-efficacy related to providing evidence-based HPV vaccine recommendations. Participants completed three online interactive learning modules and the HPV Vaccine: Same Way, Same Day™ smartphone application (app). Participants completed a pre-training survey, immediate post-training survey, and two-month post-survey. Participants demonstrated a statistically significant increase in knowledge scores from T1 to T2 and T1 to T3. Mean attitudes for recommending HPV vaccination for female patients increased from T1 to T2 and T1 to T3. Mean attitudes for recommending HPV vaccination for male patients increased from T1 to T2 and T1 to T3. Mean self-efficacy scores increased from T1 to T2 and T1 to T3. The HPV Vaccine: Same Way, Same Day™ app is a promising strategy for improving HPV vaccine recommendations among physicians. Future research should explore long-term effects and enroll attending and community physicians to examine its efficacy in other physician populations.

Social Risk Screening in Pediatric Primary Care Anticipates Acute Care Utilization.

OBJECTIVE: The aim of the study was to assess whether responses to a standardized social risk screen administered during pediatric well-child visits (WCV) were associated with emergency department (ED) or urgent care (UC) utilization. METHODS: This was a retrospective cohort study of 26,509 children younger than 13 years with a WCV between January 1, 2012, and December 31, 2013. Exposure was positive response(s) on a standardized social risk screening questionnaire at the index WCV. Primary outcome was number of ED or UC visits in the 12 months after the WCV. RESULTS: The cohort was 50.9% male and 65.7% black, with a median age of 3.6 years. More than 20% had a positive response to at least one question on the social risk screen. For those reporting any social risk, 46.7% had 1 or more EDs or UC visit within 12 months. Each additional reported risk was associated with a 4% increase in the rate of ED utilization (incidence rate ratio = 1.04, 95% confidence interval = 1.02-1.07) and a 16% increase in the rate of hospitalizations (incidence rate ratio = 1.16, 95% confidence interval = 1.08-1.24). Similar patterns were noted for those visiting the ED 4 times or more (adjusted odds ratio = 1.09, 1.03-1.15) and hospitalization 2 times or more (adjusted odds ratio = 1.19, 1.04-1.35) in the year after the WCV. Those who screened positive on food insecurity, safety, and desire to meet with a social worker questions also had higher odds of ED or UC utilization. CONCLUSIONS: Families reporting a social concern on a standardized screen during a WCV had increased acute care utilization in the subsequent year. Identifying socially at-risk families may allow for the creation of more effective strategies to prevent future utilization.

Frequency and clinical outcomes of CYP2C19 genotype-guided escalation and de-escalation of antiplatelet therapy in a real-world clinical setting.

PURPOSE: To evaluate the frequency and clinical impact of switches in antiplatelet therapy following implementation of CYP2C19 genotyping after percutaneous coronary intervention (PCI). METHODS: The frequency of escalation (clopidogrel switched to prasugrel/ticagrelor) and de-escalation (prasugrel/ticagrelor switched to clopidogrel) was evaluated in 1063 PCI patients who underwent CYP2C19 genotyping. Risk of major adverse cardiovascular or cerebrovascular (MACCE) and bleeding events over one year was evaluated. RESULTS: Antiplatelet therapy switches were common (19%), with escalation (101/115: 88%) and de-escalation (77/84: 92%) occurring predominantly in patients with and without a CYP2C19 nonfunctional allele, respectively. Nonfunctional allele carriers initiated and continued on clopidogrel had a significantly higher risk of experiencing either a MACCE or bleeding event compared with those escalated to prasugrel/ticagrelor (52 vs. 19 events/100 patient-years; adjusted hazard ratio [HR] 2.89 [1.44-6.13], p = 0.003). Patients without a nonfunctional allele de-escalated to clopidogrel had no difference in risk compared with those initiated and continued on prasugrel/ticagrelor (21 vs. 19 events/100 patient-years; adjusted HR 1.13 [0.51-2.34], p = 0.751). CONCLUSION: CYP2C19-guided escalation and de-escalation is common in a real-world setting. Continuation of clopidogrel in nonfunctional allele carriers is associated with adverse outcomes. De-escalation to clopidogrel in patients without a nonfunctional allele appears safe and warrants prospective study.

Clinical Utility of CYP2C19 Genotyping to Guide Antiplatelet Therapy in Patients With an Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention.

Current guidelines recommend dual antiplatelet therapy-a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin-for patients undergoing percutaneous coronary intervention. Although clopidogrel is the most commonly prescribed P2Y12 inhibitor, it is associated with an increased risk of major adverse cardiovascular events in patients carrying loss-of-function CYP2C19 alleles. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Nevertheless, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial because of the lack of large randomized controlled trials evaluating this strategy. Emerging results from registry studies and small clinical trials of CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention offer new insight and contribute to a growing evidence base that supports the clinical utility of a genotyping strategy to personalize antiplatelet therapy selection.

Impact of an Immersive Virtual Reality Curriculum on Medical Students' Clinical Assessment of Infants With Respiratory Distress.

OBJECTIVE: To determine whether exposure to an immersive virtual reality curriculum on pediatric respiratory distress improves medical students' recognition of impending respiratory failure. DESIGN: Randomized, controlled, prospective study conducted from July 2017 to June 2018. Evaluators blinded to student groupings. SETTING: Academic, free-standing children's hospital. PARTICIPANTS: All third-year medical students (n = 168) were eligible. The standard curriculum was delivered to all students during their pediatric rotation with optional inclusion of research data per Institutional Review Board review. A randomized selection of students was exposed to the virtual reality curriculum. INTERVENTION: All students received standard training on respiratory distress through didactics and high-fidelity mannequin simulation. Intervention students underwent an additional 30-minute immersive virtual reality curriculum, experienced through an OculusRift headset, with three simulations of an infant with 1) no distress, 2) respiratory distress, and 3) impending respiratory failure. MEASUREMENTS AND MAIN RESULTS: The impact of the virtual reality curriculum on recognition/interpretation of key examination findings, assignment of an appropriate respiratory status assessment, and recognition of the need for escalation of care for patients in impending respiratory failure was assessed via a free response clinical assessment of video vignettes at the end of the pediatric rotation. Responses were scored on standardized rubrics by physician experts. All eligible students participated (78 intervention and 90 control). Significant differences between intervention and control were demonstrated for consideration/interpretation of mental status (p < 0.01), assignment of the appropriate respiratory status assessment (p < 0.01), and recognition of a need for escalation of care (p = 0.0004). CONCLUSIONS: Exposure to an immersive virtual reality curriculum led to improvement in objective competence at the assessment of respiratory distress and recognition of the need for escalation of care for patients with signs of impending respiratory failure. This study represents a novel application of immersive virtual reality and suggests that it may be effective for clinical assessment training.

Phase 1b trial of docetaxel, prednisone, and pazopanib in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Docetaxel prednisone is a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), and plasma vascular endothelial growth factor (VEGF) levels are a poor prognostic factor in this population; therefore, we evaluated the combination of docetaxel prednisone with pazopanib, an oral VEGF receptor inhibitor, for safety and preliminary efficacy. METHODS: This is a two-site phase 1b Department of Defense Prostate Cancer Clinical Trials Consortium trial of docetaxel, prednisone, and pazopanib once daily and ongoing androgen deprivation therapy and prophylactic pegfilgrastim in men with mCRPC. The primary endpoint was safety and the determination of a maximum tolerated dose (MTD) through a dose-escalation and expansion design; secondary endpoints included progression-free and overall survival (OS), prostate specific antigen (PSA) declines, radiographic responses, and pharmacokinetic and plasma angiokine biomarker analyses. RESULTS: Twenty-five men were treated over six dose levels. Pegfilgrastim was added to the regimen after myelosuppression limited dose escalation. With pegfilgrastim, our target MTD of docetaxel 75 mg/m2 q3 weeks; prednisone 10 mg daily; and pazopanib 800 mg daily was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. Dose-limiting toxicities included neutropenia, syncope, and hypertension. Three deaths attributed to study treatment occurred. The objective response rate was 31%; median PFS was 14.1 months (95% confidence interval [CI]: 7.1 and 22.2); and OS was 18.6 months (95% CI: 11.8 and 22.2). CONCLUSIONS: The combination of docetaxel, prednisone, and pazopanib (with pegfilgrastim) was tolerable at full doses and demonstrated promising efficacy in a relatively poor risk patients with mCRPC. Further development of predictive biomarkers may enrich for patients who receive clinical benefit from this regimen.

Online Simulated Cases Assess Retention of Virtual Neighborhood Tour Curriculum.

Background Learning to identify and address social determinants of health (SDH) is a crucial component of pediatric residency training. A virtual tour of an impoverished neighborhood previously demonstrated efficacy in increasing residents' self-assessed knowledge and competence, but its impact on performance has not yet been reported. Online simulated cases are emerging as feasible assessment tools to measure trainees' skills across various healthcare settings. We developed online simulated cases to evaluate residents' retention of the virtual tour's key SDH-related learning objectives 1 month after completing this curriculum. Methods Three online simulated cases with interpolated open-ended questions were created to assess residents' ability to identify SDH, recommend appropriate resources, and display empathy. Scoring rubrics to objectively evaluate responses were developed and borderline scores were decided by a team of educators. Results 19 residents participated. Mean scores for all cases exceeded pre-established borderline scores (statistically significant in two of the three cases). More than 90% of residents identified relevant SDH in the primary care and emergency department cases. Ninety-five percent of residents recommended appropriate resources in all cases, and 89% displayed empathy. Discussion Residents' performance in online simulated cases demonstrated retention and application of the virtual tour's learning objectives, including recognizing SDH, offering appropriate resources, and displaying empathy, which supports the long-term effectiveness of the virtual tour curriculum to train pediatricians about SDH. Online simulated cases provided a standardized and cost-effective way to measure residents' skills related to curricular uptake, suggesting that this assessment approach may be adapted to evaluate other educational interventions.