Explore the vast range of titles available.

Background At birth, the majority of neonates born at <30 weeks of gestation require respiratory support to facilitate transition and ensure adequate gas exchange. Although the optimal approach to the initial respiratory management is uncertain, the American Academy of Pediatrics endorses noninvasive respiratory support with nasal continuous positive airway pressure (nCPAP) for premature neonates with respiratory insufficiency. Despite evidence for its use, nCPAP failure, requiring intubation and mechanical ventilation, is common. Recently, investigators have described a novel method to deliver bubble nCPAP, termed Seattle-PAP. While preclinical and pilot studies are encouraging regarding the potential value of Seattle-PAP, a large trial is needed to compare Seattle-PAP directly with the current standard of care for bubble nCPAP (Fisher & Paykel CPAP or FP-CPAP). Methods/design We designed a multicenter, non-blinded, randomized controlled trial that will enroll 230 premature infants (22 0/7 to 29 6/7 weeks of gestation). Infants will be randomized to receive Seattle-PAP or FP-CPAP. The primary outcome is respiratory failure requiring intubation and mechanical ventilation. Secondary outcomes include measures of short- and long-term respiratory morbidity and cost-effectiveness. Discussion This trial will assess whether Seattle-PAP is more efficacious and cost-effective than FP-CPAP in real-world practice among premature neonates. Trial registration ClinicalTrials.gov, NCT03085329 . Registered on 21 March 2017.

ObjectiveTo test the hypothesis that infants born <30 weeks’ gestation supported by Seattle-PAP will have lower rates of continuous positive airway pressure (CPAP) failure than infants supported with conventional, Fisher&Paykel-CPAP (FP-CPAP).Study designRandomized trial (3/2017-01/2019) at 5 NICUs. The primary outcome was CPAP failure; subgroup analyses (gestational age, receipt antenatal corticosteroids) were performed.ResultsA total of 232 infants were randomized. Infants in the Seattle-PAP and FP-CPAP groups had mean gestational ages of 27.0 and 27.2 weeks, respectively. We observed no differences in rates of treatment failure between Seattle-PAP (40/112, 35.7%) and FP-CPAP (38/120, 31.7%; risk difference, 4.1%; 95% CI, −8.1–16.2; P = 0.51). Subgroup analysis indicated no differences in rates of CPAP failure. We observed no differences between the two groups in frequencies of adverse events or duration of respiratory support.ConclusionsAmong infants born <30 weeks’ gestation, rates of CPAP failure did not differ between Seattle-PAP and FP-CPAP.

Background: At birth, the majority of neonates born at <30 weeks of gestation require respiratory support to facilitate transition and ensure adequate gas exchange. Although the optimal approach to the initial respiratory management is uncertain, the American Academy of Pediatrics endorses noninvasive respiratory support with nasal continuous positive airway pressure (nCPAP) for premature neonates with respiratory insufficiency. Despite evidence for its use, nCPAP failure, requiring intubation and mechanical ventilation is common. Recently, investigators have described a novel method to deliver bubble nCPAP, termed Seattle-PAP. While preclinical and pilot studies are encouraging with regard to the potential value of Seattle-PAP, a large trial is needed to compare Seattle-PAP directly with the current standard of care for bubble nCPAP (Fisher Paykel-CPAP; FP-CPAP). Methods: We designed a multicenter, non-blinded, randomized controlled trial that will enroll 230 premature infants (220/7 to 296/7 weeks of gestation). Infants will be randomized to receive Seattle-PAP or FP-CPAP. The primary outcome is respiratory failure requiring intubation and mechanical ventilation. Secondary outcomes include measures of short and long-term respiratory morbidity and cost effectiveness. Discussion: This trial will assess whether Seattle-PAP is more efficacious and cost effective than FP-CPAP in real-world practice among premature neonates. Trial Registration: This trial has been registered with the United States National Library of Medicine (www.clinicaltrials.gov, Trial Identifier #NCT03085329). Registered on 21 March 2017.

Background Early behavioral intervention to promote development is recommended as the standard of care for preterm infants, yet is not provided in Malawi. One such intervention is H-HOPE (Hospital to Home: Optimizing the Premature Infant’s Environment). In US studies, H-HOPE increased mother-preterm infant responsivity at 6-weeks corrected age (CA). Kangaroo Mother Care (KMC) improves infant survival and is the standard of care for preterm infants in Malawi. This is the first study to examine whether H-HOPE is feasible and promotes mother-preterm infant responsivity in Malawi, and the first to examine the impact of H-HOPE when KMC is the standard of care. Method This pilot was conducted in a KMC unit using a prospective cohort comparison design. Because the unit is an open room without privacy, random assignment would have led to contamination of the control cohort. H-HOPE includes participatory guidance for mothers and Massage + , a 15 min multisensory session provided by mothers twice daily. H-HOPE began when infants were clinically stable and at least 32 weeks postmenstrual age. Mothers participated if they were physically stable and willing to return for follow-up. Mother-preterm infant dyads were video-recorded during a play session at 6-weeks CA. Responsivity was measured using the Dyadic Mutuality Code (DMC). Results The final sample included 60 H-HOPE + KMC and 59 KMC only mother-preterm infant dyads. Controlling for significant maternal and infant characteristics, the H-HOPE + KMC dyads were over 11 times more likely to have higher responsivity than those in the KMC only dyads (AOR = 11.51, CI = 4.56, 29.04). The only other factor related to higher responsivity was vaginal vs. Caesarian delivery (AOR = 5.44, CI = .096, 30.96). Conclusion This study demonstrated that H-HOPE can be provided in Malawi. Mother-infant dyads receiving both H-HOPE and KMC had higher responsivity at 6-weeks CA than those receiving KMC only. H-HOPE was taught by nurses in this study, however the nursing shortage in Malawi makes H-HOPE delivery by nurses challenging. Training patient attendants in the KMC unit is a cost-effective alternative. H-HOPE as the standard of care offers benefits to preterm infants and mothers that KMC alone does not provide.

Background Dysregulated amino acid metabolism creates cancer-specific vulnerabilities. Neuroblastoma tumors have dysregulated arginine metabolism that renders them sensitive to systemic arginine deprivation. Arginase therapy has been proposed as a therapeutic approach for neuroblastoma treatment and has a favorable safety profile in pediatric cancer patients, however optimal therapeutic combinations remain unexplored. Methods The anti-tumor effects of BCT-100, a pegylated human arginase, were studied in neuroblastoma cell models by metabolite profiling, proteomics, and viability, clonogenicity, and protein translation assays. BCT-100 efficacy was assessed in the Th- MYCN transgenic neuroblastoma mouse model and in neuroblastoma cell line and patient-derived xenograft models. Results In vitro, depletion of arginine by BCT-100 arrested protein translation and cellular proliferation, with effects on clonogenicity enhanced in combination with standard-of-care chemotherapeutics SN-38/temozolomide and mafosfamide/topotecan. In vivo, BCT-100 treatment spared liver arginine while significantly depleting plasma and tumor arginine in Th- MYCN mice, and extended tumor latency (> 100 vs. 45.5 days) in mice pre-emptively treated at weaning. In mice with established tumors, BCT-100 prolonged tumor progression delay when combined with standard-of-care chemo- (> 90 vs. 25 days) or chemo-immuno-therapy (49.5 vs. 35.5 days). Tumor progression delay was also observed in cell line and patient-derived xenografts with BCT-100 treatment, including relapsed/refractory disease models. No increased toxicity was observed with the addition of BCT-100 to established therapies. Conclusions The arginase BCT-100 profoundly disrupts neuroblastoma growth in vitro and in vivo, an effect enhanced in combination with standard-of-care chemo-immuno-therapy. Our data supports further assessment of arginine-depleting combination therapies as a new treatment strategy for neuroblastoma.

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID 1 . To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria 2 , as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa ( n  = 7,453), but not among individuals living in malaria-free areas ( n  = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%. A genetic link suggests that interventions that halve the risk of malaria episodes could reduce the prevalence of iron deficiency in African children by nearly 50%.

Introduction Data‐to‐care programmes utilize surveillance data to identify persons who are out of HIV care, re‐engage them in care and improve HIV care outcomes. We assess the costs and cost‐effectiveness of re‐engagement in an HIV care intervention in the United States. Methods The Cooperative Re‐engagement Control Trial (CoRECT) employed a data‐to‐care collaborative model between health departments and HIV care providers, August 2016–July 2018. The health departments in Connecticut (CT), Massachusetts (MA) and Philadelphia (PHL) collaborated with HIV clinics to identify newly out‐of‐care patients and randomize them to receive usual linkage and engagement in care services (standard‐of‐care control arm) or health department‐initiated active re‐engagement services (intervention arm). We used a microcosting approach to identify the activities and resources involved in the CoRECT intervention, separate from the standard‐of‐care, and quantified the costs. The cost data were collected at the start‐up and recurrent phases of the trial to incorporate potential variation in the intervention costs. The costs were estimated from the healthcare provider perspective. Results The CoRECT trial in CT, MA and PHL randomly assigned on average 327, 316 and 305 participants per year either to the intervention arm (n = 166, 159 and 155) or the standard‐of‐care arm (n = 161, 157 and 150), respectively. Of those randomized, the number of participants re‐engaged in care within 90 days in the intervention and standard‐of‐care arms was 85 and 70 in CT, 84 and 70 in MA, and 98 and 67 in PHL. The additional number of participants re‐engaged in care in the intervention arm compared with those in the standard‐of‐care arm was 15 (CT), 14 (MA) and 31 (PHL). We estimated the annual total cost of the CoRECT intervention at$490,040 in CT, $ 473,297 in MA and$439,237 in PHL. The average cost per participant enrolled was $ 2952,$2977 and $ 2834 and the average cost per participant re‐engaged in care was$5765, $ 5634 and$4482. We estimated an incremental cost per participant re‐engaged in care at $ 32,669 (CT),$33,807 (MA) and $ 14,169 (PHL). Conclusions The costs of the CoRECT intervention that identified newly out‐of‐care patients and re‐engaged them in HIV care are comparable with other similar interventions, suggesting a potential for its cost‐effectiveness in the US context.

Objective:We describe the baseline characteristics and complications of individuals with influenza in the US FDA’s Sentinel System by antiviral treatment timing.Design:Retrospective cohort design.Patients:Individuals aged ≥6 months with outpatient diagnoses of influenza in June 2014–July 2017, 3 influenza seasons.Methods:We identified the comorbidities, vaccination history, influenza testing, and outpatient antiviral dispensings of individuals with influenza using administrative claims data from 13 data partners including the Centers for Medicare and Medicaid Services, integrated delivery systems, and commercial health plans. We assessed complications within 30 days: hospitalization, oxygen use, mechanical ventilation, critical care, ECMO, and death.Results:There were 1,090,333 influenza diagnoses in 2014–2015; 1,005,240 in 2016–2017; and 578,548 in 2017–2018. Between 49% and 55% of patients were dispensed outpatient treatment within 5 days. In all periods >80% of treated individuals received treatment on the day of diagnosis. Those treated on days 1–5 after diagnosis had higher prevalences of diabetes, chronic obstructive pulmonary disease, asthma, and obesity compared to those treated on the day of diagnosis or not treated at all. They also had higher rates of hospitalization, oxygen use, and critical care. In 2014–2015, among those aged ≥65 years, the rates of hospitalization were 45 per 1,000 diagnoses among those treated on day 0; 74 per 1,000 among those treated on days 1–5; and 50 per 1,000 among those who were untreated.Conclusions:In a large, national analysis, approximately half of people diagnosed with influenza in the outpatient setting were treated with antiviral medications. Delays in outpatient dispensed treatment were associated with higher prevalence of comorbidities and higher rates of complication.

Opioid use disorder (OUD) is influenced by genetic and environmental factors. While recent research suggests epigenetic disturbances in OUD, this is mostly limited to DNA methylation (5mC). DNA hydroxymethylation (5hmC) has been widely understudied. We conducted a multi-omics profiling of OUD in a male cohort, integrating neuronal-specific 5mC and 5hmC as well as gene expression profiles from human postmortem orbitofrontal cortex (OUD = 12; non-OUD = 26). Single locus methylomic analysis and co-methylation analysis showed a higher number of OUD-associated genes and gene networks for 5hmC compared to 5mC; these were enriched for GPCR, Wnt, neurogenesis, and opioid signaling. 5hmC marks also showed a higher correlation with gene expression patterns and enriched for GWAS of psychiatric traits. Drug interaction analysis revealed interactions with opioid-related drugs, some used as OUD treatments. Our multi-omics findings suggest an important role of 5hmC and reveal loci epigenetically dysregulated in OFC neurons of individuals with OUD. Opioid use disorder (OUD) is influenced by genetic and environmental factors. Here, authors use a multi-omics approach to reveal DNA hydroxymethylation as an important gene regulatory mechanism for OUD in the human brain.

Abstract Rationale Clinical and research training opportunities in global health are of increasing interest to medical trainees, but little is known about such opportunities in U.S.-based pulmonary and pulmonary/critical care medicine (PCCM) fellowship programs. Objectives Summarize currently available global health–related training opportunities and identify potential barriers to implementing global health curricula among U.S.-based PCCM fellowship programs. Methods We sent a confidential, online, targeted needs assessment to PCCM fellowship program directors and associate program directors. Data collected included program demographics, currently available global health–related clinical and research training opportunities, potential barriers to the implementation of global health–related programmatic content, and perceived interest in global health–related training opportunities by current and/or prospective trainees. To evaluate for nonresponse bias, we performed an online search to identify global health–related training opportunities offered by nonresponding programs. Results Out of 171 surveyed programs, 63 PCCM fellowship programs (37%) provided survey responses. Most responses (n = 56, 89%) were from combined PCCM training programs; 66% (n = 40) of programs offered at least one component of global health–related clinical or research training. Overall, 27% (n = 17) had a Ruth L. Kirschstein National Research Service Award Institutional Research Training Grant (National Institutes of Health T32), 73% (n = 46) had fewer than 35 faculty members, and 51% (n = 32) had at least one faculty member conducting global health–focused research. Most responding programs (66%, n = 40) offered at least one global health–related educational component. Among programs that would like to offer global health–related training components, the most common barriers included competing priorities for lecture content and a lack of in-division mentors with global health experience, a champion for global health–related activities, and established partnerships outside the United States. Conclusions PCCM program leaders are interested in offering global health–related training opportunities, but important barriers include lack of mentorship, dedicated fellowship time, and established global partnerships. Future research is needed to better understand global health–related interests and training needs of incoming fellows and to design creative solutions for providing global health–related training across academic institutions with variable global health–related training capacities.