rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial.

OBJECTIVE: To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants. STUDY DESIGN: This phase 2 trial was conducted from September 2014 to March 2016. Infants born at a gestational age of 230/7 weeks to 276/7 weeks were randomly allocated to rhIGF-1/rhIGFBP-3 (250 µg/kg/ 24 hours, continuous intravenous infusion from <24 hours of birth to postmenstrual age 296/7 weeks) or standard neonatal care, with follow-up to a postmenstrual age of 404/7 weeks. Target exposure was ≥70% IGF-1 measurements within 28-109 µg/L and ≥70% intended therapy duration. The primary endpoint was maximum severity of ROP. Secondary endpoints included time to discharge from neonatal care, bronchopulmonary dysplasia, intraventricular hemorrhage, and growth measures. RESULTS: Overall, 61 infants were allocated to rhIGF-1/rhIGFBP-3, 60 to standard care (full analysis set); 24 of 61 treated infants achieved target exposure (evaluable set). rhIGF-1/rhIGFBP-3 did not decrease ROP severity or ROP occurrence. There was, however, a 53% decrease in severe bronchopulmonary dysplasia in the full analysis set (21.3% treated vs 44.9% standard care), and an 89% decrease in the evaluable set (4.8% vs 44.9%; P = .04 and P = .02, respectively) for severity distribution between groups. There was also a nonsignificant trend toward decrease in grades 3-4 intraventricular hemorrhage in the full analysis set (13.1% vs 23.3%) and in the evaluable set (8.3% vs 23.3%). Fatal serious adverse events were reported in 19.7% of treated infants (12/61) and 11.7% of control infants (7/60). No effect was observed on time to discharge from neonatal care/growth measures. CONCLUSIONS: rhIGF-1/rhIGFBP-3 did not affect development of ROP, but decreased the occurrence of severe bronchopulmonary dysplasia, with a nonsignificant decrease in grades 3-4 intraventricular hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01096784.

Novel noninvasive anthropometric measure in preterm and full-term infants: normative values for waist circumference:length ratio at birth.

BACKGROUND: Waist circumference:length ratio (WLR) and ponderal index (PI) appear to be useful markers of visceral and total adiposity, respectively. However, there are no normative birth data across the full range of gestational ages. METHODS: In this retrospective cohort study of 500 preterm and 1,426 full-term infants, born in 1998 and 2008 at three military hospitals, the percentile growth curves for WLR and PI were calculated. There were no sex differences, and results were combined to obtain values from 26 to 42 wk gestation. RESULTS: Between 26 and 42 wk gestation, median birth WLR increased from 0.55 to 0.62, and median PI increased from 21.1 to 25.6. The adjusted mean WLR at birth among infants born <34 wk increased from 0.55 in 1998 to 0.58 in 2008 (P = 0.048), suggesting that early-preterm infants born in 2008 had greater abdominal adiposity than those born in 1998. CONCLUSION: We report normative birth data for WLR and PI in preterm and full-term infants by gestational age and sex. WLR and PI may be useful as clinical markers of visceral and overall adiposity. In conjunction with other anthropometric measures, WLR and PI may be useful to monitor postnatal nutrition and growth and assess risk for later obesity and cardiometabolic disorders.

Cardiomyopathy with inverted tako-tsubo pattern in the setting of subarachnoid hemorrhage: a series of four cases.

BACKGROUND: Severe subarachnoid hemorrhage may be associated with regional wall motion abnormalities (RWMA) in the absence of epicardial coronary occlusion. The RWMA extends beyond the distribution of a single coronary artery and may present in a typical tako-tsubo cardiomyopathy pattern. Other variants have also been recognized, including an inverted tako-tsubo pattern of severe basal hypokinesis that spares the apex. The mechanism of this cardiomyopathy is not well understood but likely involves catecholamine excess. While classic tako-tsubo cardiomyopathy from emotional stress carries a favorable prognosis, cardiac dysfunction from subarachnoid hemorrhage is a marker of overall poor prognosis. METHODS: We collected cases over a period of 4 years at a large teaching hospital. The cases represent cardiac dysfunction in the setting of subarachnoid hemorrhage in the unusual distribution of basal hypokinesis with relative sparing of the apex (inverted tako-tsubo pattern). RESULTS: A total of four cases were identified. All cases were female between the ages 43-67 years and had echocardiographic evidence of basal hypokinesis after suffering from an intracranial hemorrhage. CONCLUSIONS: The typical and inverted patterns may represent a spectrum within the same disease process or distinct clinical entities with dramatically different prognostic implications. Larger studies comparing the two presentations will help elucidate this further.

COVID-19 Vaccine Hesitancy Among Deployed Personnel in a Joint Environment.

INTRODUCTION: In the United States, vaccine hesitancy has been identified as a major barrier to vaccination against COVID-19, but attitudes toward COVID-19 vaccination among military personnel are not well understood. We evaluated the prevalence and correlates of COVID-19 vaccine consent or refusal among deployed personnel in a joint environment. MATERIALS AND METHODS: Deidentified data were retrospectively extracted from the electronic medical record of the Military Health System in May 2021. All personnel currently assigned to the deployment area of operations were included in the analysis if their choice to receive the vaccine was known. Personnel characteristics were compared by vaccine acceptance status using chi-square tests, Fisher's exact tests, or correlation coefficients. This analysis was exempted from Institutional Review Board review. RESULTS: The sample included 1,809 individuals, primarily members of the Army (72%) and members of Reserve (53%) or National Guard (27%) units. In the overall sample, 61% accepted the vaccine, with vaccine acceptance rates being lowest among Black or African American personnel (54%; P = .03 for comparison across racial groups) and members of Reserve or National Guard units (59%; P < .001 for comparison by component). No differences in vaccine acceptance were found according to sex or health status (including prior COVID-19 infection). CONCLUSIONS: Overall vaccine acceptance was greater among deployed military personnel than that reported in the U.S. population as a whole. However, lower vaccine acceptance among personnel from marginalized populations suggests a need to ensure that all service members have sufficient opportunities to have a frank and ongoing discussion with health care providers to address concerns related to vaccination. Additionally, lower vaccine acceptance among Reserve and National Guard personnel indicates a need for innovative educational approaches to counter vaccine hesitancy in the premobilization phase of deployment.

Preterm infants of lower gestational age at birth have greater waist circumference-length ratio and ponderal index at term age than preterm infants of higher gestational ages.

OBJECTIVE: To assess anthropometric changes from birth to hospital discharge in infants born preterm and compare with a reference birth cohort of infants born full-term. STUDY DESIGN: Retrospective chart review was conducted of 501 preterm and 1423 full-term infants. We evaluated birth and hospital discharge weight, length, and waist circumference (WC). WC/length ratio (WLR), ponderal index, and body mass index (BMI) were calculated. Preterm infants were categorized into quartiles (Q1-4) based on birth weight (BW). RESULTS: At birth mean length, WC, WLR, BMI, and ponderal index were all significantly less for preterm infants in the lowest BW quartile (Q1) than preterm infants in higher BW quartiles or full-term infants. Although their weight, length, and BMI remained significantly less at discharge, preterm infants in Q1 had a disproportionate increase in WLR and ponderal index such that at discharge their WLR and ponderal index were greater than infants in Q2-3 and comparable with infants in Q4 and full-term infants. Discharge WLR and ponderal index in Q1 were significantly higher with decreasing postmenstrual age at birth. CONCLUSIONS: Preterm infants of a lower birth postmenstrual age have disproportionate increases in WLR and ponderal index that are suggestive of increased visceral and total adiposity.

Late onset of pulmonary hypertension in very low birth weight infants.

INTRODUCTION: Pulmonary hypertension (PH) is a recognized complication of bronchopulmonary dysplasia (BPD). Recent guidelines recommend evaluating all infants with BPD for PH via echocardiogram, but the specific timing of this screening is controversial. We aimed to identify the timing of PH diagnosis in a cohort of very low birthweight infants (VLBW) to determine appropriate age at screening. METHODS: We retrospectively reviewed data on 455 VLBW infants undergoing echocardiography at our institution. The timing of all echocardiograms, PH diagnosis on echocardiography, and BPD diagnosis at 36 weeks corrected age were extracted. PH was defined as dilation of the right sided chambers or RVH, flattening or leftward deviation of the septum, TR >25 mmHg, or 2/3 systemic pressures, or right to left shunting. RESULTS: Fifteen VLBW infants had PH identified on echocardiography, of whom 11 had BPD and 2 died before BPD status at 36 weeks could be ascertained. PH was most often identified on echocardiography after 36 weeks corrected age, and typically around 40 weeks. Ten of the infants ultimately diagnosed with PH had previous echocardiograms performed that were negative for PH at 25-46 weeks. CONCLUSIONS: In our cohort of VLBW infants, onset of PH was typically found later than the 36-38 week range used by recently described screening programs. These findings suggest a need to examine echocardiograms obtained after 36 weeks for evidence of late-onset PH in vulnerable infants born at VLBW.

Increasing Pediatricians' Scholarly Productivity on and off the Tenure Track.

INTRODUCTION: Physician faculty have increasingly been appointed to nontenure track positions, which provide limited support for scholarly activity. We evaluated how a centralized departmental research group affected the scholarly productivity of faculty on and off the tenure track. METHODS: A research team providing both mentorship and logistical study support was implemented in 2018. We identified a pre-intervention cohort of physician faculty employed in July 2016, and a postintervention cohort, employed in July 2018. A publication search was conducted for these cohorts in the period 2017 to 2018 and 2019 to 2020, respectively. RESULTS: Seventy-five faculty were included in the analysis, with approximately two-thirds appointed on the clinical (nontenure) track. In the pre-intervention cohort (n = 59), 15 faculty (25%) had at least one publication in the period 2017 to 2018. In the postintervention cohort (n = 59), 33 faculty (56%) published at least one article in the period 2019 to 2020 (P = .001). Multivariable random-effects regression analysis confirmed that postintervention, odds of publishing in a given year increased for both clinical-track and tenure-track faculty. CONCLUSION: Both clinical and tenure-track faculty contribute to the academic mission at medical schools, yet scholarly activity is supported and rewarded for tenure-track faculty more often than for clinical-track faculty. Our centralized research team successfully fostered scholarly activity among both clinical-track and tenure-track faculty.

Preparing Faculty to Incorporate Health Systems Science into the Clinical Learning Environment: Factors Associated with Sustained Outcomes.

This study assesses participants' perceptions of long-term impacts of the Teachers of Quality Academy, a medical school faculty development program designed to prepare faculty to both practice and teach health system science. A previously published 1-year evaluation of the first cohort of 27 participants showed improved perceived skills, with positive career and health system impacts. In this 5-year evaluation, a mixed-methods design included a questionnaire followed by semistructured interviews to assess perceived long-term impacts on participants. Quantitative and qualitative analyses were completed. Questionnaire response rate was 88% (N = 22), and 14 interviews were analyzed. Results demonstrated that participants had incorporated quality improvement concepts into their clinical work and teaching, better understood interprofessionalism, and observed continued improvements in care delivery. They felt the longitudinal training, delivered in a shared setting, created a learning community with lasting positive effects in institutional culture, supported long-term professional development, and had broader institutional impact. Advancements in clinical care, medical education, and professional and academic advancements were noted.

Development of the PREMature Infant Index (PREMII™), a clinician-reported outcome measure assessing functional status of extremely preterm infants.

BACKGROUND: Comprehensive measures to evaluate the effectiveness of medical interventions in extremely preterm infants are lacking. Although length of stay is used as an indicator of overall health among preterm infants in clinical studies, it is confounded by nonmedical factors (e.g. parental readiness and availability of home nursing support). OBJECTIVES: To develop the PREMature Infant Index (PREMII™), an electronic content-valid clinician-reported outcome measure for assessing functional status of extremely preterm infants (<28 weeks gestational age) serially over time in the neonatal intensive care unit. We report the development stages of the PREMII, including suggestions for scoring. METHODS: We developed the PREMII according to US Food and Drug Administration regulatory standards. Development included five stages: (1) literature review, (2) clinical expert interviews, (3) Delphi panel survey, (4) development of items/levels, and (5) cognitive interviews/usability testing. Scoring approaches were explored via an online clinician survey. RESULTS: Key factors reflective of functional status were identified by physicians and nurses during development of the PREMII, as were levels within each factor to assess functional status. The resulting PREMII evaluates eight infant health factors: respiratory support, oxygen administration, apnea, bradycardia, desaturation, thermoregulation, feeding, and weight gain, each scored with three to six gradations. Factor levels are standardized on a 0-100 scale; resultant scores are 0-100. No usability issues were identified. The online clinician survey identified optimal scoring methods to capture functional status at a given time point. CONCLUSIONS: Our findings support the content validity and usability of the PREMII as a multifunction outcome measure to assess functional status over time in extremely preterm infants. Psychometric validation is ongoing.

Discovery of new cargo proteins that enter cells through clathrin-independent endocytosis.

Clathrin-independent endocytosis (CIE) allows internalization of plasma membrane proteins lacking clathrin-targeting sequences, such as the major histocompatibility complex class I protein (MHCI), into cells. After internalization, vesicles containing MHCI fuse with transferrin-containing endosomes generated from clathrin-dependent endocytosis. In HeLa cells, MHCI is subsequently routed to late endosomes or recycled back out to the plasma membrane (PM) in distinctive tubular carriers. Arf6 is associated with endosomal membranes carrying CIE cargo and expression of an active form of Arf6 leads to the generation of vacuolar structures that trap CIE cargo immediately after endocytosis, blocking the convergence with transferrin-containing endosomes. We isolated these trapped vacuolar structures and analyzed their protein composition by mass spectrometry. Here we identify and validate six new endogenous cargo proteins (CD44, CD55, CD98, CD147, Glut1, and ICAM1) that use CIE to enter cells. CD55 and Glut1 appear to closely parallel the trafficking of MHCI, merging with transferrin endosomes before entering the recycling tubules. In contrast, CD44, CD98, and CD147 appear to directly enter the recycling tubules and by-pass the merge with EEA1-positive, transferrin-containing endosomes. This divergent itinerary suggests that sorting may occur along this CIE pathway. Furthermore, the identification of new cargo proteins will assist others studying CIE in different cell types and tissues.

Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.

Ablepharon-macrostomia syndrome (AMS) is characterized by absent or short eyelids, macrostomia, ear anomalies, absent lanugo and hair, redundant skin, abnormal genitalia, and developmental delay in two-thirds of the reported patients. Additional anomalies include dry skin, growth retardation, hearing loss, camptodactyly, hypertelorism, absent zygomatic arches, and umbilical abnormalities. We present the second familial case of ablepharon-macrostomia syndrome in a newborn female and her 22-year-old father making autosomal dominant inheritance more likely than the previously proposed autosomal recessive transmission for this disorder. These cases likely represent the 16th and 17th reported cases of AMS and the first case suspected on prenatal ultrasound. Additionally, the child shows more prominent features of the disorder when compared to her father documenting variable expression and possible anticipation.

Dissemination of Quality Improvement Project Results After Local Presentation.

Among quality improvement (QI) projects submitted for local presentation, the authors sought to understand how often project results were eventually disseminated through national/international presentation or peer-reviewed journal publication. Projects submitted for local presentation from 2016 to 2019 were linked to resulting publications or national/international conference presentations. Submitting authors were surveyed about their intentions, experience, and satisfaction with the process of disseminating their project results. Of 83 projects, 5 were published and another 10 were presented nationally/internationally. External dissemination was more likely with fewer project cycles and cost-focused outcomes. Survey responses indicated that most project leaders wanted to see their results published but held mixed opinions about resources and encouragement available to reach this goal. Few QI projects submitted for local presentation resulted in wider dissemination of project results. Sharing results and lessons learned beyond the local institution requires long-term planning, education, and support beginning early in the QI process.

Improved Use of Human Milk, Growth, and Central Line Utilization With Standard Feeding Roadmap in an Academic NICU.

BACKGROUND: Before the initiation of a standardized feeding roadmap in our regional, level IV academic neonatal intensive care unit, utilization of central lines was high, and initiation of enteral feeds delayed in the very low-birth-weight population (<1500 g). Given our review of the literature, it appeared that the standardization of feeding advancement would likely result in improved performance in both issues. METHODS: This was a retrospective cohort comparison of very low-birth-weight patients before initiation of any feeding roadmap with a second cohort following completion of the final roadmap. Infants were examined retrospectively in 2 historical cohorts: Phase 1, infants fed before roadmap development and rollout, October 1, 2012-March 31, 2013; and Phase 2, following promulgation of the final feeding roadmap, January 1, 2017-June 30, 2017. RESULTS: During Phase 2, we observed a significant reduction in median (interquartile range) days to first feed (3 [1] vs 1 [1] [P < 0.0001]) and utilization of a second central line (35% vs 12% [P < 0.01]). Weight gain was significantly improved from before roadmap implementation to final, mean (SD) (g/d, 21 [5] vs 24 [4]; [P < .0001]). Percentage of first enteral feedings that were human milk also increased significantly from 71% to 91% (P = 0.0007). CONCLUSION: Implementation of a standardized feeding roadmap was associated with a reduction in days to first enteral feeds, an increase in the primary use of human milk for initiation of enteral feeds, and a decrease in the utilization of central lines while improving weight gain in very low-birth-weight infants.

The Teachers of Quality Academy: Evaluation of the Effectiveness and Impact of a Health Systems Science Training Program.

This project aimed to evaluate the effectiveness of a faculty development program in health systems science (HSS)-the Teachers of Quality Academy (TQA). Participants in TQA and a comparison group were evaluated before, during, and 1 year after the program using self-perception questionnaires, tests of HSS knowledge, and tracking of academic productivity and career advancement. Among program completers (n = 27), the mean self-assessed ratings of knowledge and skills of HSS topics immediately after the program, as compared to baseline, increased significantly compared to controls (n = 30). Participants demonstrated progressive improvement of self-perceived skills and attitudes, and retention of HSS knowledge, from baseline to completion of the program. Participants also demonstrated substantially higher HSS scholarly productivity, leadership, and career advancement compared to the comparison group. The TQA effectively created a faculty cadre able to role model, teach, and create a curriculum in HSS competencies for medical students, resident physicians, and other health professionals.

When a Mother Changes Her Mind About a DNR.

Generally, wide latitude is granted to parents when making decisions for their child on the basis of the wide acceptance of the special relationship between parent and child and the important role played by parents in the lives of children. However, when high-risk decisions are made, health care teams serve as an important societal safeguard that questions whether a parent is an appropriate decision-maker for their child. Child advocacy is an essential function of the pediatric health care team. In this ethics rounds, we examine a case of an infant with a complex medical condition requiring prolonged hospitalization that results in a clash of understanding between a mother and medical team when the mother abruptly requests removal of life-sustaining treatment. We present an ethical decision-making framework for such cases and examine the impact of barriers and unconscious bias that can exclude parents from their rightful role in directing care for their child.

The Teachers of Quality Academy: A Learning Community Approach to Preparing Faculty to Teach Health Systems Science.

PROBLEM: Although efforts to integrate health systems science (HSS) topics, such as patient safety, quality improvement (QI), interprofessionalism, and population health, into health professions curricula are increasing, the rate of change has been slow. APPROACH: The Teachers of Quality Academy (TQA), Brody School of Medicine at East Carolina University, was established in January 2014 with the dual goal of preparing faculty to lead frontline clinical transformation while becoming proficient in the pedagogy and curriculum design necessary to prepare students in HSS competencies. The TQA included the completion of the Institute for Healthcare Improvement Open School Basic Certificate in Quality and Safety; participation in six 2-day learning sessions on key HSS topics; completion of a QI project; and participation in three online graduate courses. OUTCOMES: Twenty-seven faculty from four health science programs completed the program. All completed their QI projects. Nineteen (70%) have been formally engaged in the design and delivery of the medical student curriculum in HSS. Early into their training, TQA participants began to apply new knowledge and skills in HSS to the development of educational initiatives beyond the medical student curriculum. NEXT STEPS: Important next steps for TQA participants and program planners include further incorporation as faculty advisors and contributors to the full implementation of the longitudinal HSS curriculum; expanded involvement with the Leaders in Innovative Care Scholars student leadership distinction track; continued in-depth evaluation of the impact of TQA participation on patient care, teaching, and role modeling; and the recruitment of the next cohort of TQA participants.

Correlates of tricuspid regurgitation as determined by 3D echocardiography: pulmonary arterial pressure, ventricle geometry, annular dilatation, and papillary muscle displacement.

BACKGROUND: While it is understood that annular dilatation contributes to tricuspid regurgitation (TR), other factors are less clear. The geometry of the right ventricle (RV) and left ventricle (LV) may alter tricuspid annulus size and papillary muscle (PM) positions leading to TR. METHODS AND RESULTS: Three-dimensional echocardiographic images were obtained at Emory University Hospital using a GE Vivid 7 ultrasound system. End-diastolic area was used to classify ventricle geometry: control (n=21), isolated RV dilatation (n=17), isolated LV dilatation (n=13), and both RV and LV dilatation (n=13). GE EchoPAC was used to measure annulus area and position of the PM tips. Patients with RV dilatation had significant (P≤ 0.05) displacement of all PMs apically and the septal PM and posterior PM away from the center of the RV toward the LV. Patients with LV dilatation had significant (P≤0.05) apical displacement of the anterior PM. Pulmonary arterial pressure (r=0.66), annulus area (r=0.51), apical displacement of the anterior PM (r=0.26), posterior PM (r=0.49), and septal PM (r=0.40), lateral displacement of the septal PM (r=0.37) and posterior PM (r=0.40), and tenting area and height (r=0.54, 0.49), were significantly (P≤0.05) correlated to the grade of TR. Ventricle classification (r=0.46) and RV end-diastolic area (r=0.48) also were correlated with the grade of TR. A regression analysis found ventricle classification (P=0.001), pulmonary arterial pressure (P≤0.001) annulus area (P=0.027), and apical displacement of the anterior PM (P=0.061) to be associated with the grade of TR. CONCLUSIONS: Alterations in ventricular geometry can lead to TR by altering both tricuspid annulus size and PM position. Understanding these geometric interactions with the aim of correcting pathological alterations of the tricuspid valve apparatus may lead to more robust repairs.

Perspective: limiting resident work hours is a moral concern.

The author outlines the cross-cultural and widespread expectation that the moral character of physicians is built on dual possession of skill and compassion. The details of the moral makeup of physicians are often hotly debated in the biomedical literature. Despite a lack of consensus regarding the required aspects of character, the author demonstrates that little debate exists that at a minimum physicians should possess not only knowledge but also a willingness to care for and comfort patients. The primacy of the patient in the physician's life is reflected in the panoply of oaths taken by new physicians despite great variability in other aspects of these oaths. The author details recent worrisome reports demonstrating the erosion of medical trainees' empathy and compassion by long work hours. Further, the continued linkage of these attitude changes and fatigue to poor medical outcomes is a call to action. Changes enacted by the Accreditation Council for Graduate Medical Education to reduce resident work hours are insufficient to achieve the goal of improved patient care while promoting moral development among resident physicians. The debate regarding resident work hours is often framed as an idealistic discussion of placing patients first. However, residents are used as an inexpensive labor force, and efforts to curtail this usage would have a significant economic impact. Economic concerns play a larger part in decision making than is generally discussed. The author calls for further alterations of resident work schedules to improve patient care and ensure the preservation of the moral ethos of medicine.