Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality.

BACKGROUND: The molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored. METHODS AND RESULTS: We report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent-offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic. CONCLUSION: Our findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene.

Pregnancy alters interleukin-1 beta expression and antiviral antibody responses during severe acute respiratory syndrome coronavirus 2 infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2, the disease-causing pathogen of the coronavirus disease 2019 pandemic, has resulted in morbidity and mortality worldwide. Pregnant women are more susceptible to severe coronavirus disease 2019 and are at higher risk of preterm birth than uninfected pregnant women. Despite this evidence, the immunologic effects of severe acute respiratory syndrome coronavirus 2 infection during pregnancy remain understudied. OBJECTIVE: This study aimed to assess the impact of severe acute respiratory syndrome coronavirus 2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to severe acute respiratory syndrome coronavirus 2 among pregnant and nonpregnant women. STUDY DESIGN: Immune responses to severe acute respiratory syndrome coronavirus 2 were analyzed using samples from pregnant (n=33) and nonpregnant (n=17) women who tested either positive (pregnant, 22; nonpregnant, 17) or negative for severe acute respiratory syndrome coronavirus 2 (pregnant, 11) at Johns Hopkins Hospital. We measured proinflammatory and placental cytokine messenger RNAs, neonatal Fc receptor expression, and tetanus antibody transfer in maternal and cord blood samples. In addition, we evaluated antispike immunoglobulin G, antispike receptor-binding domain immunoglobulin G, and neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 in serum or plasma collected from nonpregnant women, pregnant women, and cord blood. RESULTS: Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection expressed more interleukin-1 beta, but not interleukin 6, in blood samples collected within 14 days vs >14 days after performing severe acute respiratory syndrome coronavirus 2 test. Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection also had reduced antispike receptor-binding domain immunoglobulin G titers and were less likely to have detectable neutralizing antibody than nonpregnant women. Although severe acute respiratory syndrome coronavirus 2 infection did not disrupt neonatal Fc receptor expression in the placenta, maternal transfer of severe acute respiratory syndrome coronavirus 2 neutralizing antibody was inhibited by infection during pregnancy. CONCLUSION: Severe acute respiratory syndrome coronavirus 2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of coronavirus disease 2019 treatment in pregnancy. In addition, the long-term implications of placental inflammation for neonatal health require greater consideration.

Promoting clinical reasoning with meta-memory techniques to teach broad differential diagnosis generation in a pediatric core clerkship.

OBJECTIVES: Clinical reasoning with generation and prioritization of differential diagnoses (DDx) is a key skill for medical students, but no consensus exists on the best method to teach these skills. Meta-memory techniques (MMTs) may be useful, but the efficacy of individual MMTs is unclear. METHODS: We designed a 3-part curriculum for pediatric clerkship students to teach one of 3 MMTs and provide practice in DDx generation through case-based sessions. Students submitted DDx lists during two sessions and completed pre- and post-curriculum surveys assessing self-reported confidence and perceived helpfulness of the curriculum. Results were analyzed using ANOVA with multiple linear regression. RESULTS: A total of 130 students participated in the curriculum, with 96 % (125/130) completing at least one DDx session, and 44 % (57/130) completing the post-curriculum survey. On average, 66 % of students rated all three sessions as "quite helpful" (4/5 on 5-point Likert scale) or "extremely helpful" (5/5) without difference between MMT groups. Students generated an average of 8.8, 7.1 and 6.4 diagnoses using the VINDICATES, Mental CT, and Constellations methods, respectively. When controlling for case, case order, and number of prior rotations, students using VINDICATES produced 2.8 more diagnoses than those using Constellations (95 % CI [1.1,4.5], p<0.001). There was no significant difference between VINDICATES and Mental CT (Δ=1.6, 95 % CI [-0.2,3.4], p=0.11) or Mental CT and Constellations (Δ=1.2, 95 % CI [-0.7,3.1], p=0.36). CONCLUSIONS: Medical education should include curricula focused on enhancing DDx development. Although VINDICATES helped students produce the most DDx, further research is needed to identify which MMT generates more accurate DDx.

Experience and Outcomes of Breastfed Infants of Women Living With HIV in the United States: Findings From a Single-Center Breastfeeding Support Initiative.

We assessed breastfeeding outcomes for a cohort of infants born to women living with HIV (WLHIV) at an urban health care center in the United States. Ten infants were exclusively breastfed for a mean duration of 4.4 (1.0-8.6) months. All had negative HIV RNA PCRs at a median age of 16 months.

Health Disparities and Their Effects on Children and Their Caregivers During the Coronavirus Disease 2019 Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has uncovered long-standing health disparities in marginalized communities, including racial and ethnic minorities and children with underlying medical and social problems. African Americans, Hispanics, and Native Americans have higher rates of COVID-19 infections and deaths than their population percentages in the United States. Unique populations of children, including children with developmental disabilities, children in the foster care system, children with chronic medical problems, and children who are homeless are particularly vulnerable to COVID-19 infection. This article explores how the COVID-19 pandemic superimposed on health disparities directly and indirectly affects children, adolescents, and their caregivers.

Dysregulated immunity in SARS-CoV-2 infected pregnant women.

IMPORTANCE: The effects of SARS-CoV-2 infection on immune responses during pregnancy have not been systematically evaluated. OBJECTIVE: To assess the impact of SARS-CoV-2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to SARS-CoV-2 among pregnant and non-pregnant women. DESIGN: Immune responses to SARS-CoV-2 were analyzed using samples from pregnant and non-pregnant women who had either tested positive or negative for SARS-CoV-2. We measured, proinflammatory and placental cytokine mRNAs, neonatal Fc receptor (FcRn) receptor expression, and tetanus antibody transfer in maternal and cord blood samples. Additionally, we measured anti-spike (S) IgG, anti-S-receptor binding domain (RBD) IgG, and neutralizing antibody (nAb) responses to SARS-CoV-2 in serum or plasma collected from non-pregnant women, pregnant women, and cord blood. SETTING: Johns Hopkins Hospital (JHH). PARTICIPANTS: Pregnant women were recruited through JHH outpatient obstetric clinics and the JHH Labor & Delivery unit. Non-pregnant women were recruited after receiving outpatient SARS-CoV-2 testing within Johns Hopkins Health System, USA. Adult non-pregnant women with positive RT-PCR results for SARS-CoV-2, within the age range of 18-48 years, were included in the study. EXPOSURES: SARS-CoV-2. MAIN OUTCOMES AND MEASURES: Participant demographic characteristics, antibody titers, cytokine mRNA expression, and FcRn receptor expression. RESULTS: SARS-COV-2 positive pregnant women expressed more IL1ß , but not IL6 , in blood samples collected within 14 days versus > 14 days after a confirmed SARS-CoV-2 test, with similar patterns observed in the fetal side of placentas, particularly among asymptomatic pregnant women. Pregnant women with confirmed SARS-CoV-2 infection also had reduced anti-S-RBD IgG titers and were less likely to have detectable nAb as compared with non-pregnant women. Although SARS-CoV-2 infection did not disrupt FcRn expression in the placenta, maternal transfer of nAb was inhibited by SARS-CoV-2 infection during pregnancy. CONCLUSIONS AND RELEVANCE: SARS-CoV-2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of COVID-19 therapeutics in pregnancy. The long-term implications of placental inflammation for neonatal health also requires greater consideration.

Anatomic Distribution of the Morphologic Variation of the Upper Lip Frenulum Among Healthy Newborns.

IMPORTANCE: The maxillary labial frenulum and its potential contribution to breastfeeding difficulty may substantially affect public health. However, objective studies of the frenulum are limited. OBJECTIVE: To measure the variations in length, thickness, and attachments of the maxillary labial frenulum in healthy newborns and to identify which anatomic measurements could be used in further research investigating the maxillary labial frenulum. DESIGN, SETTING, AND PARTICIPANTS: This prospective cross-sectional study conducted measurements on images of maxillary labial frenula captured by digital photography from 150 healthy newborns admitted to the newborn nursery at a tertiary care children's hospital in Maryland between September 1, 2017, and April 1, 2018. MAIN OUTCOMES AND MEASURES: The primary outcome was the measurement of numerous frenulum morphologic components. RESULTS: Of 150 newborns enrolled, 77 were female, the mean (SD) gestational age was 38.60 (1.72) weeks, and the mean (SD) birth weight was 3180 (570) g. The means and SDs of the morphologic components of the frenulum with the broadest distributions, which were most helpful in differentiating degrees of lip tethering, included the following: alveolar edge to frenulum gingival attachment, 1.53 (0.85) mm; frenulum length on stretch, 5.19 (1.68) mm; frenulum gingival attachment thickness, 0.84 (0.36) mm; frenulum labial attachment thickness, 2.83 (1.33) mm; and the percentage of free lip to total lip length, 87.38% (7.67%). Gingival attachment mean (SD) thickness differed between late-preterm (0.69 [0.24] mm) and term (0.88 [0.37] mm) infants (Cohen d, -0.52; 95% CI, -0.94 to -0.10). CONCLUSIONS AND RELEVANCE: To our knowledge, this cross-sectional study was the first to objectively measure the numerous morphologic components of the upper lip anatomy in healthy newborns. Variations in maxillary labial frenulum morphology were identified, and some combination of the stated measurements may be used to create a more robust classification system to advance quality research in the association of lip-tie with breastfeeding difficulty.

Ocular effects of Zika virus-a review.

Zika virus was considered an innocent pathogen while restricted to the African and Asian population; however, after reaching the Americas in March 2015, it became a global threat. Despite usually causing mild or no symptoms in infected adults, Zika virus displays a different behavior toward fetuses. When infected during gestation, fetuses have their immature neural cells killed by the virus and consequently have devastating findings at birth. In the past year the drastic effects of Zika virus infection in newborns include neurological, ophthalmological, audiological, and skeletal abnormalities. These findings represent a new entity called congenital Zika syndrome. We summarize the ocular findings of congenital Zika Syndrome, as well as the current understanding of the illness, systemic manifestations, laboratory investigation, differential diagnosis, prophylaxis, and treatment for this disorder.

Missed Opportunities for Repeat HIV Testing in Pregnancy: Implications for Elimination of Mother-to-Child Transmission in the United States.

HIV testing is an effective intervention that is used for reducing perinatal HIV transmission. Centers for Disease Control and Prevention recommends a second HIV test during the third trimester of pregnancy for women in settings with an elevated HIV incidence (≥17 cases per 100,000 person-years). We conducted a retrospective cohort study at a single hospital in Baltimore, Maryland, to determine whether a second HIV test was done and to compare HIV retesting with mandated syphilis retesting. Of women who delivered at this hospital, 98.8% received prenatal care. Descriptive, bivariate, and multivariable analyses were performed. Among 1632 women, mean age was 27.6 years (standard deviation: 6.3), 59.6% were black, and 55.5% were single. HIV retesting was done in 28.4% of women, which was significantly less often compared with the state-mandated syphilis retesting (78.7%, p < 0.001). The odds of having an HIV retest were 15 times higher among women who received prenatal care at a teaching clinic [adjusted odds ratio (aOR): 15.58; 95% confidence interval (CI): 11.12-21.81], and they were lower among women with private insurance (aOR: 0.54, 95% CI: 0.34-0.86). The odds of having a syphilis retest were twice as high among women who received prenatal care at a faculty practice (aOR: 2.17; 95% CI: 1.53-3.09), and they were lower among women with private insurance (aOR: 0.61, 95% CI: 0.43-0.88). Emphasizing an "opt-out" HIV retesting approach through state laws may minimize risk perception, and this is one strategy that can be considered in areas of high HIV incidence to reach the goal of eliminating perinatal HIV transmission in the United States.

Evaluation of a simulation-based pediatric clinical skills curriculum for medical students.

INTRODUCTION: Simulation-based education is expensive and requires greater resources than traditional methods, yet there is limited evidence to justify such expenditures for medical student education. METHODS: We describe the implementation and evaluation of a simulation-based curriculum delivered to medical students during a pediatric clerkship. This prospective mixed-methods study evaluated a 5-day long simulation-based clinical skills curriculum (PRE-Clerkship EDucational Exercises [PRECEDE]) at the Johns Hopkins University School of Medicine. Two hundred medical students participated in PRECEDE during a 2-year period and were compared with 236 students who had not. Outcomes were assessed across 3 levels of Kirkpatrick's framework for evaluation. The 4-level model consists of reaction, learning, behavior, and results criteria. Secondary outcomes measured changes in assessment scores across 16 student performance domains during clerkship, changes in performance on the National Board of Medical Examiners subject examination in pediatrics, and student assessments of the curriculum. RESULTS: Improvements were noted across 3 levels of the Kirkpatrick's model. Student performance evaluations were significantly higher across all 16 evaluation components, with effect sizes ranging from small to medium (Cohen's d, 0.23-0.44). Students scored significantly higher on the National Board of Medical Examiners pediatric shelf examination (80 vs. 77, P<0.001). Ninety-seven percent of the medical students agreed that their skills increased and that the time lost to real clinical experiences was a worthwhile trade-off for this curriculum CONCLUSIONS: The implementation of a simulation-based curriculum within a pediatrics clerkship resulted in higher knowledge scores and led to improvements in medical student clinical performance during the clerkship.