Recent Insights into the Environmental Determinants of Childhood Asthma.

PURPOSE OF REVIEW: Ubiquitous environmental exposures, including ambient air pollutants, are linked to the development and severity of childhood asthma. Advances in our understanding of these links have increasingly led to clinical interventions to reduce asthma morbidity. RECENT FINDINGS: We review recent work untangling the complex relationship between air pollutants, including particulate matter, nitrogen dioxide, and ozone and asthma, such as vulnerable windows of pediatric exposure and their interaction with other factors influencing asthma development and severity. These have led to interventions to reduce air pollutant levels in children's homes and schools. We also highlight emerging environmental exposures increasingly associated with childhood asthma. Growing evidence supports the present threat of climate change to children with asthma. Environmental factors play a large role in the pathogenesis and persistence of pediatric asthma; in turn, this poses an opportunity to intervene to change the course of disease early in life.

Prenatal exposure to polycyclic aromatic hydrocarbons is not associated with behavior problems in preschool and early school-aged children: A prospective multi-cohort study.

BACKGROUND: Epidemiological study findings are inconsistent regarding associations between prenatal polycyclic aromatic hydrocarbon (PAH) exposures and childhood behavior. This study examined associations of prenatal PAH exposure with behavior at age 4-6 years in a large, diverse, multi-region prospective cohort. Secondary aims included examination of PAH mixtures and effect modification by child sex, breastfeeding, and child neighborhood opportunity. METHODS: The ECHO PATHWAYS Consortium pooled 1118 mother-child dyads from three prospective pregnancy cohorts in six U.S. cities. Seven PAH metabolites were measured in prenatal urine. Child behavior was assessed at age 4-6 using the Total Problems score from the Child Behavior Checklist (CBCL). Neighborhood opportunity was assessed using the socioeconomic and educational scales of the Child Opportunity Index. Multivariable linear regression was used to estimate associations per 2-fold increase in each PAH metabolite, adjusted for demographic, prenatal, and maternal factors and using interaction terms for effect modifiers. Associations with PAH mixtures were estimated using Weighted Quantile Sum Regression (WQSR). RESULTS: The sample was racially and sociodemographically diverse (38% Black, 49% White, 7% Other; household-adjusted income range $2651-$221,102). In fully adjusted models, each 2-fold increase in 2-hydroxynaphthalene was associated with a lower Total Problems score, contrary to hypotheses (b = -0.80, 95% CI = -1.51, -0.08). Associations were notable in boys (b = -1.10, 95% CI = -2.11, -0.08) and among children breastfed 6+ months (b = -1.31, 95% CI = -2.25, -0.37), although there was no statistically significant evidence for interaction by child sex, breastfeeding, or neighborhood child opportunity. Associations were null for other PAH metabolites; there was no evidence of associations with PAH mixtures from WQSR. CONCLUSION: In this large, well-characterized, prospective study of mother-child pairs, prenatal PAH exposure was not associated with child behavior problems. Future studies characterizing the magnitude of prenatal PAH exposure and studies in older childhood are needed.

Caregiver COVID-19 vaccination for solid organ transplant candidates.

An increasing proportion of transplant centers have implemented a mandate for vaccination against COVID-19 for solid organ transplant candidates. There has been comparatively little exploration of the ethical considerations of mandating vaccination of a candidate's primary caregiver, despite a high risk of transmission given the close nature of contact between the candidate and caregiver. We examine how a caregiver mandate can improve overall utility in organ allocation, particularly in circumstances where vaccine effectiveness at preventing transmission and serious disease is low among recipients but high in caregivers. Our analysis reveals how sensitive such mandates must be to the evolving circumstances of disease severity, transmissibility, and vaccine effectiveness: as the facts change, the degree of benefit gained and therefore the degree of infringement on access to transplant and caregiver choice that is tolerated will likewise change.

Early breast development in overweight girls: does estrogen made by adipose tissue play a role?

BACKGROUND: Girls who are overweight/obese (OB) develop breast tissue but do not undergo menarche (the first menstrual period) significantly earlier than girls of normal weight (NW). It has been proposed that estrogen synthesized by adipose tissue may be contributory, yet OB do not have higher serum estrogen levels than NW matched on breast stage. We hypothesized that estrogen synthesized locally, in mammary fat, may contribute to breast development. This hypothesis would predict that breast development would be more advanced than other estrogen-sensitive tissues as a function of obesity and body fat. METHODS: Eighty premenarchal girls (26 OB, 54 NW), aged 8.2-14.7 years, underwent dual-energy x-ray absorptiometry to calculate percent body fat (%BF), Tanner staging of the breast, breast ultrasound for morphological staging, trans-abdominal pelvic ultrasound, hand x-ray (bone age, BA), a blood test for reproductive hormones, and urine collection to determine the vaginal maturation index (VMI), an index of estrogen exposure in urogenital epithelial cells. RESULTS: When controlling for breast morphological stage determined by ultrasound, %BF was not associated with serum estrogen or gonadotropin (LH and FSH) levels or with indices of systemic estrogen action (uterine volume, endometrial thickness, BA advancement, and VMI). Tanner breast stage did not correlate with breast morphological stage and led to misclassification of chest fatty tissue as breast tissue in some OB. CONCLUSIONS: These studies do not support the hypothesis that estrogen derived from total body fat or local (mammary) fat contributes to breast development in OB girls.

Advances in Care and Outcomes for Children with Cystic Fibrosis.

The landscape of care for children with cystic fibrosis (CF), a genetic disorder of chloride transport with multisystem manifestations including inspissated mucus, recurrent sinopulmonary infections, obstructive lung disease, and exocrine pancreatic insufficiency, is rapidly changing. Early diagnosis via newborn screening enabling timely nutritional support, chronic therapies to improve mucociliary clearance, and prompt treatment of pulmonary infections have improved overall outcomes in children with CF. More widespread availability of novel cystic fibrosis transmembrane conductance regulator modulator therapies for children continues to revolutionize pediatric CF care.However, significant challenges exist to optimize care and outcomes for all children with CF.

Comparison of home-based spirometry and oscillometry measurements in school-age children with bronchopulmonary dysplasia.

INTRODUCTION: This study compares home-based oscillometry and spirometry for characterizing respiratory system disease in school-aged children with bronchopulmonary dysplasia (BPD) in clinical research. We hypothesized higher rates of successful completion and abnormal cases identified through oscillometry, with correlations between device measurements. METHODS: Participants 6-12 years old with BPD in the ongoing Air Quality, Environment and Respiratory Outcomes in BPD (AERO-BPD) study performed oscillometry followed by spirometry at two separate home visits. Parameters measured included airway resistance at 5 Hz(R5), resistance from 5 to 19 Hz(R5-19), resonance frequency(Fres), reactance at 5 Hz(X5), area under the curve between Fres and X5(AX), forced expiratory volume in 1 second(FEV1), forced vital capacity(FVC), and FEV1/FVC. Descriptive statistics identified the proportion of successful tests, correlation in measurements, and rate of lung disease for each device. RESULTS: Among 76 subjects with 120 paired observations, 95% and 71% of participants successfully performed oscillometry and spirometry, respectively, at home visit one. 98% and 77% successfully performed oscillometry and spirometry, respectively, at home visit two. Odds ratios favored oscillometry (range 5.31-10.13, p < 0.01). FEV1 correlated with AX (correlation coefficient r = -0.27, p = 0.03); FEV1/FVC with AX (r = -0.32, p = 0.02); and FEV1/FVC with R5 (r = -0.37, p = 0.01). AX exhibited the highest prevalence of abnormality at 25%; other oscillometry parameters ranged from 5%-22%. Forty-five to sixty-four percent of participants had abnormal spirometry. Oscillometry assessments had significantly lower odds of capturing lung disease (odds ratios 0.07-0.24, p < 0.0001). CONCLUSIONS: School-aged children with BPD demonstrated higher success rates in field-based oscillometry than spirometry. Spirometry exhibited higher rates of abnormality than oscillometry. Moderate correlation exists between device measurements.

Longitudinal Investigation of Pubertal Milestones and Hormones as a Function of Body Fat in Girls.

CONTEXT: Epidemiologic studies have demonstrated that overweight/obese girls (OW/OB) undergo thelarche and menarche earlier than normal weight girls (NW). There have been no longitudinal studies to specifically investigate how body weight/fat affects both clinical and biochemical pubertal markers in girls. OBJECTIVE: To investigate the effect of total body fat on reproductive hormones and on the maturation of estrogen-sensitive tissues during puberty in girls. METHODS: Ninety girls (36 OW/OB, 54 NW), aged 8.2 to 14.7 years, completed 2.8 ±â€…1.7 study visits over 4 years. Visits included dual-energy x-ray absorptiometry to calculate total body fat (TBF), Tanner staging, breast ultrasound for morphological staging (BMORPH; A-E), pelvic ultrasound, hormone tests, and assessment of menarchal status. The effect of TBF on pubertal markers was determined using a mixed, multistate, or Cox proportional hazards model, controlling for baseline BMORPH. RESULTS: NW were older than OW/OB (11.3 vs 10.2 years, P < .01) at baseline and had more advanced BMORPH (P < .01). Luteinizing hormone, estradiol, and ovarian and uterine volumes increased with time with no effect of TBF. There was a time × TBF interaction for follicle-stimulating hormone, inhibin B, estrone, total and free testosterone, and androstenedione: Levels were initially similar, but after 1 year, levels increased in girls with higher TBF, plateaued in girls with midrange TBF, and decreased in girls with lower TBF. Girls with higher TBF progressed through BMORPH stage D more slowly but achieved menarche earlier than girls with lower TBF. CONCLUSION: In late puberty, girls with higher TBF demonstrate differences in standard hormonal and clinical markers of puberty. Investigation of the underlying causes and clinical consequences of these differences in girls with higher TBF deserves further study.

Association of Preeclampsia in Term Births With Neurodevelopmental Disorders in Offspring.

Importance: Preeclampsia during pregnancy has been linked to an increased risk of cerebral palsy in offspring. Less is known about the role of preeclampsia in other neurodevelopmental disorders. Objective: To determine the association between preeclampsia and a range of adverse neurodevelopmental outcomes in offspring after excluding preterm births. Design, Setting, and Participants: This prospective, population-based cohort study included singleton children born at term from January 1, 1991, through December 31, 2009, and followed up through December 31, 2014 (to 5 years of age), using Norway's Medical Birth Registry and linked to other demographic, social, and health information by Statistics Norway. Data were analyzed from May 30, 2018, to November 17, 2019. Exposures: Maternal preeclampsia. Main Outcomes and Measures: Associations between preeclampsia in term pregnancies and cerebral palsy, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), epilepsy, intellectual disability, and vision or hearing loss using multivariable logistic regression. Results: The cohort consisted of 980 560 children born at term (48.8% female and 51.2% male; mean [SD] gestational age, 39.8 [1.4] weeks) with a mean (SD) follow-up of 14.0 (5.6) years. Among these children, 28 068 (2.9%) were exposed to preeclampsia. Exposed children were at increased risk of ADHD (adjusted odds ratio [OR], 1.18; 95% CI, 1.05-1.33), ASD (adjusted OR, 1.29; 95% CI, 1.08-1.54), epilepsy (adjusted OR, 1.50; 95% CI, 1.16-1.93), and intellectual disability (adjusted OR, 1.50; 95% CI, 1.13-1.97); there was also an apparent association between preeclampsia exposure and cerebral palsy (adjusted OR, 1.30; 95% CI, 0.94-1.80). Conclusions and Relevance: Preeclampsia is a well-established threat to the mother. Other than the hazards associated with preterm delivery, the risks to offspring from preeclampsia are usually regarded as less important. This study's findings suggest that preeclampsia at term may have lasting effects on neurodevelopment of the child.

The Relationship Between Progesterone, Sleep, and LH and FSH Secretory Dynamics in Early Postmenarchal Girls.

CONTEXT: During puberty, LH pulse frequency increases during sleep; in women, LH pulse frequency slows during sleep in the early/middle follicular phase (FP) of the menstrual cycle. The origin and significance of this developmental transition are unknown. OBJECTIVE: To determine the relationship between progesterone (P4) exposure, sleep-related slowing of LH pulses in the FP, and the intercycle FSH rise, which promotes folliculogenesis, in early postmenarchal girls. METHODS: 23 girls (gynecologic age 0.4 to 3.5 years) underwent hormone measurements and pelvic ultrasounds during two consecutive cycles and one frequent blood sampling study with concurrent polysomnography during the FP. RESULTS: Subjects demonstrated one of four patterns during cycle 1 that represent a continuum of P4 exposure: ovulatory cycles with normal or short luteal phase lengths or anovulatory cycles ± follicle luteinization. Peak serum P4 and urine pregnanediol (Pd) in cycle 1 were inversely correlated with LH pulse frequency during sleep in the FP of cycle 2 (r = -0.5; P = 0.02 for both). The intercycle FSH rise and folliculogenesis in cycle 2 were maintained after anovulatory cycles without P4 or Pd exposure or nocturnal slowing of LH pulse frequency in the FP. CONCLUSIONS: During late puberty, rising P4 levels from follicle luteinization and ovulation may promote a slower LH pulse frequency during sleep in the FP. However, a normal FSH rise and follicle growth can occur in the absence of P4-associated slowing. These studies therefore suggest that an immature LH secretory pattern during sleep is unlikely to contribute to menstrual irregularity in the early postmenarchal years.

Healthy Post-Menarchal Adolescent Girls Demonstrate Multi-Level Reproductive Axis Immaturity.

Context: Menstrual irregularity after menarche has been attributed to immature estrogen positive feedback activity (E+FB) but data are conflicting. Objective: To determine the hypothalamic-pituitary-ovarian contributions to menstrual irregularity in adolescents. Methods: Twenty-three healthy girls [aged 12.8 to 17.6 years; 0.4 to 3.5 years postmenarche; body mass index (BMI) percentile, 41.0 to 99.3] underwent serial hormone measurements and pelvic ultrasounds during two consecutive menstrual cycles. Hormones and follicle growth were compared with 65 adult historic controls with ovulatory cycles (OVs). Results: Girls had anovulatory cycles (ANOVs; 30%), OVs with a short luteal phase (short OVs; 22%), or OVs with normal luteal phase (normal OVs; 48%) without differences in cycle length, chronologic or gynecologic age, or BMI. Adolescents showed a spectrum of E+FB [midcycle LH adjusted for preovulatory estradiol (E2)]; only normal OV girls were comparable to adults. All OV girls had lower E2, progesterone, and gonadotropins during the luteal phase and luteal-follicular transition compared with adults. Normal OV girls also had lower follicular phase LH and FSH levels, a longer follicular phase, a slower dominant follicle growth rate, and smaller estimated preovulatory follicle size than adults. Follicular phase E2 and inhibin B levels were lower in normal OV girls than in adults even after adjusting for differences in FSH and follicle size. Conclusions: Early postmenarchal girls with normal OVs demonstrate mature E+FB but continue to have lower gonadotropin levels, diminished ovarian responsiveness, and decreased corpus luteum sex steroid synthesis compared with adults, indicating that reproductive axis maturity requires coordinated development of all components of the hypothalamic-pituitary-ovarian axis.

Empathy, burnout, and antibiotic prescribing for acute respiratory infections: a cross-sectional primary care study in the US.

BACKGROUND: The impact of physician-patient relationship factors, such as physician empathy and burnout, on antibiotic prescribing has not been characterised. AIM: To assess associations between physician empathy and burnout and antibiotic prescribing for acute respiratory infections (ARIs) in primary care. DESIGN AND SETTING: Cross-sectional study of primary care practices in the Cleveland Clinic Health System in the US. METHOD: Patient and prescribing data were obtained from the medical record. All patients with primary diagnoses of ARIs from 1 January 2012 to 31 December 2013, except those with chronic obstructive pulmonary disease (COPD) or who were immunocompromised, were included. Physician empathy was measured using the Jefferson Scale of Empathy while physician burnout was measured using the Maslach Burnout Inventory. The relationship between empathy and burnout and antibiotic prescribing, adjusted for patient and provider characteristics, was analysed using multiple linear regression. RESULTS: In 5937 ARI visits to 102 primary care physicians, the median proportion resulting in antibiotic prescribing was 48.6% (interquartile range [IQR] 24.1% to 70.0%). Neither physician empathy (correlation coefficient [ß] 0.005, 95% confidence interval [CI] = -0.001 to 0.010, P = 0.07) nor any burnout measures were significantly associated with antibiotic prescribing: emotional exhaustion (ß 0.001, 95% CI = -0.005 to 0.006, P = 0.79), tendency to depersonalise patients (ß -0.009, 95% CI = -0.021 to 0.003, P = 0.13), and sense of personal accomplishment (ß -0.004, 95% CI = -0.014 to 0.006, P = 0.44). CONCLUSION: The authors found no significant association between empathy or burnout measures and antibiotic prescribing for ARIs in primary care. Other physician characteristics should be investigated to explain individual variation in antibiotic prescribing.