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 and cognition in early childhood.

BACKGROUND: Epidemiological evidence for gestational polycyclic aromatic hydrocarbon (PAH) exposure and adverse child cognitive outcomes is mixed; little is known about critical windows of exposure. OBJECTIVE: We investigated associations between prenatal PAH exposure and child cognition in a large, multi-site study. METHODS: We included mother-child dyads from two pooled prospective pregnancy cohorts (CANDLE and TIDES, N = 1,223) in the ECHO-PATHWAYS Consortium. Seven urinary mono-hydroxylated PAH metabolites were measured in mid-pregnancy in both cohorts as well as early and late pregnancy in TIDES. Child intelligence quotient (IQ) was assessed between ages 4-6. Associations between individual PAH metabolites and IQ were estimated with multivariable linear regression. Interaction terms were used to examine effect modification by child sex and maternal obesity. We explored associations of PAH metabolite mixtures with IQ using weighted quantile sum regression. In TIDES, we averaged PAH metabolites over three periods of pregnancy and by pregnancy period to investigate associations between PAH metabolites and IQ. RESULTS: In the combined sample, PAH metabolites were not associated with IQ after full adjustment, nor did we observe associations with PAH mixtures. Tests of effect modification were null except for the association between 2-hydroxynaphthalene and IQ, which was negative in males (ßmales = -0.67 [95%CI:-1.47,0.13]) and positive in females (ßfemales = 0.31 [95%CI:-0.52,1.13])(pinteraction = 0.04). In analyses across pregnancy (TIDES-only), inverse associations with IQ were observed for 2-hydroxyphenanthrene averaged across pregnancy (ß = -1.28 [95%CI:-2.53,-0.03]) and in early pregnancy (ß = -1.14 [95%CI:-2.00,-0.28]). SIGNIFICANCE: In this multi-cohort analysis, we observed limited evidence of adverse associations of early pregnancy PAHs with child IQ. Analyses in the pooled cohorts were null. However, results also indicated that utilizing more than one exposure measures across pregnancy could improve the ability to detect associations by identifying sensitive windows and improving the reliability of exposure measurement. More research with multiple timepoints of PAH assessment is warranted.

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.

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.

Isolated testicular vasculitis due to immune checkpoint inhibitor.

Immune checkpoint inhibitors are increasingly being used to treat various malignancies; consequently, more rheumatological side effects, ranging from arthritis to vasculitis, are being reported. Here we present, for the first time, a case of vasculitis involving the testicle in the setting of an immune checkpoint inhibitor. As reported in previous cases, recurrence of a malignancy, as opposed to vasculitis, was initially suspected, thus creating a diagnostic dilemma. These rheumatological side effects have garnered attention as they potentially provide a window into in the pathogenesis of rheumatological diseases.

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.

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.

Associations Between Physician Empathy, Physician Characteristics, and Standardized Measures of Patient Experience.

PURPOSE: To identify correlates of physician empathy and determine whether physician empathy is related to standardized measures of patient experience. METHOD: Demographic, professional, and empathy data were collected during 2013-2015 from Cleveland Clinic Health System physicians prior to participation in mandatory communication skills training. Empathy was assessed using the Jefferson Scale of Empathy. Data were also collected for seven measures (six provider communication items and overall provider rating) from the visit-specific and 12-month Consumer Assessment of Healthcare Providers and Systems Clinician and Group (CG-CAHPS) surveys. Associations between empathy and provider characteristics were assessed by linear regression, ANOVA, or a nonparametric equivalent. Significant predictors were included in a multivariable linear regression model. Correlations between empathy and CG-CAHPS scores were assessed using Spearman rank correlation coefficients. RESULTS: In bivariable analysis (n = 847 physicians), female sex (P < .001), specialty (P < .01), outpatient practice setting (P < .05), and DO degree (P < .05) were associated with higher empathy scores. In multivariable analysis, female sex (P < .001) and four specialties (obstetrics-gynecology, pediatrics, psychiatry, and thoracic surgery; all P < .05) were significantly associated with higher empathy scores. Of the seven CG-CAHPS measures, scores on five for the 583 physicians with visit-specific data and on three for the 277 physicians with 12-month data were positively correlated with empathy. CONCLUSIONS: Specialty and sex were independently associated with physician empathy. Empathy was correlated with higher scores on multiple CG-CAHPS items, suggesting improving physician empathy might play a role in improving patient experience.

Inflammatory characteristics on ultrasound predict poorer longterm response to intraarticular corticosteroid injections in knee osteoarthritis.

OBJECTIVE: To assess whether inflammation on ultrasound is predictive of clinical response to intraarticular (IA) corticosteroid injections in patients with knee osteoarthritis (OA). METHODS: Patients with symptomatic knee OA were randomized to receive either an IA injection of 40 mg triamcinolone acetonide in the treatment group or 1 cc 0.9% saline in the placebo group. Clinical response was assessed by changes in baseline Western Ontario and McMaster Universities (WOMAC) index scores and physician global assessment at 4 and 12 weeks. Ultrasounds were performed at each visit. Patients and assessors were blinded to treatment status. RESULTS: Seventy-nine patients were enrolled into the study. Four-week data were available for 67 patients in the primary analysis comparing change in WOMAC pain score from baseline to 4 weeks. There was almost no change in the WOMAC pain subscale score from baseline to 4 weeks in the control group, but there was a significant improvement in WOMAC pain subscale score from 10.8 (SD +/- 3.2) at baseline to 8.75 (SD +/- 4.0) at 4 weeks in the treatment group (adjusted p = 0.001). Of the 34 patients in the treatment group; 16 (47%) had inflammatory disease and 18 (53%) had noninflammatory disease as determined by ultrasound. There was no difference in the change in WOMAC pain score between the inflammatory and noninflammatory patients in the treatment group at 4 weeks. There was a statistically significant greater improvement in pain subscale scores among noninflammatory patients than among inflammatory patients at 12 weeks. CONCLUSION: Intraarticular corticosteroid injections are an effective short-term treatment for symptomatic knee OA compared to placebo. Patients with noninflammatory characteristics on ultrasound had a more prolonged benefit from IA corticosteroids compared to inflammatory patients.

New developments in osteoarthritis.

Osteoarthritis (OA) has been a frustrating disease for both the patient and the physician. Its current impact on society is tremendous and rivals that of ischemic heart disease in many regards. As the baby boomers reach late adulthood and the obesity epidemic rages on, OA will assume an even greater impact on society. The current OA armamentarium only reduces pain and perhaps improves function, but has no impact on the disease incidence or progression. Thus, the challenge for researchers to develop disease-modifying OA drugs becomes an issue of paramount importance. Several advances in the understanding of OA pathophysiology have provided a glimpse of optimism that disease modification is a real possibility.