Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level.

BACKGROUND: In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS: In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (<2% or ≥2%). The primary outcome was the response to mometasone as compared with placebo and to tiotropium as compared with placebo among patients with a low sputum eosinophil level who had a prespecified differential response to one of the trial agents. The response was determined according to a hierarchical composite outcome that incorporated treatment failure, asthma control days, and the forced expiratory volume in 1 second; a two-sided P value of less than 0.025 denoted statistical significance. A secondary outcome was a comparison of results in patients with a high sputum eosinophil level and those with a low level. RESULTS: A total of 73% of the patients had a low eosinophil level; of these patients, 59% had a differential response to a trial agent. However, there was no significant difference in the response to mometasone or tiotropium, as compared with placebo. Among the patients with a low eosinophil level who had a differential treatment response, 57% (95% confidence interval [CI], 48 to 66) had a better response to mometasone, and 43% (95% CI, 34 to 52) had a better response to placebo (P = 0.14). In contrast 60% (95% CI, 51 to 68) had a better response to tiotropium, whereas 40% (95% CI, 32 to 49) had a better response to placebo (P = 0.029). Among patients with a high eosinophil level, the response to mometasone was significantly better than the response to placebo (74% vs. 26%) but the response to tiotropium was not (57% vs. 43%). CONCLUSIONS: The majority of patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo. These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level. (Funded by the National Heart, Lung, and Blood Institute; SIENA ClinicalTrials.gov number, NCT02066298.).

Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

BACKGROUND: Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. METHODS: We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 µg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 µg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. RESULTS: The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). CONCLUSIONS: In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).

Severe asthma during childhood and adolescence: A longitudinal study.

BACKGROUND: Morbidity and mortality associated with childhood asthma are driven disproportionately by children with severe asthma. However, it is not known from longitudinal studies whether children outgrow severe asthma. OBJECTIVE: We sought to study prospectively whether well-characterized children with severe asthma outgrow their asthma during adolescence. METHODS: Children with asthma were assessed at baseline with detailed questionnaires, allergy tests, and lung function tests and were reassessed annually for 3 years. The population was enriched for children with severe asthma, as assessed by the American Thoracic Society/European Respiratory Society guidelines, and subject classification was reassessed annually. RESULTS: At baseline, 111 (59%) children had severe asthma. Year to year, there was a decrease in the proportion meeting the criteria for severe asthma. After 3 years, only 30% of subjects met the criteria for severe asthma (P < .001 compared with enrollment). Subjects experienced improvements in most indices of severity, including symptom scores, exacerbations, and controller medication requirements, but not lung function. Surprisingly, boys and girls were equally likely to has resolved asthma (33% vs 29%). The odds ratio in favor of resolution of severe asthma was 2.75 (95% CI, 1.02-7.43) for those with a peripheral eosinophil count of greater than 436 cells/µL. CONCLUSIONS: In longitudinal analysis of this well-characterized cohort, half of the children with severe asthma no longer had severe asthma after 3 years; there was a stepwise decrease in the proportion meeting severe asthma criteria. Surprisingly, asthma severity decreased equally in male and female subjects. Peripheral eosinophilia predicted resolution. These data will be important for planning clinical trials in this population.

Trauma on the high seas: an overview of recreational water use injuries.

Recreational water use (RWU) injuries span from superficial lacerations to even death. Given the global popularity of RWU, radiologists should be aware of the common mechanisms and key imaging findings related to injuries in this setting. The goal of this article is to depict common RWU injuries and their emergent radiographic findings, which may have both important surgical and management implications. We present a broad review with case illustrations of these injuries seen at our level 1 trauma center showing the breadth of injury that can occur, general mechanisms and sample imaging findings.

Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.

BACKGROUND: Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. METHODS: In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. RESULTS: Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. CONCLUSIONS: Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).

Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations.

RATIONALE: Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation-prone asthma (EPA) remain incompletely defined. OBJECTIVES: To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA. METHODS: Baseline data from the NHLBI Severe Asthma Research Program (SARP)-3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (≥3). Replication of a multivariable model was performed with data from the SARP-1 + 2 cohort. MEASUREMENTS AND MAIN RESULTS: Of 709 subjects in the SARP-3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP-3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP-3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval], 1.6 [1.2-2.1] for every log unit of eosinophils, 1.3 [1.1-1.4] for every 10 body mass index units, and 1.2 [1.1-1.4] for every 10% increase in bronchodilatory responsiveness). Chronic sinusitis and gastroesophageal reflux were also associated with exacerbation frequency (1.7 [1.4-2.1] and 1.6 [1.3-2.0]), even after adjustment for multiple factors. These effects were replicated in the SARP-1 + 2 multivariable model. CONCLUSIONS: EPA may be a distinct susceptibility phenotype with implications for the targeting of exacerbation prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 01760915).

Effects of endogenous sex hormones on lung function and symptom control in adolescents with asthma.

BACKGROUND: Although pre-puberty asthma is more prevalent in males, after puberty through middle-age, asthma is more prevalent in females. The surge of sex hormones with puberty might explain this gender switch. METHODS: To examine the effects of sex hormones on lung function and symptoms with puberty, Tanner stage was assessed in 187 children 6-18 years of age (59% severe) enrolled in the NIH/NHLBI Severe Asthma Research Program (SARP). The effects of circulating sex hormones (n = 68; testosterone, dehydroepiandrosterone sulfate (DHEA-S), estrogen, and progesterone) on lung function and 4 week symptom control (ACQ6) in cross-section were tested by linear regression. RESULTS: From pre-/early to late puberty, lung function did not change significantly but ACQ6 scores improved in males with severe asthma. By contrast females had lower post-BD FEV1% and FVC% and worse ACQ6 scores with late puberty assessed by breast development. In males log DHEA-S levels, which increased by Tanner stage, associated positively with pre- and post-BD FEV1%, pre-BD FVC %, and negatively (improved) with ACQ6. Patients treated with high-dose inhaled corticosteroids had similar levels of circulating DHEA-S. In females, estradiol levels increased by Tanner stage, and associated negatively with pre-BD FEV1% and FVC %. CONCLUSIONS: These results support beneficial effects of androgens on lung function and symptom control and weak deleterious effects of estradiol on lung function in children with asthma. Longitudinal data are necessary to confirm these cross-sectional findings and to further elucidate hormonal mechanisms informing sex differences in asthma features with puberty. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT01748175 .

Individualized therapy for persistent asthma in young children.

BACKGROUND: Phenotypic presentations in young children with asthma are varied and might contribute to differential responses to asthma controller medications. METHODS: The Individualized Therapy for Asthma in Toddlers study was a multicenter, randomized, double-blind, double-dummy clinical trial in children aged 12 to 59 months (n = 300) with asthma necessitating treatment with daily controller (Step 2) therapy. Participants completed a 2- to 8-week run-in period followed by 3 crossover periods with daily inhaled corticosteroids (ICSs), daily leukotriene receptor antagonists, and as-needed ICS treatment coadministered with albuterol. The primary outcome was differential response to asthma medication based on a composite measure of asthma control. The primary analysis involved 2 stages: determination of differential response and assessment of whether 3 prespecified features (aeroallergen sensitization, previous exacerbations, and sex) predicted a differential response. RESULTS: Seventy-four percent (170/230) of children with analyzable data had a differential response to the 3 treatment strategies. Within differential responders, the probability of best response was highest for a daily ICS and was predicted by aeroallergen sensitization but not exacerbation history or sex. The probability of best response to daily ICS was further increased in children with both aeroallergen sensitization and blood eosinophil counts of 300/µL or greater. In these children daily ICS use was associated with more asthma control days and fewer exacerbations compared with the other treatments. CONCLUSIONS: In young children with asthma necessitating Step 2 treatment, phenotyping with aeroallergen sensitization and blood eosinophil counts is useful for guiding treatment selection and identifies children with a high exacerbation probability for whom treatment with a daily ICS is beneficial despite possible risks of growth suppression.

A midline pelvic mass: Ovarian fibroma appearing vaginal in nature.

Introduction: Ovarian fibroma is an uncommon, benign, stromal neoplasm that is a mixture of collagen-producing mesenchymal cells. There are varying sonographic and computed tomography features described in literature of smaller scale studies. Case Report: We describe a case of an ovarian fibroma presenting as a midline pelvic mass mimicking a vaginal cuff tumour in a 67-year-old patient with surgical history of a hysterectomy. Computed tomography and ultrasound were utilised to evaluate the mass and guide management of the patient. The mass was initially suspected on CT-guided biopsy as a vaginal spindle cell epithelioma amongst other potential differential considerations. With robot-assisted laparoscopic surgery and histologic analysis, the true diagnosis of an ovarian fibroma was reached. Discussion: An ovarian fibroma is an uncommon, benign, stromal ovarian tumour, representing just 1-4% of all ovarian tumours. Its widely varying imaging features present a challenge when radiologically evaluating ovarian fibromas or pelvic tumours, as the differential diagnoses are extensive and ovarian fibromas are often misdiagnosed until surgical resection. We highlight the features of ovarian fibromas and the potential value of pelvic/transvaginal ultrasonography in management of ovarian fibroma and other pelvic masses. Conclusion: The use of computed tomography and ultrasound aided in the diagnostic and treatment pathway of this patient with a pelvic mass. There is high utility of sonography in evaluating such tumours to elucidate salient features, expedite diagnosis, and guide further management.

Interaction with CREB binding protein modulates the activities of Nrf2 and NF-κB in cystic fibrosis airway epithelial cells.

Cystic fibrosis (CF) is characterized by inflammatory lung disease that significantly contributes to morbidity and mortality. Airway epithelial cells play a role in the inflammatory signaling in CF and have been reported to exhibit a number of dysfunctions in signaling cascades that modulate inflammation. Previously, we reported that the activity of nuclear factor erythroid-derived-like 2 (Nrf2), a transcription factor that regulates antioxidant and cytoprotective protein expression, is diminished in CF epithelia (7). In this report, we examined the mechanism of Nrf2 dysregulation in vitro in human airway epithelial cell lines and primary cells and in vivo in nasal epithelia excised from ΔF508 CF mutant mice. We found that cAMP-mediated signaling markedly reduces Nrf2 activity in CF vs. non-CF cells. Rp-cAMPS, a cAMP competitor, significantly corrected Nrf2 activity in CF cells, predominantly by increasing the nuclear accumulation of the transcription factor. Furthermore, we found that Rp-cAMPS significantly decreased NF-κB activation following inflammatory stimulation of CF cells. Further investigation revealed that Nrf2 and NF-κB compete for the transcriptional coactivator cAMP responsive element-binding protein (CREB) binding protein (CBP) and that Rp-cAMPS shifts CBP association in favor of Nrf2. Thus our findings provide a link between feedback to CF transmembrane regulator dysfunction and dysregulation of an inflammatory signaling pathway that modulates the coordinated activities of Nrf2 and NF-κB. Furthermore, our studies suggest that strategies that shift CBP association away from NF-κB and toward Nrf2 could have potential therapeutic efficacy for reducing inflammation in patients with CF.

Three Years of X + Y Scheduling: Longitudinal Assessment of Resident and Faculty Perceptions.

OBJECTIVE: Five pediatric residency programs implemented true X + Y scheduling in 2018 where residents have continuity clinic in "blocks" rather than half-day per week experiences. We report the impact X + Y scheduling has on pediatric resident and faculty perceptions of patient care and other educational experiences over a 3-year timeframe. METHODS: Electronic surveys were sent to residents and faculty of the participating programs prior to implementing X + Y scheduling and annually thereafter (2018-2021). Survey questions measured resident and faculty perception of continuity clinic schedule satisfaction and the impact of continuity clinic schedules on inpatient and subspecialty rotations. Data were analyzed using z-tests for proportion differences. RESULTS: One hundred and eight six residents were sent the survey preimplementation and 254 to 289 postimplementation with response rates ranging from 47% to 69%. Three hundred and seventy-eight to 395 faculty members were sent the survey with response rates ranging from 26% to 51%. Statistically significant (P < .05) sustained perceived improvements over 3 years with X+Y were seen in outpatient continuity, inpatient workflow, and time for teaching both inpatient and in continuity clinic. CONCLUSIONS: X + Y scheduling can lead to perceived improvements in various aspects of pediatric residency programs. Our study demonstrates these improvements have been sustained over 3 years in the participating programs.

The Impact of the COVID-19 Pandemic on Pediatric Graduate Medical Education: Lessons Learned and Pathways Forward.

In this article, the authors describe the impact of the COVID-19 pandemic on pediatric graduate medical education (GME), including the impact on clinical experiences for trainees, teaching methods used, trainee wellness, GME leader wellness and support, and the traditional interview process. A thorough literature review was done to identify impacts of the COVID-19 pandemic on pediatric GME. In addition, information was collected through Association of Pediatric Program Directors virtual cafes and conferences. Positive changes for GME from the COVID-19 pandemic included: the rapid transition to telehealth; asynchronous learning allowing for increased cross-program collaboration; innovative online teaching modalities; increased flexibility and decreased cost of online recruitment; and shared innovations across pediatric GME. Challenging aspects of the COVID-19 pandemic included: decreased learning about common childhood illnesses, such as bronchiolitis, acute otitis media, and influenza; decreased patient volumes and patient complexity in clinics and inpatient wards, leading to less practice developing efficiency, time management, and triaging skills; and an increased burden on trainees, including moral distress and decreased support from one another and other social supports. The COVID-19 pandemic has highlighted important opportunities in U.S. educational systems. As medical educators move forward, it will be important to learn from these while mitigating the negative impacts.

Pediatric Resident Perspectives on the Impact of COVID-19 on Training.

OBJECTIVES: At the onset of the coronavirus disease 2019 pandemic, disruptions to pediatric care and training were immediate and significant. We sought to understand the impact of the pandemic on residency training from the perspective of pediatric residents. METHODS: We conducted a cross-sectional survey of categorical pediatric residents at US training programs at the end of the 2019-2020 academic year. This voluntary survey included questions that explored the impact of the coronavirus disease 2019 pandemic on resident training experiences, postresidency employment plans, and attitudes and perceptions. Data were analyzed by using descriptive statistics and mixed-effects regression models. We performed a sensitivity analysis using respondents from programs with a >40% response rate for questions regarding resident attitudes and perceptions. RESULTS: Residents from 127 of 201 training programs (63.2%) completed the survey, with a response rate of 18.9% (1141 of 6032). Respondents reported multiple changes to their training experience including rotation schedule adjustments, clinic cancellations, and an increase in the use of telemedicine. Respondents also reported inconsistent access to personal protective equipment and increased involvement in the care of adult patients. Graduating resident respondents reported concerns related to employment. Respondents also noted a negative impact on their personal wellness. CONCLUSIONS: Responding residents reported that nearly every aspect of their training was impacted by the pandemic. Describing their experiences may help residency program and hospital leaders supplement missed educational experiences, better support residents through the remaining months of the pandemic, and better prepare for extraordinary circumstances in the future.

Impact of X+Y Scheduling on Pediatric Resident and Faculty Perceptions of Education and Patient Care.

PURPOSE: Traditional half-day per week continuity clinic experiences can lead to fragmented education in both the inpatient and outpatient arenas. Five pediatric residency programs were granted the ability from the ACGME to create X+Y scheduling where residents have continuity clinic in "blocks" rather than half-day per week experiences. The aim of this study is to assess the impact X+Y scheduling has on pediatric resident and faculty perceptions of patient care and other educational experiences. METHODS: Electronic surveys were sent to residents and faculty of the participating programs both prior to and 12 months after implementing X+Y scheduling. Survey questions measured resident and faculty perception of continuity clinic schedule satisfaction and the impact of continuity clinic schedules on inpatient and subspecialty rotation experiences using a 5-point Likert Scale. Data were analyzed using z-tests for proportion differences for those answering Agree or Strongly Agree between baseline and post-implementation respondents. RESULTS: Hundred and twenty-six out of 186 residents (68%) responded preimplementation and 120 out of 259 residents (47%) responded post-implementation. 384 faculty members were sent the survey with 51% response pre-implementation and 26% response at 12 months. Statistically significant (P < .05) improvements were noted in resident and faculty perceptions of ability to have continuity with patients and inpatient workflow affected by clinic scheduling. CONCLUSIONS: From both resident and faculty perspectives, X+Y scheduling may improve several aspects of patient care and education. X+Y scheduling could be considered as a potential option by pediatric residency programs, especially if validated with more objective data.

Pediatric Chief Resident Exchange Program-A Novel Method to Share Educational Ideas Across Training Programs.

BACKGROUND: Pediatric residency programs offer many conferences and activities to meet the educational needs of their residents. We developed and assessed the Pediatric Chief Resident Exchange Program where pediatric chief residents visited another institution for a day with the goal of sharing educational and curricular innovations between residency programs in an experiential manner. APPROACH/INNOVATION: Pediatric chief residents participated in various activities during the exchange including educational conferences and discussions with residency program leadership at the host institutions. Surveys were administered to all participating chiefs to determine if any changes to educational conferences or curriculum were made or planned to be made at their home program based upon what they observed at the other institution and to have chiefs reflect on what they gained from the experience. RESULTS: Twenty-eight chief residents from 9 programs participated in the exchange program over 3 academic years (2015-2018). All respondents felt the exchange experience was worthwhile. The majority (67%) of programs planned to implement a change at their institution based on participation in the exchange with over half actually making a change by the end of the academic year. Participating chiefs gained a sense of camaraderie, appreciated that other programs experienced similar struggles, and developed further insight into the chief resident role. DISCUSSION: The Pediatric Chief Resident Exchange Program is a novel method of sharing educational practices between institutions that can lead to curricular changes at participating programs. It can also be an opportunity for chief resident professional development.

Shared Mental Models Among Clinical Competency Committees in the Context of Time-Variable, Competency-Based Advancement to Residency.

PURPOSE: To evaluate response process validity evidence for clinical competency committee (CCC) assessments of first-year residents on a subset of General Pediatrics Entrustable Professional Activities (EPAs) and milestones in the context of a national pilot of competency-based, time-variable (CBTV) advancement from undergraduate to graduate medical education. METHOD: Assessments of 2 EPAs and 8 milestones made by the trainees' actual CCCs and 2 different blinded "virtual" CCCs for 48 first-year pediatrics residents at 4 residency programs between 2016 and 2018 were compared. Residents had 3 different training paths from medical school to residency: time-variable graduation at the same institution as their residency, time-fixed graduation at the same institution, or time-fixed graduation from a different institution. Assessments were compared using ordinal mixed-effects models. RESULTS: Actual CCCs assigned residents higher scores than virtual CCCs on milestones and one EPA's supervision levels. Residents who graduated from a different institution than their residency received lower milestone ratings than either group from the same institution; CBTV residents received higher ratings on one milestone (ICS4) and similar ratings on all others compared with non-CBTV residents who completed medical school at the same institution. CONCLUSIONS: First-year residents who graduated from CBTV medical school programs were assessed as having the same level of competence as residents who graduated from traditional medical school programs, but response process evidence suggests that members of CCCs may also draw on undocumented personal knowledge of the learner to draw conclusions about resident competence.