Longitudinal mental health trends in cystic fibrosis.

BACKGROUND: Mental health screening in accordance with consensus guidelines became routine clinical practice in our cystic fibrosis (CF) Center in 2015. We hypothesized improvement in anxiety and depression symptoms over time and associations between elevated screening scores and disease severity. We aimed to observe the impact of the COVID-19 pandemic and modulator use on mental health symptoms. METHODS: Retrospective chart reviews were conducted for people 12 years and older with at least one Generalized Anxiety Disorder-7 (GAD-7) or Patient Health Questionnaire-9 (PHQ-9) screening for six years. Descriptive statistics were used to summarize demographic variables and logistic regression and linear mixed models were used to evaluate the relationship between screening scores and clinical variables. RESULTS: Analyses included 150 participants (ages 12-22 years). The percentage of minimal to no symptom scores increased over time for anxiety and depression. Increased mental health visits and CFRD were associated with higher PHQ-9 and GAD-7 scores. Higher FEV1pp was associated with lower GAD-7 and PHQ-9 scores. More effective modulator use was associated with lower PHQ-9 scores. Mean PHQ-9 and GAD-7 scores were not significantly different when comparing pre-pandemic and pandemic scores. CONCLUSION: Disruptions in screening during the pandemic were minimal and symptom scores remained stable. Individuals with higher mental health screening scores were more likely to have CFRD and utilization of mental health services. Consistent mental health monitoring and support is needed so individuals with CF can endure anticipated and unanticipated stressors including changes in physical health, healthcare, and societal stressors such as COVID-19 pandemic.

Ventilation rates measured by capnography during out-of-hospital cardiac arrest resuscitations and their association with return of spontaneous circulation.

BACKGROUND: Clinical guidelines for adult out-of-hospital cardiac arrest (OHCA) recommend a ventilation rate of 8-10 per minute yet acknowledge that few data exist to guide recommendations. The goal of this study was to evaluate the utility of continuous capnography to measure ventilation rates and the association with return of spontaneous circulation (ROSC). METHODS: This was a retrospective observational cohort study. We included all OHCA during a two-year period and excluded traumatic and pediatric patients. Ventilations were recorded using non-invasive continuous capnography. Blinded medically trained team members manually annotated all ventilations. Four techniques were used to analyze ventilation rate. The primary outcome was sustained prehospital ROSC. Secondary outcomes were vital status at the end of prehospital care and survival to hospital admission. Univariable and multivariable logistic regression models were constructed. RESULTS: A total of 790 OHCA were analyzed. Only 386 (49%) had useable capnography data. After applying inclusion and exclusion criteria, the final study cohort was 314 patients. The median ventilation rate per minute was 7 (IQR 5.4-8.5). Only 70 (22%) received a guideline-compliant ventilation rate of 8-10 per minute. Sixty-two (20%) achieved the primary outcome. No statistically significant associations were observed between any of the ventilation parameters and patient outcomes in both univariable and multivariable logistic regression models. CONCLUSIONS: We failed to detect an association between intra-arrest ventilation rates measured by continuous capnography and proximal patient outcomes after OHCA. Capnography has poor reliability as a measure of ventilation rate. Achieving guideline-compliant ventilation rates remains challenging.

Longitudinal Assessment of Educational Risk for K-12 Students with Cystic Fibrosis.

OBJECTIVES: To assess the use of services provided by a cystic fibrosis (CF) center school specialist and evaluate relationships among student educational risk scores, family concerns for school engagement and performance, and disease severity. STUDY DESIGN: This was a retrospective review of medical records for 126 children with CF in grades K-12 who were screened for educational risk or used school intervention services during the 2017- 020 school years. Regression analyses were performed to identify and quantify predictors of educational risk, family concern for school performance and ability to advocate, and use of school specialist services. RESULTS: Most children with CF (62%-82%) were at moderate-to-high educational risk. Sixteen or more school absences, family concerns for their child's school performance or inability to advocate for their school needs, child mental health visits, and greater frequency of hospitalization predicted greater educational risk scores and more encounters with the school specialist. Better lung function and lower grade level were associated with lower educational risk. Number of encounters with the School Specialist remained high across three pre-coronavirus disease 2019 school years. CONCLUSIONS: Our experience illustrates a need to identify educational risk and support school experiences of children and youth with CF as a component of the care model. Tailored support, based on identification of risk predictors, has potential to improve educational outcomes.

Increased incidence of pediatric narcolepsy following the 2009 H1N1 pandemic: a report from the pediatric working group of the sleep research network.

This study was aimed to evaluate the yearly incidence of pediatric narcolepsy prior to and following the 2009 H1N1 pandemic and to evaluate seasonal patterns of narcolepsy onset and associations with H1N1 influenza infection in the United States. This was a multicenter retrospective study with prospective follow-up. Participants were recruited from members of the Pediatric Working Group of the Sleep Research Network including 22 sites across the United States. The main outcomes were monthly and yearly incident cases of childhood narcolepsy in the United States, and its relationship to historical H1N1 influenza data. A total of 950 participants were included in the analysis; 487 participants were male (51.3%). The mean age at onset of excessive daytime sleepiness (EDS) was 9.6  ±â€… 3.9 years. Significant trend changes in pediatric narcolepsy incidence based on EDS onset (p  <  .0001) occurred over the 1998-2016 period, peaking in 2010, reflecting a 1.6-fold increase in narcolepsy incidence. In addition, there was significant seasonal variation in narcolepsy incident cases, with increased cases in spring (p  <  .05). Cross-correlation analysis demonstrated a significant correlation between monthly H1N1 infection and monthly narcolepsy incident cases (p  =  .397, p  <  .0001) with a lag time of 8 months. We conclude that there is a significant increase in pediatric narcolepsy incidence after the 2009 H1N1 pandemic in the United States. However, the magnitude of increase is lower than reported in European countries and in China. The temporal correlation between monthly H1N1 infection and monthly narcolepsy incidence, suggests that H1N1 infection may be a contributing factor to the increased pediatric narcolepsy incidence after the 2009 H1N1 pandemics.

Hematologic Toxicity Comparison of Intensity Modulated Proton Therapy and Intensity Modulated Radiation Therapy in Anal Cancer Patients.

PURPOSE: We hypothesize that hematologic toxicity will be lower in anal cancer patients treated definitively with intensity modulated proton therapy (IMPT) compared with patients treated with intensity modulated radiation therapy (IMRT). METHODS: Patients enrolled on a prospective feasibility trial assessing the use of IMPT for anal cancer were compared with contemporaneous patients treated with IMRT. Blood counts were collected during chemoradiation. Hematologic events were graded according to CTCAE version 5.0. Pelvic bone marrow (PBM) and positron emission tomography-defined active bone marrow (ABM) were defined and contoured for each patient. Toxicity rates, PBM and ABM dose metrics were compared between groups. RESULTS: Forty-one patients treated with definitive chemoradiation for anal cancer between 2015 and 2021 were included in this analysis. Of the evaluable patients, 14 patients were treated with IMPT and 27 were treated with IMRT. All PBM dose metrics were lower in patients receiving IMPT. Patients treated with IMPT versus IMRT also had a significantly lower ABM mean dose (1996 vs. 3073 Gy, P<0.01). However, there was no statistically significant difference in hematologic toxicity between the groups. Seventy percent of patients treated with IMRT had at least 1 grade ≥3 hematologic event compared with 86% in the IMPT group (P=0.48). CONCLUSION: Proton treatment reduced bone marrow doses but was not associated with lower hematologic toxicity when compared with IMRT.

Predicting critical closing pressure in children with obstructive sleep apnea using fluid-structure interaction.

Surgical treatment of obstructive sleep apnea (OSA) in children requires knowledge of upper airway dynamics, including the closing pressure (Pcrit), a measure of airway collapsibility. We applied a flow-structure interaction (FSI) computational model to estimate Pcrit in patient-specific upper airway models obtained from magnetic resonance imaging (MRI) scans. We sought to examine the agreement between measured and estimated Pcrit from FSI models in children with Down syndrome. We hypothesized that the estimated Pcrit would accurately reflect measured Pcrit during sleep and therefore reflect the severity of OSA as measured by the obstructive apnea-hypopnea index (AHI). All participants (n = 41) underwent polysomnography and sedated sleep MRI scans. We used Bland-Altman plots to examine the agreement between measured and estimated Pcrit. We determined associations between estimated Pcrit and OSA severity, as measured by AHI, using regression models. The agreement between passive and estimated Pcrit showed a fixed bias of -1.31 [confidence interval (CI) = -2.78, 0.15] and a nonsignificant proportional bias. A weaker agreement with active Pcrit was observed. A model including AHI, gender, an interaction term for AHI, and gender and neck circumference explained the largest variation (R2 = 0.61) in the relationship between AHI and estimated Pcrit (P < 0.0001). Overlap between the areas of the airway with the lowest stiffness, and areas of collapse on dynamic MRI, was 77.4 ± 30% for the nasopharyngeal region and 78.6 ± 33% for the retroglossal region. The agreement between measured and estimated Pcrit and the significant association with AHI supports the validity of Pcrit estimates from the FSI model.NEW & NOTEWORTHY We present a noninvasive method for estimating critical closing pressure (Pcrit) using fluid-structure interaction (FSI) simulations and magnetic resonance imaging (MRI) scans in patients with obstructive sleep apnea (OSA). We used patient-specific stiffness measures in our FSI model to account for any individual variability in the elasticity of soft tissues surrounding the upper airway. We validated this model by measuring the degree of agreement between measured and estimated Pcrit.

The maturation changes of sleep-related respiratory abnormalities in infants with laryngomalacia.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) and central sleep apnea (CSA) are common in infants with laryngomalacia. The purpose of this study was to evaluate developmental changes in sleep-related breathing disorders over time in infants with laryngomalacia and understand the effect of supraglottoplasty (SGP) and nonsurgical treatment. METHODS: This is a retrospective review of infants with laryngomalacia who had at least 2 diagnostic polysomnography studies performed from January 2000 and May 2015. We included infants who had either OSA or CSA. Comparison of sleep and respiratory parameters by age group (0-6, 6-12, and >12 months old) was performed in both SGP and non-SGP groups using a mixed-effect regression model. A log-normal mixed model was used to explore the changes in sleep and respiratory parameters with age. The time to resolution of CSA and OSA was analyzed using nonparametric survival analysis. RESULTS: A total of 102 infants were included; 57 had only OSA and 45 had both CSA and OSA. There were significant decreases in apnea-hypopnea index, obstructive index, central apnea index, and arousal index with increasing age in both SGP and non-SGP groups. The mean age at resolution of CSA (central apnea index < 5) was 7.60 months old for SGP and 12.57 months old for non-SGP (P < .05). There were no significant differences in the mean age at resolution of OSA (obstructive index < 1; 35.18 [SGP] vs 41.55 months [non-SGP]; P = .60) between SGP and non-SGP groups. Infants with neurologic disease, congenital anomalies, or genetic syndromes required significantly more time to resolve OSA (28.12 [normal] vs 53.13 [neurological] vs 59.53 months [congenital anomalies and genetic]; P < .01). CONCLUSIONS: Both OSA and CSA improve in infants with laryngomalacia with increasing age regardless of SGP. The mechanism underlying these changes may involve airway growth and maturation of respiratory control. Time to resolution of OSA is affected by the presence of neurologic diseases, congenital anomalies, and genetic syndromes. Further studies are needed to confirm these findings and to evaluate long-term outcomes in this population.

Neonatal complications of Down syndrome and factors necessitating intensive care.

Limited knowledge exists about how frequently newborns with Down syndrome receive a prenatal diagnosis, require intensive care, and what surgical and medical factors are contributory. A retrospective cohort study was performed for patients with a diagnosis of Down syndrome born in 2013 and 2014 who sought care at Cincinnati Children's Hospital Medical Center during the first year of life. Data were extracted from the electronic medical record through the first year of life including need for intensive care as a newborn, prenatal diagnosis, and medical and surgical complications. Of the 129 patients in the study, 65% required intensive care as newborns. The presence of a structural abnormality that required surgical correction in the neonatal period and certain types of congenital heart disease not requiring surgical intervention in the neonatal period were positively associated with the need for intensive care. A minority of infants, 8%, had a confirmed prenatal diagnosis. A majority of newborns with Down syndrome required intensive care following birth while a minority had any concern for the diagnosis prenatally. Improving prenatal diagnostic rates would allow for better prenatal counseling and delivery planning, while targeting therapeutic interventions for this population is needed to improve outcomes.

Randomized trial of lung hyperinflation therapy in children with congenital muscular dystrophy.

OBJECTIVE: Respiratory compromise in congenital muscular dystrophy (CMD) occurs, in part, from chest wall contractures. Passive stretch with hyperinsufflation therapy could reduce related costo-vertebral joint contractures. We sought to examine the impact of hyperinsufflation use on lung function and quality of life in children with CMD. STUDY DESIGN: We conducted a randomized controlled trial on hyperinsufflation therapy in children with CMD at two centers. An individualized hyperinsufflation regimen of 15 minutes twice daily using a cough assist device over a 12 months period was prescribed. We measured lung function, quality of life, and adherence. To demonstrate reproducibility, pulmonary function was measured twice on the same day. A mixed-effects regression model adjusting for confounders was used to assess the effects of hyperinsufflation. RESULTS: We enrolled 34 participants in the study; 31 completed the trial (n = 17 treatment group and n = 14 controls). Participants in the treatment group demonstrated a relative gain in lung volume measured at 4 and 8 months, but not at 12 months. The control group required increases in the maximum insufflation pressures to achieve maximum lung volumes while the treatment group did not. Adherence was best early in the study, peaking at the first visit and decreasing at subsequent visits. Caregiver-reported quality of life was higher in the treatment group. CONCLUSION: Hyperinsufflation therapy is effective in increasing and sustaining lung volume over time. Adherence, however, was inconsistent and difficult to maintain. Further research should determine if improved adherence leads to sustained benefits of hyperinsufflation.

Water Quality Impairments Due to Aquatic Life Pesticide Toxicity: Prevention and Mitigation in California, USA.

The management of pesticides to protect water quality remains a significant global challenge. Historically, despite regulatory frameworks intended to prevent, minimize, and manage off-site movement of pesticides, multiple generations of pesticide active ingredients have created a seemingly unending cycle of pesticide water pollution in both agricultural and urban watersheds. In California, the most populous and most agricultural US state, pesticide and water quality regulators realized in the 1990s that working independently of each other was not an effective approach to address pesticide water pollution. Over the years, these California agencies have developed a joint vision and have continued to develop a unified approach that has the potential to minimize pesticide risks to aquatic life through a combination of prevention, monitoring, and management actions, while maintaining pesticide availability for effective pest control. Key elements of the current California pesticide/water quality effort include: 1) pesticide and toxicity monitoring, coupled with watershed modeling, to maximize information obtained from monitoring; 2) predictive fate and exposure modeling to identify potential risks to aquatic life for new pesticide products when used as allowed by the label or to identify effective mitigation measures; and 3) management approaches tailored to the different pesticide uses, discharge sources, physical environments, and regulatory environments that exist for agricultural runoff, urban runoff, and municipal wastewater. Lessons from this effort may inform pesticide management elsewhere in the world as well as other chemical regulatory programs, such as the recently reformed US Toxic Substances Control Act and California's Safer Consumer Products regulatory program. Environ Toxicol Chem 2020;39:953-966. © 2020 SETAC.

Tube feeding outcomes of infants in a Level IV NICU.

BACKGROUND: NICU patients are commonly discharged home with nasogastric (NG) or gastrostomy (G-tube) feeding, but wide practice variation exists. The objective of this study was to evaluate feeding and growth outcomes and complications in NICU patients discharged home with NG or G-tube feeding. STUDY DESIGN: Retrospective cohort study of infants discharged from a Level IV NICU with an NG or G-tube who had follow up to 1 year. Clinical characteristics and outcomes were compared between groups. RESULTS: The study sample included 264 infants: 140 with NG and 124 with G-tube. More infants in the G-tube group (65%) still required tube feedings 12 months post-discharge than infants in the NG group (24%). Infants in the G-tube group had more tube-related ER visits than infants in the NG group. Growth outcomes did not differ. CONCLUSION: Home NG feeding may be a safe alternative to a surgically placed G-tube in select NICU patients.

The effect of 220 kHz insonation scheme on rt-PA thrombolytic efficacy in vitro.

Ultrasound-enhanced recombinant tissue plasminogen activator (rt-PA) thrombolysis is under development as an adjuvant to ischemic stroke therapy. The goal of this study was to design a pulsed ultrasound (US) exposure scheme that reduced intracranial constructive interference and tissue heating, and maintained thrombolytic efficacy relative to continuous wave (CW) insonation. Three 220 kHz US schemes were evaluated, two pulsed insonation schemes (15 cycles, 68 µs pulse duration, 33% or 62.5% duty cycle) and an intermittent CW insonation scheme (50 s active, 30 s quiescent) over a 30-min treatment period. An in silico study using a finite-difference model of transcranial US propagation was performed to estimate the intracranial acoustic field and temperature rise in the skull for each insonation scheme. In vitro measurements with flow were performed to assess thrombolysis using time-lapse microscopy. Intracranial constructive interference was not reduced with pulsed US using a pulse length of 15 cycles compared to intermittent CW US. The 33.3% duty cycle pulsed US scheme reduced heating in the temporal bone as much as 60% relative to the intermittent CW scheme. All insonation schemes promoted sustained stable cavitation in vitro and augmented thrombolysis compared to rt-PA alone (p  < 0.05). Ultraharmonic (UH) and harmonic cumulative energy over a 30 min treatment period was significantly higher (p  < 0.05) for the intermittent CW US scheme compared to either pulsed US scheme. Despite the difference in cavitation emissions, no difference was observed in the clot lysis between the three US schemes. These findings demonstrate that a 33.3% duty cycle pulsed US scheme with a 15-cycle burst can reduce bone heating and achieve equivalent thrombolytic efficacy as an intermittent CW scheme.

Coughing, sneezing, and aching online: Twitter and the volume of influenza-like illness in a pediatric hospital.

This study investigates the relation of the incidence of georeferenced tweets related to respiratory illness to the incidence of influenza-like illness (ILI) in the emergency department (ED) and urgent care clinics (UCCs) of a large pediatric hospital. We collected (1) tweets in English originating in our hospital's primary service area between 11/1/2014 and 5/1/2015 and containing one or more specific terms related to respiratory illness and (2) the daily number of patients presenting to our hospital's EDs and UCCs with ILI, as captured by ICD-9 codes. A Support Vector Machine classifier was applied to the set of tweets to remove those unlikely to be related to ILI. Time series of the pooled set of remaining tweets involving any term, of tweets involving individual terms, and of the ICD-9 data were constructed, and temporal cross-correlation between the social media and clinical data was computed. A statistically significant correlation (Spearman ρ = 0.23) between tweets involving the term flu and ED and UCC volume related to ILI 11 days in the future was observed. Tweets involving the terms coughing (Spearman ρ = 0.24) and headache (Spearman ρ = 0.19) individually were also significantly correlated to ILI-related clinical volume four and two days in the future, respectively. In the 2014-2015 cold and flu season, the incidence of local tweets containing the terms flu, coughing, and headache were early indicators of the incidence of ILI-related cases presenting to EDs and UCCs at our children's hospital.

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aß Reduction.

Inhibition of BACE1 to prevent brain Aß peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aß levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aß40 levels when administered orally to rats.

Piperazine sulfonamide BACE1 inhibitors: design, synthesis, and in vivo characterization.

With collaboration between chemistry, X-ray crystallography, and molecular modeling, we designed and synthesized a series of novel piperazine sulfonamide BACE1 inhibitors. Iterative exploration of the non-prime side and S2' sub-pocket of the enzyme culminated in identification of an analog that potently lowers peripheral Abeta(40) in transgenic mice with a single subcutaneous dose.