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OBJECTIVE To assess risk factors associated with 30-day hospital readmission after a prolonged neonatal intensive care stay. STUDY DESIGN Retrospective analysis of 57,035 infants discharged >14 days from the NICU between 2013 and 2016. Primary outcome was 30-day, all-cause hospital readmission. Adjusted likelihood of readmission accounting for demographic and clinical characteristics, including chronic conditions was also estimated. RESULTS The 30-day readmission rate was 10.7%. Respiratory problems accounted for most (31.0%) readmissions. In multivariable analysis, shunted hydrocephalus [OR 2.2 (95%CI 1.8-2.7)], gastrostomy tube [OR 2.0 (95%CI 1.8-2.3)], tracheostomy [OR 1.5 (95%CI 1.2-1.8)], and use of public insurance [OR 1.3 (95%CI 1.2-1.4)] had the highest likelihood of readmission. Adjusted hospital readmission rates varied significantly (p

Cerebral palsy (CP) is the most common cause of childhood physical disability, with incidence between 1/500 and 1/700 births in the developed world. Despite increasing evidence for a major contribution of genetics to CP aetiology, genetic testing is currently not performed systematically. We assessed the diagnostic rate of genome sequencing (GS) in a clinically unselected cohort of 150 singleton CP patients, with CP confirmed at >4 years of age. Clinical grade GS was performed on the proband and variants were filtered, and classified according to American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines. Variants classified as pathogenic or likely pathogenic (P/LP) were further assessed for their contribution to CP. In total, 24.7% of individuals carried a P/LP variant(s) causing or increasing risk of CP, with 4.7% resolved by copy number variant analysis and 20% carrying single nucleotide or indel variants. A further 34.7% carried one or more rare, high impact variants of uncertain significance (VUS) in variation intolerant genes. Variants were identified in a heterogeneous group of genes, including genes associated with hereditary spastic paraplegia, clotting and thrombophilic disorders, small vessel disease, and other neurodevelopmental disorders. Approximately 1/2 of individuals were classified as likely to benefit from changed clinical management as a result of genetic findings. In addition, no significant association between genetic findings and clinical factors was detectable in this cohort, suggesting that systematic sequencing of CP will be required to avoid missed diagnoses.

Anti-Wolbachia therapy has been identified as a viable treatment for combating filarial diseases. Phenotypic screening revealed a series of pyrazolopyrimidine hits with potent anti-Wolbachia activity. This paper focuses on the exploration of the SAR for this chemotype, with improvement of metabolic stability and solubility profiles using medicinal chemistry approaches. Organic synthesis has enabled functionalization of the pyrazolopyrimidine core at multiple positions, generating a library of compounds of which many analogues possess nanomolar activity against Wolbachia in vitro with improved DMPK parameters. A lead compound, 15f, was selected for in vivo pharmacokinetics (PK) profiling in mice. The combination of potent anti-Wolbachia activity in two in vitro assessments plus the exceptional oral PK profiles in mice puts this lead compound in a strong position for in vivo proof-of-concept pharmacodynamics studies and demonstrates the strong potential for further optimization and development of this series for treatment of filariasis in the future.

Here, we present a rare case of a patient who developed multiple primary melanomas within the boundaries of two nevi depigmentosa. The melanomas were excised, and as a preventive measure, the remainder of the nevi depigmentosa were removed. We performed whole-exome sequencing on excised tissue from the nevus depigmentosus, adjacent normal skin, and saliva to explain this intriguing phenomenon. We also performed a GeneTrails Comprehensive Solid Tumor Panel analysis on one of the melanoma tissues. Genetic analysis revealed germline MC1R V92M and TYR R402Q polymorphisms and a MET E168D germline mutation that may have increased the risk of melanoma development. This genetic predisposition, combined with a patient-reported history of substantial sun exposure and sunburns, which were more severe within the boundaries of the nevi depigmentosa due to the lack of photoprotective melanin, produced numerous somatic mutations in the melanocytes of the nevi depigmentosa. Fitting with this paradigm for melanoma development in chronically sun-damaged skin, the patient's melanomas harbored somatic mutations in CDKN2A (splice site), NF1, and ATRX and had a tumor mutation burden in the 90-95th percentile for melanoma.

Background Since 2011, the therapeutic landscape of melanoma has changed dramatically because of the adoption of immune checkpoint inhibitor and targeted therapies. The authors sought to quantify the effects of these changes on short-term treatment costs by comparing the first-year cancer-attributable costs in novel (2011-2015) and historical (2004-2010) treatment eras. Methods The authors estimated the first-year cancer-attributable and out-of-pocket (OOP) costs by cancer stage at diagnosis by using a case-control approach. Patients aged ≥67 years with melanoma results were used to calculate the total direct costs of treatment during the first year after the diagnosis of melanoma in the US Medicare population older than 65 years. Costs were reported in 2018 dollars. Results Costs increased with the stage at diagnosis. Average first-year cancer-attributable costs per patient for stage IV patients increased significantly by 61.7% from $45,952 to $74,297 after the adoption of novel treatments. Per-patient OOP responsibility decreased by almost 30.8% across all stages of cancer but increased by 16.5% for stage IV patients from 2004 ($7646) to 2015 ($8911). The total direct cost of treatment for persons with melanoma older than 65 years increased by $16.03 million (4.93%) from $324.68 million in 2010 to $340.71 million in 2015. The largest increase in yearly total cost, $23.64 million (56.53%), was observed among stage IV patients. Conclusions The direct cost of melanoma increased significantly in the Medicare population, particularly for advanced-stage disease. Prevention and early detection initiatives may reduce the economic burden of melanoma.

OBJECTIVE: To describe the prevalence and characteristics of infection-related readmissions in children and to identify opportunities for readmission reduction and estimate associated cost savings. STUDY DESIGN: Retrospective analysis of 380,067 nationally representative index hospitalizations for children using the 2014 Nationwide Readmissions Database. We compared 30-day, all-cause unplanned readmissions and costs across 22 infection categories. We used the Inpatient Essentials database to measure hospital-level readmission rates and to establish readmission benchmarks for individual infections. We then estimated the number of readmissions avoided and costs saved if hospitals achieved the 10th percentile of hospitals’ readmission rates (ie, readmission benchmark). All analyses were stratified by the presence/absence of a complex chronic condition (CCC). RESULTS: The overall 30-day readmission rate was 4.9%. Readmission rates varied substantially across infections and by presence/absence of a CCC (CCC: range, 0%-21.6%; no CCC: range, 1.5%-8.6%). Approximately 42.6% of readmissions (n = 3,576) for children with a CCC and 54.7% of readmissions (n = 5,507) for children without a CCC could have been potentially avoided if hospitals achieved infection-specific benchmark readmission rates, which could result in an estimated savings of $70.8 million and $44.5 million, respectively. Bronchiolitis, pneumonia, and upper respiratory tract infections were among infections with the greatest number of potentially avoidable readmissions and cost savings for children with and without a CCC. CONCLUSION: Readmissions following hospitalizations for infection in children vary significantly by infection type. To improve hospital resource use for infections, future preventative measures may prioritize children with complex chronic conditions and those with specific diagnoses (eg, respiratory illnesses).

Prospective cerebral palsy (CP) registry review. (1) Evaluate the incidence/risk factors of gastrointestinal (GI) complications in CP patients after spinal fusion (SF); and (2) investigate the validity of the modified Clavien–Dindo–Sink classification. Perioperative GI complications result in increased length of stay (LOS) and patient morbidity/mortality. However, none have analyzed the outcomes of GI complications using an objective classification system. A prospective/multicenter CP database identified 425 children (mean, 14.4 ± 2.9 years; range, 7.9–21 years) who underwent SF. GI complications were categorized using the modified Clavien–Dindo–Sink classification. Grades I–II were minor complications and grades III–V major. Patients with and without GI complications were compared. 87 GI complications developed in 69 patients (16.2%): 39 minor (57%) and 30 major (43%). Most common were pancreatitis (n = 45) and ileus (n = 22). Patients with preoperative G-tubes had 2.2 × odds of developing a GI complication compared to oral-only feeders (OR 2.2; 95% CI 0.98–4.78; p = 0.006). Similarly, combined G-tube/oral feeders had 6.7 × odds compared to oral-only (OR 6.7; 95% CI 3.10–14.66; p

AIM To assess how co-occurring conditions influence recovery after hip reconstruction surgery in children with neurological complex chronic conditions (CCCs). METHOD This was a retrospective analysis of 4058 children age 4 years or older with neurological CCCs who underwent hip reconstructive surgery between 1st January 2015 and 31st December 2018 in 49 children's hospitals. The presence of co-occurring chronic conditions was assessed using the Agency for Healthcare Research Chronic Condition Indicator system. Multivariable, hierarchical regression was used to assess the relationship between co-existing conditions and postoperative hospital length of stay (LOS), cost, and 30-day readmission rate. RESULTS The most common co-occurring conditions were digestive (60.1%) and respiratory (37.9%). As the number of co-existing conditions increased from one to four or more, median LOS increased 67% (3d [interquartile range {IQR} 2-4d] to 5d [IQR 3-8d]); median hospital cost increased 41% ($20 248 [IQR $14 921-$27 842] to $28 692 [IQR $19 236-$45 887]); and readmission rates increased 250% (5.5-13.9%), p

Background The incidence of venous thromboembolism (VTE) after elective surgery in children with mobility impairments, including those with a neuromuscular complex chronic condition (NCCC), is unknown. Therefore, our objectives were to assess the incidence of VTE after elective spine and lower-extremity surgery in children with NCCC. Methods A retrospective analysis of children with NCCC undergoing elective lower-extremity and/or spinal surgeries from 2005 to 2009 included in the Pediatric Health Information Systems Plus (PHIS+) database. VTE during hospitalization for surgery was assessed through abstraction and review of ultrasound (U/S) and computed tomography results by 2 independent reviewers. VTEs related to pre-existing central venous catheters were excluded. Results There were 4,583 children with NCCC who underwent orthopaedic surgery during the study period at 6 centers. Most were male (56.3%), non-Hispanic whites (72.7%), and had private insurance (52.2%). The most common NCCC diagnoses were cerebral palsy (46.7%), brain and spinal cord malformations (31.1%), and central nervous system degenerative conditions (14.5%). Forty children (0.9%) underwent U/S to assess VTE. Eighteen children (0.4%) underwent computed tomography to assess VTE. Four children (with cerebral palsy) had a positive U/S for a lower-extremity VTE (10-18 y of age), yet 2 had their VTE before surgery. Therefore, the adjusted VTE rate for children with NCCC undergoing orthopaedic lower-extremity or spine surgery was 4 per 10,000 (2 cases per 4583 surgeries). Each of the 2 cases had a known coagulation disorder preoperatively. Only 10% of the cohort used compression devices, 3% enoxaparin, and 1.6% aspirin for prophylaxis. Conclusion The rate of non-central-venous-catheter-related VTE associated with orthopaedic surgery in children with NCCC is very low and lower than rates reported in healthy children. Significance To our knowledge, this is the first multi-institutional study reporting the incidence of VTE in children with NCCCs undergoing elective hip and spine surgery. These data support no additional prophylaxis is required in children with NCCC undergoing elective hip and spine surgery unless other known risk factors are also present.

Aortic root aneurysm formation is a cardinal feature of Marfan syndrome (MFS) and likely TGF‐β driven via Smad (canonical) and ERK (non‐canonical) signalling. The current study assesses human MFS vascular smooth muscle cell (SMC) phenotype, focusing on individual contributions by Smad and ERK, with Notch3 signalling identified as a novel compensatory mechanism against TGF‐β‐driven pathology. Although significant ERK activation and mixed contractile gene expression patterns were observed by traditional analysis, this did not directly correlate with the anatomic site of the aneurysm. Smooth muscle cell phenotypic changes were TGF‐β‐dependent and opposed by ERK in vitro, implicating the canonical Smad pathway. Bulk SMC RNA sequencing after ERK inhibition showed that ERK modulates cell proliferation, apoptosis, inflammation, and Notch signalling via Notch3 in MFS. Reversing Notch3 overexpression with siRNA demonstrated that Notch3 promotes several protective remodelling pathways, including increased SMC proliferation, decreased apoptosis and reduced matrix metalloproteinase activity, in vitro. In conclusion, in human MFS aortic SMCs: (a) ERK activation is enhanced but not specific to the site of aneurysm formation; (b) ERK opposes TGF‐β‐dependent negative effects on SMC phenotype; (c) multiple distinct SMC subtypes contribute to a ‘mixed’ contractile‐synthetic phenotype in MFS aortic aneurysm; and (d) ERK drives Notch3 overexpression, a potential pathway for tissue remodelling in response to aneurysm formation.

The aim of this study is to assess the impact of preoperative comanagement with complex care pediatricians (CCP) on children with neuromuscular scoliosis undergoing spinal fusion. We performed chart review of 79 children aged 5–21 years undergoing spinal fusion 1/2014–6/2016 at a children’s hospital, with abstraction of clinical documentation from preoperative health evaluations performed regularly by anesthesiologists and irregularly by a CCP. Preoperative referrals to specialists, labs, tests, and care plans needed last minute for surgical clearance were measured. The mean age at surgery was 14 (SD 3) years; cerebral palsy (64%) was the most common neuromuscular condition. Thirty-nine children (49%) had a preoperative CCP evaluation a median 63 days (interquartile range (IQR) 33–156) before the preanesthesia visit. Children with CCP evaluation had more organ systems affected by coexisting conditions than children without an evaluation (median 11 (IQR 9–12) vs. 8 (IQR 5–11); p < .001). The rate of last-minute care coordination activities required for surgical clearance was lower for children with versus without CCP evaluation (1.8 vs. 3.6). A lower percentage of children with CCP evaluation required last-minute development of new preoperative plans (26% vs. 50%, p = .002). Children with CCP involvement were better prepared for surgery, requiring fewer last-minute care coordination activities for surgical clearance.

Design Retrospective comparative study. Objective The purpose of this study is to measure SSI outcomes before and after implementation of our center’s multidisciplinary clinical pathway protocol for high-risk spinal surgery. Background Surgical site infections (SSIs) after spinal fusion harm patients and are associated with significant health care costs. Given the high rate of SSI in neuromuscular populations, there is a rationale to develop infection prevention strategies. Methods An institutional clinical pathway was created in 2012 and based on nationally published Best Practice Guidelines as well as hospital practices with a goal of reducing the rate of deep SSI in high-risk patients. Patient and procedure characteristics were compared prior to (2008-2011) and after (2012-2016) implementation of the pathway. Logistic regression using penalized maximum likelihood was used to assess differences in rate of infection before and after implementation. Results Cohorts of 132 and 115 high-risk patients were analyzed before and after pathway implementation. Rate of deep infections decreased from 8% to 1% of patients (p = .005). Preoperative antibiotics were dosed within 1 hour in 90% of the postpathway cohort. Redosing was successful in 94% of patients for first redose and 79% for second redose. Betadine irrigation was used in 76% of cases and vancomycin administered in 86%. Multivariable analysis determined that instances of compliant antibiotics dosing had 63% lower odds of infection compared with instances of noncompliance (p = .04). Conclusions Implementation of a multidisciplinary pathway aimed to reduce infection in patients at high risk for SSI after spinal fusion led to a significant reduction in deep SSI rate. It is impossible to attribute the drop in the deep SSI rate to any one factor. Our results demonstrate that adherence to a protocol using multiple strategies to reduce infection results in a lower SSI rate, lower care costs, and improved patient-related outcomes. Level of Evidence Level III.

Objective To determine whether differences in combination DTaP vaccine types at 2, 4 and 6 months of age were associated with mortality (all-cause or non-specific), within 30 days of vaccination. Design Observational nationwide cohort study. Setting Linked population data from the Australian Childhood Immunisation Register and National Death Index. Participants Australian infants administered a combination trivalent, quadrivalent or hexavalent DTaP vaccine (DTaP types) between January 1999 and December 2010 at 2, 4 and 6 months as part of the primary vaccination series. The study population included 2.9, 2.6, & 2.3 million children in the 2, 4 and 6 month vaccine cohorts, respectively. Main outcome measures Infants were evaluated for the primary outcome of all-cause mortality within 30 days. A secondary outcome was non-specific mortality (unknown cause of death) within 30 days of vaccination. Non-specific mortality was defined as underlying or other cause of death codes, R95 ‘Sudden infant death syndrome’, R96 ‘Other sudden death, cause unknown’, R98 ‘Unattended death’, R99 ‘Other ill-defined and unspecified cause of mortality’ or where no cause of death was recorded. Results The rate of 30 day all-cause mortality was low and declined from 127.4 to 59.3 deaths per 100,000 person-years between 2 and 6 month cohorts. When compared with trivalent DTaP vaccines, no elevated risk in all-cause or non-specific mortality was seen with any quadrivalent or hexavalent DTaP vaccines, for any cohort. Conclusion Use of routine DTaP combination vaccines with differing disease antigens administered during the first six months of life is not associated with infant mortality.

This cross-sectional study compares cost and payer reimbursement for hospital admissions of children and assesses associations of underpayment by patients’ demographic and clinical characteristics.

Children’s hospitals responded to COVID-19 by limiting nonurgent healthcare encounters, conserving personal protective equipment, and restructuring care processes to mitigate viral spread. We assessed year-over-year trends in healthcare encounters and hospital charges across US children’s hospitals before and during the COVID-19 pandemic. We performed a retrospective analysis, comparing healthcare encounters and inflation-adjusted charges from 26 tertiary children’s hospitals reporting to the PROSPECT database from February 1 to June 30 in 2019 (before the COVID-19 pandemic) and 2020 (during the COVID-19 pandemic). All children’s hospitals experienced similar trends in healthcare encounters and charges during the study period. Inpatient bed-days, emergency department visits, and surgeries were lower by a median 36%, 65%, and 77%, respectively, per hospital by the week of April 15 (the nadir) in 2020 compared with 2019. Across the study period in 2020, children’s hospitals experienced a median decrease of $276 million in charges.

INTRODUCTION: Primary care providers have greater access to patients despite often lacking the appropriate training or time to implement effective skin cancer screenings in their busy practices.(1) Through collaborative efforts with Oregon’s War on Melanoma public health campaign and other primary care trainings, we created “Melanoma Toolkit for Early Detection” (MTED): a training curriculum and resource repository for primary care providers. METHODS AND RESULTS: MTED consisted of three self-paced modules. Each participant completed a pre- and post-test consisting of demographic, confidence, and image identification questions. A subsequent optional 6-month follow-up image identification test was also provided. Of the 96 participants, 40 completed all the modules, the pre, and post-test. On average, scores increased by 6.0 (95% CI: 3.5 to 8.6) percentage points (P

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata511 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata511 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

Background: Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence. Methods: Principal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users. Findings: During prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p Interpretation: If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.

Meckel's diverticulum (MD) is a well-defined diagnosis in children presenting with either bleeding or obstruction. Although anecdotally adult patients may present with complications from MD, their presentation seems to be different, with a reported predominance of non-bleed-related presentations. Reports in this population, however, are limited, and little is known of the epidemiology of MD in older patients. We performed a retrospective analysis of the Agency of Healthcare Research and Quality National Inpatient Sample of all US hospital discharges from 2012 to 2016. We identified patients with a primary discharge diagnosis of MD. Data were abstracted as raw numbers and population weighted rates of discharge with age group, income level, length of stay (LOS) and hospital charges as additional information. On average, 2030 individuals were discharged annually; most (71.1%) were adults (>18 years). Although MD was predominant in males in all age groups, the gender ratio decreased with older age categories from 3.5:1.0 (1-17 years) to 1.6:1.0 (65-84 years). LOS averaged 5.3 days with no clear relationship to other parameters. Median income category, however, closely correlated (R2=0.9996) with diagnosis in older age categories. MD may be significantly more prevalent in adult patients than was previously understood. Differences in gender preponderance suggest that gender may influence the pattern of presentation. Diagnosis in older individuals is closely associated with income or socioeconomic status but not hospital charges or LOS.

BACKGROUND: Children with neurologic impairment (NI) are at risk for developing co-occurring chronic conditions, increasing their medical complexity and morbidity. We assessed the prevalence and timing of onset for those conditions in children with NI. METHODS: This longitudinal analysis included 6229 children born in 2009 and continuously enrolled in Medicaid through 2015 with a diagnosis of NI by age 3 in the IBM Watson Medicaid MarketScan Database. NI was defined with an existing diagnostic code set encompassing neurologic, genetic, and metabolic conditions that result in substantial functional impairments requiring subspecialty medical care. The prevalence and timing of co-occurring chronic conditions was assessed with the Agency for Healthcare Research and Quality Chronic Condition Indicator system. Mean cumulative function was used to measure age trends in multimorbidity. RESULTS: The most common type of NI was static (56.3%), with cerebral palsy (10.0%) being the most common NI diagnosis. Respiratory (86.5%) and digestive (49.4%) organ systems were most frequently affected by co-occurring chronic conditions. By ages 2, 4, and 6 years, the mean (95% confidence interval [CI]) numbers of co-occurring chronic conditions were 3.7 (95% CI 3.7–3.8), 4.6 (95% CI 4.5–4.7), and 5.1 (95% CI 5.1–5.2). An increasing percentage of children had ≥9 co-occurring chronic conditions as they aged: 5.3% by 2 years, 10.0% by 4 years, and 12.8% by 6 years. CONCLUSIONS: Children with NI enrolled in Medicaid have substantial multimorbidity that develops early in life. Increased attention to the timing and types of multimorbidity in children with NI may help optimize their preventive care and case management health services.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

Background Lung-protective ventilation (LPV) improves outcomes for patients with acute respiratory distress syndrome (ARDS) through the administration of low tidal volumes (≤ 6.5 ml/kg predicted body weight [PBW]) with co-titration of positive end-expiratory pressure and fraction of inspired oxygen. Many patients with ARDS, however, are not managed with LPV. The purpose of this study was to understand the implementation barriers and facilitators to the use of LPV and a computerized LPV clinical decision support (CDS) tool in intensive care units (ICUs) in preparation for a pilot hybrid implementation-effectiveness clinical trial. Methods We performed an explanatory sequential mixed methods study from June 2018 to March 2019 to evaluate the variation in LPV adherence across 17 ICUs in an integrated healthcare system with > 4000 mechanically ventilated patients annually. We analyzed 47 key informant interviews of ICU physicians, respiratory therapists (RTs), and nurses in 3 of the ICUs using a qualitative content analysis paradigm to investigate site variation as defined by adherence level (low, medium, high) and to identify barriers and facilitators to LPV and LPV CDS tool use. Results Forty-two percent of patients had an initial set tidal volume of ≤ 6.5 ml/kg PBW during the measurement period (site range 21–80%). LPV CDS tool use was 28% (site range 6–91%). This study’s main findings revealed multi-factorial facilitators and barriers to use that varied by ICU site adherence level. The primary facilitator was that LPV and the LPV CDS tool could be used on all mechanically ventilated patients. Barriers included a persistent gap between clinician attitudes regarding the use of LPV and actual use, the perceived loss of autonomy associated with using a computerized protocol, the nature of physician-RT interaction in ventilation management, and the lack of clear organization measures of success. Conclusions Variation in adherence to LPV persists in ICUs within a healthcare delivery system that was an early adopter of LPV. Potentially promising strategies to increase adherence to LPV and the LPV CDS tool for ARDS patients include initiating low tidal ventilation on all mechanically ventilated patients, establishing and measuring adherence measures, and focused education addressing the physician-RT interaction. These strategies represent a blueprint for a future hybrid implementation-effectiveness trial.

Objective To compare hospital outcomes associated with commonly used antibiotic therapies for aspiration pneumonia in children with neurologic impairment (NI). Design/methods A retrospective study of children with NI hospitalized with aspiration pneumonia at 39 children's hospitals in the Pediatric Health Information System database. Exposure was empiric antibiotic therapy classified by antimicrobial activity. Outcomes included acute respiratory failure, intensive care unit (ICU) transfer, and hospital length of stay (LOS). Multivariable regression evaluated associations between exposure and outcomes and adjusted for confounders, including medical complexity and acute illness severity. Results In the adjusted analysis, children receiving Gram-negative coverage alone had two-fold greater odds of respiratory failure (odds ratio [OR] 2.15; 95% CI: 1.41-3.27), greater odds of ICU transfer (OR 1.80; 95% CI: 1.03-3.14), and longer LOS [adjusted rate ratio (RR) 1.28; 95% CI: 1.16-1.41] than those receiving anaerobic coverage alone. Children receiving anaerobic and Gram-negative coverage had higher odds of respiratory failure (OR 1.65; 95% CI: 1.19-2.28) than those receiving anaerobic coverage alone, but ICU transfer (OR 1.15; 95% CI: 0.73-1.80) and length of stay (RR 1.07; 95% CI: 0.98-1.16) did not statistically differ. For children receiving anaerobic, Gram-negative, and P. aeruginosa coverage, LOS was shorter (RR 0.83; 95% CI: 0.76-0.90) than those receiving anaerobic coverage alone; odds of respiratory failure and ICU transfer rates did not significantly differ. Conclusions Anaerobic therapy appears to be important in the treatment of aspiration pneumonia in children with NI. While Gram-negative coverage alone was associated with worse outcomes, its addition to anaerobic therapy may not yield improved outcomes.

Background: Benefit–harm tradeoffs of melanoma screening depend on disease risk and treatment efficacy. We developed a model to project outcomes of screening for melanoma in populations with different risks under historic and novel systemic treatments. Methods: Computer simulation model of a screening program with specified impact on overall and advanced-stage incidence. Inputs included meta-analyses of treatment trials, cancer registry data, and a melanoma risk prediction study Results: Assuming 50% reduction in advanced stage under screening, the model projected 59 and 38 lives saved per 100,000 men under historic and novel treatments, respectively. With 10% increase in stage I, the model projects 2.9 and 4.7 overdiagnosed cases per life saved and number needed to be screened (NNS) equal to 1695 and 2632 under historical and novel treatments. When screening was performed only for the 20% of individuals with highest predicted risk, 34 and 22 lives per 100,000 were saved under historic and novel treatments. Similar results were obtained for women, but lives saved were lower. Conclusions: Melanoma early detection programs must shift a substantial fraction of cases from advanced to localized stage to be sustainable. Advances in systemic therapies for melanoma might noticeably reduce benefits of screening, but restricting screening to individuals at highest risk will likely reduce intervention efforts and harms while preserving >50% of the benefit of nontargeted screening. Impact: Our accessible modeling framework will help to guide population melanoma screening programs in an era of novel treatments for advanced disease.

To conduct a systematic review of phenotypic definition and case ascertainment in published genetic studies of cerebral palsy (CP) to inform guidelines for the reporting of such studies.Inclusion criteria comprised genetic studies of candidate genes, with CP as the outcome, published between 1990 and 2019 in the PubMed, Embase, and BIOSIS Citation Index databases.Fifty-seven studies met the inclusion criteria. We appraised how CP was defined, the quality of information on case ascertainment, and compliance with international consensus guidelines. Seven studies (12%) were poorly described, 33 studies (58%) gave incomplete information, and 17 studies (30%) were well described. Missing key information precluded determining how many studies complied with the definition by Rosenbaum et al. Only 18 out of 57 studies (32%) were compliant with the Surveillance of Cerebral Palsy in Europe (SCPE) international guidelines on defining CP.Limited compliance with international consensus guidelines on phenotypic definition and mediocre reporting of CP case ascertainment hinders the comparison of results among genetic studies of CP (including meta-analyses), thereby limiting the quality, interpretability, and generalizability of study findings. Compliance with the SCPE guidelines is important for ongoing gene discovery efforts in CP, given the potential for misclassification of unrelated neurological conditions as CP.

The parents of a child recently hospitalized for 3 days for bronchiolitis receive the bill in the mail for their child’s hospital stay. They are stunned by the total amount of the bill. They notice that the hospital room charge accounts for nearly three-fourths of the billed amount. The bill provides no information about the room charge. The parents wonder, “What is this charge? What goes into it? Why is it so expensive?” They are grateful that the bill is covered almost fully by their child’s health insurance. In the current issue of Pediatrics , Synhorst et al1 assessed variation across children’s hospitals in the cost of care for pediatric patients hospitalized with asthma, bronchiolitis, and other common pediatric illnesses. Patients’ hospital rooms accounted for the majority of total hospital costs, whereas nonroom costs (eg, medications, laboratory testing) contributed much less. The authors concluded that initiatives to improve the quality of hospital care for common pediatric illnesses have limited opportunity to meaningfully reduce costs without addressing hospital room costs. Synhorst et al1 highlight the difficulty of conducting research on hospital cost of care using administrative data that provide little information about the biggest expense on the bill: the patient’s room. Although Synhorst et al1 suggest that room costs broadly include overhead and staffing expenses, there are neither established definitions nor … Address correspondence to Jay Berry, MD, MPH, Department of Medicine, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02130. E-mail: jay.berry{at}childrens.harvard.edu

Purpose Hospital discharge for children with medical complexity (CMC) can be challenging for families. Home visits could potentially benefit CMC and their families after leaving the hospital. We assessed the utility of post-discharge home visits to identify and address health problems for recently hospitalized CMC. Design and Methods A prospective study of 36 CMC admitted to a children's hospital from 4/15/2015 to 4/14/2016 identified with a possible high risk of hospital readmission and offered a post-discharge home visit within 72 h of discharge. The visit was staffed by a hospital nurse familiar with the child's admission. The home visit goals were to reinforce education of the discharge plan, assess the child's home environment, and identify and address any problems or issues that emerged post-discharge. Results The children's median age was 6 years [interquartile range (IQR) 2–18]. The median distance from hospital to their home was 38 miles (IQR 8–78). All (n = 36) children had multiple chronic conditions; 89% (n = 32) were assisted with medical technology. The nurse identified and helped with a post-discharge problem during every (n = 36) visit. Of the 147 problems identified, 26.5% (n = 39) pertained to social/family issues (e.g., financial instability), 23.8% (n = 35) medications (e.g., wrong dose), 20.4% (n = 30) durable medical equipment (e.g., insufficient supply or faulty function), 20.4% (n = 30) child's home environment (e.g., unsafe sleeping arrangement), and 8.8% (n = 13) child's health (e.g., unresolved health problem). Conclusions Home visits helped identify and address post-discharge issues that occurred for discharged CMC. Practical Implications Hospitals should consider home visits when optimizing discharge care for CMC.

Aim To assess a total population of school‐age children with cerebral palsy (CP) for autism and attention‐deficit/hyperactivity disorder (ADHD) with a view to determining their prevalence and to relate findings to motor function, intellectual disability, and other associated impairments. Method Of 264 children, born between 1999 and 2006, from the CP register of western Sweden, 200 children (109 males, 91 females, median age at assessment 14y, range 7–18y) completed comprehensive screening and further neuropsychiatric clinical assessments. Results Ninety children (45%) were diagnosed with autism, ADHD, or both, 59 (30%) were diagnosed with autism, and 60 (30%) were diagnosed with ADHD. Intellectual disability was present in 51%. Two‐thirds had autism, ADHD, and/or intellectual disability. In regression models, autism was mainly predicted by intellectual disability (odds ratio [OR]=4.1) and ADHD (OR=3.2), and ADHD was predicted by intellectual disability (OR=2.3) and autism (OR=3.0). Autism was more common in children born preterm (OR=2.0). Gross motor function was not associated with autism. ADHD prevalence was low in children with severe motor impairment, possibly due to diagnostic limitations. Interpretation Autism and ADHD were common in this population of children with CP and were mainlyindependent of motor severity and CP type. The strongest predictor of autism/ADHD was intellectual disability. Assessment for autism and ADHD is warranted as part of the evaluation in CP. What this paper adds Forty‐five percent of the children with cerebral palsy also had autism, attention‐deficit/hyperactivity disorder (ADHD), or both.Autism and ADHD were predicted mainly by intellectual disability.Established diagnostic instruments worked well for all but the most disabled group of children., What this paper adds Forty‐five percent of the children with cerebral palsy also had autism, attention‐deficit/hyperactivity disorder (ADHD), or both.Autism and ADHD were predicted mainly by intellectual disability.Established diagnostic instruments worked well for all but the most disabled group of children. This article is commented on by Gecz and Berry on pages 247–248 of this issue.

Purpose African American (AA) patients are at risk for increased rates of rejection after heart transplantation (HT).We compared cell-free DNA (cf-DNA) levels after HT by recipient race. Methods This was a retrospective analysis of 96 HT recipients from the Genomic Research Alliance for Transplantation (GRAFT) Registry, of which 63 patients had cf-DNA values. Cf-DNA values were compared by race withan exponential decay model and Kaplan-Meier (KM) analysis was performed to compare time-to-first rejection. Results Compared to non-AA patients, AA recipients had a similar prevalence of diabetes and hypertension,proportion of males, and donor characteristics. AA recipients had higher cf-DNA values compared to non-AA recipients for the first five days following transplant (8.3% vs. 3.2% p=0.001 Table 1/figure 1). The stable state cf-DNA values decayed rapidly for AA patients and equalized to non-AA patients over the first 7 days (0.46% vs 0.45%, p=0.8 Table 1). Cellular rejection did not differ by race (HR [CI]=1.4 [0.62,3.2], p=0.4). However AA were at higher risk of antibody mediated rejection (HR [CI]=3.8 [1.3,10.9], p=0.01). Conclusion African American patients had increased cf-DNA values in the first week following heart transplant. This may be a marker of early injury contributing to increased rates of allograft rejection in AA patients. Further analysisadjusting for confounding variables and determining predictors of clinical outcomes will be included at the time of presentation once follow-up of the GRAFT registry is complete.

Background In patients with acute respiratory distress syndrome (ARDS), low tidal volume ventilation has been associated with reduced mortality. Driving pressure (tidal volume normalized to respiratory system compliance) may be an even stronger predictor of ARDS survival than tidal volume. We sought to study whether these associations hold true in acute respiratory failure patients without ARDS. Methods This is a retrospectively cohort analysis of mechanically ventilated adult patients admitted to ICUs from 12 hospitals over 2 years. We used natural language processing of chest radiograph reports and data from the electronic medical record to identify patients who had ARDS. We used multivariable logistic regression and generalized linear models to estimate associations between tidal volume, driving pressure, and respiratory system compliance with adjusted 30-day mortality using covariates of Acute Physiology Score (APS), Charlson Comorbidity Index (CCI), age, and PaO2/FiO2 ratio. Results We studied 2641 patients; 48% had ARDS (n = 1273). Patients with ARDS had higher mean APS (25 vs. 23, p p = 0.6) scores. For non-ARDS patients, tidal volume was associated with increased adjusted mortality (OR 1.18 per 1 mL/kg PBW increase in tidal volume, CI 1.04 to 1.35, p = 0.010). We observed no association between driving pressure or respiratory compliance and mortality in patients without ARDS. In ARDS patients, both ΔP (OR1.1, CI 1.06–1.14, p p = 0.007) were associated with mortality. Conclusions In a large retrospective analysis of critically ill non-ARDS patients receiving mechanical ventilation, we found that tidal volume was associated with 30-day mortality, while driving pressure was not.

Globally recognised botulinum neurotoxin is known primarily for its aesthetic effects. It seems to attract a negative media slant disproportionate to its wealth of clinically documented attributes in fields as disparate as paediatrics, urology, ophthalmology and, most recently, neurology for its treatment of migraine. This chapter introduces some of its important facts, fundaments of physiology and basic pharmacology.

A growing body of evidence points to a considerable and heterogeneous genetic aetiology of cerebral palsy (CP). To identify recurrently variant CP genes, we designed a custom gene panel of 112 candidate genes. We tested 366 clinically unselected singleton cases with CP, including 271 cases not previously examined using next-generation sequencing technologies. Overall, 5.2% of the naïve cases (14/271) harboured a genetic variant of clinical significance in a known disease gene, with a further 4.8% of individuals (13/271) having a variant in a candidate gene classified as intolerant to variation. In the aggregate cohort of individuals from this study and our previous genomic investigations, six recurrently hit genes contributed at least 4% of disease burden to CP: COL4A1, TUBA1A, AGAP1, L1CAM, MAOB and KIF1A. Significance of Rare VAriants (SORVA) burden analysis identified four genes with a genome-wide significant burden of variants, AGAP1, ERLIN1, ZDHHC9 and PROC, of which we functionally assessed AGAP1 using a zebrafish model. Our investigations reinforce that CP is a heterogeneous neurodevelopmental disorder with known as well as novel genetic determinants.

BACKGROUND The American Society of Anesthesiologists physical status (ASA-PS) classification system is used worldwide to classify patients based on comorbid conditions before general anesthesia. Despite its popularity, the ASA-PS classification system has been shown to have poor interrater reliability due to its subjective definitions, especially when applied to the pediatric population. We hypothesized that the clarification of ASA-PS definitions to better reflect pediatric conditions would improve the accuracy of ASA-PS applied to this population. METHODS A stratified, randomized sample of 120 pediatric surgical cases was collected from a tertiary-care pediatric hospital. A team of senior anesthesiologists reclassified ASA-PS within this patient sample using the suggested pediatric-specific ASA-PS definitions. Interrater reliability was measured using intraclass correlation (ICC) and Fleiss κ statistic. In addition, a qualitative study component using small focus groups of senior anesthesiologists identified areas of ambiguity within the ASA-PS system. RESULTS Among the 90 reclassifications within each ASA-PS group, 42.2% (n = 38) of ASA-PS I were upgraded to ASA-PS II, and 36.7% (n = 33) of ASA-PS II were upgraded to ASA-PS III. In addition, 28.9% (n = 26) of ASA-PS III were upgraded to ASA-PS IV, and 24.4% (n = 22) of ASA-PS IV were downgraded to III. ICC across the reclassified ASA-PS categories was 0.77 (95% confidence interval [CI], 0.71-0.83; P < .001) demonstrating strong overall agreement. Fleiss κ statistic was lowest in ASA-PS II and III patients (κ = 0.41 and κ = 0.30, respectively) indicating lower agreement beyond chance within these subgroups. Focus groups revealed common themes such as active sequelae of disease, active versus well-controlled presence of comorbidities, and the possible inclusion of functional limitations as important considerations. CONCLUSIONS The ASA-PS classification system has several benefits including ease-of-use, simplicity, and flexibility. However, revising the ASA-PS system to provide better guidance for pediatric patients could be valuable. While this study demonstrates good interrater reliability with the included ASA-PS pediatric definitions, further work is needed to clarify accurate assignment of ASA-PS within the midrange of the scale (ASA-PS II and III) and explore its implementation in other institutions.

Cerebral palsy (CP) is the most frequent movement disorder of childhood affecting 1 in 500 live births in developed countries. We previously identified likely pathogenic de novo or inherited single nucleotide variants (SNV) in 14% (14/98) of trios by exome sequencing and a further 5% (9/182) from evidence of outlier gene expression using RNA sequencing. Here, we detected copy number variants (CNV) from exomes of 186 unrelated individuals with CP (including our original 98 trios) using the CoNIFER algorithm. CNV were validated with Illumina 850 K SNP arrays and compared with RNA-Seq outlier gene expression analysis from lymphoblastoid cell lines (LCL). Gene expression was highly correlated with gene dosage effect. We resolved an additional 3.7% (7/186) of this cohort with pathogenic or likely pathogenic CNV while a further 7.7% (14/186) had CNV of uncertain significance. We identified recurrent genomic rearrangements previously associated with CP due to 2p25.3 deletion, 22q11.2 deletions and duplications and Xp monosomy. We also discovered a deletion of a single gene, PDCD6IP, and performed additional zebrafish model studies to support its single allele loss in CP aetiology. Combined SNV and CNV analysis revealed pathogenic and likely pathogenic variants in 22.7% of unselected individuals with CP., Neurodevelopment: Copy number variants underlie cases of cerebral palsy At least 23% of cerebral palsy has a genetic basis, due to either point mutations or large chromosomal abnormalities. Using sequence data from 186 unrelated patients, a team led by Mark Corbett from the University of Adelaide, Australia, searched the protein-coding portion of the genome for disease-causing duplications or deletions, types of mutations collectively known as copy number variants, or CNVs. The researchers singled out 7 pathogenic CNVs that they corroborated through microarray profiling and gene expression analyses. Using a zebrafish model, the researchers identified a new gene “PDCD6IP” associated with cerebral palsy and epilepsy. They also flagged another 14 CNVs that were likely pathogenic but could not be confirmed. The work highlights the need for comprehensive genetic testing to be considered early in the diagnosis of cerebral palsy.

Background Caregivers are essential for assisting people with disabilities to fully participate in their communities. Past research has primarily focused on family caregivers in the U.S. providing care to older adults rather than children and adults with disabilities. Objective This paper examines the demographic and health characteristics of caregivers of children and adults with disabilities across the lifespan using data from the 2017 Health Information National Trends Survey (HINTS). Methods Chi square, t-test, linear and logistic regression analyses show differences between caregivers and non-caregivers related to gender, age, employment, and specific health outcomes. Results Of 3285 respondents, 18% self-identified as caregivers of children or adults with disabilities (n = 546). Almost one-third of all caregivers reported being diagnosed with depression or an anxiety disorder as compared to one-fifth of non-caregivers. Psychological distress was associated with an increased risk for a diagnosis of depression/anxiety. We also found that distress decreased with age when controlling for other factors. Conclusion This paper increases knowledge of a growing segment of family caregivers providing care for members with disabilities across the lifespan. Research and policy needs are discussed.

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.

Purpose Long-term survival after a lung transplantation (LTx) remains limited by Chronic Lung Allograft Dysfunction (CLAD), which includes two main phenotypes: bronchiolitis obliterans syndrome (BOS), characterized by airway fibrosis and obliteration, and restrictive allograft syndrome (RAS), presenting with parenchymal and sub-pleural fibrosis (2019 ISHLT consensus). There can be overlap between these phenotypes. We aimed to detail and quantify pathological features of human CLAD sub-types. Methods Peripheral (from outer 1/3 of the lung tissue) and central (from middle 1/3) paraffin-embedded explanted lung samples were obtained from 20 consecutive patients undergoing a second LTx for CLAD (phenotyped clinically prior to retransplant), from 3 lobes: left lower lobe (LLL), left upper lobe (LUL) and right upper lobe (RUL). Thirteen lung samples, collected from lobectomies or pre-transplant donor lungs, were used as “normal” controls. Sections were stained with Hematoxylin & Eosin and Elastic Trichrome. Blinded semi-quantitative grading was performed: the percentage of evaluable lung tissue area affected by parenchymal fibrosis was estimated; peri-airway fibrosis and bronchiolitis obliterans (BO) were graded 0-4 for each airway. Pleural fibrosis, epithelial flattening and hyperplasia were graded on a scale 0-4 (fig 1A-C). Results CLAD lung samples had higher scores for all parameters compared to controls. There was a notable overlap in pathological scores between BOS (n=11) and RAS (RAS n=8, Mixed n=1), with a wide range of scores in both conditions. Parenchymal fibrosis score was significantly higher in RAS compared to BOS (p=0.0007), but other scores were not significantly different (figure 1D). BO was significantly heterogeneous between the lobes (p=0.008) (figure 1E). Conclusion Our results confirm that BO and parenchymal fibrosis can coexist to different degrees of severity in both patients with RAS and BOS. This scoring strategy will be useful for pathologic correlations in future studies.

Early detection of melanoma has several advantages over treatment of late-stage disease. Cure rates are higher, disfigurement is reduced, both short-term and long-term side effects from unnecessary systemic therapies are avoided, and most importantly, a large number of lives of individuals who would never have responded to these treatments in the first place are saved. Early detection is also likely to reduce the overall cost of care because early-stage treatments are far less expensive than those used in advanced disease. Despite the potential benefits of screening and early detection, relatively few prospective interventional studies have been performed to objectively demonstrate effectiveness or quantify the effects. However, multivariate data do show that a basic awareness of skin health and appearance (not requiring specialized knowledge of melanoma features) is associated with early detection of melanoma. The purpose of the War on Melanoma research study is to prospectively test whether a statewide early-detection campaign can improve melanoma outcomes. We will compare three objective metrics before and after the intervention (the education campaign): (1) melanoma knowledge in the general public by survey of a representative population sample; (2) state cancer registry data on stage, mortality, etc.; and (3) cost information from an all-claims, all-payers database. We hypothesize that there will be an increase in melanoma-specific knowledge in the general public, an improved prognosis at the time of diagnosis, and a decrease in melanoma mortality in Oregon compared to two control states (Utah and Washington). We will also quantify the difference in cost of care for melanoma before and after the campaign and will determine if these costs are associated with knowledge levels and/or prognostic/mortality data. These results will provide a model for future early-detection campaigns in other states or for other cancers, by providing evidence for the impact of public health education. Citation Format: Sancy A. Leachman, Jodi Lapidus, Kemal Sonmez, Michael Heath, Brian Detweiler-Bedell, Jerusha Detweiler-Bedell, Elizabeth G. Berry, Elizabeth Stoos. The War on Melanoma: Oregon’s early detection experiment [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA11.

IMPORTANCE: Posthospitalization follow-up visits are prescribed frequently for children with bronchiolitis. The rationale for this practice is unclear, but prior work has indicated that families value these visits for the reassurance provided. The overall risks and benefits of scheduled visits have not been evaluated. OBJECTIVE: To assess whether an as-needed posthospitalization follow-up visit is noninferior to a scheduled posthospitalization follow-up visit with respect to reducing anxiety among parents of children hospitalized for bronchiolitis. DESIGN, SETTING, AND PARTICIPANTS: This open-label, noninferiority randomized clinical trial, performed between January 1, 2018, and April 31, 2019, assessed children younger than 24 months of age hospitalized for bronchiolitis at 2 children’s hospitals (Primary Children’s Hospital, Salt Lake City, Utah, and Lucile Packard Children’s Hospital, Palo Alto, California) and 2 community hospitals (Intermountain Riverton Hospital, Riverton, Utah, and Packard El Camino Hospital, Mountain View, California). Data analysis was performed in an intention-to-treat manner. INTERVENTIONS: Randomization (1:1) to a scheduled (n = 151) vs an as-needed (n = 153) posthospitalization follow-up visit. MAIN OUTCOME AND MEASURES: The primary outcome was parental anxiety 7 days after hospital discharge, measured using the anxiety portion of the Hospital Anxiety and Depression Scale, which ranged from 0 to 28 points, with higher scores indicating greater anxiety. Fourteen prespecified secondary outcomes were assessed. RESULTS: Among 304 children randomized (median age, 8 months; interquartile range, 3-14 months; 179 [59%] male), the primary outcome was available for 269 patients (88%). A total of 106 children (81%) in the scheduled follow-up group attended a scheduled posthospitalization visit compared with 26 children (19%) in the as-needed group (absolute difference, 62%; 95% CI, 53%-71%). The mean (SD) 7-day parental anxiety score was 3.9 (3.5) among the as-needed posthospitalization follow-up group and 4.2 (3.5) among the scheduled group (absolute difference, −0.3 points; 95% CI, −1.0 to 0.4 points), with the upper bound of the 95% CI within the prespecified noninferiority margin of 1.1 points. Aside from a decreased mean number of clinic visits (absolute difference, −0.6 visits per patient; 95% CI, −0.4 to −0.8 visits per patient) among the as-needed group, there were no significant between-group differences in secondary outcomes, including readmissions (any hospital readmission before symptom resolution: absolute difference, −1.6%; 95% CI, −5.7% to 2.5%) and symptom duration (time from discharge to cough resolution: absolute difference, −0.6 days; 95% CI, −2.4 to 1.2 days; time from discharge to child reported “back to normal”: absolute difference, −0.8 days; 95% CI, −2.7 to 1.0 days; and time from discharge to symptom resolution: absolute difference, −0.6 days; 95% CI, −2.5 to 1.3 days). CONCLUSIONS AND RELEVANCE: Among parents of children hospitalized for bronchiolitis, an as-needed posthospitalization follow-up visit is noninferior to a scheduled posthospitalization follow-up visit with respect to reducing parental anxiety. These findings support as-needed follow-up as an effective posthospitalization follow-up strategy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03354325

Little evidence exists to guide the management of moderately dysplastic nevi excisionally biopsied without residual clinical pigmentation but with positive histologic margins (hereafter referred to as moderately dysplastic nevi with positive histologic margins).To determine outcomes and risk for the development of subsequent cutaneous melanoma (CM) from moderately dysplastic nevi with positive histologic margins observed for 3 years or more.A multicenter (9 US academic dermatology sites) retrospective cohort study was conducted of patients 18 years or older with moderately dysplastic nevi with positive histologic margins and 3 years or more of follow-up data collected consecutively from January 1, 1990, to August 31, 2014. Records were reviewed for patient demographics, biopsy type, pathologic findings, and development of subsequent CM at the biopsy site or elsewhere on the body. The χ2 test, the Fisher exact test, and analysis of variance were used to assess univariate association for risk of subsequent CMs, in addition to multivariable logistic regression models. To confirm histologic grading, each site submitted 5 random representative slide cases for central dermatopathologic review. Statistical analysis was performed from October 1, 2017, to June 22, 2018.Development of CM at a biopsy site or elsewhere on the body where there were moderately dysplastic nevi with positive histologic margins.A total of 467 moderately dysplastic nevi with positive histologic margins from 438 patients (193 women and 245 men; mean [SD] age, 46.7 [16.1] years) were evaluated. No cases developed into CM at biopsy sites, with a mean (SD) follow-up time of 6.9 (3.4) years. However, 100 patients (22.8%) developed a CM at a separate site. Results of multivariate analyses revealed that history of CM was significantly associated with the risk of development of subsequent CM at a separate site (odds ratio, 11.74; 95% CI, 5.71-24.15; P .001), as were prior biopsied dysplastic nevi (odds ratio, 2.55; 95% CI, 1.23-5.28; P = .01). The results of a central dermatopathologic review revealed agreement in 35 of 40 cases (87.5%). Three of 40 cases (7.5%) were upgraded in degree of atypia; of these, 1 was interpreted as melanoma in situ. That patient remains without recurrence or evidence of CM after 5 years of follow-up.This study suggests that close observation with routine skin surveillance is a reasonable management approach for moderately dysplastic nevi with positive histologic margins. However, having 2 or more biopsied dysplastic nevi (with 1 that is a moderately dysplastic nevus) appears to be associated with increased risk for subsequent CM at a separate site.

OBJECTIVE Mental health conditions (MHCs) are prevalent among hospitalized children and could influence the success of hospital discharge. We assessed the relationship between MHCs and 30-day readmissions. METHODS This retrospective, cross-sectional study of the 2013 Nationwide Readmissions Database included 512,997 hospitalizations of patients ages 3 to 21 years for the 10 medical and 10 procedure conditions with the highest number of 30-day readmissions. MHCs were identified by using the International Classification of Diseases, 9th Revision-Clinical Modification codes. We derived logistic regression models to measure the associations between MHC and 30-day, all-cause, unplanned readmissions, adjusting for demographic, clinical, and hospital characteristics. RESULTS An MHC was present in 17.5% of medical and 13.1% of procedure index hospitalizations. Readmission rates were 17.0% and 6.2% for medical and procedure hospitalizations, respectively. In the multivariable analysis, compared with hospitalizations with no MHC, hospitalizations with MHCs had higher odds of readmission for medical admissions (adjusted odds ratio [AOR], 1.23; 95% confidence interval [CI], 1.19-1.26] and procedure admissions (AOR, 1.24; 95% CI, 1.15-1.33). Three types of MHCs were associated with higher odds of readmission for both medical and procedure hospitalizations: depression (medical AOR, 1.57; 95% CI, 1.49-1.66; procedure AOR, 1.39; 95% CI, 1.17-1.65), substance abuse (medical AOR, 1.24; 95% CI, 1.18-1.30; procedure AOR, 1.26; 95% CI, 1.11-1.43), and multiple MHCs (medical AOR, 1.43; 95% CI, 1.37-1.50; procedure AOR, 1.26; 95% CI, 1.11-1.44). CONCLUSIONS MHCs are associated with a higher likelihood of hospital readmission in children admitted for medical conditions and procedures. Understanding the influence of MHCs on readmissions could guide strategic planning to reduce unplanned readmissions for children with cooccurring physical and mental health conditions.

Objectives Published cost estimates for cystic fibrosis (CF) are based on older data and do not reflect increased use of specialty drugs in recent years. We assessed recent trends in healthcare expenditures for CF patients in the United States (US) with employer-sponsored health insurance. Methods The study is a retrospective analysis of claims data for privately insured individuals aged 0-64 years who were continuously enrolled in non-capitated plans for at least 1 calendar year during 2010-2016. Mean annual expenditures during a calendar year were calculated for individuals who met a claims-based CF case definition. Average annual growth rates were calculated through linear regression of the natural logarithm of annual expenditures. Results The annual CF prevalence was 1.1-1.4 per 10 000 adults and 2.9-3.0 per 10 000 children. Average spending adjusted for inflation nearly doubled from roughly $67 000 per patient in 2010 and 2011 to approximately $131 000 per patient in 2016. Inflation-adjusted spending on outpatient and inpatient care increased by 0.5% and 2.5% per year, respectively, whereas pharmaceutical spending increased by 20.2% per year. Virtually all of the growth in pharmaceutical spending was accounted for by spending on specialty drugs; inflation-adjusted spending on other medications increased by 1.3% per year. The annual growth rate in pharmaceutical spending rose by 33.1% during 2014-2016, the years during which lumacaftor/ivacaftor was introduced. Conclusions Per-patient expenditures for privately-insured patients with CF almost doubled during 2010-2016; specialty drugs were largely responsible for this increase, with a major contribution from new, genotype-targeted CFTR modulator medications.

Current therapeutic options for cryptococcal meningitis are limited by toxicity, global supply, and emergence of resistance. There is an urgent need to develop additional antifungal agents that are fungicidal within the central nervous system and preferably orally bioavailable. The benzimidazoles have broad-spectrum antiparasitic activity but also have in vitro antifungal activity that includes Cryptococcus neoformans . Flubendazole (a benzimidazole) has been reformulated by Janssen Pharmaceutica as an amorphous solid drug nanodispersion to develop an orally bioavailable medicine for the treatment of neglected tropical diseases such as onchocerciasis. We investigated the in vitro activity, the structure-activity-relationships, and both in vitro and in vivo pharmacodynamics of flubendazole for cryptococcal meningitis. Flubendazole has potent in vitro activity against Cryptococcus neoformans , with a modal MIC of 0.125 mg/liter using European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology. Computer models provided an insight into the residues responsible for the binding of flubendazole to cryptococcal β-tubulin. Rapid fungicidal activity was evident in a hollow-fiber infection model of cryptococcal meningitis. The solid drug nanodispersion was orally bioavailable in mice with higher drug exposure in the cerebrum. The maximal dose of flubendazole (12 mg/kg of body weight/day) orally resulted in an ∼2 log 10 CFU/g reduction in fungal burden compared with that in vehicle-treated controls. Flubendazole was orally bioavailable in rabbits, but there were no quantifiable drug concentrations in the cerebrospinal fluid (CSF) or cerebrum and no antifungal activity was demonstrated in either CSF or cerebrum. These studies provide evidence for the further study and development of the benzimidazole scaffold for the treatment of cryptococcal meningitis.

* Abbreviations: ED — : emergency department HSV — : herpes simplex virus LP — : lumbar puncture PCR — : polymerase chain reaction In this issue of Pediatrics , Cruz et al1 address the following clinical question: what is the probability that an infant

Objective To evaluate and compare readmission causes and timing within the first 30 days after hospitalization for 3 acute and 3 chronic common pediatric conditions. Study design Data from the 2013 to 2014 Nationwide Readmissions Database were used to examine the daily percentage of readmissions occurring on days 1-30 and the leading causes of readmission after hospitalization for 3 acute (appendicitis, bronchiolitis/croup, and gastroenteritis) and 3 chronic (asthma, epilepsy, and sickle cell) conditions for patients aged 1-17 years (n = 2 753 488). Data were analyzed using Cox proportional hazards regression. Results The 30-day readmission rates ranged from 2.6% (SE, 0.1) after hospitalizations for appendectomy to 19.1% (SE, 0.5) after hospitalizations for sickle cell anemia. More than 50% of 30-day readmissions after acute conditions occurred within 15 days after discharge, whereas readmissions after chronic conditions occurred more uniformly throughout the 30 days after discharge. Higher numbers of patient comorbidities were associated with increased risk of readmission at days 1-7, 8-15, and 16-30 after discharge for all conditions examined. Most 30-day readmissions after chronic conditions were for the same diagnosis or closely related conditions as the index admission (67% for asthma, 65% for seizure disorder, and 82% for sickle cell anemia) in contrast with 50% or fewer readmissions after acute conditions (46% for appendectomy, 47% for bronchiolitis/croup, and 19% for gastroenteritis). Conclusions The timing and causes of pediatric readmissions vary greatly across pediatric conditions. To be effective, strategies for reducing readmissions need to account for the index diagnosis to better target the highest risk period and causes for readmission.

Background/Objectives: Racial/ethnic disparities exist in healthcare, including readmission rates, but there is limited data describing racial/ethnic disparities across pediatric inpatient conditions. Our objective was to describe readmission patterns, in terms of timing and extent, in pediatrics for different conditions by racial/ethnic groups over a 1-year period. Methods: 96,094 admissions for asthma (n= 36,910), seizure (n=35,361), diabetes …

BACKGROUND: Hospital quality-of-care measures are publicly reported to inform consumer choice and stimulate quality improvement. The number of hospitals and states with enough pediatric hospital discharges to detect worse-than-average inpatient care remains unknown. METHODS: This study was a retrospective analysis of hospital discharges for children aged 0 to 17 years from 3974 hospitals in 44 states in the 2009 Kids’ Inpatient Database. For 11 measures of all-condition or condition-specific quality, we assessed the number of hospitals and states that met a “power standard” of 80% power for a 5% level significance test to detect when care is 20% worse than average over a 3-year period. For this assessment, we approximated volume as 3 times actual 2009 admission volumes. RESULTS: For all-condition quality, 1380 hospitals (87% of all pediatric discharges) and all states met the power standard for the family experience-of-care measure; 1958 hospitals (95% of discharges) and all states met the standard for adverse drug events. For condition-specific quality measures of asthma, birth, and mental health, 203 to 482 hospitals (52%–90% of condition-specific discharges) met the power standard and 40 to 44 states met the standard. One hospital and 16 states met the standard for sickle cell disease. No hospital and ≤27 states met the standard for the remaining measures studied (appendectomy, cerebrospinal fluid shunt surgery, gastroenteritis, heart surgery, and seizure). CONCLUSIONS: Most children are admitted to hospitals in which all-condition measures of quality have adequate power to show modest differences in performance from average, but most condition-specific measures do not. Policies regarding incentives for pediatric inpatient quality should take these findings into account.