Development and Temporal Validation of a Machine Learning Model to Predict Clinical Deterioration.

OBJECTIVES: Early warning scores detecting clinical deterioration in pediatric inpatients have wide-ranging performance and use a limited number of clinical features. This study developed a machine learning model leveraging multiple static and dynamic clinical features from the electronic health record to predict the composite outcome of unplanned transfer to the ICU within 24 hours and inpatient mortality within 48 hours in hospitalized children. METHODS: Using a retrospective development cohort of 17 630 encounters across 10 388 patients, 2 machine learning models (light gradient boosting machine [LGBM] and random forest) were trained on 542 features and compared with our institutional Pediatric Early Warning Score (I-PEWS). RESULTS: The LGBM model significantly outperformed I-PEWS based on receiver operating characteristic curve (AUROC) for the composite outcome of ICU transfer or mortality for both internal validation and temporal validation cohorts (AUROC 0.785 95% confidence interval [0.780-0.791] vs 0.708 [0.701-0.715] for temporal validation) as well as lead-time before deterioration events (median 11 hours vs 3 hours; P = .004). However, LGBM performance as evaluated by precision recall curve was lesser in the temporal validation cohort with associated decreased positive predictive value (6% vs 29%) and increased number needed to evaluate (17 vs 3) compared with I-PEWS. CONCLUSIONS: Our electronic health record based machine learning model demonstrated improved AUROC and lead-time in predicting clinical deterioration in pediatric inpatients 24 to 48 hours in advance compared with I-PEWS. Further work is needed to optimize model positive predictive value to allow for integration into clinical practice.

A schoolwide approach to promoting student bystander behavior in response to the use of the word "retard".

BACKGROUND AND AIMS: The use of the word retard ("the r-word") among adolescents sheds light on societal views about individuals with intellectual disability and the need to address the colloquial use of this word and its underlying stigma. Schools provide an important platform for intervening to promote social change among youth. The present study examined the impact of a schoolwide social inclusion program on students' bystander behavior against the use of the r-word. METHODS AND PROCEDURES: 1233 students from 5 high schools were surveyed about the prevalence of the r-word in their school, the contexts in which it is used, and their bystander behavior in response to the word. Approximately 40% of surveyed students participated in an R-word Campaign, Unified Sports team, and/or Unified Club as part of the Special Olympics Unified Champion Schools (UCS) program. OUTCOMES AND RESULTS: Students' prosocialness, the context in which the r-word was used, and participation in UCS activities significantly predicted active bystander behavior in response to the r-word. CONCLUSIONS AND IMPLICATIONS: By empowering students to be active bystanders against the use of the r-word in school, school-based interventions provide a promising avenue for addressing both the use of the r-word and its underlying stigma.

ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non-Small Cell Lung Cancer (NSCLC).

INTRODUCTION: Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure. METHODS: ASCEND-8 is a multicenter, randomized, open-label, phase 1 study. Part 1 investigated the steady-state pharmacokinetics (PK) and safety of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg fasted in patients with advanced ALK-positive NSCLC who were either treatment naive or pretreated with chemotherapy and/or crizotinib. Part 2 will assess efficacy and safety of ceritinib in treatment-naive patients. RESULTS: As of June 16, 2016, 137 patients were randomized (450 mg fed [n = 44], 600 mg fed [n = 47], and 750 mg fasted [n = 46]); 135 patients received ceritinib. Median follow-up duration was 4.14 months. At steady state, relative to 750 mg fasted, 450 mg with food demonstrated comparable PK as assessed by maximum (peak) concentration of drug in plasma and area under the plasma concentration-time curve from time zero to 24 hours, whereas 600 mg with food demonstrated approximately 25% higher PK. Relative to 750 mg fasted, 450 mg with food was associated with a lower proportion of patients with GI toxicities, mostly grade 1 (diarrhea [43.2%], nausea [29.5%], and vomiting [18.2%]); there were no grade 3 or 4 events, study drug discontinuations, or serious AEs due to GI toxicities. CONCLUSION: Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than ceritinib, 750 mg in fasted patients with ALK-positive NSCLC.

Accommodation Decision Making for Postsecondary Students With Learning Disabilities: Individually Tailored or One Size Fits All?

Clinicians uniformly recommend accommodations for college students with learning disabilities; however, we know very little about which accommodations they select and the validity of their recommendations. We examined the assessment documentation of a large sample of community college students receiving academic accommodations for learning disabilities to determine (a) which accommodations their clinicians recommended and (b) whether clinicians' recommendations were supported by objective data gathered during the assessment process. In addition to test and instructional accommodations, many clinicians recommended that students with learning disabilities should have different educational expectations, standards, and methods of evaluation (i.e., grading) than their nondisabled classmates. Many of their recommendations for accommodations were not supported by objective evidence from students' history, diagnosis, test data, and current functioning. Furthermore, clinicians often recommended accommodations that were not specific to the student's diagnosis or area of disability. Our findings highlight the need for individually selected accommodations matched to students' needs and academic contexts.

Definitions of cardiovascular insufficiency and relation to outcomes in critically ill newborn infants.

BACKGROUND: We previously reported on the overall incidence, management, and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short-term outcomes in term and late preterm newborn infants. OBJECTIVE: This study aims to evaluate how four definitions of CVI relate to short-term outcomes and death. STUDY DESIGN: The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short-term outcomes at discharge and four different definitions of CVI were further analyzed. RESULTS: All the four definitions were associated with greater number of days on MV and days on O2. The definition using a threshold blood pressure (BP) measurement alone was not associated with days of full feeding, days in the NICU or death. The definition based on the treatment of CVI was associated with all the outcomes including death. CONCLUSIONS: The definition using a threshold BP alone was not consistently associated with adverse short-term outcomes. Using only a threshold BP to determine therapy may not improve outcomes.

Incidence, management, and outcomes of cardiovascular insufficiency in critically ill term and late preterm newborn infants.

OBJECTIVE: The objective of this study was to characterize the incidence, management, and short-term outcomes of cardiovascular insufficiency (CVI) in mechanically ventilated newborns, evaluating four separate prespecified definitions. STUDY DESIGN: Multicenter, prospective cohort study of infants ≥34 weeks gestational age (GA) and on mechanical ventilation during the first 72 hours. CVI was prospectively defined as either (1) mean arterial pressure (MAP) < GA; (2) MAP < GA + signs of inadequate perfusion; (3) any therapy for CVI; or (4) inotropic therapy. Short-term outcomes included death, days on ventilation, oxygen, and to full feedings and discharge. RESULTS: Of 647 who met inclusion criteria, 419 (65%) met ≥1 definition of CVI. Of these, 98% received fluid boluses, 36% inotropes, and 17% corticosteroids. Of treated infants, 46% did not have CVI as defined by a MAP < GA ± signs of inadequate perfusion. Inotropic therapy was associated with increased mortality (11.1 vs. 1.3%; p < 0.05). CONCLUSION: More than half of the infants met at least one definition of CVI. However, almost half of the treated infants met none of the definitions. Inotropic therapy was associated with increased mortality. These findings can help guide the design of future studies of CVI in newborns.

The Global Invertebrate Genomics Alliance (GIGA): developing community resources to study diverse invertebrate genomes.

Over 95% of all metazoan (animal) species comprise the "invertebrates," but very few genomes from these organisms have been sequenced. We have, therefore, formed a "Global Invertebrate Genomics Alliance" (GIGA). Our intent is to build a collaborative network of diverse scientists to tackle major challenges (e.g., species selection, sample collection and storage, sequence assembly, annotation, analytical tools) associated with genome/transcriptome sequencing across a large taxonomic spectrum. We aim to promote standards that will facilitate comparative approaches to invertebrate genomics and collaborations across the international scientific community. Candidate study taxa include species from Porifera, Ctenophora, Cnidaria, Placozoa, Mollusca, Arthropoda, Echinodermata, Annelida, Bryozoa, and Platyhelminthes, among others. GIGA will target 7000 noninsect/nonnematode species, with an emphasis on marine taxa because of the unrivaled phyletic diversity in the oceans. Priorities for selecting invertebrates for sequencing will include, but are not restricted to, their phylogenetic placement; relevance to organismal, ecological, and conservation research; and their importance to fisheries and human health. We highlight benefits of sequencing both whole genomes (DNA) and transcriptomes and also suggest policies for genomic-level data access and sharing based on transparency and inclusiveness. The GIGA Web site (http://giga.nova.edu) has been launched to facilitate this collaborative venture.

Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor-positive breast cancer in BOLERO-2.

BACKGROUND: Postmenopausal women with hormone receptor-positive (HR(+)) breast cancer in whom disease progresses or there is recurrence while taking a nonsteroidal aromatase inhibitor (NSAI) are usually treated with exemestane (EXE), but no single standard of care exists in this setting. The BOLERO-2 trial demonstrated that adding everolimus (EVE) to EXE improved progression-free survival (PFS) while maintaining quality of life when compared with EXE alone. Because many women with HR(+) advanced breast cancer are elderly, the tolerability profile of EVE plus EXE in this population is of interest. PATIENTS AND METHODS: BOLERO-2, a phase III randomized trial, compared EVE (10 mg/d) and placebo (PBO), both plus EXE (25 mg/d), in 724 postmenopausal women with HR(+) advanced breast cancer recurring/progressing after treatment with NSAIs. Safety and efficacy data in elderly patients are reported at 18-month median follow-up. RESULTS: Baseline disease characteristics and treatment histories among the elderly subsets (≥ 65 years, n = 275; ≥ 70 years, n = 164) were generally comparable with younger patients. The addition of EVE to EXE improved PFS regardless of age (hazard ratio, 0.59 [≥ 65 years] and 0.45 [≥ 70 years]). Adverse events (AEs) of special interest (all grades) that occurred more frequently with EVE than with PBO included stomatitis, infections, rash, pneumonitis, and hyperglycemia. Elderly EVE-treated patients had similar incidences of these AEs as did younger patients but had more on-treatment deaths. CONCLUSION: Adding EVE to EXE offers substantially improved PFS over EXE and was generally well tolerated in elderly patients with HR(+) advanced breast cancer. Careful monitoring and appropriate dose reductions or interruptions for AE management are recommended during treatment with EVE in this patient population.

A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high-density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, that is, 2q11.2-q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, that is, 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family-based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non-coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH.

Stewardship and accountability.

In March 2003 The Chronicle for Philanthropy reported a sea change in fund development. After 25 years of consistent research on donor motivation, a study came out with new information. Donors ranked on a scale of 1-10 what mattered most to them when considering giving. Until now, most donors reported that a belief in the mission of the organization and the desire to have an impact on the people served was their number one motivation. Certainly gratitude for life-saving or life-changing service made that belief in mission and impact that much more powerful as a motivation. Improving their community was consistently the number two reason for giving. But, according to the 2003 survey, something changed. Six of the 10 reasons involve stewardship and accountability.

Establishing a practice climate in academic settings.

This article describes an innovative educational approach that was introduced and developed in one occupational therapy program, favorably assessed by students, and promoted within the occupational therapy literature. A review of educational literature from other disciplines suggests that the approach characterized as creating a practice climate, may be useful to most allied health educators. We discuss (1) the meaning of the term practice climate, (2) the rationale for creating such a climate in larger classroom sessions, (3) nine process strategies that can establish this climate, and (4) an assessment of the approach by two groups of undergraduate students. Although introduced in a senior-level undergraduate course, the approach has merit for implementation in less advanced courses and in graduate education.