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CYP2D6 substrates are among the most highly prescribed medications in teenagers and also commonly associated with serious adverse events. To investigate the relative contributions of genetic variation, growth, and development on CYP2D6 activity during puberty, healthy children and adolescents 7-15 years of age at enrollment participated in a longitudinal phenotyping study involving administration of 0.3 mg/kg dextromethorphan (DM) and 4-h urine collection every 6 months for 3 years (7 total visits). At each visit, height, weight, and sexual maturity were recorded, and CYP2D6 activity was determined as the urinary molar ratio of DM to its metabolite dextrorphan (DX). A total of 188 participants completed at least one visit, and 102 completed all seven study visits. Following univariate analysis, only CYP2D6 activity score (p 0.001), urinary pH (p 0.001), weight (p = 0.018), and attention-deficit/hyperactivity disorder (ADHD) diagnosis (p 0.001) were significantly correlated with log(DM/DX). Results of linear mixed model analysis with random intercept, random slope covariance structure revealed that CYP2D6 activity score had the strongest effect on log(DM/DX), with model-estimated average log(DM/DX) being 3.8 SDs higher for poor metabolizers than for patients with activity score 3. A moderate effect on log(DM/DX) was observed for sex, and smaller effects were observed for ADHD diagnosis and urinary pH. The log(DM/DX) did not change meaningfully with age or pubertal development. CYP2D6 genotype remains the single, largest determinant of variability in CYP2D6 activity during puberty. Incorporation of genotype-based dosing guidelines should be considered for CYP2D6 substrates given the prevalent use of these agents in this pediatric age group.

Background A better understanding of the extent to which psychosocial and environmental correlates of physical activity are specific to locations would inform intervention optimization. Purpose To investigate cross-sectional associations of location-general and location-specific variables with physical activity and sedentary time in three common locations adolescents spend time. Methods Adolescents (N = 472,Mage = 14.1,SD = 1.5) wore an accelerometer and global positioning systems (GPS) tracker and self-reported on psychosocial (e.g., self-efficacy) and environmental (e.g., equipment) factors relevant to physical activity and sedentary time. We categorized each survey item based on whether it was specific to a location to generate psychosocial and environmental indices that were location-general or specific to either school, non-school, or home location. Physical activity (MVPA) and sedentary time were based on time/location match to home, school, or all “other” locations. Mixed-effects models investigated the relation of each index with location-specific activity. Results The location-general and non-school physical activity psychosocial indices were related to greater MVPA at school and “other” locations. The school physical activity environment index was related to greater MVPA and less sedentary time at school. The home activity environment index was related to greater MVPA at home. The non-school sedentary psychosocial index was related to less sedentary time at home. Interactions among indices revealed adolescents with low support on one index benefited (i.e., exhibited more optimal behavior) from high support on another index (e.g., higher scores on the location-general PA psychosocial index moderated lower scores on the home PA environment index). Concurrent high support on two indices did not provide additional benefit. Conclusions No psychosocial or environment indices, including location-general indices, were related to activity in all locations. Most of the location-specific indices were associated with activity in the matching location(s). These findings provide preliminary evidence that psychosocial and environmental correlates of activity are location specific. Future studies should further develop location-specific measures and evaluate these constructs and whether interventions may be optimized by targeting location-specific psychosocial and environmental variables across multiple locations.

rs5758550 has been associated with enhanced transcription and suggested to be a useful marker of CYP2D6 activity. As there are limited and inconsistent data regarding the utility of this distant "enhancer" single nucleotide polymorphism (SNP), our goal was to further assess the impact of rs5758550 on CYP2D6 activity toward two probe substrates, atomoxetine (ATX) and dextromethorphan (DM), using in vivo urinary metabolite (DM; n = 188) and pharmacokinetic (ATX; n = 70) and in vitro metabolite formation (ATX and DM; n = 166) data. All subjects and tissues were extensively genotyped, the "enhancer" SNP phased with established CYP2D6 haplotypes either computationally or experimentally, and the impact on CYP2D6 activity investigated using several linear models of varying complexity to determine the proportion of variability in CYP2D6 activity captured by each model. For all datasets and models, the "enhancer" SNP had no or only a modest impact on CYP2D6 activity prediction. An increased effect, when present, was more pronounced for ATX than DM suggesting potential substate-dependency. In addition, CYP2D6*2 alleles with the "enhancer" SNP were associated with modestly higher metabolite formation rates in vitro, but not in vivo; no effect was detected for CYP2D6*1 alleles with "enhancer" SNP. In summary, it remains inconclusive whether the small effects detected in this investigation are indeed caused by the "enhancer" SNP or are rather due to its incomplete linkage with other variants within the gene. Taken together, there does not appear to be sufficient evidence to warrant the "enhancer" SNP be included in clinical CYP2D6 pharmacogenetic testing.

Naltrexone, an opioid antagonist primarily metabolized by aldo-keto reductase 1C4 (AKR1C4), treats pediatric conditions involving compulsiveness (e.g., autism spectrum, Prader-Willi, eating disorders, non-suicidal self-injury). Pharmacokinetic variability is apparent in adults, yet no data are available for children. This study aimed to examine the impact of age and genetic variation on naltrexone biotransformation. Human liver cytosol (HLC) samples (n = 158) isolated from children and adult organ donors were incubated with therapeutically relevant concentrations of naltrexone (0.1, 1 µM). Naltrexone biotransformation was determined by ultraperformance mass spectrometry quantification of the primary metabolite, 6-beta-naltrexol (6βN), and 6βN formation rates (pmol/mg protein/min) were calculated. HLCs from organ donors, age range 0–79 y (mean 16.0 ± 18.2 y), 37% (n = 60) female, 20% (n = 33) heterozygous and 1.2% (n = 2) homozygous for co-occurring AKR1C4 variants (S145C/L311V) showed >200-fold range in 6βN formation (0.37–76.5 pmol/mg protein/min). Source of donor samples was found to be a substantial contributor to variability. Model estimates for a trimmed data set of source-adjusted pediatric samples (aged 0–18 y) suggested that AKR1C4 genetic variation, age, and sex explained 36% of the variability in 6βN formation. Although activity increased steadily from birth and peaked in middle childhood (2–5 years), genetic variation (S145C/L311V) demonstrated a greater effect on activity than did age. Naltrexone biotransformation is highly variable in pediatric and adult livers and can be partly accounted for by individual factors feasible to obtain (e.g., genetic variability, age, sex). These data may inform a precision therapeutics approach (e.g., exposure optimization) to further study Naltrexone responsiveness in children and adults. SIGNIFICANCE STATEMENT: Biotransformation of the commonly used opioid antagonist naltrexone is highly variable and may contribute to reduced therapeutic response. Age, sex, and genetic variation in the drug-metabolizing enzyme, AKR1C4, are potential factors contributing to this variability. In pediatric samples, genetic variation (S145C/L311V) demonstrates a greater impact on activity than age. Additionally, the source of donor samples was identified as an important contributor and must be accounted for to confidently elucidate the biological variables most impactful to drug biotransformation.

Microsomal protein per gram of liver (MPPGL) is an important scaling factor for bottom-up physiology-based pharmacokinetic modeling and simulation, but data in pediatrics are limited. Therefore, MPPGL was determined in 160 liver samples from pediatric (n = 129) and adult (n = 31) donors obtained from four sources: the University of Maryland Brain and Tissue Bank (UMBTB), tissue retrieval services at the University of Minnesota and University of Pittsburgh, and Sekisui-Xenotech. Tissues were homogenized and subjected to differential centrifugation to prepare microsomes, and cytochrome c reductase activities in tissue homogenates and microsomes were used to estimate cytochrome P450 reductase (POR) activity as a marker of microsomal recovery; microsomal POR content was also assessed by quantitative proteomics. MPPGL values varied 5- to 10-fold within various age groups/developmental stages, and tissue source was identified as a contributing factor. Using a “trimmed” dataset comprised of samples ranging from 3 to 18 years of age common to the four sources, POR protein abundance and activity in microsomes and POR activity in homogenates was lower in UMBTB samples (autopsy) compared with other sources (perfused/flash-frozen). Regression analyses revealed that the UMBTB samples were driving an apparent age effect as no effect of age on log-transformed MPPGL values was observed when the UMBTB samples were excluded. We conclude that a mean±SD MPPGL value of 30.4±1.7 mg/g is representative between one month postnatal age and early adulthood. Potential source effects should be considered for studies involving tissue samples from multiple sources with different procurement and processing procedures. SIGNIFICANCE STATEMENT: Microsomal protein per gram of liver (MPPGL) is an important scaling factor for bottom up PBPK modeling and simulation, but data in pediatrics are limited. Although MPPGL varies 5- to 10-fold at a given developmental stage, a value of 30.4 ± 1.7 mg/g (mean ± SD) is representative between one month postnatal age and early adulthood. However, when tissue samples are obtained from multiple sources, different procurement and processing procedures may influence the results and should be taken into consideration.

Objective Children with attention-deficit/hyperactivity disorder (ADHD) are at risk for accidental injuries, but little is known about age-related changes in early childhood. We predicted that ADHD would be associated with greater frequency and volume of accidental injuries. We explored associations between ADHD and injury types and examined age-related changes within the preschool period. Methods Retrospective chart review data of 21,520 preschool children with accidental injury visits within a large pediatric hospital network were examined. We compared children with ADHD (n = 524) and without ADHD (n = 20,996) on number of injury visits by age, total number of injury visits, injury volume, and injury type. Results Children with ADHD averaged fewer injury visits at age 3 and 90% more visits at age 6. Children with ADHD had injury visits in more years during the 3–6 age. There were no differences in injury volumes. Among patients with an injury visit at age 3, children with ADHD had 6 times the probability of a subsequent visit at age 6. At age 3, children with ADHD were estimated to have 50% fewer injury visits than children without ADHD, but by age 6, children with ADHD had an estimated 74% more injury visits than children without ADHD. Risk for several injury types for children with ADHD exceeded that for patients without ADHD by at least 50%. Conclusions Early identification and treatment of preschool ADHD following accidental injury may prevent subsequent injuries. Clinical implications and future directions are discussed with emphasis on the maintenance of parental monitoring into the older preschool years.

The goal of this study was to estimate the incidence of falls (total, injurious, and assisted) in U.S. psychiatric care across 6 years (April 2013-March 2019).Data on falls among patients of adult and geriatric psychiatric units of general, acute care, and psychiatric hospital inpatient units from the National Database of Nursing Quality Indicators were used for this 6-year study. Total falls, assisted falls (i.e., falls broken or slowed by staff), and injurious falls were calculated, along with trends in total and injurious fall rates.The sample included 1,159 units in 720 hospitals. Of the 119,246 falls reported, 25,807 (21.6%) resulted in injury. Only 7.0% of the total falls in psychiatric units were assisted by a staff member. Falling unassisted was associated with a higher likelihood of fall-related injury (adjusted odds ratio=1.69, 95% confidence interval=1.59 to 1.80). The total fall rate (8.55 per 1,000 patient-days) and injurious fall rate (1.97 per 1,000 patient-days) were highest for geriatric psychiatric units in general hospitals. Total and injurious fall rates in psychiatric units in general hospitals declined during the study (total fall rate declined by 10% for adult psychiatric units in general hospitals). There was no clear trend in total or injurious fall rates for units in psychiatric hospitals.Falls are a persistent problem in psychiatric care settings. Few fall-prevention programs have been tested in these settings, which have unique risk factors for falls. Additional research is needed to develop fall-prevention interventions in psychiatric care.

Objective Our study examines how consistently fall prevention practices and implementation strategies are used by U.S. hospitals. Methods We conducted a cross-sectional, descriptive study of 60 general adult hospital units.We administered a survey measuring 5 domains of fall prevention practices: visibility and identification, bed modification, patient monitoring, patient safety, and education. We measured 4 domains of implementation strategies including quality management (e.g., providing data and support for quality improvement), planning (e.g., designating leadership), education (e.g., providing consultation and training), and restructuring (e.g., revising staff roles and modifying equipment). Results Of 60 units, 43% were medical units and 57% were medical-surgical units. The hospital units varied in fall prevention practices, with practices such as keeping a patient's bed in a locked position (73% strongly agree) being used more consistently than other practices, such as scheduled toileting (15% strongly agree). Our study observed variation in fall prevention implementation strategies. For example, publicly posting fall rates (60% strongly agree) was more consistently used than having a multidisciplinary huddle after a fall event (12% strongly agree). Conclusions There is substantial variation in the implementation of fall prevention practices and implementation strategies across inpatient units. Our study found that resource-intensive practices (e.g., scheduled toileting) are less consistently used than less resource-intensive practices and that interdisciplinary approaches to fall prevention are limited. Future studies should examine how units tailor fall prevention practices based on patient risk factors and how units decide, based on their available resources, which implementation strategies should be used.

This study investigated the impact of SLCO1B1 genotype on rosuvastatin systemic exposure in hypercholesterolemic children and adolescents. Participants (8-21 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n = 13; 521CC, n = 2) and wild type controls (521TT, n = 13) completed a single oral dose pharmacokinetic study. The variability contributed by SLCO1B1 c.521 sequence variation to rosuvastatin (RVA) systemic exposure among our pediatric cohort was comparable to previous studies in adults. RVA concentration-time curve from 0-24 hours (AUC0-24 ) was 1.4-fold and 2.2-fold higher in participants with c.521TC and c.521CC genotype compared 521TT participants, respectively. Interindividual variability of RVA exposure within SLCO1B1 genotype groups exceeded the ~ 1.5-fold to 2-fold difference in mean RVA exposure observed among SLCO1B1 genotype groups, suggesting that other factors also contribute to interindividual variability in the rosuvastatin dose-exposure relationship. A multivariate model performed confirmed SLCO1B1 c.521T>C genotype as the primary factor contributing to RVA systemic exposure in this pediatric cohort, accounting for ~ 30% of the variability RVA AUC0-24 . However, of the statins investigated to date in the pediatric population, RVA has the lowest magnitude of variability in systemic exposure.

BackgroundTo guide fall prevention efforts, United States organisations, such as the Joint Commission and the Agency for Healthcare Research and Quality, have recommended organisational-level implementation strategies: leadership support, interdisciplinary falls committees, electronic health record tools, and staff, family and patient education. It is unclear whether hospitals adhere to such strategies or how these strategies are operationalised.ObjectiveTo identify and describe the prevalence of specific hospital fall prevention implementation strategies.MethodsIn 2017, we surveyed 80 US hospitals participating in the National Database of Nursing Quality Indicators who volunteered for the study. We conducted descriptive statistics by calculating percentages for categorical variables and the median and IQR for count variables.ResultsA total of 60/80 (75%) of hospitals completed the survey. The majority of hospitals were not-for-profit (98%) and urban (90%); more than half were Magnet (53%), small (53%) and teaching (52%). Hospitals were more likely to use leadership strategies, such as updating fall policies in the past 3 years (98%) but less likely to reward staff (40%). Hospitals commonly used interdisciplinary falls committees (83%) but membership rarely included physicians. Hospitals lacked access to electronic health record tools, such as high-risk medication warnings (27%). Education strategies were commonly used; 100% of hospitals provided fall education at staff orientation, but only 22% educated all employees (not just nursing staff).ConclusionsOur study is the first to our knowledge to examine which expert-recommended implementation strategies are being used and how they are being operationalised in US hospitals. Future studies are needed to document fall prevention implementation strategies in detail and to test which implementation strategies are most effective at reducing falls. Additionally, research is needed to evaluate the quality of implementation (eg, fidelity) of fall prevention interventions.

Purpose To test the validity of the Ecological Video Identification of Physical Activity (EVIP) computer vision algorithms for automated video-based ecological assessment of physical activity in settings such as parks and schoolyards. Methods Twenty-seven hours of video were collected from stationary overhead video cameras across 22 visits in nine sites capturing organized activities. Each person in the setting wore an accelerometer, and each second was classified as moderate-to-vigorous physical activity or sedentary/light activity. Data with 57,987 s were used to train and test computer vision algorithms for estimating the total number of people in the video and number of people active (in moderate-to-vigorous physical activity) each second. In the testing data set (38,658 s), video-based System for Observing Play and Recreation in Communities (SOPARC) observations were conducted every 5 min (130 observations). Concordance correlation coefficients (CCC) and mean absolute errors (MAE) assessed agreement between (1) EVIP and ground truth (people counts+accelerometry) and (2) SOPARC observation and ground truth. Site and scene-level correlates of error were investigated. Results Agreement between EVIP and ground truth was high for number of people in the scene (CCC = 0.88; MAE = 2.70) and moderate for number of people active (CCC = 0.55; MAE = 2.57). The EVIP error was uncorrelated with camera placement, presence of obstructions or shadows, and setting type. For both number in scene and number active, EVIP outperformed SOPARC observations in estimating ground truth values (CCC were larger by 0.11–0.12 and MAE smaller by 41%–48%). Conclusions Computer vision algorithms are promising for automated assessment of setting-based physical activity. Such tools would require less manpower than human observation, produce more and potentially more accurate data, and allow for ongoing monitoring and feedback to inform interventions.

Purpose:Dismissal of families who refuse mandated childhood vaccines from pediatric practices has become more common among US pediatricians over the past 2 decades. While nurses (registered nurses [RNs] and advanced practice registered nurses [APRNs]) often are the first health-care professional to encounter parents’ vaccine hesitancy and serve as a primary source of information, there are no published data on nurses’ perspectives on dismissal as a response to vaccine refusal. This study examined nurses’ perspectives on dismissal of vaccine-refusing families from primary care practices.Design:Cross-sectional survey administered electronically from February to September 2018. Data analysis was conducted from November 2018 to March 2019.Setting:Data were collected electronically from a national sample of nurses.Subjects:A convenience sample of 488 primary care nurses (74% APRNs) was recruited and enrolled in the study through collaboration with 4 professional nursing associations.Measure and Analysis:A cross-sectional survey was conducted from February to September 2018. We explored correlates of nurses’ (n = 488) attitudes toward dismissal by modeling attitude scores as a function of practice and respondent characteristics. We also modeled odds of encountering vaccine refusal and odds of reporting dismissal of a vaccine-refusing family in the last 12 months, each as a function of respondents’ practice characteristics.Results:Eighty-four percent of respondents encountered vaccine refusal in the previous 12 months, and 22% reported that their practice had dismissed a vaccine-refusing family within the previous 12 months. Twenty-eight percent agreed/strongly agreed that they would dismiss or support a decision to dismiss families who refuse all vaccines, and 12% supported dismissal of families for refusal of some but not all vaccines. Thirty-nine percent of respondents disagreed/strongly disagreed with dismissing families who refuse all vaccines, and 50% disagreed/strongly disagreed with dismissal for refusal of some but not all.Conclusion:Almost all nurses working in primary care encounter vaccine refusal, and most consider all Centers for Disease Control and Prevention–recommended childhood vaccines to be important to public health. There is significant polarization of nurses’ attitudes toward the appropriateness of dismissal as a response to vaccine refusal. We recommend the development of professional nursing guidelines for responding to vaccine refusal. However, because there are no data on the community health impact of dismissal policies, we recommend further research on outcomes of dismissal policies to inform such guidelines.

Objective Lumbar mobilization is a standard intervention for the management of low back pain, yet ways to quantify lumbar mobilization are limited. An inertial measurement unit (IMU) is a small and inexpensive device that can be used to quantify lumbar mobilization. The objective of this study was to determine the validity and reliability of an IMU in measuring the amplitude of displacement of a clinician's hand movement during oscillatory lumbar mobilization. Methods An IMU was secured on a clinician's hand during application of mobilization forces at the L4 segment of 16 healthy participants. The validity of the IMU was tested against common laboratory methods of measurements (force plate and motion capture system). The reliability of the IMU measurements was determined between 2 clinicians (inter-rater reliability) and between 2 sessions (intra-rater reliability) by calculating percent error of measurement (%e) and limits of agreement (LOA). The reliability was considered high when |%e| ≤ 10% and |LOA| ≤ 20%; moderate when |%e| 10% to 20% and |LOA| 21% to 40%; and non-acceptable when |%e| > 20% and |LOA| > 40%. Results The IMU measurements had high correlation with the force plate measurements (rs = 0.94) and high agreement with the motion capture system measurements (%e = 4%, LOA = -11% and 20%). Both the inter-rater reliability (%e = 6%, LOA = -25% and 37%) and the intrarater reliability (%e = -1%, LOA = -29% and 27%) of IMU measurements were moderate. Conclusion The IMU seems to be a valid device to measure the amplitude of a clinician's hand movement. The moderate reliability found in this study may not reflect poor reliability of the IMU as much as inconsistency in reapplication of lumbar mobilization.

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Early infant diagnosis (EID) involves age-specific tracking and testing of HIV-exposed infants during the first 18 months of life and rapid initiation of life-saving treatment for those infected. In Kenya, pre-2013 data estimate EID lost to follow-up (LTFU) at 39–65%, yet no study has documented LTFU rates and predictors throughout the EID cascade since Option B+ fundamentally changed services by placing all HIV-positive expectant mothers on lifelong treatment. Using an explanatory mixed-method design, we assessed LTFU rates and predictors among 870 mother–infant dyads enrolled in EID in six urban/peri-urban Kenyan government hospitals. Mothers completed baseline surveys, and dyads were tracked through EID. We selected 12 baseline variables and modeled odds of LTFU at 9 and 18 months using mixed logistic regression. Qualitative interviews were conducted with 61 mothers to assess barriers and facilitators to completing EID. Thematically coded transcripts were used to interpret quantitative predictors of LTFU. By the 18-month test, 145 dyads (22%) were LTFU, with three-quarters of LTFU occurring between 9- and 18-month tests. Odds of LTFU at 18 months decreased by 10% for each additional year of maternal age and by 66% with HIV status disclosure. Qualitative data revealed how disclosure facilitated essential social support for EID completion and how older mothers attributed maturity and life experience to successful engagement in care. Findings suggest LTFU rates in Kenya have declined, but gaps remain in ensuring universal coverage. Efforts to improve retention should focus on increasing support for younger mothers and those who have not disclosed their HIV status.

BACKGROUND Pediatric functional gastrointestinal disorders (FGIDs) are common and well-accepted to be etiologically complex in terms of the contribution of biological, psychological, and social factors to symptom presentations. Nonetheless, despite its documented benefits, interdisciplinary treatment, designed to address all of these factors, for pediatric FGIDs remains rare. The current study hypothesized that the majority of pediatric patients seen in an interdisciplinary abdominal pain clinic (APC) would demonstrate clinical resolution of symptoms during the study period and that specific psychosocial variables would be significantly predictive of GI symptom improvement. AIM To evaluate outcomes with interdisciplinary treatment in pediatric patients with pain-related FGIDs and identify patient characteristics that predicted clinical outcomes. METHODS Participants were 392 children, ages 8-18 [M = 13.8; standard deviation (SD) = 2.7], seen between August 1, 2013 and June 15, 2016 in an interdisciplinary APC housed within the Division of Gastroenterology in a medium-sized Midwestern children’s hospital. To be eligible, patients had to be 8 years of age or older and have had abdominal pain for ≥ 8 wk at the time of initial evaluation. Medical and psychosocial data collected as part of standard of care were retrospectively reviewed and analyzed in the context of the observational study. Logistic regression was used to model odds of reporting vs never reporting improvement, as well as to differentiate rapid from slower improvers. RESULTS Nearly 70% of patients followed during the study period achieved resolution on at least one of the employed outcome indices. Among those who achieved resolution during follow up, 43% to 49% did so by the first follow up (i.e., within roughly 2 mo after initial evaluation and initiation of interdisciplinary treatment). Patient age, sleep, ease of relaxation, and depression all significantly predicted the likelihood of resolution. More specifically, the odds of clinical resolution were 14% to 16% lower per additional year of patient age (P < 0.001 to P = 0.016). The odds of resolution were 28% to 42% lower per 1-standard deviation (SD) increase on a pediatric sleep measure (P = 0.006 to P < 0.040). Additionally, odds of clinical resolution were 58% lower per 1-SD increase on parent-reported measure of depression (P = 0.006), and doubled in cases where parents agreed that their children found it easy to relax (P = 0.045). Furthermore, sleep predicted the rapidity of clinical resolution; that is, the odds of achieving resolution by the first follow up visit were 47% to 60% lower per 1-SD increase on the pediatric sleep measure (P = 0.002). CONCLUSION Outcomes for youth with FGIDs may be significantly improved by paying specific attention to sleep, ensuring adequate skills for relaxation, and screening of and referral for treatment of comorbid depression.

Ewing sarcoma (ES) are aggressive pediatric bone and soft tissue tumors driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. Treatment of ES patients consists of up to 9 months of alternating courses of 2 chemotherapeutic regimens. Furthermore, EWS-ETS-targeted therapies have yet to demonstrate clinical benefit, thereby emphasizing a clinical responsibility to search for new therapeutic approaches. Our previous in silico drug screening identified entinostat as a drug hit that was predicted to reverse the ES disease signatures and EWS-FLI1-mediated gene signatures. Here, we establish preclinical proof of principle by investigating the in vitro and in vivo efficacy of entinostat in preclinical ES models, as well as characterizing the mechanisms of action and in vivo pharmacokinetics of entinostat. ES cells are preferentially sensitive to entinostat in an EWS-FLI1 or EWS-ERG-dependent manner. Entinostat induces apoptosis of ES cells through G0/G1 cell cycle arrest, intracellular reactive oxygen species (ROS) elevation, DNA damage, homologous recombination (HR) repair impairment, and caspase activation. Mechanistically, we demonstrate for the first time that HDAC3 is a transcriptional target of EWS-FLI1 and that entinostat inhibits growth of ES cells through suppressing a previously unexplored EWS-FLI1/HDAC3/HSP90 signaling axis. Importantly, entinostat significantly reduces tumor burden by 97.4% (89.5 vs. 3397.3 mm3 of vehicle, p

BACKGROUND Hepatic sinusoidal obstruction syndrome (SOS) is a potentially fatal complication after hematopoietic stem cell transplantation (HSCT). Current clinical guidelines state that spectral Doppler changes occur late in the disease, and imaging is only useful for confirming SOS diagnosis. OBJECTIVE Our primary objective was to examine abdominal ultrasound variables as predictors of development of SOS in pediatric HSCT patients. MATERIALS AND METHODS A single-center cohort retrospective study was conducted on patients aged 0 to 21 years who underwent HSCT between September 2001 and May 2017 at our institution. Patients were excluded if they did not have abdominal ultrasounds after HSCT. Clinical, demographic, grayscale, and spectral Doppler liver ultrasound findings were evaluated. We modeled the odds of SOS diagnosis within 100 days after HSCT as a function of each of the 15 ultrasound variables. RESULTS A total of 333 patients received an HSCT. One hundred forty subjects had ultrasound data available. Thirty-two patients developed SOS, and 9 of these patients died. Sinusoidal obstruction syndrome odds more than double per 1-SD increase in peak systolic velocity in common hepatic artery or left hepatic artery and more than triple per 1-SD decrease in main portal vein velocity or change in ascites severity. Several ultrasound variables were statistically significant predictors in the Cox models for time to SOS diagnosis. CONCLUSION Several ultrasound variables can be used as predictors for a patient's risk of developing SOS. The strongest predictors are ascites severity, main portal vein velocity, common hepatic artery peak systolic velocity, and left hepatic artery peak systolic velocity.

Ductal carcinoma in situ (DCIS) is the most common type of pre-invasive breast cancer diagnosed in women. Because the majority of DCIS cases are unlikely to progress to invasive breast cancer, many women are over-treated for DCIS. By understanding the molecular basis of early stage breast cancer progression, we may identify better prognostic factors and design treatments tailored specifically to the predicted outcome of DCIS. Chemokines are small soluble molecules with complex roles in inflammation and cancer progression. Previously, we demonstrated that CCL2/CCR2 chemokine signaling in breast cancer cell lines regulated growth and invasion through p42/44MAPK and SMAD3 dependent mechanisms. Here, we sought to determine the clinical and functional relevance of CCL2/CCR2 signaling proteins to DCIS progression. Through immunostaining analysis of DCIS and IDC tissues, we show that expression of CCL2, CCR2, phospho-SMAD3 and phospho-p42/44MAPK correlate with IDC. Using PDX models and an immortalized hDCIS.01 breast epithelial cell line, we show that breast epithelial cells with high CCR2 and high CCL2 levels form invasive breast lesions that express phospho-SMAD3 and phospho-p42/44MAPK. These studies demonstrate that increased CCL2/CCR2 signaling in breast tissues is associated with DCIS progression, and could be a signature to predict the likelihood of DCIS progression to IDC.

Background Safer conception counseling (SCC) to promote the use of safer conception methods (SCM) is not yet part of routine family planning or HIV care. Guidelines for the use of SCM have been published, but to date there are no published controlled evaluations of SCC. Furthermore, it is unknown whether standard methods commonly used in resource constrained settings to integrate new services would be sufficient, or if enhanced training and supervision would result in a more efficacious approach to implementing SCC. Methods In a hybrid, cluster randomized controlled trial, six HIV clinics were randomly assigned to implement the SCC intervention Our Choice using either a high (SCC1) or low intensity (SCC2) approach (differentiated by amount of training and supervision), or existing family planning services (usual care). Three hundred eighty-nine HIV clients considering childbearing with an HIV-negative partner enrolled. The primary outcome was self-reported use of appropriate reproductive method (SCM if trying to conceive; modern contraceptives if not) over 12 months or until pregnancy. Results The combined intervention groups used appropriate reproductive methods more than usual care [20.8% vs. 6.9%; adjusted OR (95% CI)=10.63 (2.79, 40.49)], and SCC1 reported a higher rate than SCC2 [27.1% vs. 14.6%; OR (95% CI)=4.50 (1.44, 14.01)]. Among those trying to conceive, the intervention arms reported greater accurate use of SCM compared to usual care [24.1% vs. 0%; OR (95% CI)=91.84 (4.94, 1709.0)], and SCC1 performed better than SCC2 [34.6% vs. 11.5%; OR (95% CI)=6.43 (1.90, 21.73)]. The arms did not vary on modern contraception use among those not trying to conceive. A cost of $631 per person was estimated to obtain accurate use of SCM in SCC1, compared to $1014 in SCC2. Conclusions More intensive provider training and more frequent supervision leads to greater adoption of complex SCM behaviors and is more cost-effective than the standard low intensity implementation approach. Trial registration Clinicaltrials.gov, NCT03167879; date registered May 23, 2017.

Aims The use of mechanical restraint is a challenging area for psychiatry. Although mechanical restraint remains accepted as standard practice in some regions, there are ethical, legal and medical reasons to minimise or abolish its use. These concerns have intensified following the Convention on the Rights of Persons with Disabilities. Despite national policies to reduce use, the reporting of mechanical restraint has been poor, hampering a reasonable understanding of the epidemiology of restraint. This paper aims to develop a consistent measure of mechanical restraint and compare the measure within and across countries in the Pacific Rim. Methods We used the publicly available data from four Pacific Rim countries (Australia, New Zealand, Japan and the United States) to compare and contrast the reported rates of mechanical restraint. Summary measures were computed so as to enable international comparisons. Variation within each jurisdiction was also analysed. Results International rates of mechanical restraint in 2017 varied from 0.03 (New Zealand) to 98.8 (Japan) restraint events per million population per day, a variation greater than 3000-fold. Restraint in Australia (0.17 events per million) and the United States (0.37 events per million) fell between these two extremes. Variation as measured by restraint events per 1000 bed-days was less extreme but still substantial. Within all four countries there was also significant variation in restraint across districts. Variation across time did not show a steady reduction in restraint in any country during the period for which data were available (starting from 2003 at the earliest). Conclusions Policies to reduce or abolish mechanical restraint do not appear to be effecting change. It is improbable that the variation in restraint within the four examined Pacific Rim countries is accountable for by psychopathology. Greater efforts at reporting, monitoring and carrying out interventions to achieve the stated aim of reducing restraint are urgently needed.

We conducted a novel pilot randomized controlled trial of the Treatment Ambassador Program (TAP), an 8-session, peer-based, behavioral intervention for people with HIV (PWH) in South Africa not on antiretroviral therapy (ART). PWH (43 intervention, 41 controls) completed baseline, three- and six-month assessments. TAP was highly feasible (90% completion), with peer counselors demonstrating good intervention fidelity. Post-intervention interviews showed high acceptability of TAP and counselors, who supported autonomy, assisted with clinical navigation, and provided psychosocial support. Intention-to-treat analyses indicated increased ART initiation by three months in the intervention vs. control arm (12.2% [5/41] vs. 2.3% [1/43], Fisher exact p-value = 0.105; Cohen’s h = 0.41). Among those previously on ART (off for >6 months), 33.3% initiated ART by three months in the intervention vs. 14.3% in the control arm (Cohen’s h = 0.45). Results suggest that TAP was highly acceptable and feasible among PWH not on ART.

Background Investigation of physical activity and dietary behaviors across locations can inform “setting-specific” health behavior interventions and improve understanding of contextual vulnerabilities to poor health. This study examined how physical activity, sedentary time, and dietary behaviors differed across home, school, and other locations in young adolescents. Methods Participants were adolescents aged 12–16 years from the Baltimore-Washington, DC and the Seattle areas from a larger cross-sectional study. Participants (n = 472) wore an accelerometer and Global Positioning Systems (GPS) tracker (Mean days = 5.12, SD = 1.62) to collect location-based physical activity and sedentary data. Participants (n = 789) completed 24-h dietary recalls to assess dietary behaviors and eating locations. Spatial analyses were performed to classify daily physical activity, sedentary time patterns, and dietary behaviors by location, categorized as home, school, and “other” locations. Results Adolescents were least physically active at home (2.5 min/hour of wear time) and school (2.9 min/hour of wear time) compared to “other” locations (5.9 min/hour of wear time). Participants spent a slightly greater proportion of wear time in sedentary time when at school (41 min/hour of wear time) than at home (39 min/hour of wear time), and time in bouts lasting ≥30 min (10 min/hour of wear time) and mean sedentary bout duration (5 min) were highest at school. About 61% of daily energy intake occurred at home, 25% at school, and 14% at “other” locations. Proportionately to energy intake, daily added sugar intake (5 g/100 kcal), fruits and vegetables (0.16 servings/100 kcal), high calorie beverages (0.09 beverages/100 kcal), whole grains (0.04 servings/100 kcal), grams of fiber (0.65 g/100 kcal), and calories of fat (33 kcal/100 kcal) and saturated fat (12 kcal/100 kcal) consumed were nutritionally least favorable at “other” locations. Daily sweet and savory snacks consumed was highest at school (0.14 snacks/100 kcal). Conclusions Adolescents’ health behaviors differed based on the location/environment they were in. Although dietary behaviors were generally more favorable in the home and school locations, physical activity was generally low and sedentary time was higher in these locations. Health behavior interventions that address the multiple locations in which adolescents spend time and use location-specific behavior change strategies should be explored to optimize health behaviors in each location.

Introduction Tracheostomy in children is often performed to alleviate airway obstruction (AO) or to facilitate long-term ventilator support due to respiratory failure of various etiologies, such as heart failure, and postoperative respiratory failure. Although many of these pathologies are common among trisomy 21 patients, tracheostomy rates among this population have not previously been reported. The aim of our study was to determine the incidence of trisomy 21 patients undergoing tracheostomy. Secondary objectives include decannulation rates and mortality associated with tracheostomy. Materials and methods A retrospective cohort study was conducted on pediatric trisomy 21 patients undergoing tracheostomy between 2004 and 2013. Results Twenty patients underwent tracheostomy at a median age of 7.1 months (interquartile range [IQR] = 3.5,21.3). The estimated incidence of tracheostomy in trisomy 21 patients among our tracheostomy population was 1.7% (20/1173) over 10 years. The most common indications were airway obstruction (AO) (55%), cardiac/pulmonary respiratory failure (CRF) (25%), or both (20%). Overall mortality was 30%, much lower among AO patients (9%) than CRF (40%) or both (60%), (P = 0.029). Nine patients (45%) were successfully decannulated, with median duration of cannulation of 2.2 years (IQR = 1.7,3). Conclusions This study suggests a rate of tracheostomy in the pediatric trisomy 21 population approximately 3 times that of the general pediatric population. Over half in this cohort underwent tracheostomy for isolated AO, while the general pediatric tracheostomy population demonstrates a much higher prevalence of prematurity-related CRF. Overall mortality rate and decannulation rate approximated that of the general pediatric tracheostomy population, although outcomes were significantly poorer among patients trisomy 21 patients undergoing tracheostomy for CRF.

The aim of this study was to describe use of seclusion and restraint after injurious assaults by psychiatric inpatients in U.S. hospitals, including examination of hospital, unit, assaultive patient, and assault characteristics as predictors of seclusion/restraint use.Data from 2004 to 2017 on 23,630 injurious assaults reported by 747 psychiatric units in 482 general hospitals were analyzed. Odds of seclusion, odds of three restraint types (device, hold, pharmacological), and duration of seclusion and device restraint were modeled as functions of hospital, unit, assaultive patient, and assault characteristics.Compared with teaching hospitals, nonteaching hospitals had lower rates of seclusion but higher rates of all three types of restraint. Seclusion and restraint rates were lower in government hospitals and hospitals in metropolitan settings. Pharmacological restraint was most common in for-profit hospitals; seclusion was most common in nonprofit hospitals. Episodes of seclusion and device restraint were approximately 20% shorter in teaching hospitals than in nonteaching hospitals and lasted markedly longer in federal government hospitals. Hospitals in metropolitan settings reported 30% longer time spent in seclusion, on average. Involuntary admission was associated with higher odds of seclusion, device restraint, and hold. Female patients were less likely than males to be restrained with a device, and their seclusion and device restraint episodes tended to be shorter. The number of persons injured in an assault predicted odds of seclusion and all three types of restraint. The maximum level of injury sustained predicted odds of seclusion, device restraint, and hold, as well as duration of both seclusion and device restraint. Odds of seclusion/restraint were lower when the most severely injured person was a patient rather than a clinical health care worker.Inconsistencies were observed in seclusion and restraint use, which varied by hospital type, patient sex and admission status, maximum level of injury sustained, and type of person most severely injured. Thus, there may be room for improvement in hospital and unit policies and practices. More comprehensive data are needed for further research on use of seclusion and restraint in response to incidents other than injurious assault.

Bed and chair alarms are widely used in hospitals, despite lack of effectiveness and unintended negative consequences. In this cross-sectional, observational study, we examined alarm prevalence and contributions of patient- and unit-level factors to alarm use on 59 acute care nursing units in 57 U.S. hospitals participating in the National Database of Nursing Quality Indicators®. Nursing unit staff reported data on patient-level fall risk and fall prevention measures for 1,489 patients. Patient-level propensity scores for alarm use were estimated using logistic regression. Expected alarm use on each unit, defined as the mean patient propensity-for-alarm score, was compared to the observed rate of alarm use. Over one-third of patients assessed had an alarm in the “on” position. Patient characteristics associated with higher odds of alarm use included recent fall, need for ambulation assistance, poor mobility judgment, and altered mental status. Observed rates of unit alarm use ranged from 0%-100% (median 33%, 10(th) percentile 5%, 90(th) percentile 67%). Expected alarm use varied less (median 31%, 10(th) percentile 27%, 90(th) percentile 45%). Only 29% of variability in observed alarm use was accounted for by expected alarm use. Unit assignment was a stronger predictor of alarm use than patient-level fall risk variables. Alarm use is common, varies widely across hospitals, and cannot be fully explained by patient fall risk factors; alarm use is driven largely by unit practices. Alarms are used too frequently and too indiscriminately, and guidance is needed for optimizing alarm use to reduce noise and encourage mobility in appropriate patients.

Rejection is responsible for just under 50% of graft loss in the pediatric kidney transplant population. Early identification and treatment of allograft injury, specifically modifiable pathologies such as subclinical rejection (SCR), calcineurin inhibitor toxicity, and BK virus nephropathy, may improve allograft survival. Protocol surveillance biopsy (SB) currently offers the earliest opportunity for targeted interventions. This is a single-center retrospective review of 215 kidney SBs obtained from 2008 to 2016 in 97 pediatric kidney transplant recipients. SBs were obtained at 6, 12, and 24 months post-transplantation. Frequency of abnormal histologic findings, estimated glomerular filtration rate at time of SB, and SB-related complications were recorded. Data were analyzed to investigate possible time trends and the presence of demographic or clinical associations with abnormal histologic findings. Potentially modifiable histologic findings were seen in 38.1% of all SBs. SCR was found with increasing frequency across all time points with an estimated 49% increase in the odds of a SCR finding per additional 6 months post-transplantation (aOR 1.49, 95% CI 1.06–2.09, p = 0.022). Among follow-up biopsies in patients who underwent treatment for SCR, 50% had no SCR and 18.8% showed histologic improvement. The complication rate associated with SB was 1.9% (4/215 SBs) and consisted of only minor complications. SBs are safe and offer the opportunity to identify and treat modifiable histologic changes in the pediatric kidney transplant population. The performance of SBs for up to 2 years after transplantation can have meaningful clinical impact.

Contains fulltext : 220573.pdf (Publisher’s version ) (Open Access) The hepatic influx transporter OATP1B1 (SLCO1B1) plays an important role in the disposition of endogenous substrates and drugs prescribed to children. Alternative splicing increases the diversity of protein products from > 90% of human genes and may be triggered by developmental signals. As concentrations of several endogenous OATP1B1 substrates change during growth and development, with this exploratory study we investigated age-dependent alternative splicing of SLCO1B1 mRNA in 97 postmortem livers (fetus-adolescents). Twenty-seven splice variants were detected; 10 were confirmed by additional bioinformatic analyses and verified by quantitative polymerase chain reaction, and selected for detailed analysis based on relative abundance, association with age, and overlap with an adjacent gene. Two splice variants code for reference OATP1B1 protein, and eight code for truncated proteins. The expression of eight isoforms was associated with age. We conclude that alternative splicing of SLCO1B1 occurs frequently in children; although the functional consequences remain unknown, the data raise the possibility of a regulatory role for alternative splicing in mediating developmental changes in drug disposition.

High rates of fertility desires, childbearing and serodiscordant partnerships among people living with HIV (PLHIV) in Uganda underscore the need to promote use of safer conception methods (SCM). Effective SCM exist but few PLHIV benefit from provider-led safer conception counseling (SCC) and comprehensive national SCC guidelines are still lacking. Providers' self-efficacy, intentions and attitudes for SCC impact provision and should inform development of services, but there are no longitudinal studies that assess these important constructs. This study reports on changes in providers' knowledge, attitudes, motivation and confidence to provide SCC among a 24-month observational cohort of Ugandan HIV providers. Compared to baseline, providers evidenced increased awareness of SCM, perceived greater value in providing SCC, saw all SCM but sperm washing as likely to be acceptable to clients, reported consistently high interest in and peer support for providing SCC, and perceived fewer barriers at the 24-month follow-up. Providers' intentions for providing SCC stayed consistently high for all SCM except manual self-insemination which decreased at 24 months. Self-efficacy for providing SCC increased from baseline with the greatest improvement in providers' confidence in advising serodiscordant couples where the man is HIV-infected. Providers consistently cite the lack of established guidelines, training, and their own reluctance to broach the issue with clients as significant barriers to providing SCC. Despite providers being more interested and open to providing SCC than ever, integration of SCC into standard HIV services has not happened. Concerted efforts are needed to address remaining barriers by establishing national SCC guidelines and implementing quality provider training.

To test the hypothesis that our motivational sexual health intervention (SexHealth) would increase health service uptake when compared with control.In a randomized controlled trial at a pediatric emergency department, sexually active adolescents received either the SexHealth intervention or printed materials (control). SexHealth, delivered by a health educator, was a tablet-based, interactive intervention that included motivational techniques to promote sexual health, condom skills training, and tailored service recommendations. We assessed feasibility (eg, intervention completion, recommendations discussed, intervention duration), acceptability (ie, proportion enrolled and rating intervention as satisfactory), and efficacy; secondary outcomes were sexual and care-seeking behaviors at 6 months. The efficacy outcome was completion of ≥1 service at the index visit (ie, counseling, condoms, emergency contraception for immediate or future use, pregnancy/sexually transmitted infection/HIV testing, sexually transmitted infection treatment, and clinic referral).We enrolled 91 participants (intervention = 44; control = 47). The intervention demonstrated high feasibility: 98% completed the intervention; 98% of recommendations were discussed; duration was 24.6 minutes, and acceptability: 87% of eligible adolescents enrolled and 93% rated the intervention as fairly to very satisfactory. Compared with controls, intervention participants were more likely to complete ≥1 service (98% vs 70%, P .001) including HIV testing (33% vs 6%, P = .02) and emergency contraception (80% vs 0%, P = .01). There were no meaningful differences between arms in behaviors at follow-up.SexHealth was feasible to implement, acceptable to youth, and resulted in increased uptake of health services during the emergency department visit. Additional strategies may be needed to extend intervention effects over time.ClinicalTrials.gov; NCT03341975.

Background Executive function (EF) is considered an important mediator of health outcomes. It is hypothesized that those with better EF are more likely to succeed in turning their intentions into actual health behaviors. Prior studies indicate EF is associated with smoking cessation. Experimental and longitudinal studies, however, have yielded mixed results. Few studies have examined whether EF predicts post-treatment smoking behavior. Fewer still have done so prospectively in a large trial. We sought to determine if EF predicts quit attempts and cessation among community smokers in a large randomized trial evaluating the efficacy of motivational interventions for encouraging cessation. Methods Participants (N = 255) completed a baseline assessment that included a cognitive battery to assess EF (Oral Trail Making Test B, Stroop, Controlled Oral Word Association Test). Participants were then randomized to 4 sessions of Motivational Interviewing or Health Education or one session of Brief Advice to quit. Quit attempts and cessation were assessed at weeks 12 and 26. Results In regression analyses, none of the EF measures were statistically significant predictors of quit attempts or cessation (all ps > 0.20). Conclusions Our data did not support models of health behavior that emphasize EF as a mediator of health outcomes. Methodological shortcomings weaken the existing support for an association between EF and smoking behavior. We suggest methodological improvements that could help move this potentially important area of research forward.

Many individuals with type 1 diabetes (T1D) upload and review blood glucose data between clinic visits. Mobile phone applications that receive data from a "connected" glucometer and that support pattern management are available and have the capacity to make data upload and review less burdensome. Whether mobile apps can improve diabetes self-management among individuals with type 1 diabetes remains unknown.We analyzed retrospective data on 81 youths with T1D who were trained to use a glucometer-connected mobile app in their self-management. To assess the effect of glucometer synchronization ("sync") rate on hemoglobin A1c (HbA1c), mean blood glucose (mBG), and daily frequency of SMBG, we regressed those clinical outcomes on the frequency of glucometer syncs with the mobile app after controlling for other clinical care variables.Median age was 14.0 (IQR 10.4-15.9) years, median duration of diabetes was 4.9 (2.7, 7.5) years, and median baseline HbA1c was 8.6% (7.9, 9.8). The sample was 49% male and 86% white. Youths with T1D synchronized glucometer data with the mobile app an average of 0.22 times per week (range 0-2.25). The glucometer sync rate did not have a statistically significant association with HbA1c or mean BG; in contrast, data sync frequency was associated with the frequency of self-monitoring of blood glucose (SMBG) such that each additional sync was associated with a 2.3-fold increase in SMBG frequency ( P.01).A glucometer-connected mobile app may increase an individual's engagement with other aspects of care (eg, SMBG frequency). Whether diabetes device-connected mobile apps can improve glycemic control remains to be determined.

Introduction Hyperfiltration is a major contributor to progression of chronic kidney disease (CKD) in diabetes, obesity and in individuals with solitary functioning kidney (SFK). We have proposed hyperfiltration-induced injury as a continuum of overlapping glomerular changes caused by increased biomechanical forces namely, fluid flow shear stress (FFSS) and tensile stress. We have shown that FFSS is elevated in animals with SFK and, it upregulates prostaglandin E2 (PGE2), cyclooxygenase-2 and PGE2 receptor EP2 in cultured podocytes and in uninephrectomized mice. We conceptualized urinary PGE2 as a biomarker of early effects of hyperfiltration-induced injury preceding microalbuminuria in individuals with SFK. We studied children with SFK to validate our hypothesis. Methods Urine samples from children with SFK and controls were analyzed for PGE2, albumin (glomerular injury biomarker) and epidermal growth factor (EGF, tubular injury biomarker). Age, gender, and Z-scores for height, weight, BMI, and blood pressure were obtained. Results Children with SFK were comparable to controls except for lower BMI Z-scores. The median values were elevated in SFK compared to control for urine PGE2 [9.1 (n = 57) vs. 5.7 (n = 72), p = 0.009] ng/mgCr and albumin [7.6 (n = 40) vs. 7.0 (n = 41), p = 0.085] μg/mgCr, but not for EGF [20098 (n = 44) vs. 18637 (n = 44), p = 0.746] pg/mgCr. Significant increase in urinary PGE2 (p = 0.024) and albumin (p = 0.019) but not EGF (p = 0.412) was observed using additional regression modeling. These three urinary analytes were independent of each other. Conclusion Increased urinary PGE2 from elevated SNGFR and consequently increased FFSS during early stage of CKD precedes overt microalbuminuria and is a biomarker for early hyperfiltration-induced injury in individuals with SFK.

BACKGROUND:Substantial variability exists in the care of febrile, well-appearing infants. We aimed to assess the impact of a national quality initiative on appropriate hospitalization and length of stay (LOS) in this population.METHODS:The initiative, entitled Reducing Variability in the Infant Sepsis Evaluation (REVISE), was designed to standardize care for well-appearing infants ages 7 to 60 days evaluated for fever without an obvious source. Twelve months of baseline and 12 months of implementation data were collected from emergency departments and inpatient units. Ill-appearing infants and those with comorbid conditions were excluded. Participating sites received change tools, run charts, a mobile application, live webinars, coaching, and a LISTSERV. Analyses were performed via statistical process control charts and interrupted time series regression. The 2 outcome measures were the percentage of hospitalized infants who were evaluated and hospitalized appropriately and the percentage of hospitalized infants who were discharged with an appropriate LOS.RESULTS:In total, 124 hospitals from 38 states provided data on 20 570 infants. The median site improvement in percentages of infants who were evaluated and hospitalized appropriately and in those with appropriate LOS was 5.3% (interquartile range = −2.5% to 13.7%) and 15.5% (interquartile range = 2.9 to 31.3), respectively. Special cause variation toward the target was identified for both measures. There was no change in delayed treatment or missed bacterial infections (slope difference 0.1; 95% confidence interval, −8.3 to 9.1).CONCLUSIONS:Reducing Variability in the Infant Sepsis Evaluation noted improvement in key aspects of febrile infant management. Similar projects may be used to improve care in other clinical conditions.

The present study describes the development and initial validation of a newly developed measure of child and caregiver knowledge of the child's own IBD and treatment, called IBD KNOW-IT. One hundred and fifty-five children and their caregivers completed the IBD KNOW-IT as well as a scale designed to compare each dyad's perceived knowledge to their actual knowledge. Initial psychometric evaluation of IBD KNOW-IT was completed by conducting factor analysis and determining internal consistency, convergent validity, and associations with demographic and medical characteristics. Results supported the validity of a 12-item measure with 4 subscales including Symptoms, Medication Regimen, Disease Monitoring, and Medical Team. Support for the internal consistency of IBD KNOW-IT was obtained. Evidence of validity was demonstrated by significant correlations between child and caregiver scales, and high congruence between perceived and actual knowledge across all subscales. The reliability of the measure was demonstrated by good internal consistency and test-retest reliability. Preliminary psychometric evaluation suggests that IBD KNOW-IT is reliable and valid.

The purpose of this study was to examine national trends and variation in nurse staffing on inpatient psychiatric units in US general hospitals from 2005-2017. The National Database of Nursing Quality Indicators® provided data on nurse staffing from 1,143 psychiatric units in 610 US hospitals. A weighted linear mixed model was fitted for each of two staffing measures: Registered nurse (RN) hours per patient day (HPPD) and non-RN HPPD. Monthly staffing levels were modeled as a function of study year, unit type, and hospital bed size, teaching status, government ownership, for-profit status, metropolitan location, and US census division. Very gradual upward trends in staffing were observed. Compared with adult units, child/adolescent units had lower RN staffing and higher non-RN staffing. Levels of both types of staffing were lower in for-profit facilities. The Pacific census division had higher RN staffing than every other census division by an estimated margin of 0.52-1.54 HPPD, and census divisions with the lowest levels of RN staffing had the highest levels of non-RN staffing. Despite concerns expressed over the past 15 years about patient violence, staffing levels, and use of seclusion and restraint on psychiatric units, average staffing levels have apparently increased only modestly since 2005, and increases in RN staffing on psychiatric units have not kept pace with increases in general care units. Marked regional differences in staffing merit further investigation.

Background: Resting energy expenditure (REE) is a valuable measure in clinical management of obesity and other chronic illnesses. Gold standard methods for measuring REE (e.g., Douglas bags and metabolic cart) are too expensive and cumbersome for an outpatient clinical setting. The purpose of this study was to determine the accuracy of a handheld indirect calorimeter (HHIC) and prediction equations (PEs) for measurement of REE in youth with and without obesity. Methods: Fifty-three children and adolescents (12.8 ± 4.3 years, 50.9% female) had REE measured first with a MedGem™ HHIC for 10 minutes, followed by a reference indirect calorimeter system (ParvoMedics TrueOne 2400™) with hood canopy and dilution pump for 30 minutes. REE was also estimated using nine PEs as follows: Henry-1, Henry-2, Schofield, World Health Organization, Molnar, Muller, Herrmann, Schmelzle, and Harris–Benedict. Concordance correlation coefficients and Bland–Altman analyses were used for comparisons among PEs, MedGem HHIC, and metabolic cart. Results: The observed correlation between the HHIC and the reference system was r(c) = 0.89 with a mean bias of 2.27 ± 3.41 kcal/(kg·d) (9.1% ± 14.7%). Regarding PE, Molnar had the highest agreement with the reference system [r(c) = 0.93, bias of 2.17 ± 2.04 kcal/(kg·d); 9.8% ± 8.1%], followed by Harris–Benedict (r(c) = 0.89; 13.8% ± 8.9%), Henry-2 (r(c) = 0.89; 15% ± 7.6%), and Henry-1 (r(c) = 0.86; 16.7% ± 7.3%). All PEs were less accurate for children with overweight/obesity. Conclusions: Compared to PE, the HHIC provided more accurate REE estimates for children across the age and BMI spectrum, although positive bias was present throughout. Difference in positive bias between the HHIC and the Molnar equation may be clinically significant for youth with overweight/obesity.

Psychiatric mental health clinicians often rely on proxy and self-report evaluations to determine the cognitive function of older adults however, performance measures have greater accuracy and predictive ability for everyday function. This study tested physical and cognitive predictors of functional abilities in fifty-one community residing older adults. We administered a computerized battery of executive function tasks, a performance-based measure of instrumental activities of daily living (IADL), and three physical function measures (grip strength, 30-second Chair Stand Test, and 8-foot Up and Go). Regression models assessed the associations of three components of executive function (updating, shifting, and inhibition) with IADLs and physical functions. Updating was a significant predictor of the Medications and Financial DAFS scores and of grip strength. Shifting also predicted grip strength. In conclusion, different executive functions predict different domains of IADL functioning. Working memory was a robust predictor of IADL functioning in older adults, especially medication management skills.

Objective Estimate the impact on clinical practice of using a mobile device–based electronic clinical decision support (mECDS) tool within a national standardization project. Materials and Methods An mECDS tool (app) was released as part of a change package to provide febrile infant management guidance to clinicians. App usage was analyzed using 2 measures: metric hits per case (metric-related screen view count divided by site-reported febrile infant cases in each designated market area [DMA] monthly) and cumulative prior metric hits per site (DMA metric hits summed from study month 1 until the month preceding the index, divided by sites in the DMA). For each metric, a mixed logistic regression model was fit to model site performance as a function of app usage. Results An increase of 200 cumulative prior metric hits per site was associated with increased odds of adherence to 3 metrics: appropriate admission (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.06-1.18), appropriate length of stay (OR, 1.20; 95% CI, 1.12-1.28), and inappropriate chest x-ray (OR, 0.82; 95% CI, 0.75-0.91). Ten additional metric hits per case were also associated: OR were 1.18 (95% CI, 1.02-1.36), 1.36 (95% CI, 1.14-1.62), and 0.74 (95% CI, 0.62-0.89). Discussion mECDS tools are increasingly being implemented, but their impact on clinical practice is poorly described. To our knowledge, although ecologic in nature, this report is the first to link clinical practice to mECDS use on a national scale and outside of an electronic health record. Conclusions mECDS use was associated with changes in adherence to targeted metrics. Future studies should seek to link mECDS usage more directly to clinical practice and assess other site-level factors.

Despite advances in treatment, up to 30% of breast cancer patients experience disease recurrence accompanied by more aggressive disease and poorer prognosis. Treatment of breast cancer is complicated by the presence of multiple breast cancer subtypes, including: luminal, Her2 overexpressing, and aggressive basal-like breast cancers. Identifying new biomarkers specific to breast cancer subtypes could enhance the prediction of patient prognosis and contribute to improved treatment strategies. The microenvironment influences breast cancer progression through expression of growth factors, angiogenic factors and other soluble proteins. In particular, chemokine C-C ligand 2 (CCL2) regulates macrophage recruitment to primary tumors and signals to cancer cells to promote breast tumor progression. Here we employed a software-based approach to evaluate the prognostic significance of CCL2 protein expression in breast cancer subtypes in relation to its expression in the epithelium or stroma or in relation to fibroblast-specific protein 1 (Fsp1), a mesenchymal marker. Immunohistochemistry analysis of tissue microarrays revealed that CCL2 significantly correlated with Fsp1 expression in the stroma and tumor epithelium of invasive ductal carcinoma. In the overall cohort of invasive ductal carcinomas (n=427), CCL2 and Fsp1 expression in whole tissues, stroma and epithelium were inversely associated with cancer stage and tumor size. When factoring in molecular subtype, stromal CCL2 was observed to be most highly expressed in basal-like breast cancers. By Cox regression modeling, stromal CCL2, but not epithelial CCL2, expression was significantly associated with decreased recurrence-free survival. Furthermore, stromal CCL2 (HR=7.51 P=0.007) was associated with a greater hazard than cancer stage (HR=2.45, P=0.048) in multivariate analysis. These studies indicate that stromal CCL2 is associated with decreased recurrence-free survival in patients with basal-like breast cancer, with important implications on the use of stromal markers for predicting patient prognosis.

Hospital performance reports often include rankings of unit pressure ulcer rates. Differentiating among units on the basis of quality requires reliable measurement. Our objectives were to describe and apply methods for assessing reliability of hospital‐acquired pressure ulcer rates and evaluate a standard signal‐noise reliability measure as an indicator of precision of differentiation among units. Quarterly pressure ulcer data from 8,199 critical care, step‐down, medical, surgical, and medical‐surgical nursing units from 1,299 US hospitals were analyzed. Using beta‐binomial models, we estimated between‐unit variability (signal) and within‐unit variability (noise) in annual unit pressure ulcer rates. Signal‐noise reliability was computed as the ratio of between‐unit variability to the total of between‐ and within‐unit variability. To assess precision of differentiation among units based on ranked pressure ulcer rates, we simulated data to estimate the probabilities of a unit's observed pressure ulcer rate rank in a given sample falling within five and ten percentiles of its true rank, and the probabilities of units with ulcer rates in the highest quartile and highest decile being identified as such. We assessed the signal‐noise measure as an indicator of differentiation precision by computing its correlations with these probabilities. Pressure ulcer rates based on a single year of quarterly or weekly prevalence surveys were too susceptible to noise to allow for precise differentiation among units, and signal‐noise reliability was a poor indicator of precision of differentiation. To ensure precise differentiation on the basis of true differences, alternative methods of assessing reliability should be applied to measures purported to differentiate among providers or units based on quality. © 2016 The Authors. Research in Nursing & Health published by Wiley Periodicals, Inc.

This study determined if a SystemCHANGE™ intervention was more efficacious than attention control in increasing immunosuppressive medication adherence and improving outcomes in adult kidney transplant recipients during a 6-month intervention phase and subsequent 6-month (no intervention) maintenance phase. The SystemCHANGE™ intervention taught patients to use person-level quality improvement strategies to link adherence to established daily routines, environmental cues, and supportive people. Eighty-nine patients (average age 51.8 years, 58% male, 61% African American) completed the 6-month intervention phase. Using an intent-to-treat analysis, at 6 months, medication adherence for SystemCHANGE™ (median 0.91, IQR 0.76-0.96) and attention control (median 0.67, IQR 0.52-0.72) patients differed markedly (difference in medians 0.24, 95% CI 0.13-0.30, P < .001). At the conclusion of the subsequent 6-month maintenance phase, the gap between medication adherence for SystemCHANGE™ (median 0.77, IQR 0.56-0.94) and attention control (median 0.60, IQR 0.44-0.73) patients remained large (difference in medians 0.17, 95% CI 0.06-0.33, P = .004). SystemCHANGE™ patients evidenced lower mean creatinine and BUN at 12 months and more infections at 6 and 12 months. This first fully powered RCT testing SystemCHANGE™ to improve and maintain medication adherence in kidney transplant recipients demonstrated large, clinically meaningful improvements in medication adherence. Clinical Trial Registration: NCT02416479.

Objective Data on early miscarriage incidence is limited due to various social and methodological barriers. We report on 24-month pregnancy outcomes of 299 female Ugandan HIV clients in committed relationships with an intention to conceive. Miscarriage data are reported as auxiliary findings to a larger study (5R01HD072633). Results 127 (42%) participants reported a pregnancy during the study; among the remaining 172, 82 indicated they stopped trying to conceive, and 16 dropped out prior to month 24. Of the 127 pregnancies, 55 (43%) resulted in live births, 67 (53%) in spontaneous miscarriage, 1 (

Background Despite the recognized importance of human milk (HM) use, breastfeeding is often discouraged for infants with cleft lip and/or palate because of their anatomical abnormalities. Poor weight gain may require formula for calorie supplementation. Stresses associated with caring for infants with cleft lip/palate may decrease rates of HM provision to these infants. Purpose This study investigates the experiences of mothers of infants with cleft lip/palate (CL/P) to determine choices and factors associated with providing HM to their infants. Methods A retrospective telephone survey was administered to a cohort of mothers of infants with CL/P. Results Fifty mothers agreed to participate in the survey. Most (78%) initiated use of HM for a median duration of 4 months, 32% provided HM for 6 months or more, and 79% exclusively expressed their HM. Poor supply was the most frequent challenge to providing HM and led to cessation in 46% of the mothers. Formula was used to supplement for poor supply or poor infant weight gain in 90% of the mothers. The best predictors of a mother's use of HM were child not in day care, genetic diagnosis, and gestational age at birth. Only 36% of mothers reported individual encouragement to provide HM, and 18% reported they were specifically discouraged from providing HM for their infants. Implications for practice Although initiation rates were high, there are opportunities to improve support for mothers to increase duration of HM provision in children with CL/P. Implications for research This study establishes a baseline for future prospective studies looking at the impact of active encouragement and provision of lactation support within the cleft team setting.

This study investigated the impact of SLCO1B1 genotype on pravastatin systemic exposure in children and adolescents with hypercholesterolemia. Participants (8-20 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n = 15; 521CC, n = 2) and wild-type controls (521TT, n = 15) completed a single oral dose pharmacokinetic study. Interindividual variability of pravastatin acid (PVA) exposure within SLCO1B1 genotype groups exceeded the approximately twofold difference in mean PVA exposure observed between SLCO1B1 genotype groups (P > 0.05, q > 0.10). The 3'α-iso-pravastatin acid and lactone isomer formation in the acidic environment of the stomach prior to absorption also was variable and affected PVA exposure in all genotype groups. The SLCO1B1 c.521 gene variant contributing to variability in systemic exposure to PVA in our pediatric cohort was comparable to previous studies in adults. However, other demographic and physicochemical factors seem to also contribute to interindividual variability in the dose-exposure relationship.

Lumbar mobilization is a standard intervention for lower back pain (LBP). However, its effect on the activity of back muscles is not well known.To investigate the effects of lumbar mobilization on the activity/contraction of erector spinae (ES) and lumbar multifidus (LM) muscles in people with LBP.Randomized controlled study.21 subjects with LBP received either grade III central lumbar mobilization or placebo (light touch) intervention on lumbar segment level 4 (L4). Surface electromyography (EMG) signals of ES and ultrasound (US) images of LM were captured before and after the intervention. The contraction of LM was calculated from US images at L4 level. The normalized amplitude of EMG signals (nEMG) and activity onset of ES were calculated from the EMG signals at both L1 and L4 levels.Significant differences were found between the mobilization and placebo groups in LM contraction (p=0.03), nEMG of ES at L1 (p=0.01) and L4 (p=0.05), and activity onset of ES at L1 (p=0.02).Lumbar mobilization decreased both the activity amplitude and the activity onset of ES in people with LBP. However, the significant difference in LM contraction was small and may not have clinical significance.

With data from 400 HIV clients with fertility intentions and 57 HIV providers in Uganda, we evaluated the psychometrics of new client and provider scales measuring constructs related to safer conception methods (SCM) and safer conception counselling (SCC). Several forms of validity (i.e., content, face, and construct validity) were examined using standard methods including exploratory and confirmatory factor analysis. Internal consistency was established using Cronbach's alpha correlation coefficient. The final scales consisted of measures of attitudes towards use of SCM and delivery of SCC, including measures of self-efficacy and motivation to use SCM, and perceived community stigma towards child-bearing. Most client and all provider measures had moderate to high internal consistency (alphas 0.60–0.94), most had convergent validity (associations with other SCM or SCC-related measures), and client measures had divergent validity (poor associations with depression). These findings establish preliminary psychometric properties of these scales and should facilitate future studies of SCM and SCC.