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Much of the current data on nonalcoholic fatty liver disease (NAFLD) are derived from biopsy‐based studies that may introduce ascertainment and selection bias. Selection of patients for liver biopsy has implications for clinical practice and the reported epidemiology of NAFLD. The aim of this study was to determine patient factors predictive of histologic versus empiric clinical diagnosis of NAFLD in real‐world practice. Adults from TARGET‐NASH were included in this study. Descriptive statistics are provided for the cohort and compare the characteristics of histologic NAFLD versus patients with clinically diagnosed NAFLD, followed by logistic regression and machine‐learning models to describe predictors of liver biopsy. The records of 3,474 subjects were analyzed; median age was 59 years, 59% were female, 75% were White, and median body mass index was 32 kg/m2. Using histologic and/or clinical criteria, a diagnosis of nonalcoholic steatohepatitis was made in 37%, and cirrhosis in 33%. Comorbid conditions included cardiovascular disease (19%), mental health diagnoses (49%), and osteoarthritis (10%). Predictors of a biopsy diagnosis included White race, female sex, diabetes, and elevated alanine aminotransferase (ALT). ALT increased the odds of liver biopsy by 14% per 10‐point rise. Machine‐learning analyses showed non‐White patients with ALT, The aim of this study was to determine patient factors predictive of histologic versus empiric clinical diagnosis of NAFLD in real world practice in adults enrolled in the TARGET‐NASH study. The records of 3,474 subjects were analyzed; median age was 59 years, 59% were female, 75% were white, and median BMI was 32 kg/m2. In this real‐world cohort of patients with NAFLD, two thirds of patients did not have a liver biopsy; these patients were more likely to be non‐white, older, with a normal ALT.

This study describes the design of the TARGET‐hepatocellular carcinoma (HCC) cohort and descriptive characteristics of the patient population at diagnosis among those who were enrolled in the cohort across academic and community clinical centers. TARGET‐HCC is a 5‐year, longitudinal, observational cohort of patients with HCC receiving care in usual clinical practice. Redacted clinical information, obtained from medical records, captures the natural history and management of the disease, including the safety and efficacy of treatment interventions used in usual clinical practice. Patients can complete patient‐reported outcome measures and provide biological specimens for future translational studies. The TARGET‐HCC study includes adults with histologic, cytologic, or radiologic diagnosis of HCC from academic and community centers in both the United States and Europe. A total of 1,841 participants were enrolled between January 9, 2017, and July 23, 2019, at 67 sites in the United States and Europe. To date, the most common liver disease etiology in the cohort continues to be hepatitis C, although nearly half had a nonviral etiology, including alcohol‐related liver disease or nonalcoholic steatohepatitis. Most included patients were diagnosed at an early stage (Barcelona Clinic Liver Cancer Stage [BCLC] 0/A), but only approximately one third underwent curative treatment. Systemic therapy has been used in 7.3% of enrolled patients, including 45.7% of those with BCLC stage C tumors. Conclusion: Overall, the TARGET‐HCC cohort allows for the assessment of patient characteristics and investigation of new treatment paradigms and sequencing with existing agents as well as novel regimens for HCC., TARGET‐HCC is a 5‐year, longitudinal, observational cohort of patients with hepatocellular carcinoma receiving care in usual clinical practice. The objective of this manuscript is to describe the design of the TARGET‐HCC cohort and descriptive characteristics of the patient population at diagnosis across academic and community clinical centers.

Background As coronavirus disease 2019 (COVID-19) disseminates throughout the United States, a better understanding of the patient characteristics associated with hospitalization, morbidity, and mortality in diverse geographic regions is essential. Methods Hospital chargemaster data on adult patients with COVID-19 admitted to 245 hospitals across 38 states between 15 February and 20 April 2020 were assessed. The clinical course from admission, through hospitalization, and to discharge or death was analyzed. Results A total of 11 721 patients were included (majority were >60 years of age [59.9%] and male [53.4%]). Comorbidities included hypertension (46.7%), diabetes (27.8%), cardiovascular disease (18.6%), obesity (16.1%), and chronic kidney disease (12.2%). Mechanical ventilation was required by 1967 patients (16.8%). Mortality among hospitalized patients was 21.4% and increased to 70.5% among those on mechanical ventilation. Male sex, older age, obesity, geographic region, and the presence of chronic kidney disease or a preexisting cardiovascular disease were associated with increased odds of mechanical ventilation. All aforementioned risk factors, with the exception of obesity, were associated with increased odds of death (all P values < .001). Many patients received investigational medications for treatment of COVID-19, including 48 patients on remdesivir and 4232 on hydroxychloroquine. Conclusions This large observational cohort describes the clinical course and identifies factors associated with the outcomes of hospitalized patients with COVID-19 across the United States. These data can inform strategies to prioritize prevention and treatment for this disease.

First-line treatment for nonalcoholic fatty liver disease (NAFLD) focuses on weight loss through lifestyle modifications.1,2 Weight loss ≥5% results in reduction of steatosis and weight loss ≥10% has been associated with improvement in hepatic inflammation and fibrosis.3 The incidence and sustainability of weight loss among patients with NAFLD were estimated and associating factors identified.

Objective:Children with orofacial clefts (OFCs) may experience poor reading proficiency, learning disabilities, and academic underachievement. We examined the association between nonsyndromic (NS) OFCs and end-of-grade (EOG) performance in reading and math from third through eighth grade in a sample subgroup.Participants:We identified a cohort of 559 children with NS-OFCs and 6822 children without birth defects, classifying cleft type by cleft lip alone, with or without cleft alveolar ridge (CL); cleft lip with cleft palate (CL+P); and cleft palate only (CP).Main Outcome Measures:Using logistic regression, we estimated the odds of not meeting grade-level standards among children with NS-OFCs compared to unaffected peers. Using longitudinal analyses, we estimated the odds of not meeting grade-level standards and average change in test scores through eighth grade.Results:Children with NS-OFCs were 1.22 (95% CI: 0.96, 1.83) times as likely not to meet grade-level standards in reading compared to unaffected peers. The effect was similar for math (OR: 1.17; 95% CI: 0.92, 1.48). Children with CL+P were 1.33 (95% CI: 0.86, 1.83) and 1.74 (95% CI: 1.19, 2.56) times as likely not to meet grade-level standard in reading and in both subjects, respectively, compared to unaffected peers. The average rate of change in both scores was similar for children with and without OFCs.Conclusions:Poor academic performance appears greatest for children with CL+P, a finding compatible with previous observations and hypothesized mechanisms associating orofacial clefts with subtle abnormalities in brain development. Academic performance monitoring and referral for academic assistance is warranted.

External gear pumps (EGPs) are one of the most common choices in aerospace engines as a fuel delivery pump. These units usually include a pressure compensation system that defines the lubricating gap at the lateral side of the gears. This lubricating interface is a critical design aspect, which strongly affects the reliability as well as the mechanical and volumetric efficiencies of the pump. Major challenges in designing these lubricating gaps in aero engine fuel pumps, include high operating speeds, delivery pressures and low viscosity of the working fluids. Virtual prototyping methods present a fast and efficient design tool and have the potential to improve the EGP’s reliability and efficiency. This paper presents a study on the pressure compensation system of a fuel delivery EGP and shows how the presence of frictional forces opposing the motion of the compensating element significantly affect the lubricating performance of the unit. The presence of these frictional forces produces an effect of hysteresis on the axial balance system, so that the lubricating gaps that develop within the pump at a certain operating condition depend on the previous operating state. This effect was captured in an experimental setup purposely developed for this study at Rolls-Royce. Within this work, this behavior was also reproduced numerically, through a coupled fluid structure interaction – elastohydrodynamic (EHD) model that includes the modeling of these frictional forces. After detailing the implementation of the lateral gap model, this paper presents measurements from carefully conducted experiments which correlate with the simulated predictions of the influence of frictional forces on the performance of a reference EGP design under study.

STUDY QUESTION What is the association between ART conception and treatment parameters and the risk of birth defects? SUMMARY ANSWER Compared to naturally conceived singleton infants, the risk of a major nonchromosomal defect among ART singletons conceived with autologous oocytes and fresh embryos without use of ICSI was increased by 18%, with increases of 42% and 30% for use of ICSI with and without male factor diagnosis, respectively. WHAT IS KNOWN ALREADY Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects but have been limited by small sample size and inadequate statistical power, failure to differentiate results by plurality, differences in birth defect definitions and methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2015 that resulted in live births from 1 September 2004 to 31 December 2016 in Massachusetts and North Carolina and from 1 September 2004 to 31 December 2015 for Texas and New York: these were large and ethnically diverse States, with birth defect registries utilizing the same case definitions and data collected, and with high numbers of ART births annually. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Naturally conceived ART siblings were identified through the mother’s information. Non-ART children were classified as being born to women who conceived with ovulation induction (OI)/IUI when there was an indication of infertility treatment on the birth certificate, but the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS The study population included 135 051 ART children (78 362 singletons and 56 689 twins), 23 647 naturally conceived ART siblings (22 301 singletons and 1346 twins) and 9396 children born to women treated with OI/IUI (6597 singletons and 2799 twins) and 1 067 922 naturally conceived children (1 037 757 singletons and 30 165 twins). All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal). Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CI to evaluate the risk of birth defects due to conception with ART (using autologous oocytes and fresh embryos), and with and without the use of ICSI in the absence or presence of male factor infertility, with naturally conceived children as the reference. Analyses within the ART group were stratified by combinations of oocyte source (autologous, donor) and embryo state (fresh, thawed), with births from autologous oocytes and fresh embryos as the reference. Analyses limited to fresh embryos were stratified by oocyte source (autologous, donor) and the use of ICSI. Triplets and higher-order multiples were excluded. MAIN RESULTS AND THE ROLE OF CHANCE A total of 21 998 singleton children (1.9%) and 3037 twin children (3.3%) had a major birth defect. Compared to naturally conceived children, ART singletons (conceived from autologous oocytes, fresh embryos without the use of ICSI) had increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% 1.05, 1.32), cardiovascular defects (AOR 1.20, 95% CI 1.03, 1.40), and any birth defect (AOR 1.18, 95% CI 1.09, 1.27). Compared to naturally conceived children, ART singletons conceived (from autologous oocytes, fresh embryos) with the use of ICSI, the risks were increased for a major nonchromosomal birth defect (AOR 1.30, 95% CI 1.16, 1.45 without male factor diagnosis; AOR 1.42, 95% CI 1.28, 1.57 with male factor diagnosis); blastogenesis defects (AOR 1.49, 95% CI 1.08, 2.05 without male factor; AOR 1.56, 95% CI 1.17, 2.08 with male factor); cardiovascular defects (AOR 1.28, 95% CI 1.10,1.48 without male factor; AOR 1.45, 95% CI 1.27, 1.66 with male factor); in addition, the risk for musculoskeletal defects was increased (AOR 1.34, 95% CI 1.01, 1.78 without male factor) and the risk for genitourinary defects in male infants was increased (AOR 1.33, 95% CI 1.08, 1.65 with male factor). Comparisons within ART singleton births conceived from autologous oocytes and fresh embryos indicated that the use of ICSI was associated with increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% CI 1.03, 1.35), blastogenesis defects (AOR 1.65, 95% CI 1.08, 2.51), gastrointestinal defects (AOR 2.21, 95% CI 1.28, 3.82) and any defect (AOR 1.11, 95% CI 1.01, 1.22). Compared to naturally conceived children, ART singleton siblings had increased risks of musculoskeletal defects (AOR 1.32, 95% CI 1.04, 1.67) and any defect (AOR 1.15, 95% CI 1.08, 1.23). ART twins (conceived with autologous oocytes, fresh embryos, without ICSI) were at increased risk of chromosomal defects (AOR 1.89, 95% CI 1.10, 3.24) and ART twin siblings were at increased risk of any defect (AOR 1.26, 95% CI 1.01, 1.57). The 18% increased risk of a major nonchromosomal birth defect in singleton infants conceived with ART without ICSI (∼36% of ART births), the 30% increased risk with ICSI without male factor (∼33% of ART births), and the 42% increased risk with ICSI and male factor (∼31% of ART births) translates into an estimated excess of 386 major birth defects among the 68 908 singleton children born by ART in 2017. LIMITATIONS, REASONS FOR CAUTION In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing vs vitrification), and data on ICSI was only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. WIDER IMPLICATIONS OF THE FINDINGS The use of ART is associated with increased risks of a major nonchromosomal birth defect, cardiovascular defect and any defect in singleton children, and chromosomal defects in twins; the use of ICSI further increases this risk, the most with male factor infertility. These findings support the judicious use of ICSI only when medically indicated. The relative contribution of ART treatment parameters versus the biology of the subfertile couple to this increased risk remains unclear and warrants further study. STUDY FUNDING/COMPETING INTEREST(S) This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. E.W. is a contract vendor for SART; all other authors report no conflicts. TRIAL REGISTRATION NUMBER N/A.

Objective:The aim of the present study was to develop and validate a vitamin D FFQ for assessment of dietary vitamin D intake in healthy adults in England, UK.Design:The current study assessed the agreement between a four-day food diary (4 d-FD) and a new vitamin D FFQ to measure dietary intake of vitamin D. Dietary intake was estimated using Nutritics dietary analysis software, and Spearman’s and Bland–Altman tests were utilised to assess correlation and agreement, respectively. Participants also provided a blood sample for plasma analysis of vitamin D concentrations.Setting:Home setting.Participants:Fifty participants were recruited to the study from the University of Chester and vicinity.Results:Results showed a strong correlation between vitamin D intake recorded by the FFQ and the 4 d-FD (r = 0·609; P < 0·0001) within 95 % limits of agreement. Furthermore, a significant correlation between plasma 25(OH)D concentrations and vitamin D intake measured by the FFQ (r = 0·290, P = 0·041) and the 4 d-FD (r = 0·360, P = 0·01) was observed.Conclusion:Our analysis suggests this FFQ is a useful and rapid tool for researchers and health professionals to assess vitamin D dietary intakes in healthy adults in the UK.

Objective To evaluate if there are differences in standardized testing results at the end of third grade between children conceived with the use of in vitro fertilization (IVF) and those conceived spontaneously. Design Retrospective population-based cohort. Setting Texas public school system. Patient(s) Singleton and twin children 8–9 years of age who took the third-grade public school standardized testing in Texas from 2012 to 2018. Intervention(s) None. Main Outcome Measure(s) Standardized testing in reading and mathematics. Result(s) After exclusions, there were 6,970 IVF and 12,690 non-IVF children with reading scores and 6,973 IVF and 12,729 non-IVF children with mathematics scores. IVF children scored significantly higher in reading (singletons: 1,543 ± 2 vs. 1,525 ± 1; twins: 1,534 ± 2 vs. 1,504 ± 5 [mean ± SE]), and mathematics (singletons: 1,566 ± 2 vs. 1,550 ± 1; twins: 1,557 ± 2 vs. 1,529 ± 5). Children of mothers ≥30 years of age scored consistently higher than children of mothers 18–29 years of age. The differences were of similar magnitude between IVF and control children for older ages, but not significant for IVF. Within the IVF group, there were no significant differences between children born from fresh versus froze-thawed embryos. Conclusion(s) Children of ages 8–9 years who were conceived with the use of IVF performed as well on third-grade reading and math assessments as their counterparts who were conceived spontaneously. We also found consistent racial and ethnic differences, gender differences, and beneficial effects of older maternal age. Because we were not able to adjust adequately for socioeconomic status and other confounding factors, which may explain some of the observed differences, we conclude that there is no negative effect of IVF conception on academic achievement in third grade.

Background: Opioid use is a topic of growing concern among patients with nonalcoholic fatty liver disease (NAFLD). Given safety concerns of opioids, proactively identifying subgroups of patients with an increased probability of opioid use may encourage practitioners to recommend alternative therapies for pain, thus reducing the likelihood of opioid misuse. This work assessed the prevalence and patient characteristics associated with opioid use in a real-world cohort of patients with NAFLD. Methods: TARGET-NASH, an observational study of participants at 55 academic and community sites in the United States, includes patients with NAFLD defined by pragmatic case definitions. Opioid use was defined as any documented opioid prescriptions in the year prior to enrollment. The association between patient characteristics and the odds of opioid use were modeled with stepwise multivariable logistic regression and tree ensemble methods (Classification and regression tree/Boosted Tree). Results: The cohort included 3,474 adult patients with NAFLD including 18.0% with documented opioid use. Variables associated with opioid use included presence of cirrhosis (OR 1.51, 95% CI 1.16–1.98), BMI ≥32 kg/m2 (OR 1.29, 95% CI 1.05–1.59), depression (OR 1.87, 95% CI 1.50–2.33), and anxiety (OR 1.59, 95% CI 1.27–1.98). In the boosted tree analysis, history of back pain, depression, and fibromyalgia had the greatest relative importance in predicting opioid use. Conclusion: Prescription opioids were used in nearly 1 of 5 patients with NAFLD. Given the safety concerns of opioids in patients with NAFLD, alternative therapies including low-dose acetaminophen and nonpharmacologic treatments should be considered for these patients.

Nonalcoholic fatty liver disease (NAFLD) is typically associated with obesity. Little is known about the prevalence of cirrhosis in patients with NAFLD and a normal body mass index (BMI).We determined prevalence of cirrhosis, cardiovascular disease (CVD), and metabolic abnormalities among participants in all BMI categories in the TARGET-NASH study. A total of 3386 patients with NAFLD were enrolled from August 2016 through March 2019. The odds ratios of cirrhosis, CVD, and metabolic abnormalities were estimated by age and race, adjusting for sex and center type.Based on standard BMI cutoff values, 12.8% of study subjects were lean, 27.1% were overweight, 26.5% had class 1 obesity, and 33.7% had class 2 or 3 obesity. Asians accounted for 48.7% of lean participants, and proportions decreased as BMI categories increased (P .0001). Lower proportions of lean participants had cirrhosis (22.6% vs 40.2% of non-lean participants), CVD history (9.0% vs 14.8% of nonlean participants), diabetes (32.6% vs 53.5% of non-lean participants), hypertension (47.8% vs 67.4% of non-lean participants), or dyslipidemia (54.0% vs 64.1% of non-lean participants). Asian participants had a lower prevalence of cirrhosis, history of CVD, cardiovascular events, and diabetes compared with non-Asians, independent of BMI category. After we adjusted for age, sex, and center type and site, the odds of NAFLD-associated cirrhosis in Asians who were lean was almost half the odds of NAFLD-associated cirrhosis in non-Asians who were lean (odds ratio, 0.47; 95% CI, 0.29-0.77).More than 10% participants in a cohort of persons with NAFLD in the United States are lean; Asians account for almost half of the lean persons with NAFLD. Lean participants had a lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-lean persons with NAFLD. Asian participants had a significantly lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-Asians in all BMI categories. ClinicalTrials.gov, Number: NCT02815891.

Background American College of Gastroenterology (ACG) guidelines for the management of adults with Crohn’s disease (CD) in March 2018 state that oral mesalamine, ‘should not be used…to treat CD.’ 1 This abstract estimates the prevalence of any use of mesalamine among patients with CD before and after the implementation of the guideline. It also aims to describe current utilisation patterns of mesalamine in CD by disease phenotype, location, and concomitant use of biologic agents. Methods TARGET-IBD is a longitudinal cohort of IBD patients receiving usual care in the USA; this abstract includes CD patients enrolled between March 2017 and December 2018. Medication use was captured as any use in the follow-up period. Use of mesalamine was stratified into patients who were on mesalamine alone or patients on mesalamine and a biologic. The proportion of patients on mesalamine was estimated in time windows after the policy change to discern penetration into usual practice. Results 732 patients from TARGET-IBD who had baseline data prior to the new recommendation were included. Of these, 14% used mesalamine only, 8% used mesalamine plus a biologic, and 78% did not use mesalamine. A total of 65% received care in academic centres and the median duration of disease at enrolment was 12 years. The distribution of patient characteristics was similar after the policy change. Six months after the ACG recommendation, 11% of patients used mesalamine only, 7% of patients were on mesalamine plus a biologic, and 82% did not use mesalamine. Prevalence of use for the 3 and 6 month time windows was similar. Subsequent therapy changes and additions in patients on mesalamine are shown in Figure 1. Location (colon vs. ileum) and type of CD (inflammatory vs. fistulising) were statistically significant predictors of the odds of any mesalamine use both before and after the policy change (OR 3.233 (CI 1.725–6.061) and 3.334 (CI 1.931–5.755, respectively)). Conclusion Mesalamine use remained stable in the TARGET-IBD CD population, despite the release of the ACG guideline. Individuals with colonic, inflammatory disease were more likely to receive mesalamine, as were Medicare recipients. There was little difference between academic and community practice in implementation of the new standards. Given that the guidelines are relatively new, it is important to follow these participants over a longer period and monitor practice differences and ways to reinforce the practice recommendations to improve the quality and cost of care.

BACKGROUND Children with nonsyndromic orofacial clefts (NS OFCs) may require exceptional children's (EC) services for academic delays. We examined EC service use of children with and without NS OFCs in NC in elementary school. METHODS We included 559 children with NS OFCs and 6,822 children without birth defects who had NC educational records. We estimated prevalence ratios, trends in enrollment, and characteristics of eligibility classification using descriptive statistics and logistic regression by cleft subtype and race/ethnicity. We estimated the odds of third grade retention by EC enrollment using logistic regression with inverse probability of treatment weights. RESULTS Children with NS OFCs were 3.02 (95% CI: 2.50, 3.64) times as likely to receive third grade special education (SE) services compared to unaffected peers. The prevalence odds was highest among children with CL+P (OR: 4.61, 95% CI: 3.49, 6.09) declining by 54% by fifth grade. The prevalence odds of SE for white children was approximately 1.50 times that for African American children in fourth and fifth grades. Approximately 33% of children with NS OFCs within each racial/ethnic group received SE in third grade. African American children were twice as likely to receive services under specific learning disability. Children with NS OFCs receiving EC services were 44% (OR: 0.56; 95% CI: 0.13, 2.38) less likely to be retained in third grade compared to children with NS OFCs who were not receiving services. CONCLUSIONS Children with NS OFCs are more likely to receive SE services in elementary school compared to their unaffected peers. The eligibility category differed by racial/ethnic group.

Background: Epidemiologic studies involving birth defects are extremely sensitive to phenotype accuracy and precision. We devised a case review and classification protocol for a project to study school achievement in children with idiopathic, nonsyndromic orofacial clefts to improve the reliability of phenotypic classification from the statewide birth defects registry. Methods: Surveillance-program abstraction data and medical records at the birth or treating hospitals were used when available. Exclusion criteria included: median cleft lip; Tessier cleft; premaxillary agenesis; presence of a recognizable syndrome, phenotype, association, or sequence (other than Robin sequence); clefts with other malformations not considered to be normal or common variants in the newborn; and cases with documented or suspected genetic or teratogenic causes. Results: Of 712 children identified with orofacial clefts, 153 were excluded, leaving 559 nonsyndromic orofacial cleft cases of unknown cause in the final study. These cases were grouped into the following clinically meaningful types: cleft lip with or without cleft alveolus; cleft lip and cleft palate; and cleft palate only. This review and classification process resulted in the elimination of 21.5% of the original cohort of identified cases, with most exclusions being due to suspected syndromic associations. Conclusion: Verbatim descriptions of the clinical findings are critical for accurate classification of diagnoses. This review process improved the precision of orofacial cleft phenotype classification for our study. Precision would have been further improved if all of the cases had verbatim descriptions of diagnoses and all medical records could have been reviewed by the classification team. Birth Defects Research (Part A) 103:899–903, 2015. © 2015 Wiley Periodicals, Inc.

Background: Clefts of the lip and/or palate (CL/P) carry a social stigma that often causes psychosocial stress. The purpose of this study was to consider the association of cleft phenotype and age with self-reported aspects of psychosocial stress. Methods: Children with nonsyndromic CL/P and unaffected children born between 1997 and 2003 were identified through the North Carolina Birth Defects Monitoring Program and North Carolina birth records, respectively. The psychosocial concerns of children with CL/P were assessed via a 29-question subset of a larger survey. Responses were analyzed according to school age and cleft phenotype (cleft lip with/without cleft alveolus, CL ± A; cleft palate only, CP; or cleft lip with cleft palate, CL + P). Results: Surveys were returned for 176 children with CL/P and 333 unaffected children. When compared with unaffected children, responses differed for CL ± A in 4/29 questions, for CP in 7/29 questions, and for CL + P in 8/29 questions (P < 0.05). When stratified by school age, children with CL/P in elementary, middle, and high school differed from unaffected children by 1/29, 7/29, and 2/29 questions, respectively. Middle school–aged children with CL/P were more affected by aesthetic concerns, bullying, and difficulties with friendship, and social interaction. Children with CL + P reported more severe aesthetic-related concerns than children with CL ± A or CP but experienced similar speech-related distress as children with CP only. Conclusion: Social implications associated with CL/P are most pronounced during middle school, and less so during elementary and high school. This information identifies areas of social improvement aimed at reducing the stigma of CL/P.

Background— Most studies evaluating neurocognitive outcomes in children with congenital heart defects (CHD) have focused on high-risk patients or used specialized, resource-intensive testing. To determine the association of CHD with academic outcomes and compare outcomes according to the severity of CHD, we linked state educational records with a birth defects registry and birth certificates. Methods and Results— We performed a retrospective cohort study using data from the North Carolina Birth Defects Monitoring Program, North Carolina Department of Public Instruction, and North Carolina Department of Health and Human Services vital records. We performed logistic regression, adjusting for maternal education, race/ethnicity, enrollment in public pre-Kindergarten, and gestational age, to determine the association of CHD with not meeting standards on reading and math end-of-grade examinations in third grade in 2006 to 2012. Of 5624 subjects with CHD and 10 832 with no structural birth defects, 2807 (50%) and 6355 (59%) were linked, respectively. Children with CHD had 1.24× the odds of not meeting standards in either reading or math (95% confidence interval, 1.12–1.37), with 44.6% of children with CHD not meeting standards in at least one of these areas compared with 37.5% without CHD. Although children with both critical and noncritical CHD had poorer outcomes, those with critical CHD were significantly more likely to receive exceptional services compared with the noncritical group (adjusted odds ratio, 1.46; 95% confidence interval, 1.15–1.86). Conclusions— Children with all types of CHD have poorer academic outcomes compared with their peers. Evaluation for exceptional services should be considered in children with any type of CHD.

Children born very low birth weight (VLBW) are at an increased risk of delayed development of motor skills. Physical and occupational therapy services may reduce this risk. Among VLBW children, we evaluated whether receipt of physical or occupational therapy services between 9 months and 2 years of age is associated with improved preschool age motor ability. Using data from the Early Childhood Longitudinal Study Birth Cohort we estimated the association between receipt of therapy and the following preschool motor milestones: skipping eight consecutive steps, hopping five times, standing on one leg for 10 seconds, walking backwards six steps on a line, and jumping distance. We used propensity score methods to adjust for differences in baseline characteristics between children who did and did not receive physical or occupational therapy, since children receiving therapy may be at higher risk of impairment. We applied propensity score weights and modeled the estimated effect of therapy on the distance that the child jumped using linear regression. We modeled all other end points using logistic regression. Treated VLBW children were 1.70 times as likely to skip eight steps (RR 1.70, 95 % CI 0.84, 3.44) compared to the untreated group and 30 % more likely to walk six steps backwards (RR 1.30, 95 % CI 0.63, 2.71), although these differences were not statistically significant. We found little effect of therapy on other endpoints. Providing therapy to VLBW children during early childhood may improve select preschool motor skills involving complex motor planning.

The aesthetic aspects of the cleft lip nasal deformity have been appreciated for over a century, but the functional implications have remained largely underappreciated or misunderstood. This study describes the frequency and severity of nasal obstructive symptoms among children with cleft lip and/or cleft palate, addressing the hypotheses that age, cleft type, and severity are associated with the development of nasal obstructive symptoms. Children with nonsyndromic cleft lip and/or cleft palate and a comparison group of unaffected children born from 1997 to 2003 were identified through the North Carolina Birth Defects Monitoring Program and birth certificates. Nasal airway obstruction was measured using the validated Nasal Obstruction Symptom Evaluation scale. The survey was completed by parental proxy for 176 children with cleft lip and/or cleft palate and 333 unaffected children. Nasal obstructive symptoms were more frequently reported in cleft lip with cleft palate compared with unaffected children (p < 0.0001); children who had isolated cleft lip with or without alveolus and isolated cleft palate were not statistically different from unaffected children. Patients with unilateral cleft lip with cleft palate were found to be more severely affected than bilateral cases. Nasal obstruction was observed in early childhood, although severity worsened in adolescence. This population-based study reports a high prevalence of nasal obstructive symptoms in children with cleft lip and/or cleft palate based on type and severity of the cleft. The authors encourage cleft teams to consider using this or similar screening methods to identify which children may benefit from functional rhinoplasty. Risk, I.

The first weeks after childbirth are a critical period for mother and newborn. Women may present with lactation failure and postpartum depression. It is unclear how a woman's early breastfeeding experiences relate to postpartum depression.We estimated the association between early breastfeeding experiences and postpartum depression at 2 months.We modeled this association with logistic regression in a secondary analysis of data from the Infant Feeding Practices Study II. We assessed postpartum depression status with the Edinburgh Postnatal Depression Scale.In the neonatal period, 2,586 women reported ever breastfeeding, among whom 223 (8.6%) met criteria for major depression (Edinburgh Postnatal Depression Scale 13 or greater) at 2 months postpartum. Women who disliked breastfeeding in the first week were more likely to experience postpartum depression at 2 months (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.04-1.93) adjusting for maternal age, parity, education, ethnicity, and postnatal WIC participation. Women with severe breastfeeding pain in the first day (adjusted OR 1.96, 95% CI 1.17-3.29), the first week (adjusted OR 2.13, 95% CI 0.74-6.15 compared with no pain), and the second week (adjusted OR 2.24, 95% CI 1.18-4.26 compared with no pain) were more likely to be depressed. Breastfeeding help appeared protective among women with moderate (adjusted OR 0.22, 95% CI 0.05-0.94) or severe (adjusted OR 0.17, 95% CI 0.04-0.75) pain with nursing.Women with negative early breastfeeding experiences were more likely to have depressive symptoms at 2 months postpartum. Women with breastfeeding difficulties should be screened for depressive symptoms.II.

There has been inconsistent evidence on the association between use of inhaled corticosteroids (ICS) and increased risk of nonvertebral fractures in patients with asthma or chronic obstructive pulmonary disease (COPD). In a large population-based study in the United Kingdom, we estimated the association between fluticasone propionate/salmeterol fixed-dose combination (FSC) and other ICS use and nonvertebral fracture incidence among patients with COPD.We identified a cohort of patients aged ≥ 45 years with COPD in the General Practice Research Database (GPRD) between 2003 and 2006. We used a nested case-control design to estimate the odds of incident nonvertebral fractures associated with prior prescriptions of FSC and other ICS, applying conditional logistic regression and controlling for potential confounders. Exposure to FSC and other ICS was assessed by recency, duration, and number of prescriptions. Average daily dose was defined as low, medium, high, or very high using fluticasone propionate equivalents.We identified 1523 nonvertebral fracture cases among 53 191 patients with COPD at risk in the cohort. Use of FSC in the year prior to the index date was associated with a statistically significant increase in the odds of nonvertebral fractures (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.07-1.47); however, there was no increase in the odds of nonvertebral fractures for other ICS use (OR, 1.12; 95% CI, 0.97-1.30). When examining results by the recent use of prescriptions, an exposure that occurred farther from the index date was associated with a significant increase in nonvertebral fracture (26-52 days prior OR, 1.36; 95% CI, 1.04-1.77; 53-365 days prior OR, 1.39; 95% CI, 1.07-1.78), whereas categories of more recent use (0-12 days prior or 13-25 days prior) were not associated with nonvertebral fractures relative to no FSC use. No pattern of association between increasing levels of FSC or other ICS average daily dose and increased odds of nonvertebral fracture was observed.We did not observe a consistent association between prescriptions of FSC or other ICS in terms of recent use or average daily dose in the prior year and increases in the odds of nonvertebral fractures in patients with COPD, although ever use of FSC was associated with a slight elevation in the odds.

Orofacial clefts (OFCs) include a broad range of facial conditions that differ in cause and disease burden. In the published literature, there is substantial ambiguity in both terminology and classification of OFCs. This article discusses the terminology and classification of OFCs and the epidemiology of OFCs. Demographic, environmental, and genetic risk factors for OFCs are described, including suggestions for family counseling. This article enables clinicians to counsel families regarding the occurrence and recurrence of OFCs. Although much of the information is detailed, it is intended to be accessible to all health professionals for use in their clinical practices.

Breastfeeding durations in the United States fall short of public health objectives. We sought to quantify the prevalence and identify risk factors for early, undesired weaning that mothers attribute to physiologic difficulties with breastfeeding.We analyzed data from the Infant Feeding Practices Study (IFPS) II, a longitudinal study of US women. We defined disrupted lactation as early, undesired weaning attributed to at least two of the following three problems: breast pain, low milk supply, and difficulty with infant latch. We used logistic regression to estimate the association maternal body mass index (BMI), postpartum depressive symptoms, and disrupted lactation.Of 4,902 women enrolled in the IFPS II, we analyzed 2,335 women who reported prenatal intention and breastfeeding initiation. The prevalence of disrupted lactation was 12 per 100 women (95% confidence interval [CI] 11, 13) during the first year of life. Women in this group weaned earlier (median 1.2 months, interquartile range [IQR] 0.5-2.8) than women without disrupted lactation (median 7.0 months, IQR 2.8-2.0, p0.01). In multivariable-adjusted (MV-adj.) models, we found increased odds of disrupted lactation among overweight (odds ratio [OR] 1.6, 95% CI 1.1-2.3) or obese (OR 1.7, 95% CI 1.2-2.6) women, compared with women with a normal pregravid BMI. Maternal depressive symptoms at 2 months, defined as Edinburgh Postnatal Depression Scale ≥13, were also associated with disrupted lactation (MV-adj. OR 1.7, 95% CI 1.1-2.7).In a longitudinal sample of US women, disrupted lactation affected one in eight mothers who initiated breastfeeding. These findings underscore the need for both improved early breastfeeding support and targeted research to define the underlying pathophysiology and to determine management strategies that will enable more mothers to achieve their breastfeeding goals.

The Federal Emergency Management Agency (FEMA) has developed an emergency response training program, which is divided into five sections: orientation, drill, tabletop, functional, and full-scale. Each section provides skills that are expanded through subsequent exercises. Suggestions are given for implementing the FEMA training model to the needs of cultural institutions. The Missouri Local Records Preservation Program's archivists were trained in emergency preparedness and response methods for books, papers, photographs, and electronic media by adapting FEMA's model. This article concludes with resources for developing similar training programs.

An investigation of 20th-centuzy Customark chemical watermarks beginning with methods of identification is reported. Experimentation with various conservation treatment steps on these materials gave conflicting results. Erasers seemed not to affect the watermark. Organic chemicals quickly altered the chemical watermark visually, yet under ultraviolet examination the mark appeared unaltered. Conversely, exposure to other solutions left the watermark visually undisturbed yet indistinct under ultraviolet illumination. It is hypothesized that component parts of the chemical watermark and perhaps paper brighteners, fillers, and/or sizing agents were moved by treatment methods, altering the mark.

Long-Term Clinical and Holistic Outcomes in Children with Cleft Lip and/or Palate: A Multidisciplinary, MixedMethods Approach Alexander C Allori, MD, MPH, Irene J Pien, Danielle L Sobol, Anna R Carlson, MD, Stephanie Watkins, MD, MSPH, Arthur S Aylsworth, MD, Robert E Meyer, PhD, Luiz Pimenta, DDS, PhD, Ronald Strauss, DMD, PhD, Jeffrey R Marcus, MD, FACS Duke University, Durham, NC, University of North Carolina, Chapel Hill, NC, Department of Health and Human Services, Raleigh, NC

Zolmitriptan is a potent selective 5HT1B/1D receptor agonist for acute migraine therapy. Zolmitriptan has vasoconstrictor activity in cerebral vessels and may cause slight elevations of blood pressure in subjects without hypertension. Therefore, the pharmacokinetics and pharmacodynamics of zolmitriptan (5, 10, and 20 mg) were evaluated in 16 patients with mild to moderate hypertension (controlled by hydrochlorothiazide 50 mg once daily) and 17 healthy age- and sex-matched control subjects in a randomized, placebo-controlled, double-blind, four-period crossover study. The pharmacokinetics of zolmitriptan and its metabolites were dose proportional. Although area under the concentration-time curve (AUC0-infinity) and maximum concentration (Cmax) were slightly higher in patients with hypertension at all doses, this was only statistically significant for AUC at the 20-mg dose. Differences between subjects with and without hypertension were not clinically significant. Zolmitriptan produced a small increase in blood pressure, but this was similar in subjects with and without hypertension and was of no clinical significance. Zolmitriptan was well tolerated in both groups. Zolmitriptan plasma concentrations were higher in women than in men, with higher values of AUC and Cmax and lower total clearance in women. These results indicate that zolmitriptan can be administered for treatment of migraine in patients with controlled hypertension without dose adjustment.

Reports suggest that people who drive while intoxicated by alcohol may do so repeatedly. We hypothesized that persons arrested for driving while impaired might be at increased risk for death in an alcohol-related motor vehicle crash. To evaluate this possibility, we studied the deaths of drivers in alcohol-related motor vehicle accidents in North Carolina over a 10-year period.We compared drivers who died in motor vehicle crashes from 1980 through 1989 and who had blood alcohol concentrations of at least 20 mg per deciliter (4.3 mmol per liter), referred to as the case drivers, with those who died in crashes but had blood alcohol concentrations below 20 mg per deciliter, referred to as the control drivers. We identified case drivers and control drivers through the state Medical Examiner System. We then searched North Carolina driver-history files for the five years before each death to identify arrests for driving while impaired.We linked a total of 1646 case drivers and 1474 control drivers to their driver-history files. Case drivers were more likely than control drivers to have been arrested for driving while impaired (26 percent vs. 3 percent). After we controlled for potential confounding variables, case drivers 21 to 34 years of age were 4.3 times more likely (95 percent confidence interval, 2.7 to 6.8) than control drivers to have been arrested for driving while impaired; case drivers 35 years of age or older were 11.7 times more likely (95 percent confidence interval, 6.8 to 20.1). The strength of the association appeared to increase with the number of prior arrests. Case drivers were also more likely than the general population of currently licensed drivers to have been arrested.Arrests for driving while impaired substantially increase the risk of eventual death in an alcohol-related crash. Aggressive intervention in the cases of people arrested for driving while impaired may decrease the likelihood of a future fatal alcohol-related crash.

David P Miller, Stephanie E Watkins, Tim Sampson, Kourtney J Davis WorldWide Epidemiology, GlaxoSmithKline, Durham, NC, USA Objectives: Some large population-based studies have reported a dose-related increased risk of cataracts and glaucoma associated with use of inhaled corticosteroids (ICS) in patients with asthma or chronic obstructive pulmonary disease (COPD). We evaluated the association between use of ICS-containing products, specifically fluticasone propionate/salmeterol fixed-dose combination (FSC), and incidence of cataracts and glaucoma among patients with COPD in a large electronic medical record database in the United Kingdom. Methods: We identified a cohort of patients aged 45 years and over with COPD in the General Practice Research Database (GPRD) between 2003 and 2006. Cases of incident cataracts or glaucoma were defined based on diagnosis and procedure codes and matched to controls from the risk set to estimate odds ratios (OR) and 95% confidence intervals (CI). The association with FSC or ICS exposure was modeled using conditional logistic regression. Medication exposure was assessed with respect to recency, duration, and number of prescriptions prior to the index date. Average daily dose was defined as none, low (1–250 mcg), medium (251–500 mcg), high (501–1000 mcg), or very high (1001+ mcg) using fluticasone propionate (FP) equivalents. Results: We identified 2941 incident cataract cases and 327 incident glaucoma cases in the COPD cohort (n = 53,191). FSC or ICS prescriptions were not associated with risk of incident cataracts or glaucoma for any exposure category, after adjusting for confounders. We observed a lack of a dose response in all analyses, where low dose was the reference group. The odds of cataracts associated with FSC dose were medium OR: 1.1 (95% CI: 0.9–1.4); high OR: 1.2 (95% CI: 0.9–1.5); and very high OR: 1.2 (95% CI: 0.9–1.7). The odds of glaucoma associated with FSC dose: medium OR: 1.0 (95% CI: 0.5–2.1); high OR: 1.0 (95% CI: 0.5–2.0); and very high OR: 1.0 (95% CI: 0.4–2.8). Conclusions: FSC or other ICS exposure was not associated with an increased odds of cataracts or glaucoma, nor was a dose–response relationship observed in this population-based nested case-control study of COPD patients in the United Kingdom. Keywords: inhaled corticosteroids, fluticasone ropionate/salmeterol, cataracts, glaucoma, risk

• Few data are available on energy requirements of mechanically ventilated, critically ill children. We measured the resting energy expenditure in 18 mechanically ventilated patients between ages 2 and 18 years, using indirect calorimetry. All patients had fractional inspired oxygen concentration less than 0.6, no spontaneous respirations, hemodynamic stability, and no fever or active infection, and were receiving 5% dextrose. All subjects were hypermetabolic, since the measured resting energy expenditure divided by the predicted basal energy expenditure from the Harris-Benedict equations was 1.48 ±0.09 (mean±SEM). The energy requirements calculated using "injury factors" and "activity factors" adapted for adults is 1.62 times basal energy expenditure. The injury factor for the pediatric multiple trauma patients should be 1.25 compared with 1.35 in adults. In these pediatric intensive care patients 33% ± 8% of the energy is derived from carbohydrates, 53% ± 8% from fat, and 14% ± 2% from protein oxidation. In individual critically ill pediatric patients, energy requirements should be estimated by measuring their resting energy expenditure whenever possible and adding 5% for their activity. In the absence of the actual measurement of resting energy expenditure, the recommended energy requirement is 1.5 times basal energy expenditure. In this acute phase of injury, the daily nitrogen requirement is 250 mg per kilogram of body weight. ( AJDC . 1989;143:490-492)