BACKGROUND: Fentanyl is commonly used in preterm infants. Relatively little is known regarding the neurodevelopmental outcomes of preterm infants exposed to fentanyl. OBJECTIVE: To investigate the association between cumulative fentanyl dose and brain injury and diameters in a cohort of preterm infants. METHODS: Data on demographics, perinatal course, and neonatal course, including total fentanyl exposure prior to term equivalent age, were retrospectively evaluated for 103 infants born at ≤30 weeks gestational age (mean gestational age 26.9 ± 1.8 weeks) who underwent magnetic resonance imaging at term equivalent age. Magnetic resonance images were evaluated for brain injury and regional brain diameters. Developmental testing was conducted at term equivalent and 2 years of age. RESULTS: Seventy-eight infants (76%) received fentanyl (median cumulative dose 3 µg/kg, interquartile range 1-441 µg/kg). Cumulative fentanyl dose in the first week of life correlated with the incidence of cerebellar hemorrhage after correction for covariates (odds ratio 2.1, 95% confidence interval 1.1-4.1). Cumulative fentanyl dose before term equivalent age correlated with reductions in transverse cerebellar diameter after correction for covariates, including the presence of cerebellar hemorrhage (r = 0.461, P = 0.002). No correlation was detected between cumulative fentanyl dose and development at 2 years of age. CONCLUSIONS: Higher cumulative fentanyl dose in preterm infants correlated with a higher incidence of cerebellar injury and lower cerebellar diameter at term equivalent age. Our findings must be taken with caution, but emphasize the need for future prospective trials examining the risks and benefits of commonly used analgesic agents in preterm infants.

BACKGROUND: Few treatments are available to directly address employment or work functioning among individuals with bipolar disorder (BD) and currently available treatment models have not been evaluated to examine their impact employment outcomes. We examined impact of affective symptoms and health-related quality of life (HRQoL) on longitudinal employment outcomes in a community-based sample of individuals with bipolar disorder who completed the Life Goals-Collaborative Care (LG-CC) intervention. METHODS: Participants (N=178) were assessed based on HRQoL, employment status, affective symptoms (depressive/manic), and work hours at baseline, 6-, 12- and 24-months after initiation of LG-CC. Frequency of LG-CC sessions and number of care-manager contacts also were ascertained. RESULTS: At baseline, 21% were employed, 29.5% were unemployed, and 49.6% were on disability. Improvement in affective symptoms was seen over the 24-month period, but not in HRQoL. Lower depression symptoms, but not mania, at baseline predicted greater likelihood of employment status in 24-months. Degree of LG-CC participation was associated with a reduced likelihood of becoming disabled/unemployed and increased number of hours worked in 24-months. LIMITATIONS: The study was originally designed to compare implementation strategies and not the effectiveness of LG-CC on employment outcomes. Further, it was unclear whether improvement in work functioning were personal goals of the participants of this study. CONCLUSIONS: Fewer depressive symptoms were associated with positive employment outcomes over time. Collaborative Care Models that are already implemented by existing providers that focus on management of affective symptoms show promise in positively impacting employment outcomes.

Histone lysine demethylase KDM4/JMJD2s are overexpressed in many human tumors including prostate cancer (PCa). KDM4s are co-activators of androgen receptor (AR) and are thus potential therapeutic targets. Yet to date few KDM4 inhibitors that have anti-prostate tumor activity in vivo have been developed. Here, we report the anti-tumor growth effect and molecular mechanisms of three novel KDM4 inhibitors (A1, I9, and B3). These inhibitors repressed the transcription of both AR and BMYB-regulated genes. Compound B3 is highly selective for a variety of cancer cell lines including PC3 cells that lack AR. B3 inhibited the in vivo growth of tumors derived from PC3 cells and ex vivo human PCa explants. We identified a novel mechanism by which KDM4B activates the transcription of Polo-like kinase 1 (PLK1). B3 blocked the binding of KDM4B to the PLK1 promoter. Our studies suggest a potential mechanism-based therapeutic strategy for PCa and tumors with elevated KDM4B/PLK1 expression.

BACKGROUND: Children and adolescents with autism spectrum disorder (ASD) have many well-known health concerns, yet health conditions in adults with ASD remain poorly defined. OBJECTIVE: To examine health conditions and functional status in adults with ASD and identify factors associated with health and functional status across age cohorts. DESIGN AND SUBJECTS: We collected cross-sectional data from 255 adult subjects aged 18 to 71 years with ASD using the Rochester Health Status Survey IV (RHSS-IV), a 58-item validated survey instrument. We used the National Health and Nutritional Examination Survey and National Health Interview Survey to provide comparative prevalence rates in the general population. RESULTS: Compared to the general population, young adults aged 18-29 with ASD had a substantially higher prevalence of seizure disorder (11.2 % vs. 1.4 %; p = 0.002), depression (16.4 % vs. 6.4 %; p = 0.007), hypertension (12.9 % vs. 6.3 %; p = 0.05), and allergies (39.7 % vs. 8.4 %; p < 0.001). In contrast, young adults with ASD had considerably lower rates of sexually transmitted illness (STI) (0.9 % vs. 4.3 %; p = 0.03), tobacco use (5.2 % vs. 31.9 %; p < 0.001), and alcohol misuse (0.9 % vs. 11.9 %; p < 0.001). Adults 40 and over with ASD also had higher rates of seizure disorder (29.2 % vs. 1.7 %; p < 0.001), lower tobacco use (2.8 % vs. 24.5 %; p < 0.001), and lower alcohol misuse (1.4 % vs. 18.2 %; p < 0.001) compared to the general population. Amongst the 55 % of participants with a documented IQ score, 91 % had an intellectual disability (IQ < 70). Within the cohort aged 40 years old and older, only 54.2 % were independent with eating, 43.0 % independent with dressing, and 43.1 % independent with bathing. Lower IQ and depression were associated with lower functional status. CONCLUSIONS: Adults with ASD have a high prevalence of seizure disorders and depression, but low rates of STIs, tobacco use, and alcohol misuse. Within our cohort, the majority of older adults with ASD required some assistance with activities of daily living.

BACKGROUND: Lysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile. RESULTS: Substantial disease burden at baseline included a very high level of low-density lipoprotein cholesterol (≥190 mg per deciliter) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase level was normal in 11 of 36 patients (31%) in the sebelipase alfa group and in 2 of 30 (7%) in the placebo group (P=0.03), with mean changes from baseline of -58 U per liter versus -7 U per liter (P<0.001). With respect to prespecified key secondary efficacy end points, we observed improvements in lipid levels and reduction in hepatic fat content (P<0.001 for all comparisons, except P=0.04 for triglycerides). The number of patients with adverse events was similar in the two groups; most events were mild and were considered by the investigator to be unrelated to treatment. CONCLUSIONS: Sebelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency. (Funded by Synageva BioPharma and others; ARISE ClinicalTrials.gov number, NCT01757184.).

Motor impairments are prevalent in children with autism spectrum disorder. The Serial Reaction Time Task, a well-established visuomotor sequence learning probe, has produced inconsistent behavioral findings in individuals with autism. Moreover, it remains unclear how underlying neural processes for visuomotor learning in children with autism compare to processes for typically developing children. Neural activity differences were assessed using functional magnetic resonance imaging during a modified version of the Serial Reaction Time Task in children with and without autism. Though there was no group difference in visuomotor sequence learning, underlying patterns of neural activation significantly differed when comparing sequence (i.e., learning) to random (i.e., nonlearning) blocks. Children with autism demonstrated decreased activity in brain regions implicated in visuomotor sequence learning: superior temporal sulcus and posterior cingulate cortex. The findings implicate differences in brain mechanisms that support initial sequence learning in autism and can help explain behavioral observations of autism-associated impairments in skill development (motor, social, communicative) reliant on visuomotor integration.

IMPORTANCE: Clostridium difficile is a major cause of health care-associated infection, but disagreement between diagnostic tests is an ongoing barrier to clinical decision making and public health reporting. Molecular tests are increasingly used to diagnose C difficile infection (CDI), but many molecular test-positive patients lack toxins that historically defined disease, making it unclear if they need treatment. OBJECTIVE: To determine the natural history and need for treatment of patients who are toxin immunoassay negative and polymerase chain reaction (PCR) positive (Tox-/PCR+) for CDI. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational cohort study at a single academic medical center among 1416 hospitalized adults tested for C difficile toxins 72 hours or longer after admission between December 1, 2010, and October 20, 2012. The analysis was conducted in stages with revisions from April 27, 2013, to January 13, 2015. MAIN OUTCOMES AND MEASURES: Patients undergoing C difficile testing were grouped by US Food and Drug Administration-approved toxin and PCR tests as Tox+/PCR+, Tox-/PCR+, or Tox-/PCR-. Toxin results were reported clinically. Polymerase chain reaction results were not reported. The main study outcomes were duration of diarrhea during up to 14 days of treatment, rate of CDI-related complications (ie, colectomy, megacolon, or intensive care unit care) and CDI-related death within 30 days. RESULTS: Twenty-one percent (293 of 1416) of hospitalized adults tested for C difficile were positive by PCR, but 44.7% (131 of 293) had toxins detected by the clinical toxin test. At baseline, Tox-/PCR+ patients had lower C difficile bacterial load and less antibiotic exposure, fecal inflammation, and diarrhea than Tox+/PCR+ patients (P < .001 for all). The median duration of diarrhea was shorter in Tox-/PCR+ patients (2 days; interquartile range, 1-4 days) than in Tox+/PCR+ patients (3 days; interquartile range, 1-6 days) (P = .003) and was similar to that in Tox-/PCR- patients (2 days; interquartile range, 1-3 days), despite minimal empirical treatment of Tox-/PCR+ patients. No CDI-related complications occurred in Tox-/PCR+ patients vs 10 complications in Tox+/PCR+ patients (0% vs 7.6%, P < .001). One Tox-/PCR+ patient had recurrent CDI as a contributing factor to death within 30 days vs 11 CDI-related deaths in Tox+/PCR+ patients (0.6% vs 8.4%, P = .001). CONCLUSIONS AND RELEVANCE: Among hospitalized adults with suspected CDI, virtually all CDI-related complications and deaths occurred in patients with positive toxin immunoassay test results. Patients with a positive molecular test result and a negative toxin immunoassay test result had outcomes that were comparable to patients without C difficile by either method. Exclusive reliance on molecular tests for CDI diagnosis without tests for toxins or host response is likely to result in overdiagnosis, overtreatment, and increased health care costs.

IMPORTANCE: Electronic cigarettes (e-cigarettes) may help smokers reduce the use of traditional combustible cigarettes. However, adolescents and young adults who have never smoked traditional cigarettes are now using e-cigarettes, and these individuals may be at risk for subsequent progression to traditional cigarette smoking. OBJECTIVE: To determine whether baseline use of e-cigarettes among nonsmoking and nonsusceptible adolescents and young adults is associated with subsequent progression along an established trajectory to traditional cigarette smoking. DESIGN, SETTING, AND PARTICIPANTS: In this longitudinal cohort study, a national US sample of 694 participants aged 16 to 26 years who were never cigarette smokers and were attitudinally nonsusceptible to smoking cigarettes completed baseline surveys from October 1, 2012, to May 1, 2014, regarding smoking in 2012-2013. They were reassessed 1 year later. Analysis was conducted from July 1, 2014, to March 1, 2015. Multinomial logistic regression was used to assess the independent association between baseline e-cigarette use and cigarette smoking, controlling for sex, age, race/ethnicity, maternal educational level, sensation-seeking tendency, parental cigarette smoking, and cigarette smoking among friends. Sensitivity analyses were performed, with varying approaches to missing data and recanting. EXPOSURES: Use of e-cigarettes at baseline. MAIN OUTCOMES AND MEASURES: Progression to cigarette smoking, defined using 3 specific states along a trajectory: nonsusceptible nonsmokers, susceptible nonsmokers, and smokers. Individuals who could not rule out smoking in the future were defined as susceptible. RESULTS: Among the 694 respondents, 374 (53.9%) were female and 531 (76.5%) were non-Hispanic white. At baseline, 16 participants (2.3%) used e-cigarettes. Over the 1-year follow-up, 11 of 16 e-cigarette users and 128 of 678 of those who had not used e-cigarettes (18.9%) progressed toward cigarette smoking. In the primary fully adjusted models, baseline e-cigarette use was independently associated with progression to smoking (adjusted odds ratio [AOR], 8.3; 95% CI, 1.2-58.6) and to susceptibility among nonsmokers (AOR, 8.5; 95% CI, 1.3-57.2). Sensitivity analyses showed consistent results in the level of significance and slightly larger magnitude of AORs. CONCLUSIONS AND RELEVANCE: In this national sample of US adolescents and young adults, use of e-cigarettes at baseline was associated with progression to traditional cigarette smoking. These findings support regulations to limit sales and decrease the appeal of e-cigarettes to adolescents and young adults.

OBJECTIVE: To examine the association between expanded access to collaborative midwifery and laborist services and cesarean delivery rates. METHODS: This was a prospective cohort study at a community hospital between 2005 and 2014. In 2011, privately insured women changed from a private practice model to one that included 24-hour midwifery and laborist coverage. Primary cesarean delivery rates among nulliparous, term, singleton, vertex women and vaginal birth after cesarean delivery (VBAC) rates among women with prior cesarean delivery were compared before and after the change. Multivariable logistic regression models estimated the effects of the change on the odds of primary cesarean delivery and VBAC; an interrupted time-series analysis estimated the annual rates before and after the expansion. RESULTS: There were 3,560 nulliparous term singleton vertex deliveries and 1,324 deliveries with prior cesarean delivery during the study period; 45% were among privately insured women whose care model changed. The primary cesarean delivery rate among these privately insured women decreased after the change, from 31.7% to 25.0% (P=.005, adjusted odds ratio [OR] 0.56, 95% confidence interval [CI] 0.39-0.81). The interrupted time-series analysis estimated a 7% drop in the primary cesarean delivery rate in the year after the expansion and a decrease of 1.7% per year thereafter. The VBAC rate increased from 13.3% before to 22.4% afterward (adjusted OR 2.03, 95% CI 1.08-3.80). CONCLUSION: The change from a private practice to a collaborative midwifery-laborist model was associated with a decrease in primary cesarean rates and an increase in VBAC rates. LEVEL OF EVIDENCE: II.

TP53 (which encodes p53 protein) is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumour suppressive function and lead to a 'gain-of-function' (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (also known as KMT2A), MLL2 (also known as KMT2D), and acetyltransferase MOZ (also known as KAT6A or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumours, but not in wild-type p53 or p53 null tumours. Cancer cell proliferation is markedly lowered by genetic knockdown of MLL1 or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumours with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.