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Summary Background Adults hospitalised to a non-intensive care unit (ICU) ward with moderately severe community-acquired pneumonia are frequently treated with broad-spectrum antibiotics, despite Dutch guidelines recommending narrow-spectrum antibiotics. Therefore, we investigated whether an antibiotic stewardship intervention would reduce the use of broad-spectrum antibiotics in patients with moderately severe community-acquired pneumonia without compromising their safety. Methods In this cross-sectional, stepped-wedge, cluster-randomised, non-inferiority trial (CAP-PACT) done in 12 hospitals in the Netherlands, we enrolled immunocompetent adults (≥18 years) who were admitted to a non-ICU ward and had a working diagnosis of moderately severe community-acquired pneumonia. All participating hospitals started in a control period and every 3 months a block of two hospitals transitioned from the control to the intervention period, with all hospitals eventually ending in the intervention period. The unit of randomisation was the hospital (cluster), and electronic randomisation (by an independent data manager) decided the sequence (the time of intervention) by which hospitals would cross over from the control period to the intervention period. Blinding was not possible. The antimicrobial stewardship intervention was a bundle targeting health-care providers and comprised education, engaging opinion leaders, and prospective audit and feedback of antibiotic use. The co-primary outcomes were broad-spectrum days of therapy per patient, tested by superiority, and 90-day all-cause mortality, tested by non-inferiority with a non-inferiority margin of 3%, and were analysed in the intention-to-treat population, comprising all patients who were enrolled in the control and intervention periods. This trial was prospectively registered at ClinicalTrials.gov , NCT02604628 . Findings Between Nov 1, 2015, and Nov 1, 2017, 5683 patients were assessed for eligibility, of whom 4084 (2235 in the control period and 1849 in the intervention period) were included in the intention-to-treat analysis. The adjusted mean broad-spectrum days of therapy per patient were reduced from 6·5 days in the control period to 4·8 days in the intervention period, yielding an absolute reduction of –1·7 days (95% CI –2·4 to –1·1) and a relative reduction of 26·6% (95% CI 18·0–35·3). Crude 90-day mortality was 10·9% (242 of 2228 died) in the control period and 10·8% (199 of 1841) in the intervention period, yielding an adjusted absolute risk difference of 0·4% (90% CI –2·7 to 2·4), indicating non-inferiority. Interpretation In patients hospitalised with moderately severe community-acquired pneumonia, a multifaceted antibiotic stewardship intervention might safely reduce broad-spectrum antibiotic use. Funding None.

There is a positive cross-sectional relationship between alcohol-related proactive dietary restriction to feel the effects of alcohol faster (APDR) and binge drinking, a health and safety issue impacting college students.Ordinal logistic regression was used to model the relationship between APDR and binge drinking frequency.Main findings suggest APDR of students who reported eating less than usual (low APDR) prior to drinking to feel the effects of alcohol faster was a significant predictor of binge drinking frequency (1.27 (95% CI, 0.06 to 0.42), WaldLow APDR is a significant predictor of binge drinking frequency that is established early in the first semester of college with no significant change occurring in binge drinking frequency over the course of students' freshman year at 7-month follow-up. Campus health professionals are urged to emphasize the detrimental health effects of low APDR early in the first semester of college.

Zusammenfassung Einleitung Die perioperative Betreuung kolorektalchirurgischer Patienten nach dem Fast-Track-Konzept wurde in den letzten Jahren zunehmend standardisiert und ist als strukturierte Betreuungsmethode zur Reduktion perioperativer Komplikationen weithin akzeptiert. Erste Untersuchungen lassen sogar einen langfristigen positiven Effekt auf das onkologische Outcome vermuten, sofern eine Adhärenz der Einzelmaßnahmen von mindestens 70% besteht. Trotz eindeutiger Evidenz für die Wirksamkeit des modernen perioperativen Behandlungskonzeptes bleibt die Einhaltung des Protokolls im klinischen Alltag, insbesondere in Deutschland, eine Herausforderung. Ziel dieser Studie war es, die Adhärenzrate vor und nach Einführung einer SOP zu erfassen und deren Wirksamkeit zu evaluieren. Methoden Es erfolgte eine retrospektive Analyse der Patientendaten aller elektiven kolorektalchirurgischen Operationen der Bonner Universitätsklinik von 2017 bis 2020. 153 Patienten wurden vor der Implementierung der SOP im Januar 2019 operiert (Gruppe I), die restlichen 153 Patienten wurden nach der Implementierung der SOP operiert und entsprechend betreut (Gruppe II). Die Protokolladhärenz wurde sowohl für die einzelnen Schlüsselinterventionen als auch für das Gesamtkonzept analysiert. Ergebnisse Zwar konnte sowohl für verschiedene Einzelmaßnahmen (Prähabilitation Gruppe I: 5,9%, Gruppe II: 42,5%, p Fazit Obwohl die Implementierung der SOP zu einer signifikanten Verbesserung der Umsetzungsrate geführt hat, besteht noch weiterer Optimierungsbedarf, um die empfohlene Protokolladhärenz von 70% zu erreichen. Klinikintern kann hierbei neben der Gründung interdisziplinärer Fast-Track-Teams eine spezialisierte Fast-Track-Pflegekraft als Bindeglied zwischen Patienten, Pflege und Ärzten hilfreich sein. Für eine flächendeckende, deutschlandweite Implementierung hingegen sind Maßnahmen mit größerer Hebelkraft notwendig. Eine Hilfestellung wird hierbei die in Arbeit befindliche S3-Leitlinie zum perioperativen Management gastrointestinaler Tumoren geben, insbesondere als Argumentationsgrundlage gegenüber Kostenträgern.

Objectives This systematic review evaluated the evidence for the effectiveness of Photodynamic therapy (PDT) in treating oral fungal infections, as an alternative to conventional antifungal medications. Methods Five randomized control trials (168 participants) comparing the treatment of oral fungal infections using met with our inclusion criteria. Clinical and microbiological improvement was assessed by random‐effects meta‐analysis. Methodological quality assessment and heterogeneity were performed using peer‐reviewed criteria. PROSPERO registration: CRD42017076. Results PDT showed statistically non‐significant increased clinical efficacy (risk ratio (RR) = 1.47 [95% confidence interval (CI), 0.68; 3.17]; three studies, n = 108 participants, I 2 = 50%) and mycological efficacy (mean difference (MD) = 0.54 [95%CI, −0.71; 1.79]; three studies, n = 100; I 2 = 39%) at 30 days, as compared with conventional antifungal therapy. Lack of standardization of treatment parameters and variability in the assessment of outcomes was observed across the studies. All included studies had a moderate to low risk of bias. Conclusions PDT showed comparable effectiveness at treating oral fungal infections, particularly denture stomatitis. The small number of studies in this review, small sample size and variability of methods and outcome measures across studies, highlight the need for more standardized studies with longer follow‐up periods to enable recommendation of PDT as an alternative to conventional antifungal therapy.

Background Ondansetron is commonly used to treat nausea and vomiting in pregnancy despite inconclusive evidence of its safety. Previous studies have reported no increase in risk of miscarriage but relied on methods that failed to account for gestational weeks at risk and non-user comparators, which may increase the potential for unmeasured confounding. Our objective was to estimate the risk of miscarriage among women prescribed ondansetron vs alternative antiemetics during the first 20 weeks of pregnancy. Methods A pregnancy cohort was created using electronic health record data from a health care system in North Carolina. Women were classified as exposed to either ondansetron or comparator antiemetics (metoclopramide or promethazine) based on the first antiemetic prescription received in the first 20 weeks of gestation. Cumulative incidence of miscarriage at 20 weeks was estimated in each antiemetic group. Hazard ratios (HR) were estimated with 95% confidence intervals and measured confounding was controlled using inverse probability of treatment weights. Sensitivity analyses assessed the potential impact of exposure misclassification, latency period, and selection bias. Results We identified 2620 eligible pregnancies with antiemetic orders; 65% had a first ondansetron order and 35% had a first comparator antiemetic order. In total, 95 women had a miscarriage. After adjustment, there was no difference in risk of miscarriage (HR 1.21, 95% CI 0.77, 1.90). Results from the per-protocol and other sensitivity analyses were similar to the main analysis. Conclusions We did not observe an increase in the risk of miscarriage for pregnancies exposed to ondansetron vs comparator antiemetics.

Almost half of chronic obstructive pulmonary disease (COPD) exacerbations are estimated to be inaccurately reported by patients, inconsistently recorded in medical records, or not measured due to coding errors inherent to administrative claims. This retrospective observational study aimed to develop an algorithm capable of detecting acute COPD exacerbations (AECOPD) in healthcare claims and estimate costs associated with AECOPD over a 12-month period. Commercial and Medicare Advantage healthcare plan members (≥40 years old) with evidence of COPD were identified from US healthcare-claims database. To refine the algorithm detecting AECOPD in claims data, sensitivity and positive-predictive value calculations were performed to compare AECOPD identification in healthcare claims versus medical charts. Analyses were also performed to examine total exacerbation-related costs for events identified with the new claims algorithm plus events missed. The final algorithm had a sensitivity of 84.9%, with a positive-predictive value of 67.5%. Medical records were abstracted for 402 patients. In the overall sample of healthcare claims (

Hypercalcemia is an ominous development in the course of malignancy associated with a mean survival of only several months. A majority of cases of hypercalcemia are related to humoral hypercalcemia of malignancy (HHM), where hypercalcemia is caused by increased levels of circulating parathyroid hormone-related protein (PTHrP). Mainstay treatments in the management of HHM are intravenous fluids, intravenous bisphosphonates, and subcutaneous denosumab, although hypercalcemia oftentimes recurs despite these efforts. We present a case of advanced non-small cell lung cancer with PTHrP-mediated hypercalcemia that proved resistant to standard therapy. A trial of oral cinacalcet was initiated and improved calcium levels for 2 months despite a progressive rise in PTHrP and prior to subsequent disease progression. Based on the current body of literature, we propose that this calcium-lowering effect of cinacalcet occurs due to a potential effect on renal calcium excretion.

The United States Environmental Protection Agency (US EPA) is currently refining its approach for risk assessments conducted under the amended Toxic Substances Control Act (TSCA), largely based on recommendations from the National Academies of Sciences, Engineering, and Medicine (NASEM). We identified several issues with the current TSCA risk assessment approach that were not addressed by NASEM in its recommendations. Here, we demonstrate these issues with a case study of the 'Risk Evaluation for Asbestos, Part 1: Chrysotile Asbestos,' which US EPA released in December 2020. In this evaluation, US EPA found that occupational and some consumer uses of automotive brakes and clutches that contain asbestos result in unreasonable risks. These risks were calculated from estimated exposures during brake work and an inhalation unit risk (IUR) developed for chrysotile asbestos. We found that US EPA overestimated risk as a result of unrealistic inputs to both the exposure and toxicity components of the risk equation, and because the Agency did not fully consider relevant epidemiology and toxicity evidence in its systematic review. Our evaluation demonstrates areas in which the TSCA risk assessment approach could be improved to result in risk evaluations that are supported by the available scientific evidence.

Background: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may be a risk factor for neurodevelopmental deficits and disorders, but evidence is inconsistent. Objectives: We investigated whether prenatal exposure to PFAS were associated with childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). Methods: This study was based on the Norwegian Mother, Father and Child Cohort Study and included n = 821 ADHD cases, n = 400 ASD cases and n = 980 controls. Diagnostic cases were identified by linkage with the Norwegian Patient Registry. In addition, we used data from the Medical Birth Registry of Norway. The study included the following PFAS measured in maternal plasma sampled mid-pregnancy: Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptanesulfonic acid (PFHpS), and perfluorooctane sulfonate (PFOS). Relationships between individual PFAS and ADHD or ASD diagnoses were examined using multivariable adjusted logistic regression models. We also tested for possible non-linear exposure-outcome associations. Further, we investigated the PFAS mixture associations with ASD and ADHD diagnoses using a quantile-based g-computation approach. Results: Odds of ASD was significantly elevated in PFOA quartile 2 [OR = 1.71 (95% CI: 1.20, 2.45)] compared to quartile 1, and PFOA appeared to have a non-linear, inverted U-shaped dose-response relationship with ASD. PFOA was also associated with increased odds of ADHD, mainly in quartile 2 [OR = 1.54 (95% CI: 1.16, 2.04)] compared to quartile 1, and displayed a non-linear relationship in the restricted cubic spline model. Several PFAS (PFUnDA, PFDA, and PFOS) were inversely associated with odds of ADHD and/or ASD. Some of the associations were modified by child sex and maternal education. The overall PFAS mixture was inversely associated with ASD [OR = 0.76 (95% CI: 0.64, 0.90)] as well as the carboxylate mixture [OR = 0.79 (95% CI: 0.68, 0.93)] and the sulfonate mixture [OR = 0.84 (95% CI: 0.73, 0.96)]. Conclusion: Prenatal exposure to PFOA was associated with increased risk of ASD and ADHD in children. For some PFAS, as well as their mixtures, there were inverse associations with ASD and/or ADHD. However, the inverse associations reported herein should not be interpreted as protective effects, but rather that there could be some unresolved confounding for these relationships. The epidemiologic literature linking PFAS exposures with neurodevelopmental outcomes is still inconclusive, suggesting the need for more research to elucidate the neurotoxicological potential of PFAS during early development.

Background The vaginal microbiome has been associated with adverse pregnancy outcomes, but information on the impact of diet on microbiome composition is largely unexamined. Objective To estimate the association between prenatal diet and vaginal microbiota composition overall and by race. Methods We leveraged a racially diverse prenatal cohort of North Carolina women enrolled between 1995 and 2001 to conduct this analysis using cross-sectional data. Women completed food frequency questionnaires about diet in the previous 3 months and foods were categorised into subgroups: fruits, vegetables, nuts/seeds, whole grains, low-fat dairy, sweetened beverages and red meat. We additionally assessed dietary vitamin D, fibre and yogurt consumption. Stored vaginal swabs collected in mid-pregnancy were sequenced using 16S taxonomic profiling. Women were categorised into three groups based on predominance of species: Lactobacillus iners, Lactobacillus miscellaneous and Bacterial Vaginosis (BV)-associated bacteria. Adjusted Poisson models with robust variance estimators were run to assess the risk of being in a specific vagitype compared to the referent. Race-stratified models (Black/White) were also run. Results In this study of 634 women, higher consumption of dairy was associated with increased likelihood of membership in the L. crispatus group compared to the L. iners group in a dose-dependent manner (RR quartile 4 vs. 1: 2.01 [95% CI: 1.36, 2.95]). Increased intake of fruit, vitamin D, fibre and yogurt was also associated with increased likelihood of membership in L. crispatus compared to L. iners, but only among black women. Statistical heterogeneity was only detected for fibre intake. There were no detected associations between any other food groups or risk of membership in the BV group. Conclusions Higher consumption of low-fat dairy was associated with increased likelihood of membership in a beneficial vagitype, potentially driven by probiotics.

Background Organophosphate esters (OPEs) are a class of flame retardants in common use. OPEs can easily leach from materials, resulting in human exposure. Increasing concentrations have been reported in human populations over the past decade. Recent studies have linked prenatal OPE exposure to hyperactivity and attention problems in children. Such behaviors are often found among children with attention-deficit hyperactivity disorder (ADHD), however, no study has investigated OPEs in relation to clinically assessed ADHD. Objective To evaluate prenatal exposure to OPEs as risk factors for clinically assessed ADHD using a case-cohort study nested within the Norwegian Mother, Father, and Child Cohort Study (MoBa). Methods We included in the case group 295 ADHD cases obtained via linkage with the Norwegian Patient Registry, and the sub-cohort group 555 children sampled at baseline, irrespective of their ADHD case status. Prenatal concentrations of OPE metabolites were measured in maternal urine collected at 17 weeks of gestation, and included diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), bis(2-butoxyethyl) hydrogen phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We estimated risk ratios and the corresponding 95% confidence intervals [95% CI] using logistic regression, adjusting for season of urine collection, child sex, birth year, and maternal depression, education, and sum of urinary di(2-ethylhexyl) phthalate metabolites (∑DEHP) concentration during pregnancy. To assess the overall impact of simultaneously decreasing exposure to all chemical constituents of an OPE-phthalate mixture, quantile based g-computation was implemented. The mixture constituents included OPE and phthalate metabolites commonly detected in our study. In all models, we considered effect measure modification by child sex and polymorphisms in genes encoding paraoxonase 1 (PON1) and cytochrome P450 (P450) enzymes. Mediation analysis was conducted using thyroid function biomarkers estimated from maternal blood collected at 17 weeks of gestation. Results DPHP was detected in nearly all samples (97.2%), with a higher geometric mean among the case group (0.70 µg/L) as compared to the sub-cohort (0.52 µg/L). DNBP was commonly detected as well (93.8%), while BBOEP (52.9%) and BDCIPP (22.9%) were detected less frequently. A higher risk of ADHD was observed in children with greater than median exposure to DPHP during pregnancy (risk ratio: 1.38 [95% CI: 0.96, 1.99]), which was slightly higher among girls (2.04 [1.03, 4.02]) and children of mothers with PON1 Q192R genotype QR (1.69 [0.89, 3.19]) or PON1 Q192R genotype RR (4.59 [1.38, 15.29]). The relationship between DPHP and ADHD (total risk ratio: 1.34 [0.90, 2.02]) was partially mediated through total triiodothyronine to total thyroxine ratio (natural direct effect: 1.29 [0.87, 1.94]; natural indirect effect: 1.04 [1.00, 1.10]; 12.48% mediated). We also observed an elevated risk of ADHD in relation to BDCIPP detection during pregnancy (1.50 [0.98, 2.28]). We did not observe notable differences in ADHD by DNBP (0.88 [0.62, 1.26]) or BBOEP (1.03 [0.73, 1.46]) during pregnancy. Simultaneously decreasing all constituents of common-detect OPE-phthalate mixture, specifically DPHP, DNBP, and 6 phthalate metabolites, by a quartile resulted in an ADHD risk ratio of 0.68 [0.64, 0.72]. Conclusion Prenatal exposure to DPHP and BDCIPP may increase the risk of ADHD. For DPHP, we observed potential modification by child sex and maternal PON1 Q192R genotype and partial mediation through maternal thyroid hormone imbalance at 17 weeks gestation.

Background Mental health diagnoses (MHDs) were identified as significant drivers of inflammatory bowel disease (IBD)-related costs in an analysis titled “Cost of Care Initiative” supported by the Crohn’s & Colitis Foundation. In this subanalysis, we sought to characterize and compare IBD patients with and without MHDs based on insurance claims data in terms of demographic traits, medical utilization, and annualized costs of care. Methods We analyzed the Optum Research Database of administrative claims from years 2007 to 2016 representing commercially insured and Medicare Advantage insured IBD patients in the United States. Inflammatory bowel disease patients with and without an MHD were compared in terms of demographics (age, gender, race), insurance type, IBD-related medical utilization (ambulatory visits, emergency department [ED] visits, and inpatient hospitalizations), and total IBD-related costs. Only patients with costs >$0 in each of the utilization categories were included in the cost estimates. Results Of the total IBD study cohort of 52,782 patients representing 179,314 person-years of data, 22,483 (42.6%) patients had at least 1 MHD coded in their claims data with a total of 46,510 person-years in which a patient had a coded MHD. The most commonly coded diagnostic categories were depressive disorders, anxiety disorders, adjustment disorders, substance use disorders, and bipolar and related disorders. Compared with patients without an MHD, a significantly greater percentage of IBD patients with MHDs were female (61.59% vs 48.63%), older than 75 years of age (9.59% vs 6.32%), white (73.80% vs 70.17%), and significantly less likely to be younger than 25 years of age (9.18% vs 11.39%) compared with those without mental illness (P < 0.001). Patients with MHDs had significantly more ED visits (14.34% vs 7.62%, P < 0.001) and inpatient stays (19.65% vs 8.63%, P < 0.001) compared with those without an MHD. Concomitantly, patients with MHDs had significantly higher ED costs ($970 vs $754, P < 0.001) and inpatient costs ($39,205 vs $29,550, P < 0.001) compared with IBD patients without MHDs. Patients with MHDs also had significantly higher total annual IBD-related surgical costs ($55,693 vs $40,486, P < 0.001) and nonsurgical costs (medical and pharmacy) ($17,220 vs $11,073, P < 0.001), and paid a larger portion of the total out-of-pocket cost for IBD services ($1017 vs $905, P < 0.001). Conclusion Patients whose claims data contained both IBD-related and MHD-related diagnoses generated significantly higher costs compared with IBD patients without an MHD diagnosis. Based on these data, we speculate that health care costs might be reduced and the course of patients IBD might be improved if the IBD-treating provider recognized this link and implemented effective behavioral health screening and intervention as soon as an MHD was suspected during management of IBD patients. Studies investigating best screening and intervention strategies for MHDs are needed.

OBJECTIVE: To examine the association between neonatal jaundice and autism spectrum disorder (ASD) and non-ASD developmental disorder (DD). STUDY DESIGN: We analyzed data from the Study to Explore Early Development, a US multisite, case-control study conducted from 2007 to 2011. Developmental assessment classified children aged 2–5 years into: ASD (n= 636), DD (n= 777), or controls (POP; n= 926). Neonatal jaundice (n= 1054) was identified from medical records and maternal interviews. We examined associations between neonatal jaundice and ASD and DD using regression models to obtain adjusted odds ratios (aOR). RESULTS: Our results showed interaction between gestational age and neonatal jaundice. Neonatal jaundice was associated with ASD at 35–37 weeks (aOR = 1.83, 95%CI 1.05, 3.19), but not ≥38 weeks gestation (aOR = 0.97, 95%CI 0.76, 1.24). Similar results were observed with DD. CONCLUSIONS: Further exploration of timing and severity of neonatal jaundice and ASD/DD is warranted.

BACKGROUND: There is evidence vitamin A plays a role in neuroblastoma. Not only is 13-cis-retinoic acid used as maintenance therapy for high-risk cases, but prenatal vitamin intake use may decrease neuroblastoma risk. We hypothesized that single nucleotide polymorphisms (SNPs) in vitamin A-related genes are may be associated with neuroblastoma risk and potentially be modified by vitamin A intake. METHODS: The Neuroblastoma Epidemiology in North America (NENA) study recruited 563 case-parent sets through the Children’s Oncology Group’s Childhood Cancer Research Network. We ascertained dietary nutrient intake through questionnaires and genotyped 463 SNPs in vitamin A-related genes from saliva DNA. Offspring and maternal log-additive risk ratios (RR) and stratum-specific RR for gene-environment interaction were estimated with a log-linear model. We avoided false positives due to multiple testing by using the false discovery rate (FDR). RESULTS: When all neuroblastoma cases were considered together, no offspring variants met the significance criteria (FDR Q-value

This study quantifies the wide-ranging health care costs affecting patients living with IBD, including the annualized direct and indirect costs of care for patients with IBD, the longitudinal drivers of these costs, and the cost of care for newly diagnosed patients., Background The Crohn’s & Colitis Foundation’s Cost of Inflammatory Bowel Disease (IBD) Care Initiative seeks to quantify the wide-ranging health care costs affecting patients living with IBD. We aimed to (1) describe the annualized direct and indirect costs of care for patients with Crohn’s disease (CD) or ulcerative colitis (UC), (2) determine the longitudinal drivers of these costs, and (3) characterize the cost of care for newly diagnosed patients. Methods We analyzed the Optum Research Database from the years 2007 to 2016, representing commercially insured and Medicare Advantage–insured patients in the United States. Inclusion for the study was limited to those who had continuous enrollment with medical and pharmacy benefit coverage for at least 24 months (12 months before through 12 months after the index date of diagnosis). The value of patient time spent on health care was calculated as number of workplace hours lost due to health care encounters multiplied by the patients’ estimated average wage derived from the Bureau of Labor Statistics. Comparisons between IBD patients and non-IBD patients were analyzed based on demographics, health plan type, and length of follow-up. We used generalized linear models to estimate the association between total annual costs and various patient variables. Results There were 52,782 IBD patients (29,062 UC; 23,720 CD) included in the analysis (54.1% females). On a per-annual basis, patients with IBD incurred a greater than 3-fold higher direct cost of care compared with non-IBD controls ($22,987 vs $6956 per-member per-year paid claims) and more than twice the out-of-pocket costs ($2213 vs $979 per-year reported costs), with all-cause IBD costs rising after 2013. Patients with IBD also experienced significantly higher costs associated with time spent on health care as compared with controls. The burden of costs was most notable in the first year after initial IBD diagnosis (mean = $26,555). The study identified several key drivers of cost for IBD patients: treatment with specific therapeutics (biologics, opioids, or steroids); ED use; and health care services associated with relapsing disease, anemia, or mental health comorbidity. Conclusion The costs of care for IBD have increased in the last 5 years and are driven by specific therapeutics and disease features. In addition, compared with non-IBD controls, IBD patients are increasingly incurring higher costs associated with health care utilization, out-of-pocket expenditures, and workplace productivity losses. There is a pressing need for cost-effective strategies to address these burdens on patients and families affected by IBD.

Previous studies have shown complications of pregnancy, often examined in aggregate, to be associated with autism spectrum disorder (ASD). Results for specific complications, such as maternal diabetes and hypertension, have not been uniformly consistent and should be investigated independently in relation to ASD in a large community-based sample. The Study to Explore Early Development (SEED), a US multisite case-control study, enrolled children born in 2003-2006 at 2-5 years of age. Children were classified into three groups based on confirmation of ASD (n = 698), non-ASD developmental delay (DD; n = 887), or controls drawn from the general population (POP; n = 979). Diagnoses of any diabetes or hypertensive disorder during pregnancy were identified from prenatal medical records and maternal self-report. Logistic regression models estimated adjusted odds ratios (aOR) and confidence intervals (CI) adjusting for maternal age, race/ethnicity, education, smoking during pregnancy, and study site. Models for hypertension were additionally adjusted for parity and plurality. Among 2,564 mothers, we identified 246 (9.6%) with any diabetes and 386 (15.1%) with any hypertension in pregnancy. After adjustment for covariates, any diabetes during pregnancy was not associated with ASD (aOR = 1.10 [95% CI 0.77, 1.56]), but any hypertension was associated with ASD (aOR = 1.69 [95% CI 1.26, 2.26]). Results were similar for DD, and any diabetes (aOR = 1.29 [95% CI 0.94, 1.78]) or any hypertension (aOR = 1.71 [95% CI 1.30, 2.25]). Some pregnancy complications, such as hypertension, may play a role in autism etiology and can possibly serve as a prompt for more vigilant ASD screening efforts. Autism Res 2019, 12: 967-975. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We studied if common complications in pregnancy are associated with autism spectrum disorder (ASD) in a large sample of mothers and children. Our results show an association between conditions marked by high blood pressure and ASD, but no association with conditions marked by high blood sugar and ASD. Associations were similar for children who had a developmental disorder that was not ASD, suggesting that this relationship may not be specific to ASD.

Regional anesthesia is a commonly used adjunct to orofacial dental and surgical procedures in companion animals and humans. However, appropriate techniques for anesthetizing branches of the mandibular and maxillary nerves have not been described for rhesus monkeys. Skulls of 3 adult rhesus monkeys were examined to identify relevant foramina, establish appropriate landmarks for injection, and estimate injection angles and depth. Cadaver heads of 7 adult rhesus monkeys (4 male, 3 female) were then injected with thiazine dye to demonstrate correct placement of solution to immerse specific branches of the mandibular and maxillary nerves. Different volumes of dye were injected on each side of each head to visualize area of diffusion, and to estimate the minimum volume needed to saturate the area of interest. After injection, the heads were dissected to expose the relevant nerves and skull foramina. We describe techniques for blocking the maxillary nerve as well as its branches: the greater palatine nerve, nasopalatine nerve, and infraorbital nerve. We also describe techniques for blocking branches of the mandibular nerve: inferior alveolar nerve, mental (or incisive) nerve, lingual nerve, and long buccal nerve. Local anesthesia for the mandibular and maxillary nerves can be accomplished in rhesus macaques and is a practical and efficient way to maximize animal welfare during potentially painful orofacial procedures.

Background The existence of oestrogen receptor-negative (ER-)/progesterone receptor-positive (PR+) breast cancer continues to be an area of controversy amongst oncologists and pathologists. Methods To re-evaluate breast cancers originally classified as ER-/PR+ via Oncotype DX® assay and compare molecular phenotype with Recurrence Score® (RS) result, clinicopathologic features and clinical outcomes were retrospectively obtained from electronic health records between January 1998 and June 2005. Archived formalin-fixed, paraffin-embedded (FFPE) tumour specimens were tested for the expression of ER, PR and human-epidermal-growth-factor-2. The number of positive ER-/PR+ samples confirmed by transcriptional analysis was the primary outcome of interest with event-free and overall survival as secondary outcomes. Biopsies from 26 patients underwent Oncotype DX testing and analysis. Results Approximately 60% were middle-aged (40-50 years old) women, and 84.6% had invasive ductal carcinoma. Based on the Oncotype DX assay, approximately 65% (N = 17) had ER+/PR+ status; 23% (N = 6) had ER-/PR- status; and 12% had a single hormone positive receptor (1 ER-/PR+, 2 ER+/PR-) status. Almost one-quarter of patients were stratified into the low-RS ( 30) result. Conclusion Our findings suggest the ER-/PR+ subtype is not a reproducible entity and emphasises the value of retesting this subtype via molecular methods for appropriate treatment selection and patient outcomes. Multigene assay analysis may serve as a second-line or confirming tool for clinical determination of ER/PR phenotype in breast cancer patients for targeted therapies.

Respiratory tract infections (RTI) are a major cause of morbidity and mortality in humans. A large number of RTIs is caused by viruses, often resulting in more severe disease in infants, elderly and the immunocompromised. Upon viral infection, most individuals experience common cold-like symptoms associated with an upper RTI. However, in some cases a severe and sometimes life-threatening lower RTI may develop. Reproducible and scalablein vitroculture models that accurately reflect the human respiratory tract are needed to study interactions between respiratory viruses and the host, and to test novel therapeutic interventions. Multiplein vitrorespiratory cell culture systems have been described, but the majority of these are based on immortalized cell lines. Although useful for studying certain aspects of viral infections, such monomorphic, unicellular systems fall short in creating an understanding of the processes that occur at an integrated tissue level. Novelin vitromodels involving primary human airway epithelial cells and, more recently, human airway organoids, are now in use. In this review, we describe the evolution ofin vitrocell culture systems and their characteristics in the context of viral RTIs, starting from advances after immortalized cell cultures to more recently developed organoid systems. Furthermore, we describe how these models are used in studying virus-host interactions, e.g. tropism and receptor studies as well as interactions with the innate immune system. Finally, we provide an outlook for future developments in this field, including co-factors that mimic the microenvironment in the respiratory tract.

Background Prenatal exposure to toxic metals or variations in maternal levels of essential elements during pregnancy may be a risk factor for neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in offspring. Objectives We investigated whether maternal levels of toxic metals and essential elements measured in mid-pregnancy, individually and as mixtures, were associated with childhood diagnosis of ADHD or ASD. Methods This study is based on the Norwegian Mother, Father and Child Cohort Study and included 705 ADHD cases, 397 ASD cases and 1034 controls. Cases were identified through linkage with the Norwegian Patient Registry. Maternal concentrations of 11 metals/elements were measured in blood at week 17 of gestation; cadmium; cesium; cobalt; copper; lead; magnesium; manganese; selenium; zinc; total arsenic; and total mercury. Multivariable adjusted logistic regression models were used to examine associations between quartile levels of individual metals/elements and outcomes. We also investigated non-linear associations using restricted cubic spline models. The joint effects of the metal/element mixture on ASD and ADHD diagnoses were estimated using a quantile-based g-computation approach. Results For ASD, we identified positive associations (increased risks) in the second quartile of arsenic [OR = 1.77 (CI: 1.26, 2.49)] and the fourth quartiles of cadmium and manganese [OR = 1.57 (CI: 1.07 2.31); OR = 1.84 (CI: 1.30, 2.59)], respectively. In addition, there were negative associations between cesium, copper, mercury, and zinc and ASD. For ADHD, we found increased risk in the fourth quartiles of cadmium and magnesium [OR = 1.59 (CI: 1.15, 2.18); [OR = 1.42 (CI: 1.06, 1.91)]. There were also some negative associations, among others with mercury. In addition, we identified non-linear associations between ASD and arsenic, mercury, magnesium, and lead, and between ADHD and arsenic, copper, manganese, and mercury. There were no significant findings in the mixture approach analyses. Conclusion Results from the present study show several associations between levels of metals and elements during gestation and ASD and ADHD in children. The most notable ones involved arsenic, cadmium, copper, mercury, manganese, magnesium, and lead. Our results suggest that even population levels of these compounds may have negative impacts on neurodevelopment. As we observed mainly similarities among the metals’ and elements’ impact on ASD and ADHD, it could be that the two disorders share some neurochemical and neurodevelopmental pathways. The results warrant further investigation and replication, as well as studies of combined effects of metals/elements and mechanistic underpinnings.

Background Exposure to multiple psychosocial risk factors may increase vulnerability for mental health conditions during pregnancy. This analysis examined the relationship of a novel psychosocial adversity index with the co-occurrence and persistence of depression and anxiety throughout pregnancy. Methods This cross-sectional analysis included 1797 pregnant women screened in the second/third trimesters for depression and anxiety symptoms and for eight contextual and individual psychosocial factors. The factors were summed to create a psychosocial adversity index; reporting four or more factors indicated high adversity. Elevated symptoms in both trimesters indicated persistent depression/anxiety and elevated symptoms at the same trimester indicated comorbid symptoms. The associations between the psychosocial adversity index and mental health were estimated. Results Compared with a low psychosocial adversity index, women reporting a high level of psychosocial adversities had 2.06 (95% confidence interval [CI]: 1.51-2.82) times higher adjusted odds of only depressive or anxiety symptoms, and 5.57 (95% CI: 3.95-7.85) times higher adjusted odds of comorbid symptoms. The associations for persistent symptoms were of similar direction and magnitude. Conclusion High psychosocial adversity was associated with persistent and comorbid depressive symptoms and anxiety during pregnancy. Assessing psychosocial adversity can help identify women at increased risk who would benefit from tailored mental health interventions.

Background Androgenetic alopecia (AGA) is the most common form of non‐scarring alopecia in humans. Several studies have used different laboratory models to study the pathogenesis and interventions for AGA. These study models have proved beneficial and have led to the approval of two drugs. However, the need to build on existing knowledge remains by examining the relevance of study models to the disease. Objective We sought to appraise laboratory or pre‐clinical models of AGA. Method We searched through databases (PubMed, ScienceDirect, Web of Science, World CAT, Scopus and Google Scholar) for articles on AGA‐related studies from 1942 to March 2019 with a focus on study models. Results The search rendered 101 studies after screening and deduplication. Several studies (70) used in vitro models, mostly consisting of two‐dimensional monolayer cells for experiments involving the characterization of androgen and 5‐alpha reductase (5AR) and inhibition thereof, the effects of dihydrotestosterone (DHT) and biomarker(s) of AGA. Twenty‐seven studies used in vivo models of mice and monkeys to investigate DHT synthesis, the expression and inhibition of 5AR and hair growth. Only four studies used AGA‐related or healthy excisional/punch biopsy explants as ex vivo models to study the action of 5AR inhibitors and AGA‐associated genes. No study used three‐dimensional [3‐D] organoids or organotypic human skin culture models. Conclusion We recommend clinically relevant laboratory models like human or patient‐derived 3‐D organoids or organotypic skin in AGA‐related studies. These models are closer to human scalp tissue and minimize the use of laboratory animals and could ultimately facilitate novel therapeutics.

Occupational therapists (OTs) and physical therapists (PTs) are rehabilitation therapists with distinct but complementary roles who contribute to pain assessment and management in young people either as solo providers, or as a critical component of the interdisciplinary treatment team. Pain in infants, children, and adolescents interferes with their ability to engage in essential interactions with caregivers, acquisition of developmental milestones, and with participation in activities related to self-care, leisure, play, school, and work. OTs and PTs use specific treatment strategies, such as positioning, splinting, adaptive equipment, exercise, manual therapy, electrophysical agents, education on energy conservation, joint protection strategies, and pain self-management training to facilitate participation in valued life activities and occupations. This chapter provides an overview of important theoretical frameworks for rehabilitation therapists, reviews evidence for OT and PT interventions, and describes a framework for planning procedural pain management for rehabilitation therapists when working with pediatric clients.

Preeclampsia is a heterogeneous disease characterized by new onset of hypertension along with signs of organ damage, affects 2% to 8% of pregnancies, and can result in serious complications to the mother and her child. There is little empirical evidence on the clinical importance of differences in blood pressure trajectories over the course of pregnancy, particularly in pregnancies affected by preeclampsia. We undertook an investigation of longitudinal changes in gestational blood pressure in a nested case-control study of preeclampsia in MoBa (Norwegian Mother, Father and Child Cohort Study). We included 1906 validated preeclampsia cases and 1413 validated controls. We derived blood pressure trajectory clusters using longitudinal k-means clustering and examined demographic and early-pregnancy predictors and birth outcomes, in relation to clusters. Maternal age, prepregnancy body mass index, and parity were substantially different across blood pressure clusters of cases. Pregnancy outcomes, including preterm birth, small for gestational age, and birthweight Z score, were meaningfully worse for individuals with a more rapid increase in blood pressure, as well as for individuals with a high starting blood pressure. For example, risk of preterm birth was 11-fold to 35-fold higher for steep and high trajectory clusters, and risk of small for gestational age was 2-fold higher compared with the reference cluster. Future studies may leverage these trajectories to differentiate preeclampsia cases in relation to circulating biomarkers, which may help in the development of preeclampsia prediction tools.

Background Opioid use by patients with inflammatory bowel disease (IBD) has been associated with poorer health outcomes. This study describes socioeconomic characteristics; health utilization trends; and costs of patients with IBD and either no opioid prescriptions, or in 1 of 3 opioid duration categories based on Center for Disease Control guidelines: acute (0–30 days), moderate (31–90 days), or chronic (>90 days). We utilized the Cost of IBD Care Optum research database results for this study. Methods The Optum Research Database from years 2007 to 2016 including IBD patients with commercial or Medicare Advantage insurance in the United States was used. Additional inclusion criteria included continuous enrollment with medical and pharmacy benefit coverage for at least 24 months (12 months before and 12 months after the index date of IBD diagnosis). The association between costs and patient characteristics were assessed across a no opioid use group during this period and the 3 opioid duration groups. Results Among 51,178 IBD patients, 33,229 (64.93%) were part of the no opioid use group, while 13,635 (26.64%) were in acute, 1698 (3.32%) were in moderate, and 2616 (5.11%) were in chronic use groups, as determined by pharmacy claims data. Patients in the chronic group were more likely to be white (75.38%) compared to all the other groups (no opioid use, acute, and moderate), have attained less education (only high school diploma), have had lower incomes, and have had Medicare instead of commercial insurance. Patients across all opioid prescription groups were more likely to have had diagnoses associated with pain in the prior year, with rates increasing by the length of opioid prescription (63.68%, 80.17%, and 86.11% for acute, moderate, and chronic groups). Compared to the no-use group, the acute group had more ambulatory (outpatient) visits, while the chronic group had fewer. Emergency department visits and inpatient hospitalizations were higher in all 3 opioid groups compared to the no opioid use group. Ambulatory, emergency department, inpatient, and total (medical + pharmacy) costs were higher in all 3 opioid groups, compared to the no opioid use group, even after adjusting for demographic and clinical patient characteristics. Conclusions Among patients with IBD, increasing opioid use was associated with higher healthcare resource utilization and, concomitantly, higher healthcare costs during this period.

Robust data from longitudinal birth cohort studies and experimental studies of perinatally exposed animals indicate that exposure to ortho-phthalates can impair brain development and increase risks for learning, attention, and behavioral disorders in childhood. This growing body of evidence, along with known adverse effects on male reproductive tract development, calls for immediate action. Exposures are ubiquitous; the majority of people are exposed to multiple ortho-phthalates simultaneously. We thus recommend that a class approach be used in assessing health impacts as has been done with other chemical classes. We propose critically needed policy reforms to eliminate ortho-phthalates from products that lead to exposure of pregnant women, women of reproductive age, infants, and children. Specific attention should be focused on reducing exposures among socially vulnerable populations such as communities of color, who frequently experience higher exposures. Ortho-phthalates are used in a vast array of products and elimination will thus necessitate a multipronged regulatory approach at federal and state levels. The fact that manufacturers and retailers have already voluntarily removed ortho-phthalates from a wide range of products indicates that this goal is feasible.

Background Prenatal phthalate exposure has been linked with altered neurodevelopment, including externalizing behaviors and attention-deficit hyperactivity disorder (ADHD). However, the implicated metabolite, neurobehavioral endpoint, and child sex have not always been consistent across studies, possibly due to heterogeneity in neurodevelopmental instruments. The complex set of findings may be synthesized using executive function (EF), a construct of complex cognitive processes that facilitate ongoing goal-directed behaviors. Impaired EF can be presented with various phenotypes of poor neurodevelopment, differently across structured conditions, home/community, or preschool/school. We evaluated the relationship between prenatal phthalate exposure and comprehensive assessment of preschool EF. Methods Our study comprised 262 children with clinically significant/subthreshold ADHD symptoms and 78 typically developing children who were born between 2003 and 2008 and participated in the Preschool ADHD Substudy, which is nested within a population-based prospective cohort study, the Norwegian Mother, Father, and Child Cohort (MoBa). Twelve phthalate metabolites were measured from urine samples that their mothers had provided during pregnancy, at 17 weeks’ gestation. All children, at approximately 3.5-years, took part in a detailed clinical assessment that included parent-and teacher-rated inventories and administered tests. We used instruments that measured constructs related to EF, which include a parent-and teacher-reported Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) and three performance-based tests: A Developmental NEuroPSYchological Assessment (NEPSY), Stanford-Binet intelligence test V (SB5), and the cookie delay task (CDT). The standard deviation change in test score per interquartile range (IQR) increase in phthalate metabolite was estimated with multivariable linear regression. We applied weighting in all models to account for the oversampling of children with clinically significant or subthreshold symptoms of ADHD. Additionally, we assessed modification by child sex and potential co-pollutant confounding. Results Elevated exposure to mono-benzyl phthalate (MBzP) during pregnancy was associated with poorer EF, across all domains and instruments, in both sex. For example, an IQR increase in MBzP was associated with poorer working memory rated by parent (1.23 [95% CI: 0.20, 2.26]) and teacher (1.13 [0.14, 2.13]) using BRIEF-P, and administered tests such as SB5 (no-verbal: 0.19 [0.09, 0.28]; verbal: 0.13 [0.01, 0.25]). Adverse associations were also observed for mono-n-butyl phthalate (MnBP) and mono-iso-butyl phthalate (MiBP), although results varied by instruments. EF domains reported by parents using BRIEF-P were most apparently implicated, with stronger associations among boys (e.g., MnBP and inhibition: 2.74 [1.77, 3.72]; MiBP and inhibition: 1.88 [0.84, 2.92]) than among girls (e.g., MnBP and inhibition: −0.63 [−2.08, 0.83], interaction p-value: 0.04; MiBP and inhibition: −0.15 [−1.04, 0.74], interaction p-value: 0.3). Differences by sex, however, were not found for the teacher-rated BRIEF-P or administered tests including NEPSY, SB5, and CDT. Conclusion and relevance Elevated mid-pregnancy MBzP, MiBP, and MnBP were associated with more adverse profiles of EF among preschool-aged children across a range of instruments and raters, with some associations found only among boys. Given our findings and accumulating evidence of the prenatal period as a critical window for phthalate exposure, there is a timely need to expand the current phthalate regulations focused on baby products to include pregnancy exposures.

OBJECTIVE Maternal smoking is associated with as much as a 50% reduced risk of preeclampsia, despite increasing risk of other poor pregnancy outcomes that often co-occur with preeclampsia, such as preterm birth and fetal growth restriction. Researchers have long sought to understand whether this perplexing association is biologically based, or a result of noncausal mechanisms. We examined whether smoking-response genes modify the smoking-preeclampsia association to investigate potential biological explanations. STUDY DESIGN We conducted a nested case-control study within the Norwegian Mother, Father and Child Birth Cohort (1999-2008) of 2,596 mother-child dyads. We used family-based log-linear Poisson regression to examine modification of the maternal smoking-preeclampsia relationship by maternal and fetal single nucleotide polymorphisms involved in cellular processes related to components of cigarette smoke (n = 1,915 with minor allele frequency ≥10%). We further investigated the influence of smoking cessation during pregnancy. RESULTS Three polymorphisms showed overall (p

Background We investigated the association between adverse events (AEs) suspected to be immune‐related and health care resource utilization, costs, and mortality among patients receiving programmed cell death 1/programmed cell death ligand 1 immune checkpoint inhibitor (ICI) monotherapy for urothelial carcinoma, renal cell carcinoma, non‐small cell lung cancer, or Merkel cell carcinoma. Patients and Methods We conducted a retrospective cohort study using medical and pharmacy claims and enrollment information from U.S. commercial and Medicare Advantage with Part D enrollees in the Optum Research Database from March 1, 2014, through April 30, 2019. Claims were linked with mortality data from the Social Security Death Index and the National Death Index. Eligible patients had at least one ICI claim between September 1, 2014, and April 30, 2019. Results After adjusting for potential confounding variables, we found patients with AEs had more than double the risk of an inpatient stay (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.9–2.5) and an 80% higher risk of an emergency visit (HR, 1.8; 95% CI, 1.6–2.1) than patients without AEs. Adjusted 6‐month total costs were $24,301 higher among patients with an AE versus those without ($99,037 vs. $74,736; 95% CI, $18,828–29,774; p, This article reports on the association between immune‐related adverse events and health care resource utilization, costs, and mortality among patients receiving PD‐1/PD‐L1 immune checkpoint inhibitor monotherapy for urothelial carcinoma, renal cell carcinoma, non‐small cell lung cancer, or Merkel cell carcinoma.

Background: In the United States, >45,000 adolescent and young adult (AYA) women are diagnosed with cancer annually. Reproductive issues are critically important to AYA cancer survivors, but insufficient information is available to address their concerns. The AYA Horizon Study was initiated to contribute high-quality, contemporary evidence on reproductive outcomes for female cancer survivors in the United States. Methods: The study cohort includes women diagnosed with lymphoma, breast, melanoma, thyroid, or gynecologic cancer (the five most common cancers among women ages 15–39 years) at three study sites: the state of North Carolina and the Kaiser Permanente health systems in Northern and Southern California. Detailed information on cancer treatment, fertility procedures, and pregnancy (e.g., miscarriage, live birth) and birth (e.g., birth weight, gestational length) outcomes are leveraged from state cancer registries, health system databases and administrative insurance claims, national data on assisted reproductive technology procedures, vital records, and survey data. Results: We identified a cohort of 11,072 female AYA cancer survivors that includes >1,200 African American women, >1,400 Asian women, >1,600 Medicaid enrollees, and >2,500 Hispanic women using existing data sources. Active response to the survey component was low overall (N = 1,679), and notably lower among minority groups compared with non-Hispanic white women. Conclusions: Passive data collection through linkage reduces participant burden and prevents systematic cohort attrition or potential selection biases that can occur with active participation requirements. Impact: The AYA Horizon study will inform survivorship planning as fertility and parenthood gain increasing recognition as key aspects of high-quality cancer care.

This paper presents an economic model predictive control approach for a linear microgrid model. The microgrid in grid-connected mode represents a medium-sized company building including storage systems, renewable energies and couplings between the electrical and heat energy system. Economic model predictive control together with Pareto optimization is applied to find suitable compromises between two competing objectives, i. e. monetary costs and thermal comfort. Using real-world data from 2018 and 2019, the model is simulated with auto-detection of the Pareto solution which is closest to the Utopia point. The results show that the Pareto optimization can either be used in real-time control of the microgrid, or to obtain suitable weights from long term simulations. Both approaches result in significant cost reductions.

Background Animal studies suggest that organophosphorus pesticides (OPs) may be environmental obesogens. While prenatal OP exposures have been associated with altered infant glucose metabolism, associations with pediatric adiposity remain unknown. Methods We summed concentrations of three dimethylphosphate (∑DMP) and three diethylphosphate (∑DEP) metabolites of OPs measured in third trimester spot urine samples collected from pregnant women enrolled in New York City, 1998–2002. We measured percent fat mass using bio-electrical impedance analysis and calculated age- and sex-standardized body mass index (BMI) z-scores from anthropometric measurements collected at approximately 4, 6, and 7–9 years of age (166 children, 333 observations). We assessed covariate-adjusted associations of OPs with repeated adiposity measures using linear mixed models and evaluated effect measure modification (EMM) by sex and paroxonase (PON) 1 –108C/T and Q192R polymorphisms measured in maternal peripheral blood samples. Results The geometric mean urinary concentration of ∑DMP metabolites (29.9 nmol/L, IQR: 105.2 nmol/L) was higher than ∑DEP metabolites (8.8 nmol/L, IQR: 31.2 nmol/L). Adjusted associations were null, with differences in fat mass per 10-fold increase in prenatal ∑DMP and ∑DEP concentrations of 0.7% (95% CI: −0.6, 2.0) and 0.8% (95% CI: −0.4, 2.0), respectively. Maternal PON1-108C/T polymorphisms modified relationships of prenatal ∑DMP with percent fat mass (EMM p-value = 0.18) and ∑DEP with BMI z-scores (EMM p-value = 0.12). For example, ∑DMP was modestly associated with increased percent fat mass among children of mothers with the at-risk CT or TT genotype (β = 1.2%, 95% CI: −0.6, 3.0) but not among those whose mothers had the CC genotype (β = −0.4%, 95% CI: −2.4, 1.5). Associations were not modified by sex or maternal PON1 Q192R polymorphisms. Conclusions We observed little evidence of a relationship between prenatal OP exposures and child adiposity, although there was some suggestion of increased risk among offspring of mothers who were slow OP metabolizers. Larger studies are warranted to further evaluate possible associations of prenatal OP exposures with child adiposity and differences by maternal PON1 genotype, which regulates OP metabolism and may increase susceptibility to exposure.

Spacecraft surface charging during geomagnetically disturbed times is one of the most important causes of satellite anomalies. Predicting the surface charging environment is one prevalent task of the geospace environment models. Therefore, the Geospace Environment Modeling (GEM) Focus Group "Inner Magnetosphere Crossenergy/Population Interactions" initiated a communitywide challenge study to assess the capability of several inner magnetosphere ring current models in determining surface charging environment for the Van Allen Probes orbits during the 17 March 2013 storm event. The integrated electron flux between 10 and 50 keV is used as the metrics. Various skill scores are applied to quantitatively measure the modeling performance against observations. Results indicate that no model consistently perform the best in all of the skill scores or for both satellites. We find that from these simulations the ring current model with observational flux boundary condition and Weimer electric potential driver generally reproduces the most realistic flux level around the spacecraft. A simple and weaker VollandStern electric field is not capable of effectively transporting the same plasma at the boundary toward the Earth. On the other hand, if the ring current model solves the electric field selfconsistently and obtains similar strength and pattern in the equatorial plane as the Weimer model, the boundary condition plays another crucial role in determining the electron flux level in the inner region. When the boundary flux spectra based on magnetohydrodynamics (MHD) model/empirical model deviate from the shape or magnitude of the observed distribution function, the simulation produces poor skill scores along Van Allen Probes orbits.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer in the United States. Immunotherapies and cytotoxic chemotherapies used to treat advanced NSCLC carry a substantial risk of adverse events (AEs), but real-world data on the incidence and costs associated with the unique AE profiles of these treatments are sparse.To examine the AE incidence and costs among patients initiating non-driver mutation-targeted first-line therapy for metastatic NSCLC (mNSCLC) in clinical practice.This was a retrospective administrative claims study conducted among commercial and Medicare Advantage health plan members who initiated first-line, nontargeted systemic anti-NSCLC therapy between January 1, 2008, and February 28, 2018. Patients were assigned to mutually exclusive treatment cohorts (cytotoxic chemotherapy [CHEM], immuno-oncology agents [IO], or immuno-oncology + cytotoxic chemotherapy [IO-CHEM]) and were observed from the index date (start of first-line therapy) through the earliest of health plan disenrollment, death, or March 31, 2018. AE incidence rates and associated health care costs were measured from the index date through the earliest of the start of a new therapy, 180 days after the end of first-line therapy, or the end of the study period. The factors influencing whether patients incurred high AE-related health care costs were assessed using multivariable models adjusted for patient demographic and clinical characteristics.The final study population (mean [SD] age 68.6 [9.5] years, 53.9% male) included 8,818 in the CHEM cohort, 482 in the IO cohort, and 412 in the IO-CHEM cohort. Overall, 74.4% had at least 1 AE during follow-up. The AE incidence rate was lowest for the IO cohort, with incidence rate ratios (95% CI) of 1.4 (1.3-1.6) for the CHEM cohort and 1.4 (1.2-1.6) for the IO-CHEM cohort. Mean AE-related costs were lowest for the IO cohort ($16,319) and highest for the CHEM cohort ($23,009;Among real-world patients initiating nontargeted first-line therapy for mNSCLC, those receiving immunotherapy experienced fewer AEs and had lower total AE-related costs than those treated with cytotoxic chemotherapy. Immunotherapy-treated patients were no more likely than chemotherapy-treated patients to incur AE-related costs and were less likely to have high AE costs if they incurred any at all. These findings indicate that immunotherapy-related AEs are not a differentiating factor in cost of care for this patient population in clinical practice.This study was sponsored by AstraZeneca. Ryan is an employee of AstraZeneca. Engel-Nitz, Johnson, and Bunner are employees of Optum, which was contracted by AstraZeneca to conduct this study, and shareholders in UnitedHealth Group. Engel-Nitz has also worked on cancer-related studies for which Optum received funding from Bayer AG, Clovis Oncology, Eli Lilly, EMD Serono, Exact Sciences, Janssen, and Novartis. Johnson worked on cancer-related studies for which Optum received funding from Eli Lilly, Medtronic, Sanofi, and UnitedHealthcare. Bunner has worked on cancer-related studies for which Optum received funding from Celgene and Incyte.

The Crohn'sColitis Foundation's Cost of Inflammatory Bowel Disease (IBD) Care Initiative seeks to quantify the wide-ranging health care costs affecting patients living with IBD. We aimed to (1) describe the annualized direct and indirect costs of care for patients with Crohn's disease (CD) or ulcerative colitis (UC), (2) determine the longitudinal drivers of these costs, and (3) characterize the cost of care for newly diagnosed patients.We analyzed the Optum Research Database from the years 2007 to 2016, representing commercially insured and Medicare Advantage-insured patients in the United States. Inclusion for the study was limited to those who had continuous enrollment with medical and pharmacy benefit coverage for at least 24 months (12 months before through 12 months after the index date of diagnosis). The value of patient time spent on health care was calculated as number of workplace hours lost due to health care encounters multiplied by the patients' estimated average wage derived from the Bureau of Labor Statistics. Comparisons between IBD patients and non-IBD patients were analyzed based on demographics, health plan type, and length of follow-up. We used generalized linear models to estimate the association between total annual costs and various patient variables.There were 52,782 IBD patients (29,062 UC; 23,720 CD) included in the analysis (54.1% females). On a per-annual basis, patients with IBD incurred a greater than 3-fold higher direct cost of care compared with non-IBD controls ($22,987 vs $6956 per-member per-year paid claims) and more than twice the out-of-pocket costs ($2213 vs $979 per-year reported costs), with all-cause IBD costs rising after 2013. Patients with IBD also experienced significantly higher costs associated with time spent on health care as compared with controls. The burden of costs was most notable in the first year after initial IBD diagnosis (mean = $26,555). The study identified several key drivers of cost for IBD patients: treatment with specific therapeutics (biologics, opioids, or steroids); ED use; and health care services associated with relapsing disease, anemia, or mental health comorbidity.The costs of care for IBD have increased in the last 5 years and are driven by specific therapeutics and disease features. In addition, compared with non-IBD controls, IBD patients are increasingly incurring higher costs associated with health care utilization, out-of-pocket expenditures, and workplace productivity losses. There is a pressing need for cost-effective strategies to address these burdens on patients and families affected by IBD.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is the most common neurobehavioral disorder in children, yet its etiology is poorly understood. Early thyroid hormone disruption may contribute to the development of ADHD. Disrupted maternal thyroid hormone function has been associated with adverse neurodevelopmental outcomes in children. Among newborns, early-treated congenital hypothyroidism has been consistently associated with later cognitive deficits. METHODS: We systematically reviewed literature on the association between maternal or neonatal thyroid hormones and ADHD diagnosis or symptoms. We searched Embase, Pubmed, Cinahl, PsycInfo, ERIC, Medline, Scopus, and Web of Science for articles published or available ahead of print as of April 2018. RESULTS: We identified 28 eligible articles: 16 studies of maternal thyroid hormones, seven studies of early-treated congenital hypothyroidism, and five studies of neonatal thyroid hormones. The studies provide moderate evidence for an association between maternal thyroid hormone levels and offspring ADHD, some evidence for an association between early-treated congenital hypothyroidism and ADHD, and little evidence for an association between neonatal thyroid hormone levels and later ADHD. CONCLUSIONS: The reviewed articles suggest an association between maternal thyroid function and ADHD, and possibly between early-treated congenital hypothyroidism and ADHD. Study limitations, however, weaken the conclusions in our systematic review, underlining the need for more research. Importantly, there was much variation in measurement of thyroid hormone function and of ADHD symptoms. Recommendations for future research include using population-based designs, attending to measurement issues for thyroid hormones and ADHD, considering biologically relevant covariates (e.g., iodine intake), and assessing non-linear dose–responses.

Objective: Perioperative chemotherapy can potentially downstage esophageal cancer, reducing the risk of early systemic dissemination. One recommended neoadjuvant regimen for managing gastroesophageal junction and esophageal cancer is docetaxel, cisplatin, and 5-fluorouracil (DCF). To address the high toxicity profile of DCF, modifications in dosages and treatment intervals have been studied. We integrated a modified DCF regimen (mDCF) into a multimodal treatment approach for non-metastatic esophageal cancer (nMEC). Retrospectively, we sought to describe our community experience of administrating neoadjuvant mDCF to patients with nMEC. Design: Patients diagnosed with nMEC between August 2008 and November 2017 and prescribed mDCF were identified for retrospective review. Outcomes of interest included disease-free survival (DFS), overall survival (OS), and hematologic toxicities. Analyses were performed using SAS 9.4. Results: Thirty patients met inclusion criteria with a median age of 64.9 years; 90% were male. The 2-year and 5-year DFS was 60.8% and 41.7%, respectively, for adenocarcinoma and 71.4% and 71.4% for squamous cell carcinoma (SCC). The 2-year and 5-year OS was 64.9% and 44.5%, respectively, for adenocarcinoma and 71.4% and 71.4% for SCC. Both DFS and OS decreased with increasing disease stage, histology (adenocarcinoma versus squamous), esophageal compared to esophagogastric-junction involvement, and without surgical intervention. Frequent toxicity grades for leukopenia and thrombocytopenia were Grades I and II. Conclusion: Using an mDCF regimen in combination with chemoradiation +/- surgical resection in a community setting appears to have an acceptable toxicity profile as well as DFS and OS outcomes compared to chemotherapeutic regimens reported in other similar studies.

A man, aged 61 years, with a history of hypogonadism and family history of cancer experienced persistent urinary difficulties with no visible prostate abnormalities. Laboratory testing and diagnostic imaging revealed a primary lesion in the prostate with lymph node involvement and multiple bone metastases. Treatment with androgen-deprivation therapy, 17,20-lyase inhibition, and bisphosphonates for 7 months was unsuccessful in preventing disease progression, but second-line chemotherapy and continued androgen-deprivation therapy improved prostate specific antigen levels. During the patient’s second treatment regimen, his daughter received a diagnosis of breast cancer. The patient’s daughter underwent genetic testing for oncogenic mutations, and it was discovered that she carried a mutation in RAD51C, a gene encoding a protein involved in DNA repair and genomic maintenance. Subsequent genetic testing of the patient revealed mutation in RAD51C as well. For patients with metastatic prostate cancer who are unresponsive to standard treatment and who have a positive family history of cancer, genetic testing may be warranted to develop alternative treatment regimens for the patient and guide family discussions regarding cancer risk. Targeted agents like poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors may be a consideration in prostate cancer patients with DNA repair mutations and with refractory disease.

PURPOSE: Annually, >45,000 U.S. women are diagnosed with cancer during adolescence and young adulthood (AYA). Since 2006, national guidelines have recommended fertility counseling for cancer patients. We examined childbirth after AYA cancer by calendar period, cancer diagnosis, and maternal characteristics. METHODS: We identified a cohort of women with an incident invasive AYA cancer diagnosis at ages 15–39 during 2000–2013 in North Carolina. Cancer records were linked with statewide birth certificates through 2014. Hazard ratios (HR) and 95% confidence intervals (CI) for first post-diagnosis live birth were calculated using Cox proportional hazards regression. RESULTS: Among 17,564 AYA cancer survivors, 1,989 had ≥ 1 birth after diagnosis during 98,397 person-years. The 5- and 10-year cumulative incidence of live birth after cancer was 10% and 15%, respectively. AYA survivors with a post-diagnosis birth were younger at diagnosis, had lower stage disease, and had less often received chemotherapy than those without a birth. The 5-year cumulative incidence of post-diagnosis birth was 10.0% for women diagnosed during 2007–2012, compared to 9.4% during 2000–2005 (HR=1.01; 0.91, 1.12), corresponding to periods before and after publication of American Society of Clinical Oncology fertility counseling guidelines in 2006. CONCLUSIONS: Despite advances in fertility preservation options and recognition of fertility counseling as a part of high quality cancer care, the incidence of post-diagnosis childbirth has remained stable over the last 15 years. IMPLICATIONS FOR CANCER SURVIVORS: Our study uses statewide data to provide recent, population-based estimates of how often AYA women have biological children after a cancer diagnosis.

INTRODUCTION This study assessed the clinical burden of refractory myasthenia gravis (MG), relative to nonrefractory MG. METHODS Rates of myasthenic crises, exacerbations, inpatient hospitalizations, and emergency room (ER) visits over a 1-year period were measured for 403 refractory, 3,811 nonrefractory, and 403 non-MG control patients from two administrative health plan databases. RESULTS Compared with nonrefractory patients, a significantly greater percentage of refractory patients had at least one myasthenic crisis (21.3% vs. 6.1%; P

Importance Metformin is an emerging option for treating gestational diabetes (GDM). However, because metformin crosses the placenta, patients and clinicians are concerned with its long-term effect on child health. Objective To estimate the association of treating GDM with metformin vs insulin with child growth and development. Design, Setting, and Participants Population-based cohort study of New Zealand women treated with metformin or insulin for GDM from 2005 to 2012 and their children. This study linked national health care data to create a cohort of mothers and their children, including data from maternity care, pharmaceutical dispensing, hospitalizations, demographic records, and the B4 School Check (B4SC) preschool health assessment. Women treated pharmacologically with metformin or insulin during pregnancy were included. We excluded pregnancies with evidence of diabetes and deliveries prior to 2013. Liveborn infants were linked to their B4SC results. Data were analyzed between January 2017 and May 2018. Exposures Pharmacologic treatment for GDM with metformin or insulin, measured using pharmaceutical claims data. Main Outcomes and Measures Child growth (weight and height) and Strengths and Difficulties Questionnaire (SDQ) scores for behavioral development. All outcomes were derived from the B4SC screening program. Linear and log-binomial regression with inverse probability of treatment weighting was used to estimate the association of child growth and psychosocial outcomes with metformin vs insulin treatment for GDM. Results In both treatment groups, the mean (SD) maternal age was 32 (5) years. A large proportion of mothers who were treated with insulin identified as New Zealand European (867 [44.9%]) while 576 mothers who were treated with metformin (28.9%) identified as New Zealand European. Approximately one-third of mothers who were treated with metformin (n = 639) identified as Asian. We identified 3928 pregnancies treated with metformin (n = 1996) or insulin (n = 1932). After adjustment, we observed no meaningful difference in weight for heightzscores between children exposed to metformin compared with insulin (mean difference, –0.10; 95% CI, −0.20 to 0.01). Risk of being 85th percentile or greater for weight for height was similar between treatment groups (adjusted risk ratio, 0.92; 95% CI, 0.83-1.02). Mean SDQ scores were not meaningfully different between the treatment groups, Children of metformin-treated mothers were not significantly more likely to have parent-reported SDQ scores of 14 or more (adjusted risk ratio, 1.13; 95% CI, 0.88-1.46) than those of insulin-treated mothers. Conclusions and Relevance Our study compares long-term outcomes among school-aged children following maternal use of metformin vs insulin treatment for GDM. Children of metformin-treated mothers were indistinguishable on growth and developmental assessments from those of insulin-treated mothers. These results will help inform future GDM treatment guidelines.

Stem cells are proving to be a promising therapy for a wide range of pediatric disorders, from neonatal hypoxic-ischemic encephalopathy to pediatric leukemia. Owing to their low immunogenicity and ease of availability, umbilical cord blood (UCB) progenitor cells are increasingly replacing fetal- and adult-derived cells in therapeutic settings. Multiple environmental and demographic factors affect the number and type of stem cells extracted from UCB, and these differences have been associated with disparities in outcomes after transplantation. To avoid variations in efficacy, as well as the potential adverse effects of stem cell transplantation, evaluation of the stem cell secretome is critical to identify key paracrine signals released by the stem cells that could be used to provide similar neuroprotective effects to stem cell transplantation. This article describes the cell types found in UCB and reviews the available literature surrounding the effects of collection timing and volume, maternal risk factors, delivery characteristics, and neonatal demographics on the cellular composition of UCB. In addition, the current findings regarding the stem cell secretome are discussed to identify factors that could be used to supplement or replace stem cell transplantation in pediatric neuroprotection.

Prenatal exposure to organophosphorus pesticides (OPs) has been associated with different neurodevelopmental outcomes across different cohorts. A phenotypic approach may address some of these differences by incorporating information across scales and accounting for the complex correlational structure of neurodevelopmental outcomes. Additionally, Bayesian hierarchical modeling can account for confounding by collinear co-exposures. We use this framework to examine associations between prenatal exposure to OPs and behavior, executive functioning, and IQ assessed at age 6-9 years in a cohort of 404 mother/infant pairs recruited during pregnancy. We derived phenotypes of neurodevelopment with a factor analysis, and estimated associations between OP metabolites and these phenotypes in Bayesian hierarchical models for exposure mixtures. We report seven factors: 1) Impulsivity and Externalizing, 2) Executive Functioning, 3) Internalizing, 4) Perceptual Reasoning, 5) Adaptability, 6) Processing Speed, and 7) Verbal Intelligence. These, along with the Working Memory Index, were standardized and scaled so that positive values reflected positive attributes and negative values represented adverse outcomes. Standardized dimethylphosphate metabolites were negatively associated with Internalizing factor scores (β^ - 0.13, 95% CI - 0.26, 0.00) but positively associated with Executive Functioning factor scores (β^ 0.18, 95% CI 0.04, 0.31). Standardized diethylphosphate metabolites were negatively associated with the Working Memory Index (β^ - 0.17, 95% CI - 0.33, - 0.03). Associations with factor scores were generally stronger and more precise than associations with individual instrument-specific items. Factor analysis of outcomes may provide some advantages in etiological studies of childhood neurodevelopment by incorporating information across scales to reduce dimensionality and improve precision.

This article explores the current literature on student characteristics and performance in an accounting course. When planning to teach or design a course, student characteristics play a role as part of the “situational factors” (Fink, 2003). Research has widely shown that college graduation rates are associated with student characteristics (e.g., Astin & Oseguera, 2005; Gold & Albert, 2006). This article focuses on student characteristics and performance in an accounting course. The following factors are discussed: math, English, gender, age, and prior accounting course. These factors are chosen, as they are often available from course enrollment data. The literature shows that some characteristics (math, prior accounting course) have a positive relationship with performance in an accounting course, while other characteristics (English, age, gender) have a mixed effect on performance.

Although bariatric surgery is an effective treatment of morbid obesity, many patients fail to lose significant weight or regain weight over time. This study examined pre-surgical psychosocial predictors (stress, social support for healthy eating, emotion regulation, and sleep quality/quantity) of three-month post-surgical percent excess weight loss (EWL) in a population of adult bariatric surgery patients. Overall, findings suggest higher levels of stress (B = -.248, p =.017) and less social support for healthy eating (B =.311, p =.013) predict lower three-month post-surgery percent EWL. Emotion regulation, and sleep measures did not predict post-surgery percent EWL. Therefore, level of stress and social support should be assessed prior to bariatric surgery and considered important pre-surgical intervention targets.

Inflammasomes are a family of pro-inflammatory signaling complexes that orchestrate inflammatory responses in many tissues. The NLRP3 inflammasome has been implicated in several diseases associated with chronic inflammation. In this paper, we present an Adverse Outcome Pathway (AOP) for NLRP3-induced chronic inflammatory diseases that demonstrates how NLRP3 can cause a transition from acute to chronic inflammation, and ultimately the onset of disease. We present a simple graphical description of the main features of internal dose time courses that are important when pharmacodynamics are governed by an activation threshold. Similar considerations hold for other AOPs that are rate-limited by processes with activation thresholds. The risk analysis implications of AOPs with threshold or threshold-like pharmacodynamic responses include the need to consider how cumulative dose per unit time is distributed over time and the possibility that safe, or virtually safe, exposure concentrations can be defined for such processes.