Mortality in Patients with Parkinson's Disease-Related Psychosis Treated with Pimavanserin Compared with Other Atypical Antipsychotics: A Cohort Study.

INTRODUCTION: Pimavanserin is approved in the USA to treat hallucinations and delusions associated with Parkinson's disease psychosis (PDP). OBJECTIVES: We evaluated mortality in patients with PDP after initiation of pimavanserin or comparator atypical antipsychotics, overall, over time, and across subgroups. METHODS: A cohort of patients aged ≥65 years in the USA with PDP newly initiating pimavanserin or a comparator atypical antipsychotic (clozapine, quetiapine, risperidone, olanzapine, aripiprazole, brexpiprazole) was identified in 2016-2019 Medicare claims data. All-cause mortality in the propensity score-matched treatment groups was compared with hazard ratios (HRs) and 95% confidence intervals (CIs) estimated with Cox-proportional hazards models. Cumulative incidence curves and time period-specific models evaluated risk over time. Subgroup and sensitivity analyses were performed, including a sub-cohort of long-term care (LTC) or skilled nursing facility (SNF) residents. RESULTS: We identified 2892 pimavanserin initiators and 19,083 comparator initiators (overall 47% female, mean age = 80.9 years, LTC/SNF residents = 30%). Before matching, pimavanserin users had fewer severe comorbidities and more anti-Parkinson medication use than comparators. Matching resulted in 2891 patients in both groups, and all covariates were well balanced. In the matched cohort, the HR for mortality for pimavanserin versus comparator was 0.78 (95% CI 0.67-0.91), with the lowest time period-specific HRs in the first 180 days. Hazard ratios were similar across sensitivity analyses and subgroups. In LTC/SNF residents, the HR was 0.78 (95% CI 0.60-1.01). CONCLUSION: The observed mortality rates were lower among patients treated with pimavanserin compared with those treated with other atypical antipsychotics. STUDY REGISTRATION: European Union Post-authorization Study (EU PAS) register number 46331.

Clinical outcomes and treatment patterns of older adults with dementia-related psychosis by dementia type in the United States.

BACKGROUND: Little is known about the incidence of clinical events and treatment patterns among older adults with dementia-related psychosis. Given that dementia-related psychosis comprises various dementia types, this study describes the incidence of clinical events and treatment patterns by dementia type after patients with dementia are diagnosed with psychosis. METHODS: Adults aged ≥ 65 years with dementia and newly diagnosed with psychosis were identified in US Medicare claims during 2013-2018. Baseline characteristics were evaluated at the time of the psychosis diagnosis. After the initial psychosis diagnosis, incidence rates (IRs) of clinical events (e.g., falls/fractures, infections, healthcare utilization), mortality, and patterns of antipsychotic treatment were described for each dementia type (Alzheimer's disease [AD], Parkinson's disease dementia [PDD], dementia with Lewy bodies [DLB], frontotemporal dementia [FTD], vascular dementia [VD], and unspecified dementia). Daily mean cumulative counts were estimated to describe the incidence of recurrent events over time. Mortality was described using Kaplan-Meier survival curves. RESULTS: We identified 484,520 patients with dementia-related psychosis: mean age, 84 years (standard deviation, 7.8); female, 66%. At the time of psychosis diagnosis, the most prevalent type of dementia was unspecified dementia (56%), followed by AD (31%), VD (12%), PDD (10%), DLB (3%), and FTD (< 1%), and most patients had scores indicating severe illness on the Charlson Comorbidity Index (71%) and frailty index (62%). Across all dementia types, IRs (per 100 person-years) were high for emergency department visits, oral anti-infective use, and urinary tract infections after the initial psychosis diagnosis. Patients with DLB had the highest incidence of most clinical outcomes. After 1 year of follow-up, the cumulative probability of death was about 30% for all dementia types, and after 5 years, was about 80% among patients with DLB, VD, AD, or PDD and about 60%-65% among patients with FTD or unspecified dementia. CONCLUSIONS: Patients with dementia-related psychosis had a high burden of comorbidities, frailty, emergency department visits, infections, and death. Specifically, after DRP diagnosis, patients with DLB and VD had the highest burden of clinical events of interest.

Risk of Major Cardiovascular and Cerebrovascular Events in Users of Lisdexamfetamine and Other Medications for Attention-Deficit/Hyperactivity Disorder in Denmark and Sweden: A Population-Based Cohort Study.

INTRODUCTION: This study aimed to estimate risks of cardiovascular and cerebrovascular events in patients treated with lisdexamfetamine dimesylate (LDX) compared with patients previously treated with other attention-deficit/hyperactivity disorder (ADHD) medications (amphetamine, dexamphetamine, methylphenidate or atomoxetine). METHODS: This population-based cohort study used data from Danish and Swedish medical and administrative national registers. The LDX cohort included adult patients initiating LDX with at least 12 months' data preceding first LDX dispensing (index date). A random sample of patients treated with at least one non-LDX ADHD medication in the 6-24 months (but not less than 6 months) before index date (previous-users cohort) were matched to LDX users on age, sex, region and calendar year. The primary outcome, a composite of major adverse cardiovascular and cerebrovascular events (MACE), included first hospitalisation for acute myocardial infarction or stroke and out-of-hospital coronary heart disease or cerebrovascular disease death. Incidence rates (IRs) and IR ratios (IRRs) with 95% confidence intervals (CIs) of MACE were estimated using Poisson regression. RESULTS: From Denmark/Sweden, 5516/40,163 LDX users and 27,494/200,389 previous users were included. In Denmark, IRs of MACE/1000 person-years (95% CI) were similar for LDX (1.63 [0.85-3.14]) and previous users (1.61 [1.28-2.01]). In Sweden, IRs (95% CI) were 1.40 (1.09-1.79) in LDX users and 1.17 (1.00-1.38) in previous users. Adjusted MACE IRRs (95% CI) for LDX versus previous use were 1.01 (0.48-2.13) in Denmark, 1.13 (0.75-1.71) in Sweden, and 1.10 (0.77-1.58) in the pooled analysis. CONCLUSION: Our findings suggest little to no increased risk of cardiovascular and cerebrovascular events in patients treated with LDX compared with patients previously treated with other ADHD medications.

Falls and Fractures in Patients with Parkinson's Disease-Related Psychosis Treated with Pimavanserin vs Atypical Antipsychotics: A Cohort Study.

BACKGROUND: Parkinson's disease-related psychosis increases patients' risk of falls. Pimavanserin is an atypical antipsychotic approved in the USA in 2016 for the treatment of hallucinations and delusions associated with Parkinson's disease-related psychosis. OBJECTIVE: We aimed to compare the risk of falls/fractures among patients with Parkinson's disease-related psychosis treated with pimavanserin vs other atypical antipsychotics. PATIENTS AND METHODS: We identified a cohort of patients with Parkinson's disease-related psychosis aged ≥ 40 years initiating either pimavanserin or a comparator antipsychotic (clozapine, quetiapine, risperidone, olanzapine, aripiprazole, brexpiprazole) in US commercial insurance and supplementary Medicare claims (2015-2019). Comparators were propensity score matched 2:1 with pimavanserin initiators; incidence rates of falls/fractures were compared using incidence rate ratios (IRRs) and 95% confidence intervals (CIs). RESULTS: We identified 112 eligible pimavanserin initiators and 982 comparators. Pimavanserin initiators were younger and had fewer severe comorbidities, indicators of impairment, and healthcare encounters, though they had higher Parkinson's disease medication use. The crude incidence rates [cases/100 person-years] (95% CI) for composite falls/fractures were 17.8 (7.7-35.0) for pimavanserin and 40.8 (35.0-47.4) for comparators. Matching retained 108 pimavanserin initiators and 216 comparators-all characteristics were well balanced after matching-with a matched IRR (pimavanserin vs comparator) of 0.71 (95% CI 0.27-1.67). Sensitivity analysis IRR estimates were consistently below 1.00, with a sensitivity analysis not requiring a diagnosis of psychosis resulting in an IRR estimate of 0.55 (95% CI 0.34-0.86). CONCLUSIONS: The results of this study do not suggest an increase in the risk of falls or fractures associated with pimavanserin compared with other antipsychotics in patients with Parkinson's disease-related psychosis. Sensitivity analyses suggest a decreased risk.

Cost transferability problems in economic evaluation as a framework for an European health care and social costs database.

This article presents part of the work within Work Package 3 (WP3) of Impact HTA (Improved methods and actionable tools for enhancing HTA), a H2020 EU-funded research project, intended to enhance and promote collaboration in HTA across EU MS. Amongst other objectives, and in close collaboration with WP4, WP3 addressed setting up a multi-country unit-cost database: the European health care and social costs database (EU HCSCD). The purpose of the database is to facilitate the transference of healthcare economic evaluation analyses across countries, jurisdictions and settings. WP3 concentrates on healthcare costs; WP4 on social costs. This paper discusses the state of the art on this topic, building an appropriate conceptual and theoretical framework for Database development. We conducted a broad, but not systematic, literature and gray-literature review (LR), identifying existing practices and problems, and their implications, described in the Results section. We discuss practical implications and draw important conclusions behind the construction, and future evolution, of this database.

Walnuts, Long-Chain Polyunsaturated Fatty Acids, and Adolescent Brain Development: Protocol for the Walnuts Smart Snack Dietary Intervention Trial.

Background: Adolescence, when the most complex behaviors are refined to adult sophistication, represents a major window of opportunity and vulnerability for neuropsychological development. To support and protect this complex and active brain growth, different nutritional components considered essential need to be acquired from the diet. For instance, omega-3 fatty acids are mainly obtained from seafood, seeds, and walnuts. Known for their rich lipid profile, walnuts contain sizable amounts of an essential fatty acid, alpha-linolenic acid (ALA), the vegetable omega-3 fatty acid that is the precursor of two longer-chain omega-3 polyunsaturated fatty acids (omega-3 PUFA): docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids. While there is growing evidence of neuropsychological improvements in the young developing brain associated with omega-3 PUFA intake, few studies have examined whether consuming walnuts during adolescence entails similar beneficial effects. There is a need to further explore the ways in which walnuts influence youthful brain function, particularly for the long-term. Thus, we designed the WALNUTs study (WSS), a population-based randomized controlled trial conducted in adolescents in Barcelona, Spain. We hypothesize that walnut intake will increase omega-3 PUFA tissue availability (particularly ALA) to a level that enhances the neuropsychological development during adolescence. Methodology/Design: We conducted a 6-month population-based randomized controlled trial in teenagers (n = 800) and we aimed to determine the effectiveness of the intervention (four walnuts per day, or 30 kernel g, ~1.5g of ALA) in enhancing brain neuropsychological and socio-emotional development compared to a control group with no walnut intervention. Before randomization, different neuropsychological tests were recorded for all participants, and blood samples (in a subsample of participants) were collected to measure omega-3 PUFA levels at baseline, and all again, after randomization and the intervention. The data is now collected and we will conduct linear regression models to assess the effect of the intervention. Discussion: The WALNUTs (WSS) study results will allow us to better understand the role of plant-based omega-3 PUFA intake from regular walnut consumption on neuropsychological development during adolescence. Results could be translated into nutritional public health recommendations targeting teenagers. Trial Registration: ClinicalTrials.gov, U.S. National Library of Medicine, National Institutes of Health # NCT02590848. Retrospectively registered 29/10/2015.

Increased risk of falls and fractures in patients with psychosis and Parkinson disease.

OBJECTIVE: Evaluate whether the risk of falls and fractures differs between patients with Parkinson disease with psychosis (PDP) and patients with Parkinson disease (PD) without psychosis at similar disease stages. METHODS: Patients with PD without psychosis were identified in the Medicare claims databases (2008-2018) and followed from the first PD diagnosis date during the study period. Patients with a subsequent diagnosis of psychosis were included in the PDP group. Patients with PDP and PD without psychosis were propensity score-matched based on characteristics within blocks of time since cohort entry. The incidence rates (IRs), expressed per 100 person-years, and 95% confidence intervals (CIs) of falls and fractures were evaluated as composite and separate outcomes. Incidence rate ratios (IRRs) were used to compare patients with PDP and PD without psychosis in the matched cohort. RESULTS: 154,306 patients had PD without psychosis and no falls or fractures before cohort entry; the IR for falls and fractures was 11.41 events (95% CI, 11.29-11.53). 12,127 patients (7.8%) had a subsequent PDP diagnosis. PDP patients had a higher prevalence of most comorbidities and risk factors for falls and fractures than those without psychosis. The crude IR for falls and fractures among PDP patients was 29.03 events (95% CI, 28.27-29.81). PD without psychosis and PDP groups had more falls than fractures. After matching, 24,144 PD patients without psychosis (15.6%) and 12,077 PDP patients (99.6%) were retained. Matched PDP patients had a higher incidence of falls and fractures than PD patients without psychosis (IRR = 1.44; 95% CI, 1.39-1.49). The higher increased rate was noted separately for falls (IRR = 1.48; 95% CI, 1.43-1.54) and any fractures (IRR = 1.17; 95% CI, 1.08-1.27) as well as within specific types of fracture, including pelvis and hip fractures. CONCLUSIONS: Our findings suggest a modest but consistently higher increased risk of falls and fractures in PDP patients compared with PD patients without psychosis.

Early Life Exposure to Perfluoroalkyl Substances (PFAS) and ADHD: A Meta-Analysis of Nine European Population-Based Studies.

INTRODUCTION: To date, the evidence for an association between perfluoroalkyl substances (PFAS) exposure and attention deficit and hyperactivity disorder (ADHD) is inconclusive. OBJECTIVE: We investigated the association between early life exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), and ADHD in a collaborative study including nine European population-based studies, encompassing 4,826 mother-child pairs. METHODS: Concentrations of PFOS and PFOA were measured in maternal serum/plasma during pregnancy, or in breast milk, with different timing of sample collection in each cohort. We used a validated pharmacokinetic model of pregnancy and lactation to estimate concentrations of PFOS and PFOA in children at birth and at 3, 6, 12, and 24 months of age. We classified ADHD using recommended cutoff points for each instrument used to derive symptoms scores. We used multiple imputation for missing covariates, logistic regression to model the association between PFAS exposure and ADHD in each study, and combined all adjusted study-specific effect estimates using random-effects meta-analysis. RESULTS: A total of 399 children were classified as having ADHD, with a prevalence ranging from 2.3% to 7.3% in the studies. Early life exposure to PFOS or PFOA was not associated with ADHD during childhood [odds ratios (ORs) ranging from 0.96 (95% CI: 0.87, 1.06) to 1.02 (95% CI: 0.93, 1.11)]. Results from stratified models suggest potential differential effects of PFAS related to child sex and maternal education. CONCLUSION: We did not identify an increased prevalence of ADHD in association with early life exposure to PFOS and PFOA. However, stratified analyses suggest that there may be an increased prevalence of ADHD in association with PFAS exposure in girls, in children from nulliparous women, and in children from low-educated mothers, all of which warrant further exploration. https://doi.org/10.1289/EHP5444.

Effects of prenatal exposure to particulate matter air pollution on corpus callosum and behavioral problems in children.

OBJECTIVE: Air pollution (AP) may affect neurodevelopment, but studies about the effects of AP on the growing human brain are still scarce. We aimed to investigate the effects of prenatal exposure to AP on lateral ventricles (LV) and corpus callosum (CC) volumes in children and to determine whether the induced brain changes are associated with behavioral problems. METHODS: Among the children recruited through a set of representative schools of the city of Barcelona, (Spain) in the Brain Development and Air Pollution Ultrafine Particles in School Children (BREATHE) study, 186 typically developing participants aged 8-12 years underwent brain MRI on the same 1.5 T MR unit over a 1.5-year period (October 2012-April 2014). Brain volumes were derived from structural MRI scans using automated tissue segmentation. Behavioral problems were assessed using the Strengths and Difficulties Questionnaire (SDQ) and the criteria of the Attention Deficit Hyperactivity Disorder DSM-IV list. Prenatal fine particle (PM2.5) levels were retrospectively estimated at the mothers' residential addresses during pregnancy with land use regression (LUR) models. To determine whether brain structures might be affected by prenatal PM2.5 exposure, linear regression models were run and adjusted for age, sex, intracranial volume (ICV), maternal education, home socioeconomic vulnerability index, birthweight and mothers' smoking status during pregnancy. To test for associations between brain changes and behavioral outcomes, negative binomial regressions were performed and adjusted for age, sex, ICV. RESULTS: Prenatal PM2.5 levels ranged from 11.8 to 39.5 µg/m3 during the third trimester of pregnancy. An interquartile range increase in PM2.5 level (7 µg/m3) was significantly linked to a decrease in the body CC volume (mm3) (ß = -53.7, 95%CI [-92.0, -15.5] corresponding to a 5% decrease of the mean body CC volume) independently of ICV, age, sex, maternal education, socioeconomic vulnerability index at home, birthweight and mothers' smoking status during the third trimester of pregnancy. A 50 mm3 decrease in the body CC was associated with a significant higher hyperactivity subscore (Rate Ratio (RR) = 1.09, 95%CI [1.01, 1.17) independently of age, sex and ICV. The statistical significance of these results did not survive to False Discovery Rate correction for multiple comparisons. CONCLUSIONS: Prenatal exposure to PM2.5 may be associated with CC volume decrease in children. The consequences might be an increase in behavioral problems.

Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: A study in three European data sources.

PURPOSE: Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs). METHODS: Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers. Three ALI definitions were evaluated: primary (specific hospital discharge codes), secondary (specific and nonspecific hospital discharge codes), and tertiary (specific and nonspecific hospital and outpatient codes). The validation included review of patient profiles (EpiChron and SIDIAP) and of clinical data from medical records (EpiChron and Denmark). ALI cases were confirmed when liver enzyme values met a definition by an international working group. RESULTS: Overall PPVs (95% CIs) for the study ALI definitions were, for the primary ALI definition, 84% (60%-97%) (EpiChron), 60% (26%-88%) (SIDIAP), and 74% (60%-85%) (Denmark); for the secondary ALI definition, 65% (45%-81%) (EpiChron), 40% (19%-64%) (SIDIAP), and 70% (64%-77%) (Denmark); and for the tertiary ALI definition, 25% (18%-34%) (EpiChron), 8% (7%-9%) (SIDIAP), and 47% (42%-52%) (Denmark). The overall PPVs were higher for specific than for nonspecific codes and for hospital discharge than for outpatient codes. The nonspecific code "unspecified jaundice" had high PPVs in Denmark. CONCLUSIONS: PPVs obtained apply to patients using antidepressants without preexisting liver disease or ALI risk factors. To maximize validity, studies on ALI should prioritize hospital specific discharge codes and should include hospital codes for unspecified jaundice. Case validation is required when ALI outpatient cases are considered.

Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case-Control Study Using Automated Health Data Sources.

BACKGROUND: Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome). OBJECTIVE: The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice. METHOD: A nested case-control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009-2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined. RESULTS: We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13-1.71). Results were also < 1 when no exclusion criteria were applied (OR 0.37; CI 0.19-0.74), when all exclusion criteria except alcohol and drug abuse were applied (OR 0.47; CI 0.20-1.07), and for the secondary (OR 0.40; CI 0.05-3.11) and tertiary (OR 0.79; CI 0.50-1.25) endpoints. Regarding other antidepressants versus citalopram, most OR point estimates were also below one, although with varying widths of the 95% CIs. The result of the tertiary endpoint and the sensitivity analyses of the primary endpoint were the most precise. CONCLUSION: In this study, using citalopram as a comparator, agomelatine was not associated with an increased risk of ALI hospitalisation. The results for agomelatine should be interpreted in the context of the European risk minimisation measures in place. Those measures may have induced selective prescribing and could explain the lower risk of ALI for agomelatine when compared with citalopram. Most other antidepressants evaluated had ORs suggesting a lower risk than citalopram, but additional studies are required to confirm or refute these results.

Brain Structure and Function in School-Aged Children With Sluggish Cognitive Tempo Symptoms.

OBJECTIVE: Sluggish cognitive tempo (SCT) is a cluster of symptoms associated with poor function in various domains of major life activities that may comprise a novel attention disorder distinct from attention-deficit/hyperactivity disorder (ADHD). Nevertheless, very little is known about the neural substrate of SCT in children. The present study aimed to examine associations between SCT symptoms and brain structure and function in school-aged children. METHOD: We performed a cross-sectional MRI study in 178 children 8 to 12 years old from primary schools in Barcelona, Spain. Data were collected between January 2012 and March 2013. Parents completed the Sluggish Cognitive Tempo-Child Behavior Checklist (SCT-CBCL). Participants underwent magnetic resonance imaging to assess regional brain volume, white matter integrity using diffusion tensor imaging, and functional connectivity in major neural networks. RESULTS: SCT symptoms were associated with altered anatomy of the frontal lobe in the form of increased regional volume. The anomalously large cortical regions were less mature in terms of functional connectivity. Importantly, all the anatomical and functional anomalies identified remained significant after adjusting the analyses for ADHD symptom scores. CONCLUSION: Our results suggest that SCT symptoms are associated with distinct features of brain structure and function that differ from the classical neural substrates described in ADHD.

Early-life exposure to persistent organic pollutants (OCPs, PBDEs, PCBs, PFASs) and attention-deficit/hyperactivity disorder: A multi-pollutant analysis of a Norwegian birth cohort.

BACKGROUND: Numerous ubiquitous environmental chemicals are established or suspected neurotoxicants, and infants are exposed to a mixture of these during the critical period of brain maturation. However, evidence for associations with the risk of attention-deficit/hyperactivity disorder (ADHD) is sparse. We investigated early-life chemical exposures in relation to ADHD. METHODS: We used a birth cohort of 2606 Norwegian mother-child pairs enrolled 2002-2009 (HUMIS), and studied a subset of 1199 pairs oversampled for child neurodevelopmental outcomes. Concentrations of 27 persistent organic pollutants (14 polychlorinated biphenyls, 5 organochlorine pesticides, 6 brominated flame retardants, and 2 perfluoroalkyl substances) were measured in breast milk, reflecting the child's early-life exposures. We estimated postnatal exposures in the first 2 years of life using a pharmacokinetic model. Fifty-five children had a clinical diagnosis of ADHD (hyperkinetic disorder) by 2016, at a median age of 13 years. We used elastic net penalized logistic regression models to identify associations while adjusting for co-exposure confounding, and subsequently used multivariable logistic regression models to obtain effect estimates for the selected exposures. RESULTS: Breast milk concentrations of perfluorooctane sulfonate (PFOS) and ß­hexachlorocyclohexane (ß-HCH) were associated with increased odds of ADHD: odds ratio (OR) = 1.77, 95% confidence interval (CI): 1.16, 2.72 and OR = 1.75, 95% CI: 1.22, 2.53, per interquartile range increase in ln-transformed concentrations, respectively. Stronger associations were observed among girls than boys for PFOS (pinteraction = 0.025). p,p'­Dichlorodiphenyltrichloroethane (p,p'-DDT) levels were associated with lower odds of ADHD (OR = 0.64, 95% CI: 0.42, 0.97). Hexachlorobenzene (HCB) had a non-linear association with ADHD, with increasing risk in the low-level exposure range that switched to a decreasing risk at concentrations above 8 ng/g lipid. Postnatal exposures showed similar results, whereas effect estimates for other chemicals were weaker and imprecise. CONCLUSIONS: In a multi-pollutant analysis of four classes of chemicals, early-life exposure to ß-HCH and PFOS was associated with increased risk of ADHD, with suggestion of sex-specific effects for PFOS. The unexpected inverse associations between p,p'-DDT and higher HCB levels and ADHD could be due to live birth bias; alternatively, results may be due to chance findings.

Antidepressant use in Denmark, Germany, Spain, and Sweden between 2009 and 2014: Incidence and comorbidities of antidepressant initiators.

BACKGROUND: We aimed to describe patterns of use and characteristics of 10 commonly used antidepressants for the period 2009-2014 in Denmark, Germany, Spain, and Sweden. METHODS: Adult initiators from 2009 to 2014 of each study antidepressant were identified in four countries using five data sources: the Danish National registers, GePaRD (Germany), EpiChron (Aragon, Spain), SIDIAP (Catalonia, Spain), and the Swedish National Registers. The study included 10 study antidepressants: citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, amitriptyline, mirtazapine, and agomelatine. RESULTS: Citalopram was the most prescribed study antidepressant, followed by mirtazapine. Paroxetine and agomelatine were the least prescribed antidepressants. Mirtazapine was widely used among older antidepressant initiators with higher percentages of comorbidities at baseline, and fluoxetine was used among young patients. Citalopram and amitriptyline had the lowest percentage of multiple antidepressant use in the 12 months prior to the current treatment episode, while agomelatine, duloxetine, and venlafaxine had the highest percentage of multiple antidepressant use in the year prior to the current treatment episode. LIMITATIONS: The most important limitations are exposure information based on filled prescriptions, focus on antidepressant initiators only, lack of information on the indication, and heterogeneity of the type of data across data sources. CONCLUSIONS: Results of this study including 4.8 million study antidepressant initiators of study antidepressants suggest that citalopram and mirtazapine are the most commonly prescribed antidepressants. Agomelatine and paroxetine were the least used antidepressants in the participating populations. Mirtazapine was the antidepressant most commonly prescribed among older antidepressant initiators with high percentage of comorbidities at baseline, whereas fluoxetine was commonly used among young patients.

Burden and outcomes for complex perianal fistulas in Crohn's disease: Systematic review.

AIM: To systematically review the literature on epidemiology, disease burden, and treatment outcomes for Crohn's disease (CD) patients with complex perianal fistulas. METHODS: PubMed, Embase, and Cochrane were searched for relevant articles (published 2000-November 2016) and congress abstracts (published 2011-November 2016). RESULTS: Of 535 records reviewed, 62 relevant sources were identified (mostly small observational studies). The cumulative incidence of complex perianal fistulas in CD from two referral-centre studies was 12%-14% (follow-up time, 12 years in one study; not reported in the second study). Complex perianal fistulas result in greatly diminished quality of life; up to 59% of patients are at risk of faecal incontinence. Treatments include combinations of medical and surgical interventions and expanded allogeneic adipose-derived stem cells. High proportions of patients experience lack of or inadequate response to treatment (failure and relapse rates, respectively: medical, 12%-73% and 0%-41%; surgical: 0%-100% and 11%-20%; combined medical/surgical: 0%-80% and 0%-50%; stem cells: 29%-47% and not reported). Few studies (1 of infliximab; 3 of surgical interventions) have been conducted in treatment-refractory patients, a population with high unmet needs. Limited data exist on the clinical value of anti-tumour necrosis factor-α dose escalation in patients with complex perianal fistulas in CD. CONCLUSION: Complex perianal fistulas in CD pose substantial clinical and humanistic burden. There is a need for effective treatments, especially for patients refractory to anti-tumour necrosis factor-α agents, as evidenced by high failure and relapse rates.

Traffic-Related Air Pollution, APOEε4 Status, and Neurodevelopmental Outcomes among School Children Enrolled in the BREATHE Project (Catalonia, Spain).

BACKGROUND: Traffic-related air pollution is emerging as a risk factor for Alzheimer's disease (AD) and impaired brain development. Individual differences in vulnerability to air pollution may involve the ε4 allele of Apolipoprotein E (APOE) gene, the primary genetic risk factor for AD. OBJECTIVE: We analyzed whether the association between traffic air pollution and neurodevelopmental outcomes is modified by APOEε4 status in children. METHODS: Data on parent-reported behavior problems (total difficulties scores, Strengths and Difficulties Questionnaire), teacher-reported attention-deficit hyperactivity disorder (ADHD) symptom scores, cognitive performance trajectories (computerized tests of inattentiveness and working memory repeated 2-4 times during January 2012-March 2013), and APOE genotypes were obtained for 1,667 children age 7-11 y attending 39 schools in or near Barcelona. Basal ganglia volume (putamen, caudate, and globus pallidum) was measured in 163 of the children by MRI (October 2012-April 2014.) Average annual outdoor polycyclic aromatic hydrocarbons (PAHs), elemental carbon (EC), and nitrogen dioxide (NO2) concentrations were estimated based on measurements at each school (two 1-wk campaigns conducted 6 months apart in 2012). RESULTS: APOEε4 allele carriers had significantly higher behavior problem scores than noncarriers, and adverse associations with PAHs and NO2 were stronger or limited to ε4 carriers for behavior problem scores (P-interaction 0.03 and 0.04), caudate volume (P-interaction 0.04 and 0.03), and inattentiveness trajectories (P-interaction 0.15 and 0.08, respectively). Patterns of associations with the same outcomes were similar for EC. CONCLUSION: PAHs, EC, and NO2 were associated with higher behavior problem scores, smaller reductions in inattentiveness over time, and smaller caudate volume in APOEε4 allele carriers in our study population, and corresponding associations were weak or absent among ε4 noncarriers. These findings support a potential role of APOE in biological mechanisms that may contribute to associations between air pollution and neurobehavioral outcomes in children. https://doi.org/10.1289/EHP2246.

Air Pollution Exposure During Pregnancy and Symptoms of Attention Deficit and Hyperactivity Disorder in Children in Europe.

BACKGROUND: Exposure to air pollution during pregnancy may increase attention-deficit/hyperactivity disorder (ADHD) symptoms in children, but findings have been inconsistent. We aimed to study this association in a collaborative study of eight European population-based birth/child cohorts, including 29,127 mother-child pairs. METHODS: Air pollution concentrations (nitrogen dioxide [NO2] and particulate matter [PM]) were estimated at the birth address by land-use regression models based on monitoring campaigns performed between 2008 and 2011. We extrapolated concentrations back in time to exact pregnancy periods. Teachers or parents assessed ADHD symptoms at 3-10 years of age. We classified children as having ADHD symptoms within the borderline/clinical range and within the clinical range using validated cutoffs. We combined all adjusted area-specific effect estimates using random-effects meta-analysis and multiple imputations and applied inverse probability-weighting methods to correct for loss to follow-up. RESULTS: We classified a total of 2,801 children as having ADHD symptoms within the borderline/clinical range, and 1,590 within the clinical range. Exposure to air pollution during pregnancy was not associated with a higher odds of ADHD symptoms within the borderline/clinical range (e.g., adjusted odds ratio [OR] for ADHD symptoms of 0.95, 95% confidence interval [CI] = 0.89, 1.01 per 10 µg/m increase in NO2 and 0.98, 95% CI = 0.80, 1.19 per 5 µg/m increase in PM2.5). We observed similar associations for ADHD within the clinical range. CONCLUSIONS: There was no evidence for an increase in risk of ADHD symptoms with increasing prenatal air pollution levels in children aged 3-10 years. See video abstract at, http://links.lww.com/EDE/B379.

Prenatal and postnatal exposure to persistent organic pollutants and attention-deficit and hyperactivity disorder: a pooled analysis of seven European birth cohort studies.

Background: Attention-deficit/hyperactivity disorder (ADHD) is increasing worldwide for reasons largely unknown and environmental chemicals with neurotoxic properties, such as persistent organic pollutants (POPs), have been proposed to play a role. We investigated the association between prenatal and postnatal exposure to polychlorinated biphenyl-153 (PCB-153), p-p´-dichlorodiphenyldichloroethylene (p-p'-DDE) and hexachlorobenzene (HCB) and ADHD in childhood. Methods: We pooled seven European birth cohort studies encompassing 4437 mother-child pairs from the general population with concentrations of PCB-153, p-p´-DDE and HCB measured in cord blood, maternal blood or milk. We then calculated prenatal (birth) and postnatal (3, 6, 12 and 24 months) POP concentrations using a pharmacokinetic model. The operational definition of ADHD varied across cohorts and ranged from doctor diagnosis obtained from patient registries to maternal or teachers reports. We used multilevel (mixed) logistic regression models to estimate the associations between exposure to POPs at birth, 3, 6, 12 and 24 months and ADHD. Results: The global prevalence of ADHD in our study was 6%. The mean age at assessment of ADHD was 5.8 years (range: 3.8-9.5 years). We found no association between exposure to PCB-153, p-p´-DDE and HCB at any age point between birth and 24 months and ADHD, in the pooled analyses (pooled odds ratios ranging from 1.00 to 1.01). A number of sensitivity analyses gave basically the same results. Conclusions: In the largest study to date of 4437 children in seven European birth cohorts, we did not observe any association between either pre- or postnatal exposure (up to 24 months) to PCB-153, p-p´-DDE and HCB and the risk of ADHD before the age of 10 years.

Methodological challenges when evaluating potential off-label prescribing of drugs using electronic health care databases: A case study of dabigatran etexilate in Europe.

PURPOSE: To report and discuss estimated prevalence of potential off-label use and associated methodological challenges using a case study of dabigatran. METHODS: Observational, cross-sectional study using 3 databases with different types of clinical information available: Cegedim Strategic Data Longitudinal Patient Database (CSD-LPD), France (cardiologist panel, n = 1706; general practitioner panel, n = 2813; primary care data); National Health Databases, Denmark (n = 28 619; hospital episodes and dispensed ambulatory medications); and Clinical Practice Research Datalink (CPRD), UK (linkable to Hospital Episode Statistics [HES], n = 2150; not linkable, n = 1285; primary care data plus hospital data for HES-linkable patients). STUDY PERIOD: August 2011 to August 2015. Two definitions were used to estimate potential off-label use: a broad definition of on-label prescribing using codes for disease indication (eg, atrial fibrillation [AF]), and a restrictive definition excluding patients with conditions for which dabigatran is not indicated (eg, valvular AF). RESULTS: Prevalence estimates under the broad definition ranged from 5.7% (CPRD-HES) to 34.0% (CSD-LPD) and, under the restrictive definition, from 17.4% (CPRD-HES) to 44.1% (CSD-LPD). For the majority of potential off-label users, no diagnosis potentially related to anticoagulant use was identified. Key methodological challenges were the limited availability of detailed clinical information, likely leading to overestimation of off-label use, and differences in the information available, which may explain the disparate prevalence estimates across data sources. CONCLUSIONS: Estimates of potential off-label use should be interpreted cautiously due to limitations in available information. In this context, CPRD HES-linkable estimates are likely to be the most accurate.

Sleeping, TV, Cognitively Stimulating Activities, Physical Activity, and Attention-Deficit Hyperactivity Disorder Symptom Incidence in Children: A Prospective Study.

OBJECTIVE: To analyze associations between time spent sleeping, watching TV, engaging in cognitively stimulating activities, and engaging in physical activity, all at 4 years, and (1) attention-deficit/hyperactivity disorder (ADHD) symptoms and (2) behavior problems, both assessed at 7 years, in ADHD-free children at baseline. METHOD: In total, 817 participants of the Infancia y Medio Ambiente birth cohort, without ADHD at baseline, were included. At the 4-year follow-up, parents reported the time that their children spent sleeping, watching TV, engaging in cognitively stimulating activities, and engaging in physical activity. At the 7-year follow-up, parents completed the Conners' Parent Rating Scales and the Strengths and Difficulties Questionnaire, which measure ADHD symptoms and behavior problems, respectively. Negative binomial regression models were used to assess associations between the activities at 4 years and ADHD symptoms and behavior problems at 7 years. RESULTS: Children (48% girls) spent a median (p25-p75) of 10 (10-11) hours per day sleeping, 1.5 (0.9-2) hours per day watching TV, 1.4 (0.9-1.9) hours per day engaging in cognitively stimulating activities, and 1.5 (0.4-2.3) hours per day engaging in physical activity. Longer sleep duration (>10 hours per day) was associated with a lower ADHD symptom score (adjusted incidence rate ratio = 0.97, 95% confidence interval, 0.95-1.00). Longer time spent in cognitively stimulating activities (>1 hours per day) was associated with lower scores of both ADHD symptoms (0.96, 0.94-0.98) and behavior problems (0.89, 0.83-0.97). Time spent watching TV and engaging in physical activity were not associated with either outcomes. CONCLUSION: A shorter sleep duration and less time spent in cognitively stimulating activities were associated with an increased risk of developing ADHD symptoms and behavior problems.