DNA sequence and chromatin differentiate sequence-specific transcription factor binding in the human malaria parasite Plasmodium falciparum.

Development of the malaria parasite, Plasmodium falciparum, is regulated by a limited number of sequence-specific transcription factors (TFs). However, the mechanisms by which these TFs recognize genome-wide binding sites is largely unknown. To address TF specificity, we investigated the binding of two TF subsets that either bind CACACA or GTGCAC DNA sequence motifs and further characterized two additional ApiAP2 TFs, PfAP2-G and PfAP2-EXP, which bind unique DNA motifs (GTAC and TGCATGCA). We also interrogated the impact of DNA sequence and chromatin context on P. falciparum TF binding by integrating high-throughput in vitro and in vivo binding assays, DNA shape predictions, epigenetic post-translational modifications, and chromatin accessibility. We found that DNA sequence context minimally impacts binding site selection for paralogous CACACA-binding TFs, while chromatin accessibility, epigenetic patterns, co-factor recruitment, and dimerization correlate with differential binding. In contrast, GTGCAC-binding TFs prefer different DNA sequence context in addition to chromatin dynamics. Finally, we determined that TFs that preferentially bind divergent DNA motifs may bind overlapping genomic regions due to low-affinity binding to other sequence motifs. Our results demonstrate that TF binding site selection relies on a combination of DNA sequence and chromatin features, thereby contributing to the complexity of P. falciparum gene regulatory mechanisms.

Maternal serum persistent organic pollutant exposure and offspring diagnosed ADHD in a national birth cohort.

BACKGROUND: Evidence implicates environmental factors in attention-deficit/hyperactivity disorder (ADHD) risk. Prenatal exposures to polychlorinated biphenyls (PCBs) and the pesticide metabolite p,p'-dichlorodiphenyl dichloroethylene (DDE) have been linked to lower cognitive ability, increased impulsivity, and attention related deficits in the offspring. However, information on the relationship of these exposures to the risk of clinically diagnosed ADHD is limited. OBJECTIVES: To determine whether prenatal maternal levels of PCBs or DDE are associated with ADHD diagnosis in the offspring. METHODS: The investigation was conducted in the Finnish Prenatal Study of ADHD (FIPS-ADHD), a case-control study nested in a national birth cohort. Cases were born in 1998 or 1999 and diagnosed with ADHD (ICD-9 314x or ICD-10 F90. x) according to the national Care Register for Health Care. Each case was individually matched to a control on sex, date, and place of birth. PCB congeners (PCB 74, 99, 118, 138, 153, 156, 170, 180, 183, 187) and DDE were quantified from archived prenatal maternal sera from 359 matched case-control pairs using gas chromatography - high triple quadrupole mass spectrometry. Maternal total PCBs were quantified as the sum of concentrations of the measured congeners. Associations with ADHD were examined using conditional logistic regression. RESULTS: Maternal PCB or DDE levels greater than the 75th percentiles of the control distributions showed no evidence of association with offspring ADHD (PCBs: adjusted odds ratio (aOR) = 1.01, 95% CI = 0.63, 1.60), p = 0.98; DDE: aOR = 1.13, 95% CI = 0.71, 1.81; p = 0.60). Maternal levels of either pollutant dichotomized at the 90th percentile or considered as a continuous variable also did not show evidence for association with offspring ADHD diagnosis. DISCUSSION: This study did not find evidence for association of maternal prenatal levels of PCBs or DDE with clinical diagnosis of offspring ADHD; however, this does not rule out the possibility of an impact on subclinical phenotypes.

Increased Risk of ADHD at Short and Long Interpregnancy Intervals in a National Birth Cohort.

BACKGROUND: Short or long interpregnancy interval (IPI) may adversely impact conditions for foetal development. Whether attention deficit hyperactivity disorder (ADHD) is related to IPI has been largely unexplored. OBJECTIVES: To examine the association between IPI and ADHD in a large, population-based Finnish study. METHODS: All children born in Finland between 1991 and 2005 and diagnosed with ADHD (ICD-9 314x or ICD-10 F90.x) from 1995 to 2011 were identified using data from linked national registers. Each subject with ADHD was matched to 4 controls based on sex, date of birth, and place of birth. A total of 9564 subjects with ADHD and 34,479 matched controls were included in analyses. IPI was calculated as the time interval between sibling birth dates minus the gestational age of the second sibling. The association between IPI and ADHD was determined using conditional logistic regression and adjusted for potential confounders. RESULTS: Relative to births with an IPI of 24 to 59 months, those with the shortest IPI (<6 months) had an increased risk of ADHD (odds ratio [OR] 1.30, 95% confidence interval (CI) 1.12, 1.51) and the ORs for the longer IPI births (60-119 months and ≥120 months) were 1.12 (95% CI 1.02, 1.24) and 1.25 (95% CI 1.08, 1.45), respectively. The association of longer IPI with ADHD was attenuated by adjustment for maternal age at the preceding birth, and comorbid autism spectrum disorders did not explain the associations with ADHD. CONCLUSIONS: The risk of ADHD is higher among children born following short or long IPIs although further studies are needed to explain this association.

Maternal serum Vitamin B12 and offspring attention-deficit/hyperactivity disorder (ADHD).

Maternal Vitamin B12 deficiency during pregnancy is associated with offspring neuropsychiatric disorders. Few previous studies examining this association with attention-deficit/hyperactivity disorder (ADHD) report inconsistent findings. The study examines the association between maternal serum Vitamin B12 levels and offsprings' risk of ADHD. This study is based on the Finnish Prenatal Study of ADHD with a nested case-control design. All the singleton children born in Finland between January 1998 and December 1999 and diagnosed with ADHD were included in the study. A total of 1026 cases were matched with an equal number of controls on sex, date of birth and place of birth. Maternal Vitamin B12 levels were assessed using a chemiluminescence microparticle immunoassay and archived from maternal serum banks, collected during the first and early second trimester of pregnancy. Lower maternal Vitamin B12 levels when analyzed as a continuous variable was not associated with offspring ADHD (aOR 0.97, 95% CI 0.79-1.18, p = 0.75). No significant associations were seen in the lowest quintile of Vitamin B12 levels (aOR 0.96, 95% CI 0.73-1.27, p = 0.80). This is the first study examining maternal sera Vitamin B12 levels during early pregnancy and offspring ADHD. The result suggests that Vitamin B12 deficiency during early pregnancy has specificity for some disorders but not with offspring ADHD.

The association of serologically documented maternal thyroid conditions during pregnancy with bipolar disorder in offspring.

OBJECTIVES: Higher rates of thyroid conditions are reported in individuals with bipolar disorder. However, no study to date has considered whether maternal thyroid conditions during pregnancy are associated with offspring risk of bipolar disorder, even though the fetus exclusively relies on maternal thyroid hormones through the early second trimester. We therefore examined the association between offspring bipolar disorder and serologically documented maternal thyroid conditions. METHODS: The study was based on a nested case-control design that utilized data from the Child Health and Development Study, a birth cohort that enrolled pregnant women from 1959 to 1966. Eighty-five cases with DSM-IV-TR were ascertained and matched to controls (1:2) by date of birth, sex, gestational timing of the serum draws, and residence in Alameda County the first year receiving treatment. Archived prenatal maternal serum drawn during early to mid-gestation was used to measure two thyroid hormones, free thyroxine (fT4) and thyroid stimulating hormone (TSH). Subclinical and clinical hypothyroxinemia, hypothyroidism, and hyperthyroidism were determined based on standard methods. RESULTS: Exposure to maternal hypothyroxinemia was associated with a five-fold increased risk of offspring bipolar disorder with psychotic features, but not without psychotic features. In stratified analysis, female offspring demonstrated increased risk for bipolar disorder with exposure to maternal hypothyroxinemia. No significant association was found between maternal hypothyroidism and offspring bipolar disorder. CONCLUSIONS: These findings suggest that prenatal thyroid hormone deficiency, particularly a thyroid condition marked by low levels of thyroxine, may be an important developmental mechanism related to the risk of bipolar disorder with psychotic features.

Maternal serum C-reactive protein (CRP) and offspring attention deficit hyperactivity disorder (ADHD).

Exposure to infection and inflammation during the fetal period are associated with offspring neuropsychiatric disorders. Few previous studies have examined this association with ADHD with mixed findings. This study aims to examine the association between early gestational maternal C-reactive protein (CRP), prospectively assayed in stored maternal sera and the risk of ADHD in offspring. This study is based on the Finnish Prenatal studies of ADHD (FIPS-ADHD) with a nested case-control design. It includes all singleton-born children in Finland between January 1, 1998 and December 31, 1999 and diagnosed with ADHD. A total of 1079 cases and equal number of controls were matched on date of birth, sex and place of birth. Maternal CRP levels were assessed using a latex immunoassay from archived maternal serum specimens, collected during the first and early second trimester of pregnancy. Elevated maternal CRP when analyzed as a continuous variable was not associated with offspring ADHD (OR 1.05, 95% CI 0.96-1.15). No significant associations were seen in the highest quintile of CRP (OR 1.18, 95% CI 0.88-1.58). The results were similar in both sexes as well as among ADHD cases with or without comorbid ASD or conduct disorder. In this first study examining CRP, a biomarker for inflammation, during early pregnancy in relation to offspring ADHD, we report no significant associations. The lack of any association, when considered with positive findings seen in ASD and schizophrenia, and negative findings in bipolar disorder suggests different pathways linking maternal immune activation and development of various neuropsychiatric disorders.

Attention-deficit/hyperactivity disorder and risk for psychiatric and neurodevelopmental disorders in siblings.

BACKGROUND: Probands with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for several psychiatric and neurodevelopmental disorders. The risk of these disorders among the siblings of probands has not been thoroughly assessed in a population-based cohort. METHODS: Every child born in Finland in 1991-2005 and diagnosed with ADHD in 1995-2011 were identified from national registers. Each case was matched with four controls on sex, place, and date of birth. The full siblings of the cases and controls were born in 1981-2007 and diagnosed in 1981-2013. In total, 7369 cases with 12 565 siblings and 23 181 controls with 42 753 siblings were included in the analyses conducted using generalized estimating equations. RESULTS: 44.2% of the cases and 22.2% of the controls had at least one sibling diagnosed with any psychiatric or neurodevelopmental disorder (risk ratio, RR = 2.1; 95% CI 2.0-2.2). The strongest associations were demonstrated for childhood-onset disorders including ADHD (RR = 5.7; 95% CI 5.1-6.3), conduct and oppositional disorders (RR = 4.0; 95% CI 3.5-4.5), autism spectrum disorders (RR = 3.9; 95% CI 3.3-4.6), other emotional and social interaction disorders (RR = 2.7; 95% CI 2.4-3.1), learning and coordination disorders (RR = 2.6; 95% CI 2.4-2.8), and intellectual disability (RR = 2.4; 95% CI 2.0-2.8). Also, bipolar disorder, unipolar mood disorders, schizophrenia spectrum disorders, other neurotic and personality disorders, substance abuse disorders, and anxiety disorders occurred at increased frequency among the siblings of cases. CONCLUSIONS: The results offer potential utility for early identification of neurodevelopmental and psychiatric disorders in at-risk siblings of ADHD probands and also argue for more studies on common etiologies.

Impact of Age on the Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia.

PURPOSE: This post-hoc analysis examined whether age modified the efficacy and safety of alirocumab, a PCSK9 inhibitor, in patients with heterozygous familial hypercholesterolemia (HeFH), using pooled data from four 78-week placebo-controlled phase 3 trials (ODYSSEY FH I, FH II, LONG TERM, and HIGH FH). METHODS: Data from 1257 patients with HeFH on maximally tolerated statin ± other lipid-lowering therapies were analyzed by an alirocumab dose regimen and by age subgroups (18 to < 45, 45 to < 55, 55 to < 65, and ≥ 65 years). In the FH I and II trials, patients received 75 mg subcutaneously every 2 weeks (Q2W), with dose increase to 150 mg Q2W at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥ 70 mg/dl. In HIGH FH and LONG TERM, patients received 150 mg alirocumab Q2W. RESULTS: Baseline characteristics were similar between treatment groups across all age groups; the proportion of males decreased whereas the proportion of patients with coronary heart disease, diabetes, hypertension, and declining renal function increased with increasing age. Mean LDL-C reductions at week 24 were consistent across age groups (50.6-61.0% and 51.1-65.8% vs. placebo for the 75/150 and 150 mg alirocumab dose regimens, respectively; both non-significant interaction P-values). Treatment-emergent adverse events occurred in similar frequency in alirocumab- and placebo-treated patients regardless of age, except for injection-site reactions, which were more common in alirocumab than placebo but declined in frequency with age. CONCLUSIONS: Alirocumab treatment resulted in significant LDL-C reductions at weeks 12 and 24 and was generally well tolerated in patients with HeFH across all age groups studied.

Statin Intolerance.

Statins are critical medications to prevent and treat cardiovascular disease2 and they are generally very well tolerated. In some instances, however, statin intolerance may limit use of these lifesaving medications. Statin intolerance has many definitions but is commonly diagnosed when a patient is unable to continue statin therapy due to perceived, or objectively documented, adverse effects. A very high rate of discontinuation of statin therapy warrants a closer look at the implications from the standpoint of cardiovascular risk in statin-intolerant patients, as well as an evaluation of the available options to help patients maintain their statin therapy and understand the potential benefits of such therapy.

Familial Hypercholesterolemia: Although Identification Advances, Appreciation and Treatment Lag.

Familial hypercholesterolemia is one of the most common autosomal dominant inherited genetic disorders, yet it is frequently undiagnosed, leading to a markedly increased risk for cardiovascular events. Understanding the pathophysiology of the disease as well as the importance of cascade screening is critical to appropriate treatment of patients. Though the mainstay of therapy for heterozygous familial hypercholesterolemia remains statins, many patients require additional therapy including ezetimibe and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies to achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering. Access to PCSK9 inhibitors remains a significant clinical problem.

Replication and extension of long-term implicit memory: Perceptual priming but conceptual cessation.

We endeavored to replicate Mitchell's (2006) finding of 17-year implicit memory priming. Subjects saw word and picture stimuli in 1999-2000 (M age = 18.9) and were retested after 11-14 years (M = 13.2; M age = 32.1). Via the internet, they completed four implicit memory tasks: picture fragment identification, word fragment completion, word stem completion, and category exemplar generation. Relative to control subjects (matched on stimuli, age, and education), longitudinal subjects revealed priming on picture and word fragment identification (perceptual tasks), but no priming on word stem completion or category exemplar generation (conceptual tasks). Four longitudinal subjects who failed to recall participating in the prior laboratory session had priming similar to the 10 subjects who did remember. Thus, we replicated the longevity of perceptual priming for pictures, and extended this to word fragment priming as well.

Maternal serum cytokine levels and risk of bipolar disorder.

Prenatal exposure to influenza has previously been associated with increased risk of bipolar disorder (BD), an association that may be mediated by maternal cytokines. The objective of this study was to determine the association between maternal levels of cytokines measured during each trimester of pregnancy and the risk of BD in offspring. We conducted a case-control study nested in the Child Health and Development Study, a birth cohort that enrolled pregnant women in 1959-1966. Potential cases with DSM-IV-TR bipolar I disorder, bipolar II disorder, BD not otherwise specified, and BD with psychotic features were ascertained through electronic medical records, a public agency database, and a mailing to the cohort. Diagnoses were confirmed by clinical interview. Nine cytokines (IL-1ß, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, TNF-α and GM-CSF) were measured simultaneously by Luminex assays in archived prenatal maternal serum samples from 85 cases and 170 matched controls. Data were analyzed using conditional logistic regression. In the overall study sample, there were no significant associations between prenatal maternal cytokine levels and BD after adjustment for confounders. The risk of BD without psychotic features was decreased among subjects with higher maternal levels of first trimester log-transformed IL-4 (OR (95% CI)=0.76 (0.58, 0.98); p=0.04) and third trimester log-transformed IL-6 (OR (95% CI)=0.64 (0.42, 0.98); p=0.04). In conclusion, higher levels of prenatal maternal cytokines were not associated with increased risk for BD. Further studies with larger samples are necessary to confirm the finding.

Neurotropic virus infections as the cause of immediate and delayed neuropathology.

A wide range of viruses from different virus families in different geographical areas, may cause immediate or delayed neuropathological changes and neurological manifestations in humans and animals. Infection by neurotropic viruses as well as the resulting immune response can irreversibly disrupt the complex structural and functional architecture of the central nervous system, frequently leaving the patient or affected animal with a poor or fatal prognosis. Mechanisms that govern neuropathogenesis and immunopathogenesis of viral infections are highlighted, using examples of well-studied virus infections that are associated with these alterations in different populations throughout the world. A better understanding of the molecular, epidemiological and biological characteristics of these infections and in particular of mechanisms that underlie their clinical manifestations may be expected to provide tools for the development of more effective intervention strategies and treatment regimens.

Prenatal smoking exposure and neuropsychiatric comorbidity of ADHD: a finnish nationwide population-based cohort study.

BACKGROUND: Prenatal smoking exposure has been associated with attention-deficit/hyperactivity disorder (ADHD). ADHD is commonly associated with a wide spectrum of psychiatric comorbidity. The association between smoking and neuropsychiatric comorbidity of ADHD has remained understudied. The aim of this study is to examine the association between prenatal exposure to maternal smoking and offspring ADHD, and test whether the smoking-ADHD associations are stronger when ADHD is accompanied by other lifetime neuropsychiatric comorbidities. METHODS: The study is based on a nested case-control design and includes all Finnish singletons born between 1991 and 2005 and diagnosed with ADHD by 2011 (n = 10,132), matched with four controls (n = 38,811) on date of birth, sex and residence in Finland. RESULTS: The risk for ADHD with or without comorbidity was significantly increased among offspring exposed to maternal smoking on adjusting for potential confounders (OR = 1.75, CI 95 % = 1.65-1.86). Compared to the only ADHD cases, subjects with comorbid conduct disorder or oppositional defiant disorder had a significantly stronger association with smoking exposure (OR = 1.80, CI 95 % = 1.55-2.11). CONCLUSIONS: Prenatal smoking represents an important risk factor for the ADHD comorbid with CD/ODD. Further research on the association between prenatal smoking exposure and neuropsychiatric comorbidity of ADHD is needed considering the increased risk among these subjects of an overall poor health outcome as compared to only ADHD. In particular, studies utilizing biomarkers or including subjects with neuropsychiatric conditions with and without comorbid ADHD are needed.

Prenatal Maternal Smoking and Tourette Syndrome: A Nationwide Register Study.

This is the first nationwide register-based study to examine the relationship between prenatal maternal smoking and Tourette syndrome. A total of 767 children diagnosed with Tourette syndrome were identified from the Finnish Hospital Discharge Register. Each case was matched to four controls. Information on maternal smoking during pregnancy was obtained from the Finnish Medical Birth Register. Conditional logistic regression models were used for statistical analyses. Prenatal maternal smoking was associated with Tourette syndrome when comorbid with ADHD (OR 4.0, 95 % CI 1.2-13.5, p = 0.027 for exposure during first trimester, OR 1.7, 95 % CI, 1.05-2.7, p = 0.031 for exposure for the whole pregnancy). There was no association between maternal smoking during pregnancy and Tourette syndrome without comorbid ADHD (OR 0.5, 95 % CI 0.2-1.3, p = 0.166, OR 0.9, 95 % CI 0.7-1.3, p = 0.567). Further research is needed to elucidate the mechanisms behind the association between prenatal maternal smoking and Tourette syndrome with comorbid ADHD.

The association between congenital anomalies and autism spectrum disorders in a Finnish national birth cohort.

AIM: The first aim of this study was to evaluate the association between different subgroups of autism spectrum disorders (ASDs) (childhood autism, Asperger syndrome, and pervasive developmental disorder/pervasive developmental disorder - not otherwise specified [PDD/PDD-NOS]) and congenital anomalies. Second, we assessed the association among intellectually disabled children with ASDs in the subgroups of childhood autism and PDD/PDD-NOS. METHOD: Nationwide population-based register data for children with a diagnosis of ASD (n=4449; 3548 males, 901 females) were collected during years 1987-2000 from the Finnish Hospital Discharge Register. Data on congenital anomalies were derived from the National Register of Congenital Malformations. Conditional logistic regression models were used as a statistical method. The association between ASD subgroups and congenital anomalies was stratified by the presence or absence of intellectual disability. RESULTS: Congenital anomalies occurred more frequently in all subgroups of ASD than in comparison participants (adjusted odds ratio [OR] for major congenital anomalies 1.8, 95% confidence interval [CI] 1.5-2.2, p<0.001). The association between congenital anomalies and childhood autism (OR 2.4, 95% CI 1.6-3.6, p<0.001) and between congenital anomalies and PDD/PDD-NOS (OR 3.7, 95% CI 2.4-5.7, p<0.001) among children with an intellectual disability was strong but remained significant also without intellectual disability (childhood autism: OR 1.7, 95% CI 1.3-2.3, p<0.001; PDD/PDD-NOS: OR 2.3, 95% CI 1.9-2.8, p<0.001). INTERPRETATION: The results suggest a significant association between ASDs and congenital anomalies regardless of the ASD subgroup. The association between childhood autism and PDD/PDD-NOS and congenital anomalies is stronger among children with intellectual disability is stronger than among those without intellectual disability. These results may have relevance in examining early risk factors in autism during fetal neurodevelopment.

Parental migration and Asperger's syndrome.

Parental immigration has been suggested as a possible risk factor for autism spectrum disorders (ASD), but findings have been inconsistent. Very few studies have focused specifically on Asperger's syndrome. The aim of this study was to examine the association between maternal and paternal immigration and the diagnosis of Asperger's syndrome in offspring. The study was a nested case-control study based on a national birth cohort in Finland. Children born in 1987-2005 and diagnosed with Asperger's syndrome by the year 2007 were identified from the Finnish Hospital Discharge Register (N = 1,783). Four matched controls for each case were selected from the Finnish Medical Birth Register (N = 7,106). Information on maternal and paternal country of birth and mother tongue was collected from the Finnish Central Population Register. The study showed that children whose parents are both immigrants have a significantly lower likelihood of being diagnosed with Asperger's syndrome than those with two Finnish parents [adjusted odds ratio (aOR) 0.2, 95 % confidence interval (CI) 0.1-0.4]. No significant associations were found between having only one immigrant parent and the diagnosis of Asperger's syndrome. A regional analysis showed a significantly decreased likelihood of the diagnosis of Asperger's syndrome in children whose mother (aOR 0.1, 95 % CI 0.01-0.5) or father (aOR 0.2, 95 % CI 0.05-0.5) was born in Sub-Saharan Africa. The findings may help in identifying risk factors for different ASD subtypes. On the other hand, they might reflect service use of immigrant families in Finland.

Maternal socio-economic status based on occupation and autism spectrum disorders: a national case-control study.

BACKGROUND: The association between parental socio-economic status (SES) and autism spectrum disorders (ASD) has been studied in several countries, but the results have been contradictory. AIMS: The aim of this study was to examine the association between maternal SES and subtypes of ASD in Finland. METHODS: A national case-control study was conducted. Children born in 1991-2005 and diagnosed with ASD by the year 2007 were identified from the Finnish Hospital Discharge Register (FHDR). Their matched controls were selected from the Finnish Medical Birth Register (FMBR). There were 3468 cases and 13,868 controls. The information on maternal SES was collected from the FMBR and categorized into upper white-collar workers (referent), lower white-collar workers, blue-collar workers and "others", consisting of students, housewives and other groups with unknown SES. The statistical test used was conditional logistic regression. RESULTS: The likelihood of ASD was increased among offspring of mothers who belong to the group "others" (adjusted OR = 1.2, 95% CI 1.009-1.3). The likelihood of Asperger's syndrome was decreased among offspring of lower white-collar workers (adjusted OR = 0.8, 95% CI 0.6-0.9) and blue-collar workers (adjusted OR = 0.6, 95% CI 0.5-0.7). The likelihood of pervasive developmental disorder not otherwise specified (PDD-NOS) was increased among offspring of blue-collar workers (adjusted OR = 1.5, 1.2-1.9) and "others" (adjusted OR = 1.3, 1.1-1.7). No association was found between maternal SES and childhood autism. CONCLUSIONS: The association between maternal SES and ASD differs by ASD subtype. Socio-economic groups might differ from each other by risk factors for ASD subtypes or by their service use.

Occurrence, plausibility, and desirability for 124 Life Events Inventory items.

Imagination inflation is where imaginative elaboration of possible childhood experiences inflates (increases) participants' estimation that these events actually occurred, as indicated by pre- to post-manipulation ratings changes. This research primarily uses the Life Events Inventory (LEI), listing possible experiences that could have happened during childhood (Garry, Manning, Loftus, & Sherman, Psychonomic Bulletin & Review, 3, 208-214, 1996). Although imagination inflation research has spawned more than 50 investigations, no normative ratings exist on individual items contained in the LEI. To address this, we present descriptive statistics (mean, median, standard deviation, confidence interval) for 124 LEI items on occurrence (how likely is it that this experience happened to you), plausibility (how plausible is it that this event could have happened to someone), and desirability (how desirable is this experience). Occurrence and plausibility showed similar patterns of mean item ratings and were highly correlated, whereas desirability was moderately correlated with plausibility and unrelated to occurrence. These data should facilitate a more informed selection of specific LEI items to use in further research and can assist in clarifying the contributions of normative occurrence, plausibility, and desirability to imagination inflation effects.

Proceedings from Duke resistant hypertension think tank.

To identify patients at increased risk for cardiovascular outcomes, apparent treatment resistant hypertension (aTRH) is defined as having a blood pressure (BP) above goal despite the use of ≥3 antihypertensive therapies of different classes at maximally tolerated doses, ideally including a diuretic. In light of growing scientific interest in the treatment of this group, a multistakeholder think tank was convened to discuss the current state of knowledge, improve the care of these patients, and identify appropriate study populations for future observational and randomized trials in the field. Although recent epidemiologic studies in selected populations estimate that the prevalence of aTRH is 10% to 15% of hypertensive patients, further large-scale observational studies will be needed to better elucidate risk factors. To spur the development of therapies for aTRH, the development of an "aTRH" label for pharmacologic and device therapies with a developmental pathway including treatment added to the use of existing therapies is favored. Although demonstration of adequate BP lowering should be sufficient to gain Food and Drug Administration approval for therapies targeting aTRH, assessment of improvement in quality of life and cardiovascular outcomes is also desirable and considered in Centers for Medicare and Medicaid Services coverage decisions. Device trials under the aTRH label will need uniform and consistent processes for defining appropriate patient populations as well as postapproval registries assessing both long-term safety and duration of responses. Finally, patients with aTRH are likely to benefit from evaluation by a hypertension team to assure proper patient identification, diagnostic work-up, and therapeutic management before consideration of advanced or novel therapies to lower BP.