"Hypertension in Pregnancy Intervention Trial At Term" and "Disproportionate Intrauterine Growth Intervention Trial At Term" Studies.

In 2003, in the context of a national research funding program in which obstetric research was prioritized, several perinatal centers took the initiative to jointly submit a number of applications to the subsidy programs of Effectiveness Research and Prevention of ZonMw. This has led to the funding of the Obstetric Consortium with several projects, including the "Hypertension in Pregnancy Intervention Trial At Term" and the "Disproportionate Intrauterine Growth Intervention Trial At Term" studies. The studies showed that induction of labor for hypertension and growth restriction at term was the appropriate management. Subsequent implementation improved maternal and perinatal outcomes.

Skin temperature as a predictor of on-the-road driving performance in people with central disorders of hypersomnolence.

Excessive daytime sleepiness is the core symptom of central disorders of hypersomnolence (CDH) and can directly impair driving performance. Sleepiness is reflected in relative alterations in distal and proximal skin temperature. Therefore, we examined the predictive value of skin temperature on driving performance. Distal and proximal skin temperature and their gradient (DPG) were continuously measured in 44 participants with narcolepsy type 1, narcolepsy type 2 or idiopathic hypersomnia during a standardised 1-h driving test. Driving performance was defined as the standard deviation of lateral position (SDLP) per 5 km segment (equivalent to 3 min of driving). Distal and proximal skin temperature and DPG measurements were averaged over each segment and changes over segments were calculated. Mixed-effect model analyses showed a strong, quadratic association between proximal skin temperature and SDLP (p < 0.001) and a linear association between DPG and SDLP (p < 0.021). Proximal skin temperature changes over 3 to 15 min were predictive for SDLP. Moreover, SDLP increased over time (0.34 cm/segment, p < 0.001) and was higher in men than in women (3.50 cm, p = 0.012). We conclude that proximal skin temperature is a promising predictor for real-time assessment of driving performance in people with CDH.

Combined impact of ADHD and insomnia symptoms on quality of life, productivity, and health care use in the general population.

BACKGROUND: Both attention-deficit/hyperactivity disorder (ADHD) and insomnia have been independently related to poorer quality of life (QoL), productivity loss, and increased health care use, although most previous studies did not take the many possible comorbidities into account. Moreover, ADHD and insomnia often co-occur. Symptoms of ADHD and insomnia together may have even stronger negative effects than they do separately. We investigated the combined effects of symptoms of ADHD and insomnia, in addition to their independent effects, on QoL, productivity, and health care use, thereby controlling for a wide range of possible comorbidities and confounders. METHODS: Data from the third wave of the Netherlands Mental Health Survey and Incidence Study-2 were used, involving N = 4618 from the general population. Both the inattention and the hyperactivity ADHD symptom dimensions were studied, assessed by the ASRS Screener. RESULTS: Mental functioning and productivity were negatively associated with the co-occurrence of ADHD and insomnia symptoms, even after adjusting for comorbidity and confounders. The results show no indication of differences between inattention and hyperactivity. Poorer physical functioning and health care use were not directly influenced by the interaction between ADHD and insomnia. CONCLUSIONS: People with both ADHD and sleep problems have increased risk for poorer mental functioning and productivity loss. These results underscore the importance of screening for sleep problems when ADHD symptoms are present, and vice versa, and to target both disorders during treatment.

Comparing objective wakefulness and vigilance tests to on-the-road driving performance in narcolepsy and idiopathic hypersomnia.

Patients with narcolepsy or idiopathic hypersomnia (IH) are at increased risk of driving accidents. Both excessive daytime sleepiness, i.e. unwanted sleep episodes during the day, and disturbed vigilance are core features of these disorders. We tested on-the-road driving performance of patients with narcolepsy or IH coming in for a routine driving fitness evaluation and examined: (1) correlations between driving performance and the Maintenance of Wakefulness Test (MWT), Sustained Attention to Response Task (SART) and Psychomotor Vigilance Test (PVT) as objective tests; (2) the predictive power of the MWT and SART for increased risk of impaired driving; (3) the best set of objective predictors for increased risk of impaired driving. Participants were 44 patients (aged 18-75 years) with narcolepsy type 1 (NT1), type 2 (NT2) or IH. They completed the MWT, SART, PVT, a subjective sleepiness questionnaire, and a standardised on-the-road driving test. The standard deviation of the lateral position (SDLP) was used as outcome measure of driving performance. The MWT had low correlation with the SDLP (ρ = -0.41 to -0.49, p < 0.01). The SART and PVT had low correlations with SDLP (ρ = 0.30 and ρ = 0.39, respectively, both p < 0.05). The predictive power of MWT for an increased risk of impaired driving was significant, but low (area under the curve = 0.273, p = 0.012), and non-significant for SART. We conclude that in our present group, none of the tests had adequate ability to predict impaired driving, questioning their use for clinical driving fitness evaluation in narcolepsy and IH. Real-time monitoring of sleepiness while driving seems more promising in these patients.

Objective assessment of attention-deficit/hyperactivity disorder in older adults compared with controls using the QbTest.

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) persists into old age, with prevalence rates of 2.8% to 3.3% in adults over 60 years of age. Most diagnostic assessment tools are not validated for older adults. The Quantified behavioral Test (QbTest) is an objective assessment for the core symptoms of ADHD and is validated for children and younger adults. We investigated whether the QbTest can be used to differentiate between older adults with ADHD and healthy controls. METHODS: Older adults aged 55 to 79 years with (n = 97) or without (n = 112) ADHD were assessed with the QbTest. They also rated their ADHD symptom severity. QbTest raw scores were compared between groups. Factor scores were computed using factor loadings from a confirmatory factor analysis (CFA). Multilevel regressions were used to determine effects of background characteristics and comorbidity. Logistic regressions were performed to determine whether the QbTest differentiated between patients with ADHD and healthy controls. RESULTS: The factor structure of the CFA was comparable with that of younger age groups. Older age was associated with higher Inattention score. Parameters comprising the factors Hyperactivity and Inattention, but not Impulsivity, were shown to contribute significantly in differentiating between the groups. The QbTest had a correct classification rate of 70%, which was increased to 91% when combining QbTest scores and self-reports of ADHD symptom severity. CONCLUSIONS: The QbTest is feasible for older adults, and the factors Hyperactivity and Inattention are valid parameters for the diagnostic assessment of ADHD in older adults, when used in addition to self-reports.

Persistence and Adherence to Psychostimulants, and Psychological Well-Being Up to 3 Years After Specialized Treatment of Adult Attention-Deficit/Hyperactivity Disorder: A Naturalistic Follow-Up Study.

BACKGROUND: Little is known about the long-term persistence and adherence of psychostimulant use in adults with attention-deficit/hyperactivity disorder (ADHD) and its relationship to their psychological well-being. METHODS: The persistence and adherence to psychostimulants and psychological well-being were examined in adults with ADHD in a naturalistic follow-up, starting directly after discharge from their specialized treatment of ADHD at an outpatient ADHD clinic. Ninety-six patients were included at the time of discharge, who were interviewed by telephone at 6 months, 1 year, and 3 years after discharge. RESULTS: At the time of discharge, 78% used a psychostimulant prescribed by a psychiatrist. Of those on psychostimulants at the time of discharge, approximately half still used any of these psychostimulants 3 years after discharge. However, adherence rates were good for those who persisted to use psychostimulants. The female sex and middle educational level (relative to a higher educational level) were near-significantly related to nonpersistence, and having a higher educational level and the combined ADHD subtype were related to nonadherence. In turn, nonadherence was related to worse general functioning, lower mood, and poorer sleep quality. CONCLUSIONS: The importance of adherence should be discussed at the time of discharge, especially with female ADHD patients, those with a higher educational level, and those with a combined ADHD subtype, because nonadherence is associated with poorer outcomes.

Adult Attention-Deficit/Hyperactivity Disorder (ADHD) and Insomnia: an Update of the Literature.

PURPOSE OF REVIEW: Insomnia is diagnosed when there is dissatisfaction with sleep quantity or quality. It has a prevalence in the general population ranging from 31 to 56%. Insomnia has previously been associated with adult attention-deficit/hyperactivity disorder (ADHD). In this review, we address three topics: (1) the cross-sectional relationship between ADHD and insomnia in adulthood, (2) the longitudinal relationship between ADHD and insomnia, and (3) insomnia as a side effect of pharmacological treatments for adult ADHD. RECENT FINDINGS: Three cross-sectional, clinical, and population studies report a prevalence of insomnia in ADHD adults ranging from 43 to 80%. Longitudinal evidence for a link between childhood-onset ADHD and insomnia at later age is mixed, with one study confirming and another study not supporting such a longitudinal association. In randomized, placebo-controlled trials, insomnia is reported significantly more often in the treatment arm than in the placebo arm. In varying percentages of trial participants, insomnia is a treatment-emergent adverse effect in triple-bead mixed amphetamine salts (40-45%), dasotraline (35-45%), lisdexamfetamine (10-19%), and extended-release methylphenidate (11%). Ten to seventeen percent of subjects in placebo-controlled trials of atomoxetine report insomnia, possibly related to poor metabolizer status. The mechanisms explaining the relationship between ADHD and sleep problems are incompletely understood, but both genetic and non-shared environmental influences may be involved. Adults with ADHD should be assessed for insomnia, which is frequently comorbid, and both conditions should be treated.

Post-illumination pupil response after blue light: Reliability of optimized melanopsin-based phototransduction assessment.

Melanopsin-containing retinal ganglion cells have recently been shown highly relevant to the non-image forming effects of light, through their direct projections on brain circuits that regulate alertness, mood and circadian rhythms. A quantitative assessment of functionality of the melanopsin-signaling pathway could be highly relevant in order to mechanistically understand individual differences in the effects of light on these regulatory systems. We here propose and validate a reliable quantification of the melanopsin-dependent Post-Illumination Pupil Response (PIPR) after blue light, and evaluated its sensitivity to dark adaptation, time of day, body posture, and light exposure history. Pupil diameter of the left eye was continuously measured during a series of light exposures to the right eye, of which the pupil was dilated using tropicamide 0.5%. The light exposure paradigm consisted of the following five consecutive blocks of five minutes: baseline dark; monochromatic red light (peak wavelength: 630 nm, luminance: 375 cd/m(2)) to maximize the effect of subsequent blue light; dark; monochromatic blue light (peak wavelength: 470 nm, luminance: 375 cd/m(2)); and post-blue dark. PIPR was quantified as the difference between baseline dark pupil diameter and post-blue dark pupil diameter (PIPR-mm). In addition, a relative PIPR was calculated by dividing PIPR by baseline pupil diameter (PIPR-%). In total 54 PIPR assessments were obtained in 25 healthy young adults (10 males, mean age ± SD: 26.9 ± 4.0 yr). From repeated measurements on two consecutive days in 15 of the 25 participants (6 males, mean age ± SD: 27.8 ± 4.3 yrs) test-retest reliability of both PIPR outcome parameters was calculated. In the presence of considerable between-subject differences, both outcome parameters had very high test-retest reliability: Cronbach's α > 0.90 and Intraclass Correlation Coefficient > 0.85. In 12 of the 25 participants (6 males, mean age ± SD: 26.5 ± 3.6 yr) we examined the potential confounding effects of dark adaptation, time of the day (morning vs. afternoon), body posture (upright vs. supine position), and 24-h environmental light history on the PIPR assessment. Mixed effect regression models were used to analyze these possible confounders. A supine position caused larger PIPR-mm (ß = 0.29 mm, SE = 0.10, p = 0.01) and PIPR-% (ß = 4.34%, SE = 1.69, p = 0.02), which was due to an increase in baseline dark pupil diameter; this finding is of relevance for studies requiring a supine posture, as in functional Magnetic Resonance Imaging, constant routine protocols, and bed-ridden patients. There were no effects of dark adaptation, time of day, and light history. In conclusion, the presented method provides a reliable and robust assessment of the PIPR to allow for studies on individual differences in melanopsin-based phototransduction and effects of interventions.

Economic analysis comparing induction of labor and expectant management in women with preterm prelabor rupture of membranes between 34 and 37 weeks (PPROMEXIL trial).

OBJECTIVE: To compare the costs of induction of labor and expectant management in women with preterm prelabor rupture of membranes (PPROM). DESIGN: Economic analysis based on a randomized clinical trial. SETTING: Obstetric departments of eight academic and 52 non-academic hospitals in the Netherlands. POPULATION: Women with PPROM near term who were not in labor 24 h after PPROM. METHODS: A cost-minimization analysis was done from a health care provider perspective, using a bottom-up approach to estimate resource utilization, valued with unit-costs reflecting actual costs. MAIN OUTCOME MEASURES: Primary health outcome was the incidence of neonatal sepsis. Direct medical costs were estimated from start of randomization to hospital discharge of mother and child. RESULTS: Induction of labor did not significantly reduce the probability of neonatal sepsis [2.6% vs. 4.1%, relative risk 0.64 (95% confidence interval 0.25-1.6)]. Mean costs per woman were €8094 for induction and €7340 for expectant management (difference €754; 95% confidence interval -335 to 1802). This difference predominantly originated in the postpartum period, where the mean costs were €5669 for induction vs. €4801 for expectant management. Delivery costs were higher in women allocated to induction than in women allocated to expectant management (€1777 vs. €1153 per woman). Antepartum costs in the expectant management group were higher because of longer antepartum maternal stays in hospital. CONCLUSIONS: In women with pregnancies complicated by PPROM near term, induction of labor does not reduce neonatal sepsis, whereas costs associated with this strategy are probably higher.

Sleep in the intensive and intermediate care units: Exploring related factors of delirium, benzodiazepine use and mortality.

AIM OF THE STUDY: The primary purpose was to examine sleep difficulties and delirium in the Intensive and Intermediate Care Unit. Secondarily, factors impacting night-time sleep duration and quality, mortality, and the impact of benzodiazepine use on sleep outcomes were investigated. MATERIALS AND METHODS: This retrospective study encompassed data from 323 intensive and intermediate care unit admissions collected in the Netherlands, spanning from November 2018 to May 2020. Sleep quality was measured using the Richards-Campbell Sleep Questionnaire. Night-time sleep duration was nurse-reported. We investigated associations of these sleep outcomes with age, sex, length-of-stay, natural daylight, disease severity, mechanical ventilation, benzodiazepine use, and delirium using Generalized Estimating Equations models. Associations with one-year post-discharge mortality were analyzed using Cox regression. RESULTS: Night-time sleep duration was short (median 4.5 hours) and sleep quality poor (mean score 4.9/10). Benzodiazepine use was common (24 % of included nights) and was negatively associated with night-time sleep duration and quality (B = -0.558 and -0.533, p <.001). Delirium and overnight transfers were negatively associated with sleep quality (B = -0.716 and -1.831, p <.05). The day-to-night sleep ratio was higher in the three days before delirium onset than in non-delirious individuals (p <.05). Age, disease severity and female sex were associated with increased one-year mortality. Sleep quality was negatively, but not-significantly, associated with mortality (p =.070). CONCLUSIONS: Night-time sleep in the critical care environment has a short duration and poor quality. Benzodiazepine use was not associated with improved sleep. Sleep patterns change ahead of delirium onset. IMPLICATIONS FOR CLINICAL PRACTICE: Consistent sleep monitoring should be part of routine nursing practice, using a validated instrument like the Richards-Campbell Sleep Questionnaire. Given the lack of proven efficacy of benzodiazepines in promoting sleep in critical care settings, it is vital to develop more effective sleep treatments that include non-benzodiazepine medication and sleep hygiene strategies.

Body temperature, activity and melatonin profiles in adults with attention-deficit/hyperactivity disorder and delayed sleep: a case-control study.

Irregular sleep-wake patterns and delayed sleep times are common in adults with attention-deficit/hyperactivity disorder, but mechanisms underlying these problems are unknown. The present case-control study examined whether circadian abnormalities underlie these sleep problems in a naturalistic home setting. We included 12 medication-naïve patients with attention-deficit/hyperactivity disorder and delayed sleep phase syndrome, and 12 matched healthy controls. We examined associations between sleep/wake rhythm in attention-deficit/hyperactivity disorder and circadian parameters (i.e. salivary melatonin concentrations, core and skin temperatures, and activity patterns) of the patients and controls during five consecutive days and nights. Daily bedtimes were more variable within patients compared with controls (F = 8.19, P < 0.001), but melatonin profiles were equally stable within individuals. Dim-light melatonin onset was about 1.5 h later in the patient group (U = 771, Z = -4.63, P < 0.001). Patients slept about 1 h less on nights before work days compared with controls (F = 11.21, P = 0.002). The interval between dim-light melatonin onset and sleep onset was on average 1 h longer in patients compared with controls (U = 1117, Z = -2.62, P = 0.009). This interval was even longer in patients with extremely late chronotype. Melatonin, activity and body temperatures were delayed to comparable degrees in patients. Overall temperatures were lower in patients than controls. Sleep-onset difficulties correlated with greater distal-proximal temperature gradient (DPG; i.e. colder hands, r(2)  = -0.32, P = 0.028) in patients. Observed day-to-day bedtime variability of individuals with attention-deficit/hyperactivity disorder and delayed sleep phase syndrome were not reflected in their melatonin profiles. Irregular sleep-wake patterns and delayed sleep in individuals with attention-deficit/hyperactivity disorder and delayed sleep phase syndrome are associated with delays and dysregulations of the core and skin temperatures.

Vigilance and circadian function in daytime and nocturnal epilepsy compared to controls.

BACKGROUND: People with epilepsy often experience daytime vigilance problems and fatigue. This may be related to disturbed sleep due to nocturnal seizures. AIM: To compare subjective and objective markers of vigilance and circadian function in adults with epilepsy with nocturnal seizures to those with daytime seizures and healthy controls and to identify determinants of impaired daytime vigilance in epilepsy in an explorative study. METHODS: We included 30 adults with epilepsy (15 with daytime seizures and 15 with nocturnal seizures), and 15 healthy controls. All participants filled out the Epworth sleepiness scale (ESS), fatigue severity scale (FSS), Pittsburgh sleep quality index (PSQI) and the Munich chronotype questionnaire (MCTQ). Each participant performed two trials of the sustained attention to response task (SART) as a measure of vigilance, and had a post-illumination pupil response (PIPR) assessment as a marker for the circadian function. RESULTS: Both epilepsy groups reported more fatigue on the FSS than healthy controls (p < .001) and had higher SART error scores (p = .026). The poorer FSS and SART scores were most prominent among those with nocturnal seizures. The ESS, PSQI, MCTQ and the primary PIPR outcome did not differ between groups. Having nocturnal seizures (p = .010) and using more antiseizure medications (p = .004) were related to increased SART error scores. CONCLUSIONS: Nocturnal epilepsy is associated with poorer vigilance, indicating lower quality of wake time. We could not relate this to circadian dysfunction. Further studies should focus on vigilance problems in people with nocturnal epilepsy and explore interventions to improve the quality of wake time.

Applicability of the Sustained Attention to Response Task (SART) in hypersomnolence: Experience and results from a tertiary referral center.

OBJECTIVE/BACKGROUND: Evaluation of hypersomnolence disorders ideally includes an assessment of vigilance using the short Sustained Attention to Response Task (SART). We evaluated whether this task can differentiate between hypersomnolence disorders, whether it correlates with subjective and objective sleepiness, whether it is affected by the time of day, and symptoms of anxiety and depression. PATIENTS/METHODS: We analyzed diagnostic data of 306 individuals with hypersomnolence complaints diagnosed with narcolepsy type 1 (n=100), narcolepsy type 2 (n=20), idiopathic hypersomnia (n=49), obstructive sleep apnea (n=27) and other causes or without explanatory diagnosis (n=110). We included the Multiple Sleep Latency Test (MSLT), polysomnography, Epworth Sleepiness Scale (ESS), Hospital Anxiety and Depression Scale and SART, which were administered five times during the day (outcomes: reaction time, total, commission and omission errors). RESULTS: The SART outcomes did not differ between groups when adjusted for relevant covariates. Higher ESS scores were associated with longer reaction times and more commission errors (p<.01). The main outcome, total errors, did not differ between times of the day. Reaction times and omission errors were impacted (p<.05). CONCLUSIONS: The SART quantifies disturbed vigilance, an important dimension of disorders of hypersomnolence. Results do not suggest that depressive symptoms influence SART outcomes. A practice session is advised. Testing time should be taken into account when interpreting results. We conclude that the SART does not differentiate between central disorders of hypersomnolence. It may be a helpful addition to the standard diagnostic workup and monitoring of these disorders.

Cardiovascular risk in adults with Delayed Sleep Phase Syndrome (DSPS) and Attention-Deficit/Hyperactivity Disorder (ADHD).

TRIAL REGISTRATION: FASE, https://www.trialregister.nl/, #NTR3831.

Usefulness of the maintenance of wakefulness test in central disorders of hypersomnolence: a scoping review.

STUDY OBJECTIVES: To review the Maintenance of Wakefulness Test (MWT) as assessment of daytime sleepiness in the evaluation of treatment effects and driving fitness in central disorders of hypersomnolence (CDH). METHODS: We performed a scoping review of studies using the MWT in patients with CDH (i.e. narcolepsy types 1 and 2, and idiopathic hypersomnia). N = 20 articles were included, comprising 683 patients and 129 controls. MWT effect sizes were compared to the Clinical Global Impression (GCI) scale and the Epworth Sleepiness Scale (ESS). MWT sleep latency was correlated to objective driving performances. The role of motivation was evaluated by comparing MWTs of treatment studies (low motivation) to driving fitness studies (high motivation to stay awake). Healthy controls were compared to norm values. RESULTS: MWT and CGI were both impacted by the same treatment; however, the MWT has higher effect sizes and was more sensitive to measure these effects. The MWT correlated fairly to moderately (ρ = -0.26 to -0.56; p ≤ .05) to objective driving performance. Motivation played a major role on MWT sleep latencies (d = 0.76 to 1.43; p ≤ .001). Current norm values may not be valid, as sleep latency may be impacted by age. CONCLUSIONS: The MWTs applicability to measure treatment effects in CDH was confirmed, but age-adjusted norm values are needed. For a more complete evaluation of EDS it should be combined with subjective measures. Its reliability for driving fitness evaluation is insufficient, and motivation plays a major role. To predict or monitor driving performance in CDH, valid and easy methods should be developed.

Attention-Deficit/Hyperactivity Disorder and Delayed Sleep Phase Syndrome in Adults: A Randomized Clinical Trial on the Effects of Chronotherapy on Sleep.

Delayed sleep phase syndrome (DSPS) is the most common sleep disturbance in adults with attention-deficit/hyperactivity disorder (ADHD). We previously showed that chronotherapy with melatonin effectively advanced the dim-light melatonin onset (DLMO), a biomarker for the internal circadian rhythm, by 1.5 h and reduced ADHD symptoms by 14%. Melatonin combined with bright light therapy (BLT) advanced the DLMO by 2 h, but did not affect ADHD symptoms. This article explores whether sleep times advanced along with DLMO, leading to longer sleep duration and better sleep in general, which might explain the working mechanism behind the reduction in ADHD symptoms after treatment with melatonin. This article presents exploratory secondary analysis on objective and self-reported sleep characteristics from a three-armed double-blind randomized placebo-controlled clinical trial (RCT), which included 49 adults (18-55 years) with ADHD and DSPS. Participants were randomized to receive sleep education and 3 weeks of (1) 0.5 mg/day placebo, (2) 0.5 mg/day melatonin, or (3) 0.5 mg/day melatonin plus 30 min of bright light therapy (BLT) between 0700 and 0800 h. Sleep was assessed at baseline, directly after treatment, and 2 weeks after the end of treatment. Objective measures were obtained by actigraphy, self-reported measures by various sleep questionnaires and a sleep diary. Melatonin with or without BLT did not advance sleep times, improve sleep in general, or strengthen wake-activity rhythms. So even though the DLMO had advanced, sleep timing did not follow. Adding extensive behavioral coaching to chronotherapy is necessary for advancing sleep times along with DLMO and to further alleviate ADHD symptoms.

Intermediate hypocretin-1 cerebrospinal fluid levels and typical cataplexy: their significance in the diagnosis of narcolepsy type 1.

STUDY OBJECTIVES: The diagnosis of narcolepsy type 1 (NT1) is based upon the presence of cataplexy and/or a cerebrospinal fluid (CSF) hypocretin-1/orexin-A level ≤ 110 pg/mL. We determined the clinical and diagnostic characteristics of patients with intermediate hypocretin-1 levels (111-200 pg/mL) and the diagnostic value of cataplexy characteristics in individuals with central disorders of hypersomnolence. METHODS: Retrospective cross-sectional study of 355 people with known CSF hypocretin-1 levels who visited specialized Sleep-Wake Centers in the Netherlands. For n = 271, we had full data on cataplexy type ("typical" or "atypical" cataplexy). RESULTS: Compared to those with normal hypocretin-1 levels (>200 pg/mL), a higher percentage of individuals with intermediate hypocretin-1 levels had typical cataplexy (75% or 12/16 vs 9% or 8/88, p < .05), and/or met the diagnostic polysomnographic (PSG) and Multiple Sleep Latency Test (MSLT) criteria for narcolepsy (50 vs 6%, p < .001). Of those with typical cataplexy, 88% had low, 7% intermediate, and 5% normal hypocretin-1 levels (p < .001). Atypical cataplexy was also associated with hypocretin deficiency but to a lesser extent. A hypocretin-1 cutoff of 150 pg/mL best predicted the presence of typical cataplexy and/or positive PSG and MSLT findings. CONCLUSION: Individuals with intermediate hypocretin-1 levels or typical cataplexy more often have outcomes fitting the PSG and MSLT criteria for narcolepsy than those with normal levels or atypical cataplexy. In addition, typical cataplexy has a much stronger association with hypocretin-1 deficiency than atypical cataplexy. We suggest increasing the NT1 diagnostic hypocretin-1 cutoff and adding the presence of clearly defined typical cataplexy to the diagnostic criteria of NT1. Clinical trial information: This study is not registered in a clinical trial register, as it has a retrospective database design.

Hypocretin-1 measurements in cerebrospinal fluid using radioimmunoassay: within and between assay reliability and limit of quantification.

STUDY OBJECTIVES: The most sensitive and specific investigative method for the diagnosis of narcolepsy type 1 (NT1) is the determination of hypocretin-1 (orexin-A) deficiency (≤110 pg/mL) in cerebrospinal fluid using a radioimmunoassay (RIA). We aimed to assess the reliability of the Phoenix Pharmaceuticals hypocretin-1 RIA, by determining the lower limit of quantification (LLOQ), the variability around the cutoff of 110 pg/mL, and the inter- and intra-assay variability. METHODS: Raw data of 80 consecutive hypocretin-1 RIAs were used to estimate the intra- and inter-assay coefficient of variation (CV). The LLOQ was established and defined as the lowest converted concentration with a CV <25%; the conversion is performed using a harmonization sample which is internationally used to minimize variation between RIAs. RESULTS: The mean intra-assay CV was 4.7%, while the unconverted inter-assay CV was 28.3% (18.5% excluding 2 outliers) and 7.5% when converted to international values. The LLOQ was determined as 27.9 pg/mL. The intra-assay CV of RIAs with lower specific radioactive activity showed a median of 5.6% (n = 41, range 1.6%-17.0%), which was significantly higher than in RIAs with higher specific activity (n = 36; median 3.2%, range 0.4%-11.6%, p = .013). The CV around the 110 pg/mL cutoff was <7%. CONCLUSIONS: Hypocretin-1 RIAs should always be harmonized using standard reference material. The specific activity of an RIA has a significant impact on its reliability, because of the decay of 125I radioactivity. Values around the hypocretin-1 cut-off can reliably be measured. Hypocretin-1 concentrations below 28 pg/mL should be reported as "undetectable" when measured with the Phoenix Pharmaceuticals RIA. CLINICAL TRIAL INFORMATION: This study is not registered in a clinical trial register, as it has a retrospective database design.

Eliciting willingness to pay in obstetrics: comparing a direct and an indirect valuation method for complex health outcomes.

OBJECTIVE: To compare direct and indirect willingness to pay (WTP) elicitation methods in terms of feasibility, reliability, and comparability. The application is obstetrics, where always both a mother's and a child's health are at stake. METHODS: An open-ended contingent valuation method (CVM) as a direct WTP elicitation method, and the discrete choice experiment (DCE) as an indirect WTP elicitation method. Vignettes to be valued were based on clinical patient data. Participants were 88 laypersons who received their questionnaires by postal mail. RESULTS: The DCE task was completed faster (p=0.006) and was regarded easier (p<0.001) than the CVM task. Test-retest for CVM was substantial (ICC=0.76), and for DCE moderate (k=0.49). Female sex (p<0.001), age≥50 years (p=0.013), higher income (p<0.001), and higher education (p<0.001) were associated with higher WTP. Correlation between CVM and DCE was 0.79 (Kendall's Tau-b; p<0.001). The implied WTP as derived with DCE was between 2.3 and 10.2 times higher than with CVM. The relationship between the WTPs was linear. CONCLUSION: It is yet unclear what lies behind the numbers of DCE. DCE has no methodological benefits over the conventional CVM when eliciting WTP for complex health outcomes in obstetrics.

Maternal health-related quality of life after induction of labor or expectant monitoring in pregnancy complicated by intrauterine growth retardation beyond 36 weeks.

OBJECTIVE: Pregnancies complicated by intrauterine growth retardation (IUGR) beyond 36 weeks of gestation are at increased risk of neonatal morbidity and mortality. Optimal treatment in IUGR at term is highly debated. Results from the multicenter DIGITAT (Disproportionate Intrauterine Growth Intervention Trial At Term) trial show that induction of labor and expectant monitoring result in equal neonatal and maternal outcomes for comparable cesarean section rates. We report the maternal health-related quality of life (HR-QoL) that was measured alongside the trial at several points in time. METHODS: Both randomized and non-randomized women were asked to participate in the HR-QoL study. Women were asked to fill out written validated questionnaires, covering background characteristics, condition-specific issues and the Short Form (SF-36), European Quality of Life (EuroQoL 6D3L), Hospital Anxiety and Depression scale (HADS), and Symptom Check List (SCL-90) at baseline, 6 weeks postpartum and 6 months postpartum. We compared the difference scores of all summary measures between the two management strategies by ANOVA. A repeated measures multivariate mixed model was defined to assess the effect of the management strategies on the physical (PCS) and mental (MCS) components of the SF-36. Analysis was by intention to treat. RESULTS: We analyzed data of 361 randomized and 198 non-randomized patients. There were no clinically relevant differences between the treatments at 6 weeks or 6 months postpartum on any summary measures; e.g., on the SF-36 (PCS: P = .09; MCS: P = .48). The PCS and the MCS were below norm values at inclusion. The PCS improved over time but stayed below norm values at 6 months, while the MCS did not improve. CONCLUSION: In pregnancies complicated by IUGR beyond 36 weeks, induction of labor does not affect the long-term maternal quality of life.