Contributions of circadian tendencies and behavioral problems to sleep onset problems of children with ADHD

BACKGROUND: Children with attention-deficit/hyperactivity disorder (ADHD) are two to three times more likely to experience sleep problems. The purpose of this study is to determine the relative contributions of circadian preferences and behavioral problems to sleep onset problems experienced by children with ADHD and to test for a moderation effect of ADHD diagnosis on the impact of circadian preferences and externalizing problems on sleep onset problems. METHODS: After initial screening, parents of children meeting inclusion criteria documented child bedtime over 4 nights, using a sleep log, and completed questionnaires regarding sleep, ADHD and demographics to assess bedtime routine prior to PSG. On the fifth night of the study, sleep was recorded via ambulatory assessment of sleep architecture in the child’s natural sleep environment employing portable polysomnography equipment. Seventy-five children (26 with ADHD and 49 controls) aged 7–11 years (mean age 8.61 years, SD 1.27 years) participated in the present study. RESULTS: In both groups of children, externalizing problems yielded significant independent contributions to the explained variance in parental reports of bedtime resistance, whereas an evening circadian tendency contributed both to parental reports of sleep onset delay and to PSG-measured sleep-onset latency. No significant interaction effect of behavioral/circadian tendency with ADHD status was evident. CONCLUSIONS: Sleep onset problems in ADHD are related to different etiologies that might require different interventional strategies and can be distinguished using the parental reports on the CSHQ

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Multi-messenger Observations of a Binary Neutron Star Merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ∼ 1.7 {{s}} with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of {40}-8+8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 {M}ȯ . An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ∼ 40 {{Mpc}}) less than 11 hours after the merger by the One-Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ∼10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ∼ 9 and ∼ 16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC 4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta.</p

Composite midazolam and 1′-OH midazolam population pharmacokinetic model for constitutive, inhibited and induced CYP3A activity

CYP3A plays an important role in drug metabolism and, thus, can be a considerable liability for drug-drug interactions. Population pharmacokinetics may be an efficient tool for detecting such drug-drug interactions. Multiple models have been developed for midazolam, the typical probe substrate for CYP3A activity, but no population pharmacokinetic models have been developed for use with inhibition or induction. The objective of the current analysis was to develop a composite parent-metabolite model for midazolam which could adequately describe CYP3A drug-drug interactions. As an exploratory objective, parameters were assessed for potential cut-points which may allow for determination of drug-drug interactions when a baseline profile is not available. The final interaction model adequately described midazolam and 1'-OH midazolam concentrations for constitutive, inhibited, and induced CYP3A activity. The model showed good internal and external validity, both with full profiles and limited sampling (2, 2.5, 3, and 4 h), and the model predicted parameters were congruent with values found in clinical studies. Assessment of potential cut-points for model predicted parameters to assess drug-drug interaction liability with a single profile suggested that midazolam clearance may reasonably be used to detect inhibition (4.82-16.4 L/h), induction (41.8-88.9 L/h), and no modulation (16.4-41.8 L/h), with sensitivities for potent inhibition and induction of 87.9% and 83.3%, respectively, and a specificity of 98.2% for no modulation. Thus, the current model and cut-points could provide efficient and accurate tools for drug-drug liability detection, both during drug development and in the clinic, following prospective validation in healthy volunteers and patient populations

Contributions of circadian tendencies and behavioral problems to sleep onset problems of children with ADHD

Abstract Background Children with attention-deficit/hyperactivity disorder (ADHD) are two to three times more likely to experience sleep problems. The purpose of this study is to determine the relative contributions of circadian preferences and behavioral problems to sleep onset problems experienced by children with ADHD and to test for a moderation effect of ADHD diagnosis on the impact of circadian preferences and externalizing problems on sleep onset problems. Methods After initial screening, parents of children meeting inclusion criteria documented child bedtime over 4 nights, using a sleep log, and completed questionnaires regarding sleep, ADHD and demographics to assess bedtime routine prior to PSG. On the fifth night of the study, sleep was recorded via ambulatory assessment of sleep architecture in the child’s natural sleep environment employing portable polysomnography equipment. Seventy-five children (26 with ADHD and 49 controls) aged 7–11 years (mean age 8.61 years, SD 1.27 years) participated in the present study. Results In both groups of children, externalizing problems yielded significant independent contributions to the explained variance in parental reports of bedtime resistance, whereas an evening circadian tendency contributed both to parental reports of sleep onset delay and to PSG-measured sleep-onset latency. No significant interaction effect of behavioral/circadian tendency with ADHD status was evident. Conclusions Sleep onset problems in ADHD are related to different etiologies that might require different interventional strategies and can be distinguished using the parental reports on the CSHQ.</p