Melatonin Meta-analysis-van Geijlswijk et al SLEEP-WAKE TIMING IS REGULATED BY THE BIO-LOGIC CLOCK IN A CIRCADIAN RHYTHM: A RHYTHM CONSISTING OF APPROXIMATELY 24 HOURS. Entrainment of the biologic clock is achieved by environmental light. The endogenous rhythm of melatonin production by the pineal gland is regulated by the suprachiasmatic nucleus and is suppressed by exposure to bright light. Endogenous melatonin starts to rise in dim light (the so-called dim light melatonin onset [DLMO]), normally between 19:30 and 21:30 in adults and between 19:00 and 21:00 in children 6 to 12 years of age. 1 This DLMO can be determined for each individual, and it characterizes the individual's circadian timing.Delayed sleep phase disorder (DSPD) is a problem in which the circadian clock is entrained in the 24-hour rhythm but at a delayed phase angle. 2 This can result in sleep-wake timing that is late with respect to societal norms. 1 It has been estimated that approximately 10% of patients with chronic insomnia have DSPD. 3 Treatment of DSPD relies on the use of chronotherapy or, in other words, the shifting of sleep-wake schedules 4 using carefully timed "morning" light administration 5 to phase advance the clock and "evening" melatonin treatment to advance the clock. 6

In 2011, Dutch animal production sectors started recording veterinary antimicrobial consumption. These data are used by the Netherlands Veterinary Medicines Authority to create transparency in and define benchmark indicators for veterinary consumption of antimicrobials. This paper presents the results of sector wide consumption of antimicrobials, in the form of prescriptions or deliveries, for all pig, veal calf, and broiler farms. Data were used to calculate animal defined daily dosages per year (ADDD/Y) per pig or veal calf farm. For broiler farms, number of animal treatment days per year was calculated. Furthermore, data were used to calculate the consumption of specific antimicrobial classes per administration route per pig or veal calf farm. The distribution of antimicrobial consumption per farm varied greatly within and between farm categories. All categories, except for rosé starter farms, showed a highly right skewed distribution with a long tail. Median ADDD/Y values varied from 1.2 ADDD/Y for rosé finisher farms to 83.2 ADDD/Y for rosé starter farms, with 28.6 ADDD/Y for white veal calf farms. Median consumption in pig farms was 9.3 ADDD/Y for production pig farms and 3.0 ADDD/Y for slaughter pig farms. Median consumption in broiler farms was 20.9 ATD/Y. Regarding specific antimicrobial classes, fluoroquinolones were mainly used on veal calf farms, but in low quantities: P75 range was 0 – 0.99 ADDD/Y, and 0 – 0.04 ADDD/Y in pig farms. The P75 range for 3rd/4th-generation cephalosporins was 0 – 0.07 ADDD/Y for veal calf farms, and 0 – 0.1 ADDD/Y for pig farms. The insights obtained from these results, and the full transparency obtained by monitoring antimicrobial consumption per farm, will help reduce antimicrobial consumption and endorse antimicrobial stewardship. The wide and skewed distribution in consumption has important practical and methodological implications for benchmarking, surveillance and future analysis of trends.

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We conducted this study to assess long-term melatonin treatment course, effectiveness and safety in children with attention-deficit/hyperactivity disorder (ADHD) and chronic sleep onset insomnia (CSOI). This was conducted by means of a structured questionnaire for the parents. The subjects of this study consisted of participants who previously participated in a randomised clinical trial on melatonin efficacy. The response rate was 93% (94/101). The mean time to follow up was 3.7 yr. No serious adverse events or treatment related co-morbidities were reported. Sixty-five percent of the children still used melatonin daily and 12% occasionally. Temporal discontinuation of treatment resulted in a delay of sleep onset in 92% of the children. Nine percent of the children could discontinue melatonin completely because of improvement of sleep onset insomnia. Long-term melatonin treatment was judged to be effective against sleep onset problems in 88% of the cases. Improvement of behaviour and mood was reported in 71% and 61% respectively. We conclude that melatonin remains an effective therapy on the long term for the treatment of CSOI in children with ADHD and has no safety concerns regarding serious adverse events or treatment related co-morbidity. Discontinuation of melatonin treatment usually leads to a relapse of sleep onset insomnia and in resuming melatonin treatment, even after several years of treatment.