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1.  Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial 
Objective To assess the effectiveness and safety of melatonin in treating severe sleep problems in children with neurodevelopmental disorders.
Design 12 week double masked randomised placebo controlled phase III trial.
Setting 19 hospitals across England and Wales.
Participants 146 children aged 3 years to 15 years 8 months were randomised. They had a range of neurological and developmental disorders and a severe sleep problem that had not responded to a standardised sleep behaviour advice booklet provided to parents four to six weeks before randomisation. A sleep problem was defined as the child not falling asleep within one hour of lights out or having less than six hours’ continuous sleep.
Interventions Immediate release melatonin or matching placebo capsules administered 45 minutes before the child’s bedtime for a period of 12 weeks. All children started with a 0.5 mg capsule, which was increased through 2 mg, 6 mg, and 12 mg depending on their response to treatment.
Main outcome measures Total sleep time at night after 12 weeks adjusted for baseline recorded in sleep diaries completed by the parent. Secondary outcomes included sleep onset latency, assessments of child behaviour, family functioning, and adverse events. Sleep was measured with diaries and actigraphy.
Results Melatonin increased total sleep time by 22.4 minutes (95% confidence interval 0.5 to 44.3 minutes) measured by sleep diaries (n=110) and 13.3 (−15.5 to 42.2) measured by actigraphy (n=59). Melatonin reduced sleep onset latency measured by sleep diaries (−37.5 minutes, −55.3 to −19.7 minutes) and actigraphy (−45.3 minutes, −68.8 to −21.9 minutes) and was most effective for children with the longest sleep latency (P=0.009). Melatonin was associated with earlier waking times than placebo (29.9 minutes, 13.6 to 46.3 minutes). Child behaviour and family functioning outcomes showed some improvement and favoured use of melatonin. Adverse events were mild and similar between the two groups.
Conclusions Children gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required.
Trial registration ISRCT No 05534585.
doi:10.1136/bmj.e6664
PMCID: PMC3489506  PMID: 23129488
2.  Sleep disorders in children 
Clinical Evidence  2010;2010:2304.
Introduction
Sleep disorders may affect between 20% and 30% of young children, and include problems getting to sleep (dyssomnias), or undesirable phenomena during sleep (parasomnias), such as sleep terrors and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for dyssomnias in children? What are the effects of treatments for parasomnias in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 28 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antihistamines; behavioural therapy plus antihistamines, plus benzodiazepines, or plus chloral and derivatives; benzodiazepines alone; exercise; extinction and graduated extinction; 5-hydroxytryptophan; light therapy; melatonin; safety/protective interventions for parasomnias; scheduled waking (for parasomnias); sleep hygiene; and sleep restriction.
Key Points
Sleep disorders may affect between 20% and 30% of young children, and include problems getting to sleep (dyssomnias) or undesirable phenomena during sleep (parasomnias), such as sleep terrors and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders. Other risk factors include the child being the first born, having a difficult temperament or having had colic, and increased maternal responsiveness.
There is a paucity of evidence about effective treatments for sleep disorders in children, especially parasomnias, but behavioural interventions may be the best first-line approach.
Extinction and graduated extinction in otherwise healthy children with dyssomnia may improve sleep quality and settling, and reduce the number of tantrums and wakenings compared with no treatment. Extinction and graduated extinction in children with physical disabilities, learning disabilities, epilepsy, or attention-deficit disorder with dyssomnia may be more effective at improving settling, reducing the frequency and duration of night wakings, and improving parental sleep compared with no treatment; however, we don't know whether it is more effective in improving sleep duration.Graduated extinction may be less distressing for parents, and therefore may have better compliance.
Sleep hygiene for dyssomnia in otherwise healthy children may be more effective in reducing the number and duration of bedtime tantrums compared with placebo, but we don’t know if it is more effective at reducing night wakenings, improving sleep latency, improving total sleep duration, or improving maternal mood. Sleep hygiene and graduated extinction seem to be equally effective at reducing bedtime tantrums in otherwise healthy children with dyssomnia.We don't know whether sleep hygiene for dyssomnia in children with physical disabilities, learning disabilities, epilepsy, or attention-deficit disorder is effective.
Melatonin for dyssomnia in otherwise healthy children may be more effective at improving sleep-onset time, total sleep time, and general health compared with placebo. Evidence of improvements in dyssomnia with melatonin is slightly stronger in children with physical disabilities, learning disabilities, epilepsy, or attention-deficit disorder.
Little is known about the long-term effects of melatonin, and the quality of the product purchased could be variable as melatonin is classified as a food supplement.
Antihistamines for dyssomnia may be more effective than placebo at reducing night wakenings and decreasing sleep latency, but we don’t know if they are more effective at increasing sleep duration. The evidence for antihistamines in dyssomnia comes from only one small, short-term study.
We don’t know whether behavioural therapy plus antihistamines, plus benzodiazepines, or plus chloral and derivatives, exercise, light therapy, or sleep restriction are effective in children with dyssomnia.
We don’t know whether antihistamines, behavioural therapy plus benzodiazepines or plus chloral and derivatives, benzodiazepines, 5-hydroxytryptophan, melatonin, safety/protective interventions, scheduled waking, sleep hygiene, or sleep restriction are effective in children with parasomnia.
PMCID: PMC3217667  PMID: 21418676
3.  A systematic review of treatments for settling problems and night waking in young children 
BMJ : British Medical Journal  2000;320(7229):209-213.
Objectives
To assess the efficacy of treatments for settling problems and night waking in young children.
Design
A systematic review of randomised controlled trials of interventions for settling problems and night waking in young children.
Setting
Electronic bibliographic databases and references on identified papers, hand searches, and personal contact with specialists.
Subjects
Children aged 5 years or less who had established settling problems or night waking.
Interventions
Interventions had to be described and a placebo, waiting list, or another intervention needed to have been used as a comparison. Interventions comprised drug trials or non-drug trials.
Main outcome measures
Number of wakes at night, time to settle, or number of nights in which these problems occurred.
Results
Drugs seemed to be effective in treating night waking in the short term, but long term efficacy was questionable. In contrast, specific behavioural interventions showed both short term efficacy and possible longer term effects for dealing with settling problems and night waking.
Conclusions
Given the prevalence and persistence of childhood sleep problems and the effects they can have on children and families, treatments that offer long lasting benefits are appealing and these are likely to be behavioural interventions.
PMCID: PMC27265  PMID: 10642226
4.  Baby Business: a randomised controlled trial of a universal parenting program that aims to prevent early infant sleep and cry problems and associated parental depression 
BMC Pediatrics  2012;12:13.
Background
Infant crying and sleep problems (e.g. frequent night waking, difficulties settling to sleep) each affect up to 30% of infants and often co-exist. They are costly to manage and associated with adverse outcomes including postnatal depression symptoms, early weaning from breast milk, and later child behaviour problems. Preventing such problems could improve these adverse outcomes and reduce costs to families and the health care system. Anticipatory guidance-i.e. providing parents with information about normal infant sleep and cry patterns, ways to encourage self-settling in infants, and ways to develop feeding and settling routines before the onset of problems-could prevent such problems. This paper outlines the protocol for our study which aims to test an anticipatory guidance approach.
Methods/Design
750 families from four Local Government Areas in Melbourne, Australia have been randomised to receive the Baby Business program (intervention group) or usual care (control group) offered by health services. The Baby Business program provides parents with information about infant sleep and crying via a DVD and booklet (mailed soon after birth), telephone consultation (at infant age 6-8 weeks) and parent group session (at infant age 12 weeks). All English speaking parents of healthy newborn infants born at > 32 weeks gestation and referred by their maternal and child health nurse at their first post partum home visit (day 7-10 postpartum), are eligible. The primary outcome is parent report of infant night time sleep as a problem at four months of age and secondary outcomes include parent report of infant daytime sleep or crying as a problem, mean duration of infant sleep and crying/24 hours, parental depression symptoms, parent sleep quality and quantity and health service use. Data will be collected at two weeks (baseline), four months and six months of age. An economic evaluation using a cost-consequences approach will, from a societal perspective, compare costs and health outcomes between the intervention and control groups.
Discussion
To our knowledge this is the first randomised controlled trial of a program which aims to prevent both infant sleeping and crying problems and associated postnatal depression symptoms. If effective, it could offer an important public health prevention approach to these common, distressing problems.
Trial registration number
ISRCTN: ISRCTN63834603
doi:10.1186/1471-2431-12-13
PMCID: PMC3292472  PMID: 22309617
5.  Sleep disorders in children 
Clinical Evidence  2007;2007:2304.
Introduction
Sleep disorders may affect 20-30% of young children, and include excessive daytime sleepiness, problems getting to sleep (dysomnias), or undesirable phenomena during sleep (parasomnias), such as sleep terrors, and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for dysomnias in children? What are the effects of treatments for parasomnias in children? We searched: Medline, Embase, The Cochrane Library and other important databases up to September 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antihistamines, behavioural therapy plus benzodiazepines, or plus chloral and derivates, exercise, extinction and graduated extinction, light therapy, melatonin, safety/protective interventions for parasomnias, scheduled waking (for parasomnias), sleep hygiene, and sleep restriction.
Key Points
Sleep disorders may affect 20-30% of young children, and include excessive daytime sleepiness, problems getting to sleep (dysomnias), or undesirable phenomena during sleep (parasomnias), such as sleep terrors, and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders. Other risk factors include the child being the first born, having a difficult temperament or having had colic, and increased maternal responsiveness.
There is a paucity of evidence about effective treatments for sleep disorders in children, especially parasomnias, but behavioural interventions may be the best first-line approach.
Extinction and graduated extinction interventions improve settling and reduce night wakes compared with placebo in healthy children, and in children with learning disabilities. Graduated extinction may be less distressing for parents, and therefore may have better compliance.Sleep hygiene interventions may reduce bedtime tantrums in healthy children compared with placebo, with similar effectiveness to graduated extinction.Sleep hygiene plus graduated extinction may reduce bedtime tantrums in children with physical or learning disabilities.We don't know whether combining behavioural therapy with benzodiazepines or with chloral improves sleep or parasomnias.
Melatonin may improve sleep onset and sleep time compared with placebo in healthy children, but we don't know if it is beneficial in children with disabilities, if it improves parasomnias, or what its long-term effects might be. We don't know whether antihistamines, exercise, light therapy, or sleep restriction improve dysomnias or parasomnias in children.We don't know whether safety or protective interventions, scheduled waking, extinction, or sleep hygiene are effective in children with parasomnias.
PMCID: PMC2943792  PMID: 19450298
6.  Sleep well—be well study: improving school transition by improving child sleep: a translational randomised trial 
BMJ Open  2013;3(10):e004009.
Introduction
The transition to primary school appears crucial for a child's future academic and psychological well-being. Addressing conditions which negatively affect children during this period, such as poor sleep, may improve these outcomes. Sleep problems are common and in a previous efficacy randomised controlled trial, we demonstrated that sleep problems can be identified and improved using school-based screening followed by a brief behavioural intervention. This trial will determine whether the same intervention is beneficial and cost-effective when delivered by an existing school-based health workforce.
Methods/design
We will recruit 334 children with sleep problems from approximately 40 schools after screening for behavioural sleep problems in the first year of formal education (Grade Prep). Schools in Melbourne, Australia will be invited to participate from a randomly ordered list of eligible schools and we will approach all caregivers of Grade Prep children. Children who have a parent-reported moderate or severe sleep problem will be randomised into either ‘usual care’ or ‘intervention’ groups. Trained nurses from the Primary School Nursing programme will deliver the sleep intervention programme. Intervention: Two to three contacts between the nurse and the parent; initial 45 min face-to-face meeting or phone call, 15 min phone call 2 weeks later and an optional second 30 min face-to-face meeting. Follow-up: 6 and 12 months postrandomisation using parent and teacher surveys and child face-to-face assessments. Primary outcome: child psychosocial functioning at 6 months. Secondary outcomes: child psychosocial functioning at 12 months and child sleep, behaviour, working memory, academic achievement and parent mental health at 6 and 12 months. Cost-effectiveness analysis will compare incremental costs to difference in child psychosocial functioning at 6 months.
Registration
International Standard Randomised Controlled Trial Number Register (ISRCTN92448857).
doi:10.1136/bmjopen-2013-004009
PMCID: PMC3816243  PMID: 24165031
7.  A systematic review of treatment of settling problems and night waking in young children 
Western Journal of Medicine  2000;173(1):33-38.
Objective To assess the efficacy of treatment of settling problems and night waking in young children. Design A systematic review of randomized controlled trials of interventions. Setting Electronic bibliographic databases and references on identified papers, hand searches, and personal contact with specialists. Subjects Children aged 5 years or younger who had established settling problems or night waking.Interventions Interventions had to be described and a placebo, waiting list, or another intervention needed to have been used as a comparison.Interventions comprised drug trials or non drug trials. Main outcome measures Number of wakes at night, time to settle, or number of nights in which these problems occurred. Results Drugs seemed to be effective in treating night waking in the short term, but long-term efficacy was questionable. In contrast, specific behavioral interventions showed both short-term efficacy and possible longer term effects for dealing with settling problems and night walking. Conclusions Given the prevalence and persistence of childhood sleep problems and the effects they can have no children and families, treatments that offer long-lasting benefits are more appealing, and these are likely to be behavioral interventions.
PMCID: PMC1070969  PMID: 10903288
8.  Fatty acids and sleep in UK children: subjective and pilot objective sleep results from the DOLAB study – a randomized controlled trial 
Journal of Sleep Research  2014;23(4):364-388.
Sleep problems in children are associated with poor health, behavioural and cognitive problems, as are deficiencies of long-chain omega-3 fatty acids such as docosahexaenoic acid. Theory and some evidence support a role for these fatty acids in sleep regulation, but this issue has received little formal investigation. We examined associations between blood fatty acid concentrations (from fingerstick blood samples) and subjective sleep (using an age-standardized parent questionnaire) in a large epidemiological sample of healthy children aged 7–9 years (n = 395) from mainstream UK schools. In a randomized controlled trial, we then explored whether 16-week supplementation (600 mg day−1) with algal docosahexaenoic acid versus placebo might improve sleep in a subset of those children (n = 362) who were underperforming in reading. In a randomly selected subsample (n = 43), sleep was also assessed objectively via actigraphy. In 40% of the epidemiological sample, Child Sleep Habits Questionnaire scores indicated clinical-level sleep problems. Furthermore, poorer total sleep disturbance scores were associated weakly but significantly with lower blood docosahexaenoic acid (std coeff. −0.105*) and a lower docosahexaenoic acid : arachidonic acid ratio (std coeff. −0.119**). The treatment trial showed no significant effects on subjective sleep measures. However, in the small actigraphy subsample, docosahexaenoic acid supplementation led on average to seven fewer wake episodes and 58 min more sleep per night. Cautiously, we conclude that higher blood levels of docosahexaenoic acid may relate to better child sleep, as rated by parents. Exploratory pilot objective evidence from actigraphy suggests that docosahexaenoic acid supplementation may improve children's sleep, but further investigations are needed.
doi:10.1111/jsr.12135
PMCID: PMC4263155  PMID: 24605819
actigraphy; children; docosahexaenoic acid; omega-3; randomized controlled trial; sleep
9.  Effect of behavioural-educational intervention on sleep for primiparous women and their infants in early postpartum: multisite randomised controlled trial 
Objective To evaluate the effectiveness of a behavioural-educational sleep intervention delivered in the early postpartum in improving maternal and infant sleep.
Design Randomised controlled trial.
Setting Postpartum units of two university affiliated hospitals.
Participants 246 primiparous women and their infants randomised while in hospital with an internet based randomisation service to intervention (n=123) or usual care (n=123) groups.
Interventions The behavioural-educational sleep intervention included a 45-60 minute meeting with a nurse to discuss sleep information and strategies to promote maternal and infant sleep, a 20 page booklet with the content discussed, and phone contacts at one, two, and four weeks postpartum to reinforce information, provide support, and problem solve. The usual care group received calls at weeks one, two, and four to maintain contact without provision of advice.
Main outcome measures Primary outcome was maternal nocturnal (9 pm to 9 am) sleep (minutes) and secondary outcome was longest stretch of infant nocturnal sleep (minutes) measured at six and 12 weeks postpartum by actigraphy. Other outcomes measured at six and 12 weeks were number of maternal and infant night time awakenings by actigraphy, fatigue visual analogue scale, general sleep disturbance scale, and Edinburgh postnatal depression scale. Rates of exclusive breast feeding were measured at 12 weeks postpartum only.
Results All women who completed any outcome measures at six or 12 weeks were included in analysis. Sleep outcomes were completed at one or both of six and 12 weeks postpartum for 215 of 246 (87%) women (110/123 intervention and 105/123 usual care). Longitudinal mixed effects model analyses indicated no significant differences between the groups on any of the outcomes. The estimated mean difference in maternal nocturnal sleep between the intervention and usual care groups was 5.97 minutes (95% confidence interval −7.55 to 19.5 minutes, P=0.39). No differences in any outcomes were noted based on the specific nurse delivering the intervention or the number of phone contacts received.
Conclusion A behavioural-educational intervention delivered in the early postpartum, in hospital, and in the first weeks at home, was ineffective in improving maternal and infant sleep or other health outcomes in the first months postpartum.
Trial registration ISRCT No 13501166.
doi:10.1136/bmj.f1164
PMCID: PMC3603553  PMID: 23516146
10.  Impact of a behavioural sleep intervention on symptoms and sleep in children with attention deficit hyperactivity disorder, and parental mental health: randomised controlled trial 
Objective To examine whether behavioural strategies designed to improve children’s sleep problems could also improve the symptoms, behaviour, daily functioning, and working memory of children with attention deficit hyperactivity disorder (ADHD) and the mental health of their parents.
Design Randomised controlled trial.
Setting 21 general paediatric practices in Victoria, Australia.
Participants 244 children aged 5-12 years with ADHD attending the practices between 2010 and 2012.
Intervention Sleep hygiene practices and standardised behavioural strategies delivered by trained psychologists or trainee paediatricians during two fortnightly consultations and a follow-up telephone call. Children in the control group received usual clinical care.
Main outcome measures At three and six months after randomisation: severity of ADHD symptoms (parent and teacher ADHD rating scale IV—primary outcome), sleep problems (parent reported severity, children’s sleep habits questionnaire, actigraphy), behaviour (strengths and difficulties questionnaire), quality of life (pediatric quality of life inventory 4.0), daily functioning (daily parent rating of evening and morning behavior), working memory (working memory test battery for children, six months only), and parent mental health (depression anxiety stress scales).
Results Intervention compared with control families reported a greater decrease in ADHD symptoms at three and six months (adjusted mean difference for change in symptom severity −2.9, 95% confidence interval −5.5 to −0.3, P=0.03, effect size −0.3, and −3.7, −6.1 to −1.2, P=0.004, effect size −0.4, respectively). Compared with control children, intervention children had fewer moderate-severe sleep problems at three months (56% v 30%; adjusted odds ratio 0.30, 95% confidence interval 0.16 to 0.59; P<0.001) and six months (46% v 34%; 0.58, 0.32 to 1.0; P=0.07). At three months this equated to a reduction in absolute risk of 25.7% (95% confidence interval 14.1% to 37.3%) and an estimated number needed to treat of 3.9. At six months the number needed to treat was 7.8. Approximately a half to one third of the beneficial effect of the intervention on ADHD symptoms was mediated through improved sleep, at three and six months, respectively. Intervention families reported greater improvements in all other child and family outcomes except parental mental health. Teachers reported improved behaviour of the children at three and six months. Working memory (backwards digit recall) was higher in the intervention children compared with control children at six months. Daily sleep duration measured by actigraphy tended to be higher in the intervention children at three months (mean difference 10.9 minutes, 95% confidence interval −19.0 to 40.8 minutes, effect size 0.2) and six months (9.9 minutes, −16.3 to 36.1 minutes, effect size 0.3); however, this measure was only completed by a subset of children (n=54 at three months and n=37 at six months).
Conclusions A brief behavioural sleep intervention modestly improves the severity of ADHD symptoms in a community sample of children with ADHD, most of whom were taking stimulant medications. The intervention also improved the children’s sleep, behaviour, quality of life, and functioning, with most benefits sustained to six months post-intervention. The intervention may be suitable for use in primary and secondary care.
Trial registration Current Controlled Trials ISRCTN68819261.
doi:10.1136/bmj.h68
PMCID: PMC4299655  PMID: 25646809
11.  Study protocol: the sleeping sound with attention-deficit/hyperactivity disorder project 
BMC Pediatrics  2010;10:101.
Background
Up to 70% of children with Attention-Deficit/Hyperactivity Disorder (ADHD) experience sleep problems including difficulties initiating and maintaining sleep. Sleep problems in children with ADHD can result in poorer child functioning, impacting on school attendance, daily functioning and behaviour, as well as parental mental health and work attendance. The Sleeping Sound with ADHD trial aims to investigate the efficacy of a behavioural sleep program in treating sleep problems experienced by children with ADHD. We have demonstrated the feasibility and the acceptability of this treatment program in a pilot study.
Methods/Design
This randomised controlled trial (RCT) is being conducted with 198 children (aged between 5 to 12 years) with ADHD and moderate to severe sleep problems. Children are recruited from public and private paediatric practices across the state of Victoria, Australia. Upon receiving informed written consent, families are randomised to receive either the behavioural sleep intervention or usual care. The intervention consists of two individual, face-to-face consultations and a follow-up phone call with a trained clinician (trainee consultant paediatrician or psychologist), focusing on the assessment and management of child sleep problems. The primary outcome is parent- and teacher-reported ADHD symptoms (ADHD Rating Scale IV). Secondary outcomes are child sleep (actigraphy and parent report), behaviour, daily functioning, school attendance and working memory, as well as parent mental health and work attendance. We are also assessing the impact of children's psychiatric comorbidity (measured using a structured diagnostic interview) on treatment outcome.
Discussion
To our knowledge, this is the first RCT of a behavioural intervention aiming to treat sleep problems in children with ADHD. If effective, this program will provide a feasible non-pharmacological and acceptable intervention improving child sleep and ADHD symptoms in this patient group.
Trial Registration
Current Controlled Trials ISRCTN68819261.
ISRCTN: ISRCTN68819261
doi:10.1186/1471-2431-10-101
PMCID: PMC3022790  PMID: 21192797
12.  Identification of Redeye, a new sleep-regulating protein whose expression is modulated by sleep amount 
eLife  2014;3:e01473.
In this study, we report a new protein involved in the homeostatic regulation of sleep in Drosophila. We conducted a forward genetic screen of chemically mutagenized flies to identify short-sleeping mutants and found one, redeye (rye) that shows a severe reduction of sleep length. Cloning of rye reveals that it encodes a nicotinic acetylcholine receptor α subunit required for Drosophila sleep. Levels of RYE oscillate in light–dark cycles and peak at times of daily sleep. Cycling of RYE is independent of a functional circadian clock, but rather depends upon the sleep homeostat, as protein levels are up-regulated in short-sleeping mutants and also in wild type animals following sleep deprivation. We propose that the homeostatic drive to sleep increases levels of RYE, which responds to this drive by promoting sleep.
DOI: http://dx.doi.org/10.7554/eLife.01473.001
eLife digest
Almost all animals need to sleep, including most insects. In experiments in the 1980s, a group of rats that were completely deprived of sleep died within only a few weeks. Sleep has been implicated in processes including tissue repair, memory consolidation and, more recently, the removal of waste materials from the brain. However, a full understanding of why we sleep is still lacking.
As anyone who has experienced jetlag can testify, the timing of the sleep/wake cycle is governed by the circadian clock, which leads us to feel sleepy at certain points of the day–night cycle and alert at others. The duration of sleep is regulated by a second process called sleep/wake homeostasis. The longer we remain awake, the more the body’s need for sleep—or ‘sleep drive’—increases, until it becomes almost impossible to stay awake any longer. Whereas many components of the circadian clock have been identified, relatively little is known about the molecular basis of this second process.
Now, Shi et al. have identified a key component of the sleep/wake homeostatic system using the fruit fly and genetic model organism, Drosophila. Flies with a mutation in one particular gene, subsequently named redeye, were found to sleep only half as long as normal flies. While the insects were able to fall asleep, they would wake again only a few minutes later.
Redeye encodes a subunit of a receptor that has previously been implicated in the control of wakefulness, known as the nicotinic acetylcholine receptor. Mutant flies had normal circadian rhythms, suggesting that their sleep problems were the result of disrupted sleep/wake homeostasis. Consistent with this, levels of redeye showed two daily peaks, one corresponding to night-time sleep and the second to the time at which flies would normally take an afternoon siesta. This suggests that redeye signals an acute need for sleep, and then helps to maintain sleep once it is underway.
While redeye is not thought to be the factor that triggers sleep per se, it is directly under control of the sleep homeostat, and may be a useful biomarker for sleep deprivation. The fact that redeye was identified in fruit flies, a species whose genome has been fully sequenced, opens up the possibility of further studies to identify the genetic basis of sleep regulation.
DOI: http://dx.doi.org/10.7554/eLife.01473.002
doi:10.7554/eLife.01473
PMCID: PMC3912633  PMID: 24497543
sleep; acetylcholine signaling; cycling; Sleepless/Lynx-1; D. melanogaster
13.  Sleep characteristics of asthmatics in the first four years of life: a comparative study. 
Archives of Disease in Childhood  1993;68(4):481-483.
The association between asthma and sleep disturbances was assessed as part of a community survey of sleep patterns in children aged 4-48 months. A questionnaire covering the area of past and present sleep and settling behaviour, as well as health history and demographic data, was administered to 752 mothers of children visiting 14 well baby clinics. Fifty one (6.8%) of the children who were diagnosed as having asthma by their paediatricians were compared with the remaining healthy controls (children with perinatal problems, other chronic illnesses, developmental problems, or repeat admissions to hospital were excluded). Thirty nine per cent of the children with asthma and 38% of the normal controls were identified as regular wakers. The number of interrupted nights each week, settling time, and sleep duration were comparable. In the children with asthma an uninterrupted night's sleep was acquired later than in the control group. Parental perception of the severity of the sleep problem was similar in the two groups, as were the calming techniques. It is concluded that this study does not support a significantly increased prevalence of sleep disturbances among young children with asthma compared with their healthy peers.
PMCID: PMC1029269  PMID: 8503671
14.  Distinguishing infant prolonged crying from sleep-waking problems 
Archives of disease in childhood  2011;96(4):340-344.
Objective
Infants who cry a lot, or are unsettled in the night, are common sources of concern for parents and costly problems for health services. The two types of problems have been linked together and attributed to a general disturbance of infant regulation. Yet the infant behaviours involved present differently, at separate ages and times of day. To clarify causation, this study aims to assess whether prolonged crying at 5–6 weeks (the peak age for crying) predicts which infants are unsettled in the night at 12 weeks of age (when most infants become settled at night).
Methods
Data from two longitudinal studies are analysed. Infant crying data were obtained from validated behaviour diaries; sleep-waking data from standard parental questionnaires.
Results
A significant, weak relationship was found between crying at 5–6 weeks and 12-week night waking and signalling in one study, but not the other. Most infants who met the definition for prolonged crying/colic at 5–6 weeks were settled during the night at 12 weeks of age; they were not more likely than other infants to be unsettled.
Conclusions
Most infants who cry a lot at 5–6 weeks of age ‘sleep through the night’ at 12 weeks of age. This adds to evidence that the two types of problematic behaviour have different causes, and that infant sleep-waking problems usually involve maintenance of signalling behaviours rather than a generalised disturbance.
doi:10.1136/adc.2010.200204
PMCID: PMC3202670  PMID: 21220260
15.  Obstructive Sleep Apnea and Risk of Cardiovascular Events and All-Cause Mortality: A Decade-Long Historical Cohort Study 
PLoS Medicine  2014;11(2):e1001599.
Tetyana Kendzerska and colleagues explore the association between physiological measures of obstructive sleep apnea other than the apnea-hypopnea index and the risk of cardiovascular events.
Please see later in the article for the Editors' Summary
Background
Obstructive sleep apnea (OSA) has been reported to be a risk factor for cardiovascular (CV) disease. Although the apnea-hypopnea index (AHI) is the most commonly used measure of OSA, other less well studied OSA-related variables may be more pathophysiologically relevant and offer better prediction. The objective of this study was to evaluate the relationship between OSA-related variables and risk of CV events.
Methods and Findings
A historical cohort study was conducted using clinical database and health administrative data. Adults referred for suspected OSA who underwent diagnostic polysomnography at the sleep laboratory at St Michael's Hospital (Toronto, Canada) between 1994 and 2010 were followed through provincial health administrative data (Ontario, Canada) until May 2011 to examine the occurrence of a composite outcome (myocardial infarction, stroke, congestive heart failure, revascularization procedures, or death from any cause). Cox regression models were used to investigate the association between baseline OSA-related variables and composite outcome controlling for traditional risk factors. The results were expressed as hazard ratios (HRs) and 95% CIs; for continuous variables, HRs compare the 75th and 25th percentiles. Over a median follow-up of 68 months, 1,172 (11.5%) of 10,149 participants experienced our composite outcome. In a fully adjusted model, other than AHI OSA-related variables were significant independent predictors: time spent with oxygen saturation <90% (9 minutes versus 0; HR = 1.50, 95% CI 1.25–1.79), sleep time (4.9 versus 6.4 hours; HR = 1.20, 95% CI 1.12–1.27), awakenings (35 versus 18; HR = 1.06, 95% CI 1.02–1.10), periodic leg movements (13 versus 0/hour; HR = 1.05, 95% CI 1.03–1.07), heart rate (70 versus 56 beats per minute [bpm]; HR = 1.28, 95% CI 1.19–1.37), and daytime sleepiness (HR = 1.13, 95% CI 1.01–1.28).The main study limitation was lack of information about continuous positive airway pressure (CPAP) adherence.
Conclusion
OSA-related factors other than AHI were shown as important predictors of composite CV outcome and should be considered in future studies and clinical practice.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder, particularly among middle-aged and elderly people. It is characterized by apnea—a brief interruption in breathing that lasts at least 10 seconds—and hypopnea—a decrease of more than 50% in the amplitude of breathing that lasts at least 10 seconds or clear but smaller decrease in amplitude associated with either oxygen desaturation or an arousal. Patients with OSA experience numerous episodes of apnea and hypopnea during the night; severe OSA is defined as having 30 or more episodes per hour (an apnea-hypopnea index [AHI] of >30). These breathing interruptions occur when relaxation of the upper airway muscles decreases the airflow, which lowers the amount of oxygen in the blood. As a result, affected individuals frequently wake from deep sleep as they struggle to breathe. Symptoms of OSA include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. For severe OSA, doctors recommend continuous positive airway pressure (CPAP), in which a machine blows pressurized air through a face mask into the airway to keep it open.
Why Was This Study Done?
OSA can be life-threatening. Most directly, daytime sleepiness can cause accidents, but OSA is also associated with an increased risk of developing cardiovascular disease (CVD, disease that affects the heart and the circulation). To date, studies that have investigated the association between OSA and the risk of myocardial infarction (heart attack), congestive heart failure, stroke, and other CVDs have used the AHI to diagnose and categorize the severity of OSA. However, by focussing on AHI, clinicians and researchers may be missing opportunities to improve their ability to predict which patients are at the highest risk of CVD. In this historical cohort study, the researchers investigate the association between other OSA-related variables (for example, blood oxygen saturation and sleep fragmentation) and the risk of cardiovascular events and all-cause mortality (death). A historical cohort study examines the medical records of groups of individuals who have different characteristics at baseline for the subsequent occurrence of specific outcomes.
What Did the Researchers Do and Find?
The researchers used administrative data (including hospitalization records and physicians' claims for services supplied to patients) to follow up adults referred for suspected OSA who underwent diagnostic polysomnography (a sleep study) at a single Canadian hospital between 1994 and 2010. A database of the polysomnography results provided information on OSA-related variables for all the study participants. Over an average follow-up of about 6 years, 11.5% of the 10,149 participants were hospitalized for a myocardial infarction, stroke, or congestive heart failure, underwent a revascularization procedure (an intervention that restores the blood supply to an organ or tissue after CVD has blocked a blood vessel), or had died from any cause. After adjusting for multiple established risk factors for CVD such as smoking and age in Cox regression models (a statistical approach that examines associations between patient variables and outcomes), several OSA-related variables (but not AHI) were significant predictors of CVD. The strongest OSA-related predictor of cardiovascular events or all-cause mortality was total sleep time spent with oxygen saturation below 90%, which increased the risk of a cardiovascular event or death by 50%. Other statistically significant OSA-related predictors (predictors that were unlikely to be associated with the outcome through chance) of cardiovascular events or death included total sleep time, number of awakenings, frequency of periodic leg movements, heart rate, and daytime sleepiness.
What Do These Findings Mean?
These findings indicate that OSA-related factors other than AHI are important predictors of the composite outcome of a cardiovascular event or all-cause mortality. Indeed, although AHI was significantly associated with the researchers' composite outcome in an analysis that did not consider other established risk factors for CVD (“confounders”), the association became non-significant after controlling for potential confounders. The accuracy of these findings, which need to be confirmed in other settings, is likely to be limited by the lack of information available about the use of CPAP by study participants and by the lack of adjustment for some important confounders. Importantly, however, these findings suggest that OSA-related factors other than AHI should be considered as predictors of CVD in future studies and in clinical practice.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001599.
The US National Heart Lung and Blood Institute has information (including several videos) about obstructive sleep apnea (in English and Spanish), sleep studies, heart disease, and other cardiovascular diseases (some information in English and Spanish)
The UK National Health Service Choices website provides information (including personal stories) about sleep apnea and about cardiovascular disease
The not-for-profit American Sleep Apnea Association provides detailed information about sleep apnea for patients and health-care professionals, including personal stories about the condition
The MedlinePlus encyclopedia has pages on obstructive sleep apnea and on polysomnography; MedlinePlus provides links to further information and advice about obstructive sleep apnea, heart diseases, and vascular diseases (in English and Spanish)
doi:10.1371/journal.pmed.1001599
PMCID: PMC3913558  PMID: 24503600
16.  A ‘learning platform’ approach to outcome measurement in fragile X syndrome: a preliminary psychometric study 
Background
Clinical trials of medications to alleviate the cognitive and behavioural symptoms of individuals with fragile X syndrome (FXS) are now underway. However, there are few reliable, valid and/or sensitive outcome measures available that can be directly administered to individuals with FXS. The majority of assessments employed in clinical trials may be suboptimal for individuals with intellectual disability (ID) because they require face-to-face interaction with an examiner, taxing administration periods, and do not provide reinforcement and/or feedback during the test. We therefore examined the psychometric properties of a new computerised ‘learning platform’ approach to outcome measurement in FXS.
Method
A brief computerised test, incorporated into the Discrete Trial Trainer© – a commercially available software program designed for children with ID – was administered to 13 girls with FXS, 12 boys with FXS and 15 matched ID controls aged 10 to 23 years (mental age = 4 to 12 years). The software delivered automated contingent access to reinforcement, feedback, token delivery and prompting procedures (if necessary) on each trial to facilitate responding. The primary outcome measure was the participant’s learning rate, derived from the participant’s cumulative record of correct responses.
Results
All participants were able to complete the test and floor effects appeared to be minimal. Learning rates averaged approximately five correct responses per minute, ranging from one to eight correct responses per minute in each group. Test–retest reliability of the learning rates was 0.77 for girls with FXS, 0.90 for boys with FXS and 0.90 for matched ID controls. Concurrent validity with raw scores obtained on the Arithmetic subtest of the Wechsler Intelligence Scale for Children-III was 0.35 for girls with FXS, 0.80 for boys with FXS and 0.56 for matched ID controls. The learning rates were also highly sensitive to change, with effect sizes of 1.21, 0.89 and 1.47 in each group respectively following 15 to 20, 15-min sessions of intensive discrete trial training conducted over 1.5 days.
Conclusions
These results suggest that a learning platform approach to outcome measurement could provide investigators with a reliable, valid and highly sensitive measure to evaluate treatment efficacy, not only for individuals with FXS but also for individuals with other ID.
doi:10.1111/j.1365-2788.2012.01560.x
PMCID: PMC3417081  PMID: 22533667
behavioural measurement methods; cognitive behaviour; fragile X; intellectual disability
17.  Insomnia in school-age children with Asperger syndrome or high-functioning autism 
BMC Psychiatry  2006;6:18.
Background
Asperger syndrome (AS) and high-functioning autism (HFA) are pervasive developmental disorders (PDD) in individuals of normal intelligence. Childhood AS/HFA is considered to be often associated with disturbed sleep, in particular with difficulties initiating and/or maintaining sleep (insomnia). However, studies about the topic are still scarce. The present study investigated childhood AS/HFA regarding a wide range of parent reported sleep-wake behaviour, with a particular focus on insomnia.
Methods
Thirty-two 8–12 yr old children with AS/HFA were compared with 32 age and gender matched typically developing children regarding sleep and associated behavioural characteristics. Several aspects of sleep-wake behaviour including insomnia were surveyed using a structured paediatric sleep questionnaire in which parents reported their children's sleep patterns for the previous six months. Recent sleep patterns were monitored by use of a one-week sleep diary and actigraphy. Behavioural characteristics were surveyed by use of information gleaned from parent and teacher-ratings in the High-Functioning Autism Spectrum Screening Questionnaire, and in the Strengths and Difficulties Questionnaire.
Results
Parent-reported difficulties initiating sleep and daytime sleepiness were more common in children with AS/HFA than in controls, and 10/32 children with AS/HFA (31.2%) but none of the controls fulfilled our definition of paediatric insomnia. The parent-reported insomnia corresponded to the findings obtained by actigraphy. Children with insomnia had also more parent-reported autistic and emotional symptoms, and more teacher-reported emotional and hyperactivity symptoms than those children without insomnia.
Conclusion
Parental reports indicate that in childhood AS/HFA insomnia is a common and distressing symptom which is frequently associated with coexistent behaviour problems. Identification and treatment of sleep problems need to be a routine part of the treatment plan for children with AS/HFA.
doi:10.1186/1471-244X-6-18
PMCID: PMC1479331  PMID: 16646974
18.  A randomised controlled trial of a cognitive behavioural intervention for women who have menopausal symptoms following breast cancer treatment (MENOS 1): Trial protocol 
BMC Cancer  2011;11:44.
Background
This trial aims to evaluate the effectiveness of a group cognitive behavioural intervention to alleviate menopausal symptoms (hot flushes and night sweats) in women who have had breast cancer treatment. Hot flushes and night sweats are highly prevalent but challenging to treat in this population. Cognitive behaviour therapy has been found to reduce these symptoms in well women and results of an exploratory trial suggest that it might be effective for breast cancer patients. Two hypotheses are tested:
Compared to usual care, group cognitive behavioural therapy will:
1. Significantly reduce the problem rating and frequency of hot flushes and nights sweats after six weeks of treatment and at six months post-randomisation.
2. Improve mood and quality of life after six weeks of treatment and at six months post-randomisation.
Methods/Design
Ninety-six women who have completed their main treatment for breast cancer and who have been experiencing problematic hot flushes and night sweats for over two months are recruited into the trial from oncology and breast clinics in South East London. They are randomised to either six weekly group cognitive behavioural therapy (Group CBT) sessions or to usual care. Group CBT includes information and discussion about hot flushes and night sweats in the context of breast cancer, monitoring and modifying precipitants, relaxation and paced respiration, stress management, cognitive therapy for unhelpful thoughts and beliefs, managing sleep and night sweats and maintaining changes.
Prior to randomisation women attend a clinical interview, undergo 24-hour sternal skin conductance monitoring, and complete questionnaire measures of hot flushes and night sweats, mood, quality of life, hot flush beliefs and behaviours, optimism and somatic amplification. Post-treatment measures (sternal skin conductance and questionnaires) are collected six to eight weeks later and follow-up measures (questionnaires and a use of medical services measure) at six months post-randomisation.
Discussion
MENOS 1 is the first randomised controlled trial of cognitive behavioural therapy for hot flushes and night sweats that measures both self-reported and physiologically indexed symptoms. The results will inform future clinical practice by developing an evidence-based, non-medical treatment, which can be delivered by trained health professionals.
Trial Registration
Current Controlled Trials ISRCTN13771934
doi:10.1186/1471-2407-11-44
PMCID: PMC3045984  PMID: 21281461
19.  Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial 
Introduction
Melatonin, secreted by the pineal gland during the night phase, is a regulator of the biological clock and sleep tendency. Totally blind subjects frequently report severe, periodic sleep problems, with 50%–75% of cases displaying non-24-hour sleep–wake disorder (N24HSWD) due to inability to synchronize with the environmental day–night cycle. Melatonin immediate-release preparations are reportedly effective in N24HSWD. Here, we studied the efficacy and safety of prolonged-release melatonin (PRM), a registered drug for insomnia, for sleep disorders in totally blind subjects living in normal social environments. The primary endpoint was demonstration of clinically meaningful effects on sleep duration (upper confidence interval [CI] limit >20 minutes whether significant or not) to allow early decision-making on further drug development in this indication.
Trial registration
ClinicalTrials.gov registry – NCT00972075.
Methods
In a randomized, double-blind, placebo-controlled proof-of-principle study, 13 totally blind subjects had 2 weeks’ placebo run-in, 6 weeks’ randomized (1:1) PRM (Circadin®) or placebo nightly, and 2 weeks’ placebo run-out. Outcome measures included daily voice recorded sleep diary, Clinical Global Impression of Change (CGIC), WHO-Five Well-being Index (WHO-5), and safety.
Results
Mean nightly sleep duration improved by 43 minutes in the PRM and 16 minutes in the placebo group (mean difference: 27 minutes, 95% CI: −14.4 to 69 minutes; P=0.18; effect size: 0.82) meeting the primary endpoint. Mean sleep latency decreased by 29 minutes with PRM over placebo (P=0.13; effect size: 0.92) and nap duration decreased in the PRM but not placebo group. The variability in sleep onset/offset and latency tended to decrease during PRM but not placebo treatment. The potentially beneficial effects of PRM persisted during the 2 weeks of discontinuation period, consistent with clock stabilizing effects. PRM was well-tolerated, adverse events were of mild or moderate severity and similar between PRM and placebo.
Conclusion
Nightly use of PRM may potentially improve patient-reported sleep difficulties in totally blind individuals trying to adhere to normal social lifestyle. A larger study powered to demonstrate a statistically significant effect is warranted.
doi:10.2147/NSS.S71838
PMCID: PMC4319556
biological clock; non-24-hour sleep–wake disorder; sleep; melatonin
20.  Intermittent Preventive Treatment of Malaria Provides Substantial Protection against Malaria in Children Already Protected by an Insecticide-Treated Bednet in Mali: A Randomised, Double-Blind, Placebo-Controlled Trial 
PLoS Medicine  2011;8(2):e1000407.
A randomized trial reported by Alassane Dicko and colleagues shows that intermittent preventive treatment for malaria in children who are protected from mosquitoes by insecticide-treated bednets provides substantial protection from malaria.
Background
Previous studies have shown that in areas of seasonal malaria transmission, intermittent preventive treatment of malaria in children (IPTc), targeting the transmission season, reduces the incidence of clinical malaria. However, these studies were conducted in communities with low coverage with insecticide-treated nets (ITNs). Whether IPTc provides additional protection to children sleeping under an ITN has not been established.
Methods and Findings
To assess whether IPTc provides additional protection to children sleeping under an ITN, we conducted a randomised, double-blind, placebo-controlled trial of IPTc with sulphadoxine pyrimethamine (SP) plus amodiaquine (AQ) in three localities in Kati, Mali. After screening, eligible children aged 3–59 mo were given a long-lasting insecticide-treated net (LLIN) and randomised to receive three rounds of active drugs or placebos. Treatments were administered under observation at monthly intervals during the high malaria transmission season in August, September, and October 2008. Adverse events were monitored immediately after the administration of each course of IPTc and throughout the follow-up period. The primary endpoint was clinical episodes of malaria recorded through passive surveillance by study clinicians available at all times during the follow-up. Cross-sectional surveys were conducted in 150 randomly selected children weekly and in all children at the end of the malaria transmission season to assess usage of ITNs and the impact of IPTc on the prevalence of malaria, anaemia, and malnutrition. Cox regression was used to compare incidence rates between intervention and control arms. The effects of IPTc on the prevalence of malaria infection and anaemia were estimated using logistic regression. 3,065 children were screened and 3,017 (1,508 in the control and 1,509 in the intervention arm) were enrolled in the study. 1,485 children (98.5%) in the control arm and 1,481 (98.1%) in the intervention arm completed follow-up. During the intervention period, the proportion of children reported to have slept under an ITN was 99.7% in the control and 99.3% in intervention arm (p = 0.45). A total of 672 episodes of clinical malaria defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microlitre (incidence rate of 1.90; 95% confidence interval [CI] 1.76–2.05 episodes per person year) were observed in the control arm versus 126 (incidence rate of 0.34; 95% CI 0.29–0.41 episodes per person year) in the intervention arm, indicating a protective effect (PE) of 82% (95% CI 78%–85%) (p<0.001) on the primary endpoint. There were 15 episodes of severe malaria in children in the control arm compared to two in children in the intervention group giving a PE of 87% (95% CI 42%–99%) (p = 0.001). IPTc reduced the prevalence of malaria infection by 85% (95% CI 73%–92%) (p<0.001) during the intervention period and by 46% (95% CI 31%–68%) (p<0.001) at the end of the intervention period. The prevalence of moderate anaemia (haemoglobin [Hb] <8 g/dl) was reduced by 47% (95% CI 15%–67%) (p<0.007) at the end of intervention period. The frequencies of adverse events were similar between the two arms. There was no drug-related serious adverse event.
Conclusions
IPTc given during the malaria transmission season provided substantial protection against clinical episodes of malaria, malaria infection, and anaemia in children using an LLIN. SP+AQ was safe and well tolerated. These findings indicate that IPTc could make a valuable contribution to malaria control in areas of seasonal malaria transmission alongside other interventions.
Trial Registration
ClinicalTrials.gov NCT00738946
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria accounts for one in five of all childhood deaths in Africa and of the one million annual malarial deaths world-wide, over 75% occur in African children <5 years old infected with Plasmodium falciparum. Malaria also causes severe morbidity in children, such as anemia, low birth-weight, epilepsy, and neurological problems, which compromise the health and development of millions of children living in malaria endemic areas. As much of the impact of malaria on African children can be effectively prevented, significant efforts have been made in recent years to improve malaria control, such as the implementation of intermittent preventive treatment (IPT) of malaria.
IPT involves administration of antimalarial drugs at defined time intervals to individuals, regardless of whether they are known to be infected with malaria, to prevent morbidity and mortality. IPT was initially recommended for pregnant women and recently this strategy was extended to include infants (IPTi). Now, there is also intermittent preventive treatment of malaria in children (IPTc), which is designed to protect against seasonal malaria transmission including those above one year of age.
Why Was This Study Done?
Large clinical trials have shown that IPTc involving the administration of two to three doses of an antimalarial drug (sulphadoxine pyrimethamine [SP] and artesunate [AS] or amodiaquine [AQ]) during the high malaria transmission season effectively reduces the incidence of malaria. However, these studies were conducted in countries where the use of insecticide-treated bednets—an intervention that provides at least 50% protection against morbidity from malaria and is the main tool used for malaria control in most of sub-Saharan Africa—was relatively low. Therefore, it is unclear whether IPTc will be as effective in children who sleep under insecticide-treated bednets as has been previously shown in communities where insecticide-treated bednet usage is low. So to determine the answer to this important question, the researchers conducted a randomized, placebo controlled trial of IPTc with SP+AQ (chosen because of the effectiveness of this combination in a pilot study) in children who slept under an insecticide-treated bednet in an area of seasonal malaria transmission in Mali.
What Did the Researchers Do and Find?
The researchers enrolled 3,017 eligible children aged 3–59 months into a randomized double-blind, placebo-controlled trial during the 2008 malaria transmission season in Mali. All children were given a long-lasting insecticide-treated bednet at the start of the study with instructions to their family on the correct use of the net. Children were then randomized into two arms—1,509 were allocated to the intervention group and 1,508 to the control group—to receive three courses of IPTc with SP plus AQ or placebos given at monthly intervals during the peak malaria transmission season. The researchers monitored the incidence of malaria throughout the malaria season and also monitored the use of long-lasting insecticide-treated bednets throughout the study period. In addition, researchers conducted a cross-sectional survey in 150 randomly selected children every week and in every child enrolled in the trial 6 weeks after the last course of IPTc, to measure their temperature, height and weight, and blood hemoglobin and parasite level.
The number of children who slept under their long-lasting insecticide-treated bednet was similar in both arms. During the intervention period, the researchers observed a total of 672 episodes of clinical malaria (defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microliter) in the control arm versus 126 episodes in the intervention arm, which is an incidence rate of 1.90 episodes per person year in the control arm versus 0.34 in the interventions arm—giving a protective efficacy of 87%. IPTc reduced the prevalence of malaria infection during the intervention period by 85% and by 46% at the end of the intervention period. The prevalence of moderate anemia was also reduced (by 47%) at the end of intervention period. The frequencies of adverse events were similar between the two arms and there were no drug-related serious adverse events.
What Do These Findings Mean?
The results of this study show that in peak malarial transmission season in Mali, IPTc provides substantial additional protection against episodes of clinical malaria and severe malaria in children sleeping under long-lasting insecticide-treated bednets. In addition, intermittent preventive treatment of malaria with SP plus AQ appears to be safe and well tolerated for use in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000407.
This topic is further discussed in two PLoS Medicine research articles by Konat et al. and Bojang et al., and a PLoS Medicine Perspective by Beeson
Roll Back Malaria has information about malaria in children, including intervention strategies and an information sheet on insecticide-treated bednets
UNICEF also provides comprehensive information about malaria in children
The Intermittent Preventive Treatment in Infants Consortium (ipti) provides information on intermittent preventive treatment in infants
doi:10.1371/journal.pmed.1000407
PMCID: PMC3032550  PMID: 21304923
21.  Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study 
PLoS Medicine  2009;6(8):e1000132.
In a cohort of 6,441 volunteers followed over an average of 8.2 years, Naresh Punjabi and colleagues find sleep-disordered breathing to be independently associated with mortality and identify predictive characteristics.
Background
Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.
Methods and Findings
We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.
Conclusions
Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 1 in 10 women and 1 in 4 men have a chronic condition called sleep-disordered breathing although most are unaware of their problem. Sleep-disordered breathing, which is commonest in middle-aged and elderly people, is characterized by numerous, brief (10 second or so) interruptions of breathing during sleep. These interruptions, which usually occur when relaxation of the upper airway muscles decreases airflow, lower the level of oxygen in the blood and, as a result, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of sleep-disordered breathing include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. Affected people can also use special devices to prevent them sleeping on their backs, but for severe sleep-disordered breathing, doctors often recommend continuous positive airway pressure (CPAP), a machine that pressurizes the upper airway through a face mask to keep it open.
Why Was This Study Done?
Sleep-disordered breathing is a serious condition. It is associated with several adverse health conditions including coronary artery disease (narrowing of the blood vessels that supply the heart, a condition that can cause a heart attack) and daytime sleepiness that can affect an individual's driving ability. In addition, several clinic- and community-based studies suggest that sleep-disordered sleeping may increase a person's risk of dying. However, because these studies have been small and have often failed to allow for other conditions and characteristics that affect an individual's risk of dying (“confounding factors”), they provide inconsistent or incomplete information about the potential association between sleep-disordered breathing and the risk of death. In this prospective cohort study (part of the Sleep Heart Health Study, which is researching the effects of sleep-disordered breathing on cardiovascular health), the researchers examine whether sleep-disordered breathing is associated with all-cause mortality (death from any cause) in a large community sample of adults. A prospective cohort study is one in which a group of participants is enrolled and then followed forward in time (in this case for several years) to see what happens to them.
What Did the Researchers Do and Find?
At enrollment, the study participants—more than 6,000 people aged 40 years or older, none of whom were being treated for sleep-disordered breathing—had a health examination. Their night-time breathing, sleep patterns, and blood oxygen levels were also assessed and these data used to calculate each participant's apnea-hypopnea index (AHI)—the number of apneas and hypopneas per hour. During the study follow-up period, 1,047 participants died. Compared to participants without sleep-disordered sleeping, participants with severe sleep-disordered breathing (an AHI of ≥30) were about one and a half times as likely to die from any cause after adjustment for potential confounding factors. People with milder sleep-disordered breathing did not have a statistically significant increased risk of dying. After dividing the participants into subgroups according to their age and sex, men aged 40–70 years with severe sleep-disordered breathing had a statistically increased risk of dying from any cause (twice the risk of men of a similar age without sleep-disordered breathing). Finally, death from coronary artery disease was also associated with sleep-disordered breathing in men but not in women.
What Do These Findings Mean?
These findings indicate that sleep-disordered breathing is associated with an increased risk of all-cause mortality, particularly in men aged 40–70 years, even after allowing for known confounding factors. They also suggest that the increased risk of death is specifically associated with coronary artery disease although further studies are needed to confirm this finding because it was based on the analysis of a small subgroup of study participants. Although this study is much larger than previous investigations into the association between sleep-disordered breathing and all-cause mortality, it has several limitations including its reliance on a single night's measurements for the diagnosis of sleep-disordered breathing. Nevertheless, these findings suggest that clinical trials should now be started to assess whether treatment can reduce the increased risk of death that seems to be associated with this common disorder.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000132.
The US National Heart Lung and Blood Institute has information (including a video) about sleep-disordered breathing (sleep apnea) (in English and Spanish)
The UK National Heath Service also provides information for patients about sleep apnea
MedlinePlus provides links to further information and advice about sleep-disordered breathing (in English and Spanish)
More information on the Sleep Heart Health Study is available
doi:10.1371/journal.pmed.1000132
PMCID: PMC2722083  PMID: 19688045
22.  Intermittent Preventive Treatment of Malaria Provides Substantial Protection against Malaria in Children Already Protected by an Insecticide-Treated Bednet in Burkina Faso: A Randomised, Double-Blind, Placebo-Controlled Trial 
PLoS Medicine  2011;8(2):e1000408.
A randomized trial reported by Diadier Diallo and colleagues shows that intermittent preventive treatment for malaria in children who are protected from mosquitoes using insecticide-treated bednets provides substantial protection from malaria.
Background
Intermittent preventive treatment of malaria in children (IPTc) is a promising new approach to the control of malaria in areas of seasonal malaria transmission but it is not known if IPTc adds to the protection provided by an insecticide-treated net (ITN).
Methods and Findings
An individually randomised, double-blind, placebo-controlled trial of seasonal IPTc was conducted in Burkina Faso in children aged 3 to 59 months who were provided with a long-lasting insecticide-treated bednet (LLIN). Three rounds of treatment with sulphadoxine pyrimethamine plus amodiaquine or placebos were given at monthly intervals during the malaria transmission season. Passive surveillance for malaria episodes was established, a cross-sectional survey was conducted at the end of the malaria transmission season, and use of ITNs was monitored during the intervention period. Incidence rates of malaria were compared using a Cox regression model and generalized linear models were fitted to examine the effect of IPTc on the prevalence of malaria infection, anaemia, and on anthropometric indicators. 3,052 children were screened and 3,014 were enrolled in the trial; 1,505 in the control arm and 1,509 in the intervention arm. Similar proportions of children in the two treatment arms were reported to sleep under an LLIN during the intervention period (93%). The incidence of malaria, defined as fever or history of fever with parasitaemia ≥5,000/µl, was 2.88 (95% confidence interval [CI] 2.70–3.06) per child during the intervention period in the control arm versus 0.87 (95% CI 0.78–0.97) in the intervention arm, a protective efficacy (PE) of 70% (95% CI 66%–74%) (p<0.001). There was a 69% (95% CI 6%–90%) reduction in incidence of severe malaria (p = 0.04) and a 46% (95% CI 7%–69%) (p = 0.03) reduction in the incidence of all-cause hospital admissions. IPTc reduced the prevalence of malaria infection at the end of the malaria transmission season by 73% (95% CI 68%–77%) (p<0.001) and that of moderately severe anaemia by 56% (95% CI 36%–70%) (p<0.001). IPTc reduced the risks of wasting (risk ratio [RR] = 0.79; 95% CI 0.65–1.00) (p = 0.05) and of being underweight (RR = 0.84; 95% CI 0.72–0.99) (p = 0.03). Children who received IPTc were 2.8 (95% CI 2.3–3.5) (p<0.001) times more likely to vomit than children who received placebo but no drug-related serious adverse event was recorded.
Conclusions
IPT of malaria provides substantial protection against malaria in children who sleep under an ITN. There is now strong evidence to support the integration of IPTc into malaria control strategies in areas of seasonal malaria transmission.
Trial Registration
ClinicalTrials.gov NCT00738946
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria accounts for one in five of all childhood deaths in Africa and of the one million annual malarial deaths world-wide, over 75% occur in African children under 5 years old. Malaria also causes severe morbidity in children, such as anemia, low birth weight, and neurological problems, which compromise the health and development of millions of children living in malaria endemic areas. As much of the impact of malaria on African children can be effectively prevented, significant efforts have been made in recent years to improve malaria control, such as the implementation of intermittent preventive treatment of malaria.
Intermittent preventive treatment (IPT) involves administration of antimalarial drugs at defined time intervals to individuals, regardless of whether they are known to be infected with malaria, to prevent morbidity and mortality. IPT was initially recommended for pregnant women and recently this strategy was extended to include infants (IPTi). Now, there is also IPT of malaria in children (IPTc), which is designed to protect against malaria during the high malaria transmission season.
Why Was This Study Done?
Large clinical trials have shown that IPTc involving the administration of two to three doses of an antimalarial drug (sulphadoxine pyrimethamine [SP] and artesunate [AS] or amodiaquine [AQ]) during the high malaria transmission season effectively reduces the incidence of malaria. However, these studies were conducted in countries where the use of insecticide-treated bednets—an intervention that provides at least 50% protection against morbidity from malaria and is the main tool used for malaria control in most of sub-Saharan Africa—was relatively low. Therefore, it is unclear whether IPTc will be as effective in children who sleep under insecticide-treated bednets as has been previously shown in communities where insecticide-treated bednet usage is low. So to determine the answer to this important question, the researchers conducted a randomized, placebo-controlled trial of IPTc with SP + AQ (chosen because of the effectiveness of this combination in a pilot study) in children who slept under an insecticide-treated bednet in an area of seasonal malaria transmission in Burkina Faso.
What Did the Researchers Do and Find?
The researchers enrolled 3,014 eligible children aged 3–59 months into a randomized double-blind, placebo-controlled trial during the 2008 malaria transmission season in Burkina Faso. All children were given a long-lasting insecticide-treated bednet at the start of the study with instructions to their family on the correct use of the net. Children were then randomized into two arms—1,509 were allocated to the intervention group and 1,505 to the control group—to receive three courses of IPTc with SP plus AQ or placebos given at monthly intervals during the peak malaria transmission season. The researchers monitored the incidence of malaria throughout the malaria season and also monitored the use of long-lasting insecticide-treated bednets throughout the study period. In addition, researchers conducted a cross-sectional survey in 150 randomly selected children every week and in every child enrolled in the trial 6 weeks after the last course of IPTc, to measure their temperature, height and weight, and blood hemoglobin and parasite count levels.
The number of children who slept under their long-lasting insecticide-treated bednet was similar in both arms. During the intervention period, the researchers found that the incidence of clinical malaria (defined as fever or a history of fever and the presence of at least 5,000 asexual forms of P. falciparum per microliter) was 2.88 in the control arm versus 0.87 in the intervention arm—giving a protective efficacy of 70%. There were 13 cases of severe malaria in the control arm and four in the IPTc arm—a 69% reduction in incidence. Additionally, all-cause hospital admission rate was reduced by 46%. At the end of the malaria transmission period, IPTc reduced the proportion of children infected with malaria parasites by 73% and reduced anemia by 33%. In addition, IPTc appeared to reduce the risk of wasting (risk ratio  = 0.79) and of being underweight (risk ratio  = 0.84). However, children who received IPTc were almost three times more likely to vomit than children who received placebo but there were no drug-related serious adverse events.
What Do These Findings Mean?
The results of this study show that in peak malarial transmission season in Burkina Faso, IPTc provides substantial additional protection against episodes of clinical malaria, severe malaria, and all-cause hospital admissions in children sleeping under long-lasting insecticide-treated bednets. In addition, intermittent preventive treatment of malaria with SP plus AQ appears to be safe for use in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000408.
This topic is further discussed in two PLoS Medicine research articles: Dicko et al. and Bojang et al., and in a PLoS Medicine Perspective by Beeson
Roll Back Malaria has information about malaria in children, including intervention strategies
UNICEF also provides comprehensive information about malaria in children
The Intermittent Preventive Treatment in Infants Consortium (ipti) provides information on intermittent preventive treatment in infants
Roll Back Malaria has an information sheet on insecticide-treated bednets
doi:10.1371/journal.pmed.1000408
PMCID: PMC3032552  PMID: 21304925
23.  Sleep estimates in children: parental versus actigraphic assessments 
Nature and Science of Sleep  2011;3:115-123.
Background
In the context of increasing awareness about the need for assessment of sleep duration in community and clinical settings, the use of questionnaire-based tools may be fraught with reporter bias. Conversely, actigraphy provides objective assessments of sleep patterns. In this study, we aimed to determine the potential discrepancies between parentally-based sleep logs and concurrent actigraphic recordings in children over a one-week period.
Methods
We studied 327 children aged 3–10 years, and included otherwise healthy, nonsnoring children from the community who were reported by their parents to be nonsnorers and had normal polysomnography, habitually-snoring children from the community who completed the same protocol, and children with primary insomnia referred to the sleep clinic for evaluation in the absence of any known psychiatric illness. Actigraphy and parental sleep log were concomitantly recorded during one week.
Results
Sleep logs displayed an average error in sleep onset after bedtime of about 30 minutes (P < 0.01) and of a few minutes before risetime in all groups. Furthermore, subjective parental reports were associated with an overestimated misperception of increased sleep duration of roughly one hour per night independent of group (P < 0.001).
Conclusion
The description of a child’s sleep by the parent appears appropriate as far as symptoms are concerned, but does not result in a correct estimate of sleep onset or duration. We advocate combined parental and actigraphic assessments in the evaluation of sleep complaints, particularly to rule out misperceptions and potentially to aid treatment. Actigraphy provides a more reliable tool than parental reports for assessing sleep in healthy children and in children with sleep problems.
doi:10.2147/NSS.S25676
PMCID: PMC3630966  PMID: 23616722
actigraphy; insomnia; sleep logs; snoring; sleep duration
24.  Controlled trial of trimeprazine tartrate for night waking. 
Archives of Disease in Childhood  1987;62(3):253-257.
Mild hypnotics are often recommended for young children with sleep problems. This study assesses the efficacy of trimeprazine tartrate in 1 to 3 year old children with persistent and severe night waking in a double blind crossover trial with placebo. Children on treatment with trimeprazine had significantly fewer wakings, less time awake at night, and more night time sleep compared with those on treatment with placebo. There were no differences in these sleep variables when the first and last (fourth) week of treatment with drugs were compared. Follow up observations showed no significant difference in any sleep variables from baseline measures. The results are consistent with the idea that trimeprazine tartrate may be a useful short term treatment for night waking in young children.
PMCID: PMC1778326  PMID: 3551850
25.  Clinical and cost effectiveness of booklet based vestibular rehabilitation for chronic dizziness in primary care: single blind, parallel group, pragmatic, randomised controlled trial 
Objective To determine the clinical and cost effectiveness of booklet based vestibular rehabilitation with and without telephone support for chronic dizziness, compared with routine care.
Design Single blind, parallel group, pragmatic, randomised controlled trial.
Setting 35 general practices across southern England between October 2008 and January 2011.
Participants Patients aged 18 years or over with chronic dizziness (mean duration >five years) not attributable to non-vestibular causes (confirmed by general practitioner) and that could be aggravated by head movement (confirmed by patient).
Interventions Participants randomly allocated to receive routine medical care, booklet based vestibular rehabilitation only, or booklet based vestibular rehabilitation with telephone support. For the booklet approach, participants received self management booklets providing comprehensive advice on undertaking vestibular rehabilitation exercises at home daily for up to 12 weeks and using cognitive behavioural techniques to promote positive beliefs and treatment adherence. Participants receiving telephone support were offered up to three brief sessions of structured support from a vestibular therapist.
Main outcome measures Vertigo symptom scale-short form and total healthcare costs related to dizziness per quality adjusted life year (QALY).
Results Of 337 randomised participants, 276 (82%) completed all clinical measures at the primary endpoint, 12 weeks, and 263 (78%) at one year follow-up. We analysed clinical effectiveness by intention to treat, using analysis of covariance to compare groups after intervention, controlling for baseline symptom scores. At 12 weeks, scores on the vertigo symptom scale in the telephone support group did not differ significantly from those in the routine care group (adjusted mean difference −1.79 (95% confidence interval −3.69 tο 0.11), P=0.064). At one year, both intervention groups improved significantly relative to routine care (telephone support −2.52 (−4.52 to −0.51), P=0.014; booklet only −2.43 (−4.27 to −0.60), P=0.010). Analysis of cost effectiveness acceptability curves showed that both interventions were highly cost effective; at very low QALY values, the booklet only approach was most likely to be cost effective, but the approach with additional telephone support was most likely to be cost effective at QALY values more than £1200 (€1488; $1932). Using the booklet approach with telephone support, five (three to 12) patients would need to be treated for one patient to report subjective improvement at one year.
Conclusions Booklet based vestibular rehabilitation for chronic dizziness is a simple and cost effective means of improving patient reported outcomes in primary care.
Trial registration ClinicalTrials.gov NCT00732797.
doi:10.1136/bmj.e2237
PMCID: PMC3368486  PMID: 22674920

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