Purpose: Kaposiform lymphangiomatosis (KLA) is a rare, frequently aggressive, systemic disorder of the lymphatic vasculature, occurring primarily in children. Even with multimodal treatments, KLA has a poor prognosis and high mortality rate secondary to coagulopathy, effusions and systemic involvement. We hypothesized that, as has recently been found for other vascular anomalies, KLA may be caused by somatic mosaic variants affecting vascular development. Methods: We performed exome sequencing of tumor samples from five individuals with KLA, along with samples from uninvolved control tissue in three of the five. We used digital PCR (dPCR) to validate the exome findings and to screen KLA samples from six other individuals. Results: We identified a somatic activating NRAS variant (c.182A>G, p.Q61R) in lesional tissue from 10/11 individuals, at levels ranging from 1–28%, that was absent from the tested control tissues. Conclusion: The activating NRAS p.Q61R variant is a known ‘hotspot’ variant, frequently identified in several types of human cancer, especially melanoma. KLA, therefore, joins a growing group of vascular malformations and tumors caused by somatic activating variants in the RAS/PI3K/mTOR signalling pathways. This discovery will expand treatment options for these high risk patients as there is potential for use of targeted RAS pathway inhibitors.

BackgroundRapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients.MethodsWe sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons.ResultsThe analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations.ConclusionsClinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0314-x) contains supplementary material, which is available to authorized users.

BackgroundConflict in healthcare is a well-recognised but under-examined phenomenon. Little is known about the prevalence and causes of conflict across paediatric specialties.ObjectiveTo report the frequency and characteristics of conflict in a paediatric hospital.Design and settingAn explanatory sequential mixed-method approach was adopted. A bespoke questionnaire recorded frequency, severity, cause and staff involved in conflict prospectively. Data were recorded for the same two 12-week periods in 2013 and 2014, in one UK children's teaching hospital. Data were analysed using descriptive statistics and correlation, the findings of which informed the construction of a semistructured interview schedule. Qualitative interviews were conducted with six key informant healthcare professionals to aid data interpretation; interviews were analysed thematically.Results136 individual episodes of conflict were reported. The three most common causes were ‘communication breakdown’, ‘disagreements about treatment’ and ‘unrealistic expectations’. Over 448 h of healthcare professional time was taken up by these conflicts; most often staff nurses, consultants, doctors in training and matrons. The mean severity rating was 4.9 out of 10. Qualitative interviews revealed consensus regarding whether conflicts were ranked as low, medium or high severity, and explanations regarding why neurology recorded the highest number of conflicts in the observed period.ConclusionsConflict is prevalent across paediatric specialties, and particularly in neurology, general paediatrics and neonatology. Considerable staff time is taken in managing conflict, indicating a need to focus resources on supporting staff to resolve conflict, notably managing communication breakdown.

Introduction: Indigenous Peoples who have been colonized face a higher burden of harm from alcohol and increased risk of alcohol use disorders. Yet they often also have limited access to alcohol treatment. Limited access to withdrawal management ("detox" in particular) can be a barrier to recovery. Ambulatory or "outpatient" alcohol detox can offer improved treatment access, but no research has examined its feasibility and acceptability in Indigenous populations. Aim: To develop a model for outpatient detox delivered by an Australian Aboriginal community controlled health service (ACCHS), and to describe its feasibility and acceptability. Methods: This report describes a framework for alcohol treatment service development within an ACCHS through community, staff, and client consultation. Thematic analysis of focus groups and phone interviews were used to gain insight into the views and experiences of Aboriginal community stakeholders, service clients, and staff regarding alcohol detox services and the pilot of the outpatient detox program service model. Results: Individual, family, and community support was regarded as key to recovery from alcohol dependence. Outpatient detox was seen as a way of keeping the individual near this support. Reported positive aspects include satisfaction with the approach to care that was considered accessible, holistic, and integrated. Challenges and suggested improvements were identified. Discussion: Outpatient detox within an ACCHS was assessed as feasible and acceptable for carefully selected clients and was reported to aid access to treatment. More clinical experience is needed to fully delineate effectiveness and safety.

ObjectiveTo explore clinician and family experiences of conflict in paediatric services, in order to map the trajectory of conflict escalation.DesignQualitative interview study, employing extreme-case sampling. Interviews were analysed using an iterative thematic approach to identify common themes regarding the experience and escalation of conflict.ParticipantsThirty-eight health professionals and eight parents. All participants had direct experience of conflict, including physical assault and court proceedings, at the interface of acute and palliative care.SettingTwo teaching hospitals, one district general hospital and two paediatric hospices in England, in 2011.ResultsConflicts escalate in a predictable manner. Clearly identifiable behaviours by both clinicians and parents are defined as mild, moderate and severe. Mild describes features like the insensitive use of language and a history of unresolved conflict. Moderate involves a deterioration of trust, and a breakdown of communication and relationships. Severe marks disintegration of working relationships, characterised by behavioural changes including aggression, and a shift in focus from the child's best interests to the conflict itself. Though conflicts may remain at one level, those which escalated tended to move sequentially from one level to the next.ConclusionsUnderstanding how conflicts escalate provides clinicians with a practical, evidence-based framework to identify the warning signs of conflict in paediatrics.

The CMF substantially reduces the incidence of conflicts and is an acceptable approach for staff. Continued use of the framework would require it to be fully integrated into the working of the ward, which would need to include senior medical buy-in. Further refinements to the framework have been made and will be tested in four UK sites in 2018/2019.

Developmental topographical disorientation (DTD) is a newly discovered cognitive disorder in which individuals experience a lifelong history of getting lost in both novel and familiar surroundings. Recent studies have shown that such a selective orientation defect relies primarily on the inability of the individuals to form cognitive maps, i.e., mental representations of the surrounding that allow individuals to get anywhere from any location in the environment, although other orientation skills are additionally affected. To date, the neural correlates of this developmental condition are unknown. Here, we tested the hypothesis that DTD may be related to ineffective functional connectivity between the hippocampus (HC; known to be critical for cognitive maps) and other brain regions critical for spatial orientation. A group of individuals with DTD and a group of control subjects underwent a resting-state functional magnetic resonance imaging (rsfMRI) scan. In addition, we performed voxel-based morphometry to investigate potential structural differences between individuals with DTD and controls. The results of the rsfMRI study revealed a decreased functional connectivity between the right HC and the prefrontal cortex (PFC) in individuals with DTD. No structural differences were detected between groups. These findings provide evidence that ineffective functional connectivity between HC and PFC may affect the monitoring and processing of spatial information while moving within an environment, resulting in the lifelong selective inability of individuals with DTD to form cognitive maps that are critical for orienting in both familiar and unfamiliar surroundings.

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