Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Injury prevention: An evidence-based public health approach

Unintentional injury is the leading cause of death and disability in Americans aged 1 to 44 years. For decades, trauma has been viewed as an accidental occurrence resulting largely from chance. In recent years, experts in trauma surgery and injury prevention have changed that paradigm, viewing trauma as a disease with modifiable and nonmodifiable risk factors. Using a public health approach, we can investigate the root causes of injury and study them in a scientific manner to reduce the morbidity and mortality associated with this disease process. In this chapter, we discuss the history of injury prevention, evidence-based public health approaches, and specific evidence-based programs available for common mechanisms of injury

Fever: suppress or let it ride?

While our ability to detect and manage fever has evolved since its conceptualization in the 5(th) century BC, controversy remains over the best evidence-based practices regarding if and when to treat this physiologic derangement in the critically ill. There are two basic fields of thought: (I) fever should be suppressed because its metabolic costs outweigh its potential physiologic benefit in an already stressed host; vs. (II) fever is a protective adaptive response that should be allowed to run its course under most circumstances. The latter approach, sometime referred to as the "let it ride" philosophy, has been supported by several recent randomized controlled trials like that of Young et al. [2015], which are challenging earlier observational studies and may be pushing the pendulum away from the Pavlovian treatment response

An overview of war-related thermal injuries

Thermal injuries have always been a source of morbidity and mortality in times of war. Historically, they constitute 5% to 20% of all injuries and approximately 4% mortality. Although burn patients constitute a small number of casualties, they consume a disproportionate amount of resources and require specialized care. The current conflicts in the Middle East report similar numbers for thermal injuries despite improvement in predeployment education to reduce noncombat-related burns, flame retardant military clothing, and decline of war patterns usually associated with increased thermal injuries. However, the increased use of improvised explosive devices and vehicle-borne improvised explosive devices presents a new source of potential thermal injury. Indeed, the burden of explosion-related burns has increased as has its associated Injury Severity Score. As has been the case in previous conflicts, most burns are hand and head burns. Although usually not life threatening, burns to hands and face lead to significant physical and psychologic morbidities. In this paper, we will review the currently available literature on war-related thermal injuries in Operation Iraqi and Operation Enduring Freedom. We will describe the epidemiology of burn injuries, prewar preparation to prevent and treat thermal injuries, and the assessment, triage, and final treatment of burn patients. In addition, we will discuss the associated physical and psychologic morbidities and, finally, the role of plastic surgeon in burn rehabilitation and reconstruction

Geriatric Trauma

Geriatric trauma is becoming an increasingly important facet of trauma care. There is insufficient evidence to make any conclusions on the optimal triage guidelines for the geriatric trauma patient. There is a preponderance of evidence to suggest that elderly trauma patients have a higher level of injury-related mortality than their younger counterparts. Geriatric trauma patients are more likely to present in shock than younger patients matched for trauma and injury severity score. The only randomized trial of resuscitation in geriatric trauma patients was in hip fracture patients. Lactate levels provide better insight into the perfusion status of geriatric trauma patients. Geriatric trauma remains a significant cause of morbidity and mortality. In addition, geriatric trauma patients may present atypically and a heightened level of suspicion, starting with appropriate triage to a trauma center and continuing throughout the spectrum of care, is the only way to reduce the risk of poor outcomes

Pediatric fluid resuscitation after thermal injury

Fluid resuscitation after thermal injury in a child or infant can pose a set of unique and significant challenges. Many approaches to fluid resuscitation of children after burns exist, and most are nonevidence based. This review will highlight the important concepts involved in pediatric fluid resuscitation from thermal injury