Hepatocyte tissue factor activates the coagulation cascade in mice.

In this study, we characterized tissue factor (TF) expression in mouse hepatocytes (HPCs) and evaluated its role in mouse models of HPC transplantation and acetaminophen (APAP) overdose. TF expression was significantly reduced in isolated HPCs and liver homogenates from TF(flox/flox)/albumin-Cre mice (HPC(ΔTF) mice) compared with TF(flox/flox) mice (control mice). Isolated mouse HPCs expressed low levels of TF that clotted factor VII-deficient human plasma. In addition, HPC TF initiated factor Xa generation without exogenous factor VIIa, and TF activity was increased dramatically after cell lysis. Treatment of HPCs with an inhibitory TF antibody or a cell-impermeable lysine-conjugating reagent prior to lysis substantially reduced TF activity, suggesting that TF was mainly present on the cell surface. Thrombin generation was dramatically reduced in APAP-treated HPC(ΔTF) mice compared with APAP-treated control mice. In addition, thrombin generation was dependent on donor HPC TF expression in a model of HPC transplantation. These results suggest that mouse HPCs constitutively express cell surface TF that mediates activation of coagulation during hepatocellular injury.

Perceptions of injury and prevention practices among pregnant and parenting teenagers.

Injury is a leading cause of death for young children, and the children of teenaged parents may be at increased risk. This qualitative study explored pregnant and parenting teenagers' child safety beliefs and practices related to 4 topics: preventing accidental suffocation via safe sleeping practices, motor vehicle collision safety, prevention of inflicted head trauma, and drowning prevention. Twenty-four focus groups were held with 93 pregnant and/or parenting teenagers. Participants reported variation in their sleeping arrangements, transportation methods, caregivers, and childcare settings. Confusion over safety information was common. Child safety practices were influenced by boyfriends/husbands, parents, grandparents, and teachers.

Sleep behaviors of infants and young children: associated demographic and acculturation characteristics among Hispanic teen mothers.

Accidental suffocation and strangulation in bed is a leading cause of preventable infant death. Bed sharing, teen motherhood, and Hispanic ethnicity have been associated with infant sleep suffocation death. Fifty-five Hispanic teen mothers were surveyed regarding acculturation/demographic characteristics and their infants' sleep behaviors. Most participants had 2 foreign-born parents from Latin America. Participants with 2 US-born parents were less likely to bed share than their less-acculturated peers. Many participants reported not always placing their infant in a supine sleep position. There is a significant need to reach out to Hispanic teen mothers, particularly from newer immigrant families, with culturally and linguistically appropriate multigenerational clinical messaging on the risks of infant bed sharing and nonsupine sleep positioning.

Time to drink: Activating lateral hypothalamic area neurotensin neurons promotes intake of fluid over food in a time-dependent manner.

The lateral hypothalamic area (LHA) is essential for ingestive behavior but has primarily been studied in modulating feeding, with comparatively scant attention on drinking. This is partly because most LHA neurons simultaneously promote feeding and drinking, suggesting that ingestive behaviors track together. A notable exception are LHA neurons expressing neurotensin (LHANts neurons): activating these neurons promotes water intake but modestly restrains feeding. Here we investigated the connectivity of LHANts neurons, their necessity and sufficiency for drinking and feeding, and how timing and resource availability influence their modulation of these behaviors. LHANts neurons project broadly throughout the brain, including to the lateral preoptic area (LPO), a brain region implicated in modulating drinking behavior. LHANts neurons also receive inputs from brain regions implicated in sensing hydration and energy status. While activation of LHANts neurons is not required to maintain homeostatic water or food intake, it selectively promotes drinking during the light cycle, when ingestive drive is low. Activating LHANts neurons during this period also increases willingness to work for water or palatable fluids, regardless of their caloric content. By contrast, LHANts neuronal activation during the dark cycle does not promote drinking, but suppresses feeding during this time. Finally, we demonstrate that the activation of the LHANts â†’ LPO projection is sufficient to mediate drinking behavior, but does not suppress feeding as observed after generally activating all LHANts neurons. Overall, our work suggests how and when LHANts neurons oppositely modulate ingestive behaviors.

Molecular typing of HLA genes using whole genome amplified DNA.

BACKGROUND: The outcome of clinical transplantation and a number of disease susceptibilities show very strong associations with genetic variants within the major histocompatibility complex, particularly in the human leukocyte antigen (HLA) genes. A problem with many association studies is the lack of sufficient DNA to perform multiple genetic analyses, particularly with transplantation outcomes where donor and recipient DNA are often in short supply. This study assesses whether a multiple-strand displacement whole genome amplification (WGA) method could generate sufficient template of high quality to perform unbiased amplification for analysis of the HLA-A, -B, -C, -DRB1, and -DQB1 genes. STUDY DESIGN AND METHODS: A panel of DNA samples from various biological sources was subjected to WGA reaction using Phi29 DNA polymerase. The HLA genotypes were subsequently determined using standard polymerase chain reaction (PCR)-based methods including sequence-specific oligonucleotide probes (PCR-SSOP, Luminex, Luminex Corp.) and sequence-based typing (PCR-SBT). WGA products and original DNA samples were used to determine the sensitivity of the Luminex assay; in addition, reamplified WGA products were also genotyped. RESULTS: The WGA templates, as well as serially amplified DNA for two successive rounds, yielded HLA genotypes fully concordant with those determined for the original DNA samples. WGA products and original DNA gave reproducible HLA-DQB1 genotypes with 100 to 10 ng of template. Purification of the WGA products was required for successful PCR-SBT, but not for the PCR-SSOP method. CONCLUSION: Our study suggests that WGA can be a reliable method for generating unlimited DNA for medium- or high-resolution HLA typing using the techniques described above.

Screening for risky alcohol use among caregivers of pediatric trauma patients: a pilot study.

BACKGROUND: Injury is the leading cause of death for children and has been linked to caregiver drinking. Screening and brief intervention for risky drinking has been successful in adult trauma centers but has not been evaluated in caregivers of pediatric trauma patients. The purpose of this study was to investigate a pilot screening process for risky drinking caregivers, to determine rates of risky alcohol use, and to assess potential relationships between risky drinking and child safety behaviors. METHODS: Caregivers of pediatric trauma patients were screened by trained injury prevention educators. The screening assessed risky drinking, tobacco and illicit drug use, and child safety behaviors. Data were analyzed using descriptive analysis, frequency comparisons, and univariate logistic regression. RESULTS: Over 7 months, 295 caregivers were screened; 32.5% (n = 96) screened positive for risky alcohol use. For 173 injured children, one caregiver was screened, and for 61 children, two caregivers were screened. In the one-caregiver group, 29% (n = 50) screened positive for risky drinking. For the two-caregiver group, in 18% (n = 11) of the cases, both caregivers screened positive, whereas in 39% (n = 24) only one caregiver screened positive. Males were more likely to screen positive (p < 0.01). Relationships between reported child safety behaviors and risky drinking were of interest, but not statistically significant. CONCLUSIONS: The results of our study demonstrate that a substantial number of caregivers of pediatric trauma patients will self-report risky drinking behaviors, and therefore, an opportunity exists for these families to receive the benefits of screening and brief intervention programs in pediatric trauma care settings.

Distinct Subsets of Lateral Hypothalamic Neurotensin Neurons are Activated by Leptin or Dehydration.

The lateral hypothalamic area (LHA) is essential for ingestive behavior but it remains unclear how LHA neurons coordinate feeding vs. drinking. Most LHA populations promote food and water consumption but LHA neurotensin (Nts) neurons preferentially induce water intake while suppressing feeding. We identified two molecularly and projection-specified subpopulations of LHA Nts neurons that are positioned to coordinate either feeding or drinking. One subpopulation co-expresses the long form of the leptin receptor (LepRb) and is activated by the anorectic hormone leptin (NtsLepRb neurons). A separate subpopulation lacks LepRb and is activated by dehydration (NtsDehy neurons). These molecularly distinct LHA Nts subpopulations also differ in connectivity: NtsLepRb neurons project to the ventral tegmental area and substantia nigra compacta but NtsDehy neurons do not. Intriguingly, the LHA Nts subpopulations cannot be discriminated via their classical neurotransmitter content, as we found that all LHA Nts neurons are GABAergic. Collectively, our data identify two molecularly- and projection-specified subpopulations of LHA Nts neurons that intercept either leptin or dehydration cues, and which conceivably could regulate feeding vs. drinking behavior. Selective regulation of these LHA Nts subpopulations might be useful to specialize treatment for ingestive disorders such as polydipsia or obesity.

Mapping the populations of neurotensin neurons in the male mouse brain.

Neurotensin (Nts) is a neuropeptide implicated in the regulation of many facets of physiology, including cardiovascular tone, pain processing, ingestive behaviors, locomotor drive, sleep, addiction and social behaviors. Yet, there is incomplete understanding about how the various populations of Nts neurons distributed throughout the brain mediate such physiology. This knowledge gap largely stemmed from the inability to simultaneously identify Nts cell bodies and manipulate them in vivo. One means of overcoming this obstacle is to study NtsCre mice crossed onto a Cre-inducible green fluorescent reporter line (NtsCre;GFP mice), as these mice permit both visualization and in vivo modulation of specific populations of Nts neurons (using Cre-inducible viral and genetic tools) to reveal their function. Here we provide a comprehensive characterization of the distribution and relative densities of the Nts-GFP populations observed throughout the male NtsCre;GFP mouse brain, which will pave the way for future work to define their physiologic roles. We also compared the distribution of Nts-GFP neurons with Nts-In situ Hybridization (Nts-ISH) data from the adult mouse brain. By comparing these data sets we can distinguish Nts-GFP populations that may only transiently express Nts during development but not in the mature brain, and hence which populations may not be amenable to Cre-mediated manipulation in adult NtsCre;GFP mice. This atlas of Nts-GFP neurons will facilitate future studies using the NtsCre;GFP line to describe the physiological functions of individual Nts populations and how modulating them may be useful to treat disease.

Lateral Hypothalamic Area Neurotensin Neurons Are Required for Control of Orexin Neurons and Energy Balance.

The lateral hypothalamic area (LHA) is essential for motivated ingestive and locomotor behaviors that impact body weight, yet it remains unclear how the neurochemically defined subpopulations of LHA neurons contribute to energy balance. In particular, the role of the large population of LHA neurotensin (Nts) neurons has remained ambiguous due to the lack of methods to easily visualize and modulate these neurons. Because LHA Nts neurons are activated by leptin and other anorectic cues and they modulate dopamine or local LHA orexin neurons implicated in energy balance, they may have important, unappreciated roles for coordinating behaviors necessary for proper body weight. In this study, we genetically ablated or chemogenetically inhibited LHA Nts neurons in adult mice to determine their necessity for control of motivated behaviors and body weight. Genetic ablation of LHA Nts neurons resulted in profoundly increased adiposity compared with mice with intact LHA Nts neurons, as well as diminished locomotor activity, energy expenditure, and water intake. Complete loss of LHA Nts neurons also led to downregulation of orexin, revealing important cross-talk between the LHA Nts and orexin populations in maintenance of behavior and body weight. In contrast, chemogenetic inhibition of intact LHA Nts neurons did not disrupt orexin expression, but it suppressed locomotor activity and the adaptive response to leptin. Taken together, these data reveal the necessity of LHA Nts neurons and their activation for controlling energy balance, and that LHA Nts neurons influence behavior and body weight via orexin-dependent and orexin-independent mechanisms.

Better care: reducing length of stay and bed occupancy on an older adult psychiatric ward.

BACKGROUND: Length of stay and bed occupancy are important indicators of quality of care. Admissions are longer on older adult psychiatric wards as a result of physical comorbidity and complex care needs. The recommended bed occupancy is 85%; levels of 95% or higher are associated with violent incidents on inpatient wards. METHODS: We aimed to reduce length of stay and bed occupancy on Leadenhall ward, a functional older adult psychiatric ward serving a population of just under 40 000 older adults in two of the most deprived areas of the UK.At baseline in October 2015, the average length of stay was 47 days, and bed occupancy was at 77%. We approached the problem using quality improvement methods, established a project team and proceeded to test a number of changes over time in line with the driver diagram we produced. RESULTS: In 12 months, length of stay was reduced from an average 47 to an average 30 days and bed occupancy from 77% to 54%.At the end of 2016, the closure of some beds effected this calculation and we added an additional outcome measure of occupied bed days (OBD) better to assess the impact of the work. OBD data show a decrease over the course of the project from 251 to 194 bed days (a reduction of 23%). CONCLUSION: The most effective interventions to address length of stay and bed occupancy on an older adult functional mental health ward were the daily management round and the high-level management focus on longer-stay patients. The work depended on an effective community team and on the support of the quality improvement programme in the trust, which have led to sustained improvements.

Determination of neurotensin projections to the ventral tegmental area in mice.

Pharmacologic treatment with the neuropeptide neurotensin (Nts) modifies motivated behaviors such as feeding, locomotor activity, and reproduction. Dopamine (DA) neurons of the ventral tegmental area (VTA) control these behaviors, and Nts directly modulates the activity of DA neurons via Nts receptor-1. While Nts sources to the VTA have been described in starlings and rats, the endogenous sources of Nts to the VTA of mice remain incompletely understood, impeding determination of which Nts circuits orchestrate specific behaviors in this model. To overcome this obstacle we injected the retrograde tracer Fluoro-Gold into the VTA of mice that express GFP in Nts neurons. Identification of GFP-Nts cells that accumulate Fluoro-Gold revealed the Nts afferents to the VTA in mice. Similar to rats, most Nts afferents to the VTA of mice arise from the medial and lateral preoptic areas (POA) and the lateral hypothalamic area (LHA), brain regions that are critical for coordination of feeding and reproduction. Additionally, the VTA receives dense input from Nts neurons in the nucleus accumbens shell (NAsh) of mice, and minor Nts projections from the amygdala and periaqueductal gray area. Collectively, our data reveal multiple populations of Nts neurons that provide direct afferents to the VTA and which may regulate specific aspects of motivated behavior. This work lays the foundation for understanding endogenous Nts actions in the VTA, and how circuit-specific Nts modulation may be useful to correct motivational and affective deficits in neuropsychiatric disease.

Self and identity over time: dementia.

Here, the author revisits the discussion on the impact of dementia on experiences of self and identity over time that formed part of the workshop session on Mental Disorder and Selfhood at Kings College London, September 1, 2015. Dementia is described as being synonymous with loss, but this, in the author's view, is due to conscious and unconscious focus on the later stages of the illness that undermine all our abilities to think about and use the intervening years. Those years can deliver remarkable insights into the capacity to navigate fragmented identities. They can also remind us vividly of the importance of a relational, interactive quality to identity and the degree to which aspects of our selves and identities reside and thrive in the minds of others.

Neurotensin Receptor-1 Identifies a Subset of Ventral Tegmental Dopamine Neurons that Coordinates Energy Balance.

Dopamine (DA) neurons in the ventral tegmental area (VTA) are heterogeneous and differentially regulate ingestive and locomotor behaviors that affect energy balance. Identification of which VTA DA neurons mediate behaviors that limit weight gain has been hindered, however, by the lack of molecular markers to distinguish VTA DA populations. Here, we identified a specific subset of VTA DA neurons that express neurotensin receptor-1 (NtsR1) and preferentially comprise mesolimbic, but not mesocortical, DA neurons. Genetically targeted ablation of VTA NtsR1 neurons uncouples motivated feeding and physical activity, biasing behavior toward energy expenditure and protecting mice from age-related and diet-induced weight gain. VTA NtsR1 neurons thus represent a molecularly defined subset of DA neurons that are essential for the coordination of energy balance. Modulation of VTA NtsR1 neurons may therefore be useful to promote behaviors that prevent the development of obesity.

The Handy Approach - Quick Integrated Person Centred Support Preparation.

Cost effective care requires comprehensive person-centred formulation of solutions. The East London NHS Foundation Trust Community Health Services in Newham have piloted models of Integrated Care called 'Virtual Wards' which aim to keep people living with multiple long-term conditions, well at home by minimising system complexity. These Virtual Wards comprise Interdisciplinary Teams (IDTs) with a General Practitioner (GP) seconded to provide leadership. Historically assessments have been dominated by biomedical approaches with disability emphasised over personal aspirations and ability. New professional skills are needed to organise information from diverse approaches into a common framework, which can enable agreed goals of care to be delivered collaboratively. From June 2014 to January 2016 we aimed to improve the documentation of person-centred goals of care in 100% of our assessments. Change ideas were tested and team development addressed to improve documentation of aspirations for care for people being referred and if achieved, then to test ideas to improve coproduction of care. Change ideas included Enhanced Clinical Supervision (ECS) by a GP with additional expert skills; Flash Teaching (FT) defined as five-minute weekly discussion on topics generated from the case-mix to develop a shared understanding of Integrated Care; Structured Formulation using a novel, quick, integrated assessment framework called the Handy Approach (HA) with the hand as a memory prompt to bring the personal together with the mental, social and physical domains and finally we tested focusing on 'Team Primacy' (mutual regard within the team) to embed behaviour change. 181 cases were tracked and documentation of personal aspirations for care by case showed: ECS 0/21 (0%); FT 5/50 (10%); ECS/FT plus the HA 35/83 (42%); Team Primacy plus ECS/FT/HA 27/27 (100%). By January 2016 prompted by using the Handy Approach in a highly functional team, all members of the IDT consistently documented personal aspirations.

Loss of Action via Neurotensin-Leptin Receptor Neurons Disrupts Leptin and Ghrelin-Mediated Control of Energy Balance.

The hormones ghrelin and leptin act via the lateral hypothalamic area (LHA) to modify energy balance, but the underlying neural mechanisms remain unclear. We investigated how leptin and ghrelin engage LHA neurons to modify energy balance behaviors and whether there is any crosstalk between leptin and ghrelin-responsive circuits. We demonstrate that ghrelin activates LHA neurons expressing hypocretin/orexin (OX) to increase food intake. Leptin mediates anorectic actions via separate neurons expressing the long form of the leptin receptor (LepRb), many of which coexpress the neuropeptide neurotensin (Nts); we refer to these as NtsLepRb neurons. Because NtsLepRb neurons inhibit OX neurons, we hypothesized that disruption of the NtsLepRb neuronal circuit would impair both NtsLepRb and OX neurons from responding to their respective hormonal cues, thus compromising adaptive energy balance. Indeed, mice with developmental deletion of LepRb specifically from NtsLepRb neurons exhibit blunted adaptive responses to leptin and ghrelin that discoordinate the mesolimbic dopamine system and ingestive and locomotor behaviors, leading to weight gain. Collectively, these data reveal a crucial role for LepRb in the proper formation of LHA circuits, and that NtsLepRb neurons are important neuronal hubs within the LHA for hormone-mediated control of ingestive and locomotor behaviors.

Low stimulus environments: reducing noise levels in continuing care.

In the low stimulus environment project, we aimed to reduce the levels of intrusive background noise on an older adult mental health ward, combining a very straightforward measure on decibel levels with a downstream measure of reduced distress and agitation as expressed in incidents of violence. This project on reducing background noise levels on older adult wards stemmed from work the team had done on reducing levels of violence and aggression. We approached the problem using quality improvement methods. Reducing harm to patients and staff is a strategic aim of our Trust and in our efforts we were supported by the Trust's extensive programme of quality improvement, including training and support provided by the Institute for Healthcare Improvement and the trust's own Quality Improvement team. Prior to the project we were running a weekly multi-disciplinary quality improvement group on the ward. We established from this a sub-group to address the specific problem of noise levels and invited carers of people with dementia on our ward to the group. The project was led by nursing staff. We used a noise meter app readily downloadable from the internet to monitor background noise levels on the ward and establish a baseline measure. As a group we used a driver diagram to identify an overall aim and a clear understanding of the major factors that would drive improvements. We also used a staff and carer survey to identify further areas to work on. Change ideas that came from staff and carers included the use of the noise meter to track and report back on noise levels, the use of posters to remind staff about noise levels, the introduction of a visual indication of current noise levels (the Yacker Tracker), the addition of relaxing background music, and adaptations to furniture and environment. We tested many of these over the course of nine months in 2015, using the iterative learning gained from multiple PDSA cycles. The specific aim was a decrease from above 60dB to below 50dB in background noise on the wards. Following our interventions, we have managed to decrease noise levels on the ward to 53dB on average. The success of this project to date has relied on the involvement of ward staff and carers - those most affected by the problem - in generating workable local solutions. As many of the change ideas amounted to harm free interventions it was easier for us to make a case to test them out in the real-life setting. Nevertheless we were surprised at how effective such seemingly simple ideas have been in improving the environment on the ward. We have incorporated the change ideas into routine practice and are advising other wards on similar projects.

To ingest or rest? Specialized roles of lateral hypothalamic area neurons in coordinating energy balance.

Survival depends on an organism's ability to sense nutrient status and accordingly regulate intake and energy expenditure behaviors. Uncoupling of energy sensing and behavior, however, underlies energy balance disorders such as anorexia or obesity. The hypothalamus regulates energy balance, and in particular the lateral hypothalamic area (LHA) is poised to coordinate peripheral cues of energy status and behaviors that impact weight, such as drinking, locomotor behavior, arousal/sleep and autonomic output. There are several populations of LHA neurons that are defined by their neuropeptide content and contribute to energy balance. LHA neurons that express the neuropeptides melanin-concentrating hormone (MCH) or orexins/hypocretins (OX) are best characterized and these neurons play important roles in regulating ingestion, arousal, locomotor behavior and autonomic function via distinct neuronal circuits. Recently, another population of LHA neurons containing the neuropeptide Neurotensin (Nts) has been implicated in coordinating anorectic stimuli and behavior to regulate hydration and energy balance. Understanding the specific roles of MCH, OX and Nts neurons in harmonizing energy sensing and behavior thus has the potential to inform pharmacological strategies to modify behaviors and treat energy balance disorders.

Perceptions of injury prevention and familial adjustment among mothers of teen parents.

INTRODUCTION: Injury is a leading cause of death for infants and children. Teen mothering has been shown to put children at increased risk of injury. The mothers of teen parents often play a predominant role in the lives and caregiving of the children born to their children. METHOD: This article presents the findings of three focus groups conducted with 21 mothers of teen parents. Grounded theory methodology was used to explore family dynamics and how they relate to injury prevention beliefs and practices regarding infants and children. RESULTS: Our findings revealed the difficulty mothers of teen parents and the teens themselves have in adjusting to the knowledge of the pregnancy. Unique barriers to injury prevention were also uncovered. CONCLUSIONS: Our findings provide evidence for the need of a multigenerational approach to programs aimed at improving the safety and well-being of children in this context.

Safer Wards: reducing violence on older people's mental health wards.

Through the Safer Wards project we aimed to reduce the number of incidents of physical violence on older people's mental health wards. This was done using quality improvement methods and supported by the Trust's extensive programme of quality improvement, including training provided by the Institute for Healthcare Improvement. Violence can be an indicator of unmet needs in this patient population, with a negative effect on patient care and staff morale. Reducing harm to patients and staff is a strategic aim of our Trust. We established a multi-disciplinary group who led on the project on each ward and used a Pareto diagram to establish the focus of our work. We established a dashboard of measures based on our incident reporting system Datix, including number of incidents of violence, days between incidents, days of staff sickness, days between staff injury, use of restraint, and use of rapid tranquilisation (the last two being balancing measures in the reduction of violence). Each team identified factors driving physical violence on the wards, under headings of unmet patient needs, staff needs and staff awareness, which included lack of activity and a safe and therapeutic environment. Using driver diagrams, we identified change ideas that included hourly rounding (proactive checks on patient well-being), the addition of sensory rooms, flexible leave for patients, and a structured activity programme. We also introduced exercise to music, therapeutic groups led by patients, and focused on discharge planning and pet therapy, each of which starting sequentially over the course of a one year period from late 2013 and subject to a cycle of iterative learning using PDSA methods. The specific aim was a 20% decrease in violent incidents on three wards in City and Hackney, and Newham. Following our interventions, days between violent incidents increased from an average of three to an average of six. Days between staff injury due to physical violence rose from an average of eight (one violent incident resulting in staff injury every eight days) to 22 (one incident every 22 days). Incidents of physical violence reduced from 63 in 2013 to 39 in 2014. We were also able to quantify reduced costs associated with reduction in violence. The success of this project in our view lay in the involvement of ward staff in understanding the problems and generating local solutions which were also broadly evidenced based. Patients were also closely involved in generating ideas. We are currently incorporating much of this work into routine practice in order to sustain improvement, as well as continuing to generate new ideas for further improvement while using the skills learnt in this process to address other problems.

Genetic susceptibility to endomyocardial fibrosis.

BACKGROUND: Endomyocardial fibrosis (EMF) is the most common form of restrictive cardiomyopathy worldwide. It has been linked to poverty and various environmental factors, but-for unknown reasons-only some people who live in similar conditions develop the disease. EMF cases cluster within both families and ethnic groups, suggesting a role for a genetic factor in host susceptibility. The human leukocyte antigen (HLA) system is associated with predisposition to various diseases. This two-center study was designed to investigate variation in the HLA system between EMF patients and unaffected controls. We provide the first genetic investigation of patients with EMF, as well as a comprehensive review of the literature. METHODS: HLA class I (HLA-A, -B, -C) and class II (DRB1, DQB1) types were determined in 71 patients with severe EMF and 137 controls from Uganda and Mozambique. Chi Square analysis was used to identify any significant difference in frequency of class I and class II HLA types between cases and controls. RESULTS: Compared to ethnically matched controls, HLA-B*58 occurred more frequently in Mozambique patients with EMF and HLA-A*02:02 occurred more frequently in Ugandan patients with EMF. CONCLUSIONS: Ample subjective evidence in the historical literature suggests the importance of a genetically susceptible host in EMF development. In this first formal genetic study, we found HLA alleles associated with cases of EMF in two populations from sub-Saharan Africa, with EMF patients being more likely than controls to have the HLA-B*58 allele in Mozambique (p-0.03) and the HLA-A*02:02 in Uganda (p = 0.005). Further investigations are needed to more fully understand the role of genetics in EMF development.