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OBJECTIVES/GOALS: Mammals require iron for hemoglobin, respiration, immunity and as cofactor in enzymes. But free iron is toxic from the production of reactive oxygen species. Ferroportin is the sole exporter of cellular iron and it crucially determines cellular and systemic iron levels. Labile iron must be tightly regulated. This requires structural understanding. METHODS/STUDY POPULATION: We built structure of human ferroportin (FPN1) using the ab ignition prediction approaches of Rosetta/Robetta and by comparative modeling with distance restraints in MODELLER. Templates selected were from solute carrier protein families of distantly related orthologs and homologs including a proton coupled peptide transporter (PDB ID: 4IKV) and the bacterial iron transporter in outward-open and inward-open states, (PDB ID: 5AYM, 5AYO). Each model was validated by experimental mass spectrometry data. The energy minimized structural model was inserted into a lipid bilayer, placed in a rectangular simulation box, covered with TIP3P water solvent balanced with counterions and conditioned. Finally, we carried out 350 nanoseconds molecular dynamics simulations. RESULTS/ANTICIPATED RESULTS: Our first model of FPN1 (571aa), using Rosetta/Robetta ab initio approach, resembles the structure of the proton-dependent transporter, POT and consists of 12 transmembrane helices. The membrane spanning helices veer away from the orientation in the structure of 4IKV. The alternate model using MODELLER and the method of satisfaction of constraints, returned one template, the structure of Bdellovibrio bacteriovorus iron (Fe2+) transporter homolog (5AYN, 440aa) with sequence identity of 19%. Aligning FPN1 on the template sequence incorporating structural information revealed better conservation (29%). This model also comprises 12 transmembrane helices in two bundles separated by a large intracellular loop. The iron binding site predicted in both models match the structures of distant bacterial homologs. DISCUSSION/SIGNIFICANCE OF IMPACT: We are using these experimentally verified structures and functional data to answer questions about the mechanism of ferroportin iron transport, structural dynamics and the significance of mutations in ferroportin seen in different populations, especially the Q248H mutation found in Africans and black Americans with moderate to high prevalence.
Patients diagnosed with schizophrenia or bipolar disorder are at an elevated risk of suicide attempts and suicidal ideation. Although atypical antipsychotics are effective in treating psychotic symptoms, the risk of suicide attempts and suicidal ideation may differ across these agents. We conducted an analysis on reported rates of suicide-related events associated with the use of atypicals.
Proportional reporting rates (PRR) of suicide attempts from the World Health Organization (WHO) database (through June, 2006) were compared across atypical antipsychotics. Using additional information from FDA's AERS (Adverse Event Reporting System; through March, 2006), similar comparisons were made for suicidal ideation, suicide attempts, and completed suicides.
From the WHO database, the PRR for suicide attempts was lowest for clozapine (1.3) followed by aripiprazole (1.5), risperidone (3.3), quetiapine (4.2), ziprasidone (4.7), and olanzapine (5.2). For AERS, the respective PRRs for suicidal ideation, suicide attempts, and completed suicides were: 1.1, 3.3, and 1.9 for clozapine; 3.2, 4.3, and 2.7 for risperidone; 5.6, 2.9, and 5.4 for aripiprazole; 6.9, 4.4, and 6.4 for ziprasidone; 4.3, 4.5, and 7.2 for olanzapine; and 5.6, 4.2, and 9.3 for quetiapine.
AE reporting systems suffer limitations, which include having a problematic denominator and biased reporting. However, AE reporting is a primary tool used to identify a signal through pharmacovigilance. In the data analyzed, variability across atypical antipsychotics seemed evident, and inconsistencies between data were observed. The reasons for these findings are unclear, but these results warrant further investigation in controlled studies.
Against a backdrop of poor mental health education in UK schools a group of students from Norwich Medical School have formed a student society called ‘Headucate’ in order to create, deliver and evaluate an educational intervention for adolescents, initially to be delivered in Norfolk schools.
To create an educational intervention that:
Is the length of a standard lesson
Is age appropriate and acceptable
Contains appropriate signposting
Contains content that challenges common myths and replaces them with knowledge
Contains content that encourages empathy and understanding towards those with mental illnesses
Is easily delivered in the same way each time so that its effectiveness can be evaluated
To create an intervention effective at tackling stigma and empowering adolescents to recognise signs of poor mental health and access services appropriately.
Lesson plan created after consultation with psychiatrists, a psychologist, a GP, a university outreach professional, a teacher and secondary school age children, then trialled and revised.
Interactive workshop produced with 5 sections.
1) Myth vs Fact activity that dispels prevalent myths
2) Scenario based activity to demonstrate that mental health is a spectrum
3) An interactive presentation covering the most common mental illnesses and their symptoms
4) An activity focusing on talking to those with mental illnesses, furthering the scenario from the previous activity
5) A question and answer session. Every student leaves with a leaflet containing appropriate signposting.
We have created an educational intervention ready to be delivered and evaluated.
The symptoms of many mental illnesses often begin during high school. Interventions to improve mental health awareness amongst adolescents may lead to improved outcomes. in the UK unfortunately many schools do not fulfil this need and mental health education is not a compulsory part of the curriculum.
To develop and measure the effectiveness of and educational intervention designed to raise awareness and empower adolescents to recognise signs of poor mental health and access services appropriately.
Evaluate the effectiveness of the intervention through baseline and follow up surveys.
Students at Norwich Medical School collaborated with teachers, psychiatrists and general practitioners to design an educational intervention that aims to tackle stigma and raise awareness of mental health conditions among 13-14 year olds in the hope that they can access services when needed, support those around them and look after their mental health. To evaluate effectiveness of the intervention, a knowledge, attitudes and practices survey that utilises a social distance scale that has been adapted for this age group and will be used to gather baseline and follow up data after six months.
We have developed a one-hour educational intervention delivered by medical students, that uses a variety of teaching techniques to raise awareness of mental health issues. We will start implementation in January 2013 so will have baseline effectiveness results shortly after.
Headucate has the potential to fill an important gap in effectively raising awareness of mental health issues in schools.
UK guidelines recommend routine HIV testing in high prevalence emergency departments (ED) and targeted testing for HBV and HCV. The ‘Going Viral’ campaign implemented opt-out blood-borne virus (BBV) testing in adults in a high prevalence ED, to assess seroprevalence, uptake, linkage to care (LTC) rates and staff time taken to achieve LTC. Diagnosis status (new/known/unknown), current engagement in care, and severity of disease was established. LTC was defined as patient informed plus ⩾1 clinic visit. A total of 6211/24 981 ED attendees were tested (uptake 25%); 257 (4.1%) were BBV positive (15 co-infected), 84 (33%) required LTC. 100/147 (68%) HCV positives were viraemic; 44 (30%) required LTC (13 new, 16 disengaged). 26/54 (48%) HBV required LTC (seven new, 11 disengaged). 16/71 (23%) HIV required LTC (10 new, five disengaged). 26/84 (31%) patients requiring LTC had advanced disease (CD4 <350, APRI (AST-to-Platelet Ratio Index) >1, Fibroscan F3/F4 or liver cancer), including five with AIDS-defining conditions and three hepatocellular carcinomas. There were five BBV-related deaths. BBV prevalence was high (4.1%); most were HCV (2.4%). HIV patients were more successfully and quickly LTC than HBV or HCV patients. ED testing was valuable as one-third of those requiring LTC (new, disengaged or unknown status patients) had advanced disease.
Bovine tuberculosis (bTB) is an important disease of cattle caused by infection with Mycobacterium bovis, a pathogen that may be extremely difficult to eradicate in the presence of a true wildlife reservoir. Our objective was to identify and review relevant literature and provide a succinct summary of current knowledge of risk factors for transmission of infection of cattle. Search strings were developed to identify publications from electronic databases to February 2015. Abstracts of 4255 papers identified were reviewed by three reviewers to determine whether the entire article was likely to contain relevant information. Risk factors could be broadly grouped as follows: animal (including nutrition and genetics), herd (including bTB and testing history), environment, wildlife and social factors. Many risk factors are inter-related and study designs often do not enable differentiation between cause and consequence of infection. Despite differences in study design and location, some risk factors are consistently identified, e.g. herd size, bTB history, presence of infected wildlife, whereas the evidence for others is less consistent and coherent, e.g. nutrition, local cattle movements. We have identified knowledge gaps where further research may result in an improved understanding of bTB transmission dynamics. The application of targeted, multifactorial disease control regimens that address a range of risk factors simultaneously is likely to be a key to effective, evidence-informed control strategies.
Despite national guidance recommending testing and vaccination of household contacts of hepatitis B-infected pregnant women, provision and uptake of this is sub-optimal. The aim of this study was to evaluate the use of in-home dried blood spot (DBS) testing to increase testing and vaccination of household contacts of hepatitis B-infected pregnant women as an alternative approach to conventional primary-care follow-up. The study was conducted across two London maternity trusts (North Middlesex and Newham). All hepatitis B surface antigen-positive pregnant women identified through these trusts were eligible for inclusion. The intervention of in-home DBS testing for household contacts was introduced at North Middlesex Trust from November 2010 to December 2011. Data on testing and vaccination uptake from GP records across the two trusts were compared between baseline (2009) and intervention (2010–2011) periods. In-home DBS service increased testing uptake for all ages (P < 0·001) with the biggest impact seen in partners, where testing increased from 30·3% during the baseline period to 96·6% during the intervention period in North Middlesex Trust. Although impact on vaccine uptake was less marked, improvements were observed for adults. The provision of nurse-led home-based DBS may be useful in areas of high prevalence.
In June 2014 Public Health England confirmed a case of Legionnaires' disease (LD) in a neonate following birth at home in a hired birthing pool incorporating a heater and a recirculation pump which had been filled in advance of labour. The case triggered a public health investigation and a microbiological survey of an additional ten heated birthing pools hired or recently hired to the general public across England. The birthing pool used by the parent of the confirmed case was identified as the source of the neonate's infection following detection of Legionella pneumophila ST48 in both patient and environmental samples. Legionella species were detected by quantitative polymerase chain reaction but not culture in a further three pools together with other opportunistic pathogens identified by culture and matrix-assisted laser desorption ionization–time of flight (MALDI–ToF) mass spectrometry. A Patient Safety Alert from NHS England and Public Health England was issued stating that heated birthing pools filled in advance of labour should not be used for home births. This recommendation remains in place. This investigation in conjunction with other recent reports has highlighted a lack of awareness regarding the microbiological safety of heated birthing pools and their potential to be a source of LD and other opportunistic infections. Furthermore, the investigation raised important considerations with regards to microbiological sampling and testing in such incidents. Public health authorities and clinicians should consider LD in the differential diagnosis of severe respiratory infection in neonates within 14 days of a water birth.
Monitoring infections and risk in people who inject drugs (PWID) is important for informing public health responses. In 2011, a novel hepatitis C antibody (anti-HCV) avidity-testing algorithm to identify samples compatible with recent primary infection was introduced into a national surveillance survey. PWID are recruited annually, through >60 needle-and-syringe programmes and prescribing services. Of the 980 individuals that could have been at risk of HCV infection, there were 20 (2%) samples that were compatible with recent primary infection. These were more common among: those imprisoned ⩾5 times [8/213; adjusted odds ratio (aOR) 8·7, 95% confidence interval (CI) 2·04–37·03]; women (8/230; aOR 3·8, 95% CI 1·41–10·38); and those ever-infected with hepatitis B (5/56; aOR 6·25, 95% CI 2·12–18·43). This study is the first to apply this algorithm and to examine the risk factors associated with recently acquired HCV infection in a national sample of PWID in the UK. These findings highlight underlying risks and suggest targeted interventions are needed.
Children in care often have poor outcomes. There is a lack of evaluative
research into intervention options.
To examine the efficacy of Multidimensional Treatment Foster Care for
Adolescents (MTFC-A) compared with usual care for young people at risk in
foster care in England.
A two-arm single (assessor) blinded randomised controlled trial (RCT)
embedded within an observational quasi-experimental case–control study
involving 219 young people aged 11–16 years (trial registration: ISRCTN
68038570). The primary outcome was the Child Global Assessment Scale
(CGAS). Secondary outcomes were ratings of educational attendance,
achievement and rate of offending.
The MTFC-A group showed a non-significant improvement in CGAS outcome in
both the randomised cohort (n = 34, adjusted mean
difference 1.3, 95% CI −7.1 to 9.7, P = 0.75) and in the
trimmed observational cohort (n = 185, adjusted mean
difference 0.95, 95% CI −2.38 to 4.29, P = 0.57). No
significant effects were seen in secondary outcomes. There was a possible
differential effect of the intervention according to antisocial
There was no evidence that the use of MTFC-A resulted in better outcomes
than usual care. The intervention may be more beneficial for young people
with antisocial behaviour but less beneficial than usual treatment for
The scientific literature contains evidence suggesting that women who have been treated for breast cancer may, as a result of their diagnosis, increase their phyto-oestrogen (PE) intake. In the present paper, we describe the creation of a dietary analysis database (based on Dietplan6) for the determination of dietary intakes of specific PE (daidzein, genistein, glycitein, formononetin, biochanin A, coumestrol, matairesinol and secoisolariciresinol), in a group of women previously diagnosed and treated for postmenopausal breast cancer. The design of the database, data evaluation criteria, literature data entry for 551 foods and primary analysis by LC–MS/MS of an additional thirty-four foods for which there were no published data are described. The dietary intake of 316 women previously treated for postmenopausal breast cancer informed the identification of potential food and beverage sources of PE and the bespoke dietary analysis database was created to, ultimately, quantify their PE intake. In order that PE exposure could be comprehensively described, fifty-four of the 316 subjects completed a 24 h urine collection, and their urinary excretion results allowed for the description of exposure to include those identified as ‘equol producers’.
The aim of this study was to estimate the amount of childhood hepatitis B virus transmission in children born in the UK, a very low-prevalence country, that is preventable only by universal hepatitis B immunization of infants. Oral fluid specimens were collected from schoolchildren aged 7–11 years in four inner city multi-ethnic areas and tested for the presence of antibody to hepatitis B core antigen (anti-HBc). Those found positive or indeterminate were followed up with testing on serum to confirm their hepatitis B status. The overall prevalence of anti-HBc in children was low [0·26%, 95% confidence interval (CI) 0·14–0·44]. The estimated average annual incidence of hepatitis B was estimated to be 29·26/100 000 children (95% CI 16·00–49·08). The total incidence that is preventable only by a universal infant immunization programme in the UK was estimated to be between 5·00 and 12·49/100 000. The study demonstrates that the extent of horizontal childhood hepatitis B virus transmission is low in children born in the UK and suggests that schools in the UK are an uncommon setting for the transmission of the virus. Targeted hepatitis B testing and immunization of migrants from intermediate- and high-prevalence countries is likely to be a more effective measure to reduce childhood transmission than a universal infant immunization programme.
An unlinked anonymous survey was conducted to measure the prevalence of selected markers for HIV, hepatitis B and C infection in recruits to the UK Armed Forces to inform future screening and hepatitis B vaccination policies. During 2007, nearly 14 000 left-over samples taken from new recruits for blood typing were collected, unlinked from identifiers and anonymously tested for HIV, hepatitis C and current and past cleared hepatitis B infection. Overall, serological evidence of HIV and hepatitis C was found in 0·06% and 0·06% of recruits, respectively. Evidence of past cleared and current hepatitis B infection was found in 3·63% and 0·37% of recruits, respectively. Overall, prevalence rates were broadly consistent with UK population estimates of infection. However, HIV and hepatitis B prevalence was higher in recruits of African origin than in those from the UK (P<0·0001). Screening for these infections is an option that could be considered for those entering Services from high-prevalence countries.
The new Core-XAS (X-ray absorption spectroscopy) beamline (B18) at Diamond aims to provide a reliable spectrometer for a broad scientific community. With this in mind, B18 has been built as a general-purpose beamline and offers to users a variety of sample environments and detection methods. Here we will present the first commissioning results and some of the capabilities of this versatile instrument.
Dietary intake of isothiocyanates (ITC) has been associated with reduced cancer risk. The dietary phenethyl ITC (PEITC) has previously been shown to decrease the phosphorylation of the translation regulator 4E binding protein 1 (4E-BP1). Decreased 4E-BP1 phosphorylation has been linked to the inhibition of cancer cell survival and decreased activity of the transcription factor hypoxia-inducible factor (HIF), a key positive regulator of angiogenesis, and may therefore contribute to potential anti-cancer effects of PEITC. In the present study, we have investigated the in vitro and in vivo effects of watercress, which is a rich source of PEITC. We first demonstrated that, similar to PEITC, crude watercress extracts inhibited cancer cell growth and HIF activity in vitro. To examine the effects of dietary intake of watercress, we obtained plasma and peripheral blood mononuclear cells following the ingestion of an 80 g portion of watercress from healthy participants who had previously been treated for breast cancer. Analysis of PEITC in plasma samples from nine participants demonstrated a mean maximum plasma concentration of 297 nm following the ingestion of watercress. Flow cytometric analysis of 4E-BP1 phosphorylation in peripheral blood cells from four participants demonstrated significantly reduced 4E-BP1 phosphorylation at 6 and 8 h following the ingestion of watercress. Although further investigations with larger numbers of participants are required to confirm these findings, this pilot study suggests that flow cytometry may be a suitable approach to measure changes in 4E-BP1 phosphorylation following the ingestion of watercress, and that dietary intake of watercress may be sufficient to modulate this potential anti-cancer pathway.
Following a buffet meal served to six guests at a private domestic function, five of the guests and the host developed symptoms of food poisoning. Salmonella enteritidis phage type 4 (PT4) was isolated from all four individuals who submitted faecal samples for investigation. Leftover samples of a savoury rice dish consumed by all six ill persons contained 6×103/gm Salmonella enteritidis PT4. The rice salad comprised boiled rice, raw carrots, eggs, cheese and curry powder. The curry powder and remainder of the pack of six eggs were negative on microbiological analysis. The rice dish had been prepared by heating in a 500 W microwave oven with a rotating turntable on full power for 5 min. Although the hazards of inadequate microwave cooking are well recognized, this is only the second outbreak of food poisoning from microwave cooking to be reported.
An outbreak of Salmonella enteritidis PT 6B food poisoning, the first reported of this recently described phage type, resulted in illness among 46 of 49 members of a camping group in North Wales. 33 of whom were hospitalized. Epidemiological evidence (P < 0·0001) indicated that a lemon meringue pie was the vehicle of infection. Fresh shell eggs, stored after purchase at ambient temperature, appear to be the most likely source of infection, with multiplication during preparation and subsequent storage of the pie a significant contributory factor. Campers may be at greater risk than others and should consider the use of cold boxes for the transport and storage of eggs, and avoid the preparation of lightly cooked egg products under these basic conditions.
Single ascospore cultures from triploids were screened as a potential source of disomic tester stocks for the purpose of genetical mapping of chromosomes in yeast. A high tolerance of aneuploidy was found, and strains disomic for only one chromosome were rare. There was a high occurrence of strains disomic at specific chromosomes and in certain multiple combinations of disomic chromosomes.