ALBERT

Description: Groundwater is a critical resource in India for the supply of drinking water and for irrigation. Its usage is limited not only by its quantity but also by its quality. Among the most important contaminants of groundwater in India is arsenic, which naturally accumulates in some aquifers. In this study we create a random forest model with over 145,000 arsenic concentration measurements and over two dozen predictor variables of surface environmental parameters to produce hazard and exposure maps of the areas and populations potentially exposed to high arsenic concentrations (〉10 µg/L) in groundwater. Statistical relationships found between the predictor variables and arsenic measurements are broadly consistent with major geochemical processes known to mobilize arsenic in aquifers. In addition to known high arsenic areas, such as along the Ganges and Brahmaputra rivers, we have identified several other areas around the country that have hitherto not been identified as potential arsenic hotspots. Based on recent reported rates of household groundwater use for rural and urban areas, we estimate that between about 18–30 million people in India are currently at risk of high exposure to arsenic through their drinking water supply. The hazard models here can be used to inform prioritization of groundwater quality testing and environmental public health tracking programs.

Description: Key Points Hermansky-Pudlak syndrome type 2 confers a moderate risk for hemophagocytic lymphohistiocytosis.

Description: The genetic diagnosis of inherited anaemias is an important aspect of the diagnostic pathway for patients with haematological disorders, allowing discrimination between conditions of overlapping phenotypes therefore enabling more effective clinical treatment. Next Generation sequencing platforms are now in widespread use in diagnostic settings and are facilitating more rapid, accurate and cost-effective molecular diagnosis. The Red Cell Gene Panel developed by the Viapath Molecular Pathology laboratory based at King's College Hospital, London has harnessed this technology with the aim of identifying genetic diagnoses of rare inherited causes of anaemia. Although originally setup to diagnose inherited red cell disorders, clinical demand has led to the inclusion of inherited bone marrow failure syndromes and other related conditions such that the panel now consists of 194 genes, divided into 16 subpanels (see table 1). Here we present the data from the first 1000 diagnostic cases reported under the following referral groups: 462 cases of unexplained anaemia (including haemolytic anaemia, sideroblastic anaemia, congenital dyserythropoietic anaemia, Diamond-Blackfan Anaemia), 232 cases of inherited bone marrow failure syndromes (including thrombocytopenia and neutropenia), 163 cases of congenital erythrocytosis and 143 other cases (including but not limited to iron regulation, haemophagocytic lymphohistiocytosis (HLH) and Criggler-Najjar ). Of these 1000 cases, we have achieved an overall diagnostic yield of approximately 25%. A diagnosed case is defined here as one in which a clear pathogenic or likely pathogenic variant that explains the phenotype has been detected. The unexplained anaemia cases have achieved the highest percentage of cases diagnosed with 47% diagnostic yield and data will be presented outlining the gene-by-gene breakdown of diagnoses made. Our bespoke bioinformatics pipeline has also allowed the detection of novel disease-causing structural variants in 20 cases, contributing 2% of our diagnostic yield. These are detected using three different methods; read-depth analysis, split-read mapping and discordant insert-size analysis. All reported structural variants have been confirmed with a second method, either breakpoint mapping or dosage-sensitive PCR. A significant proportion of cases (28%) have been reported with variants of uncertain clinical significance, highlighting the need for family studies and functional characterisation to be able to accurately ascertain the significance of these variants. Future developments of the service include functional characterisation of membrane disorders using next generation ektacytometry and preliminary data from this work will be presented here. Disclosures Kulasekararaj: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Pagliuca:Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Introduction: BMT is the only proven curative treatment available for haemoglobinopathies. However, the number of patients who can benefit is seriously restricted by the lack of HLA-matched related donors not suffering from the condition and the limited number of unrelated donors available for the ethnic groups in which these conditions are prevalent. In order to expand the donor pool, haploidentical transplantation with a post-infusion of stem cells cyclophosphamide approach has been developed for young adults, but whilst well tolerated it has resulted in relatively high rates of rejection and the need for a prolonged period of immunosuppression1. Materials (or patients) and methods: 16 consecutive related haploidentical transplants (13 for sickle cell disease and 3 for β halassaemia major) were performed at St. Mary's Hospital, London, from June 2013 to May 2015. The donor was a parent in 15 cases and a sibling in one case. The median age was 10 years of age (range 3 to 18). All patients lacked a suitable HLA-matched related donor and an unrelated search had not identified a 10/10 or 9/10 donor. Endogenous haemopoieis was suppressed with hypertransfusions, hydroxycarbamide 30 mg/kg and azathioprine 3 mg/kg for at least two months pre-transplantation. The conditioning included fludarabine 150 mg/m2, thiotepa 10 mg/kg was added, cyclophosphamide 29 mg/kg, TBI 2 Gy and ATG (Thymoglobulin) 4.5 mg/kg. GvHD prophylaxis was provided with cyclophosphamide 50 mg/kg on days +3 and +4, MMF and sirolimus. The median survival was 8.19 months post-transplantation (1.28-22.96) and half of the patients are 〉150 days post-transplantation and have completed all treatment. The source of stem cells was G-CSF primed bone marrow in all cases, aiming ≥8 x 108 TNC/kg [median 9.97 x 108 TNC/kg (2.35-20.5), 3.88 x 106 CD34+/kg (1.12-9.21)]. Results: All patients engrafted, though one patient subsequently suffered secondary graft failure following macrophage activation syndrome and died. The median neutrophil engraftment was 17 days (range 16 to 29). The median platelet engraftment 〉50 x109/L was 32 days (range 20 to 64). All 15 surviving patients are cured from the manifestations of the original disease. One patient suffered VOD following autologous rescue with limited conditioning for secondary graft failure. Infectious complications occurred at a higher rate than seen for related transplants for the same conditions at our institution. Acute GvHD ≥ grade II occurred in two patients (12.5%, skin and gut GvHD respectively) responding to treatment with MSC and one patient was treated for chronic GvHD (6.3%). The median time to cessation of immunosuppression was 124 days (108-189). All patients but one achieved ≥90% donor fraction both in whole blood and T cells at day +180, with only such patient requiring continuation of immunosuppression (day +28: 93.3% patients ≥95% donor and 6.7% patients ≥90-94% in whole blood, and 73.3% patients ≥95% donor, 13.3% patients ≥90-94%, 6.7% donor ≥50-89% and 6.7% donor

Description: Abstract 4919 Hermansky Pudlak Syndrome (HPS) is a genetically heterogeneous group of rare disorders that are classified as ‘lysosome biogenesis disorders’ and are characterized by variegated pigmentation, variable immune deficiencies, and platelet dysfunction. There are 8 known variants of HPS in humans. Lysosomes are membrane-bound organelles that contain hydrolytic enzymes necessary for intracellular degradation and represent the main cellular degradation compartment within the vacuolar system of the eukaryotic cell 1. Biogenesis of lysosomes partly depends on the function of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), −2, and −3 proteins2. The mutated proteins known to give rise to the HPS variants occur in one or more of the cytosolic BLOC complexes, each being composed of different proteins, including the Adaptor Proteins 1–4 (AP1-4) 3. Also, since mutations in the AP3B1 gene encoding the b subunit of the AP3 complex cause the only HPS subtype which is associated with an immune disorder along with other lysosomal abnormalities 4, this indicates that AP3 is important for lysosome function within the immune system. In the absence of AP3, cytotoxic T lymphocyte (CTL) mediated killing is severely impaired and cytotoxic lysosomal granules are unable to move along microtubules when the CTL recognizes target cells 5. We report a case of Hermansky Pudlak Syndrome Type 2 in a consanguineous female infant of Arabic origin who presented with severe sepsis, occulocutaneous albinism, platelet nucleotide deficiency, neutropaenia and a homozygous balanced inversion of chromosome 5; inv(5)(p15q13). Further molecular genetic analysis revealed a breakpoint in the AP3B1 gene, thereby confirming a genetic diagnosis of HPS2. Case Report: A five month old female infant presented with respiratory sepsis requiring ventilation. Clinical examination revealed occulocutaneous albinism (Figure 1) and hepatosplenomegaly. Laboratory data revealed severe neutropenia (0.2×109/l), CD4 lymphopaenia (446/microlitre), normal immunoglobulins, marked reduction of platelet nucleotides and abnormal platelet aggregation studies. There was no evidence of haemophagocytic syndrome at presentation. Neutrophil activity was normal and there was no evidence of B-cell dysfunction. Unexpectedly, her CTLs demonstrated normal lysosomal granule release on activation. Karyotyping showed pericentric balanced inversion in chromosome 5, inv (5)(p15q13). Parental karyotyping revealed heterozygous inversion of chromosome 5 at the same breakpoint. Array comparative genomic hybridization confirmed absence of copy number gain or loss in the inversion. Bacterial artificial chromosome cloning using Fluorescent in situ hybridization confirmed the breakpoint to be within the APB3B1 gene. She made a good recovery from her initial sepsis and continues to remain neutropaenic and CD4 lymphopaenic on follow up for 12 months, and has required a number of admissions with viral sepsis (adenovirus and respiratory syncitial virus). In summary, this is a first report of homozygous pericentric balanced inversion of chromosome 5 inv(5)(p15q13), leading to disruption of the AP3B1 gene, giving rise to a clinical phenotype of Hermansky Pudlak Syndrome Type 2. The normal cytotoxic lymphocyte function remains unexplained. Further molecular genetic work is in progress to map the breakpoint in the AP3B1 gene and the corresponding gene(s) involved in the inversion. Disclosures: No relevant conflicts of interest to declare.

Description: The National Health Service (NHS) in England and Wales provides care for approximately 15000 children and adults with HbO. A national peer review of paediatric and adult HbO services against a set of quality standards was commenced in 2010 aiming to obtain a clear picture of service provision. These initial visits confirmed a lack of investment and marked inequalities of care highlighting the need for improved facilities, staffing and the establishment of networks of care. The results of the second national peer review programme (2015/6) are reported here with comparative analysis of performance against quality standards allowing an opportunity to establish whether the programme has led to improvements in the quality of, and access to, care. Methods Services were reviewed against a set of 51 quality standards established by a steering group of experienced UK clinicians from the UK Forum for Haemoglobin Disorders. They examined support for patients, staffing, training, facilities/equipment, service organisation, guidelines, governance/audit, clinical networks and commissioning. 32 centres were visited including all major city hospitals in England and smaller hospitals with significant HbO patient populations. Review visits were conducted by a team of doctors, nurses, patient representatives, psychologists and NHS managers and the process was overseen and supported by the West Midlands Quality Review Service. Following each review the centre received a standardised report of compliance highlighting areas of good practice and concerns. Results Overall the visits provide evidence of a progressive increase in compliance with the quality standard, more marked in paediatric services (fig 1 and 2). 14/16 (82%) of paediatric and 21/31 (68%) of adult centres showed an improvement in compliance. The percentage of change in compliance ranged from -12 to +39% in paediatric and -22 to +59% in adult centres. Other findings from the peer review visits showed:Themes from patient feedback were difficulties accessing adequate emergency care and support for Day Care units providing open access pain control.Out of hours transfusion was only available in 50% services, throughout the review process.Inequity of access to automated apheresis with several large centres not being able to provide this service.Inadequate dedicated medical and nursing time with a decrease in number of adult services with named lead nurse from 68% to 58% in successive reviews. A lack of specialist psychological support was almost universal and unchanged throughout the review period.In the 2015/16 review only 25% of services had completed audits specified in the standards, but increased numbers of services were developing a rolling programme of audit and participating in research.Assessment of pain control according to NICE Guidelines had been performed in most centres, however very few services were able to meet the 30 minute arrival to analgesia target.Transcranial Doppler services were of an inconsistent standard and no national quality assurance tool existed for this investigation.Increasing numbers of services (67% paediatrics, 75% adults) were participating in multidisciplinary meetings and this had improved from 47% in the previous review. Conclusion Peer review of NHS quality of care in England is mostly voluntary but generally valued. This is the first ever report of a nationwide iterative, quality standards-based HbO peer review programme. It was conducted with almost universal participation from individual services, highlighting the willingness of service providers to engage with this voluntary process. Thearguments to sustain such programmes include evidence of cost effectiveness but impact on outcomes is more difficult to demonstrate. This report demonstrates that higher rates of compliance with quality standards were observed following implementation of the peer review programme. In part this is likely to be driven by the peer review process and shows that this process can promote excellence in patient care. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Howard: Bluebird Bio: Consultancy, Honoraria; Novartis: Honoraria, Speakers Bureau.

Description: Introduction 17% of children with sickle cell disease (SCD) between the ages of 6 and 16 could have silent infarcts1. Depending on the area of the brain affected silent infarcts can cause problems with attention, coordination, visual-motor speed and executive function. Children with SCD in the UK do not receive routine MRI scans. Subtle defects in cognition can be assessed with neuropsychometric testing which involves multiple tests assessing many areas of cognition. However, testing is limited to those with known neurological deficits due to lack of funding and shortage of specialist staff. There is a need for a robust screening tool for assessment of cognition, which could identify children for further specialist testing. The Cogstate battery is computer-based program that assesses cognition and has been used in several clinical settings, both adult and paediatric2-3. The Cogstate battery is reported to be culturally neutral and is available in several languages. Additionally the Cogstate battery is free from practice effects and so could be used as an annual assessment tool in order to identify any declines as early as possible. The Cogstate battery has not yet been used to assess cognition in children with SCD. Research Objectives The aim of this study was to assess the feasibility of using the Cogstate Battery as a tool for the assessment of cognition in children with SCD. It was hypothesised that the Cogstate battery would be easy to use within this setting and would be acceptable to patients, parents and assessors. Methods Eight clinically well children, aged 10-17 with SCD were recruited through St Mary's Hospital paediatric haematology outpatient clinics. The Cogstate software was downloaded onto a Windows laptop computer and an anonymous profile was created for each child before testing. A battery of 6 tests (Table 1) was created aiming to assess a range of cognitive domains within a reasonable amount of time. Every child completed the battery of tests once, which included a short practice before each test. After testing each patient was asked to give an opinion of how they found the tests. Upon completion of the test the patients' results were uploaded to the Cogstate website which generated a test report and a case report form. A mark was given for each test and a score of over 90 represents normal cognition in the area tested, 81-90 represents mild impairment and below 81 represents impairment.Table 1.Tests used in the Cogstate battery and corresponding cognitive domains assessedTest NameCognitive Domain TestedContinuous paired associate learning (CPAL)Paired associate learningDetection (DET)Psychomotor functionGroton maze learning test (ME)Executive functionGroton maze learning test-delayed recall (ME)Delayed recallIdentification (IDN)AttentionOne card learning (OCL)LearningOne-back memory (ONBA)Working memory Results 8 patients completed the battery, taking on average 29 minutes (Table 2). The battery was easy to carry out and although some children reported it as boring, they all finished the tests without distress. The test report generated by the Cogstate website allowed results to be analysed quickly and with ease. An overall score from each test is clearly indicated. The Continuous Paired Associate Learning test was not displayed as part of the test report as there was insufficient normal data to draw conclusions from the results within the age group tested. Table 2. Summary Report of 8 patients tested PatientID DET(Psychomotor function) IDN(Attention) OCL(Learning) ONBS(Processing speed) ONBA(Working memory) ME(Executive function & delayed recall) 0001 87 75 82 78 83 99 0002 106 105 94 90 117 99 0003 96 101 95 95 117 98 0004 76 76 94 81 94 93 0005 86 84 98 81 89 89 0006 98 104 97 97 94 111 0007 94 90 91 83 101 86 0008 91 88 108 90 96 95 Conclusion The Cogstate battery is a feasible tool for paediatric SCD patients and can be undertaken in a clinic setting. This feasibility study will help design a prospective, comparative study of cognition in children with SCD using the Cogstate battery and conventional neuropsychometric assessment and once validated, would be a useful tool to assess cognition and institute timely educational and medical intervention. References: 1. Pegelow J Pediatr. 2002 Mar;140(3):348-54. 2. Hammers, Am J Alzheimers Dis. 2011 Jun;26(4):326-33 3. Harel PLoS One. 2014 Jul 11;9(7):e101750 Disclosures No relevant conflicts of interest to declare.

Description: Abstract 3234 Haemopoietic stem cell transplantation is the only proven curative treatment available for haemoglobinopathies. From 2000 to 2010 severty-four consecutive transplants were conditioned with busulfan 14 mg/kg, cyclophosphamide 200 mg/kg and alemtuzumab (Bu/Cy) achieving a DFS of 94.5%. In order to reduce busulfan toxicity, minimise mixed chimerism and enable the use of related mismatched and unrelated donors, the conditioning regimen was modified: fludarabine 160 mg/m2, treosulfan 42 g/m2, thiotepa 10 mg/kg and ATG (Thymoglobulin) 7.5 mg/kg or 11.25 mg/kg (FTTA). 18 patients [13 with β thalassaemia major and 5 with sickle cell disease, median age 6.5 years (2 – 16)] received a related transplant: fifteen 10/10 matched sibling, one 10/10 matched related and two 9/10 mismatched sibling. The source of stem cells was BM in 16 patients and mixed cord blood and BM in 2 with a median cell dose of 3.85 ×108 TNC.kg (range 1.50 – 6.87). Median follow-up was 6.7 months (2.40 – 20). Two patients received an unrelated transplant (α thalassaemia major, 12 years, 10/10 matched BM, 2.4 ×108 TNC/kg, survival +5 months; sickle cell disease, 7 years, 9/10 matched PBSC, 6 ×106CD34+/kg, survival +1.8 months). Endogenous haemopoiesis was suppressed with hypertransfusions. GvHD prophylaxis: ciclosporin and MMF. Patients with thalassaemia were Pesaro class I or II. Patients with sickle cell disease were transplanted for stroke or recurrent vaso-oclusive crisis and/or acute chest syndrome not responding to hydroxycarbamide. All patients are alive with transfusion-independence and donor haematological values (DFS 100%, OS 100%). Acute GvHD ≥grade 2 occurred in 1 related patient (5.6%) and both unrelated patients; chronic limited GvHD in 2 related patients (11.1%), all with resolution following steroid treatment. Neutrophil engraftment was achieved at a median of 12 days (9 – 21) in comparison to 19.5 days (12 – 28 days) with the previous protocol. Chimerism studies in whole blood demonstrated that donor haemopoiesis was higher for FTTA v Bu/Cy at all-time points (day +28: 100% 〉95% for FTTA v 81.4% 〉95%, 16% 〉90–95% and 2.4% 〉50–80%; day +90: 91.6% 〉95% and 8.3% 〉90–95% v 67.1% 〉95%, 12.8% 〉90–95%, 12.8% 〉80–90% and 12.8% 〉50–80%; day +150: 50% 〉95%, 37.5% 〉90–95% and 12.5% 〉50–80% v 55.8% 〉95%, 10.8% 〉90–95%, 14.7% 〉80–90%, 8.8% 〉50–80%, 2.9% 〉30–50% and 2.9% 〉20–30%). Donor T-cell lymphopotiesis is FTTA was day +28: 100% (68 – 100), day +90: 98.5% (55–100) and day +150: 98% (73–100). In conclusion, FTTA leads to earlier engraftment and higher donor chimerism than Bu/Cy, no graft failure, and enables the use of mismatched and unrelated donors for transplantation in haemoglobinopathies, whilst the incidence of GvHD is low. Disclosures: No relevant conflicts of interest to declare.

Description: Short-term load forecasting ensures the efficient operation of power systems besides affording continuous power supply for energy consumers. Smart meters that are capable of providing detailed information on buildings energy consumption, open several doors of opportunity to short-term load forecasting at the individual building level. In the current paper, four machine learning methods have been employed to forecast the daily peak and hourly energy consumption of domestic buildings. The utilized models depend merely on buildings historical energy consumption and are evaluated on the profiles that were not previously trained on. It is evident that developing data-driven models lacking external information such as weather and building data are of great importance under the situations that the access to such information is limited or the computational procedures are costly. Moreover, the performance evaluation of the models on separated house profiles determines their generalization ability for unseen consumption profiles. The conducted experiments on the smart meter data of several UK houses demonstrated that if the models are fed with sufficient historical data, they can be generalized to a satisfactory level and produce quite accurate results even if they only use past consumption values as the predictor variables. Furthermore, among the four applied models, the ones based on deep learning and ensemble techniques, display better performance in predicting daily peak load consumption than those of others.