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NHS genetics centres in Scotland sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. Genome sequencing was performed at Edinburgh Genomics, and phenotype and sequence data were transferred to Genomics England for variant calling, gene-based filtering and variant prioritisation. NHS Scotland genetics laboratories performed interpretation, validation and reporting. New diagnoses were made in 23% cases – 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes. Diagnostic yield varied considerably between phenotype categories and was minimal in cases with prior exome testing. Genome sequencing with gene panel filtering and reporting achieved improved diagnostic yield over previous historic testing but not over now routine trio-exome sequence tests. Re-interpretation of genomic data with updated gene panels modestly improved diagnostic yield at minimal cost. However, to justify the additional costs of genome vs exome sequencing, efficient methods for analysis of structural variation will be required and / or cost of genome analysis and storage will need to decrease.

The Gulf of California is an archetype of continental rupture through transtensional rifting, and exploitation of a thermally weakened arc to produce a rift. Volcanic rocks of central Baja California record the transition from calcalkaline arc magmatism, due to subduction of the Farallon plate (ca. 24–12 Ma), to rift magmatism, related to the opening of the Gulf of California (4%) and adakite (>56% SiO2 and MgO We describe 21 distinct volcanic and hypabyssal map units in the Santa Rosalía area, using field characteristics, petrographic data, and major- and trace-element geochemical data, as well as zircon isotopic data and ten new 40Ar-39Ar ages. Lithofacies include lavas and lava domes, block-and-ash-flow tuffs, ignimbrites, and hypabyssal intrusions (plugs, dikes, and peperites). Calcalkaline volcanic rocks (13.81–10.11 Ma) pass conformably upsection, with no time gap, into volcanic rocks with rift transitional chemistry (9.69–8.84 Ma). The onset of rifting was marked by explosive eruption of silicic ignimbrite (tuff of El Morro), possibly from a caldera, similar to the onset of rifting or accelerated rifting in other parts of the Gulf of California. Epsilon Hf zircon data are consistent with a rift transitional setting for the tuff of El Morro. Arc and rift volcanic rocks were then juxtaposed by normal faults and tilted eastward toward a north-south fault that lay offshore, likely related to the north-south normal faults documented for the early history of the Guaymas basin, prior to the onset of northwest-southeast transtenional faulting. Magmatism in the Santa Rosalía area resumed with emplacement of high-magnesian andesite lavas and intrusions, at 6.06 Ma ± 0.27 Ma, coeval with the onset of seafloor spreading in the Guaymas basin at ca. 6 Ma.The 9.69–8.84 Ma rift transitional volcanic rocks underlying the Santa Rosalía sedimentary basin provide a maximum age on its basal fill. Evaporites in the Santa Rosalía sedimentary basin formed on the margin of the Guaymas basin, where thicker evaporites formed. Overlying coarse-grained clastic sedimentary fill of the Santa Rosalía basin and its stratiform Cu-Co-Zn-Mn sulfides may have accumulated rapidly, coeval with emplacement of 6.06 Ma high-magnesian andesite intrusions and the ca. 6 Ma onset of seafloor spreading in the Guaymas basin.

The growing population of older adults requires healthcare delivery models that are both cost effective and directed toward the higher rates of chronic conditions, frailty and functional impairment often present as one ages. Analyzing healthcare utilization patterns of older adults—especially those over the age of 75—will better inform how to re-design care delivery processes.While the presence of chronic conditions requires consistent treatment, the intensity of health services required on a day-to-day basis is highly variable. Many individuals with at-risk health status are remarkably stable, exhibiting high levels of function and low utilization of care over extended periods of time. Periodically, however, these phases are punctuated by catastrophic episodes that can lead to greater health decline, morbidity, and mortality. During cycles of health decline, a cascade of other challenges stemming from an individual’s underlying risks, predispositions, and complexities can arise. This punctuated equilibrium of utilization for older adults offers insight to assess ways to improve care and lower costs. In this paper, we analyze and quantify both these states of punctuated equilibria as well as the extensive periods of stability. The associated utilization patterns are analyzed by processing Medicare claims data. Our analysis showed that over 80% of members in a group of anticipated high-risk Medicare beneficiaries over the age of 75 exhibited low utilization for 11 months out of a given year. These findings complement research exploring care redesign processes at a system level, specifically directed to high-cost episodes of care as opposed to patient-level targeting.

Mixed phenotype acute leukemia (MPAL) is a heterogeneous group of leukemias that are defined immunophenotypically by antigen expression on blasts of both myeloid and lymphoid lineage. With the exception of BCR-ABL positive and KMT2A rearranged MPAL, the biology of the majority of MPAL remains uncertain. Several recent studies have explored the genomic and epigenetic landscape of MPAL and have suggested a further refinement of the WHO classification to emphasize the genomic heterogeneity of MPAL. Further studies including single cell analysis, whole exome sequencing and time of flight cytometry will provide for further biological characterization. Treatment decisions are complicated due to this lack of classification and the dearth of prospective randomized studies. Acute lymphoblastic leukemia-type therapy appears to achieve higher remission rates, and allogenic stem cell transplantation may be beneficial in a select group of patients in first complete remission. Multi-center collaborations may answer these questions more conclusively. Our review aims to discuss the diagnostic challenges, recent genomic studies and therapeutic strategies in this poorly understood disease.

Tyrosine kinase inhibitors (TKIs) have revolutionized chronic myeloid leukemia (CML) and changed it from a fatal disease to a chronic illness. The goals of treatment are no longer survival but have...

Background and objectives: CPX-351 is a liposomal formulation of daunorubicin and cytarabine in a fixed synergistic ratio of 5:1. It has been approved by both the FDA and EMA for use in high risk AML including therapy related AML (t-AML) and AML with myelodysplastic related change (AML-MRC). When compared with '3+7', CPX-351 resulted in superior OS (9.56 vs 5.96 months) and overall response rate (47.7% v 33.3%; P = .016; Lancet JCO 2018). However, this is little data of CPX-351 in a real world setting. The primary objective of our multi-centre study was to assess outcomes and associated toxicities of CPX-351 in these high risk AML patients. Methods: Patients aged 18 and over who were treated with CPX-351 and who met the WHO criteria for t-AML and AML-MRC were included in the study. Retrospective data was collected from 6 centres throughout Canada. Targeted sequencing was performed on DNA samples using the TruSight Myeloid Sequencing Panel isolated from peripheral blood or bone marrow samples at diagnosis. Overall survival (OS) and progression free survival (PFS) rates were calculated using the Kaplan-Meier method. Results: Fifty patients treated with CPX-351 were identified from six centres. Baseline characteristics are seen in Table 1. Cytogenetics was available in 45 (90%) patients and an abnormal karyotype was seen in 30 (60%) patients. Monosomal (33%) and complex (28%) karyotype were the most common chromosomal abnormalities seen. Targeted sequencing was performed on 64% patients (32/50) and the average number of mutations was 2(0-7). RUNX1 was the most commonly mutated gene found in 22% (7/32), followed by SRSF2 in 19% (6/32) with ASXL1 and NRAS both at 16% (5/32). Other commonly mutated genes were NPM1, IDH2, DNMT3a and TP53 all occurred at a frequency of 12% (4/32). Of the 10 patients (20%) that were FLT3 mutated (80% ITD and 20% TKD), 5 patients received the FLT3 inhibitor midostaurin in combination with CPX-351. Assessing treatment responses, 50% (25/50) of patients achieved a complete remission (CR) or a complete remission with incomplete recovery (CRi). Median neutrophil recovery (≥500/μl) was 32 days (range 18-68) and median platelet recovery (≥50 000/μl) was 34 days (range 19-70). Proven or probable fungal infection was seen in 10 (20%) patients. 30 day mortality was 4% (2/50) and 60-day mortality was 10% (5/50). The median CR duration was short at 7.17 months. Of the 25 patients who did not achieve a CR, 6 (24%) had prior azacitidine use for MDS suggesting CPX-351 may not have activity in this group of patients. Median follow up was 7.43 months (range 0.2 to 18 months). OS was 44% at 12 months (0.28-0.58 95% CI) and 29% at 18 months (Fig 1; 0.13-0.46 95% CI). PFS was 28% at 12 months (0.15-0.43 95% CI) and 18% at 18 months (0.06-0.39 95% CI). There were no differences in OS when stratified by ELN risk (p=0.25), adverse risk cytogenetics (p=0.1485), or poor risk mutations such as FLT3-ITD (p=0.29), RUNX1 (p=0.123) or ASXL1 (p=0.06). This is consistent with previous studies, which suggest that CPX-351 overcomes the poor prognosis associated with these mutations. 18 (36%) patients received an allogeneic stem cell transplant (ASCT) in CR1. Patients who received a allogeneic transplant had significant improvement of OS of 62% at 18 months compared to those who did not receive a transplant of 14.5% at 18 months (Fig 2; p=0.0008). Conclusion Our study reveals that CPX-351 produces high remission rates in patients with AML with a similar efficacy and toxicity profile seen in the Phase 3 trial data (Lancet JCO 2018). However, response rates are short and therefore CPX-351 is most effective when used as a bridge for allogeneic stem cell transplantation in this high risk population. Disclosures Assouline: AbbVie: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding. Brandwein:Celgene: Honoraria; Astellas: Honoraria; Taiho: Honoraria; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Gupta:Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer: Consultancy; Takeda: Research Funding; Novartis: Honoraria. McNamara:Novartis: Honoraria. Sanford:Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Schimmer:Medivir AB: Research Funding; AbbVie Pharmaceuticals: Other: owns stock ; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Jazz: Honoraria; Otsuka: Honoraria.

ObjectivesTo determine the incidence of venous thromboembolism (VTE) and the incidence of hospital-acquired VTE (HA-VTE) arising within the population served by the Ireland East Hospital Group (IEHG).Design/home/user/Documents/Sathish Kumar G/RFO/June/21-06-2019/bmjopen_iss_9_7_20190621_1/ A retrospective observational study was conducted using hospital discharge data obtained from the hospital inpatient enquiry data reporting system. In this system, VTE events recorded as ‘primary diagnosis’ represented the reason for initial hospital admission, whereas VTE recorded as a ‘secondary diagnosis’ occurred following admission and were therefore used as an approximation of HA-VTE. These data were used to estimate the overall incidence of VTE and the proportion of these events which were hospital-acquired.SettingThe IEHG is the largest hospital group in the Irish healthcare system and serves a population of over 1 million individuals.ParticipantsData were generated from records pertaining to the 2727 patient admission episodes where a diagnosis of VTE was made during the 22-month study period.ResultsDuring the study period, 2727 VTE events were recorded within the IEHG (which serves a population of 1 036 279) corresponding to an incidence of 1.44 (95% CI 1.36 to 1.51) per 1000 per annum. 1273 (47%) of VTE events were recorded as secondary VTE. The incidence of VTE was highest among individuals over 85 years of age (16.03 per 1000;95% CI 12.81 to 19.26) and was more common following emergency hospital admission.ConclusionThese data suggest that HA-VTE accounts for at least 47% of all VTE events arising within a hospital group serving a population of over 1 million individuals within the Ireland. Given that HA-VTE is a well-recognised source of (potentially preventable) hospital deaths, these findings provide a compelling argument for prioritising strategies directed at reducing the risk of VTE among hospital patients served by the IEHG and within the Ireland as a whole.

Mixed phenotype acute leukemia (MPAL) is a heterogeneous disease consisting of acute leukemia expressing markers of both myeloid and lymphoid lineage. The role of hematopoietic stem cell transplantation (alloHSCT) remains uncertain due to lack of prospective trials . Several studies have retrospectively examined its role in pediatric and younger adult subgroups. Myeloablative conditioning (MAC) can result in an overall survival (OS) of 56% at 3 years, but is not suitable for older and frail patients. With expanding transplant availability and alternative donors, we sought to evaluate the outcomes of our cohort of MPAL patients, including older adults unfit for MAC, in a heterogeneous, real-world scenario compared with the outcomes of patients who were consolidated with chemotherapy only. Methods: Seventy four patients, aged 18 years or older, at the Princess Margaret Cancer Center between January 1, 2000 and December 31, 2018 were evaluated. All patients included in analysis met the WHO 2016 classification criteria for MPAL. Overall survival and relapse free survival rates were calculated using the Kaplan-Meier product-limit method. The log-rank test was used to compare the two groups with respect to OS and relapse free survival. Results: Baseline characteristics of the patient cohorts are shown in Table 1. Among the 74 MPAL patients included in this study, 59 (79%) received induction chemotherapy. Complete remission (CR) was achieved in 47 (79%) treated patients. Twenty-five of 36(80%) achieved a CR using ALL protocols (DFCI Protocol, Hyper-CVAD), while 9 of 23 (39%) achieved a CR using AML protocols (3+7, FLAG-Ida). Consolidation treatment post CR was evenly split, with 24(51%) receiving chemotherapy followed by an alloHSCT and 23 (49%) receiving chemotherapy only. In the alloHSCT group, RIC was used in 20 (81%) patients while MAC was used in four younger patients with a median age of 51 and 30 respectively. Donor types included sixteen matched unrelated donors, five sibling donors, two haploidentical donors, and one double umbilical cord. The median age of the transplant cohort was 50 years with a median OS of 21 months. In the chemotherapy only group, the median age was 57 with a median OS of 18 months. ALL-type treatment was used for consolidation in 74% of patients with 83% using the asparaginase-containing DFCI protocol. Univariate analysis demonstrated no difference in outcomes with several parameters including age, induction chemotherapy, donor source, and conditioning intensity. The sole predictor of poor OS on univariate analysis was acute graft versus host disease (aGVHD) with a hazard ratio of 3.3 (95% CI 0.9-11). In total, 12 patients (50%) had aGVHD with a median OS of 16 months. However, when Grade 1/2 and Grade 3/4 aGVHD were compared, median OS was not reached in patients with G1/2, compared with an OS of 11 months in those patients with G3/4 aGVHD. Chronic GVHD was present in 6 patients and did not impact OS (HR 0.9892 CI 95% 0.2-2.9). Post-transplant relapses occurred solely in the RIC group and were early, occurring within a median of 124 days (range 87-188). Although, there was no relapses in the MAC group, the non-relapse mortality (NRM) was 75%, with patients dying from either aGVHD or infection. The NRM in the RIC group was 17.65%. The 3 year OS and relapse free survival (RFS) for the entire cohort were 30% and 32%, respectively. When comparing those patients that had undergone alloSCT and those that who received chemo alone, survival in the two groups were similar with a 1 year OS of 75% vs. 68% and a 3 year OS of 29% vs 32%, respectively (Figure 1). The 3 year RFS was also similar at 29% and 34%, respectively. Subgroup analysis between the two groups was performed for patients with specific poor prognostic factors (older age, complex cytogenetics, higher WCC, conditioning regimen used), but results showed no significant survival differences. Conclusions Older patients with MPAL have an inferior prognosis and worse outcomes with alloHSCT compared with those of younger adults or children. Despite the increase in access to alloHSCT and an expanding pool of alternative donors, outcomes with RIC remain similar to consolidation with chemotherapy alone. There may be some evidence to suggest that the graft versus leukemia effect can be harnessed to improve outcomes in selected patients. Further research towards optimizing patient outcomes is clearly required to address the needs of older patients unfit for MAC. Disclosures Gupta: Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Research Funding. Mattsson:Gilead: Honoraria; Celgene: Honoraria; Therakos: Honoraria. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Michelis:CSL Behring: Other: Financial Support. McNamara:Novartis Pharmaceutical Canada Inc.: Consultancy. Schimmer:Jazz Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Consultancy. Schuh:Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Astex: Research Funding; MedImmune: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman La Roche: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement.

During backstroke, an optimum shoulder entry angle of 180° has been anecdotally suggested; however, this has yet to be investigated biomechanically. The aim of this study was to quantify shoulder entry angles for advanced and intermediate backstroke swimmers. Six advanced (season's best 150 s) and six intermediate (season's best 160 s) 200-m backstroke swimmers had markers applied to the medial humeral epicondyles and glenoid cavities. Following a familarization period, participants completed backstroke swimming trials (90 s each) in a swimming flume at 50%, 60%, 70%, and 80% of their season's best 200-m velocity. A camera positioned above the flume recorded frontal plane motion, which was digitized and analysed in Simi Motion Systems. The mean peak angle between the upper arm and the line of progression was established in ten strokes for each participant. The results showed backstroke shoulder entry angles for advanced swimmers (170°) were significantly closer to the suggested optimum 180° compared with those of intermediate swimmers (161°). The non-dominant arm displayed values closer to the optimum (171°), while swimming speed had no effect on backstroke shoulder entry angle. In conclusion, backstroke shoulder entry angle may help discriminate between advanced and intermediate backstroke swimmers and may be influenced by laterality dominance, being independent of swimming speed.

Introduction Venous thromboembolism (VTE) remains a major contributor to global disease burden and is a leading cause of cardiovascular death worldwide. Hospital-acquired VTE (HA-VTE; VTE diagnosed during hospital admission or within 90 days of discharge) accounts for a significant proportion of all VTE events. Data from countries where the use of specific VTE risk assessment tools and appropriate thromboprophylaxis is mandatory (and incentivized) have demonstrated that the implementation of these strategies significantly reduces mortality as a result of HA-VTE. Despite the evidence that these measures save lives, an ad hoc approach to the use of VTE risk assessment/thromboprophylaxis is frequently adopted. Moreover, in many healthcare systems very few data describing incidence of HA-VTE have been reported and consequently the magnitude of this potentially preventable source of hospital deaths is likely to be underestimated. We aimed to determine the incidence of VTE and of HA-VTE within the population served by the Ireland East Hospital Group (IEHG; the largest hospital group within the Irish healthcare network) as a first step towards promoting the implementation of a mandatory VTE risk assessment policy on a national level. Methods A retrospective observational study was conducted where data pertaining to the diagnosis of VTE during the period January 2016 to October 2017 were collected. The IEHG is comprised of 11 hospitals serving a population of over 1 million individuals from urban and rural areas, affluent areas as well as economically disadvantaged areas and includes large tertiary academic centers as well as smaller community hospitals and the national maternity hospital. Data were obtained from NQAIS Clinical (National Quality Assurance Intelligence system - Clinical), an online reporting tool which is populated by anonymised data extracted from the hospital in-patient enquiry system (HIPE; a reporting tool which compiles diagnostic data on all patients by ICD-10 code at the time of discharge from hospital). In NQAIS clinical, VTE events are categorised as primary if they represented the reason for hospital admission or secondary if they were diagnosed during the period of hospitalisation. The term secondary VTE can therefore be understood to represent a surrogate-marker for HA-VTE; however, this methodology would be predicted to underestimate the total number of HA-VTE events as VTE diagnosed following discharge but within 90 days would be incorrectly categorised as primary events. Currently, no measures exist within our current data recording systems which can accurately capture post-discharge HA-VTE. Results During the 22-month study period, 2727 VTE events were reported. Using population data derived from the 2016 census, we then estimated the annual incidence of VTE within the IEHG catchment area (population 1,036,279) at 1.44 per 1000 person years (95% CI 1.36-1.51). VTE incidence by gender was similar for all age groups however a progressive increase in VTE incidence was observed (predictably) with increasing age, with the highest incidence reported among individuals aged over 85 years (16.03 per 1000 person years; 95% CI 12.81-19.26). The majority of VTE events were diagnosed in the two large academic teaching hospitals of the IEHG (1620 VTE events; 59.4%). The vast majority of cases were reported in the context of an emergency hospital admission (89.2%). Of the total number of VTE events diagnosed during the study period, 1273 (47%) were reported as secondary events (i.e. diagnosed during the period of hospital admission) and, as such, this figure represents an approximation but most likely a significant underestimation of the total proportion of hospital-acquired events. Within this category of HA-VTE/secondary VTE diagnoses, the most frequently reported primary diagnoses leading to the initial hospital admission were cancers (16.4%) followed by respiratory disease (14.6%) and cardiovascular disorders (13.5%). Conclusion Within a population of over 1 million individuals, where formal VTE risk reduction strategies have yet to be implemented universally, at least 47% of all VTE are hospital-acquired. Given the compelling evidence which has shown that HA-VTE is a leading source of (preventable) hospital mortality, these findings provide a clear rationale for implementing formal VTE risk reduction strategies at hospital-group and national level. Disclosures Kevane: Leo Pharma: Research Funding. Ni Ainle:Leo Pharma: Research Funding; Actelion: Research Funding; Bayer: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Boehringer: Membership on an entity's Board of Directors or advisory committees.