Analysis of Driver Decisions at the Onset of Yellow at Signalized Intersections

Calreticulin Mutation Does Not Modify the International Prognostic Score for Predicting the Risk of Thrombosis Among 1,150 Patients with Essential Thrombocythemia

Blood ◽

10.1182/blood.v124.21.404.404 ◽

2014 ◽

Vol 124 (21) ◽

pp. 404-404

Author(s):

Guido Finazzi ◽

Alessandra Carobbio ◽

Paola Guglielmelli ◽

Elisa Rumi ◽

Silvia Salmoiraghi ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Prognostic Score ◽

Low Risk ◽

Intermediate Risk ◽

Thrombotic Risk ◽

Exon 9 ◽

International Prognostic Score ◽

Risk Categories ◽

Calr Mutation

Abstract Background An International Prognostic Score for the risk of thrombosis (IPSET-thrombosis) in Essential Thrombocythemia (ET) was developed (Barbui et al. Blood, 2012;120:5128). Risk factors included: age >60 years (1 point), cardiovascular (CV) risk factors (1 point), previous thrombosis (2 points) and the presence of JAK2V617F mutation (2 points). Low, intermediate and high risk categories were identified by scores 0-1; 2; and ≥ 3, respectively. Mutations in the exon 9 of CALreticulin (CALR) gene were recently identified in about 50-60% of patients with JAK2V617F negative ET and associated with a reduced thrombotic risk as compared with JAK2V617F positive patients. Aim To evaluate whether the identification of CALRmutation in patients with ET has any impact on the IPSET-thrombosis score Patients and Methods Under the auspices of AGIMM (AIRC Gruppo Italiano Malattie Mieloproliferative), four Italian centers with recognized experience in myeloproliferative neoplasms participated in the current study. Overall, 1,150 patients who met the 2008 WHO criteria for ET and were molecularly characterized for JAK2V617F, MPLW515L/K and CALR exon 9 mutations were included. The JAK2 and MPL mutations were assessed by real-time quantitative polymerase chain reaction and by high-resolution melting analysis followed by bidirectional Sanger sequencing. Mutations in exon 9 of CALRwere assessed by bidirectional sequencing or next generation sequencing. Results Presenting features of the study population were: median age 58 years (range 5th-95th percentile 27-82 years; 65% females), median hemoglobin 14.1 g/dL (range 5th-95th percentile 11.8-16.3), median leukocyte count 8.7x109/L (range 5th-95th percentile 5.4-14.7), median platelet count 718x109/L (range 5th-95th percentile 486-1313). CV risk factors (at least one among smoke, diabetes and hypertension) were present in 568 (49%) patients. Arterial or venous thrombosis history before or at diagnosis was documented in 167 (15%) patients. JAK2V17F, MPLW515L/K and CALRmutations were detected in 744 (65%), 44 (4%) and 164 (14%) patients respectively. The remaining 198 patients (17%) were wild-type for all three mutations. During a median follow-up of 4.1 years (range 0-29), 104 patients developed an arterial or venous thrombotic event, with a total incidence rate of 1.59% patients/year (pt-ys). The IPSET-thrombosis ability to discriminate the thrombotic risk was confirmed. In fact, in the low risk (reference category), the rate was 0.57% pt-ys; in the intermediate risk was 1.60% pt-ys (Hazard Ratio (HR) 3.10, 95% Confidence Interval (CI) 1.55-6.18, p=0.001) and in the high risk group was 2.34% pts-yr (HR 4.59, 95% CI 2.41-8.77 p<0.0001). As to the impact of CALR mutation in the three categories of the IPSET-thrombosis score, we observed that CALR mutated patients were more frequently distributed in the low risk (48%) and intermediate risk (46%) than in the high risk IPSET groups (6%). In univariate analysis, patients carrying CALR mutation had a lower incidence of thrombosis than those with JAK2V617F (HR 0.61, 95% CI 0.34-1.09, p=0.093). However, CALR mutated patients were significantly younger (median age 53.5 versus 60.8 years, p=0.001) and presented with less previous thrombosis (8% versus 17%, p=0.005) than JAK2V617F mutated patients. This could explain why in multivariable models, CALR mutation did not retain the association with the risk of thrombosis. This was demonstrated in the whole population (HR 0.81, 95% CI 0.30-2.17, p=0.674), as well as in the low risk (HR 1.01, range 0.27-3.81, p=0.987) and intermediate risk categories (HR 1.80, range 0.57-5.72, p=0.317); the high risk category was not evaluable for the low proportion of CALRmutated patients in this group. Conclusions CALR mutation does not have a significant impact on the IPSET-thrombosis prognostic score. The score can be used as it is to predict the risk of thrombosis in molecularly-annotated, WHO-2008 diagnosed ET patients. Disclosures Vannucchi: Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding.

Disease-Attributable Mortality in the Myelodysplastic Syndromes (MDS): A Study from the Spanish MDS Cooperative Group (GESMD)

Blood ◽

10.1182/blood.v126.23.1672.1672 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1672-1672

Author(s):

Meritxell Nomdedeu ◽

Xavier Calvo ◽

Dolors Costa ◽

Montserrat Arnan ◽

Helena Pomares ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Mortality Rates ◽

Low Risk ◽

Attributable Mortality ◽

Risk Category ◽

Intermediate Risk ◽

Advisory Committees ◽

Very High ◽

Risk Categories

Abstract Introduction: The MDS are a group of clonal hematopoietic disorders characterized by blood cytopenias and increased risk of transformation into acute myeloid leukemia (AML). The MDS predominate in old people (median age at diagnosis > 70 years) so that a fraction of the observed mortality would be driven by age-related factors shared with the general population rather than the MDS. Distinguishing between the MDS-related and unrelated mortality rates will help better assessment of the population health impact of the MDS and more accurate prognostication. This study was aimed at quantifying the MDS-attributable mortality and its relationship with the IPSSR risk categories. Methods: The database of the GESMD was queried for patients diagnosed with primary MDS after 1980 according to the WHO 2001 classification. Patients with CMML, younger than 16 years or who lacked the basic demographic or follow-up data were excluded. Relative survival and MDS-attributable mortality were calculated by the cohort method and statistically compared by Poisson multivariate regression as described by Dickman (Stat Med 2004; 23: 51). Three main parameters were calculated: the observed (all-cause) mortality, the MDS-attributable mortality (both as percentage of the initial cohort), and the fraction of the observed mortality attributed to the MDS. Results: In total, 7408 patients met the inclusion criteria and constitute the basis for this study. Among these patients, 5307 had enough data to be classified according to the IPSSR. Median age was 74 (IQR: 16-99) years and 58 % were males. The most frequent WHO categories were RAEB, type I or II (29% of cases), RCMD (28%), and RA with ring sideroblasts (16%). Most patients (72%) were classified within the very low and low risk categories of the IPSSR. At the study closing date (December 2014), 1022 patients had progressed to AML, 3198 had died (974 after AML) and 3210 were censored alive. The median actuarial survival for the whole series was 4.8 (95% CI: 4.6-5.1) years and 30% of patients are projected to survive longer than 10 years. The overall MDS-attributable mortality at 5 years from diagnosis was 39%, which accounted for three-quarters of the observed mortality (51%, figure). The corresponding figures at 10 years for the MDS-attributable and observed mortality were 55% and 71%, respectively. According to the IPSSR, the 5-year MDS-attributable mortality rates was 19% for the very low risk category, 39% (low risk), 70% (intermediate risk), 78% (high risk), and 92% (very high risk). On average, the incidence rate ratio for the MDS-attributable mortality increased 1.9 times (95% CI: 1.7-2.3, p<0.001) as the IPSSR worsened from one to the next risk category. The fraction of the observed mortality attributed to the MDS was 0.55 for the very low risk category, 0.79 (low risk), 0.93 (intermediate risk), 0.96 (high risk), and 0.99 (very high risk). After distinguishing between AML-related and unrelated mortality, the 5-year MDS-attributable mortality not related to AML was 10% for the very low risk category, 20% (low risk), 33% (intermediate risk), 42% (high risk), and 44% (very high risk). By comparing these figures with the above ones, we could estimate that about 50% of the MDS-attributable mortality was AML-unrelated and that such fraction kept nearly constant across the five IPSSR categories. Conclusions: About three-quarters of the mortality observed in patients with MDS is caused by the disease, the remaining one-quarter being due to MDS-independent factors shared with the general population. The MDS-attributable mortality increases with the IPSSR risk category, from half the observed mortality in the very low risk to nearly all the mortality observed in the high and very high risk groups. Half the MDS-attributable mortality is driven by factors unrelated to leukemic transformation, a proportion that keeps constant across the five IPSSR risk categories. Disclosures Valcarcel: AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ramos:AMGEN: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria; JANSSEN: Honoraria, Membership on an entity's Board of Directors or advisory committees; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Health Lifestyles in Adolescence and Self-rated Health into Adulthood

Journal of Health and Social Behavior ◽

10.1177/0022146517735313 ◽

2017 ◽

Vol 58 (4) ◽

pp. 520-536 ◽

Cited By ~ 16

Author(s):

Amy M. Burdette ◽

Belinda L. Needham ◽

Miles G. Taylor ◽

Terrence D. Hill

Keyword(s):

High Risk ◽

Life Course ◽

Physical Health ◽

Latent Class ◽

Life Course Perspective ◽

Low Risk ◽

Adult Health ◽

Moderate Risk ◽

Health Lifestyles ◽

Health Lifestyle

Do health behaviors cluster together as health lifestyles in adolescence? Are these lifestyles socially patterned? Do these lifestyles impact physical health into adulthood? To answer these questions, we employed data from Waves 1 and 4 of the National Longitudinal Study of Adolescent to Adult Health ( n = 7,827). Our latent class analysis revealed four health lifestyles: (a) low risk, (b) moderate risk with substance use, (c) moderate risk with inactivity, and (d) high risk. As suggested by health lifestyle theory, membership in these classes varied according to gender, race-ethnicity, and family structure. Consistent with the life course perspective, regression analyses indicated that those in the high-risk lifestyle tend to exhibit worse health in adolescence and adulthood than those in the low-risk lifestyle. Our findings confirm that socially patterned lifestyles can be observed in adolescence, and these lifestyles are potentially important for understanding the distribution of physical health across the early life course.

Using Latent Class Analysis to Identify Different Risk Patterns for Patients With Masked Hypertension

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.680083 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ming Fu ◽

Xiangming Hu ◽

Shixin Yi ◽

Shuo Sun ◽

Ying Zhang ◽

...

Keyword(s):

High Risk ◽

Latent Class Analysis ◽

Latent Class ◽

Latent Class Model ◽

Fasting Blood Glucose ◽

Low Risk ◽

Biological Information ◽

Masked Hypertension ◽

Class Analysis ◽

The Impact

Background: There is controversy whether masked hypertension (MHT) requires additional intervention. The aim of this study is to evaluate whether MHT accompanied with high-risk metabolic syndrome (MetS), as the subphenotype, will have a different prognosis from low-risk MetS.Methods: We applied latent class analysis to identify subphenotypes of MHT, using the clinical and biological information collected from High-risk Cardiovascular Factor Screening and Chronic Disease Management Programme. We modeled the data, examined the relationship between subphenotypes and clinical outcomes, and further explored the impact of antihypertensive medication.Results: We included a total of 140 patients with MHT for analysis. The latent class model showed that the two-class (high/low-risk MetS) model was most suitable for MHT classification. The high-risk MetS subphenotype was characterized by larger waist circumference, lower HDL-C, higher fasting blood glucose and triglycerides, and prevalence of diabetes. After four years of follow-up, participants in subphenotype 1 had a higher non-major adverse cardiovascular event (MACE) survival probability than those in subphenotype 2 (P = 0.016). There was no interaction between different subphenotypes and the use of antihypertensive medications affecting the occurrence of MACE.Conclusions: We have identified two subphenotypes in MHT that have different metabolic characteristics and prognosis, which could give a clue to the importance of tracing the clinical correlation between MHT and metabolic risk factors. For patients with MHT and high-risk MetS, antihypertensive therapy may be insufficient.

The relationship between the female athlete triad and injury rates in collegiate female athletes

PeerJ ◽

10.7717/peerj.11092 ◽

2021 ◽

Vol 9 ◽

pp. e11092

Author(s):

Mutsuaki Edama ◽

Hiromi Inaba ◽

Fumi Hoshino ◽

Saya Natsui ◽

Sae Maruyama ◽

...

Keyword(s):

Risk Assessment ◽

Body Weight ◽

High Risk ◽

Low Risk ◽

Risk Category ◽

Moderate Risk ◽

Long Distance ◽

Injury Group ◽

The Relationship ◽

Risk Categories

Background This study aimed to clarify the relationship between the triad risk assessment score and the sports injury rate in 116 female college athletes (average age, 19.8 ± 1.3 years) in seven sports at the national level of competition; 67 were teenagers, and 49 were in their 20s. Methods Those with menstrual deficiency for >3 months or <6 menses in 12 months were classified as amenorrheic athletes. Low energy availability was defined as adolescent athletes having a body weight <85% of ideal body weight, and for adult athletes in their 20s, a body mass index ≤17.5 kg/m2. Bone mineral density (BMD) was measured on the heel of the right leg using an ultrasonic bone densitometer. Low BMD was defined as a BMD Z-score <−1.0. The total score for each athlete was calculated. The cumulative risk assessment was defined as follows: low risk (a total score of 0–1), moderate risk (2–5), and high risk (6). The injury survey recorded injuries referring to the injury survey items used by the International Olympic Committee. Results In swimming, significantly more athletes were in the low-risk category than in the moderate and high-risk categories (p = 0.004). In long-distance athletics, significantly more athletes were in the moderate-risk category than in the low and high-risk categories (p = 0.004). In the moderate and high-risk categories, significantly more athletes were in the injury group, whereas significantly more athletes in the low-risk category were in the non-injury group (p = 0.01). Significantly more athletes at moderate and high-risk categories had bone stress fractures and bursitis than athletes at low risk (p = 0.023). Discussion These results suggest that athletes with relative energy deficiency may have an increased injury risk.

FC 065PREDICTING OUTCOMES IN ANCA ASSOCIATED VASCULITIS: THE COMPLETE SCOTTISH EXPERIENCE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab136.004 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Dominic McGovern ◽

Jennifer Lees ◽

Dana Kidder ◽

James Smith ◽

Jamie Traynor ◽

...

Keyword(s):

High Risk ◽

Renal Biopsy ◽

Interstitial Fibrosis ◽

Low Risk ◽

Risk Category ◽

Proportional Hazard ◽

Anca Vasculitis ◽

Cox Proportional Hazard ◽

High Risk Category ◽

Risk Categories

Abstract Background and Aims Outcomes in ANCA vasculitis remain difficult to predict and therapeutic decision-making can be challenging. We aimed to establish if a renal risk score (RRS) could predict outcomes in this population. Method The Scottish Renal Biopsy Registry is a complete national dataset of all renal biopsies performed in Scotland. Those who had a first renal biopsy between 01/01/2014 and 31/12/2017 with evidence of ANCA vasculitis were included. Demographic data, treatment regimens, episodes of relapse and patient and kidney survival were recorded, retrospectively. The RRS was calculated using the system proposed by Brix et al (1). Each patient was categorised according to % of normal glomeruli (N0 >25%, N1 10 to 25%, N2 <10%), % of tubular atrophy/interstitial fibrosis (T0 ≤25%, T1 >25%) and eGFR (CKD-EPI) at time of biopsy (eGFR: G0 >15 mL/min/1.73 m2, G1 ≤15 mL/min/1.73 m2). Individual scores were summated and patients defined as low, medium or high risk. Cox proportional hazard models were created for survival to ESKD, relapse and death, stratified by risk category. Analyses were conducted using R statistical software. Results Two-hundred and forty-six patients with biopsy proven ANCA vasculitis were identified. Fifty percent (n=123), 46% (n=112) and 5% (n=11) were stratified as low, medium and high risk respectively. Fifty-two percent (n=129) were male and mean age at biopsy was 66.7±12.2 years. This was similar across the risk categories. Mean eGFR was lower in the high-risk category (High risk 8.6±6.1 ‘v’ Low risk 45.7±26.0 ml/min/1.73m2, p<0.001) and proteinuria was higher (High risk 405 (IQR 170-767) ‘v’ Low risk 81 (IQR 41-155) mg/mmol, p<0.001). Thirty-seven percent (n=91) were PR3 antigen positive, 2% (n=5) had dual positivity. In the high risk category, 8 (73%) were PR3 or dual positive. Eighteen (n=7%) patients experienced pulmonary haemorrhage; representation similar across all risk categories. Those categorised as medium or high risk were more likely to receive plasma exchange and/or haemodialysis at presentation (p<0.001) compared with the low risk category. Overall, 16% (n=40) of patients relapsed with a trend to higher risk of relapse in the low risk group (27% of these patients, p=0.05). Thirty seven (15%) patients developed ESKD. Cox proportional hazard model for development of ESKD (Figure 1) shows that those in high risk ‘v’ low risk category were more likely to reach ESKD (HR 124.8, 95% CI 26.4-590.3, p<0.001). Patient survival was similar between risk categories. Conclusion A simple RRS, using routinely reported data, in patients with renal biopsy proven ANCA vasculitis can help to predict development of ESKD. It may also be predictive of future relapse in those with a lower RRS, most likely explained by reduced irreversible damage in this group. The RRS could inform monitoring and treatment decisions. Whilst the numbers are small, a unique strength of this data is that it is based on a complete national dataset making it less susceptible to bias from regional variations in diagnostic and therapeutic practice.

Aberrant Phenotype of Stem Cells as Assessed by Flow Cytometry Discriminates Between Low and High Risk Myelodysplastic Syndromes and Might Be Instrumental in Predicting Leukemic Evolution.

Blood ◽

10.1182/blood.v114.22.3798.3798 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3798-3798

Author(s):

Theresia M Westers ◽

Canan Alhan ◽

Monique Terwijn ◽

Claudia Cali ◽

Yvonne FCM van der Veeken ◽

...

Keyword(s):

Stem Cells ◽

Flow Cytometry ◽

Stem Cell ◽

High Risk ◽

Low Risk ◽

Refractory Anemia ◽

Lineage Infidelity ◽

Marker Expression ◽

Median Expression ◽

Risk Categories

Abstract Abstract 3798 Poster Board III-734 Myelodysplastic syndromes (MDS) can be classified into low risk and high risk categories, with evolution to acute myeloid leukemia (AML) predominantly in the latter cases. In AML, survival of leukemia-initiating cells, often referred to as leukemic stem cells, after chemotherapy is thought to result in minimal residual disease leading to relapse. A larger size of the stem cell compartment in de novo AML is predictive for poor survival [Van Rhenen et al.,Clin Cancer Res 2005,11]. A monoclonal antibody against the cell surface antigen C-type lectin-like molecule-1, CLL-1, together with lineage infidelity markers enables discrimination of normal and malignant stem cells in AML [Van Rhenen et al., Blood 2007, 110; Van Rhenen et al., Leukemia 2007, 21]. Previously, we showed that the size of the total stem cell compartment including both normal and malignant cells, defined as CD45dimCD34+CD38−, were significantly more prevalent within the blast cell fraction in high risk MDS as compared to low risk MDS (median 0.77% (n=15) and 0.25% (n=73), respectively, p=0.040) [Westers et al. Blood 2008, 112, abstract 1661]. This might reflect the differences in clinical course in these patients. It could be hypothesized that aberrant marker expression on MDS stem cells may predict leukemic evolution. Therefore, stem cells in MDS bone marrow samples were analyzed by flow cytometry for expression of CLL-1 and aberrant lineage markers. A reliable number of stem cells (>20) could be examined in 22 low risk and 14 high risk MDS patients; patients were classified by WHO2001 as refractory anemia w/o ring sideroblasts (RS; n=6) or refractory cytopenia with multilineage dysplasia w/o RS (n=16) and 14 refractory anemia with excess of blasts type 1 or 2 (n=14). Median CLL-1 expression on the CD34+CD38− stem cells was 0.0% (range 0-50, 3 out of 22 clearly (>10%) positive cases) in low risk and 2.2% (range 0-27, 3 out of 14 clearly positive cases) in high risk MDS. For comparison, median CLL-1 expression on stem cells in normal controls was 0.0% (range 0-4.7, not significantly different from MDS cases: p=0.55 and 0.20 as compared to low and high risk categories, respectively). Eleven of the low risk MDS cases were tested for aberrant lineage infidelity marker expression on their myeloid blasts and stem cells. In these cases, myeloid blasts expressed either CD5 or CD7 (n=2 and n=7, respectively; median 33% of blast cells). Median expression of these antigens on stem cells was only 1.2% (range 0-47). There was only one case with high expression (47%); the rest was below 7%. Only four of the high risk cases could be analyzed for lineage infidelity marker expression. In these patients, median 51% of the myeloid blasts expressed either CD5 (n=1), CD7 (n=1) or CD56 (n=2). Median expression of these antigens on stem cells in these high risk MDS cases was 44% (range 3-83); three of four cases had high expression (>40%). Overall, expression of CLL-1 and lineage infidelity markers was higher in high risk MDS as compared to the low risk category (p=0.047 and p=0.036 for CLL-1 and lineage infidelity markers, respectively). Of note, the only low risk case with a high percentage (47%) of aberrant stem cells as assessed by flow cytometry rapidly progressed towards AML. To conclude, CLL-1 is virtually absent on stem cells in low and high risk MDS. Nevertheless, expression of lineage infidelity markers, such as CD5, CD7 and CD56, on CD34+CD38− stem cells in some cases strongly suggests that a considerable part of these stem cells was malignant. Aberrant stem cell phenotype as assessed by flow cytometry might discriminate normal from MDS stem cells. This enables further analysis of MDS stem cells and, moreover, makes them amenable for application of targeted therapy. Future analysis might reveal whether the existence of MDS stem cells with an aberrant profile by flow cytometry predicts leukemic evolution. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of Mutations in a Large Series of Patients with Myelofibrosis

Blood ◽

10.1182/blood.v120.21.431.431 ◽

2012 ◽

Vol 120 (21) ◽

pp. 431-431

Author(s):

Paola Guglielmelli ◽

Flavia Biamonte ◽

Arturo Pereira ◽

Johannah Score ◽

Carmela Mannarelli ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Median Survival ◽

Low Risk ◽

Risk Category ◽

Prognostic Impact ◽

Bootstrap Analysis ◽

Molecular Abnormalities ◽

High Risk Category ◽

Risk Categories

Abstract Abstract 431 Background. Primary myelofibrosis (PMF) has the worst prognosis among myeloproliferative neoplasms with median overall survival (OS) of 4.6y in the International Prognostic Scoring System (IPSS) series (Cervantes F, Blood 2009;113:2895) and 6.5y in patients (pts) seen more recently (Cervantes F, JCO, 2012 in press). OS is predicted by the four risk categories of IPSS, dynamic-IPSS and IPSS-plus system, and these scores are used for therapeutic choices particularly allogeneic stem cell transplantation. Nevertheless, pts heterogeneity still remains within these categories, necessitating improved risk stratification. A number of molecular abnormalities have been reported in PMF pts, but their prognostic relevance is incompletely understood, particularly with regard to transformation to leukemia (AL). The aim of this work was to analyze the prognostic impact of known mutations detected close to diagnosis in an international series of 429 pts. Patients and methods. PMF diagnosis had to satisfy the 2008 WHO criteria. Mutations in JAK2V617F, MPLW515, EZH2, ASXL1, TET2, IDH1/2, DNMT3A, CBL, SRSF2 were genotyped in whole blood or granulocytes using allele specific RTQ-PCR, HRM and direct sequencing; all mutations were confirmed at least twice. Missense, nonsense and frameshift mutations were considered; in case of novel mutations, SNPs were excluded by database searching and when feasible by germline DNA genotyping. The prognostic value of the molecular variables with regard to overall survival (OS) was analyzed by Cox regression and adjusted for the IPSS category. The association of molecular features with the risk of progression to AL was investigated in the framework of competing risks by the Fine & Gray regression method. Replicability of the prognostic models for both OS and progression to AL was assessed by replication in 1000 bootstrap samples randomly taken from the original series. Results. Patient median age was 60y. Median follow-up was 3.7y (95% CI, 0.02–27.9), death occurred in 157 pts (32%). Frequency of pts with constitutional symptoms was 28%, splenomegaly 74%, anemia 27%, leukocytosis 8%, >1% blasts 16%, thrombocytopenia 12%. Abnormal karyotype was found in 24% (of 229 evaluated). IPSS risk category: low-risk 35%, Int-1 30%, Int-2 21%, High-risk 14%. Frequency of mutations was: JAK2V617F 59.8% with 49% of pts having <25% allele burden; MPLW515 14%; EZH2 5%; ASXL1 21.3%; TET2 9.5%; IDH1-2 2.4%; DNMT3A 5.6%; CBL 4.3%; SRSF2 8.4%. Survival Model. Median survival was 9.7y (CI, 7.9–12.2), 22y in low-risk, 10y Int-1, 6.2y Int-2, 2.5y high-risk (P<0.0001). We found a strong association between IPSS risk categories and ASXL1 and SRSF2 mutated cases that clustered in the high-risk category (41.5% and 25.4%, respectively, P<0.001). ASXL1 mutations were associated with leukocytosis, blasts and constitutional symptoms; mutations in SRSF2 with older age, leukocytosis and symptoms. No other relevant associations between IPSS and molecular parameters was found. In the final prognostic model, only mutations in ASXL1 (Hazard ratio, HR:2.02; P<0.001) were found to add to IPSS (HR: 2.40; P<0.001) with regards to OS independently of the association of ASXL1 mutations and high-risk category. Within the Int-2/high-risk category, ASXL1 mutations were associated with significantly shorter survival (median survival 2.6 years months for mutated versus 5.8 years for unmutated; P=0.0004). According to bootstrap analysis, ASXL1 mutations were selected as significant predictor for OS in 74.6% of the samples. Leukemia Model. AL occurred in 75 pts (15.2%) after of a median of 3.8y (95%, 0.04–26.5) from diagnosis. Mutations in ASXL1 and IDH1/2 were the only molecular variables associated with higher risk of AL with a SHR of 2.33 (P<0.001) and 3.63 (P=0.008), respectively. Bootstrap validation approach resulted in ASXL1 and IDH1/2 mutations being significant predictors for AL in 60% and 54% of the samples, respectively. Conclusions. In this comprehensive series of mutations profiled in PMF pts, mutations in ASXL1 emerged as a powerful prognostic variable for survival refining prognosis in the Int-2/high risk IPSS categories. ASXL1 and IDH1/2 mutations predicted for death due to AL. Therefore, genotyping for ASXL1 and IDH1-2 mutations at diagnosis may help to tailor therapy for pts with IPSS Int-2/high risk PMF. Disclosures: No relevant conflicts of interest to declare.

LO06: Development of practice recommendations for ED management of syncope by mixed methods

CJEM ◽

10.1017/cem.2020.62 ◽

2020 ◽

Vol 22 (S1) ◽

pp. S8-S9

Author(s):

V. Thiruganasambandamoorthy ◽

M. Taljaard ◽

N. Hudek ◽

J. Brehaut ◽

B. Ghaedi ◽

...

Keyword(s):

High Risk ◽

Low Risk ◽

Cardiac Monitoring ◽

Structured Interviews ◽

High Risk Patients ◽

Practice Recommendations ◽

Medium Risk ◽

Risk Patients ◽

Risk Categories

Introduction: Emergency department (ED) syncope management is extremely variable. We developed practice recommendations based on the validated Canadian Syncope Risk Score (CSRS) and outpatient cardiac monitoring strategy with physician input. Methods: We used a 2-step approach. Step-1: We pooled data from the derivation and validation prospective cohort studies (with adequate sample size) conducted at 11 Canadian sites (Sep 2010 to Apr 2018). Adults with syncope were enrolled excluding those with serious outcome identified during index ED evaluation. 30-day adjudicated serious outcomes were arrhythmic (arrhythmias, unknown cause of death) and non-arrhythmic (MI, structural heart disease, pulmonary embolism, hemorrhage)]. We compared the serious outcome proportion among risk categories using Cochran-Armitage test. Step-2: We conducted semi-structured interviews using observed risk to develop and refine the recommendations. We used purposive sampling of physicians involved in syncope care at 8 sites from Jun-Dec 2019 until theme saturation was reached. Two independent raters coded interviews using an inductive approach to identify themes; discrepancies were resolved by consensus. Results: Of the 8176 patients (mean age 54, 55% female), 293 (3.6%; 95%CI 3.2-4.0%) experienced 30-day serious outcomes; 0.4% deaths, 2.5% arrhythmic, 1.1% non-arrhythmic outcomes. The serious outcome proportion significantly increased from low to high-risk categories (p < 0.001; overall 0.6% to 27.7%; arrhythmic 0.2% to 17.3%; non-arrhythmic 0.4% to 5.9% respectively). C-statistic was 0.88 (95%CI0.86–0.90). Non-arrhythmia risk per day for the first 2 days was 0.5% for medium-risk, 2% for high-risk and very low thereafter. We recruited 31 physicians (14 ED, 7 cardiologists, 10 hospitalists/internists). 80% of physicians agreed that low risk patients can be discharged without specific follow-up with inconsistencies around length of ED observation. For cardiac monitoring of medium and high-risk, 64% indicated that they don't have access; 56% currently admit high-risk patients and an additional 20% agreed to this recommendation. A deeper exploration led to following refinement: discharge without specific follow-up for low-risk, a shared decision approach for medium-risk and short course of hospitalization for high-risk patients. Conclusion: The recommendations were developed (with online calculator) based on in-depth feedback from key stakeholders to improve uptake during implementation.

Latent Classes and Cumulative Impacts of Adverse Childhood Experiences

Child Maltreatment ◽

10.1177/1077559517736628 ◽

2017 ◽

Vol 23 (2) ◽

pp. 111-125 ◽

Cited By ~ 22

Author(s):

Gia Elise Barboza

Keyword(s):

High Risk ◽

Adverse Childhood Experiences ◽

Latent Class ◽

Cumulative Risk ◽

Psychosocial Outcomes ◽

Risk Profile ◽

Low Risk ◽

Childhood Experiences ◽

Risk Class ◽

Adverse Childhood

Studies of adverse childhood experiences (ACEs) have gauged severity using a cumulative risk (CR) index. Few studies have focused on the nature of the context of adversity and their association with psychosocial outcomes. The objective of this study was to examine the patterning of ACEs and to explore the resultant patterns’ association with HIV risk-taking, problem drinking, and depressive symptoms in adulthood. Latent class analysis (LCA) was used to identify homogeneous, mutually exclusive “classes” of 11 of the most commonly used ACEs. The LCA resulted in four high-risk profiles and one low-risk profile, which were labeled: (1) highly abusive and dysfunctional (3.3%; n = 1,983), (2) emotionally abusive alcoholic with parental conflict (6%, n = 3,303), (3) sexual abuse only (4.3%, n = 2,260), (4) emotionally abusive and alcoholic (30.3%, n = 17,460), and (5) normative, low risk (56.3%, n = 32,950). Compared to the low-risk class, each high-risk profile was differentially associated with adult psychosocial outcomes even when the conditional CR within that class was similar. The results further our understanding about the pattern of ACEs and the unique pathways to poor health. Implications for child welfare systems when dealing with individuals who have experienced multiple forms of early childhood maltreatment and/or household dysfunction are discussed.