Large Prospective Multicenter Study Research Articles

Relationship between adverse drug reactions and unlicensed/off-label drug use in hospitalized children (EREMI): A study protocol

To date, few studies have shown a significant association between off-label drug use and adverse drug reactions (ADRs). The main aims of this study is to evaluate the relationship between adverse drug reactions and unlicensed or off-label drugs in hospitalized children and to provide more information on prescribing practice, the amplitude, consequences of unlicensed or off-label drug use in pediatric inpatients. In this multicenter prospective study started from 2013, we use the French summaries of product characteristics in Theriaque (a prescription products guide) as a primary reference source for determining pediatric drug labeling. The detection of ADRs is carried out spontaneously by health professionals and actively by research groups using a trigger tool and patients' electronic health records. The causality between suspected ADRs and medication is evaluated using the Naranjo and the French methods of imputability independently by pharmacovigilance center. All suspected ADRs are submitted for a second evaluation by an independent pharmacovigilance experts. For our best knowledge, EREMI is the first large multicenter prospective and objective study in France with an active ADRs monitoring and independent ADRs validation. This study identifies the risk factors that could be used to adjust preventive actions in children's care, guides future research in the field and increases the awareness of physicians in off-label drug use and in detecting and declaring ADRs. As data are obtained through extraction of information from hospital database and medical records, there is likely to be some under-reporting of items or missing data. In this study the field specialists detect all adverse events, experts in pharmacovigilance centers assess them and finally only the ADRs assessed by the independent committee are confirmed. Although we recruit a high number of patients, this observational study is subject to different confounders.

Association of ultra-processed food consumption with cardiovascular mortality in the US population: long-term results from a large prospective multicenter study

BackgroundUltra-processed foods have now become dominant in the global food system. Whether their consumption is associated with cardiovascular mortality remains controversial. Moreover, data on ultra-processed foods and cardiovascular outcomes are scarce in the US population. We aimed to examine the association of ultra-processed food consumption with cardiovascular mortality in a US population.MethodsA population-based cohort of 91,891 participants was identified from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary data were collected through a validated 137-item food frequency questionnaire. Ultra-processed foods were defined by the NOVA classification. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cardiovascular mortality. Restricted cubic spline regression was used to test nonlinearity. Subgroup analyses were conducted to identify the potential effect modifiers.ResultsAfter an average follow-up of 13.5 years (1,236,049.2 person-years), 5490 cardiovascular deaths were documented, including 3985 heart disease deaths and 1126 cerebrovascular deaths. In the fully adjusted model, participants in the highest vs. the lowest quintiles of ultra-processed food consumption had higher risks of death from cardiovascular disease (HRquintile 5 vs. 1, 1.50; 95% CI, 1.36–1.64) and heart disease (HRquintile 5 vs. 1, 1.68; 95% CI, 1.50–1.87) but not cerebrovascular disease (HRquintile 5 vs. 1, 0.94; 95% CI, 0.76–1.17). A nonlinear dose–response pattern was observed for overall cardiovascular and heart disease mortality (all Pnonlinearity < 0.05), with a threshold effect observed at ultra-processed food consumption of 2.4 servings/day and 2.3 servings/day, respectively; below the thresholds, no significant associations were observed for these two outcomes. Subgroup analyses showed that the increased risks of mortality from ultra-processed foods were significantly higher in women than in men (all Pinteraction < 0.05).ConclusionsHigh consumption of ultra-processed foods is associated with increased risks of overall cardiovascular and heart disease mortality. These harmful associations may be more pronounced in women. Our findings need to be confirmed in other populations and settings.

Obesity and Overweight Are Independently Associated with Greater Survival in Critically Ill Diabetic Patients: A Retrospective Cohort Study.

Background The relationship between obesity and the outcomes of critically ill diabetic patients is not completely clear. We aimed to assess the effects of obesity and overweight on the outcomes among diabetic patients in the intensive care unit (ICU). Methods Critically ill diabetic patients in the ICU were classified into three groups according to their body mass index. The primary outcomes were 30-day and 90-day mortality. ICU and hospital length of stay (LOS) and incidence and duration of mechanical ventilation were also assessed. Cox regression models were developed to evaluate the relationship between obesity and overweight and mortality. Results A total of 6108 eligible patients were included. The 30-day and 90-day mortality in the normal weight group were approximately 1.8 times and 1.5 times higher than in the obesity group and overweight group, respectively (P < 0.001, respectively). Meanwhile, the ICU (median (IQ): 2.9 (1.7, 5.3) vs. 2.7 (1.6, 4.8) vs. 2.8 (1.8, 5.0)) and hospital (median (IQ): 8.3 (5.4, 14.0) vs. 7.9 (5.1, 13.0) vs. 8.3 (5.3, 13.6)) LOS in the obesity group and overweight group were not longer than in the normal weight group. Compared with normal weight patients, obese patients had significantly higher incidence of mechanical ventilation (58.8% vs. 64.7%, P < 0.001) but no longer ventilation duration (median (IQ): 19.3 (7.0, 73.1) vs. 19.0 (6.0, 93.7), P = 1). Multivariate Cox regression showed that obese and overweight patients had lower 30-day (HR (95% CI): 0.62 (0.51, 0.75); 0.76 (0.62, 0.92), respectively) and 90-day (HR (95% CI): 0.60 (0.51, 0.70); 0.79 (0.67, 0.93), respectively) mortality risks than normal weight patients. Conclusions Obesity and overweight were independently associated with greater survival in critically ill diabetic patients, without increasing the ICU and hospital LOS. Large multicenter prospective studies are needed to confirm our findings and the underlying mechanisms warrant further investigation.

Atypical Manifestations of Dengue Fever in Children

Abstract Objective The burden of dengue fever (DF) is increasing rapidly worldwide. Several atypical manifestations of DF are being increasingly reported but there are no clear guidelines on their definition and management. Their timely detection and appropriate management might improve outcomes. We describe here our experience in managing atypical manifestations of DF in children and their outcomes in a teaching hospital in South India. Methods A retrospective chart review of children (1 month–18 years) hospitalized, between August 2017 and March 2018 with a diagnosis of DF (NS1 antigen or immunoglobulin M antibodies positivity), was done. The clinical details of the atypical manifestations are described. Results During the study period, 925 children were hospitalized with DF, of which 94 (10.16%) had severe dengue and 2 (0.21%) died. Among the 925 children, 7 (0.75%) had cardiac, 5 (0.54%) had neurological, 5 (0.54%) had hepatic, and 31 (3.3%) had immunological (infection-associated immune dysregulation) manifestations. Conclusion Most children with atypical manifestations of DF recover with supportive management. There is a need for a clear definition of atypical manifestations so that large prospective multicenter studies on incidence, optimum management, and outcomes can be done.

526 Time to intervention in obstetric hypertensive emergencies in a US urban center

To examine the association between race, ethnicity and preferred language and time to intervention in obstetric hypertensive emergencies In this retrospective cohort study, patients who received anti-hypertensive therapy and/or magnesium for severe-range blood pressures on their admission for delivery from January - December 2018 were included. Cox proportional hazards modeling assessed time to anti-hypertensive treatment and time to magnesium administration. Kaplan-Meier curves describe time from end-organ-involvement to delivery. Type of anti-hypertensive was subdivided into standard of care fast-acting anti-hypertensive therapy (e.g. Intravenous labetalol, hydralazine and immediate release nifedipine) and long acting oral anti-hypertensive medications. 63 patients identified as Black, 51 as Latinx, 18 as White or other and 13 did not identify their race. 125 identified English as their preferred language and 19 identified languages other than English as preferred. Cox hazard ratios for the time from severe BP to anti-hypertensive treatment for Black and Latinx patients as compared to White or other were 1.26 and 1.33 respectively. HR patients whose preferred language was other than English was 0.79. Figures 1 and 2 describe time to magnesium by race/ethnicity and language. There was no statistical difference for time from end organ involvement to delivery by race/ethnicity or language (p-values 0.76 and 0.57) In this study of women with hypertensive emergencies during their delivery hospitalization, Black and Latinx patients as well as patients who reported a non-English preferred language did not experience significantly different time to anti-hypertensive therapy or magnesium sulfate or delivery when end-organ involvement was present. We believe this may be due to the low number of White or other patients in the study. A larger prospective multi-center study is needed to determine if disparity exists within different patient populations.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Real-world outcomes of patients with intrahepatic cholangiocarcinoma treated with trans-arterial radioembolization: Results from the CIRSE Registry for SIR-Spheres Therapy (CIRT), a large European prospective multi-center observational study.

308 Background: Trans-arterial radioembolization (TARE) is a treatment option for patients with intrahepatic cholangiocarcinoma (ICC). The CIRSE Registry for SIR-Spheres Therapy (CIRT) is the first European prospective multi-centre observational study designed to evaluate the clinical outcomes of patients treated with TARE with SIR-Spheres Y90 resin microspheres for ICC in the multi-institutional real-life clinical setting. The study was conducted by the Cardiovascular and Interventional Radiological Society of Europe (CIRSE). Methods: Patients were enrolled prospectively between Jan 2015 and 31 Dec 2017. Eligible patients were adults treated with TARE with Y90 resin microspheres for ICC. Data on baseline characteristics and treatment intention/clinical context and dosimetry were collected, as well as follow-up data (every 3 months; for 24 months after treatment), including overall survival (OS), (hepatic) progression-free survival [(h)PFS], safety and Global Health Status (GHS, using the European Organisation for the Research and Treatment of Cancer QLQ-C30). Results: 120 patients were included from 18 sites in 8 European countries. Median age was 63 years (range: 29-86) and 54.2% were male. Median tumour to liver percentage was 12.8%. Median prescribed activity was 1.32 GBq for whole liver treatments (n = 49), 1.20 GBq for right lobe treatments (n = 56) and 0.82 GBq for left lobe treatments (n = 51). 97.5% of the delivered activity was within 90% of the prescribed activity. TARE treatment as a first line (L1) global strategy was applied in 39.1%, 27.4% as second line (after systemic therapy). Treatment intention was predominantly palliative (69.2%) or tumour shrinkage (20.8%). Median OS was 14.7 months (95% confidence interval (CI) 10.9 – 17.9). Median PFS was 5.7 months (95% CI 3.9 – 7.5), whereas hPFS was 6.2 months (95% CI 4.1 – 8.5). Mean GHS was 59.3 at baseline, 61.0 after 3 months, 56.0 at 6 months, 54.4 at 9 months and 63.0 after 1 year. Severe adverse events (grade 3 and 4) were found in 13 (10.8%) patients: (abdominal pain 3.3%, fatigue 1.7%, gastrointestinal ulceration 0.8%, gastritis 0.8%, radiation cholecystitis 0.8%, radiation-induced liver disease 1.7%, other 5.8%). Detailed subgroup analyses are currently being performed. Updated data describing OS, PFS and hPFS for L1 TARE vs TARE after systemic chemotherapy, as well as prognostic factors for OS, PFS and hPFS will be shown. Conclusions: The results from this large prospective multi-centre observational study shows that in the real-world context, TARE is applied early and successfully in the treatment pathway. TARE is shown to be an effective and safe treatment with no meaningful deterioration of quality of life. Clinical trial information: NCT02305459.

Noninvasive prenatal screening in twin pregnancies with cell-free DNA using the IONA test: a prospective multicenter study

In singleton pregnancies, studies investigating cell-free DNA in maternal blood have consistently reported high detection rate and low false-positive rate for the 3 common fetal trisomies (trisomies 21, 18, and 13). The potential advantages of noninvasive prenatal testing in twin pregnancies are even greater than in singletons, in particular lower need for invasive testing and consequent fetal loss rate. However, several organizations do not recommend cell-free DNA in twin pregnancies and call for larger prospective studies. In response to this, we undertook a large prospective multicenter study to establish the screening performance of cell-free DNA for the 3 common trisomies in twin pregnancies. Moreover, we combined our data with that reported in published studies to obtain the best estimate of screening performance. This was a prospective multicenter blinded study evaluating the screening performance of cell-free DNA in maternal plasma for the detection of fetal trisomies in twin pregnancies. The study took place in 6 fetal medicine centers in England, United Kingdom. The primary outcome was the screening performance and test failure rate of cell-free DNA using next generation sequencing (the IONA test). Maternal blood was taken at the time of (or after) a conventional screening test. Data were collected at enrolment, at any relevant invasive testing throughout pregnancy, and after delivery until the time of hospital discharge. Prospective detailed outcome ascertainment was undertaken on all newborns. The study was undertaken and reported according to the Standards for Reporting of Diagnostic Accuracy Studies. A pooled analysis was also undertaken using our data and those in the studies identified by a literature search (MEDLINE, Embase, CENTRAL, Cochrane Library, and ClinicalTrials.gov) on June 6,2020. A total of 1003 women with twin pregnancies were recruited, and complete data with follow-up and reference data were available for 961 (95.8%); 276 were monochorionic and 685 were dichorionic. The failure rate was 0.31%. The mean fetal fraction was 12.2% (range, 3%-36%); all 9 samples with a 3% fetal fraction provided a valid result. There were no false-positive or false-negative results for trisomy 21 or trisomy 13, whereas there was 1 false-negative and 1 false-positive result for trisomy 18. The IONA test had a detection rate of 100% for trisomy 21 (n=13; 95% confidence interval, 75-100), 0% for trisomy 18 (n=1; 95% confidence interval, 0-98), and 100% for trisomy 13 (n=1; 95% confidence interval, 3-100). The corresponding false-positive rates were 0% (95% confidence interval, 0-0.39), 0.10% (95% confidence interval, 0-0.58), and 0% (95% confidence interval, 0-0.39), respectively. By combining data from our study with the 11 studies identified by literature search, the detection rate for trisomy 21 was 95% (n=74; 95% confidence interval, 90-99) and the false-positive rate was 0.09% (n=5598; 95% confidence interval, 0.03-0.19). The corresponding values for trisomy 18 were 82% (n=22; 95% confidence interval, 66-93) and 0.08% (n=4869; 95% confidence interval, 0.02-0.18), respectively. There were 5 cases of trisomy 13 and 3881 non-trisomy 13 pregnancies, resulting in a computed average detection rate of 80% and a false-positive rate of 0.13%. This large multicenter study confirms that cell-free DNA testing is the most accurate screening test for trisomy 21 in twin pregnancies, with screening performance similar to that in singletons and very low failure rates (0.31%). The predictive accuracy for trisomies 18 and 13 may be less. However, given the low false-positive rate, offering first-line screening with cell-free DNA to women with twin pregnancy is appropriate in our view and should be considered a primary screening test for trisomy 21 in twins.

Do Antibody Positive Healthcare Workers Have Lower SARS-CoV-2 Infection Rates than Antibody Negative Healthcare Workers? Large Multi-Centre Prospective Cohort Study (The SIREN Study), England: June to November 2020

Background: There is an urgent need to better understand whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection.Methods: A large multi-centre prospective cohort was recruited from publicly funded hospital staff in the UK. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2-4 weeks) and completed fortnightly questionnaires on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive or prior PCR/antibody test positive) or negative cohort (antibody negative, not previously known to be PCR/antibody positive). Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, possible (subdivided by symptom-status)) depending on hierarchy of evidence. Individuals in the primary infection were excluded from this analysis if infection was confirmed by antibody only. Reinfection rates in the positive cohort were compared against new PCR positives in the negative cohort using a mixed effective multivariable logistic regression analysis.Findings: Between 18 June and 09 November 2020, 44 reinfections (2 probable, 42 possible) were detected in the baseline positive cohort of 6,614 participants, collectively contributing 1,339,078 days of follow-up. This compares with 318 new PCR positive infections and 94 antibody seroconversions in the negative cohort of 14,173 participants, contributing 1,868,646 days of follow-up. The incidence density per 100,000 person days between June and November 2020 was 3.2 reinfections in the positive cohort, compared with 22.4 new PCR confirmed infections in the negative cohort. The adjusted odds ratio was 0.17 for all reinfections (95% CI 0.13-0.24) compared to PCR confirmed primary infections. The median interval between primary infection and reinfection was over 160 days.Interpretation: A prior history of SARS-CoV-2 infection was associated with an 83% lower risk of infection, with median protective effect observed five months following primary infection. This is the minimum likely effect as seroconversions were not included.Trial Registration: Trial registered with ISRCTN, Trial ID: ISRCTN11041050. https://www.isrctn.com/ISRCTN11041050.Funding Statement: Department of Health and Social Care and Public Health England, with contributions from the Scottish, Welsh and Northern Irish governments.Declaration of Interests: No conflicts of interest declared.Ethics Approval Statement: IRAS ID 284460, Berkshire Research Ethics Committee, Health Research Authority and Health and Care Research Wales approval granted 22 May 2020.

1162. Engraftment fever (EF) in Pediatric stem cell transplantation (SCT): Risk Factors, Etiology and Outcomes

BackgroundEngraftment fever (EF) during stem cell transplantation (SCT) is likely due to non infectious causes like immune reconstitution syndrome (IRS) or engraftment syndrome (ES). Few studies have looked at the rate of infection causing fever during engraftment. There is no good evidence to guide the approach to evaluation and empiric treatment of infections during EF.MethodsRetrospective record review of pediatric SCT (autologous and allogenic) patients with a diagnosis of febrile neutropenia (FN) during engraftment period (days +7 to +30 post transplant). FN episodes classified as either EF or non-engraftment fever (NEF). EF = new onset fever in temporal relationship to neutrophil recovery (4 days before through 1 day after neutrophil engraftment (ANC >500/mm3). NEF = fever without signs of neutrophil recovery (ANC < 100/mm3 without significant rise ±4 days of fever onset). Only first FN during engraftment was included. Episodes meeting neither criteria were excluded.Results112 patients had 115 FN episodes (FNEs) identified: NEF 81 (71.5%); EF 34 (29.5%). In multivariable analysis: Neuroblastoma as underlying diagnosis (odds ratio [OR]=3.2, 95% CI 2.31-6.54, P< 0.01), G-CSF administration before day +7 (OR=2.8, 95% CI 1.92-4.65, P=0.03), absolute monocyte count (AMC) >100/mm3 at FN presentation (OR=2.9, 95% CI, 1.11 to 7.55, P=0.02), were associated with an increased risk of EF compared with NEF. Most EF episodes (26/34, 76%) had no specific infectious etiology identified; 8 had IFIs (24%) [3 proven, 2 probable, 3 possible). IFI rate was higher in EF than NEF group (24% vs 5%) (OR=4.5, 95% CI, 2.11 to 9.55, P< 0.01. EF episodes were more likely to be admitted to the intensive care unit (OR=2.3, 95% CI, 1.88 to 6.35) and had higher 30-day mortality (OR =4.52, 95% CI, 0.37 to 6.55) than NEF.Table 3 table 2 ConclusionEngraftment fever may have an infectious component. Work-up to exclude IFI and empirical antifungal therapy should be considered especially with prolonged fever and supportive clinical or radiological data. Large multi-center prospective studies are needed to further define infectious complications and determine the approach to engraftment fever. Early detection of IFI in this high-risk group may lead to improved morbidity and mortality.Disclosures All Authors: No reported disclosures

Factors related to a non-localising technetium 99m sestamibi scan result during parathyroid adenoma imaging in primary hyperparathyroidism.

The aim of this study is to investigate factors that are associated with having a non-localising 99m Tc-sestamibi scan. A retrospective study was performed on patients that underwent parathyroid surgery performed within a single institution between 2001 and 2018. Single tertiary centre for parathyroid surgery. 230 patients underwent surgery for primary hyperparathyroidism due to a solitary parathyroid adenoma and had preoperative 99m Tc-sestamibi imaging. Variables including age, gender, intra-operative location of parathyroid adenoma, adenoma weight and pre- and postoperative calcium and parathyroid hormone levels were investigated through univariate and multivariate analysis to identify any association with having a non-localising (negative) 99m Tc-sestamibi scan result. Multivariate analysis identified that right-sided adenomas (P=.038), superior adenomas (P=.042) and a lower preoperative PTH level (P=.034) were all individual factors associated with having a negative 99m Tc-sestamibi scan result. Although the weight of the adenoma was significant on univariate analysis (P=.029), this was not demonstrated on multivariate analysis (P=.422). Factors that were associated with having non-localising 99m Tc-sestamibi scan were right-sided adenomas, superior adenomas and lower preoperative PTH level. Further large prospective multicentre studies are needed to further evaluate these initial findings.

The Early Detection of Breast Cancer Treatment-Related Lymphedema of the Arm.

Background: It is recognized that the early detection of breast cancer treatment related lymphedema (BCRL) leading to earlier intervention may improve long-term outcomes. This study aimed to determine whether limb volume measurement or bioimpedance spectroscopy (BIS) was the better tool for the early detection of BCRL. It also aimed to identify factors, which may be used to assess the risk of development of BCRL for individual patients. Methods and Results: This was a large prospective multicenter study of 1100 patients, who had had axillary node clearance for breast cancer, carried out in the United Kingdom. Limb volumes (by Perometer) and BIS (L-Dex by Impedimed U400) measurements were taken preoperatively and postsurgery with a follow-up period of 5 years. Details of the cancer, its treatment, body mass index (BMI), and age were recorded. BCRL was defined by relative arm volume increase (RAVI) ≥10%. At 24 months, the incidence of BCRL defined by RAVI was 22.8% and that defined by L-Dex >10 was 45.6%. Independent risk factors for the development of BCRL at 36 months were RAVI ≥5%-<10%, at 1 month, 10 or more positive nodes, BMI >30 and taxane chemotherapy. A risk assessment tool based on these was developed. Conclusions: Limb volume measurements performed better than BIS in the early detection of BCRL. Pre- and postoperative monitoring of limb volume measurements is useful in the early detection of, and prediction of those likely to develop, BCRL and allow early intervention.

Feasibility, safety, and resource utilisation of active mobilisation of patients on extracorporeal life support: a prospective observational study

BackgroundThere is scarce evidence on the feasibility, safety and resource utilisation of active mobilisation in critically ill patients on extracorporeal life support (ECLS).MethodsThis prospective observational single-centre study included all consecutive critically ill patients on ECLS admitted to an academic centre in Germany over a time period of one year. The level of mobilisation was categorised according to the ICU Mobility Scale (IMS). Primary outcome was complications during mobilisation.ResultsDuring the study period, active mobilisation with an activity level on the IMS of ≥ 3 was performed at least on one occasion in 43 out of 115 patients (37.4%). A total of 332 mobilisations with IMS ≥ 3 were performed during 1242 ECLS days (26.7%). ECLS configurations applied were va-ECMO (n = 63), vv-ECMO (n = 26), vv-ECCO2R (n = 12), av-ECCO2R (n = 10), and RVAD (n = 4). Femoral cannulation had been in place in 108 patients (93.9%). The median duration of all mobilisation activities with IMS ≥ 3 was 130 min (IQR 44–215). All mobilisations were undertaken by a multi-professional ECLS team with a median number of 3 team members involved (IQR 3–4). Bleeding from cannulation site requiring transfusion and/or surgery occurred in 6.9% of actively mobilised patients and in 15.3% of non-mobilised patients. During one mobilisation episode, accidental femoral cannula displacement occurred with immediate and effective recannulation. Sedation was the major reason for non-mobilisation.ConclusionsActive mobilisation (IMS ≥ 3) of ECLS patients undertaken by an experienced multi-professional team was feasible, and complications were infrequent and managed successfully. Larger prospective multicentre studies are needed to further evaluate early goal directed sedation and mobilisation bundles in patients on ECLS.

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.

The (T) thrombosis (I) in patients with (L) lower (L) limb (I) injuries (R)requiring (I) immobilisation (TILLIRI) study: A prospective observational multicentre study

IntroductionTemporarily immobilising an injured lower limb is a recognised predisposing factor for the development of venous thromboembolism (VTE). We aim to conduct a prospective study to measure the incidence of VTE after temporary lower limb immobilisation. The study will also measure VTE risk factors in this patient cohort and identify those risk factors that are predictors of developing VTE. Finally, this study will validate the Thrombosis Risk Prediction for patients with cast immobilisation (TRiP (cast)) risk assessment model. MethodsThe planned study design will be prospective and multicentre, including 15 participating sites within the Irish Network for VTE Research (INViTE). Consecutive patients aged 18 years and older with an immobilised injured lower limb will be eligible for inclusion. We will collect the relevant clinical variables at the index emergency department (ED) visit. The primary outcome will be the incidence of symptomatic VTE within three months after the injury. We will include VTE predictors in a multivariable logistic regression model, with VTE occurrence as the outcome variable. The TRiP (cast) model will be prospectively validated for first time using the Thrombosis In patients with Lower Limb Injuries Requiring Immobilisation (TiLLIRI) cohort. DiscussionThe association between lower limb immobilisation and VTE has been documented for over seventy-five years. However, the benefits of pharmacological thromboprophylaxis are still unclear. Identifying patients at a higher risk of VTE after immobilising an injured lower limb will help patient-focused benefit-risk analysis to inform clinical decision making and treatment decisions. The TiLLIRI study will address this critical clinical knowledge gap in the first-ever large prospective multicentre observational study of its kind. The results of this study are likely to inform future clinical trials and prospective management studies and to impact upon patient safety positively.

Abstract 16420: Double Internal Thoracic Artery Grafts are Associated to Better 10-year Outcomes After Coronary Artery Bypass Grafting

Introduction: Few data on long-term follow-up of effectiveness and advantages related to the employ of double internal thoracic artery grafts (BITA) for coronary artery bypass grafting are available and the advantage of the employ of BITA have been recently questioned. Hypothesis: This observational cohort study was designed by the PRIORITY planning committee to evaluate 10-year follow-up of isolated CABG performed with and without BITA in order to evaluate the impact of BITA on long-term outcomes. Methods: The PRIORITY project was designed to evaluate the long-term outcomes of 2 large prospective multicenter cohort studies on CABG conducted between 2002-2004 and 2007-2008. Data on isolated CABG were linked to 2 administrative datasets. The primary endpoints were death and major adverse cardiac events (MACEs) at follow-up. Time-to-event data were analyzed using Kaplan-Meier estimates and Cox regression. Models generation was performed on the full dataset and the validation was performed with Montecarlo simulations. Results: The population consisted of 11021 patients who underwent isolated CABG; double thoracic internal artery grafts was employed in 23.5%. The median follow-up time was 7.9 years (interquartile range 7.4 - 10 years). After adjustment for potential confounding factors, BITA was significantly associated with better survival (HR 0.81, 95%CI 0.73-0.89, p &lt; 0.001). Moreover, the employment of BITA reduced the incidence of MACEs at follow-up (adjusted HR 0.83, 95%CI 0.77-0.89, p &lt; 0.001). In details, BITA was demonstrated to be a protective factor for acute myocardial infarction (adjusted HR 0.83, 95%CI 0.72-0.96, p = 0.001) and for rehospitalization for percutaneous cardiac intervention (PCI; adjusted HR 0.72, 95%CI 0.63-0.84, p &lt; 0.001). Conclusions: The employment of double internal thoracic artery grafts for coronary artery bypass grafting has been associated to significant survival advantage at long-term. Moreover, it is a protective factor for acute myocardial infarction and rehospitalization for percutaneous cardiac intervention, reducing the hazard by 28%.

Total motorized spiral enteroscopy: first prospective clinical feasibility trial

Motorized spiral enteroscopy (MSE) was recently introduced into clinical practice and shown to be safe and effective for antegrade enteroscopy. The aim of the current trial was to prospectively study the efficacy and safety of MSE for visualization of the entire small bowel. All consecutive patients with indications for complete enteroscopy meeting the inclusion criteria were enrolled in a prospective observational bicentric trial, starting with antegrade MSE; a retrograde approach was performed if MSE remained incomplete from antegrade. The primary objective was to ascertain the total enteroscopy rate (TER); secondary objectives were diagnostic yield, procedural success, time, depth of maximum insertion (DMI), therapeutic yield, and adverse events (AEs). Thirty patients (16 women, 14 men; median age 64 years [range, 37-100]) were enrolled. Technical success rate of antegrade MSE (advancement beyond the ligament of Treitz) and retrograde MSE (advancement beyond the ileocecal valve [ICV]) were 100% and 100%, respectively. Overall TER was 70%: 16.6% antegrade approach alone and 53.4% bidirectional approach. Median antegrade DMI distal from the ligament of Treitz was 490 cm (range, 160-600); median insertion time 26 minutes (range, 15-110). The median retrograde DMI beyond the ICV was 120 cm (range, 40-600), and median insertion time was 17 minutes (range, 1-68). Overall diagnostic and therapeutic yields were 80% and 86.7%, respectively. Overall AE rate was 16.7%. No serious AEs occurred. This prospective study showed that complete enteroscopy is feasible with MSE, either from antegrade alone or bidirectionally, with high success rates and short procedural duration. These results justify further evaluation of MSE in a large prospective multicenter study, preferably with inclusion of a control group. (Clinical trial registration number: NCT03438695.).

Validation of the Canadian syncope risk score in a large prospective international multicenter study

Abstract Background Management and risk stratification of patients with syncope in the emergency department (ED) is often challenging. In an effort to support ED physicians in disposition decisions, the Canadian Syncope Risk Score (CSRS) was developed to predict 30-day serious outcomes. Methods The CSRS was developed in a Canadian multicenter study and contains nine predictors: predisposition to vasovagal syncope, heart disease, systolic pressure &amp;lt;90 or &amp;gt;180mmHg in the ED, troponin level &amp;gt;99th percentile, abnormal QRS axis, QRS duration &amp;gt;130ms, QTc interval &amp;gt;480ms and an ED diagnosis of vasovagal or cardiac syncope. Patients can achieve a CSRS score between −3 and +11 points. We validated the CSRS in a large prospective international multicenter study recruiting patients 40 years or older presenting to the ED with a syncopal event within the last 12 hours. Recruitment centers contained smaller provincial hospitals, as well as big University Hospitals in eight countries on three continents. Primary outcome measure were 30-day serious arrhythmic and non-arrhythmic adverse events, as defined by the authors of the original score. Results 1581 patients were eligible for this analysis. The population in this validation cohort was older (mean age 68 vs 54 years) and had a considerably higher rate of serious outcomes compared to the derivation cohort (n=186 (11.8%) vs n=147 (3.6%)). The area under the receiver operating characteristic curve (AUC) for the CSRS was 0.88 (95% confidence interval (CI) 0.86–0.91) and significantly higher compared to the validated OESIL score (AUC 0.75, 95% CI 0.71–0.78, p&amp;lt;0.001). Calibration curve analysis showed an underestimation of risk in patients with a low CSRS and an overestimation in patients with a high CSRS. The rate of observed serious outcomes within 30d increased from 0.8% in the very low risk group (CSRS equal to or below −2) to 48% in the (very) high risk group (CSRS equal to or above 4, Hazard ratio 79.4, 95% CI 11.1–570.9). A Kaplan-Meier plot was used to visualize rates of serious outcomes in three different risk groups (Figure). Conclusion This is the first validation of the Canadian Syncope Risk Score in a large international syncope cohort. The prognostic discrimination of the CSRS for 30-day serious outcomes was very good in our validation cohort and comparable to that of the Canadian derivation study. Despite suboptimal calibration, prognostic analysis showed a high rate of serious outcomes in the CSRS (very) high risk group and a low rate of serious outcomes in the very low risk group. Allowing the clinical judgement of the ED physician in the form of suspected syncope etiology to be a part of the score seems to largely contribute to the high performance of the CSRS. Additional validation studies might be needed to further increase the accuracy of the CSRS in different patient populations with a different incidence of outcomes in settings outside of Canada. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation; Swiss Heart Foundation

Validation of the FAINT risk score in a large prospective international multicenter study

Abstract Background Risk stratification of older patients presenting to the Emergency Department (ED) with syncope remains an unmet clinical need. The FAINT Score was derived in a large American cohort in an attempt to predict 30-day serious cardiac outcomes in patients &amp;gt;60y.o. While a FAINT score of 0 showed high sensitivity to exclude death and serious outcomes at 30 days in the derivation cohort, it remains unvalidated. Methods We validated the FAINT score (History of heart failure, history of arrhythmia, initial ECG result abnormal, elevate NT-proBNP, elevated hs-troponin T) in a large prospective international multicenter study recruiting patients 40 years presenting to the ED with syncope within the last 12 hours in eight countries on three continents. Main outcome measure was 30-day serious cardiac events or mortality. We assessed the performance and calibration of the FAINT score for validation and compared it to the OESIL score (Age &amp;gt;64y, cardiovascular disease history, syncope without prodromes, abnormal ECG). Results 1885 patients were eligible for this validation analysis. 169 (8.9%) patients experienced 30-day serious adverse events. A FAINT score of 0 was present for 378 patients (20% of the cohort) and allowed for a sensitivity of 0.97 to rule out adverse events and death at 30-days. A FAINT score of 0 or 1 was present for 626 patients (33% of the cohort) and allowed for a sensitivity of 0.92. The area under the receiver operating characteristic curve (AUC) for the FAINT score was 0.75 (95%, Confidence Interval (CI) 0.72–0.79), which was comparable to the performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) or high-sensitivity Troponin T (hs-cTnT) alone, which are two biomarkers used in the FAINT score. The score did not outperform the OESIL score. A calibration curve showed that the score was extremely well calibrated for low-risk patients. Conclusion This is the first validation of the FAINT score in a large international syncope cohort. The safety of a FAINT score of 0 or 1 was good and comparable to the results obtained in the derivation cohort. While the score is suitable to highlight low-risk patients and calibrates well in an external cohort, its discrimination for higher risk patients is not better than biomarkers alone or an older, less complex risk score. Figure 1. Area under the Receiver Operating Curve (ROC) for the FAINT score and for NT-proBNP and hs-cTnT as continuous markers as well as for the OESIL score. CI = Confidence Interval. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): University Hospital Basel, Switzerland

External validation of a clinical decision rule to identify patients at low risk for acute coronary syndrome who do not need objective coronary artery disease testing

Abstract Background Rapid high-sensitivity cardiac troponin (hs-cTn) based algorithms have substantially improved the early rule-out of acute myocardial infarction (AMI) and thereby facilitated the selection of patients eligible for outpatient management. However, it remains unclear, which patients after rule-out of AMI should still undergo objective anatomic or functional cardiac testing for the detection of relevant coronary artery disease. A pilot study has derived a clinical decision rule for the selection of patients who do not need objective anatomic or functional cardiac testing for coronary artery disease (“No Objective Testing” (NOT) rule). Purpose To externally validate the performance of the NOT-rule in a multicentre study. Methods Patients presenting to the ED with symptoms suggestive of an acute coronary syndrome (ACS) were enrolled in a large prospective international multicentre study at 12 study sites in five European countries. Two independent cardiologists centrally adjudicated the final diagnosis using all clinical data including cardiac imaging and at least 90-day follow-up. The NOT-rule is applied in patients, in whom a 2h accelerated diagnostic protocol (using hs-cTnI concentrations at 0h/2h and ECG data) has ruled-out AMI and based on clinical variables. In brief, the first rule is a weighted score derived from independent predictors of ACS that classifies patients as low-risk if they score ≤4 points. The second rule was simplified and ruled patients out if they were younger than 50 years, had no history of an AMI or known CAD, and no prescribed nitrates. The third rule equals the second except nitrate use was omitted. Primary objective was the safety and efficacy of the NOT-rules for rule-out of major adverse cardiac events (MACE) including AMI, unstable angina pectoris, urgent or emergency revascularisation or cardiovascular death at 30-days of follow-up. Secondary objective was the safety and efficacy for rule-out of MACE at 2-years. Results Out of 3188 enrolled patients, 2162 (68%) had hs-cTnI concentrations at 0h and 2h below the 99th centile as well as a non-diagnostic ECG and were therefore eligible for the analysis. MACE at 30-days occurred in 302 (14%) patients. The second and third rule offered highest safety and efficacy for rule-out of MACE at 30-days. Both identified 492 (23%) patients at low-risk with a sensitivity of 99.7% (95% CI 98.2–99.9%) and a negative predictive value (NPV) of 99.8% (95% CI 98.6–99.9%). One MACE was missed within 30-days (revascularisation of a one-vessel CAD). Sensitivity 98.9% (95% CI 97.1–99.7%) and NPV 99.2% (95% CI 97.8–99.7) were also very high for 1-year MACE, as well as 2-year MACE 98.4% (95% CI 96.5–99.4%) and 98.4% (95% CI 96.5–99.3%), respectively. Conclusions The NOT rules proved to be a safe tool that identifies nearly one-fourth of patients at very low risk for MACE, who may not need objective anatomic or functional cardiac testing for coronary artery disease. Performance of NOT rules Funding Acknowledgement Type of funding source: Other. Main funding source(s): Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the European Union, the Stiftung für kardiovaskuläre Forschung Basel, the University of Basel, the University Hospital Basel

Incidence, characteristics and prognosis of different cardiac etiologies underlying cardiac syncope

Abstract Background Cardiac syncope has been shown to carry the highest hazard for all-cause death compared to other causes of syncope including vasovagal and orthostatic syncope. However, little is known about the incidence, characteristics and prognosis of different cardiac etiologies underlying cardiac syncope. Purpose To evaluate the incidence, characteristics and prognosis of different cardiac etiologies underlying cardiac syncope. Methods We enrolled patients presenting to the emergency department (ED) with syncope in a large prospective international multicentre study. The cause of syncope (cardiac vs non-cardiac) including the detailed cardiac aetiology (if cardiac) was centrally adjudicated by two independent cardiologists based on detailed in-hospital as well as outpatient cardiac work-up during 360 days following presentation. Cardiac syncope was classified into four groups: bradyarrhythmia, tachyarrhythmia, structural disease and other (cardiopulmonary and great vessels), as recommended in the ESC Syncope Guidelines. All-cause death during 2-years follow-up was the primary outcome. Results Among 2025 patients presenting with syncope to the ED, cardiac syncope was the final adjudicated diagnoses in 318 (15.7%) patients. The incidence rate of all-cause death among cardiac syncope patients was 103 cases per 1000 person-years. Bradyarrhythmia was the most frequent primary cause of cardiac syncope (n=146, 45.9%) followed by tachyarrhythmia (n=75, 23.6%), structural disease (n=64, 20.1%) and other cardiac (n=26, 8.2%). Patients were 37% female with a median age of 77 years (IQR 67–83) showing no statistically significant difference between subgroups. Clinical characteristics differed significantly among the four subgroups. E.g. syncope occurred during exercise in 12 patients (8.2%) with bradyarrhythmia, 10 patients (13.3%) with tachyarrhythmia, 16 patients (25%) with structural disease, and 5 patients (19%) with other cardiac (p&amp;lt;0.01). Likely of most importance, long-term mortality differed significantly among the four different cardiac subgroups. The multivariable-adjusted hazard ratios (HR) among patients with bradyarrhythmia, tachyarrhythmia, structural disease and other cardiac as compared to patients with vasovagal syncope, the HR were 1.3 (95% CI 0.7–2.5), 4.6 (95% CI 2.3–9.1), 3.1 (95% CI 1.5–6.4) and 5.9 (95% CI 2.3–15.2), respectively (Figure 1). Conclusions Bradyarrhythmia, tachyarrhythmia, and structural cardiac disease are the dominant causes of cardiac syncope. Interestingly, with the appropriate therapy initiated long-term mortality of bradyarrhythmia is comparable to that of vasovagal syncope, while long-term mortality of tachyarrhythmia and structural cardiac disease were substantially increased 3 to 5 fold. Figure 1. Kaplan-Meier curve Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Swiss National Science Foundation, the Swiss Heart Foundation, the Stiftung für kardiovaskuläre Forschung Basel, the University of Basel and the University Hospital Basel.