Flecainide to Prevent Atrial Arrhythmia after Patent Foramen Ovale Closure, the AFLOAT Study: A Randomized Clinical Trial.

BACKGROUND: The real incidence of atrial arrhythmia (AA) after patent foramen ovale (PFO) closure and whether this complication can be prevented remain unknown. This study assessed if flecainide is effective to prevent AA during the first 3 months after PFO closure, and if 6 months treatment by flecainide is more effective than 3 months to prevent AA after PFO closure. METHODS: AFLOAT is a prospective, multicentre, randomized, open-label, superiority trial with a blind evaluation of all the endpoints (PROBE design). Patients were randomized in a 1:1:1 ratio after PFO closure to receive flecainide (150 mg once a day in a sustained-release (SR) dose) for 3 months, flecainide (150 mg od SR dose) for 6 months, or no additional treatment (standard-of-care) for 6 months. The primary endpoint was the percentage of patients with at least one episode AA (≥30s) recorded within 3 months after PFO closure on long-term monitoring with an insertable cardiac monitor (ICM). The secondary endpoint was the percentage of patients with at least one episode of AA (≥30s) recorded with ICM during the 3-6 months period after PFO closure. RESULTS: 186 patients were included (mean age 54 years, male 68.8%) and AA (≥30s) occurred in 53 (28.5%) patients during the 6-month follow-up; 86.8% of these AA events occurred in the first month after PFO closure. The primary outcome occurred in 33/123 (26.8%) and 16/63 (25.4%) patients receiving flecainide for at least 3 months or standard of care, respectively [Risk Difference (RD) 1.4%; 95% confidence interval (CI) -12.9% to 13.8%, NS]. The secondary endpoint occurred in 3/60 (5.0%), 4/63 (6.3%), and 5/63 (7.9%) patients receiving flecainide 6 months, 3 months or standard of care, respectively [RD -2.9%; 95% CI -12.7% to 6.9%, and RD -1.6%; 95% CI -11.8% to 8.6%, respectively]. CONCLUSIONS: In the first 6 months following successful PFO closure, AA (≥30s) occurred in 28.5% of cases, mostly in the first month after the procedure. Flecainide did not prevent AA after PFO closure.

Sex and the Risk of Atheromatous and Nonatheromatous Cardiovascular Disease in CKD: Findings From the CKD-REIN Cohort Study.

RATIONALE & OBJECTIVE: Sex differences in cardiovascular disease (CVD) are well established, but whether chronic kidney disease (CKD) modifies these risk differences and whether they differ between atheromatous CVD (ACVD) and nonatheromatous CVD (NACVD) is unknown. Assessing this interaction was the principal goal of this study. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adults enrolled in the CKD-REIN (CKD-Renal Epidemiology and Information Network) cohort, a nationally representative sample of 40 nephrology clinics in France, from 2013 to 2020. EXPOSURE: Sex. OUTCOMES: Fatal and nonfatal composite ACVD events (ischemic coronary, cerebral, and peripheral artery disease) and composite NACVD events (heart failure, hemorrhagic stroke, and arrhythmias). ANALYTICAL APPROACH: Multivariable cause-specific Cox proportional hazards models. RESULTS: 1,044 women and 1,976 men with moderate to severe CKD (median age, 67 vs 69y; mean estimated glomerular filtration rate [eGFR], 32±12 vs 33±12mL/min/1.73m2) were studied. During a median follow-up of 5.0 (IQR, 4.8-5.2) years, the ACVD rate (per 100 patient-years) was significantly lower in women than in men, at 2.1 (95% CI, 1.6-2.5) versus 3.6 (3.2-4.0; P<0.01), whereas the NACVD rate was not, at 5.7 (5.0-6.5) versus 6.4 (5.8-7.0; P=0.55). NACVD had a steeper relationship with eGFR than did ACVD. There was an interaction (P<0.01) between sex and baseline eGFR and the ACVD hazard: the adjusted HR for women versus men was 0.42 (0.25-0.71) at 45mL/min/1.73m2 and gradually attenuated at lower levels of eGFR, reaching 1.00 (0.62-1.63) at 16mL/min/1.73m2. In contrast, the NACVD hazard did not differ between sexes across the eGFR range studied. LIMITATIONS: Cardiovascular biomarkers and sex hormones were not assessed. CONCLUSIONS: This study shows how the lower risk of ACVD among women versus men attenuates fully with kidney disease progression. The equal risk of NACVD between sexes across CKD stages and its steeper association with eGFR suggest an important contribution of CKD to the development of this CVD type. PLAIN-LANGUAGE SUMMARY: Sex differences in the risks of atheromatous and nonatheromatous cardiovascular disease (CVD) are well established in the general population. If or how chronic kidney disease (CKD) might modify these risks is unknown. In this large cohort of 3,010 patients with CKD, women had a lower risk than men of atheromatous CVDs such as coronary artery disease or stroke when they were at an early stage of CKD. This advantage, partly due to women's better cardiovascular risk profile, tended to attenuate as CKD progressed to kidney failure. In contrast, the risk of nonatheromatous CVDs such as heart failure for women with CKD appeared similar to that of men with CKD at all kidney function levels.

Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Prevalence of prediabetes and undiagnosed diabetes in a large urban middle-aged population: the CARVAR 92 cohort.

BACKGROUND: The aim of this study was to assess the prevalence of prediabetes and unknown diabetes and its long-term change in a large middle-aged urban population. METHODS: We conducted a screening campaign between 2007 and 2018 for cardiovascular risk factors in the western suburbs of Paris including subjects aged 40-70 (CARVAR 92). Among subjects who reported no previous diabetes, prediabetes and undiagnosed diabetes were defined as follows: fasting plasma glucose (FPG) ≥ 6.1 mmol/l (110 mg/dl) and < 7 mmol/l (126 mg/dl) for prediabetes according to WHO criteria (FPG between 5.6 and 6.9 mmol/l according to ADA criteria) and FPG ≥ 7.0 mmol/l for undiagnosed diabetes. RESULTS: Of the 32,721 subjects in the CARVAR 92 cohort, 32,675 were included in this analysis. The median age of the patients was 56 years [30, 94], 45.4% were male, 5.9% had known diabetes, 36.4% were overweight and 18.7% obese. Among patients without previously known diabetes (n = 30,759), 8.1% had prediabetes according to WHO criteria (27.2% according to ADA criteria) and 2.3% had diabetes. Subjects with prediabetes and unknown diabetes were more likely to be male, older, and overweight or obese than non-diabetic subjects. From 2007 to 2018, the prevalence of prediabetes, unknown diabetes, and known diabetes decreased, except for prediabetes which remained stable for people aged 55-64. CONCLUSION: The prevalence of prediabetes and unknown diabetes remains high but decreased during a 12-year period. About one-quarter of diabetes cases remain undiagnosed. Our results highlight that there is still a room for screening and cardiovascular prevention campaigns. TRIAL REGISTRATION: IRB00012437.

External validation of Glasgow-Blatchford, modified Glasgow-Blatchford and CANUKA scores to identify low-risk patients with upper gastrointestinal bleeding in emergency departments: a retrospective cohort study.

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a medical emergency with an approximate mortality of 10%, which results in a high hospitalisation rate. The Glasgow-Blatchford score (GBS) is recommended to identify low-risk patients who can be discharged from the emergency department (ED). A modified GBS (mGBS) and CANUKA score have recently been proposed but have not been well studied. The aim of this study was to assess whether the use of GBS, mGBS or CANUKA score could identify patients at low risk of death or need for intervention. METHODS: A single-centre retrospective study was performed including patients with suspected UGIB visiting the ED of Saint-Antoine hospital (Paris, France) from January 2016 to December 2018. Demographic and medical data needed to calculate GBS and CANUKA were collected, as well as outcomes data. Need for intervention was defined as the need for blood transfusion, endoscopic haemostasis or rebleeding within 7 days. In-hospital mortality was also collected. Sensitivity, specificity and predictive values were measured for the score thresholds of interest. RESULTS: A total of 386 patients were included. Median age was 60 years (38-78), 65.3% (n=252) were male and 60% (n=233) were hospitalised. A GBS≤1, mGBS=0 and CANUKA≤2 categorised 24.9%, 18.2% and 18.9% of patients as low risk, respectively. There was a need for intervention in 2.2%, 4.6% and 0% of those patients categorised as low risk by GBS, mGBS and CANUKA, respectively. No deaths occurred in the patients identified as low risk, regardless of the score used. All scores had a high sensitivity and negative predictive value. CONCLUSIONS: In patients with UGIB, the use of a GBS≤1 or CANUKA score ≤2 appears to be safe for identifying patients at low risk of death or need for intervention.

Relevance of Cardiovascular Risk Factors Screening in People Aged over 65 Years: Results from a Large French Urban Population (The CARVAR92 Study).

BACKGROUND: Cardiovascular disease is the leading cause of death and disability in older people. Traditional cardiovascular risk factors (CVRFs) still have an impact on cardiovascular risk among older people. Nevertheless, screening campaigns rarely target subjects aged over 65 years. This study aimed to assess the distribution and relevance of conventional CVRF screening in people aged over 65 years. METHODS: Between 2007 and 2018, among a screening CVRF campaign in the western suburbs of Paris (32,692 subjects), we individualized 6,577 subjects aged 65 years and over. All conventional CVRFs have been systematically assessed. RESULTS: The screening allowed to suspect hypertension in a larger proportion of subjects over 65 years compared to subjects under 65 years (27% vs. 18%, p < 0.0001). Hypertension control was higher in women compared to men but not significantly different in the age-groups (p = 0.91). Screening for diabetes mellitus was positive in 3% of older subjects and 2.4% in younger (p = 0.005). Risk assessment with dedicated score (SCORE O.P.) allowed to move toward a low-risk estimation, resulting in the diminution of intermediate risk group in women over 65 years (from 68 to 61%, p < 0.001). CONCLUSIONS: Screening CVRFs especially hypertension remains relevant in people aged over 65 years as it enables to detect unknown CVRFs in numerous subjects. Increasing awareness of CVRFs may be the first step to CVRF control, which is known to be efficient on cardiovascular mortality and functional autonomy in later life.

Impact of chronic total occlusion and revascularization strategy in patients with infarct-related cardiogenic shock: A subanalysis of the culprit-shock trial.

BACKGROUND: The impact of coronary artery chronic total occlusion (CTO) and its management with percutaneous coronary intervention (PCI) in the setting of myocardial infarction (MI) related cardiogenic shock (CS) remains unclear. METHODS: This is a pre-specified analysis from the culprit-lesion-only PCI vs multivessel PCI in CS (CULPRIT-SHOCK) trial which randomized patients presenting with MI and multivessel disease complicated by CS to a culprit-lesion-only or immediate multivessel PCI strategy. CTO was defined by central core-laboratory evaluation. The independent associations between the presence of CTO and adverse outcomes at 30 days and 1 year were assessed using multivariate logistics models. RESULTS: A noninfarct related CTO was present in 157 of 667 (23.5%) analyzed patients. Patients presenting with CTO had more frequent diabetes mellitus or prior PCI but less frequently presented with ST segment elevation MI as index event. The presence of CTO was associated with higher rate of death at 30 days (adjusted Odds ratio 1.63; 95% confidence interval [CI] 1.01-2.60). Rate of death at 1 year was also increased but did not reach statistical significance (adjusted Odds ratio 1.62; 95%CI 0.99-2.66). Compare to immediate multivessel PCI, a strategy of culprit-lesion-only PCI was associated with lower rates of death or renal replacement therapy at 30 days in patients with and without CTO (Odds ratio 0.79 95%CI 0.42-1.49 and Odds ratio 0.67 95%CI 0.48-0.96, respectively), without significant interaction (P = .68). CONCLUSIONS: In patients with MI-related CS and multivessel disease, the presence of CTO is associated with adverse outcomes while a strategy of culprit-lesion-only PCI seems beneficial regardless of the presence of CTO.

Occurrence of pulmonary embolism related to COVID-19.

Recent reports have suggested an increased risk of pulmonary embolism (PE) related to COVID-19. The aim of this cohort study is to compare the incidence of PE during a 3-year period and to assess the characteristics of PE in COVID-19. We studied consecutive patients presenting with PE (January 2017-April 2020). Clinical presentation, computed tomography (CT) and biological markers were systematically assessed. We recorded the global number of hospitalizations during the COVID-19 pandemic and during the same period in 2018-2019. We included 347 patients: 326 without COVID-19 and 21 with COVID-19. Patients with COVID-19 experienced more likely dyspnea (p=0.04), had lower arterial oxygen saturation (p<0.001), higher C-reactive protein and white blood cell (WBC) count (p<0.0001 and p=0.001, respectively), and a significantly higher in-hospital mortality (14% versus 3.4%, p=0.04). Among COVID-19 patients, diagnosis of PE was performed at admission in 38% (n=8). COVID-19 patients with diagnosis of PE during hospitalization (n=13) had significantly more dyspnea (p=0.04), lower arterial oxygen saturation (p=0.01), less proximal PE (p=0.02), and higher heart rate (p=0.009), CT severity score (p=0.001), C-reactive protein (p=0.006) and WBC count (p=0.04). During the COVID-19 outbreak, a 97.4% increase of PE incidence was observed as compared to 2017-2019 and the proportion of hospitalizations related to PE was 3.7% versus 1.3% in 2018-2019 (p<0.0001). In conclusion, the COVID-19 pandemic leads to a dramatic increased incidence of PE. Physicians should be aware that PE may be diagnosed at admission, but also after several days of hospitalization, with a different clinical, CT and biological features of thrombotic disease.

Impact of Coronavirus Disease 2019 outbreak on acute coronary syndrome admissions: four weeks to reverse the trend.

Data whether the COVID-19 outbreak impacts the acute coronary syndromes (ACS) admissions and the time required to reverse the downward curve are scarce. We included all consecutive patients referred for an ACS who underwent PCI from February 17, 2020 to April 26, 2020 in a high-volume PCI coronary care unit. We compared the number of ACS patients in 2020 to the same period in 2018 and 2019. Predictors of adverse outcome in ST-elevation myocardial infarction (STEMI) patients were recorded: symptom-onset-to-first medical contact (FMC), and FMC-to-sheath insertion times. During the studied period (calendar weeks 8-17, 2018-2020), 144 ACS patients were included. In 2020, we observed two distinct phases in the ACS admissions: a first significant fall, with a relative reduction of 73%, from the week of lockdown (week 12) to 3 weeks later and then an increase of ACS. Median symptom-onset-to-FMC time was significantly higher in 2020 than in the two previous years (600 min [298-632] versus 121 min [55-291], p < 0.001). Median FMC-to-sheath insertion did not differ significantly (93 min [81-131] in 2020 versus 90 min [67-137] in 2018-2019, p = 0.57). The main findings are (1) a pattern of a U-curve in ACS admissions, with a first decrease in ACS admissions and a return to "normality" 4 weeks after; (2) a significant increase in the total ischemic time exclusively due to an increase in the symptom-onset-to-first-medical-contact time.

[Interventional cardiology in the elderly, at the time of TAVI and left atrial appendage occlusion]. / Cardiologie interventionnelle chez le sujet âgé.

Interventional cardiology is increasingly being offered to frail elderly people thanks to significant technical progress. Transcatheter aortic valve implantation allows the treatment of aortic stenosis by implanting an aortic bioprosthesis through a catheter, without surgery. The left atrial appendage occlusion limits the risk of ischemic stroke in patients with atrial fibrillation who have a contraindication to anticoagulants. These procedures remain invasive and must be proposed after multidisciplinary consultation.

Performance of CT Compared with 18F-FDG PET in Predicting the Efficacy of Nivolumab in Relapsed or Refractory Hodgkin Lymphoma.

Background CT and fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT performances following immune therapy are not well known in patients with relapsed or refractory Hodgkin lymphoma (RRHL). Purpose To compare CT and PET/CT for prognostic value of early response evaluation following nivolumab therapy. Materials and Methods This retrospective study included patients from 34 institutions who underwent early imaging response evaluation from July 2013 to April 2017. Three experienced readers classified imaging response by using Cheson et al and 2016 Lymphoma Response to Immunomodulatory Therapy Criteria as follows: complete (metabolic) response, partial (metabolic) response, stable disease or no metabolic response, or progressive (metabolic) disease. Primary CT and PET assessments were performed at a median of 2.0 months (interquartile range, 1.7-3.7 months) after nivolumab initiation. Kaplan-Meier analysis was used to determine the relationship of primary CT and PET assessment response categories to overall survival (OS). Agreements between primary and secondary imaging assessments were assessed by using κ analysis. Results A total of 45 patients (median age, 37 years; range, 18-77 years; 25 men) underwent a primary assessment using CT and PET/CT; 36 patients also underwent a subsequent assessment. Eleven patients (24%) died after a median follow-up of 21.2 months. CT and PET response categories were associated with OS (P = .03 for primary CT assessment; P = .02 for primary PET assessment). There was no pseudoprogression at primary CT and PET assessments. At the primary assessment, response categories by using CT were reclassified by using PET in 44% (20 of 45) of patients. Among these, 55% (11 of 20) were reclassified to complete metabolic response (complete metabolic response rate: 29% [13 of 45 patients] vs complete response rate: 4% [two of 45 patients]), with a 2-year OS probability of 100%. At the secondary assessment, complete response rate using CT increased to 17% (six of 36 patients), hence a better agreement with PET (κ = 0.78; P < .001). Conclusion Early CT and PET/CT at a median of 2 months after initiation of nivolumab predicted overall survival in relapsed or refractory Hodgkin lymphoma. Early PET detected additional patients with complete metabolic response. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Scott and Wang in this issue.

Radial versus femoral artery access for percutaneous coronary artery intervention in patients with acute myocardial infarction and multivessel disease complicated by cardiogenic shock: Subanalysis from the CULPRIT-SHOCK trial.

BACKGROUND: The use and impact of transradial artery access (TRA) compared to transfemoral artery access (TFA) in patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (MI) complicated by cardiogenic shock (CS) remain unclear. METHODS: This is a post hoc analysis of the CULPRIT-SHOCK trial where patients presenting with MI and multivessel disease complicated by CS were randomized to a strategy of culprit-lesion-only or immediate multivessel PCI. Arterial access was left at operator's discretion. Adjudicated outcomes of interest were the composite of death or renal replacement therapy (RRT) at 30 days and 1 year. Multivariate logistic models were used to assess the association between the arterial access and outcomes. RESULTS: Among the 673 analyzed patients, TRA and TFA were successfully performed in 118 (17.5%) and 555 (82.5%) patients, respectively. Compared to TFA, TRA was associated with a lower 30-day rate of death or RRT (37.3% vs 53.2%, adjusted odds ratio [aOR]: 0.57; 95% confidence interval [CI] 0.34-0.96), a lower 30-day rate of death (34.7% vs 49.7%; aOR: 0.56; 95% CI 0.33-0.96), and a lower 30-day rate of RRT (5.9% vs 15.9%; aOR: 0.40; 95% CI 0.16-0.97). No significant differences were observed regarding the 30-day risks of type 3 or 5 Bleeding Academic Research Consortium bleeding and stroke. The observed reduction of death or RRT and death with TRA was no longer significant at 1 year (44.9% vs 57.8%; aOR: 0.85; 95% CI 0.50-1.45 and 42.4% vs 55.5%, aOR: 0.78; 95% CI 0.46-1.32, respectively). CONCLUSIONS: In patients undergoing PCI for acute MI complicated by CS, TRA may be associated with improved early outcomes, although the reason for this finding needs further research.

Blunting periprocedural myocardial necrosis: Rationale and design of the randomized ALPHEUS study.

BACKGROUND: Clopidogrel associated with aspirin is the recommended treatment for patients undergoing elective percutaneous coronary intervention (PCI). Although severe PCI-related events are rare, evidence suggests that PCI-related myocardial infarction and myocardial injury are frequent complications that can impact the clinical prognosis of the patients. Antiplatelet therapy with a potent P2Y12 receptor inhibitor such as ticagrelor may reduce periprocedural ischemic complications while maintaining a similar safety profile as compared with conventional dual antiplatelet therapy by aspirin and clopidogrel in this setting. METHODS: Assessment of Loading with the P2Y12 inhibitor ticagrelor or clopidogrel to Halt ischemic Events in patients Undergoing elective coronary Stenting (ALPHEUS) (NCT02617290) is an international, multicenter, randomized, parallel-group, open-label study in patients with stable coronary artery disease who are planned for an elective PCI. In total, 1,900 patients will be randomized before a planned PCI to a loading dose of ticagrelor 180 mg or a loading dose of clopidogrel (300 or 600 mg) in addition to aspirin. Patients will then receive a dual antiplatelet therapy with aspirin and ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 30 days. The primary ischemic end point is PCI-related myocardial infarction (myocardial infarction type 4a or 4b) or major myocardial injury within 48 hours (or at hospital discharge if earlier) after elective PCI/stent. Safety will be evaluated by major bleeding events (Bleeding Academic Research Consortium type 3 or 5) at 48 hours (or discharge if it occurs earlier). CONCLUSION: ALPHEUS is the first properly sized trial comparing ticagrelor to clopidogrel in the setting of elective PCI and is especially designed to show a reduction in periprocedural events, a surrogate end point for mortality.

Impact of mode of conception on neonatal and neurodevelopmental outcomes in preterm infants.

STUDY QUESTION: Is assisted conception associated with neonatal morbidity and mortality and with neurodevelopmental impairment at 2 years of corrected age in preterm infants born before 34 weeks of gestational age? SUMMARY ANSWER: Assisted conception is not associated with an increase in neonatal morbidity and mortality and is even significantly associated with a better 2-year neurodevelopmental outcome in preterm infants. WHAT IS KNOWN ALREADY: Assisted conception appears to increase the rate of preterm births, though few studies have analysed outcomes for these preterm infants. STUDY DESIGN, SIZE, DURATION: This prospective observational study included 703 preterm infants born between January 2009 and December 2013 and 573 of them were assessed at 2 years of corrected age. PARTICIPANTS/MATERIALS, SETTING, METHODS: All infants born alive between 24+0 and 33+6 weeks of gestational age and hospitalised at the Angers University Hospital were eligible as long as the mode of conception was known for neonatal outcome assessment. They were enroled in the Loire Infant Follow-up Team (LIFT) prospective longitudinal cohort and included for neurodevelopmental outcome assessment. Neonatal morbidity and mortality were evaluated during hospitalisation based on a composite score including death, intraventricular haemorrhage Grade ≥3, periventricular leukomalacia, treated patent ductus arteriosus and bronchopulmonary dysplasia at 36 weeks of gestational age. The neurodevelopmental outcome at 2 years of corrected age was determined by a physical examination, a neuropsychological test and a parental questionnaire. In order to ensure comparability, infants were matched 1:1 according to maternal age, twin status and propensity score,calculated from variables usually associated (positively or negatively) with assisted conception, including gestational age, z-score of birth weight, antenatal corticosteroids and magnesium sulphate treatments, gender, parity, maternal body mass index, tobacco consumption, outborn delivery (i.e. not at a tertiary-care medical centre) and maternal socio-economic status. MAIN RESULTS AND THE ROLE OF CHANCE: There were 703 preterm infants included in the analysis of neonatal morbidity and mortality, including 137 born after assisted conception. After matching, 184 preterm infants were included for neonatal morbidity and mortality analysis. There was no significant association between assisted conception and neonatal morbidity and mortality (aOR 0.67, 95% CI [0.25, 1.77], P = 0.422). 573 infants were assessed at 2 years, including 121 born after assisted conception. After matching, 154 preterm infants were included for neurodevelopmental outcome analysis. Assisted conception was significantly associated with a reduction in the probability of non-optimal neurological development at 2 years (aOR 0.26, 95% CI [0.09, 0.80], P = 0.019). LIMITATION, REASONS FOR CAUTION: Further studies remain necessary to fully confirm these results. This was a monocentric study and 14% of enroled infants were lost to follow up at 2 years of corrected age. WIDER IMPLICATIONS OF THE FINDINGS: These findings are relevant for providing appropriate information to parents considering assisted conception, and more importantly for those with a preterm infant following a pregnancy achieved by assisted conception. STUDY FUNDING/COMPETING INTEREST(S): The authors report external funding and no conflicts of interest for this work. TRIAL REGISTRATION NUMBER: N/A.

Periprocedural myocardial infarction and injury in elective coronary stenting.

Aims: To assess the incidence, risk factors and prognosis of periprocedural myocardial infarction (MI) and myocardial injury in patients undergoing elective percutaneous coronary intervention (PCI). Methods and results: We included all consecutive patients who underwent elective PCI with a negative troponin level at admission from 1 January 2014 to 31 December 2015. The primary endpoint was defined as the composite of periprocedural MI (Type 4a MI), stent thrombosis (Type 4b MI), and myocardial injury according to the Third universal definition of MI. Multivariable analysis was performed to identify independent predictors of periprocedural MI and myocardial injury and its relation to 30-day and 1-year clinical outcome. Of the 1390 elective PCI patients, the primary endpoint occurred in 28.7% of patients, including 7.0% of Type 4a MI, 0.14% of Type 4b MI, and 21.6% of myocardial injury. Independent risk factors for the occurrence of the primary endpoint were left main PCI, total stent length >30 mm, multiple stenting, chronic kidney disease (estimated glomerular filtration rate <60 mL/min) and age >75 years. At 30 days, patients with periprocedural MI and myocardial injury had a higher rate of cardiovascular events [5.5% vs. 1.2%, adjusted hazard ratio (adjHR) = 3.8, 95% confidence interval (CI) 1.9-6.9; P < 0.001] mainly driven by ischaemic events (3.2% vs. 0.6%, HR 5.9, 95% CI 2.9-20; P < 0.0001). At 1-year, the risk of ischemic events remained higher in the periprocedural MI and myocardial injury group (adjHR = 1.7, 95% CI 1.1-2.6; P = 0.004). Conclusions: Periprocedural MI and injury are frequent complications of elective PCI associated with an increased rate of cardiovascular events at 30 days and 1 year.

Impact of front line relative dose intensity for methotrexate and comorbidities in immunocompetent elderly patients with primary central nervous system lymphoma.

Primary central nervous system lymphomas (PCNSL) are non-Hodgkin lymphomas strictly localized to the CNS, occurring mainly in elderly patients with comorbidities. Current treatment in fit patients relies on high-dose methotrexate and high-dose cytarabine. The aim of this study was to evaluate the efficacy and feasibility of this treatment in elderly patients and to assess potential prognostic factors associated with survival. We conducted a retrospective study in two centers between January 2008 and September 2015 including 35 elderly immunocompetent patients who received first-line treatment with high-dose methotrexate. With a median follow-up of 19.8 months (range: 1.7-73.4 months), median overall survival (OS) was 39.5 months (95% confidence interval (95% CI): 18.3-60.7) and median progression-free survival (PFS) was 25.8 months (95% CI: 5.2-46.4). In univariate analysis, administration of high-dose cytarabine and achieving a relative dose intensity for methotrexate > 75% were associated with increased OS (p = 0.006 and p = 0.003, respectively) and PFS (p = 0.003 and p = 0.04, respectively) whereas comorbidities, defined by a CIRS-G score ≥ 8, were associated with decreased OS and PFS (p = 0.02 and p = 0.04, respectively). A high MSKCC score was associated with decreased OS (p = 0.02). In multivariate analysis, administration of high-dose cytarabine was associated with increased OS and PFS (p = 0.02 and p = 0.007, respectively). Comorbidities and relative dose intensity for methotrexate are important for the prognosis of elderly patients with PCNSL. These results must be confirmed in prospective trials.

Platelet reactivity in human immunodeficiency virus infected patients on dual antiplatelet therapy for an acute coronary syndrome: the EVERE2ST-HIV study.

AIM: To explore platelet reactivity on dual antiplatelet therapy (DAPT) of acute coronary syndrome (ACS) patients infected with HIV. METHODS AND RESULTS: Acute coronary syndrome patients infected with HIV (n = 80) were matched to ACS patients without HIV (n = 160) on age, sex, diabetes, and DAPT (aspirin 100%, clopidogrel 68%, prasugrel 31%, ticagrelor 1%). Platelet reactivity was evaluated after ACS (>30 days) by measuring residual platelet aggregation (RPA) to aspirin and to P2Y12 inhibitors with light transmission aggregometry (LTA), VerifyNow aspirin assay (ARU), and P2Y12 assay (PRU) and with the VASP platelet reactivity index (VASP-PRI). Proportion of patients with high residual platelet reactivity (HPR) was evaluated. HIV-infected ACS patients had higher levels of platelet reactivity in response to P2Y12 inhibitors (RPA: 23.8 ± 2.7% vs. 15.3 ± 1.3%; P = 0.001; PRU: 132 ± 10 vs. 107.4 ± 6.6; P = 0.04; and VASP-PRI: 45.2 ± 2.6% vs. 32.0 ± 2.0%; P < 0.001) and to aspirin (RPA: 3.6 ± 1.5% vs. 0.4 ± 0.1%; P = 0.004 and ARU: 442 ± 11 vs. 407 ± 5; P = 0.002) compared with non-HIV. HIV-infection was independently associated with increased platelet reactivity regardless of the test used (RPA: P = 0.005; PRU: P < 0.001 and VASP-PRI: P < 0.001) and a higher proportion of HPR (OR = 7.6; P < 0.001; OR = 2.06; P = 0.06; OR = 2.91; P = 0.004, respectively) in response to P2Y12 inhibitors. Similar results were found with aspirin. Protease inhibitors use was associated with increased platelet reactivity and higher rate of HPR. CONCLUSIONS: Acute coronary syndrome patients infected with HIV have increased levels of platelet reactivity and higher prevalence of HPR to P2Y12 inhibitors and aspirin than non-HIV patients. These results could provide potential explanations for the observed increase risk of recurrent ischemic events in the HIV-infected population.

NOD1 Participates in the Innate Immune Response Triggered by Hepatitis C Virus Polymerase.

UNLABELLED: Hepatitis C virus (HCV) triggers innate immunity signaling in the infected cell. Replication of the viral genome is dispensable for this phenotype, and we along with others have recently shown that NS5B, the viral RNA-dependent RNA polymerase, synthesizes double-stranded RNA (dsRNA) from cellular templates, thus eliciting an inflammatory response, notably via activation of type I interferon and lymphotoxin ß. Here, we investigated intracellular signal transduction pathways involved in this process. Using HepaRG cells, a model that largely recapitulates the in vivo complexities of the innate immunity receptor signaling, we have confirmed that NS5B triggered increased expression of the canonical pattern recognition receptors (PRRs) specific for dsRNA, namely, RIG-I, MDA5, and Toll-like receptor 3 (TLR3). Unexpectedly, intracellular dsRNA also led to accumulation of NOD1, a receptor classically involved in recognition of bacterial peptidoglycans. NOD1 activation, confirmed by analysis of its downstream targets, was likely due to its interaction with dsRNA and was independent of RIG-I and mitochondrial antiviral signaling protein (MAVS/IPS-1/Cardif/VISA) signaling. It is likely to have a functional significance in the cellular response in the context of HCV infection since interference with the NOD1 pathway severely reduced the inflammatory response elicited by NS5B. IMPORTANCE: In this study, we show that NOD1, a PRR that normally senses bacterial peptidoglycans, is activated by HCV viral polymerase, probably through an interaction with dsRNA, suggesting that NOD1 acts as an RNA ligand recognition receptor. In consequence, interference with NOD1-mediated signaling significantly weakens the inflammatory response to dsRNA. These results add a new level of complexity to the understanding of the cross talk between different classes of pattern recognition receptors and may be related to certain complications of chronic hepatitis C virus infection.