I-CARE, a European Prospective Cohort Study Assessing Safety and Effectiveness of Biologics in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators. METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment. RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia. CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Combination of serum and peritoneal 1.3-beta-D-glucan can rule out intra-abdominal candidiasis in surgical critically ill patients: a multicenter prospective study.

BACKGROUND: Intra-abdominal candidiasis (IAC) is difficult to predict in critically ill patients with intra-abdominal infection, leading to the overuse of antifungal treatments. Serum and peritoneal 1.3-beta-D-glucan (sBDG and pBDG) have been proposed to confirm or invalidate the diagnosis of IAC, but clinical studies have reported inconsistent results, notably because of heterogeneous populations with a low IAC prevalence. This study aimed to identify a high-risk IAC population and evaluate pBDG and sBDG in diagnosing IAC. METHODS: This prospective multicenter noninterventional French study included consecutive critically ill patients undergoing abdominal surgery for abdominal sepsis. The primary objective was to establish the IAC prevalence. The secondary objective was to explore whether sBDG and pBDG could be used to diagnose IAC. Wako® beta-glucan test (WT, Fujifilm Wako Chemicals Europe, Neuss, Germany) was used for pBDG measurements. WT and Fungitell® beta-D-glucan assay (FA, Associate of Cape Cod, East Falmouth, USA) were used for sBDG measurements. RESULTS: Between 1 January 2020 and 31 December 2022, 199 patients were included. Patients were predominantly male (63%), with a median age of 66 [54-72] years. The IAC prevalence was 44% (87/199). The main IAC type was secondary peritonitis. Septic shock occurred in 63% of cases. After multivariate analysis, a nosocomial origin was associated with more IAC cases (P = 0.0399). The median pBDG level was significantly elevated in IAC (448 [107.5-1578.0] pg/ml) compared to non-IAC patients (133 [16.0-831.0] pg/ml), P = 0.0021. For a pBDG threshold of 45 pg/ml, the negative predictive value in assessing IAC was 82.3%. The median sBDG level with WT (n = 42) at day 1 was higher in IAC (5 [3.0-9.0] pg/ml) than in non-IAC patients (3 [3.0-3.0] pg/ml), P = 0.012. Similarly, median sBDG level with FA (n = 140) at day 1 was higher in IAC (104 [38.0-211.0] pg/ml) than in non-IAC patients (50 [23.0-141.0] pg/ml), P = 0.009. Combining a peritonitis score < 3, sBDG < 3.3 pg/ml (WT) and pBDG < 45 pg/ml (WT) yielded a negative predictive value of 100%. CONCLUSION: In critically ill patients with intra-abdominal infection requiring surgery, the IAC prevalence was 44%. Combining low sBDG and pBDG with a low peritonitis score effectively excluded IAC and could limit unnecessary antifungal agent exposure. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (ID number 03997929, first registered on June 24, 2019).

Measuring COVID-19 related stress and its associated factors among the parents of school-aged children during the first lockdown in France.

BACKGROUND: The COVID-19 pandemic placed important challenges on parents, as they had to meet various demands during lockdown, including childcare, work and homeschooling. Therefore, the current study aimed to investigate perceived stress levels among the parents of school-aged children and explore their association with sociodemographic, environmental and psychological factors during lockdown. METHODS: A cross-sectional study was conducted among the parents of school-aged children ages 8 to 18, who lived in the Grand Est region of France during the first wave of the pandemic. An online survey collected sociodemographic data, living and working conditions, and exposure to COVID-19 as well as parent's levels of perceived stress (PSS-10), self-perceived health status (SF-12), social support (MSPSS) and resilience (BRS). Multivariable logistic regression models were conducted to evaluate the association between moderate to severe perceived stress and various factors. RESULTS: In total, 734 parents were included. The results indicated that 47% were experiencing moderate stress and 7.2% were experiencing severe stress. Factors most strongly associated with risk of moderate to severe levels of stress were lower levels of parental resilience (OR = 3.8, 95% CI: 2.2-6.6) and poor self-perceived mental health status (OR = 7.3, 95% CI: 5.0-10.8). The following risk factors were also identified: female sex; being in the age range of 35-44; difficulties isolating and contracting COVID-19, which involved hospitalization and separation or isolation from family. The support of friends (OR = 0.8, 95% CI: 0.7-1.0) and family (OR = 0.5, 95% CI: 0.3-0.8) were protective factors. CONCLUSIONS: These findings suggest that supportive and preventive programs should focus on the improvement of resilience and mental health management to promote parents' wellbeing. Research has to focus both on individuals' inner potential for increasing resilience and the environmental resources to be activated. Building and boosting resilience among parents could serve as a protective factor against negative outcomes for them and their families.

Child self-report and child-parent agreement regarding health-related quality of life under COVID-19 lockdown in the French Grand Est area.

Nearly 1.6 billion of children and young people in more than 190 countries have been affected by school closures under the first lockdown due to the coronavirus disease. This study aimed to investigate child-reported and parent-rated health-related quality of life among 8- to 18-year-olds and the agreement between the children's assessments and those of their parents during lockdown. A cross-sectional study was conducted among French children living in the Grand Est area. An online survey was used to collect data on the children's sociodemographics, living environments, education and HRQoL. The latter was assessed with KIDSCREEN-27, which consists of five domains. Sex and age differences in parent ratings and child-reported data were analyzed using Mann-Whitney tests. Child-parent agreement was analyzed using the intraclass correlation coefficient (ICC). In total, 471 child-parent pairs from 341 households were included. Compared to European norms, children scored lower on all dimensions during the first lockdown: physical well-being (45.9/49.94 EU), psychological well-being (48.8/49.77 EU), parent relations and autonomy (47.7/49.99 EU), social support and peers (36.4/49.94 EU) and school (48.2/50 EU). Significant child-reported sex and age differences were identified for both psychological and physical well-being dimensions. Moderate to good agreement existed between children's and parents' ratings on all KIDSCREEN dimensions (ICC ranged from 0.60 to 0.76). The study suggests the need to focus on children's social support and peers during epidemics and to consider the children's self-reported HRQoL. Additional research should be conducted to identify ways of minimizing the gap between mental health needs and the services available and to help more children maintain their physical and mental health during the current crisis.

Impact of HIV Infection on the Course of Inflammatory Bowel Disease and Drug Safety Profile: A Multicenter GETAID Study.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), and human immunodeficiency virus (HIV) both impact innate and adaptive immunity in the intestinal mucosa. As it is a rare situation, the intersection between HIV and IBD remains unclear, especially the impact of HIV infection on the course of IBD, and the drug safety profile is unknown. METHODS: We conducted a multicenter retrospective cohort study between January 2019 and August 2020. All adult patients with IBD and concomitant HIV infection were included. Each IBD patient with HIV was matched to two HIV-uninfected IBD patients. RESULTS: Overall, 195 patients with IBD were included, including 65 HIV-infected patients and 130 without HIV infection. Of the 65 infected patients, 22 (33.8%) required immunosuppressants and 31 (47.7%) biologics. In the HIV-infected group, the need for immunosuppressants (p = 0.034 for CD and p = 0.012 for UC) and biologics (p = 0.004 for CD and p = 0.008 for UC) was significantly lower. The disease course, using a severity composite criterion, was not significantly different between the two groups for CD (hazard ration (HR) = 1.3 [0.7; 2.4], p = 0.45) and UC (HR, 1.1 [0.5; 2.7], p = 0.767). The overall drug safety profile was statistically similar between the two groups. CONCLUSION: Although HIV-infected patients receive less treatments, the course of their IBD did not differ than uninfected, suggesting that HIV infection might attenuate IBD. The drug safety profile is reassuring, allowing physician to treat these patients according to current recommendations.

Health-related quality of life in outpatients with substance use disorder: evolution over time and associated factors.

BACKGROUND: Health-related quality of life (HRQoL) is an important element of patient care and clinical research. The aim of this study was to describe HRQoL changes and identify associated factors during a 6-month follow-up of outpatients starting care for alcohol or opioid dependence. METHODS: HRQoL was measured at baseline and 3 and 6 months later using the SF-12. Data on the patients' sociodemographics, clinical characteristics and levels of anxiety and depression were collected using the Hospital Anxiety and Depression Scale (HADS). Repeated-measures analyses were performed to assess factors associated with global HRQoL differences and the evolution of HRQoL indicated by both physical and mental scores (PCS and MCS, respectively). RESULTS: The mean PCS and MCS scores were initially low at 45.4 (SD = 8.6) and 36.0 (SD = 10.9), respectively. The improvement in HRQoL was rapid in the first 3-month period and then slowed and remained stable over the subsequent 3-month period. Being employed (p = 0.012), having no comorbidities (p = 0.014) and having no depression (p = 0.004) were associated with significant differences in the average PCS scores at the 3 time points. Patients who had lower overall HRQoL MCS scores on average were those for whom a medication was initiated (p = 0.009), as was the case for patients with anxiety (p < 0.001) and depression (p < 0.001). Patients with depression at baseline were also those for whom a significantly greater increase in MCS score during the 6 months of follow-up was observed. CONCLUSION: Our findings highlight the importance of screening early psychological distress and considering other factors associated with HRQoL changes in outpatients after the first 3-month period of treatment for substance use disorder.

The effects of living and learning conditions on the health-related quality of life of children and adolescents during the COVID-19 lockdown in the French Grand Est region.

INTRODUCTION: COVID-19 lockdown measures resulted in children and adolescents staying and learning at home. This study investigated health-related quality of life (HRQoL) and its associated factors among youth during the first lockdown. METHODS: A cross-sectional study was conducted among 8- to 18-year-olds from the French Grand Est region. Sociodemographic data and information on living and learning conditions were collected using an online survey. HRQoL was assessed using the KIDSCREEN-27. Multiple regression analysis was performed to explore factors related to low HRQoL in each dimension. RESULTS: In total, 471 children from 341 households were included. Difficulties isolating at home were associated with low HRQoL in the psychological well-being (OR = 2.2, 95% CI: 1.2-4.0) and parent relations and autonomy (OR = 2.1, 95% CI: 1.2-3.8) dimensions. Conflicts with dwelling occupants were related to increased ORs in the psychological well-being (OR = 2.9, 95% CI: 1.9-4.6), parent relations and autonomy (OR = 2.2, 95% CI: 1.4-3.4) and school environment (OR = 2.4, 95% CI: 1.5-3.7) dimensions. Living in an apartment (OR = 1.8, 95% CI: 1.1-3.1), never leaving home (OR = 2.6, 95% CI: 1.2-5.9), having indoor noise at home (OR = 2.3, 95% CI: 1.2-4.6), and having a parent with high anxiety (OR = 1.8, 95% CI: 1.1-3.1) were associated with low HRQoL in the social support and peers dimension. Children working less than 1 h/day on schoolwork had an increased OR of 3.5 (95% CI: 1.4-9.0) in the school environment dimension. CONCLUSION: Living and learning conditions were associated with low HRQoL among children and adolescents during the COVID-19 lockdown. Prevention and intervention programs are needed to support youth by facilitating their interactions and improving their coping and to prepare for future waves.

Effect of the COVID-19 outbreak and lockdown on mental health among post-secondary students in the Grand Est region of France: results of the PIMS-CoV19 study.

BACKGROUND: The COVID-19 epidemic has sent students around the world in to lockdown. This study sought to assess the prevalence of impaired self-perceived mental health and identify associated factors among French post-secondary students during the lockdown. METHODS: A cross-sectional study was conducted among French students living in the Grand Est area in France from May 7 to 17, 2020 during the first lockdown. An online survey was used to collect sociodemographic data, learning and teaching conditions, living conditions, and exposure to COVID-19, and self-perceived mental health was assessed with mental composite score (MCS) of the SF-12. RESULTS: Overall, 4018 were analyzed. Most participants were female (70.7%), and the mean age was 21.7 years (SD 4.0). The mean MCS score was 44.5 (SD 17.3). Impaired mental health, defined by a MCS < 1st Quartile, was mainly associated with female sex; decreased time for learning; not having access to the outside with a garden, a terrace or a balcony; difficulties with the living situation and having someone in the home affected by the SARS-COV2 requiring hospitalization or not. CONCLUSIONS: This study showed that living conditions during lockdown had a clear impact on the mental health of French post-secondary students. There is a need to improve prevention and to access distance education as well as an urgent need for measures to develop healthy coping strategies for students. This is significant challenge and will assist in moderating the risk for the development of further distress and mental health concerns.

Burnout profiles among French workers in health units for inmates: results of the EHCAU study.

BACKGROUND: Health care personnel who work in penitentiary environments are at risk of burnout due to a variety of factors. Latest research have brought forward a classification system consisting of five burnout profiles on a continuum between engagement and burnout. The objective of this study was to measure the prevalence of these profiles among professionals working in French health units providing health services for inmates according to the three levels of care and to investigate their characteristics to propose appropriate management and prevention approaches. METHODS: This study involved a cross-sectional analysis of data from the Evaluation of Health CAre in Units for inmates (EHCAU) study, a multicentric cohort study of professionals practising in health units for inmates in eastern France. Burnout was assessed by the Maslach Burnout Inventory (MBI) at the levels of emotional exhaustion, depersonalization and personal accomplishment. Job conditions and characteristics were measured using the Karasek Job Content Questionnaire and the Effort-Reward Imbalance Questionnaire. Data on sociodemographic characteristics and self-reported health status were also collected. Differences between MBI profiles were identified using Fisher's exact test and the Wilcoxon test. RESULTS: Of the 350 professionals surveyed, 150 responded (42.9%). The most frequent profiles were ineffective (36.9%) and engagement (34.8%). The burnout (7.8%), overextended (15.6%) and disengaged (5.0%) profiles made up the remaining quarter. Significant differences in the burnout profiles were observed in regard to professional occupation (p = 0.01), irregular eating hours (p = 0.04), history of complaint procedures (p = 0.05), anxiety (p < 0.0001), depression (p < 0.0001) and the mental component of self-reported quality of life (p < 0.0001). CONCLUSIONS: These results confirm that special attention should be given to professionals working in these challenging settings. The results have important implications for theory and research and for more customized approach interventions. TRIAL REGISTRATION: ID RCB: 2018-A03029-46.

Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial.

BACKGROUND: Elderly patients are at high risk of ischaemic and bleeding events. Platelet function monitoring offers the possibility to individualise antiplatelet therapy to improve the therapeutic risk-benefit ratio. We aimed to assess the effect of platelet function monitoring with treatment adjustment in elderly patients stented for an acute coronary syndrome. METHODS: We did this multicentre, open-label, blinded-endpoint, randomised controlled superiority study at 35 centres in France. Patients aged 75 years or older who had undergone coronary stenting for acute coronary syndrome were randomly assigned (1:1), via a central interactive voice-response system based on a computer-generated permuted-block randomisation schedule with randomly selected block sizes, to receive oral prasugrel 5 mg daily with dose or drug adjustment in case of inadequate response (monitoring group) or oral prasugrel 5 mg daily with no monitoring or treatment adjustment (conventional group). Randomisation was stratified by centre. Platelet function testing was done 14 days after randomisation and repeated 14 days after treatment adjustment in patients in the monitoring group. Study investigators and patients were not masked to treatment allocation, but allocation was concealed from an independent clinical events committee responsible for endpoint adjudication. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, urgent revascularisation, and Bleeding Academic Research Consortium-defined bleeding complications (types 2, 3, or 5) at 12 months' follow-up. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01538446. FINDINGS: Between March 27, 2012, and May 19, 2015, we randomly assigned 877 patients to the monitoring group (n=442) or the conventional group (n=435). The primary endpoint occurred in 120 (28%) patients in the monitoring group compared with 123 (28%) patients in the conventional group (hazard ratio [HR], 1·003, 95% CI 0·78-1·29; p=0·98). Rates of bleeding events did not differ significantly between groups. INTERPRETATION: Platelet function monitoring with treatment adjustment did not improve the clinical outcome of elderly patients treated with coronary stenting for an acute coronary syndrome. Platelet function testing is still being used in many centres and international guidelines still recommend platelet function testing in high-risk situations. Our study does not support this practice or these recommendations. FUNDING: Eli Lilly and Company, Daiichi Sankyo, Stentys, Accriva Diagnostics, Medtronic, and Fondation Coeur et Recherche.

Evolution of DMSP (dimethylsulfoniopropionate) biosynthesis pathway: Origin and phylogenetic distribution in polyploid Spartina (Poaceae, Chloridoideae).

DMSP (dimethylsulfoniopropionate) is an ecologically important sulfur metabolite commonly produced by marine algae and by some higher plant lineages, including the polyploid salt marsh genus Spartina (Poaceae). The molecular mechanisms and genes involved in the DMSP biosynthesis pathways are still unknown. In this study, we performed comparative analyses of DMSP amounts and molecular phylogenetic analyses to decipher the origin of DMSP in Spartina that represents one of the major source of terrestrial DMSP in coastal marshes. DMSP content was explored in 14 Spartina species using 1H Nuclear Magnetic Resonance (NMR) spectroscopy and Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). Putative genes encoding the four enzymatic steps of the DMSP biosynthesis pathway in Spartina were examined and their evolutionary dynamics were studied. We found that the hexaploid lineage containing S. alterniflora, S. foliosa and S. maritima and their derived hybrids and allopolyploids are all able to produce DMSP, in contrast to species in the tetraploid clade. Thus, examination of DMSP synthesis in a phylogenetic context implicated a single origin of this physiological innovation, which occurred in the ancestor of the hexaploid Spartina lineage, 3-6MYA. Candidate genes specific to the Spartina DMSP biosynthesis pathway were also retrieved from Spartina transcriptomes, and provide a framework for future investigations to decipher the molecular mechanisms involved in this plant phenotypic novelty that has major ecological impacts in saltmarsh ecosystems.

Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results.

AIM: The MITOCARE study evaluated the efficacy and safety of TRO40303 for the reduction of reperfusion injury in patients undergoing revascularization for ST-elevation myocardial infarction (STEMI). METHODS: Patients presenting with STEMI within 6 h of the onset of pain randomly received TRO40303 (n = 83) or placebo (n = 80) via i.v. bolus injection prior to balloon inflation during primary percutaneous coronary intervention in a double-blind manner. The primary endpoint was infarct size expressed as area under the curve (AUC) for creatine kinase (CK) and for troponin I (TnI) over 3 days. Secondary endpoints included measures of infarct size using cardiac magnetic resonance (CMR) and safety outcomes. RESULTS: The median pain-to-balloon time was 180 min for both groups, and the median (mean) door-to-balloon time was 60 (38) min for all sites. Infarct size, as measured by CK and TnI AUCs at 3 days, was not significantly different between treatment groups. There were no significant differences in the CMR-assessed myocardial salvage index (1-infarct size/myocardium at risk) (mean 52 vs. 58% with placebo, P = 0.1000), mean CMR-assessed infarct size (21.9 g vs. 20.0 g, or 17 vs. 15% of LV-mass) or left ventricular ejection fraction (LVEF) (46 vs. 48%), or in the mean 30-day echocardiographic LVEF (51.5 vs. 52.2%) between TRO40303 and placebo. A greater number of adjudicated safety events occurred in the TRO40303 group for unexplained reasons. CONCLUSION: This study in STEMI patients treated with contemporary mechanical revascularization principles did not show any effect of TRO40303 in limiting reperfusion injury of the ischaemic myocardium.

High on-treatment platelet reactivity as a risk factor for secondary prevention after coronary stent revascularization: A landmark analysis of the ARCTIC study.

BACKGROUND: Individualizing antiplatelet therapy after platelet function testing did not improve outcome after coronary stenting in the Assessment by a Double Randomization of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption Versus Continuation One Year After Stenting (ARCTIC) study. Whether results are different during the phase of secondary prevention starting after hospital discharge, when periprocedural events have been excluded, is unknown. METHODS AND RESULTS: In ARCTIC, 2440 patients were randomized before coronary stenting to a strategy of platelet function monitoring (VerifyNow P2Y12/aspirin point-of-care assay) with drug adjustment in suboptimal responders to antiplatelet therapy or to a conventional strategy without monitoring and without drug or dose changes. We performed a landmark analysis starting at the time of hospital discharge evaluating the primary end point of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization through 1 year. After discharge, the primary end point occurred in 8.6% of patients in the monitoring arm and 7.9% in the conventional arm (hazard ratio, 1.105; 95% confidence interval, 0.835-1.461; P=0.48). Stent thrombosis or urgent revascularization occurred in 4.4% and 4.5% in the monitoring and conventional arms, respectively (P=0.99). There was no difference for any of the other ischemic end points. Major bleeding event rates were 1.8% in the monitoring arm and 2.8% in the conventional arm (P=0.11), whereas major or minor bleeding event rates were 2.3% and 3.4%, respectively (P=0.10). CONCLUSIONS: Detection of platelet hyper-reactivity by platelet function testing in patients undergoing coronary stenting with further therapeutic adjustment does not reduce ischemic recurrences after intervention. On-treatment platelet hyperreactivity cannot be considered as a risk factor requiring intervention for secondary prevention after percutaneous coronary revascularization. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00827411.

Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial.

BACKGROUND: Optimum duration of dual antiplatelet treatment (DAPT) after coronary stenting remains uncertain, with an unknown efficacy to safety ratio of extended treatment leading to discrepancies between international guidelines and clinical practice. We assessed whether DAPT continuation beyond 1 year after coronary stenting is beneficial. METHODS: This analysis was a planned extension of the previously published ARCTIC-Monitoring trial, in which we randomly allocated 2440 patients to a strategy of platelet function testing with antiplatelet treatment adjustment or a conventional strategy after coronary stenting with drug-eluting stent (DES). We recruited patients (aged 18 years or older) scheduled for planned DES implantation at 38 centres in France. After 1 year of follow-up, patients without contraindication to interruption of DAPT were eligible for a second randomisation to this second phase of the study (ARCTIC-Interruption). Using a computer-generated randomisation sequence (1:1; stratified by centre), we allocated patients to a strategy of interruption of DAPT where the thienopyridine was interrupted and single aspirin antiplatelet treatment was maintained (interruption group) or a strategy of DAPT continuation for 6-18 months (continuation group). The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularisation, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00827411. FINDINGS: Between Jan 4, 2011, and March 3, 2012, 1259 eligible patients were randomly allocated to treatment in ARCTIC-Interruption: 624 to the interruption group and 635 to the continuation group. After a median follow-up of 17 months (IQR 15-18), the primary endpoint occurred in 27 (4%) patients in the interruption group and 24 (4%) patients in the continuation group (hazard ratio [HR] 1·17 [95% CI 0·68-2·03]; p=0·58). STEEPLE major bleeding events occurred more often in the continuation group (seven [1%] patients) compared with the interruption group (one [<0·5%] patient; HR 0·15 [0·02-1·20]; p=0·073). Major or minor bleedings were also more common in the continuation group compared with the interruption group (12 [2%] patients vs three [1%] patients; HR 0·26 [0·07-0·91]; p=0·04). INTERPRETATION: Our finding suggests no apparent benefit but instead harm with extension of DAPT beyond 1 year after stenting with DES when no event has occurred within the first year after stenting. No conclusion can be drawn for high-risk patients who could not be randomised. The consistency between findings from all trials of such interruption suggests the need for a reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of treatment. FUNDING: Allies in Cardiovascular Trials Initiatives and Organized Networks (ACTION Study Group), Fondation de France, Sanofi-Aventis, Cordis, Medtronic, Boston Scientific, Fondation SGAM.

Bedside monitoring to adjust antiplatelet therapy for coronary stenting.

BACKGROUND: Patients' responses to oral antiplatelet therapy are subject to variation. Bedside monitoring offers the opportunity to improve outcomes after coronary stenting by individualizing therapy. METHODS: We randomly assigned 2440 patients scheduled for coronary stenting at 38 centers to a strategy of platelet-function monitoring, with drug adjustment in patients who had a poor response to antiplatelet therapy, or to a conventional strategy without monitoring and drug adjustment. The primary end point was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation. For patients in the monitoring group, the VerifyNow P2Y12 and aspirin point-of-care assays were used in the catheterization laboratory before stent implantation and in the outpatient clinic 2 to 4 weeks later. RESULTS: In the monitoring group, high platelet reactivity in patients taking clopidogrel (34.5% of patients) or aspirin (7.6%) led to the administration of an additional bolus of clopidogrel, prasugrel, or aspirin along with glycoprotein IIb/IIIa inhibitors during the procedure. The primary end point occurred in 34.6% of the patients in the monitoring group, as compared with 31.1% of those in the conventional-treatment group (hazard ratio, 1.13; 95% confidence interval [CI], 0.98 to 1.29; P=0.10). The main secondary end point, stent thrombosis or any urgent revascularization, occurred in 4.9% of the patients in the monitoring group and 4.6% of those in the conventional-treatment group (hazard ratio, 1.06; 95% CI, 0.74 to 1.52; P=0.77). The rate of major bleeding events did not differ significantly between groups. CONCLUSIONS: This study showed no significant improvements in clinical outcomes with platelet-function monitoring and treatment adjustment for coronary stenting, as compared with standard antiplatelet therapy without monitoring. (Funded by Allies in Cardiovascular Trials Initiatives and Organized Networks and others; ARCTIC ClinicalTrials.gov number, NCT00827411.).

Noninvasive study of coronary microcirculation response to a cold pressor test.

BACKGROUND: The aims of this study were to noninvasively (i) assess the coronary microcirculation changes in response to a cold pressor test (CPT) in control subjects, nondiabetic obese patients and patients with type 2 diabetes and (ii) investigate the response of the coronary microcirculation in patients with diabetes according to the presence or the absence of silent myocardial ischaemia (SMI), asymptomatic coronary stenosis (CS) and left ventricle hypertrophy (LVH). METHODS: The mean left anterior descending coronary flow velocity (mCFV) was measured using transthoracic Doppler before and after a CPT in 16 control subjects, 11 obese and 66 asymptomatic diabetic patients with a high cardiovascular risk. Patients with diabetes were screened for SMI using stress myocardial scintigraphy and/or echocardiography. A coronary angiography was performed in those with SMI. RESULTS: At baseline, pressure-rate product (PRP) was correlated with mCFV (r = 0.23; P < 0.05) and left ventricle mass (r = 0.26; P < 0.05) in the whole population. Changes in PRP and mCFV during CPT were correlated with controls (r = 0.58, P < 0.05), obese (r = 0.75, P < 0.01) and diabetic patients without CS (r = 0.56, P < 0.0001) or without LVH (r = 0.63, P < 0.05) but not in diabetic patients with CS or with LVH. In patients with diabetes, SMI was associated with mCFV changes, independent of other parameters (P < 0.05). CONCLUSION: Transthoracic coronary Doppler allows noninvasive study of changes in the coronary microcirculation during CPT. In asymptomatic patients with type 2 diabetes, this method showed that SMI was associated with mCFV changes during CPT and the presence of CS or LVH was associated with a mismatch between coronary microcirculation and myocardial oxygen demand.

Genetic and platelet function testing of antiplatelet therapy for percutaneous coronary intervention: the ARCTIC-GENE study.

BACKGROUND: The ARCTIC study randomized 2440 patients scheduled for stent implantation to a strategy of platelet function monitoring with drug adjustment in patients who had a poor response to antiplatelet therapy or to a conventional strategy without monitoring and drug adjustment. No significant improvement in clinical outcomes with platelet function monitoring was observed. OBJECTIVE: The purpose of this study is to assess the relationships between CYP2C19 genotypes, clopidogrel pharmacodynamic response, and clinical outcome. METHODS AND RESULTS: In the ARCTIC-GENE study, 1394 patients were genotyped for loss- and gain-of-function CYP2C19 alleles. Randomization of treatment strategy was well balanced. Slow metabolizers identified as carriers of at least one loss-of-function allele CYP2C19*2 (n = 459) were more likely poor responders at randomization (41.6 vs. 31.6%, p = 0.0112) and 14 days later (23.8 vs. 10.4%, p < 0.0001) and more frequently on prasugrel (11.5 vs. 8.1%, p = 0.039) as compared with rapid metabolizers (n = 935). Intensification of antiplatelet treatment did not differ between slow and rapid metabolizers according to the study algorithm based on platelet function only. The primary study outcome defined as the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation did not differ between slow and rapid metabolizers (HR 0.988, 95% CI [0.812;1.202], p = 0.90). Likewise, the primary safety outcome did not differ between rapid and slow metabolizer phenotype. CONCLUSIONS: The genetic clopidogrel profile was a good marker of platelet function response on clopidogrel but was not related to clinical outcome suggesting that the genetic added little to the pharmacodynamic information used in the study to adjust antiplatelet therapy. ClinicalTrials.gov: NCT00827411.

Flow-mediated-paradoxical vasoconstriction is independently associated with asymptomatic myocardial ischemia and coronary artery disease in type 2 diabetic patients.

BACKGROUND: To investigate whether flow-mediated dilation (FMD) impairment, which precedes overt atherosclerosis, is associated with silent myocardial ischemia (SMI) and asymptomatic coronary artery disease (CAD) in type 2 diabetes. METHODS: Forearm FMD was measured by ultrasonography in 25 healthy control, 30 non-diabetic overweight or obese patients and 118 asymptomatic type 2 diabetic patients with a high cardiovascular risk profile. SMI (abnormal stress myocardial scintiscan and/or stress dobutamine echocardiogram) and CAD (coronary angiography in the patients with SMI) were assessed in the diabetic cohort. RESULTS: FMD was lower in diabetic patients (median 0.61% (upper limits of first and third quartiles -1.22;3.2)) than in healthy controls (3.95% (1.43;5.25), p < 0.01) and overweight/obese patients (4.25% (1.74;5.56), p < 0.01). SMI was present in 60 diabetic patients, including 21 subjects with CAD. FMD was lower in patients with SMI than in those without (0.12% (-2.3;1.58) vs 1.64% (0;3.69), p < 0.01), with a higher prevalence of paradoxical vasoconstriction (50.0% vs 29.3%, p < 0.05). FMD was also lower in patients with than without CAD (-1.22% (-2.5;1) vs 1.13% (-0.4;3.28), p < 0.01; paradoxical vasoconstriction 61.9% vs 34.4%, p < 0.05). Logistic regression analyses considering the parameters predicting SMI or CAD in univariate analyses with a p value <0.10 showed that paradoxical vasoconstriction (odds ratio 2.7 [95% confidence interval 1.2-5.9], p < 0.05) and nephropathy (OR 2.6 [1.2-5.7], p < 0.05) were independently associated with SMI; and only paradoxical vasoconstriction (OR 3.1 [1.2-8.2], p < 0.05) with CAD. The negative predictive value of paradoxical vasoconstriction to detect CAD was 88.7%. CONCLUSIONS: In diabetic patients, FMD was independently associated with SMI and asymptomatic CAD. TRIAL REGISTRATION: Trial registration number NCT00685984.

Factors associated with an increased risk of anxiety among adolescents during the COVID-19 lockdown in the French Grand Est area.

The COVID-19 pandemic has impacted adolescent mental health worldwide. The current study aims to assess the feelings of French adolescents and the factors related to anxiety among these adolescents during the first lockdown due to COVID-19. A sample of 284 French adolescents from the Grand Est region aged 12-18 years completed an online survey evaluating their pandemic-related anxiety symptoms, behaviors, and feelings regarding the contingent strategies of lockdown that were taken and their living and learning conditions, family relationships, and social support. The Generalized Anxiety Disorder Scale (GAD-6) was used to assess anxiety. Data on parents' mental health status were also collected. A word cloud was generated to visualize respondents' feelings according to word use frequency. Cross-sectional analysis with linear regression was performed to identify the factors associated with a higher level of anxiety in adolescents. Higher anxiety scale scores were observed among females than among males (ß = 1.2; P = 0.0005), among adolescents experiencing conflicts at home (ß = 0.9; P = 0.03) and difficulties in isolation (ß = 1.1; P = 0.02) than among those who did not report any difficulty, and among those working less than 2 h a day (ß = 1.1; P = 0.003) than among those working more. Anxiety scale scores were lower in adolescents with higher family social support (ß = -0.66; P < 0.001) and those with parents with no anxiety (ß = -2.28; P < 0.001), lower anxiety (ß = -1.38; P = 0.018), and higher mental health-related quality of life (ß = -0.04; P = 0.03). These findings suggest a need to support interventions targeting parents' anxiety, develop strategies to increase family support, and establish consistent work schedules for children.