Cost-effectiveness of weekly adaptive radiotherapy versus standard IMRT in head and neck cancer alongside the ARTIX trial.

BACKGROUND AND PURPOSE: We performed a cost-effectiveness analysis (CEA) comparing an adaptive radiotherapy (ART) strategy, based on weekly replanning, aiming to correct the parotid gland overdose during treatment and expecting therefore to decrease xerostomia, when compared to a standard IMRT. MATERIALS AND METHODS: We conducted the ARTIX trial, a randomized, parallel-group, multicentric study comparing a systematic weekly replanning ART to a standard IMRT. The primary endpoint was the frequency of xerostomia at 12 months, measured by stimulating salivary flow with paraffin. The CEA was designed alongside the ARTIX trial which was linked to the French national health data system (SNDS). For each patient, healthcare consumptions and costs were provided by the SNDS. The reference case analysis was based on the primary endpoint of the trial. Sensitivity and scenario analyses were performed. RESULTS: Of the 129 patients randomly assigned between 2013 and 2018, only 2 records were not linked to the SNDS, which provides a linkage proportion of 98.4%. All of the other 127 records were linked with good to very good robustness. On the intent-to-treat population at 12 months, mean total costs per patient were €41,564 (SD 23,624) and €33,063 (SD 16,886) for ART and standard IMRT arms, respectively (p = 0.033). Incremental cost effectiveness ratio (ICER) was €162,444 per xerostomia avoided. At 24 months, ICER was €194,521 per xerostomia avoided. For both progression-free and overall survival, ART was dominated by standard IMRT. CONCLUSION: The ART strategy was deemed to be not cost-effective compared with standard IMRT for patients with locally advanced oropharyngeal cancer.

Clinical and histological features of histiocytoid Sweet syndrome associated with VEXAS syndrome.

BACKGROUND: "Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic" (VEXAS) syndrome is caused by acquired somatic mutations in the ubiquitin-activating enzyme 1 (UBA1) gene. Sweet-syndrome-like skin disorders (and especially histiocytoid Sweet syndrome (HSS)) may be associated with VEXAS syndrome. OBJECTIVE: To characterize the clinical and histopathological features of HSS in patients with VEXAS syndrome. METHODS: The skin biopsies with a histological diagnosis of HSS had been collected at Rennes University Medical Center (Rennes, France) between October 2011 and January 2022. Sanger sequencing and digital PCR were used to screen skin, blood, and bone marrow samples for UBA1 variants, and thus classify patients as having VEXAS syndrome or not. We evaluated the clinical, histological, and molecular (UBA1) characteristics of patients with or without VEXAS syndrome. RESULTS: We compared 15 skin biopsies from seven patients found to have VEXAS syndrome and 19 skin biopsies from 15 patients without VEXAS syndrome. Persistent inflammatory syndrome, macrocytosis, anemia, and hematological malignancies were more prevalent in patients with VEXAS syndrome (86%, 86%, 100%, and 86%, respectively) than in patients without (36%, 40%, 53%, and 53%, respectively). These features sometimes appeared after the first skin manifestations, and a UBA1 mutation was found in the skin of five patients with VEXAS syndrome. Dermal infiltration by myeloperoxidase-positive, CD163-positive, reniform histiocytoid cells and a periadnexal distribution were more frequently observed in VEXAS syndrome biopsies (100% and 20% respectively, vs. 58% and 0% in non-VEXAS syndrome biopsies, respectively). CONCLUSION: Our findings might help the pathologist to consider a diagnosis of VEXAS syndrome and to initiate early genetic testing.

Transcatheter aortic valve implantation impact on left ventricular myocardial damage: long term follow-up.

INTRODUCTION: Aortic stenosis (AS) is causing myocardial damages and replacement is mainly indicated based on symptoms. Non-invasive estimation of myocardial work (MW) provide a less afterload dependent tool that, we sought to look at the impact of transcatheter aortic valve implantation (TAVI) on the myocardium at long-term follow-up and according to current indications. METHODS: We conducted an observational, cross-sectional, single-center study. Patients were selected based on the validated indication for a TAVI. Standardized echocardiographies were repeated. RESULTS: 102 patients were included. Mean age was 85-year-old, 45% were female, 68% get high-blood pressure and 52% had a coronary disease. One fifth was suffering from low-flow low-gradient aortic stenosis. Follow-up was performed at 22 ± 9.5 months after the TAVI. No TAVI-dysfunction was observed. LVEF was stable (62 ± 8%), and global longitudinal strain get improved (-14.0% ± 3.7 vs -16.0% ± 3.6, p-value <0.0001). No improvement of the MW-parameters was noticed (Global Work Index (LV GWI) 2099 ± 692mmHg% vs 2066 ± 706mmHg%, p=0.8, Global Constructive (LV GCW) 2463 ± 736mmHg% vs 2463 ± 676mmHg%, p=0.8). Global Wasted Work increased (214 [149; 357] mmHg% vs 247 [177; 394] mmHg%, p= 0.0008). CONCLUSION: In a population of severe symptomatic AS-patients who had undergone a TAVI, the non-invasive myocardial indices that assess the LV performance at long term follow-up did not improve. These results are questioning the timing of the intervention and the need for a more attention in the pharmacological management of these AS-patients.

Primary mitral regurgitation: Toward a better quantification on left ventricular consequences.

BACKGROUND: Left ventricular end-systolic diameter (LVESD) and ejection fraction (LVEF) are the parameters to look for when discussing repair in asymptomatic patients with a primary mitral regurgitation (PMR). Loading conditions are altering LV-function quantification. LV-myocardial work (LVMW) is a method based on pressure-strain loops. HYPOTHESIS: We sought to evaluate the additive value of the LVMW for predicting clinical events in patients with PMR. METHODS: 103 patients (66% men, median age 57 years) with asymptomatic severe PMR were explored at rest and during an exercise stress echocardiography. LV myocardial global work index (GWI), constructive work (GCW), wasted work (GWW), and work efficiency (GWE) were measured with speckle-tracking echocardiography at rest and low workload. The indication for surgery was based on the heart teams' decision. The median follow-up was 670 days. RESULTS: Clinical events occurred for 50 patients (48.5%) with a median of event-free survival distribution of 289 days. Systolic pulmonary artery pressure (sPAP) at rest was 32.61 ± 8.56 mmHg and did not predict the risk of event like LVEF and LVESD. Changes in, GLS (hazard ratio [HR] 0.55; 95% confidence interval (Cl): 0.36-0.83; p = .005), GWI (HR 1.01; 95% Cl: 1.00-1.02; p = .002) and GCW (HR 1.85; 95% Cl: 1.28-2.68; p = .001) in addition to Left Atrial Volume Index (HR 1.73; 95% CI: 1.28 - 2.33; p < 0,001) were independent predictors of events. CONCLUSION: Changes in myocardial work indices related to low-dose exercise are relevant to best predict PMR patient prognosis It might help to better select patient's candidate for "early-surgery."

Cox regression with linked data.

Record linkage is increasingly used, especially in medical studies, to combine data from different databases that refer to the same entities. The linked data can bring analysts novel and valuable knowledge that is impossible to obtain from a single database. However, linkage errors are usually unavoidable, regardless of record linkage methods, and ignoring these errors may lead to biased estimates. While different methods have been developed to deal with the linkage errors in the generalized linear model, there is not much interest on Cox regression model, although this is one of the most important statistical models in clinical and epidemiological research. In this work, we propose an adjusted estimating equation for secondary Cox regression analysis, where linked data have been prepared by a third-party operator, and no information on matching variables is available to the analyst. Through a Monte Carlo simulation study, the proposed method is shown to lead to substantial bias reductions in the estimation of the parameters of the Cox model caused by false links. An asymptotically unbiased variance estimator for the adjusted estimators of Cox regression coefficients is also proposed. Finally, the proposed method is applied to a linked database from the Brest stroke registry in France.

Evolution and prognostic value of left ventricular deformation and myocardial work parameters in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized condition. It remains challenging to estimate the extent of disease and the prognosis for most patients. Myocardial work is a sensitive echocardiographic approach that improves the characterization of myocardial damage. OBJECTIVE: We sought to investigate myocardial work parameters in ATTR-CM patients and it changes over time. METHOD: We analyzed clinical, electrocardiographic, biological, and echocardiographic characteristics in 113 consecutive patients (median age 82 [77-85], 90.4% male) diagnosed with wild-type ATTR-CM based on international consensus at a single centre. Baseline and follow up data at 18-month were assessed. RESULTS: Thirty-four patients died and twelve were hospitalized for heart failure at a median follow-up of 935 days (IQR 691-1159 days). Left ventricular end-diastolic diameter, left atrial strain during reservoir phase (LASr), left ventricular longitudinal strain, Global Work Index (GWI), Global Constructive Work, and TAPSE significantly decreased from baseline to 18 months while wall thickness increased. Left ventricular Ejection Fraction (LVEF), Right Ventricular Free Wall Strain, Global Wasted Work (GWW) and Global Work Efficiency (GWE) did not alter significantly. Using a multivariate analysis, strain parameters were identified as prognostic on baseline evaluation: GWW and RV-free wall-Strain (FWS) especially. They were significantly associated with the risk of death and hospitalization for heart failure. CONCLUSION: Myocardial Work parameters, particularly GWW, were valuable predictors for outcome in ATTR-CM patients.

Major adverse cardiovascular events in patients with atopic dermatitis treated with oral Janus kinase inhibitors: a systematic review and meta-analysis.

BACKGROUND: On the basis of safety data for patients with inflammatory rheumatism or inflammatory bowel disease, treatment with Janus kinase (JAK) inhibitors (JAKi) has been linked to the occurrence of major adverse cardiovascular events (MACE). However, these inflammatory diseases are proatherogenic; in contrast, patients with atopic dermatitis (AD) do not usually have a high cardiovascular (CV) comorbidity burden. OBJECTIVES: To perform a systematic review and meta-analysis of MACE in patients with AD treated with JAKi. METHODS: We systematically searched PubMed, Embase, Cochrane Library and Google Scholar from their inception to 2 September 2022. Cohort studies, randomized controlled trials and pooled safety analyses providing CV safety data on patients taking JAKi for AD were selected. We included patients aged ≥ 12 years. We built a 'controlled-period' cohort (n = 9309; 6000 exposed to JAKi and 3309 exposed to comparators) and an 'all-JAKi' cohort (n = 9118 patients exposed to a JAKi in any of the included studies). The primary outcome was a composite of acute coronary syndrome (ACS), ischaemic stroke and CV death. The broader secondary MACE outcome encompassed ACS, stroke (whether ischaemic or haemorrhagic), transient ischaemic attack and CV death. The frequency of primary and secondary MACE was assessed in both cohorts. A fixed-effects meta-analysis using the Peto method was used to calculate the odds ratio (OR) for MACE in the 'controlled-period' cohort. Evaluation of the risk of bias was done using the Cochrane risk-of-bias tool (version 2). Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Eight per cent of the records identified initially met the selection criteria, corresponding to 23 records included in the 'all-JAKi' cohort. Patients had been exposed to baricitinib, upadacitinib, abrocitinib, ivarmacitinib, placebo or dupilumab. Four primary events (three with JAKi and one with placebo) and five secondary events (four with JAKi and one with placebo) occurred among 9309 patients in the 'controlled-period' cohort (MACE frequency 0.04% and 0.05%, respectively). Eight primary events and 13 secondary events occurred among 9118 patients in the 'all-JAKi' cohort (MACE frequency 0.08% and 0.14%, respectively). The OR for primary MACE in patients with AD treated with JAKi vs. placebo or dupilumab was 1.35 (95% confidence interval 0.15-12.21; I2 = 12%, very low certainty of evidence). CONCLUSIONS: Our review highlights rare cases of MACE among JAKi users for AD. JAKi may have little-to-no effect on the occurrence of MACE in patients with AD vs. comparators, but the evidence is uncertain. Real-life long-term population-level safety studies are needed.

Risk of suicide attempt and suicide associated with benzodiazepine: A nationwide case crossover study.

BACKGROUND: Previous studies that found an association between benzodiazepines and suicidal behaviours were confounded by indication bias. AIMS: To limit this bias, a case crossover study (CCO) was conducted to estimate the risk of suicide attempt and suicide associated with benzodiazepines. METHOD: Patients ≥16 years, with hospitalised suicide attempt or suicide between 2013 and 2016, and at least one benzodiazepine dispensing within the 120 days before their act were selected in the nationwide French reimbursement healthcare system databases (SNDS). For each patient, frequency of benzodiazepine dispensing was compared between a risk period (days -30 to -1 before the event) and two matched reference periods (days -120 to -91, and -90 to -61). RESULTS: A total of 111,550 individuals who attempted suicide and 12,312 suicide victims were included, of who, respectively, 77,474 and 7958 had recent psychiatric history. Benzodiazepine dispensing appeared higher in the 30-day risk period than in reference ones. The comparison yielded adjusted odds ratios of 1.74 for hospitalised suicide attempt (95% confidence interval 1.69-1.78) and 1.45 for suicide (1.34-1.57) in individuals with recent psychiatric history, and of 2.77 (2.69-2.86) and 1.80 (1.65-1.97) for individuals without. CONCLUSION: This nationwide study supports an association between recent benzodiazepine use and both suicide attempt and suicide. These results strengthen the need for screening for suicidal risk carefully before initiation and during treatment when prescribing benzodiazepines. REGISTRATION NO: EUPAS48070 (http://www.ENCEPP.eu).

Real-World Treatment Patterns Among French Patients With Metastatic Castration-Resistant Prostate Cancer Under Abiraterone or Enzalutamide.

PURPOSE: Using large French retrospective study cohort of chemotherapy-naïve metastatic castration-resistant prostate cancer patients (mCRPC; n = 10,308) comparing survival between patients who initiated abiraterone (ABI; 64%) and those initiating enzalutamide (ENZ; 36%), the present objective was to describe treatment patterns in the 2 years following initiation. METHOD: Using the national health data system (SNDS) from 2014 to 2018, we first explored the number of treatment lines, and secondly, patterns of patient management using state sequence analysis; cluster analyses were performed on the 0 to 12 month and 13 to 24 month periods. Age, Charlson score, and duration of androgen deprivation therapy (ADT) were obtained for each cluster in the first year of follow-up. RESULTS: Patients with only 1 treatment line accounted for 52%. In the 0 to 12 month sequence analysis, the main clusters among ABI/ENZ new users involved patients who continued the initial treatment (54% of 65% respectively) and discontinued active treatment (14.5% for both). Less than 2 years exposure to ADT prior to ABI/ENZ initiation was frequently observed for noncontrolled mCRPC, as shown in the death and switch from ABI/ENZ to docetaxel clusters. The clusters for a switch ABI/ENZ to ENZ/ABI involved 6% to 11% of the patients. CONCLUSION: Our study suggested fairly similar patterns between ABI and ENZ initiation. The cluster of patients with active treatment discontinuation needs to be further investigated, as well as factors influencing therapeutic choice. Better understanding for the use of second-generation hormone therapy in mCRPC in real life, could improve its implementation by clinicians in the early stages of prostate cancer.

Evolution of non-invasive myocardial work variables after transcatheter aortic valve implantation in patients with severe aortic stenosis.

INTRODUCTION: Guidelines recommend aortic valve replacement in patients with severe aortic stenosis who present with symptoms or left ventricular ejection fraction<50%, both conditions representing a late stage of the disease. Whereas global longitudinal strain is load dependent, but interesting for assessing prognosis, myocardial work has emerged. AIM: To evaluate acute changes in myocardial work occurring in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: Patients who underwent TAVI were evaluated before and after by echocardiography. Complete echocardiographies were considered. Myocardial work indices (global work index, global constructive work, global work efficiency, global wasted work) were calculated integrating mean transaortic pressure gradient and brachial cuff systolic pressure. RESULTS: One hundred and twenty-five patients underwent successful TAVI, with a significant decrease in mean transaortic gradient (from 52.5±16.1 to 12.2±5.0; P<0.0001). There was no significant change in left ventricular ejection fraction after TAVI. Myocardial work data after TAVI showed a significant reduction in global work index (1389±537 vs. 2014±714; P<0.0001), global constructive work (1693±543 vs. 2379±761; P<0.0001) and global work efficiency (85.0±7.06 vs. 87.1±5.98; P=0.0034). The decrease in global work index and global constructive work after TAVI was homogeneous among different subgroups, based on global longitudinal strain, left ventricular ejection fraction and New York Heart Association status before TAVI. We observed a significant association between global work index and global constructive work before TAVI, and global longitudinal strain degradation after TAVI. CONCLUSIONS: Myocardial work variables show promising potential in best understanding the left ventricular myocardial consequences of aortic stenosis and its correction. Given their ability to discriminate between New York Heart Association status and global longitudinal strain evolution, we can hypothesize about their clinical value.

Long-term outcomes in heart failure with preserved ejection fraction: Predictors of cardiac and non-cardiac mortality.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with cardiovascular (CV) and non-CV events, but long-term risk is poorly studied. We assessed incidence and predictors of the long-term CV and non-CV events. METHODS AND RESULTS: Patients presenting with acute HF, EF ≥ 45%, and N-terminal pro-brain natriuretic peptide > 300 ng/L were enrolled in the Karolinska-Rennes study in 2007-11 and were reassessed after 4-8 weeks in a stable state. Long-term follow-up was conducted in 2018. The Fine-Gray sub-distribution hazard regression was used to detect predictors of CV and non-CV deaths, investigated separately from baseline acute presentation (demographic data only) and from the 4-8 week outpatient visit (including echocardiographic data). Of 539 patients enrolled [median age 78 (interquartile range: 72-84) years; 52% female], 397 patients were available for the long-term follow-up. Over a median follow-up time from acute presentation of 5.4 (2.1-7.9) years, 269 (68%) patients died, 128 (47%) from CV and 120 (45%) from non-CV causes. Incidence rates per 1000 patient-years were 62 [95% confidence interval (CI) 52-74] for CV and 58 (95% CI 48-69) for non-CV death. Higher age and coronary artery disease (CAD) were independent predictors of CV death, and anaemia, stroke, kidney disease, and lower body mass index (BMI) and sodium concentrations of non-CV death. From the stable 4-8 week visit, anaemia, CAD, and tricuspid regurgitation (>3.1 m/s) were independent predictors of CV death, and higher age of non-CV death. CONCLUSIONS: In patients with acute decompensated HFpEF, over 5 years of follow-up, nearly two-thirds of patients died, half from CV and the other half from non-CV causes. CAD and tricuspid regurgitation were associated with CV death. Stroke, kidney disease, lower BMI, and lower sodium were associated with non-CV death. Anaemia and higher age were associated with both outcomes. [Correction added on 24 March 2023, after first online publication: In the first sentence of the Conclusions, 'two-thirds' has been inserted before 'of patients died...' in this version.].

Isolated functional tricuspid regurgitation: how to define patients at risk for event?

AIMS: Functional tricuspid regurgitation (TR) is a turning point in cardiac diseases. Symptoms typically appear late. The optimal timing for proposing a valve repair remains a challenge. We sought to analyse the characteristics of right heart remodelling in patients with significant functional TR to identify the parameters that could be used in a simple prognostic model predicting clinical events. METHODS AND RESULTS: We designed a prospective observational French multicentre study including 160 patients with significant functional TR (effective regurgitant orifice area > 30 mm2 ) and left ventricular ejection fraction > 40%. Clinical, echocardiographic, and electrocardiogram data were collected at baseline and at the 1 and 2 year follow-up. The primary outcome was all-cause death or hospitalization for heart failure. At 2 years, 56 patients (35%) achieved the primary outcome. The subset with events showed more advanced right heart remodelling at baseline, but similar TR severity. Right atrial volume index (RAVI) and the tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure (TAPSE/sPAP) ratio, reflecting right ventricular-pulmonary arterial coupling, were 73 mL/m2 and 0.40 vs. 64.7 mL/m2 and 0.50 in the event vs. event-free groups, respectively (both P < 0.05). None among all the clinical and imaging parameters tested had a significant group × time interaction. The multivariable analysis leads to a model including TAPSE/sPAP ratio > 0.4 (odds ratio = 0.41, 95% confidence limit 0.2 to 0.82) and RAVI > 60 mL/m2 (odds ratio = 2.13, 95% confidence limit 0.96 to 4.75), providing a clinically valid prognostic evaluation. CONCLUSIONS: RAVI and TAPSE/sPAP are relevant for predicting the risk for event at 2 year follow-up in patients with an isolated functional TR.

The concomitant use of proton pump inhibitors and BRAF/MEK inhibitors in metastatic melanoma.

BACKGROUND: Proton-pump inhibitors (PPIs) are commonly used by patients with cancer, although they could reduce the absorption of oral anticancer targeted therapies. The US Food and Drug Administration states that the effect of PPIs on the efficacy of dabrafenib use by patients with metastatic melanoma is unknown. As a precautionary measure, the European Society for Medical Oncology recommends avoiding PPIs for patients receiving dabrafenib. OBJECTIVES: To determine the effect of the concomitant use of PPIs and BRAF/MEK inhibitors in patients with metastatic melanoma. METHODS: Patients with advanced melanoma receiving BRAF/MEK inhibitors as first-line treatments between 2015 and 2017 in France were selected using the French National Health Insurance database. We compared time-to-treatment discontinuation (TTD) and overall survival (OS) according to concomitant PPI exposure. We balanced the baseline characteristics of patients exposed and nonexposed to PPIs using an overlap weighting method based on a propensity score. RESULTS: The metastatic melanoma cohort comprised 1028 patients receiving BRAF/MEK inhibitors, including 361 (35.1%) patients using PPIs. PPI users had more comorbidities and a more severe metastatic disease. After having equally distributed metastatic sites and comorbidities across patients exposed and nonexposed to PPIs, concomitant PPI use was not associated with shorter TTD [weighted hazard ratio (wHR) 1.03, 95% confidence interval (CI) 0.86-1.24] or OS (wHR 1.11, 95% CI 0.88-1.39). Consistent results were observed when restricting the population to patients receiving dabrafenib, or when narrowing exposure to PPIs with stronger inhibition of cytochromes. CONCLUSIONS: In a population-based cohort of patients with advanced melanoma, the concomitant use of PPIs and BRAF/MEK inhibitors was not associated with worse outcome.

Management of epistaxis associated with oral antithrombotic drugs in emergency department and impact on prescription thereafter.

OBJECTIVES: To describe management, and to assess factors associated with antithrombotic prescription thereafter in patients who had epistaxis referred to emergency department (ED). DESIGN: Prospective cohort study. From EDs, clinical, biological and hospital data were collected. The clinical database was linked to the French Health Insurance Database where we retrieved antithrombotic drug deliveries in a 3-month period before and after referral. SETTING: Multicentric population-based cohort study within five well-defined areas. PARTICIPANTS: We considered 306 patients referred for epistaxis with a stable oral antithrombotic regimen before referral. MAIN OUTCOME MEASURES: We considered management, hospital outcome and case fatality. Antithrombotic prescription in a 3-month follow-up period was categorised into three classes: no change, class change, or discontinuation. During follow-up, hospitalisation for epistaxis or ischaemic events was searched. RESULTS: Among 306 adult individuals (mean age: 76 years), 166 took oral anticoagulant and 140 an antiplatelet drug. Blood transfusion was needed in 13.7% of patients and anterior packing alone in 61%. Half of the patients were hospitalised; 301 were discharged alive. Considering antithrombotic prescription thereafter we observed no change in 219 patients (72.8%), class changes in 47 patients (15.6%) and discontinuation in 35 patients (11.6%). We identified four independent predictors for antithrombotic prescription: hospitalisation (vs. returning home, p = .05), age (p = .03), haemoglobin level (p = .03) and oral anticoagulant (vs. antiplatelet agent, p < .001). During the 3 months following discharge, 2 thrombotic and 15 bleeding events were identified. CONCLUSIONS: Epistaxis referred to emergency department had an impact on subsequent antithrombotic prescription. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT02886533.

Could echocardiographic left atrial characterization have additive value for detecting risks of atrial arrhythmias and stroke in patients with hypertrophic cardiomyopathy?

AIMS: Atrial arrhythmia (AA) is considered a turning point for prognosis in patients with hypertrophic cardiomyopathy (HCM). We sought to assess whether the occurrence of AA and stroke could be estimated by an echocardiographic evaluation. METHODS AND RESULTS: A total of 216 patients with HCM (52 ± 16 years old) were analysed. All patients underwent transthoracic echocardiography for the evaluation of left atrial volume (LAV), peak left atrial strain (PLAS), and peak atrial contraction strain. The patients were followed for 2.9 years for the occurrence of a composite endpoint including AA and/or stroke and peripheral embolism. Among the 216 patients, 78 (36%) met the composite endpoint. These patients were older (57.1 ± 14.4 vs. 50.3 ± 16.7 years; P = 0.0035), had a higher prevalence of arterial hypertension (62.3 vs. 42.3%; P = 0.005), and had higher NT-proBNP. The LAV (47 ± 20 vs. 37.2 ± 15.7 mL/m²; P = 0.0001) was significantly higher in patients who met the composite endpoint, whereas PLAS was significantly impaired (19.3 ± 9.54 vs. 26.6 ± 9.12%; P < 0.0001). After adjustment, PLAS was independently associated with events with an odds ratio of 0.42 (95% confidence interval 0.29-0.61; P < 0.0001). Stroke occurred in 67% of the patients without any clinical AA. The PLAS with a cut-off of under 15.5% provided event prediction with 91% specificity. Using a 15% cut-off, PLAS also demonstrated a predictive value for new-onset of AA. CONCLUSION: The decrease in PLAS was strongly associated with the risk of stroke, even in patients without any documented AA. Its value for guiding the management of patients with HCM requires further investigation.

Oral Janus kinase inhibitors and venous thromboembolic events in atopic dermatitis: protocols for a case-time control study and a nested case-control study based on the French national health insurance (SNDS) cohort.

INTRODUCTION: Atopic dermatitis (AD) is a highly prevalent, chronic, inflammatory skin disease. Several orally administered Janus kinase inhibitors (JAKis, including baricitinib, upadacitinib and abrocitinib) have received a marketing authorisation for AD.Clinical trials in rheumatoid arthritis (RA) have flagged up a potential risk of JAKi-induced venous thromboembolic events (VTEs). Accordingly, the summary of product characteristics for a JAKi must mention VTEs as potential adverse drug reactions. In contrast to RA, AD per se is not associated with an elevated risk of VTEs. Assessing this potential risk among patients with AD would shed further light on the putative underlying relationship between JAKis and VTEs.Our research question is to investigate whether JAKi administration increases the risk of VTEs in adults with AD. Our primary objective is to assess the risk of VTEs in adults with AD exposed to JAKis compared to AD adults not exposed to JAKis, and our secondary objective is to evaluate whether JAKi initiation acts as a trigger of VTEs in adults with AD within 3 months. METHODS AND ANALYSIS: Hence, we have designed (1) a nested case-control study and (2) a case-time control study in a cohort of adults with AD with data from the French national health insurance system (2017-2025).Here, we describe the study protocol, our methodological choices and certain novel aspects, including the combined value of the two assumptions and the use of an exhaustive national health insurance database with potentially greater statistical power for studying rare events in the population of patients with AD at a low risk of VTEs (thus limiting the influence of confounding factors). ETHICS AND DISSEMINATION: The protocol has been approved by an independent ethics committee and registered with the French National Data Protection Commission. The study's findings will be published in peer-reviewed scientific journals and presented at international conferences.

Functional tricuspid regurgitation: A clustering analysis and prognostic validation of three echocardiographic phenotypes in an external cohort.

BACKGROUND: Functional tricuspid regurgitation (FTR) is an independent risk factor for morbidity and mortality. New pathophysiological concepts but also new therapeutic options are justifying new knowledges for characterizing FTRs and their prognoses. AIM: To study echocardiographic criteria associated with prognosis in FTR-patients using a clustering method in two cohorts. METHODS AND RESULTS: Two hundred forty-one patients with at least severe (≥grade 3) TR were enrolled: 92 in the retrospective cohort (mean age 77.9 ± 13 years) and 149 in the prospective validation cohort. Hierarchical clustering analysis was conducted. Four parameters explained the clustering categorization according to a multinomial regression (right ventricular (RV) end-diastolic mid-cavity diameter, RV free-wall strain, right atrial (RA) volume index, RA strain; p = 0.0039). Three clusters were identified in the retrospective cohort: Cluster 1 had better right ventricular, left ventricular, and right atrial function than Cluster 2 (reduced RV and RA strain despite similar sizes). Cluster 3 included patients with severely dilated heart chambers associated to RV and RA dysfunctions. When applying the model in the validation (external) cohort, the rate of the primary endpoint (hospitalization for heart failure and/or death from any cause) was lowest in Cluster 1 (30.8% versus 48% and 58.8% in Clusters 2 and 3, respectively; p < 0.05). CONCLUSION: In FTR patients, different profiles of RV and RA remodeling are associated with different outcomes. Therefore, the diagnostic work-up in this clinical setting should include RV and RA characteristics. Under noninterventional management, the phenotype corresponding to preserved RV size and preserved RA and RV functions appears to have a better prognosis.

Malnutrition and decreased food intake at diagnosis are associated with hospitalization and mortality of idiopathic pulmonary fibrosis patients.

INTRODUCTION AND AIMS: Malnutrition is frequent in patients with idiopathic pulmonary fibrosis (IPF). We examined the relationship between malnutrition at diagnosis and all-cause hospitalization, survival, and acute exacerbation in newly diagnosed IPF patients. METHODS: In this prospective cohort study, the nutritional status of 153 consecutive newly-diagnosed IPF outpatients was evaluated by measuring body mass index (BMI), fat-free mass index (FFMI) with bioelectrical impedance analysis, and food intake with the Self Evaluation of Food Intake (SEFI)®. Diagnosis was taken as the baseline date and malnutrition was defined as an FFMI below 17 (men) or 15 kg/m2 (women). To determine the factors associated with all-cause hospitalization and mortality, univariate Cox regression analyses were performed and variables with P < 0.2 were included in a stepwise multivariable analysis. RESULTS: A quarter (26%; 40/153) of the patients were suffering from malnutrition at baseline, which was more frequent (62%) in patients whose BMI was <25 kg/m2. Patients whose baseline FFMI was low were more likely to be hospitalized (Hazard Ratio (HR) = 1.98 [95% confidence interval, 1.15; 3.41], P = 0.0139) and/or die (HR = 1.79 [1.11; 2.89], P = 0.0165), but their acute exacerbation rate was similar to that of patients with normal FFMIs. Decreased food intake (SEFI®<7) at baseline was associated with all-cause hospitalization (P = 0.003) and mortality (P < 0.0001) during follow-up. Baseline higher gender-age-physiology (GAP) scores (HR = 1.24 [1.01; 1.52], P = 0.0434; HR = 1.71 [1.37; 2.14], P < 0.0001, respectively), lower BMI (HR = 0.89 [0.83; 0.96], P = 0.003; HR = 0.89 [0.82; 0.96], P = 0.003), and decreased food intake (SEFI® score) (HR = 0.81 [0.71; 0.93], P = 0.003; HR = 0.72 [0.64; 0.81], P < 0.0001), but not FFMI, were independently associated with all-cause hospitalization and mortality rates during follow-up. CONCLUSIONS: Malnutrition and decreased food intake at IPF diagnosis are associated with all-cause hospitalization and mortality. Future studies will determine whether dedicated interventions to improve food intake and nutritional status could improve outcomes for IPF patients.

Clinical use of low-dose parenteral anticoagulation, incidence of major bleeding and mortality: a multi-centre cohort study using the French national health data system.

PURPOSE: Low-dose parenteral anticoagulation has demonstrated its efficacy for venous thromboembolism prophylaxis in randomized trials. However, current practice is not widely documented. In ambulatory settings, we aimed to provide an overview of the clinical use of low-dose parenteral anticoagulation in France and to assess the incidence of major bleeding and death rates. METHODS: A population-based prospective cohort study using the French national health data system (SNIIRAM) identified 142,815 adults living in five well-defined geographical areas who had a course of low-dose parenteral anticoagulants (a total of 150,389 courses) in the period 2013-2015. The main outcome measures were the types of low-dose parenteral anticoagulant, the duration and the clinical context. Adjusted incidence rate ratios (IRR) were derived from Poisson models. RESULTS: Enoxaparin was the most frequently prescribed anticoagulant (58.9%) followed by tinzaparin (27.3%) and fondaparinux (10.9%). Patients receiving unfractionated heparin (N = 766, 0.53%) were older, more frequently had renal disease (48.75%) and had a higher modified HAS-B(L)ED score (≥ 3 in 61.6%) than patients receiving low-molecular weight heparin (LMWH). Surgical thrombo-prophylaxis was the most frequent indication (47.6%), followed by medical prophylaxis (29.9%). Course durations were in line with regulatory agency specifications. Only 43 (0.028%) major bleeding events and 478 (0.32%) deaths were observed. Adjusted IRRs for major bleeding or death were not significantly different for dalteparin/nadroparin, tinzaparin or fondaparinux compared to enoxaparin. CONCLUSION: Very low incidence rates of major bleeding and all-cause mortality were observed. Our study confirms the safety of LMWHs and fondaparinux in thrombo-prophylaxis in ambulatory settings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02886533.