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Data on venous thromboembolic events (VTEs) in patients receiving immune checkpoint inhibitors (ICIs) are scarce and conflicting. This study investigated the risk of reporting VTEs associated with ICIs in comparison with all other anticancer drugs. The World Health Organization pharmacovigilance database (VigiBase), comprising30 million individual case safety reports, was queried. All reports on patients with cancer, involving at least one anticancer drug as a suspect or interacting drug and registered from January 1, 2008, to May 31, 2021, were included. The association between ICIs and the risk of reporting VTEs was estimated using the reporting odds ratio (ROR) as a measure of disproportionality with all other anticancer drugs as comparators. RORs were estimated as crude and adjusted RORs for age, sex, and other medications (excluding anticancer drugs) associated with risk of VTEs. Among 1,196 patients experiencing VTEs after ICI treatment, the median age was 65 years and 57.6% were men. Anti-PD-1 agents (62.5%) were the most frequently reported. ICIs were not associated with higher reporting of VTEs when compared with other anticancer drugs (crude ROR 0.63, 95% confidence interval (CI) 0.60 to 0.67 and adjusted ROR 0.70, 95% CI 0.65-0.74). No signal of disproportionate reporting was found when considering each class of ICIs. In conclusion, ICIs were not associated with higher reporting of VTEs, in comparison with all other anticancer drugs in a large-scale pharmacovigilance database. Owing to the limitations inherent to pharmacovigilance studies, prospective studies, including an adequate comparison group, are needed to assess the risk of VTEs in ICI-treated patients.

This study aimed to describe severe infections in patients treated with tocilizumab for systemic diseases other than rheumatoid arthritis.Data from patients receiving at least 2 doses of tocilizumab for systemic diseases other than rheumatoid arthritis between January 1, 2012, and July 1, 2020, in the region Poitou-Charentes (France) were retrospectively collected from medical records. Psoriatic arthritis and systemic juvenile idiopathic arthritis were also excluded as usually treated with similar modalities to rheumatoid arthritis.Of 37 patients, mainly suffering from giant cell arteritis, 25 patients (68%) had at least 1 infectious event and 15 severe infections occurred in 6 patients (3.2/100 patient-years), mainly bacterial. Lower respiratory tract and skin were the main sites. Severe bacterial infections were associated with a marked biological inflammatory syndrome, even under a cycle of administration of tocilizumab. Two severe zonas and 1 severe diverticulitis occurred. No tuberculosis or viral hepatitis reactivation was observed.The incidence rate of severe infections was 3.2/100 patient-years and seems lower than that reported in rheumatoid arthritis. C-reactive protein dosage could be helpful for the diagnosis of bacterial infectious adverse events in patients on tocilizumab. Further larger studies are needed to confirm these results to assess potential risk factors for severe infections.

Background Training volume is paramount in the magnitude of physiological adaptations following resistance training. However, patients with severe COPD are limited by dyspnea during traditional two-limb low-load/high-repetition resistance training (LLHR-RT), resulting in suboptimal training volumes. During a single exercise session, single-limb LLHR-RT decreases the ventilatory load and enables higher localized training volumes compared with two-limb LLHR-RT. Research Question Does single-limb LLHR-RT lead to more profound effects compared with two-limb LLHR-RT on exercise capacity (6-min walk distance [6MWD]), health status, muscle function, and limb adaptations in patients with severe COPD? Study Design and Methods Thirty-three patients (mean age 66 ± 7 years; FEV1 39 ± 10% predicted) were randomized to 8 weeks of single- or two-limb LLHR-RT. Exercise capacity (6MWD), health status, and muscle function were compared between groups. Quadriceps muscle biopsy specimens were collected to examine physiological responses. Results Single-limb LLHR-RT did not further enhance 6MWD compared with two-limb LLHR-RT (difference, 14 [–12 to 39 m]. However, 73% in the single-limb group exceeded the known minimal clinically important difference of 30 m compared with 25% in the two-limb group (P = .02). Health status and muscle function improved to a similar extent in both groups. During training, single-limb LLHR-RT resulted in a clinically relevant reduction in dyspnea during training compared with two-limb LLHR-RT (–1.75; P = .01), but training volume was not significantly increased (23%; P = .179). Quadriceps muscle citrate synthase activity (19%; P = .03), hydroxyacyl-coenzyme A dehydrogenase protein levels (32%; P Interpretation Single-limb LLHR-RT did not further increase mean 6MWD compared with two-limb LLHR-RT, but it reduced exertional dyspnea and enabled more people to reach clinically relevant improvements in 6MWD. Independent of execution strategy, LLHR-RT improved exercise capacity, health status, muscle endurance, and enabled several physiological muscle adaptations, reducing the negative consequences of limb muscle dysfunction in COPD. Clinical Trial Registration ClinicalTrials.gov ; No.: NCT02283580; URL: www.clinicaltrials.gov

Purpose Fatty liver disease is associated with cardiometabolic disorders and represents a potential key comorbidity in Chronic Obstructive Pulmonary Disease (COPD). Some intermediary mechanisms of fatty liver disease (including its histological component steatosis) include tissue hypoxia, low-grade inflammation and oxidative stress that are key features of COPD. Despite these shared physiological pathways, the effect of COPD on the prevalence of hepatic steatosis, and the association between hepatic steatosis and comorbidities in this population remain unclear. Liver density measured by computed tomography (CT)-scan is a non-invasive surrogate of fat infiltration, with lower liver densities reflecting more fat infiltration and a liver density of 40 Hounsfield Units (HU) corresponding to a severe 30% fat infiltration. Patients and Methods We took advantage of the international cohort ECLIPSE in which non-enhanced chest CT-scans were obtained in 1554 patients with COPD and 387 healthy controls to analyse the liver density at T12-L1. Results The distribution of liver density was similar and the prevalence of severe steatosis (density

Background: The current subclassification of systemic sclerosis into cutaneous subtypes does not fully capture the heterogeneity of the disease. We aimed to compare the performances of stratification into LeRoy's cutaneous subtypes versus stratification by autoantibody status in systemic sclerosis. Methods: For this cohort study, we assessed people with systemic sclerosis in the multicentre international European Scleroderma Trials and Research (EUSTAR) database. Individuals positive for systemic-sclerosis autoantibodies of two specificities were excluded, and remaining individuals were classified by cutaneous subtype, according to their systemic sclerosis-specific autoantibodies, or both. We assessed the performance of each model to predict overall survival, progression-free survival, disease progression, and different organ involvement. The three models were compared by use of the area under the curve (AUC) of the receiver operating characteristic and the net reclassification improvement (NRI). Missing data were imputed. Findings: We assessed the database on July 26, 2019. Of 16 939 patients assessed for eligibility, 10 711 patients were included: 1647 (15·4%) of 10 709 were male, 9062 (84·6%) were female, mean age was 54·4 (SD 13·8) years, and mean disease duration was 7·9 (SD 8·2) years. Information regarding cutaneous subtype was available for 10 176 participants and antibody data were available for 9643 participants. In the prognostic analysis, there was no difference in AUC for overall survival (0·82, 95% CI 0·81–0·84 for cutaneous only vs 0·84, 0·82–0·85 for antibody only vs 0·84, 0·83–0·86 for combined) or for progression-free survival (0·70, 0·69–0·71 vs 0·71, 0·70–0·72 vs 0·71, 0·70–0·72). However, at 4 years the NRI showed substantial improvement for the antibody-only model compared with the cutaneous-only model in prediction of overall survival (0·57, 0·46–0·71 for antibody only vs 0·29, 0·19–0·39 for cutaneous only) and disease progression (0·36, 0·29–0·46 vs 0·21, 0·14–0·28). The antibody-only model did better than the cutaneous-only model in predicting renal crisis (AUC 0·72, 0·70–0·74 for antibody only vs 0·66, 0·64–0·69 for cutaneous only) and lung fibrosis leading to restrictive lung function (AUC 0·76, 0·75–0·77 vs 0·71, 0·70–0·72). The combined model improved the prediction of digital ulcers and elevated systolic pulmonary artery pressure, but did poorly for cardiac involvement. Interpretation: The autoantibody-only model outperforms cutaneous-only subsetting for risk stratifying people with systemic sclerosis in the EUSTAR cohort. Physicians should be aware of these findings at the time of decision making for patient management. Funding: World Scleroderma Foundation.

Immune checkpoint inhibitor (ICI)-related cytopenias have been poorly described. This study aimed to further characterize ICI-related cytopenias, using the French pharmacovigilance database. All grade ≥ 2 hematological adverse drug reactions involving at least one ICI coded as suspected or interacting drug according to the World Health Organization criteria and reported up to 31 March 2022, were extracted from the French pharmacovigilance database. Patients were included if they experienced ICI-related grade ≥ 2 cytopenia. We included 68 patients (75 ICI-related cytopenias). Sixty-three percent were male, and the median age was 63.0 years. Seven patients (10.3%) had a previous history of autoimmune disease. Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) were the most frequently reported (50.7% and 25.3%, respectively). The median time to onset of ICI-related cytopenias was 2 months. Nearly half were grade ≥ 4, and three patients died from bleeding complications of refractory ITP and from thromboembolic disease with active AIHA. Out of 61 evaluable responses, complete or partial remission was observed after conventional treatment in 72.1% of ICI-related cytopenias. Among the 10 patients with ICI resumption after grade ≥ 2 ICI-related cytopenia, three relapsed. ICI-related cytopenias are rare but potentially life-threatening. Further studies are needed to identify risk factors of ICI-related cytopenias.

This study aimed to investigate cardiorespiratory responses and intercostal muscle oxygenation during normocapnic hyperpnea exercise in chronic obstructive pulmonary disease (COPD).Twenty-two patients with COPD performed a cardiopulmonary cycling exercise test to assess peak oxygen consumption (V˙O2peak) and minute ventilation (V˙Epeak). They also performed a normocapnic hyperpnea exercise alone, at 50%-60% of V˙Epeak to exhaustion, using a respiratory device (Spirotiger) connected to a gas analyzer to monitor V˙O2, V˙E, and end-tidal CO2 partial pressure. Cardiac output, and intercostal and vastus lateralis muscle oxygenation were continuously measured during exercise using finger photoplethysmography and near-infrared spectroscopy, respectively. Arterial blood gases (arterial PCO2) and inspiratory capacity were obtained at rest and at the end of hyperpnea exercise.The hyperpnea exercise lasted 576 ± 277 s at a V˙E of 34.5 ± 12.1 L·min-1 (58% ± 6% of V˙Epeak), a respiratory rate of 22 ± 4 breaths per minute, and a tidal volume of 1.43 ± 0.43 L. From rest to the end of hyperpnea exercise, V˙O2 increased by 0.35 ± 0.16 L·min-1 (P0.001), whereas end-tidal CO2 partial pressure and arterial PCO2 decreased by ~2 mm Hg (P = 0.031) and ~5 mm Hg (P = 0.002, n = 13), respectively. Moreover, inspiratory capacity fell from 2.44 ± 0.84 L at rest to 1.96 ± 0.59 L (P = 0.002). During the same period, heart rate and cardiac output increased from 69 ± 12 bpm and 4.94 ± 1.15 L·min-1 at rest to 87 ± 17 bpm (P = 0.002) and 5.92 ± 1.58 L·min-1 (P = 0.007), respectively. During hyperpnea exercise, intercostal deoxyhemoglobin and total hemoglobin increased by 14.26% ± 13.72% (P = 0.001) and 8.69% ± 12.49% (P = 0.003) compared with their resting value. However, during the same period, vastus lateralis oxygenation remained stable (P0.05).In patients with COPD, normocapnic hyperpnea exercise provided a potent cardiorespiratory physiological stimulus, including dynamic hyperinflation, and increased intercostal deoxyhemoglobin consistent with enhanced requirement for muscle O2 extraction.

Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies. acceptedVersion

International audience; A high prevalence of intermediate cardiometabolic risk factors and obesity in chronic obstructive pulmonary disease (COPD) has suggested the existence of pathophysiological links between hypertriglyceridemia, insulin resistance, visceral adiposity, and hypoxia or impaired pulmonary function. However, whether COPD contributes independently to the development of these cardiometabolic risk factors remains unclear. Our objective was to compare ectopic fat and metabolic profiles among representative individuals with COPD and control subjects and to evaluate whether the presence of COPD alters the metabolic risk profile. Study participants were randomly selected from the general population and prospectively classified as non-COPD controls and COPD, according to the Global Initiative for Chronic Obstructive Lung Disease classification. The metabolic phenotype, which consisted of visceral adipose tissue area, metabolic markers including homeostasis model assessment of insulin resistance (HOMA-IR), and blood lipid profile, was obtained in 144 subjects with COPD and 119 non-COPD controls. The metabolic phenotype was similar in COPD and controls. The odds ratios for having pathologic values for HOMA-IR, lipids and visceral adipose tissue area were similar in individuals with COPD and control subjects in multivariate analyses that took into account age, sex, body mass index, tobacco status and current medications. In a population-based cohort, no difference was found in the metabolic phenotype, including visceral adipose tissue accumulation, between COPD and controls. Discrepancies between the present and previous studies as to whether or not COPD is a risk factor for metabolic abnormalities could be related to differences in COPD phenotype or disease severity of the study populations.

Immune checkpoint inhibitors (ICIs) have become the standard of care for several types of cancer due to their superiority in terms of survival benefits in first- and second-line treatments compared to conventional therapies, and they present a better safety profile (lower absolute number of grade 1–5 adverse events), especially if used in monotherapy. However, the pattern of ICI-related adverse events is totally different, as they are characterized by the development of specific immune-related adverse events (irAEs) that are unique in terms of the organs involved, onset patterns, and severity. The decision to resume ICI treatment after its interruption due to irAEs is challenged by the need for tumor control versus the risk of occurrence of the same or different irAEs. Studies that specifically assess this point remain scarce, heterogenous and mostly based on small samples of patients or focused only on the recurrence rate of the same irAE after ICI resumption. Moreover, patients with grade ≥3 irAEs were excluded from many of these studies. Herein, we provide a narrative review on the field of safety of ICI resumption after interruption due to irAE(s).

Objective: To investigate the interday test–retest reliability of volitional and non-volitional measurements of isometric quadriceps strength using a strain-gauge in people with severe to very severe chronic obstructive pulmonary disease. Design: Cross-sectional study. Volitional quadriceps measurements consisted of isometric maximal voluntary contractions. Non-volitional measurements were obtained during magnetic potentiated twitch stimulations of the femoral nerve. Setting: Research centre laboratory. Participants: Twenty-four individuals with severe to very severe chronic obstructive pulmonary disease (percentage of predicted forced expiratory volume in 1 s, 37% predicted). Results: Maximal voluntary contractions and potentiated twitch stimulations measures demonstrated excellent interday test–retest relative reliability (ICC 0.97 and 0.80, respectively), while absolute reliability measures were different between techniques (SEM 1.4 kg, CV 3.2%, MDC 3.9 kg vs SEM 1.5 kg, CV 12.2%, MDC 4.2 kg for maximal voluntary contractions and potentiated twitch stimulations, respectively). Conclusion: The results supports that maximal voluntary contraction and potentiated twitch stimulation measurements of isometric quadriceps strength are reliable in people with severe to very severe chronic obstructive pulmonary disease as evident excellent relative reliability using both techniques, although the former technique appears to have better absolute reliability.

The phenotypic characterization of self-reactive B cells producing autoantibodies is one of the challenges to get further insight in the physiopathology of autoimmune diseases. We took advantage of our previously developed flow cytometry method, using labeled nucleosomes, prominent autoantigens in systemic lupus erythematosus, to analyze the phenotype of self-reactive B cells in the anti-DNA B6.56R mouse model. We showed that splenic anti-nucleosome B cells express mostly kappa light chains and harbor a marginal zone phenotype. Moreover, these autoreactive B cells fail to acquire a germinal center phenotype and are less abundant in the transitional T3 compartment. In conclusion, the direct detection of autoreactive B cells helped determine their phenotypic characteristics and provided a more direct insight into the B cell tolerance process in B6.56R mice. This method constitutes an interesting new tool to study the mechanisms of B cell tolerance breakdown in B6.56R mice crossed with autoimmune prone models.

Mickaël Martin,1 Natalie Almeras,1 Jean-Pierre Després,1 Harvey O Coxson,2 George R Washko,3 Isabelle Vivodtzev,4 Emiel FM Wouters,5 Erica Rutten,6 Michelle C Williams,7 John T Murchison,8 William MacNee,7 Don D Sin,2 François Maltais1 On behalf of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study Group 1Research Centre, Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, QC, 2Department of Radiology, University of British Columbia, Vancouver, BC, Canada; 3Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 4Hypoxia Pathophysiology Laboratory, Grenoble University Hospital, Grenoble, France; 5Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, 6Research and Development, CIRO, Horn, the Netherlands; 7Department of Respiratory Medicine, University of Edinburgh, 8Department of Radiology, Royal Infirmary of Edinburgh, Edinburgh, UK Background: Obesity is increasingly associated with COPD, but little is known about the prevalence of ectopic fat accumulation in COPD and whether this can possibly be associated with poor clinical outcomes and comorbidities. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) substudy tested the hypothesis that COPD is associated with increased ectopic fat accumulation and that this would be associated with COPD-related outcomes and comorbidities.Methods: Computed tomography (CT) images of the thorax obtained in ECLIPSE were used to quantify ectopic fat accumulation at L2–L3 (eg, cross-sectional area [CSA] of visceral adipose tissue [VAT] and muscle tissue [MT] attenuation, a reflection of muscle fat infiltration) and CSA of MT. A dose–response relationship between CSA of VAT, MT attenuation and CSA of MT and COPD-related outcomes (6-minute walking distance [6MWD], exacerbation rate, quality of life, and forced expiratory volume in 1second [FEV1] decline) was addressed with the Cochran–Armitage trend test. Regression models were used to investigate possible relationships between CT body composition indices and comorbidities.Results: From the entire ECLIPSE cohort, we identified 585 subjects with valid CT images at L2–L3 to assess body composition. CSA of VAT was increased (P

Exercising small muscle groups at a time allows higher muscle specific workloads compared with whole body aerobic exercises in people with chronic obstructive pulmonary disease (COPD). Whether similar effects also occur with partitioning exercise during low load/high-repetition resistance exercises is uncertain.To investigate the acute effects of partitioning exercise on exercise workload, exertional symptoms and quadriceps muscle fatigue during low load/high-repetition resistance exercises in people with COPD and healthy controls.We compared the acute physiological effects of single-limb (SL) versus two-limb (TL) execution of isokinetic knee extension and of six low load/high-repetition elastic resistance exercises in 20 people with COPD (forced expiratory volume in 1 s = 38% predicted) and 15 healthy controls.Among people with COPD, SL exercises resulted in higher exercise workloads during isokinetic knee extension (17% ± 31%, P0.05) and elastic exercises (rowing, 17% ± 23%; leg curl, 23% ± 21%; elbow flexion, 19% ± 26%; chest press, 14% ± 15%; shoulder flexion, 33% ± 24%; and knee extension, 24% ± 18%, all P0.05). Muscle fatigue ratings were similar during SL compared with TL exercises, whereas dyspnea ratings were similar between conditions during isokinetic exercises and lower during SL compared with TL elastic exercises (P0.05). In COPD, SL knee extension resulted in greater quadriceps fatigue than TL knee extension as evidenced by a greater fall in quadriceps potentiated twitch force after the former exercise (-24% ± 10% vs -16% ± 8%, P = 0.025). In healthy controls, partitioning exercise with SL exercise did not modify workload, quadriceps fatigue nor dyspnea achieved during the various exercises.Partitioning exercise by exercising using an SL allowed higher muscle localized exercise workloads, larger amount of quadriceps muscle fatigue with lower, or similar level of exertional symptoms during low load/high-repetition resistance exercises in people with advanced COPD.

Purpose Fatty liver disease is associated with cardiometabolic disorders and represents a potential key comorbidity in Chronic Obstructive Pulmonary Disease (COPD). Some intermediary mechanisms of fatty liver disease (including its histological component steatosis) include tissue hypoxia, low-grade inflammation and oxidative stress that are key features of COPD. Despite these shared physiological pathways, the effect of COPD on the prevalence of hepatic steatosis, and the association between hepatic steatosis and comorbidities in this population remain unclear. Liver density measured by computed tomography (CT)-scan is a non-invasive surrogate of fat infiltration, with lower liver densities reflecting more fat infiltration and a liver density of 40 Hounsfield Units (HU) corresponding to a severe 30% fat infiltration. Patients and Methods We took advantage of the international cohort ECLIPSE in which non-enhanced chest CT-scans were obtained in 1554 patients with COPD and 387 healthy controls to analyse the liver density at T12-L1. Results The distribution of liver density was similar and the prevalence of severe steatosis (density

Discovering trend reversals between two data cubes provides users with novel and interesting knowledge when the real-world context fluctuates: What is new? Which trends appear or emerge? With the concept of emerging cube, the authors capture such trend reversals by enforcing an emergence constraint. In a big data context, trend reversal predictions promote a just-in-time reaction to these strategic phenomena. In addition to prediction, a business intelligence approach aids to understand observed phenomena origins. In order to exhibit them, the proposal must be as fast as possible, without redundancy but with ideally an incremental computation. Moreover, the authors propose an algorithm called C-Idea to compute reduced and lossless representations of the emerging cube by using the concept of cube closure. This approach aims to improve efficiency and scalability while preserving integration capability. The C-Idea algorithm works à la Buc and takes the specific features of emerging cubes into account. The proposals are validated by various experiments for which we measure the size of representations.

Valérie Coats,1 Jean-Pierre Després,1 Natalie Alméras,1 Mickaël Martin,1 Don D Sin,2 Rémi Rabasa-Lhoret,3 Éric Larose,1 Wan C Tan,2 Jean Bourbeau,4 François Maltais1On behalf of the CanCOLD Collaborative Research Group and the Canadian Respiratory Research Network 1Centre de recherche, Institut universitaire de cardiologie et de pneumologie de Québec, Université, Laval, QC, Canada; 2University of British Columbia, Vancouver, BC, Canada; 3Institut de Recherches Cliniques de Montréal, Département de Nutrition et Service d’Endocrinologie, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada; 4Respiratory Epidemiology and Clinical Research Unit, Research Institute of the McGill University Health Centre, Montreal, QC, CanadaRationale: Obesity/overweight is the most prevalent body composition abnormality in COPD. However, little is known about the impact of fat distribution on cardiometabolic health in COPD.Objective: To study the associations between ectopic adiposity, cardiometabolic health, and COPD.Methods: A total of 263 subjects (166 males; age=65±9 years) were randomly selected from the general population. Subjects were classified as non-COPD controls and COPD, according to the Global initiative for chronic Obstructive Lung Disease (GOLD) classification, and the presence of cardiometabolic comorbidities was recorded. Ectopic fat accumulation was documented from computed tomography measurements of visceral adipose tissue cross-sectional areas and muscle mean attenuation, assessed at L4–L5. Blood glucose, lipid, and adipokine profiles were also evaluated.Results: After correcting for age, sex, and tobacco exposure, visceral adipose tissue cross-sectional area was higher in GOLD 2+ compared to GOLD 1 individuals. Consistent with this, mean muscle tissue attenuation was lower in GOLD 2+ vs GOLD 1 and non-COPD controls (P

During the course of a typical strength training program, neural factors account for approx. 90% of gain in strength during the first 2-weeks and 40-50% during the subsequent 2-weeks while muscular adaptations become progressively more important. We aimed to investigate the impact of the rate of progression of muscle work performed during training sessions on intramuscular adaptations in people with COPD following resistance training designed to improve quadriceps muscle endurance. Fourteen participants with COPD (age: 65±7 years, FEV1 :39±10 % predicted) performed a muscle biopsy before and after an 8-week training intervention consisting of low-load/high-repetition knee extension exercise. Those in whom the gain in muscle endurance occurred the first 4 weeks were considered as the "neural" group while those who showed continuous progression throughout the whole 8-week period constituted the "muscular" group. Results are seen in Figure 1. Conclusion: Eight weeks of low-load/high-repetition resistance training was associated with an increase in the proportion of type I fibers with a recriprocal decrease in percentage of Type IIa fibers among patients with COPD with a continuous progression in knee extension work capacity throughout an 8-week training intervention in comparison to those in whom the gain in muscle endurance occurred the first 4 weeks of training.

Thirty-two participants with COPD (FEV1:38±10% predicted) were randomized to either 8-weeks of SL or TL LLHR-RT. LLHR-RT was performed three times/week for 8 weeks and consisted of knee extension (KE), leg curl (LC), latissimus row (ROW), chest press (CP), elbow flexion (EF) shoulder flexion (SF), and calf-raise exercises. Outcomes: 6MWT (primary outcome), unsupported upper limb exercise test (UULEX), COPD assessment test (CAT), isotonic muscle endurance (KE, LC, ROW, CP, EF, SF), exercise workloads and dyspnea. In addition, exertional symptoms were assessed at two exercise sessions with matched workloads that were performed before and post intervention. Intention to treat analysis was performed using multiple imputation. Results: During the 8-week intervention period, exercise workloads were similar, mean difference per week SL versus TL: (56 [-47 to 161 kg]) but dyspnea ratings were lower (-1.4 [- 0.1 to - 2.8]) during SL. Impact of LLHR-RT on clinical outcomes are shown in Table. *p Conclusion: SL and TL LLHR-RT results in similarly positive effects but with lower level of exertional dyspnea during the former.

Introduction: During whole body exercise, respiratory muscle work may affect locomotor muscle oxygenation and consequently reduce exercise capacity1. Respiratory muscle training using normocapnic hyperpnoea exercise (NHE) is a promising strategy to improve exercise capacity in COPD. Aims: To investigate the acute effects of NHE on intercostal and locomotor muscle oxygenation in COPD. Methods: Eight patients with COPD (FEV1 = 55±8% of pred) performed a NHE at 50-60% of peak ventilation (VEpeak) assessed during maximal cycling test. The NHE was conducted to exhaustion, using a respiratory device (SpiroTiger®) connected to a gas analyzer to monitor VE, VO2 and PETCO2. Cardiac output (CO) and intercostal and vastus lateralis muscle oxygenation were continuously measured during NHE by means of finger photoplethysmography and NIRS, respectively. Arterial blood gases (PaCO2) and inspiratory capacities (IC) were obtained at rest and at end-exercise. Results: The NHE was maintained for 653±397s, at a VE averaging 25±10 l/min or 52±5% of VEpeak and with a VO2 corresponded to 52±6% of VO2peak. Intercostal muscle deoxyhemoglobin and total hemoglobin increased by 14±6% and 13±8% respectively (p Conclusions: NHE promotes muscle deoxygenation in the intercostals but not in the vastus lateralis but it was not accompanied by changes in CO or dynamic hyperinflation in COPD. Our results suggest that NHE stimulates the intercostal muscles, which could potentially improve exercise tolerance following a NHE training. 1 Harms et al JAP 1997

session III-V Devices on Group IV Substrates (6A-2.2); International audience

Single-limb exercises have been used as a strategy to improve aerobic exercise tolerance in patients with chronic obstructive pulmonary disease (COPD) by alleviating the cardiopulmonary demand. We asked whether this strategy would also apply to cardiorespiratory demand and amount of work performed during single-limb and two-limb low-load/high-repetition resistance exercises in 20 patients with COPD [forced expiratory volume in 1 s (FEV1) = 1.0 liters, 38% of predicted] and 15 age-, sex-, and activity-matched healthy controls. Peak ventilation, peak oxygen consumption (V̇o2), and peak heart rate (HR) were assessed to document cardiorespiratory demand during shoulder flexion and knee extension exercises while exercise tolerance was assessed by the total amount of work achieved. In addition, changes in myoglobin-deoxyhemoglobin level (Δdeoxy-[Hb/Mb]) were measured during single-limb knee extension. In COPD, single-limb shoulder flexion and knee extension elicited higher localized workloads than two-limb exercises (21 and 24% higher workloads for the former exercise) while cardiopulmonary demand was 8–16% higher during two-limb exercises. When expressed as a percentage of peak values achieved during incremental cycle ergometry, peak V̇O2 and HR were similarly high during single-limb shoulder flexion and knee extension exercises, representing 90% of peak HR and 60% of peak V̇O2. Apart from single-limb knee extension, cardiorespiratory demand per kilogram work during low-load/high-repetition knee extension and shoulder flexion exercises was higher in patients with COPD than in healthy controls (range 27–122%, P < 0.0125). Δdeoxy-[Hb/Mb] of the quadriceps during knee extension was similar between the two groups, while Δdeoxy-[Hb/Mb] per kilogram work was higher in patients with COPD. We conclude that 1) in patients with COPD, single-limb exercises resulted in lower peak cardiorespiratory demand as well as higher localized workloads compared with two-limb exercises; 2) compared with healthy controls, the cardiorespiratory demand, either expressed per unit of work or relative to peak capacity, was higher in patients with COPD than in controls during low-load/high-repetition resistance exercises, irrespective of the involvement of one or two limbs or of the upper or lower extremity; 3) quadriceps muscle deoxygenation per unit of work during low-load/high-repetition knee extension was increased in COPD compared with controls; and 4) single- and two-limb low-load/high-repetition knee extension and shoulder flexion resistance exercises imposed a similar burden on the cardiorespiratory system, resulting in a higher cardiorespiratory demand per kilogram work performed during shoulder flexion compared with knee extension, in both COPD and healthy controls. NEW & NOTEWORTHY In chronic obstructive pulmonary disease (COPD), single-limb knee extension and shoulder flexion resulted in a lower peak cardiorespiratory response as well as larger localized exercise workloads compared with two-limb exercises. Cardiorespiratory and quadriceps deoxygenation cost per kilogram work was greater in COPD compared with healthy controls, despite similar acute responses. Compared with knee extension, shoulder flexion imposed a similar burden on the cardiorespiratory system in patients with COPD and healthy controls.

Acute and fatal cardiotoxicity following high-dose cyclophosphamide in a patient undergoing autologous stem cell transplantation for systemic sclerosis despite satisfactory cardiopulmonary screening

session ED3.5; International audience

International audience

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Although utilization of vasopressors recently has been associated with reduced cerebral oxygenation, the influence of vasopressors on cerebral oxygenation during cardiopulmonary bypass in patients with diabetes is unknown. The aim of this study was to document the impact of norepinephrine and phenylephrine utilization on cerebral oxygenation in patients with and without diabetes during cardiopulmonary bypass.Prospective, clinical study.Academic medical center.Fourteen patients with diabetes and 17 patients without diabetes undergoing cardiac surgery.During cardiopulmonary bypass, norepinephrine (diabetics n = 6; non-diabetics n = 8) or phenylephrine (diabetics n = 8; non-diabetics n = 9) was administered intravenously to maintain mean arterial pressure above 60 mmHg.Mean arterial pressure, venous temperature, arterial oxygenation, and frontal lobe oxygenation (monitored by near-infrared spectroscopy) were recorded before anesthesia induction (baseline) and continuously during cardiopulmonary bypass. Frontal lobe oxygenation was lowered to a greater extent in diabetics versus non-diabetics with administration of norepinephrine (-14±13 v 3±12%; p0.05). There was also a trend towards a greater reduction in cerebral oxygenation in diabetics versus non-diabetics with administration of phenylephrine (-12±8 v -6±7%; p = 0.1) during cardiopulmonary bypass.Administration of norepinephrine to restore mean arterial pressure during cardiopulmonary bypass is associated with a reduction in frontal lobe oxygenation in diabetics but not in patients without diabetes. Administration of phenylephrine also were associated with a trend towards a greater reduction in frontal lobe oxygenation in diabetics. The clinical implications of these findings deserve future consideration.

Rationale: Ectopic fat deposition in the abdomen and in the limb muscles has been reported in patients with COPD. The objective of this study was to document the prevalence and consequences of fatty liver infiltration in patients with COPD in comparison with healthy controls. Methods: Using chest CT-scans obtained in the ECLIPSE study, we quantified mean liver attenuation. Hepatic steatosis was defined by CT scan criteria (liver density Results: 2,047 images at T12-L1 were retrieved from the initial ECLIPSE cohort of 2,118 subjects. Although mean liver density was similar between COPD and controls, hepatic steatosis was more prevalent in patients with COPD patients than in controls (17.5% vs 12.9%, p p ) and CRP ( p ) serum levels were closely related to liver density. Conclusion: The prevalence of hepatic steatosis was increased in patients with COPD in comparison to controls. This was associated with worsened inflammatory status and diabetes.

In addition to voluntary activation strategies, limb muscle function can also be assessed during non-voluntary limb muscle contractions by calculating activation using un-potentiated (Qtwunpot) and potentiated twitch force (Qtwpot) from a series of twitches induced by magnetic stimulation. The test-retest reliability of these measurement techniques was investigated in the present study. Patients with COPD (n=20) (FEV1 38 % predicted) and healthy subjects (n=15) completed two testing sessions (> 48h between sessions) to assess quadriceps muscle function using magnetic stimulation. At each occasion, a ramp protocol of non-potentiated stimulations at increasing intensities (40, 50, 60, 70, 80, 85, 90, 95, 100% of stimulator output) was performed. After participants were asked to perform a set of three maximal 5-s voluntary contractions (MVCs). This was followed by potentiated twitches at 100% stimulator output. Qtwunpot and Qtwpot are defined as the peak response observed during the ramp protocol and potentiated twitches, respectively. MVC was defined as the peak of the strongest voluntary contraction. Results presented in Table 1. Magnetic stimulation of the femoral nerve provides a reliable method for assessing muscle function in patients with COPD and healthy subjects, which, in contrast, to a MVC is independent of the subjects9 motivation and cooperation.

Abnormal expression of the tyrosine kinase ZAP-70 by tumoral B cells in chronic lymphocytic leukemia (CLL) is associated with bad prognosis, related to B cell receptor (BCR) hypersignalling, clonal expansion and autoimmune cytopenia (AIC) occurrence, these latter being mostly induced by polyclonal IgG from the residual non tumoral B cells. We previously shown that ZAP-70 is expressed by these non tumoral B cells in CLL, positively associated with its expression in CLL B cells and with AIC occurrence (Ghergus et al. Poster ASH 2017). Here, we show for the first time a potential role of ZAP-70 expression in tolerance breakdown in CLL and in an original knock in mouse model overexpressing ZAP-70 conditionally in B cells. First, to assess a potential molecular link between ZAP-70+ CLL and non tumoral B cells, an analysis of their BCR repertoire has performed on FACS-sorting CD19+CD5-IgM-IgD- (non tumoral) and CD19+CD5+IgM-IgD- (tumoral) single B cells from blood samples of CLL patients with AIC. ZAP-70 positivity was screened by RT-PCR, and variable regions of heavy (IGVH) and light (IGVK/VL) immunoglobulin genes amplified by RT-PCR on ZAP-70+ cells. To date, analysis of 24 BCR sequences from 7 patients showed that non tumoral ZAP-70+ B cells were polyclonal, without stereotypy, using different V(D)J and CDR3 in comparison with those of the corresponding CLL B cells. IGVH of non tumoral ZAP-70+ B were mostly mutated, of replacement type, suggesting antigenic contact, contrary to CLL B cells. To determine potential autoreactivity of the non-tumoral ZAP-70+ B cells, IGVH and corresponding IGVK/VL were amplified for production of recombinant antibodies (rAb). To date, among 17 rAB from 7 different patients, 2/13 (15.4%) have an antinuclear autoreactivity on HEp-2 cells and 4/17 (23.5%) were polyreactive on ELISA (DNA, lipopolysaccharide, insulin), compared respectively to 6% and 4,3% of control B cells (Wardemann et al., Science 2003). Production of 7 additional rAb and tests for anti-erythrocytes and anti-platelets reactivity are in process. To study functional consequences of early ZAP-70 expression in B cells in vivo, we generated a knock in Zap-70+/Mb1-Cre+mouse model (KI ZAP), to induce conditional expression of ZAP-70 in the B cell compartment from the proB stage, with KI Zap-70+/Mb1-Cre-mice as controls (CTRL). The ZAP-70 mRNAs levels in B cells from KI ZAP mice were on average 20 times higher than that in CTRL B cells. Up to 20 months-old, KI ZAP mice did not develop signs of lymphoproliferation. KI ZAP mice had hypo-IgG since 16 weeks-old (p After immunization by ovalbumin + Freund's adjuvant, a reduced production of specific IgG and IgM was observed (p=0.01 and p=0.03 respectively) with a trend in decreased number of antibody-secreting cells (p=0.07). KI ZAP B cells shown increased spontaneous activation and proliferation levels holding after BCR stimulation (p Our findings highlight for the first time that non tumoral B cells ZAP-70+ are distinct from CLL cells at cellular level, but probably enriched in autoreactive cells. Moreover, we shown that early ZAP-70 expression in normal B cells in vivois associated with autoimmune characteristics, together with partial block in B cells peripheral maturation, and a conversely early increased activation and proliferation status. ZAP-70 could interfere early with SYK leading to an altered BCR signaling responsible for defect in normal B maturation promoting emergence of autoreactive B cells. Mechanistic role of ZAP-70 in BCR signaling has to be further analyzed but our data open new opportunities involving ZAP-70 in the understanding of B cell development and physiopathology of tolerance breakdown. Disclosures No relevant conflicts of interest to declare.

Single-leg cycling and knee-extensor endurance exercise allow higher muscle specific workloads compared to using both legs in patients with COPD. The role of partitioning exercise during resistance exercise is less known. Study aims to elucidate the role of partitioning exercise in determining workload and quadriceps fatigue during resistance exercise in patients with COPD. Workload, quadriceps fatigue and dyspnea (Borg rating) were collected during both single-leg (SL) and two-leg (TL) isokinetic (1 set of 25 maximal repetitions) and elastic (3 sets of maximum amount of repetitions) knee-extension (KE) in 8 COPD patients (FEV1 34 % predicted). Total work (Joules (J)) during isokinetic KE, mean number of repetitions and area under the curve (AUC) of the relationship between elastic length and duration of contraction, a reflexion of the work performed by the contracting muscles. To quantify quadriceps fatigue, supramaximal magnetic femoral nerve stimulation (Qtw.pot) was performed before and 15 minutes after elastic KE. Total work (2863±1232 vs. 2410±1103 J, p=0.028), number of repetitions (18.3±4.0 vs. 15.0±4.0, p=0.025) and AUC (241±134 vs. 196±81, p=0.028) was higher in SL than TL during isokinetic KE and elastic KE, respectively. SL resulted in greater quadriceps fatigue than TL, Qtw.pot (−23±10 vs. -16±7%, p=0.025). There was no difference in dyspnea ratings during isokinetic (SL 3.8±1.8 vs. TL 3.8±1.5, p=0.831) or elastic exercise (SL 5.6±2.1 vs. TL 6.1±2.0, p=0.750). Using one limb at a time seems to result in a greater exercise workload and quadriceps muscle fatigue with similar level of dyspnea during resistance exercise in patients with COPD.

Background Low-load, high-repetitive single-limb resistance training may increase limb muscle function and functional exercise capacity in patients with chronic obstructive pulmonary disease (COPD) while minimizing the occurrence of limiting exertional symptoms. Whether high-repetitive single-limb resistance training would perform better than high-repetitive two-limb resistance training is unknown. In addition, the mechanisms underlying possible benefits of high-repetitive resistance training has not been investigated. The aims of this study are to compare single versus two-limb high-repetitive resistance training in patients with COPD and to investigate mechanisms of action of these training modalities. Methods/Design This trial is a prospective, assessor-blind, randomized controlled trial. The participants are patients with stable severe to very severe COPD who are older than 40 years of age and healthy controls. The intervention is single-limb, high-repetitive, resistance training with elastic bands, three times/week for 8 weeks. The control is two-limb high-repetitive resistance training with elastic bands, three times/week for 8 weeks. The primary outcomes is change in the 6-min walking distance after 8 weeks of single-limb or two-limb high-repetitive resistance training. The secondary outcomes are changes in limb muscle strength and endurance capacity, key protein involved in quadriceps anabolic/catabolic signalization, fiber-type distribution and capillarization, subjective dyspnea and muscle fatigue, muscle oxygenation, cardiorespiratory demand and health-related quality-of-life after 8 weeks of single-limb or two-limb high-repetitive resistance training. The acute effects of single-limb versus two-limb high-repetitive resistance training on contractile fatigue, exercise stimulus (the product of number of repetition and load), subjective dyspnea and muscle fatigue, muscle oxygenation, and cardiorespiratory demand during upper and lower limb exercises will also be investigated in patients with COPD and healthy controls. Randomization will be performed using a random number generator by a person independent of the recruitment process, using 1:1 allocation to the intervention and the control group using random block sizes. Blinding: All outcome assessors will be blinded to group assignment. Discussion The results of this project will provide important information to help developing and implementing customized exercise training programs for patients with COPD. Trial registration ClinicalTrials.gov Identifier NCT02283580 Registration date: 4 November 2014. First participant randomized: 10 November 2014. Electronic supplementary material The online version of this article (doi:10.1186/s13063-015-0698-x) contains supplementary material, which is available to authorized users.