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Dave Singh,1 Gerard J Criner,2 Alvar Agustí,3 Mona Bafadhel,4 Johan Söderström,5 Gabriela Luporini Saraiva,6 Yue Song,6 Idlir Licaj,7 Maria Jison,6 Ubaldo J Martin,6 Ioannis Psallidas8 1Manchester University NHS Foundation Hospital Trust, the University of Manchester, Manchester, UK; 2Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA; 3Respiratory Institute (Hospital Clinic), IDIBAPS, CIBERES, Catedra Salud Respiratoria (University of Barcelona), Barcelona, Spain; 4School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK; 5Late-stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 6Late-stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 7Cytel Inc, Cambridge, MA, USA; 8Late-Stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UKCorrespondence: Dave Singh, Medicines Evaluation Unit, Langley Building, University Hospital of South Manchester, NHS Foundation Trust, Southmoor Road, Manchester, M23 9QZ, UK, Tel +44 (0)161 946 4073, Email dsingh@meu.org.ukAbstract: Exacerbations in chronic obstructive pulmonary disease (COPD), which tend to occur in clusters and increase with disease severity, come with high societal and economic burdens. Prevention and delay of recurrent exacerbations is an unmet and significant therapeutic need for patients with COPD. GALATHEA (NCT02138916) and TERRANOVA (NCT02155660) were trials assessing efficacy of benralizumab in patients with frequent COPD exacerbations despite treatment. Although these studies found that benralizumab given as an add-on treatment did not significantly reduce annual rates of COPD exacerbations after 56 weeks of treatment, in the following exploratory post hoc analysis of the GALATHEA and TERRANOVA trials we identified a potential responder population in which treatment with benralizumab prevents recurrent COPD exacerbations during 30- and 90-day periods following an initial exacerbation, a vulnerable period for an exacerbation to occur. This responder population was characterized by high blood eosinophil counts and frequent previous exacerbations despite optimized triple therapy. These results highlight the importance of targeted therapies for high-risk populations and merit further research into the benefits of biologic therapies for COPD exacerbations.Keywords: COPD, recurrent exacerbations, benralizumab, eosinophil

V Prevost,1 C Delorme,2,3 N Heutte,4 A Leconte,4 C Bechet,5 I Licaj,4 R Bignon,3,6 C Bisson,2,3 S Cauchin,3,7 M Gicquère,3,8 MC Grach,3,8 C Guillaumé,3,9 J Le Garrec,3,7 MC Ropartz,3,10 N Roux,3,9 V Sep Hieng,3,6 A Le Chevalier,3,10 B Clarisse41UMR 1086 Inserm ANTICIPE (Interdisciplinary Research Unit for Cancer Treatment and Prevention) and University of Normandy, Caen, France; 2Pain Assessment and Treatment Centre, Bayeux Hospital, Bayeux, France; 3Regional Pain Network for Lower Normandy, Bayeux, France; 4Clinical Research Unit, Centre François Baclesse, Caen, France; 5Pharmacie de la Croix d’Or, Paris, France; 6Pain and Palliative Care Unit, Lisieux Hospital, Lisieux, France; 7Pain Assessment and Treatment Consultation, Alençon-Mamers Intercommunal Hospital, Alençon, France; 8Pain and Palliative Care Unit, Centre François Baclesse, Caen, France; 9Pain and Palliative Care Unit, University Hospital, Caen, France; 10Pain Assessment and Treatment Centre, Avranches-Granville Hospital, Avranches, FrancePurpose: Patient education constitutes a relevant strategy to improve pain management. In the field of therapeutic patient education (TPE), we aimed 1) to assess pain impact in cancer patients, 2) to identify patients’ educative needs in pain management, and 3) to refine research criteria for its future evaluation.Patients and methods: Pain intensity, relief and interference were assessed in 75 cancer patients with unbalanced background pain. Self-assessment questionnaire evaluated i) patients’ pain management and ii) their knowledge and needs in TPE.Results: Most patients experienced pain for more than 6 months and 41.6% reported adequate pain relief. Understanding pain and pain management were major patients’ preferences (>58%). Most patients declared they knew their pain treatments, but fewer than half of them were able to name them. However, education concerning pain treatment was considered as essential in

Climate change is leading to an increase in the intensity, duration, and frequency of severe droughts, especially in southern and southeastern Europe, thus aggravating water scarcity problems. Water deficit stress harms the growth, physiology, and yield of crops like durum wheat. Hence, studying ancient wheat varieties' stress responses could help identify genetic traits to enhance crop tolerance to environmental stresses. In this background, this study aimed to investigate the effects of PEG 6000-stimulated drought stress in the ancient wheat variety Saragolla and the modern one Svevo by analyzing various biochemical and molecular parameters that can especially condition the stomatal movement. Our data revealed that drought stress caused a significant increase in the levels of total soluble sugars, ABA, and IAA in both selected cultivars to a greater extent in the Saragolla than in the Svevo. We demonstrated that, under water deficit stress, calcium dynamics as well as the expression of ERF109 , MAPK3/6 , MYB60 , and TaTPC1 , involved in the activation of drought-related calcium-sensitive pathways, display significant differences between the two varieties. Therefore, our study provided further evidence regarding the ability of the ancient wheat variety Saragolla to better cope with drought stress compared to the modern variety Svevo.

Introduction: COVID-19 may have negatively impacted the mental health of front-line healthcare workers, including general practitioners (GPs). This study sought to assess the psychological impact (stress, burnout and self-efficacy) of the COVID-19 outbreak in French GPs., Methods: We carried out a postal-based survey of all GPs who worked in the French region of Normandy (departments of Calvados, Manche and Orne) from the exhaustive database of the Union Régionale des Médecins libéraux (URML Normandie) as of 15th April 2020 (one month after the first French COVID-19 sanitary lockdown). The second survey was conducted four months later. Four validated self-report questionnaires were used at both inclusion and follow-up: Perceived Stress scale (PSS), Impact of Event Scale-revised (IES-R), Maslach Burnout Inventory (MBI) and General Self-Efficacy scale (GSE). Demographic data were also collected., Results: The sample consists of 351 GPs. At the follow-up, 182 answered the questionnaires (response rate: 51.8%). The mean scores of MBI significantly increased during follow-up [Emotional exhaustion (EE) and Personal accomplishment, P<0.01]. Higher burnout symptoms were found at the 4-month follow-up in 64 (35.7%) and 86 (48.0%) participants (43 and 70 participant at baseline), according respectively to EE and depersonalisation scores (P=0.01 and 0.09, respectively)., Conclusion: This is the first longitudinal study that has shown the psychological impact of COVID-19 in French GPs. Based on validated a self-report questionnaire, burnout symptoms increased during follow-up. It is necessary to continue monitoring psychological difficulties of healthcare workers especially during consecutive waves of COVID-19 outbreak., (Copyright © 2023 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Drought stress is increasing in frequency and severity with the progression of global climate change, thereby becoming a major concern for the growth and yield of crop plants, including wheat. The current challenge is to explore different ways of developing wheat genotypes with increased tolerance to drought. Therefore, we renewed interest in 'ancient' varieties expected to be more tolerant to environmental stress than the few elite varieties nowadays cultivated. This study aimed to perform comparative analysis of the effect of drought-simulating polyethylene glycol (PEG-6000) treatment on morpho-anatomical and physiological foliar traits of two durum wheat seedlings cultivars, Saragolla and Svevo, as these can reflect the adaptability of the plant to the environment to a certain extent. Results demonstrated that drought-stressed Saragolla leaves exhibited a greater reduction of stomatal density, a minor reduction of stomatal pore width, a wider xylem vessel mean area, greater compactness of mesophyll cells, a minor loss of chlorophyll content, as well as better photosynthetic and growth performance compared to the other variety. From such behaviours, we consider the Saragolla cultivar more drought tolerant than Svevo and therefore probably very promising for cultivation in dry areas.

Due to drought stress, durum wheat production in the Mediterranean basin will be severely affected in the coming years. Durum wheat cultivation relies on a few genetically uniform "modern" varieties, more productive but less tolerant to stresses, and "traditional" varieties, still representing a source of genetic biodiversity for drought tolerance. Root architecture plasticity is crucial for plant adaptation to drought stress and the relationship linking root structures to drought is complex and still largely under-explored. In this study, we examined the effect of drought stress on the roots' characteristics of the "traditional" Saragolla cultivar and the "modern" Svevo. By means of "SmartRoot" software, we demonstrated that drought stress affected primary and lateral roots as well as root hair at different extents in Saragolla and Svevo cultivars. Indeed, we observed that under drought stress Saragolla possibly revamped its root architecture, by significantly increasing the length of lateral roots, and the length/density of root hairs compared to the Svevo cultivar. Scanning Electron Microscopy analysis of root anatomical traits demonstrated that under drought stress a greater stele area and an increase of the xylem lumen size vessel occurred in Saragolla, indicating that the Saragolla variety had a more efficient adaptive response to osmotic stress than the Svevo. Furthermore, for the analysis of root structural data, Artificial Intelligence (AI) algorithms have been used: Their application allowed to predict from root structural traits modified by the osmotic stress the type of cultivar observed and to infer the relationship stress-cultivar type, thus demonstrating that root structural traits are clear and incontrovertible indicators of the higher tolerance to osmotic stress of the Saragolla cultivar. Finally, to obtain an integrated view of root morphogenesis, phytohormone levels were investigated. According to the phenotypic effects, under drought stress,a larger increase in IAA and ABA levels, as well as a more pronounced reduction in GA levels occurred in Saragolla as compared to Svevo. In conclusion, these results show that the root growth and hormonal profile of Saragolla are less affected by osmotic stress than those of Svevo, demonstrating the great potential of ancient varieties as reservoirs of genetic variability for improving crop responses to environmental stresses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Licaj, Felice, Germinario, Zanotti, Fiorillo, Marra and Rocco.)

Background: Hypertension (HTN) is a well-established and a major risk factor for cardiovascular disease. Lifestyle behaviours for its prevention and control are recommended within worldwide guidelines. Their relationship with HTN need more investigations., Aim: We aimed to investigate the associations between lifestyle, anthropometric and biological measurements and BP in the Gubbio residential study., Methods: Cross-sectional analyses were performed using data from Gubbio study. Information concerning lifestyle factors were collected using self-reported questionnaire and were further completed with a baseline clinical examination and blood exams. Three BP measurements were performed following a standard protocol. Age-adjusted and multivariable logistic regressions were used to examine the relationships between lifestyle parameters and HTN separately for each sex. We used heterogeneity test to observe sex differences., Results: There were 3,183 persons included (48% men, 43 ± 17 years old). Mean systolic BP (SBP) was 119 ± 16 mmHg and 10.6% were hypertensives. Age [OR: 129.70 (95%CI: 18.57-905.79) in women and OR: 8.37 (95%CI: 4.01-17.48) ( p  < 0.0001) in men] and BMI [OR: 2.14 (95%CI: 1.32-3.46) ( p  = 0.006) in women and OR: 1.81 (95%CI: 1.05-3.12), p  = 0.03 in men], were positively associated with SBP in both sexes. Serum uric acid [OR: 3.86 (95%CI: 2.03-7.26), p  = 0.04] was positively associated with HTN in women while fasting blood glucose [OR: 3.04 (95%CI: 1.55-5.97), p  < 0.001] were associated to HTN only in men., Discussion: In addition to age, BMI is associated with HTN in both sexes while sex differences were observed in the associations between serum uric acid, fasting blood glucose and HTN.

Given the constant pressure to increase patient throughput while respecting radiation protection, global body PET image quality (IQ) is not satisfactory in all patients. We first studied the association between IQ and other variables, in particular body habitus, on a digital PET/CT. Second, to improve and homogenize IQ, we evaluated a deep learning PET denoising solution (Subtle PET TM ) using convolutional neural networks. We analysed retrospectively in 113 patients visual IQ (by a 5-point Likert score in two readers) and semi-quantitative IQ (by the coefficient of variation in the liver, CV liv ) as well as lesion detection and quantification in native and denoised PET. In native PET, visual and semi-quantitative IQ were lower in patients with larger body habitus ( p < 0.0001 for both) and in men vs. women ( p ≤ 0.03 for CV liv ). After PET denoising, visual IQ scores increased and became more homogeneous between patients (4.8 ± 0.3 in denoised vs. 3.6 ± 0.6 in native PET; p < 0.0001). CV liv were lower in denoised PET than in native PET, 6.9 ± 0.9% vs. 12.2 ± 1.6%; p < 0.0001. The slope calculated by linear regression of CV liv according to weight was significantly lower in denoised than in native PET ( p = 0.0002), demonstrating more uniform CV liv . Lesion concordance rate between both PET series was 369/371 (99.5%), with two lesions exclusively detected in native PET. SUV max and SUV peak of up to the five most intense native PET lesions per patient were lower in denoised PET ( p < 0.001), with an average relative bias of -7.7% and -2.8%, respectively. DL-based PET denoising by Subtle PET TM allowed [ 18 F]FDG PET global image quality to be improved and homogenized, while maintaining satisfactory lesion detection and quantification. DL-based denoising may render body habitus adaptive PET protocols unnecessary, and pave the way for the improvement and homogenization of PET modalities.

Background: The authors used the French breast cancer Cancer and Toxicities (CANTO) cohort to study the associations between baseline quality of life and chemotherapy dose-reductions (CDRs) or postchemotherapy-toxicities (PCTs)., Methods: In total, 3079 patients with breast cancer who received chemotherapy were included in this analysis. The associations between baseline physical functioning (PF) and fatigue measured using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30, and two endpoints-CDRs during adjuvant or neoadjuvant chemotherapy; and selected PCTs were estimated with odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) using logistic regression models., Results: Among the 3079 patients from the CANTO cohort who were included, 718 (33.0%) received chemotherapy in the neoadjuvant setting, and 2361 (67.0%) received chemotherapy as adjuvant treatment. The chemotherapy included taxanes in 94.2% of patients and anthracyclines in 90.5% of patients. Overall, 15.5% of patients experienced CDRs and, 31.0% developed PCTs. Women with low baseline PF scores (<83) had higher multivariate odds of developing CDRs compared with those who had PF scores ≥83 (OR, 1.54; 95% CI, 1.13-2.09). The corresponding OR for PCTs was 1.50 (95% CI, 1.13-2.00). Women with high baseline fatigue scores had higher odds of CDRs (OR, 1.43; 95% CI, 1.13-1.76) and PCTs (OR, 1.32; 95% CI, 1.10-1.59)., Conclusions: By using the national CANTO cohort, baseline PF and fatigue were independently associated with CDRs and PCTs., (© 2023 American Cancer Society.)

Durum wheat is widely cultivated in the Mediterranean, where it is the basis for the production of high added-value food derivatives such as pasta. In the next few years, the detrimental effects of global climate change will represent a serious challenge to crop yields. For durum wheat, the threat of climate change is worsened by the fact that cultivation relies on a few genetically uniform, elite varieties, better suited to intensive cultivation than "traditional" ones but less resistant to environmental stress. Hence, the renewed interest in "ancient" traditional varieties are expected to be more tolerant to environmental stress as a source of genetic resources to be exploited for the selection of useful agronomic traits such as drought tolerance. The aim of this study was to perform a comparative analysis of the effect and response of roots from the seedlings of two durum wheat cultivars: Svevo, a widely cultivated elite variety, and Saragolla, a traditional variety appreciated for its organoleptic characteristics, to Polyethylene glycol-simulated drought stress. The effect of water stress on root growth was analyzed and related to biochemical data such as hydrogen peroxide production, electrolyte leakage, membrane lipid peroxidation, proline synthesis, as well as to molecular data such as qRT-PCR analysis of drought responsive genes and proteomic analysis of changes in the protein repertoire of roots from the two cultivars.

Colon cancer is the second most frequently diagnosed cancer in women in Norway, where incidence rates of colon cancer increased 3-fold between 1955 and 2014, for unknown reasons. We aimed to assess the burden of colon cancer attributable to modifiable risk factors in Norwegian women using the data from the Norwegian Women and Cancer (NOWAC) study. Self-reported information from 35 525 women from the NOWAC study were available. These included the following exposures: smoking status, alcohol consumption, body mass index, physical activity, intake of calcium, fibers, and red and processed meat. Colon cancer cases were identified from the Cancer Registry of Norway. A parametric piecewise constant hazards model was used to estimate the strength of exposure-cancer associations. Population attributable fractions with 95% confidence intervals (CIs) were calculated considering competing risk of death. The fraction of incident colon cancer attributable to ever smoking was 18.7% (95% CI 4.7%-30.6%), low physical activity 10.8% (95% CI -0.7% to 21.0%), alcohol consumption 14.5% (95% CI -2.8% to 28.9%), and low intake of calcium 10.0% (95% CI -7.8% to 24.8%). A small proportion of colon cancer cases was attributable to combined intake of red and processed meat over 500 g/week, overweight/obesity, and low intake of fibers. Jointly, these seven risk factors could explain 46.0% (95% CI 23.0%-62.4%) of the colon cancer incidence burden. Between 23% and 62% of the colon cancer burden among women in Norway was attributable to modifiable risk factors, indicating an important preventive potential of a healthy lifestyle., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Coronavirus disease 2019 (COVID-19) has negatively affected the mental health of frontline health care workers, including pharmacists., Objectives: The aim of this longitudinal study was to assess the psychological impact of the COVID-19 outbreak in French owner community pharmacists., Methods: We conducted a postal-based survey to assess the psychological difficulties of the COVID-19 outbreak in French owner community pharmacists based on 3 psychologically validated self-report questionnaires: Perceived Stress Scale (PSS), Impact of Event Scale-revised (IES-R), and Maslach Burnout Inventory. The baseline assessment was during the first sanitary lockdown period and the second one 5 months later., Results: The sample consists of 135 owner community pharmacists. At follow-up, 67 answered the questionnaires (response rate: 49.6%). The mean scores of the PSS and IES-R significantly decreased (P = 0.002). Fifteen pharmacists reported significant posttraumatic stress symptoms (23.1%) at baseline and 11 at follow-up (16.4%, P = 0.02). Age and sex were not significantly associated with persistent posttraumatic stress or burnout symptoms., Conclusion: This is the first longitudinal study that showed the psychological impact of owner community pharmacists as health care workers dealing with their community's COVID-19 outbreak. Based on validated self-report questionnaires, stress, posttraumatic stress, and burnout symptoms decreased during follow-up. It is necessary to continue monitoring psychological difficulties for health care workers, especially during consecutive waves of the COVID-19 outbreak., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Purpose: Thyroid cancer (TC) incidence is increasing. With its good prognosis and the young population concerned, the number of survivors is rising. However, their quality of life appears worse than expected. This study aims to assess the social and sexual health (SSH) of TC survivors and associated factors after a 2- and 5-year follow-up., Methods: This study belongs to the National VICAN Survey implemented in France among TC patients diagnosed between January and June 2010. Data were collected via phone interviews, medical surveys, and from medico-administrative register in 2012 and 2015. We used multivariable logistic regressions to qualify TC impact on SSH., Results: Across 146 patients, 121 were women, 50.7% were less than 42 years old, 77.5% were diagnosed at an early-stage, and 97.6% underwent thyroidectomy. At 2 years, 60.0% experienced social life discomfort because of cancer, 40.6% reported a decreased sexual desire, 37.4% fewer intercourse, 31.9% felt dissatisfied with this frequency, 30% reported difficulties achieving orgasm, and 15.2% considered that cancer had a negative influence for procreation. No significant difference was observed at 5 years. SSH was never discussed with medical professionals for 96.7% patients, as it was not proposed as a topic of concern (79.1%). In multivariable analysis, depression, embarrassment regarding their physical appearance since treatment, and reduced gestures of affection remained associated with decreased sexual desire., Conclusion: This study highlights that TC is associated with an alteration of SSH which remains even at 5 years post-diagnosis. SSH should be discussed during diagnosis and considered during follow-up., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Pain is an increasing concern in the growing number of head and neck cancer survivors. This study aimed to analyze the 5-year prevalence of pain in French survivors of head and neck cancer and to identify associated factors., Methods: Analyses were performed among 296 5-year cancer survivors diagnosed in 2010. Using multivariable logistic regressions, we studied the associations between pain and factors collected in the French representative national "vie après le cancer" (VICAN) survey. Eligible participants were aged from 18 to 82 years; patients' living conditions, socioeconomic characteristics, and medical data were collected., Results: Pain was reported by 72.6% of the participants. In the multivariable analyses, decreasing level of physical activity was the only determinant of increased overall pain (OR= 2.77, CI= 1.48-5.17). The chronic pain prevalence was 62.3%. The main risk factors found were tumor localization in the oropharynx (OR= 2.49, CI= 1.27-4.88), education (at least a high school's degree) (OR= 0.33, CI= 0.13-0.9), and decreased physical activity (OR= 2.20, CI= 1.24-3.9)., Conclusions: Five years after diagnosis, pain is a very frequent sequelae that has a significant impact on quality of life in head and neck cancer survivors. Reduced physical activity, a low level of education, and tumor localization in the oropharynx are factors associated with pain., Implications for Cancer Survivors: Pain frequency and its impact on patients' lives imply that an adaptation must be made in terms of both pain diagnosis and management and the training of healthcare professionals., Clinical Trial Registration: This is not a clinical trial. ISP number: INSERM C11-63., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)