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On-board embedded software developed for spaceflight systems (space software) must adhere to stringent software quality assurance procedures. For example, verification and validation activities are typically performed and assessed by third party organizations. To further minimize the risk of human mistakes, space agencies, such as the European Space Agency (ESA), are looking for automated solutions for the assessment of software testing activities, which play a crucial role in this context. Over the years, mutation analysis has shown to be a promising solution for the automated assessment of test suites; it consists of measuring the quality of a test suite in terms of the percentage of injected faults leading to a test failure. A number of optimization techniques, addressing scalability and accuracy problems, have been proposed to facilitate the industrial adoption of mutation analysis. However, to date, two major problems prevent space agencies from enforcing mutation analysis in space software development. In this paper, we enhance mutation analysis optimization techniques to enable their applicability to embedded software and propose a pipeline that successfully integrates them to address scalability and accuracy issues in this context, as described above. Further, we report on the largest study involving embedded software systems in the mutation analysis literature. Our research is part of a research project funded by ESA ESTEC involving private companies (GomSpace Luxembourg and LuxSpace) in the space sector. These industry partners provided the case studies reported in this paper; they include an on-board software system managing a microsatellite currently on-orbit, a set of libraries used in deployed cubesats, and a mathematical library certified by ESA., Accepted for publication on IEEE TRANSACTIONS ON SOFTWARE ENGINEERING

OBJECTIVE The Patient Generated Index (PGI) is a personalized quality of life (QOL) measure. This secondary analysis examined its psychometric properties with people with severe mental illness. METHODS Three hundred and eleven people with severe mental illness participated in structured interviews at baseline, 9 months, and 18 months. RESULTS The PGI captured a range of self-defined life areas. PGI scores were correlated with measures of QOL, hope, and functioning, indicating concurrent (criterion) validity. The correlation with QOL, with the finding that PGI scores were significantly higher for people who were employed (n = 42) versus unemployed (n = 269) and for people without substance use disorder (n = 269) versus those with substance use disorder (n = 42), is indicative of construct validity. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE The results support the suitability of the PGI as an idiographic measure for monitoring personalized QOL of people with severe mental illness. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background Diffuse large B cell lymphoma (DLBCL) is an aggressive disease. The first-line treatment is well defined in young patients, however in oldest old patients treatment remains unclear. Objectives To investigate the impact of therapeutics management and geriatric evaluation on survival in aged patients with DLBCL. Methods We performed a systematic review of PUBMED and COCHRANE databases of published report on elderly patients (median age 80 and above) with DLBCL, from January 2002 to January 2020. Results We included 32 studies (6 prospective and 26 retrospective). Patients treated with anthracyclines-containing chemoimmunotherapy had a two-years overall survival (OS) of 59% to 74.3% in prospective studies, and 48.1 to 64.6% in retrospective studies. With less intensive treatment without anthracyclines, two-years OS was 28% to 53%. Without specific treatment, median OS was two months. History of falls and severe comorbidities were associated with a decrease survival. Conclusions Chemoimmunotherapy with anthracyclines increase survival in selected very elderly patients in compared to less intensive regimen. Geriatric assessment, in particular altered mobility disorders and severe comorbidities, are predictive of survival and should be associated to the therapeutic decision. More comparative studies are needed to guide the management of frailer patients.

Summary Viral variants of concern may emerge with dangerous resistance to the immunity generated by the current vaccines to prevent coronavirus disease 2019 (Covid-19). Moreover, if some variants of concern have increased transmissibility or virulence, the importance of efficient public health measures and vaccination programs will increase. The global response must be both timely and science based.

International audience; The excess consumption of added sugar is consistently found to be associated with weight gain, and a higher risk of type 2 diabetes mellitus, coronary heart disease, and stroke. In an effort to reduce the risk of cardiometabolic disease, sugar is frequently replaced by low- and null-calorie sweeteners (LCSs). Alarmingly, though, emerging evidence indicates that the consumption of LCSs is associated with an increase in cardiovascular mortality risk that is amplified in those who are overweight or obese. Sucralose, a null-caloric high-intensity sweetener, is the most commonly used LCS worldwide, which is regularly consumed by healthy individuals and patients with metabolic disease. To explore a potential causal role for sucralose in increased cardiovascular risk, this present review summarizes the preclinical and clinical data from current research detailing the effects of sucralose on systems controlling food intake, glucose homeostasis, and gut microbiota.

Cancer is a leading cause of death in Samoa, with cancer patients presenting late and experiencing poor outcomes. Barriers to early diagnosis are complex, and cultural factors play an important part. This qualitative study explored the barriers to cancer diagnosis in Samoa through semistructured interviews conducted with 19 Samoan patients. Thematic data analysis was informed by socioecological theory and yielded 4 themes: knowledge and beliefs about cancer; pain as a trigger for health care–seeking behavior; follow-up issues; and communication and trust. Cancer knowledge and attitudes toward pain were strongly influenced by culture and community beliefs. Lack of follow-up resulted in significant delays, and ineffective patient-doctor communication triggered feelings of uncertainty and mistrust in the health care system. Efforts to address knowledge gaps will not be effective unless they are accompanied by broader strategies addressing local health care capacity issues. Adopting a socioecological framework lens within a regional collaborative approach provides a way forward.

BACKGROUND Societal demographic shifts are occurring globally. Within Quebec, Canada, the percentage of adults over 65 (older adults) is predicted to increase from 19.3% to >25.9% by the year 2036. Older adults (OAs) experience hospitalizations more frequently than persons aged 15-64 years old, and hospitalizations for OAs can be detrimental due to naturally occurring physiological changes. To address the needs of this population, the Quebec government mandated that all acute care hospitals implement OA-friendly care standards called AAPA ("l'Approche Adaptee a la Personne Âgee"). AIMS To describe an approach for identifying barriers and facilitators (BFs) to AAPA implementation at the McGill University Health Centre, an academic healthcare centre in Montreal that provides tertiary and quaternary care. METHODS Our approach included an organizational quality improvement (QI) model based on the Institute for Healthcare Improvement QI approach and the use of the Theoretical Domains Framework (TDF) to guide the assessment of BFs to AAPA implementation. To identify the BFs of AAPA implementation, themes were generated from the raw data. RESULTS In total, 32 barriers and 88 facilitators were identified. Each BF was linked to one or more corresponding domain from the TDF. Seven of the most frequently occurring domains were: (1) knowledge, (2) beliefs about consequences, (3) social/professional role and identity, (4) social influences, (5) environmental context and resources, (6) intentions, and (7) goals. LINKING EVIDENCE TO ACTION A theory-informed approach, such as the TDF, can be used to facilitate the implementation of evidence-based guidelines.

[Abstract] Aims. This study aimed to assess age‐ and sex‐related differences in management and 1‐year risk for all‐cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results. Of 16 354 patients included in the European Society of Cardiology Heart Failure Long‐Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline‐directed medical therapy (GDMT) were high (angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, beta‐blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P ≤ 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1‐year follow‐up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all‐cause mortality were lower in women than in men (7.1% vs. 8.7%; P = 0.015), as were rates of all‐cause hospitalization (21.9% vs. 27.3%; P < 0.001) and there were no differences in causes of death. All‐cause mortality and all‐cause hospitalization increased with greater age in both sexes. Sex was not an independent predictor of 1‐year all‐cause mortality (restricted to patients with LVEF ≤45%). Mortality risk was significantly lower in patients of younger age, compared to patients aged >75 years. Conclusions. There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all‐cause mortality in patients with LVEF ≤45%.

Objectives Cefazolin is one of curative treatments for infections due to methicillin-sensitive Staphylococcus aureus (MSSA). Both growth and critical illness may impact the pharmacokinetic (PK) parameters. We aimed to build a population PK model for cefazolin in critically ill children in order to optimize individual dosing regimens. Methods We included all children (age 2.5 kg) receiving cefazolin for MSSA infection. Cefazolin total plasma concentrations were quantified by high-performance liquid chromatography. A data modelling process was performed with the software MONOLIX. Monte Carlo simulations were used in order to attain the PK target of 100% fT > 4 ×MIC. Results Thirty-nine patients with a median (range) age of 7 (0.1-17) years and a BW of 21 (2.8-79) kg were included. The PK was ascribed to a one-compartment model, where typical clearance and volume of distribution estimations were 1.4 L/h and 3.3 L respectively. BW, according to the allometric rules, and estimated glomerular filtration rate (eGFR) on clearance were the two influential covariates. Continuous infusion with a dosing of 100 mg/kg/day to increase to 150 mg/kg/day for children with a BW 200 mL/min/1.73m2 were the best schemes to reach the PK target of 100% fT> 4 ×MIC. Conclusions In critically ill children infected with MSSA, continuous infusion seems to be the most appropriate scheme to reach the PK target of 100 % fT > 4 ×MIC in children with normal and augmented renal function.

Purpose Until now, results evaluating the expression of PSMA in ovarian cancer were sparse and contradictory. The aim was to reinvestigate the feasibility of a PSMA targeted theranostic approach in epithelial ovarian cancers with data from the tumour bank of a referring cancer centre. Materials and methods The OvaRessources Biological Resources Center database was screened from January 2004 to December 2017 to seek patients referred for the initial management of a serous epithelial ovarian cancer and for whom peritoneal histological samples were available in the tumour bank. Immunodetection of PSMA was performed to assess its cellular and neovascular expression. Slides were controlled by a certified pathologist, recorded as tiled tiff images and processed to compute the proportion of DAB stained surface. Results Of the 51 patients identified by the database screening, 32 patients were included resulting in 57 samples (32 pre-chemotherapy and 25 post-chemotherapy histological samples). Nine patients were chemo-sensitive, 10 were partially chemo-sensitive and 13 were chemo-resistant/refractory. In the entire dataset, the expression of PSMA was quasi-inexistent: %DABPSMA = 0.04 (± 0.12) %. There was no significant difference in the %DABPSMA of sensitive, partially sensitive and resistant/refractory patients. There was also no significant difference in %DABPSMA in tumours before and after chemotherapy in the 25 patients for whom both samples were available. Conclusion The present work demonstrates that PSMA expression is negligible and a fortiori non-sufficient to ensure its usefulness as a prognosticator or a target for a theranostic strategy in ovarian cancers.

AIMS Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are first-line agents to prevent and treat cytomegalovirus in transplant recipients. There is high pharmacokinetic (PK) interindividual variability and PK data are scarce, especially in paediatric stem cell transplant (SCT) recipients. We sought to determine the optimal GCV and VGCV dosing in transplanted children. METHODS We conducted a single-centre retrospective population PK (POPPK) study of IV GCV and enteral VGCV in paediatric solid organ transplant (SOT) and SCT recipients. We included children who were transplanted and had available plasma GCV concentrations, done per standard of care. POPPK analysis was performed using a nonlinear mixed effects modelling approach with NONMEM. Optimal dosing was determined based on the achievement of the surrogate efficacy target: GCV 24 h area under the concentration-time curve (AUC0-24h ) of 40-60 mg.h.L-1 . RESULTS Fifty children with a median [range] age of 7.5 years [0.5-17.4] contributed 580 PK samples. A two-compartment model with first-order absorption with a lag time and first-order elimination fit the data well. Creatinine clearance and body weight (WT) were significant covariates for GCV clearance (CL); and WT for the volumes of distribution. IV GCV 15-20 mg.kg-1 .day-1 divided every 12 hours achieved the highest probability of target achievement (PTA) (33.0-33.8%). Enteral VGCV 30 and 40 mg.kg-1 .day-1 divided every 12 hours in children 0

This report describes an outbreak of hairy vetch toxicosis afflicting a herd of cattle with a fatal cutaneous and systemic granulomatous disease. It highlights how this condition remains poorly recognized by cattle production professionals in Europe and the need for communication about vetch-associated diseases.

Type 2 diabetes mellitus represents an international health concern with its growing number of patients worldwide. At the same time, excessive salt consumption is also seen as a major cause of diseases such as hypertension and may expedite renal complications in diabetic patients. In this study, we investigated the effects of excessive sodium chloride supplementation on the kidney of the Spontaneously Diabetic Torii-Leprfa (SDT fatty) rat, an obese type 2 diabetes model. Male and female SDT fatty rats and normal Sprague-Dawley (SD) rats at 5 weeks of age were loaded with 0.3% sodium chloride (NaCl) in drinking water for 13 weeks. Blood serum and urinary parameters were observed throughout the experiment and kidney samples were examined in histopathological and genetical analyses. Significant changes on the body weight, blood pressure, urine volume, creatinine clearance, blood urea nitrogen (BUN), relative gene expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1) and transforming growth factor-β (TGF-β) were observed in the salt-loaded male SDT fatty rats. Urinary L-type fatty acid-binding protein (L-FABP) and albumin levels were higher observed in the salt-loaded male SDT fatty rats throughout the period, but urinary albumin levels in the female SDT fatty rats remain unchanged. In the kidney, slight Armani-Ebstein changes, tubular degeneration, hyaline cast, and inflammatory cell infiltration were observed in female SDT fatty rats while the levels of some changes were higher in the salt-loaded group. The kidney of the salt-loaded male SDT fatty rats demonstrated a higher degree of lesions compared to the female group and the male unloaded group. Histopathological changes in salt-loaded SDT fatty rats show that excessive salt consumption may act as a diabetic pathology exacerbation factor, but the pathology may be influenced by gender difference. Urinary L-FABP levels may act as a useful biomarker to detect slight tubular damages in the kidney. Excessive salt loading was shown to exacerbate the renal injury in SDT fatty rats.

Purpose: Desmoid-type fibromatosis (DF) are locally aggressive neoplasms, with a need for effective systemic treatment in case of progression to avoid the short- and long-term complications of local treatments. Experimental Design: We retrospectively analyzed the outcomes of adult patients with DF treated with oral vinorelbine (90 mg once weekly) at Gustave Roussy Cancer Institute (Villejuif, Paris, France). Only patients with documented progressive disease according to RECIST v1.1 for more than 3 months (±2 weeks) before treatment initiation were included. Results: From 2009 to 2019, 90 out of 438 patients with DF were eligible for this analysis. Vinorelbine was given alone in 56 patients (62%), or concomitantly with endocrine therapy in 34 patients, for a median duration of 6.7 months. A partial response was observed in 29% and stable disease in another 57%. With a median follow-up of 52.4 months, the median time to treatment failure (TTF) was not reached. Progression-free rates at 6 and 12 months were 88.7% and 77.5%, respectively. Concomitant endocrine therapy was associated with longer TTF in women [HR, 2.16; 95% confidence interval (CI), 1.06–4.37; P = 0.03). Among 64 patients with documented CTNNB1 mutational status, p.S45F or p.S45P mutations were associated with longer TTF compared with p.T41A or wild-type tumors (HR, 2.78; 95% CI, 1.23–6.27; P = 0.04). Toxicity profile was favorable, without grade 3–4 toxicity, except for one grade 3 neutropenia. Conclusions: Oral vinorelbine is an effective, affordable, and well-tolerated regimen in patients with advanced, progressive DF. Prolonged activity was observed in patients with tumors harboring CTNNB1 p.S45F or p.S45P mutations.

In most developed countries, health systems are attempting to compensate for underuse scientific evidence and its integration into healthcare services and practices. This qualitative study aimed to identify perceived benefits of a knowledge translation program implemented within mental health community services ((At your fingertips, Quebec, 2016-2018)). Results suggests that the production of a collaborative platform composed of a variety of activities and techno-educational tools, derived from integrated knowledge, facilitates the uptake by professionals in a context of reflective practices. Dissemination of these tools through technology of information and communication provides access to best recovery-oriented practices at your fingertips.

Aims Risk stratification of sudden cardiac arrest (SCA) in Brugada syndrome (Brs) remains the main challenge for physicians. Several scores have been suggested to improve risk stratification but never replicated. We aim to investigate the accuracy of the Brs risk scores. Methods and results A total of 1613 patients [mean age 45 ± 15 years, 69% male, 323 (20%) symptomatic] were prospectively enrolled from 1993 to 2016 in a multicentric database. All data described in the risk score were double reviewed for the study. Among them, all patients were evaluated with Shanghai score and 461 (29%) with Sieira score. After a mean follow-up of 6.5 ± 4.7 years, an arrhythmic event occurred in 75 (5%) patients including 16 SCA, 11 symptomatic ventricular arrhythmia, and 48 appropriate therapies. Predictive capacity of the Shanghai score (n = 1613) and the Sieira (n = 461) score was, respectively, estimated by an area under the curve of 0.73 (0.67–0.79) and 0.71 (0.61–0.81). Considering Sieira score, the event rate at 10 years was significantly higher with a score of 5 (26.4%) than with a score of 0 (0.9%) or 1 (1.1%) (P Conclusions In the largest cohort of Brs patient ever described, risk scores do not allow stratifying the risk of arrhythmic event in intermediate-risk patient.

Aims Excessive activation of Ca/calmodulin-dependent kinase II (CaMKII) is of critical importance in heart failure (HF) and atrial fibrillation. Unfortunately, lack of selectivity, specificity, and bioavailability have slowed down development of inhibitors for clinical use. We investigated a novel CaMKII delta/CaMKII-selective, ATP-competitive, orally available CaMKII inhibitor (RA608) on right atrial biopsies of 119 patients undergoing heart surgery. Furthermore, we evaluated its oral efficacy to prevent deterioration of HF in mice after transverse aortic constriction (TAC). Methods and results In human atrial cardiomyocytes and trabeculae, respectively, RA608 significantly reduced sarcoplasmic reticulum Ca leak, reduced diastolic tension, and increased sarcoplasmic reticulum Ca content. Patch-clamp recordings confirmed the safety of RA608 in human cardiomyocytes. C57BL6/J mice were subjected to TAC, and left ventricular function was monitored by echocardiography. Two weeks after TAC, RA608 was administered by oral gavage for 7 days. Oral RA608 treatment prevented deterioration of ejection fraction. At 3 weeks after TAC, ejection fraction was 46.1 +/- 3.7% (RA608) vs. 34.9 +/- 2.6% (vehicle), n = 9 vs.n = 12, P < 0.05, ANOVA, which correlated with significantly less CaMKII autophosphorylation at threonine 287. Moreover, a single oral dose significantly reduced inducibility of atrial and ventricular arrhythmias in CaMKII delta transgenic mice 4 h after administration. Atrial fibrillation was induced in 6/6 mice for vehicle vs. 1/7 for RA608,P < 0.05, 'n - 1' chi(2) test. Ventricular tachycardia was induced in 6/7 for vehicle vs. 2/7 for RA608,P < 0.05, 'n - 1' chi(2) test. Conclusions RA608 is the first orally administrable CaMKII inhibitor with potent efficacy in human myocytes. Moreover, oral administration potently inhibits arrhythmogenesis and attenuates HF development in micein vivo.

A simple but important task during the analysis of a textual requirements specification is to determine which statements in the specification represent requirements. In principle, by following suitable writing and markup conventions, one can provide an immediate and unequivocal demarcation of requirements at the time a specification is being developed. However, neither the presence nor a fully accurate enforcement of such conventions is guaranteed. The result is that, in many practical situations, analysts end up resorting to after-the-fact reviews for sifting requirements from other material in a requirements specification. This is both tedious and time-consuming. We propose an automated approach for demarcating requirements in free-form requirements specifications. The approach, which is based on machine learning, can be applied to a wide variety of specifications in different domains and with different writing styles. We train and evaluate our approach over an independently labeled dataset comprised of 33 industrial requirements specifications. Over this dataset, our approach yields an average precision of 81.2% and an average recall of 95.7%. Compared to simple baselines that demarcate requirements based on the presence of modal verbs and identifiers, our approach leads to an average gain of 16.4% in precision and 25.5% in recall. We collect and analyze expert feedback on the demarcations produced by our approach for industrial requirements specifications. The results indicate that experts find our approach useful and efficient in practice. We developed a prototype tool, named DemaRQ, in support of our approach. To facilitate replication, we make available to the research community this prototype tool alongside the non-proprietary portion of our training data.

Solution processing is an attractive alternative to standard vacuum fabrication techniques for the large-area manufacturing of metal oxide (MOx)-based electron devices. Here, we report on thin-film...

In 2017, an endangered North Atlantic right whale mortality event in the Gulf of St. Lawrence, Canada, triggered the implementation of dynamic mitigation measures that required real-time information on whale distribution. Underwater glider-based acoustic monitoring offers a possible solution for collecting near real-time information but has many practical challenges including self-noise, energy restrictions, and computing capacity, as well as limited glider-to-shore data transfer bandwidth. This paper describes the development of a near real-time baleen whale acoustic monitoring glider system and its evaluation in the Gulf of St. Lawrence in 2018. Development focused on identifying and prioritizing important acoustic events and on sending contextual information to shore for human validation. The system performance was evaluated post-retrieval, then the trial was simulated using optimized parameters. Trial simulation evaluation revealed that the validated detections of right, fin, and blue whales produced by the system were all correct; the proportion of species occurrence missed varied depending on the timeframe considered. Glider-based near real-time monitoring can be an effective and reliable technique to inform dynamic mitigation strategies for species such as the North Atlantic right whale.

Since the first recovery college (RC) opened in England in 2009, many more have begun operating around the world. The body of knowledge regarding the effects of RCs is growing, suggesting their benefit to recovery, well-being, goal achievement, knowledge, self-management, social support, reduced stigma, and service use. The objective of this review was to establish the state of knowledge about RCs from current empirical literature and to document the methods used to evaluate them.In consultation with an international expert panel, two independent evaluators performed a literature review with no date limits on publications in the Medline and Scopus electronic databases.A total of 460 articles were found, and 31 publications were retained. RC attendance was associated with high satisfaction among students, attainment of recovery goals, changes in service providers' practice, and reductions in service use and cost.To our knowledge, this is the first literature review of peer-reviewed publications about original studies evaluating the impacts of RCs, including studies pertaining to students, health service providers' practices, education and management practitioners, and citizens. Quantitative studies with a high level of evidence were underrepresented and should be considered as a future evaluation design. Furthermore, outcomes such as empowerment and reduced stigma should be assessed with standardized tools. The impact of RCs on attendees, family, friends, and caregivers and on the everyday practice of health service providers who attend RCs for continuing education or as tutors should also be assessed.

Despite a strong genetic background, Brugada syndrome (BrS) mainly affects middle-age patients. Data are scarce in the youngest and oldest age groups.The purpose of this study was to describe the clinical characteristics and variations in rhythmic risk in BrS patients according to age.Consecutive BrS patients diagnosed in 15 French tertiary centers in France were enrolled from 1993 to 2016 and followed up prospectively. All of the clinical and ECG data were double reviewed.Among the 1613 patients enrolled (age 45 ± 15 years; 69% male), 3 groups were defined according to age (52 patients17 years; 1285 between 17 and 59 years; and 27660 years). In the youngest patients, we identified more female gender (42%), diagnosis by familial screening (63%), previous sudden cardiac death (15%), SCN5A mutation (62%) sinus dysfunction (8%) and aVR sign (37%) (P.001). The oldest patients had the same clinical characteristics except for gender (40% women; P.001). During median follow-up of 5.5 [2.1, 10.0] years, 91 patients experienced an arrhythmic event, including 7 (13%) in the youngest patients, 80 (6%) in middle-age patients, and 4 (1%) in the oldest patients. Annual event rates were 2.1%, 1%, and 0.3%, respectively (P.01).Age on diagnosis changes the clinical presentation of BrS. Although children are identified more during familial screening, they present the highest risk of sudden cardiac death, which is an argument for early and extensive familial screening. The oldest patients present the lowest risk of SCD.

Chronic kidney disease (CKD) remains a common disorder, leading to growing health and economic burden without curative treatment. In diabetic patients, CKD may result from a combination of metabolic and nonmetabolic-related factors, with mortality mainly driven by cardiovascular events. The marked overactivity of the urotensinergic system in diabetic patients implicates this vasoactive peptide as a possible contributor to the pathogenesis of renal as well as heart failure. Previous preclinical studies with urotensin II (UII) antagonists in chronic kidney disease were based on simple end points that did not reflect the complex etiology of the disease. Given this, our studies revisited the therapeutic value of UII antagonism in CKD and extensively characterized 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino) cyclohexanecarboxylic acid hydrochloride (SAR101099), a potent, selective, and orally long-acting UII receptor competitive antagonist, inhibiting not only UII but also urotensin-related peptide activities. SR101099 treatment more than halved proteinurea and albumin/creatinine ratio in spontaneously hypertensive stroke-prone (SHR-SP) rats fed with salt/fat diet and Dahl-salt-sensitive rats, respectively, and it halved albuminuria in streptozotocin-induced diabetes rats. Importantly, these effects were accompanied by a decrease in mortality of 50% in SHR-SP and of 35% in the Dahl salt-sensitive rats. SAR101099 was also active on CKD-related cardiovascular pathologies and partly preserved contractile reserve in models of heart failure induced by myocardial infarction or ischemia/reperfusion in rats and pigs, respectively. SAR101099 exhibited a good safety/tolerability profile at all tested doses in clinical phase-I studies. Together, these data suggest that CKD patient selection considering comorbidities together with new stratification modalities should unveil the urotensin antagonists' therapeutic potential. SIGNIFICANCE STATEMENT: Chronic kidney disease (CKD) is a pathology with growing health and economic burden, without curative treatment. For years, the impact of urotensin II receptor (UT) antagonism to treat CKD may have been compromised by available tools or models to deeper characterize the urotensinergic system. New potent, selective, orally long-acting cross-species UT antagonist such as SAR101099 exerting reno- and cardioprotective effects could offer novel therapeutic opportunities. Its preclinical and clinical results suggest that UT antagonism remains an attractive target in CKD on top of current standard of care.

In many domains such as healthcare and banking, IT systems need to fulfill various requirements related to security. The elaboration of security requirements for a given system is in part guided by the controls envisaged by the applicable security standards and best practices. An important difficulty that analysts have to contend with during security requirements elaboration is sifting through a large number of security controls and determining which ones have a bearing on the security requirements for a given system. This challenge is often exacerbated by the scarce security expertise available in most organizations. In this article, we develop automated decision support for the identification of security controls that are relevant to a specific system in a particular context. Our approach, which is based on machine learning, leverages historical data from security assessments performed over past systems in order to recommend security controls for a new system. We operationalize and empirically evaluate our approach using real historical data from the banking domain. Our results show that, when one excludes security controls that are rare in the historical data, our approach has an average recall of ≈ 94% and average precision of ≈ 63%. We further examine through a survey the perceptions of security analysts about the usefulness of the classification models derived from historical data. The high recall – indicating only a few relevant security controls are missed – combined with the reasonable level of precision – indicating that the effort required to confirm recommendations is not excessive – suggests that our approach is a useful aid to analysts for more efficiently identifying the relevant security controls, and also for decreasing the likelihood that important controls would be overlooked. Further, our survey results suggest that the generated classification models help provide a documented and explicit rationale for choosing the applicable security controls.

There is growing evidence that apelin plays a role in the regulation of the cardiovascular system by increasing myocardial contractility and acting as a vasodilator. However, it remains unclear whether apelin improves cardiac contractility in a load-dependent or independent manner in pathological conditions. For this purpose we investigated the cardiovascular effects of apelin in α-actin transgenic mice (mActin-Tg mice), a model of cardiomyopathy. [Pyr1]apelin-13 was administered by continuous infusion at 2 mg/kg/d for 3 weeks. Effects on cardiac function were determined by echocardiography and a Pressure-Volume (PV) analysis. mActin-Tg mice showed a dilated cardiomyopathy (DCM) phenotype similar to that encountered in patients expressing the same mutation. Compared to WT animals, mActin-Tg mice displayed cardiac systolic impairment [significant decrease in ejection fraction (EF), cardiac output (CO), and stroke volume (SV)] associated with cardiac ventricular dilation and diastolic dysfunction, characterized by an impairment in mitral flow velocity (E/A) and in deceleration time (DT). Load-independent myocardial contractility was strongly decreased in mActin-Tg mice while total peripheral vascular resistance (TPR) was significantly increased. As compared to vehicle-treated animals, a 3-week treatment with [Pyr1]apelin-13 significantly improved EF%, SV, E/A, DT and corrected TPR, with no significant effect on load-independent indices of myocardial contractility, blood pressure and heart rate. In conclusion [Pyr1]apelin-13 displayed no intrinsic contractile effect but improved cardiac function in dilated cardiomyopathy mainly by reducing peripheral vascular resistance, with no change in blood pressure.

[Abstract] Aims. We assessed the interplay between hyperkalaemia (HK) and renin–angiotensin–aldosterone system inhibitor (RAASi) use, dose and discontinuation, and their association with all‐cause or cardiovascular death in patients with chronic heart failure (HF). We hypothesized that HK‐associated increased death may be related to RAASi withdrawal. Methods and results. The ESC‐HFA‐EORP Heart Failure Long‐Term Registry was used. Among 9222 outpatients (HF with reduced ejection fraction: 60.6%, HF with mid‐range ejection fraction: 22.9%, HF with preserved ejection fraction: 16.5%) from 31 countries, 16.6% had HK (≥5.0 mmol/L) at baseline. Angiotensin‐converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) was used in 88.3%, a mineralocorticoid receptor antagonist (MRA) in 58.7%, or a combination in 53.2%; of these, at ≥50% of target dose in ACEi: 61.8%; ARB: 64.7%; and MRA: 90.3%. At a median follow‐up of 12.2 months, there were 789 deaths (8.6%). Both hypokalaemia and HK were independently associated with higher mortality, and ACEi/ARB prescription at baseline with lower mortality. MRA prescription was not retained in the model. In multivariable analyses, HK at baseline was independently associated with MRA non‐prescription at baseline and subsequent discontinuation. When considering subsequent discontinuation of RAASi (instead of baseline use), HK was no longer found associated with all‐cause deaths. Importantly, all RAASi (ACEi, ARB, or MRA) discontinuations were strongly associated with mortality. Conclusions. In HF, hyper‐ and hypokalaemia were associated with mortality. However, when adjusting for RAASi discontinuation, HK was no longer associated with mortality, suggesting that HK may be a risk marker for RAASi discontinuation rather than a risk factor for worse outcomes. Funding for open access charge: Universidad de Granada / CBUA. The work was funded by the Courel Mountains UGGp

International audience; We read with real enthusiasm the paper by Hoertel et al. showing an “association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19”. Their observation reinforces preliminary data of a double-blind, randomized clinical trial showing significant reduction of COVID-19 worsening in outpatients treated with fluvoxamine. By the time those promising results should obviously stimulate organization of large randomized clinical trials on the use of antidepressants in the fight against COVID-19, we want to plead for introducing rimonabant combined to an antidepressant in some of those trials as well as in preclinical studies.

International audience; Background - Iron deficiency is a common nutritional deficiency that impacts maternal health and fetal development and is also associated with increased uptake of toxic metals. Women in sub-Saharan Africa are highly exposed to both iron deficiency and metals in the environment. As research on the developmental origins of health and disease increasingly shows impacts of pre-conception maternal health on pregnancy and fetal health, these environmental exposures are of concern. Objectives - This study investigated the association between iron status pre-pregnancy and blood metal concentrations in the first trimester of pregnancy with potential implications for iron supplementation. Methods - Pre-conception and first trimester blood samples taken from 262 Beninese women were tested for serum ferritin, inflammation markers, manganese (Mn), cadmium (Cd), lead (Pb), copper, zinc, selenium, mercury and arsenic. Associations between serum ferritin adjusted for inflammation and metal concentrations were analyzed using multivariate linear regression. Results - Women with iron deficiency before conception (13%) were more likely to remain iron deficient in the first trimester (4%) (adjusted OR = 41.2, 95%CI 6.2; 275.0) even within the context of routine iron supplementation during pregnancy. Lower pre-pregnancy serum ferritin concentrations were significantly related to higher concentrations of Mn, Cd and Pb in the first trimester. Every 1% increase in serum ferritin concentration was associated with a 0.13% decrease in Mn (adjusted β = -0.13, 95%CI -0.18; -0.07), a 0.22% decrease in Cd (adjusted β = -0.22, 95%CI -0.28; -0.15) and a 0.06% decrease in Pb concentration (adjusted β = -0.06, 95%CI -0.12; -0.006). Discussion - These results suggest that increasing iron stores prior to pregnancy may prevent excessive uptake of toxic concentrations of the metals Mn, Cd and Pb and argue in favour of testing the effects of iron supplementation prior to pregnancy on metal concentrations.

Issue The World Health Organization describes an infodemic as an “overabundance of information - good or bad - that makes it difficult for people to make decisions for their health.” Description of the problem On April 7-8, 2020, the WHO Information Network for Epidemics (EPI-WIN) held a global online to crowdsource ideas from an interdisciplinary group of experts to form a novel COVID-19 infodemic response framework. The online consultation comprised of four plenary sessions and a brainstorming session conducted entirely online. Nearly 1500 individuals from over 100 countries and territories spanning social scientists, epidemiologists, staff from ministries of health and institutes of public health, registered for the consultation. Results A set of 50 proposed actions for a framework for managing infodemics in health emergencies was developed that will provide guidance for governments and public health institutions to take in five key areas of action that emerged from the consultation: strengthening evidence and information simplifying and explaining what is known fact-checking and addressing misinformation amplifying messages and reaching the communities and individuals who need the information quantifying and analysing the infodemic, including information flows, monitoring the acceptance of public health interventions, and assessing factors affecting behaviour at individual and population levels strengthening systems for infodemic management in health emergencies Lessons Everyone has a role to play Read the Call for Action Sign the Call for Action https://www.who.int/news/item/11-12-2020-call-for-action-managing-the-infode Key messages The confusion due to Infodemic can lead people to ignore public health measures and take risks that can cause serious harm. Recognizing this WHO convened an interdisciplinary group of experts 7-8 April 2020 virtually to form a novel COVID-19 infodemic response framework.

Background COVID-19 pandemic was accompanied by an Infodemic (overabundance of information, including misinformation and disinformation, both online and offline); in response to this Infodemic, WHO launched the EARS platform (Early AI-assisted Response with Social Listening), showing real-time information about how people are talking about COVID-19 online. This information is intended to serve health information professionals to understand narratives and needs of the general public, in order to inform policy or communications decisions. Methods Data is collected daily from online conversations in publicly available sources, including Twitter, online forums, and blogs in English, French, Spanish and Portuguese, for 20 pilot countries. Once the data is collected, it is processed and classified into 39 categories, according to a set of pandemic public health taxonomy. The classification is made based on semi-supervised machine learning. Results Top 5 categories across regions are Covid-19 vaccine, Transmission settings, Personal measures, Testing and Industry (industry refers to the impact of the pandemic on the economy). We find that conversations around Covid-19 vaccines usually rank in the second or third position in all regions and represent 9%-12% of the conversation. Conclusions The configuration and application of the EARS platform has enabled progress towards more scalable and sustainable social listening to inform Infodemic management and response, compared to previous methods which were more manual, required data scientists in the team, or had fewer analytics capabilities. Future work will focus on gradually adding more data sources which can expand coverage and representativity. Key messages Discuss social listening methods for greater accountability to affected populations. Formulate insights into how digital media and information technology can be better utilized for more rapidly responding to the evolving needs of communities.

Background Following the World Health Organization's initial infodemic consultation in April 2020, a major infodemic conference was organised virtually in June-July 2020. Hundreds of experts participated to define science of infodemiology and build a public health research agenda that serves as a playbook for conducting relevant researches. Research Agenda provides guidance to invest in research and innovation so that we have better interventions and tools to understand, measure and respond to infodemics, and steer people towards timely, accessible, understandable information for good health choices. Methods The research agenda was developed during a virtual meeting, followed by research question prioritization exercise. It consisted of eight days spread out over four weeks. These were made up of: public preconference meeting; scientific conference, consisting of opening/closing plenary meetings either side of four separate “topic sprint” days; final public meeting to present the meeting outcomes. After the meeting, a process took place to gather and rank research questions based on the research agenda created during the meeting. Results The following five streams and 65 research questions were developed. Measuring and monitoring the impact of infodemics during health emergencies Detecting and understanding the spread and impact of infodemics Responding and deploying interventions that protect against the infodemic and mitigate its harmful effects Evaluating infodemic interventions and strengthening resilience of individuals and communities to infodemics Promoting the development, adaptation and application of tools for managing infodemics. Conclusions Five streams with 65 research questions were developed and prioritized to structuralise infodemic management based on evidence. The conference yielded on the development of an infodemiology glossary, which can be used by the community of research. Key messages Discuss investments in research and innovation to enable a whole-of-society response to infodemics. Explain the practice of infodemic management as a discipline.

Background The Infodemic (too much information including false or misleading information in digital and physical environments) during the COVID-19 pandemic has led to confusion, risk-taking and behaviors that can amplify outbreaks, and reduce effectiveness of pandemic response efforts. To address this challenge, the WHO Information Network for Epidemics (EPI-WIN), in collaboration with research partners, developed a public health Infodemic intelligence analysis methodology for weekly analysis of digital media data to identify, categorize, and understand key concerns expressed in online conversations. Methods Thirty-five keyword-based searches (per language) using Meltwater Explore and Google Trends were created and grouped according to a set of pandemic public health taxonomy categories developed specifically for this analysis. The taxonomy has five thematic categories of conversation about COVID-19 and public health response: (1) the cause of the illness, (2) the illness, (3) the treatment, (4) the interventions and (5) Information. Results The two most recurring topics to attract increasing interest were Vaccines and Asymptomatic transmission followed by Immunity, Cause of the virus, Vulnerable communities and Reduction of movement, and Risk factors based on demographics and risk of misinformation. Conclusions The application of this taxonomy to online social listening week-on-week resulted in a better in-time understanding of the evolution and dynamics of high velocity conversations about COVID-19 globally during the pandemic and proposes a quantifiable approach to support planning of risk communication response. Key messages Describe widespread innovation in social listening methods for greater accountability to affected populations. Formulate insights into how digital media can be better utilized for more rapidly responding to the evolving needs of communities.

We report the case of a 5-year-old girl with congenital right-sided facial hemihypertrophy and right hemi-macroglossia with lingual mucosal neuromas. The segmental presentation of findings suggested the diagnosis of congenital infiltrating lipomatosis of the face (CILF), which belongs within the PIK3CA-related overgrowth spectrum (PROS). This was confirmed by genetic analysis showing a mosaic mutation in PIK3CA H1047R. CILF/PROS should be considered in the differential diagnosis of mucosal neuromas.

Background Pediatric neurofibromatosis type 1 (NF1)–associated optic pathway gliomas (OPGs) exhibit different clinico-radiological features, treatment, and outcome compared with sporadic OPGs. While NF1-associated OPGs are caused by complete loss-of-function of the NF1 gene, other genetic alterations of the RAS-MAPK pathway are frequently described in the sporadic cases. We identified a group of patients who presented OPGs with typical radiological features of NF1-associated OPGs but without the NF1 diagnostic criteria. We aim to investigate into the possible molecular mechanisms underlying this “NF1-like” pediatric OPGs presentation. Methods We analyzed clinico-radiological features of 16 children with NF1-like OPGs and without NF1 diagnostic criteria. We performed targeted sequencing of the NF1 gene in constitutional samples (n = 16). The RAS-MAPK pathway major genes were sequenced in OPG tumor samples (n = 11); BRAF FISH and IHC analyses were also performed. Results In one patient’s blood and tumor samples, we identified a NF1 nonsense mutation (exon 50: c.7285C>T, p.Arg2429*) with ~8% and ~70% VAFs, respectively, suggesting a mosaic NF1 mutation limited to the brain (segmental NF1). This patient presented signs of neurodevelopmental disorder. We identified a somatic alteration of the RAS-MAPK pathway in eight tumors: four BRAF activating p.Val600Glu mutations, three BRAF:KIAA oncogenic fusions, and one putative gain-of-function complex KRAS indel inframe mutation. Conclusions NF1-like OPGs can rarely be associated with mosaic NF1 that needs specific constitutional DNA analyses for diagnosis. Further studies are warranted to explore unknown predisposition condition leading to the NF1-like OPG presentation, particularly in patients with the association of a neurodevelopmental disorder.

Introduction The capacity of the hydroxyapatite-coated trochanteric screwed plates used with modular hip implants to restore abductor system efficacy after proximal femoral tumor resection has never been assessed. We therefore conducted a retrospective study aiming to: (1) quantitatively evaluate abduction conservation on dynamometry according to use of digastric reinsertion, conserving continuity between the gluteus medius and vastus lateralis muscles, or not, and of standard versus small-offset; (2) assess radiographic trochanteric plate fixation; (3) assess functional scores; and (4) assess complications. Hypothesis Trochanteric reinsertion better conserves abduction strength when reinsertion is digastric. Patients and methods Thirty-one patients undergoing proximal femoral tumor resection between 2006 and 2016 with reconstruction by Stanmore METS™ modular implant with trochanteric plate were included. Twenty-one had digastric fixation between the gluteus medius and vastus lateralis and 10 had simple trochanteric fixation without digastric continuity. Abduction strength was compared between sides on dynamometer. Sixteen patients had full assessment of muscle strength, by a single observer; there were 8 deaths, 5 patients lost to follow-up, and 2 cases of material removal. Results Abduction strength conservation versus the contralateral side was 55.2 ± 23.3% (range, 5.8–86.1%): 66.6 ± 13.0% (46.4–86.1) with versus 36.0 ± 24.7% (5.8–63.2%) without digastric continuity (p = 0.01); severe limp rate was 4/21 when digastric continuity was preserved (19%) versus 6/10 (60%) (p = 0.04), and radiologic trochanteric reinsertion stability rate was 19/21 (90%) versus 4/10 (40%) (p = 0.005). Standard femoral offset conserved greater abduction strength: 64.9 ± 20.0% versus small-offset 45.4 ± 23.2% (p = 0.05). Toronto Extremity Salvage Score (TESS) was 89 ± 9.4%, and Musculoskeletal Tumor Society (MSTS) score 75.4 ± 5.4%. There were 6 complications (19%): 4 infections, 1 dislocation, and 1 plate removal; the single dislocation (3%) was in the digastric conservation group. TESS (90.7 ± 7.8% vs 88.3 ± 4) and MSTS score (75.6 ± 4.0% vs 75.1 ± 3.7) and complications [4/21 (19%) vs 2/10 (20%)] did not differ according to digastric or non-digastric reinsertion (p = 1). Conclusions Abduction strength with a modular implant using a hydroxyapatite-coated trochanteric plate was better conserved by digastric trochanteric reinsertion, resulting in less limping, although the complications rate and functional scores were unaffected. Longer term assessment is needed to confirm this conservation of abduction strength. Level of evidence IV, retrospective study without control group.

Pregnant women constitute a promising sentinel group for continuous monitoring of malaria transmission. To identify antibody signatures of recent Plasmodium falciparum exposure during pregnancy, we dissected IgG responses against VAR2CSA, the parasite antigen that mediates placental sequestration. We used a multiplex peptide-based suspension array in 2,354 samples from pregnant women from Mozambique, Benin, Kenya, Gabon, Tanzania, and Spain. Two VAR2CSA peptides of limited polymorphism were immunogenic and targeted by IgG responses readily boosted during infection and with estimated half-lives of

Background In the context of global malaria elimination efforts, special attention is being paid to submicroscopic Plasmodium falciparum infections. In pregnant, sub-Saharan African women, such infections are more prevalent than microscopic infections, and are thought to have adverse effects on both mothers’ and newborns’ health. However, no study has studied the dynamics and determinants of these infections throughout pregnancy. Retard de Croissance Intra-uterin et Paludisme (RECIPAL), a preconception cohort study carried out in Benin between 2014 and 2017, represented a unique opportunity to assess this issue. Methods We used data from 273 pregnant Beninese women who were followed-up from preconception to delivery. We studied the dynamics of and factors influencing submicroscopic (and microscopic) P. falciparum infections during the 3 trimesters of pregnancy, using an ordinal logistic mixed model. Results The incidence rate of submicroscopic P. falciparum infections during pregnancy was 12.7 per 100 person-months (95% confidence interval [CI] 10.8–14.9), compared to 6.7 per 100 person-months (95% CI 5.5–8.1) for microscopic infections. The prevalences were highest in the first trimester for both submicroscopic and microscopic infections. After adjustment for potential confounding factors, we found that those of young age and those with a submicroscopic P. falciparum infection prior to pregnancy were at significantly higher risks of submicroscopic and microscopic infections throughout pregnancy, with a more pronounced effect in the first trimester of pregnancy. Conclusions The first trimester of pregnancy is a particularly high-risk period for P. falciparum infection during pregnancy, especially for the youngest women. Malaria prevention tools covering the preconception period and early pregnancy are urgently needed to better protect pregnant women and their newborns., In a preconception malaria cohort study, the prevalence of submicroscopic versus microscopic Plasmodium falciparum infections was higher throughout pregnancy, most markedly in the first trimester, and young women with submicroscopic infections before pregnancy had a higher subsequent risk of infection.

Background Studying the neural consequences of tobacco smoking during adolescence, including those associated with early light use, may help expose the mechanisms that underlie the transition from initial use to nicotine dependence in adulthood. However, only a few studies in adolescents exist, and they include small samples. In addition, the neural mechanism, if one exists, that links nicotinic receptor genes to smoking behavior in adolescents is still unknown. Methods Structural and diffusion tensor magnetic resonance imaging data were acquired from a large sample of 14-year-old adolescents who completed an extensive battery of neuropsychological, clinical, personality, and drug-use assessments. Additional assessments were conducted at 16 years of age. Results Exposure to smoking in adolescents, even at low doses, is linked to volume changes in the ventromedial prefrontal cortex and to altered neuronal connectivity in the corpus callosum. The longitudinal analyses strongly suggest that these effects are not preexisting conditions in those who progress to smoking. There was a genetic contribution wherein the volume reduction effects were magnified in smokers who were carriers of the high-risk genotype of the alpha 5 nicotinic receptor subunit gene, rs16969968. Conclusions These findings give insight into a mechanism involving genes, brain structure, and connectivity underlying why some adolescents find nicotine especially addictive.

Background Terminal deletions of the long arm of chromosome 7 are well known and frequently associated with syndromic holoprosencephaly due to the involvement of the SHH (aliases HHG1, SMMCI, TPT, TPTPS, and MCOPCB5) gene region. However, interstitial deletions including CNTNAP2 (aliases Caspr2, KIAA0868, and NRXN4) and excluding the SHH region are less common. Methods We report the clinical and molecular characterization associated with pure 7q35 and 7q35q36.1 deletion in two unrelated patients as detected by oligonucleotide‐based array‐CGH analysis. Results The common clinical features were abnormal maternal serum screening during first‐trimester pregnancy, low occipitofrontal circumference at birth, hypotonia, abnormal feet, developmental delay, impaired language development, generalized seizures, hyperactive behavior, friendly personality, and cranio‐facial dysmorphism. Both deletions occurred de novo and sequencing of CNTNAP2, a candidate gene for epilepsy and autism showed absence of mutation on the contralateral allele. Conclusion Combined haploinsufficiency of GALNTL5 (alias GalNAc‐T5L), CUL1, SSPO (aliases SCO‐spondin, KIAA0543, and FLJ36112), AOC1 (alias DAO), RHEB, and especially KMT2C (alias KIAA1506 and HALR) with monoallelic disruption of CNTNAP2 may explain neurologic abnormalities, hypotonia, and exostoses. Haploinsufficiency of PRKAG2 (aliases AAKG, AAKG2, H91620p, WPWS, and CMH6) and KCNH2 (aliases Kv11.1, HERG, and erg1) genes may be responsible of long QT syndrome observed for one patient., Interstitial deletions of the long arm of chromosome 7 including CNTNAP2 and excluding the SHH region are not common. We report the clinical and molecular characterization associated with pure 7q35 and 7q35q36.1 deletion in two unrelated patients. Combined haploinsufficiency of GALNTL5, CUL1, SSPO, AOC1, RHEB and KMT2C with monoallelic disruption of CNTNAP2 may explain neurologic abnormalities, hypotonia and exostoses; haploinsufficiency of PRKAG2 and KCNH2 may be responsible of long QT syndrome observed for one patient.

Background An infodemic is an overflow of information of varying quality that surges across digital and physical environments during an acute public health event. It leads to confusion, risk-taking, and behaviors that can harm health and lead to erosion of trust in health authorities and public health responses. Owing to the global scale and high stakes of the health emergency, responding to the infodemic related to the pandemic is particularly urgent. Building on diverse research disciplines and expanding the discipline of infodemiology, more evidence-based interventions are needed to design infodemic management interventions and tools and implement them by health emergency responders. Objective The World Health Organization organized the first global infodemiology conference, entirely online, during June and July 2020, with a follow-up process from August to October 2020, to review current multidisciplinary evidence, interventions, and practices that can be applied to the COVID-19 infodemic response. This resulted in the creation of a public health research agenda for managing infodemics. Methods As part of the conference, a structured expert judgment synthesis method was used to formulate a public health research agenda. A total of 110 participants represented diverse scientific disciplines from over 35 countries and global public health implementing partners. The conference used a laddered discussion sprint methodology by rotating participant teams, and a managed follow-up process was used to assemble a research agenda based on the discussion and structured expert feedback. This resulted in a five-workstream frame of the research agenda for infodemic management and 166 suggested research questions. The participants then ranked the questions for feasibility and expected public health impact. The expert consensus was summarized in a public health research agenda that included a list of priority research questions. Results The public health research agenda for infodemic management has five workstreams: (1) measuring and continuously monitoring the impact of infodemics during health emergencies; (2) detecting signals and understanding the spread and risk of infodemics; (3) responding and deploying interventions that mitigate and protect against infodemics and their harmful effects; (4) evaluating infodemic interventions and strengthening the resilience of individuals and communities to infodemics; and (5) promoting the development, adaptation, and application of interventions and toolkits for infodemic management. Each workstream identifies research questions and highlights 49 high priority research questions. Conclusions Public health authorities need to develop, validate, implement, and adapt tools and interventions for managing infodemics in acute public health events in ways that are appropriate for their countries and contexts. Infodemiology provides a scientific foundation to make this possible. This research agenda proposes a structured framework for targeted investment for the scientific community, policy makers, implementing organizations, and other stakeholders to consider.

Accurate assessment of plant symptoms plays a key role for measuring the impact of pathogens during plant-pathogen interaction. Common bacterial blight caused by Xanthomonas phaseoli pv. phaseoli and Xanthomonas citri pv. fuscans (Xpp-Xcf) is a major threat to common bean. The pathogenicity of these bacteria is variable among strains, and depends mainly on a type III secretion system and associated type III effectors such as transcription activator-like effectors (TALEs). Because the impact of a single gene is often small and difficult to detect, a discriminating methodology is required to distinguish the slight phenotype changes induced during the progression of the disease. Here, we compared two different inoculation and symptom assessment methods for their ability to distinguish two tal mutants from their corresponding wild-type strains. Interestingly, rub-inoculation of the first leaves combined with symptom assessment by machine learning-based imaging allowed significant distinction between wild-type and mutant strains. By contrast, dip-inoculation of first trifoliate leaves combined with chlorophyll fluorescence imaging did not differentiate the strains. Furthermore, the new method developed here led to the miniaturization of pathogenicity tests and significant time savings.

Background: Few biomarkers for sepsis diagnosis are commonly used in neonatal sepsis. Whilst host response is increasingly recognized in sepsis pathogenesis and prognosis, there is a need for evaluating the accuracy of new biomarkers targeting host response in regions where sepsis burden is high and medico-economic resources are scarce. The objective of the study is to evaluate diagnostic and prognostic accuracy of biomarkers of neonatal sepsis in Sub Saharan Africa. Methods: Prospective multicentre study conducted between April 2016 and March 2018 in three University hospitals and two sub-urbans healthcare centres in the south Benin region. Patients were followed from birth to 3 months of age. Accuracy of transcriptional (CD74, CX3CR1), proteic (PCT, IL-6, IL-10, IP-10) biomarkers and clinical characteristics to diagnose and prognose neonatal sepsis were measured. At delivery, cord blood from all consecutive newborns were sampled and analysed, and infants were followed for a 12 weeks’ period. Results: From April 17, 2016 through March 12, 2018, a total of 581 newborns were enrolled. One hundred and seventy-two newborns developed neonatal sepsis (29.6%) and death occurred in forty-nine infants (8.4%). Among all tested biomarkers and clinical criteria, CD74/IP-10 ratio showed the best accuracy for neonatal sepsis diagnosis, while PCT accuracy was low. Among biomarkers and clinical criteria studied, only CD74 and PCT were independently associated with mortality, with CD74 showing an elevated predictive accuracy. Conclusion: Cord blood PCT had a low accuracy for diagnosing early onset neonatal sepsis in Sub Saharan African neonates, while CD74/IP-10 ratio had the best diagnostic accuracy. CD74 expression at birth had the best accuracy in prognosing sepsis mortality.Trial registration: Clinicaltrial.gov registration number: NCT03780712. Registered 19 December 2018. Retrospectively registered

Automatically detecting the positions of key-points (e.g., facial key-points or finger key-points) in an image is an essential problem in many applications, such as driver's gaze detection and drowsiness detection in automated driving systems. With the recent advances of Deep Neural Networks (DNNs), Key-Points detection DNNs (KP-DNNs) have been increasingly employed for that purpose. Nevertheless, KP-DNN testing and validation have remained a challenging problem because KP-DNNs predict many independent key-points at the same time -- where each individual key-point may be critical in the targeted application -- and images can vary a great deal according to many factors. In this paper, we present an approach to automatically generate test data for KP-DNNs using many-objective search. In our experiments, focused on facial key-points detection DNNs developed for an industrial automotive application, we show that our approach can generate test suites to severely mispredict, on average, more than 93% of all key-points. In comparison, random search-based test data generation can only severely mispredict 41% of them. Many of these mispredictions, however, are not avoidable and should not therefore be considered failures. We also empirically compare state-of-the-art, many-objective search algorithms and their variants, tailored for test suite generation. Furthermore, we investigate and demonstrate how to learn specific conditions, based on image characteristics (e.g., head posture and skin color), that lead to severe mispredictions. Such conditions serve as a basis for risk analysis or DNN retraining., to appear in ISSTA 2021

We distinguish two general modes of testing for Deep Neural Networks (DNNs): Offline testing where DNNs are tested as individual units based on test datasets obtained without involving the DNNs under test, and online testing where DNNs are embedded into a specific application environment and tested in a closed-loop mode in interaction with the application environment. Typically, DNNs are subjected to both types of testing during their development life cycle where offline testing is applied immediately after DNN training and online testing follows after offline testing and once a DNN is deployed within a specific application environment. In this paper, we study the relationship between offline and online testing. Our goal is to determine how offline testing and online testing differ or complement one another and if offline testing results can be used to help reduce the cost of online testing? Though these questions are generally relevant to all autonomous systems, we study them in the context of automated driving systems where, as study subjects, we use DNNs automating end-to-end controls of steering functions of self-driving vehicles. Our results show that offline testing is less effective than online testing as many safety violations identified by online testing could not be identified by offline testing, while large prediction errors generated by offline testing always led to severe safety violations detectable by online testing. Further, we cannot exploit offline testing results to reduce the cost of online testing in practice since we are not able to identify specific situations where offline testing could be as accurate as online testing in identifying safety requirement violations.

Ambiguity in natural-language requirements is a pervasive issue that has been studied by the requirements engineering community for more than two decades. A fully manual approach for addressing ambiguity in requirements is tedious and time-consuming, and may further overlook unacknowledged ambiguity - the situation where different stakeholders perceive a requirement as unambiguous but, in reality, interpret the requirement differently. In this paper, we propose an automated approach that uses natural language processing for handling ambiguity in requirements. Our approach is based on the automatic generation of a domain-specific corpus from Wikipedia. Integrating domain knowledge, as we show in our evaluation, leads to a significant positive improvement in the accuracy of ambiguity detection and interpretation. We scope our work to coordination ambiguity (CA) and prepositional-phrase attachment ambiguity (PAA) because of the prevalence of these types of ambiguity in natural-language requirements [1]. We evaluate our approach on 20 industrial requirements documents. These documents collectively contain more than 5000 requirements from seven distinct application domains. Over this dataset, our approach detects CA and PAA with an average precision of a80% and an average recall of a89% (a90% for cases of unacknowledged ambiguity). The automatic interpretations that our approach yields have an average accuracy of a85%. Compared to baselines that use generic corpora, our approach, which uses domain-specific corpora, has a33% better accuracy in ambiguity detection and a16% better accuracy in interpretation.

International audience; The design and implementation of Convolutional Neural Networks (CNNs) for deep learning (DL) is currently receiving a lot of attention from both industrials and academics. However, the computational workload involved with CNNs is often out of reach for low power embedded devices and is still very costly when running on datacenters. By relaxing the need for fully precise operations, approximate computing substantially improves performance and energy efficiency. Deep learning is very relevant in this context, since playing with the accuracy to reach adequate computations will significantly enhance performance, while keeping quality of results in a user-constrained range. AdequateDL is a project aiming to explore how approximations can improve performance and energy efficiency of hardware accelerators in DL applications. This paper presents the main concepts and techniques related to approximation of CNNs and preliminary results obtained in the AdequateDL framework.

Background Children have a low rate of COVID-19 and secondary severe multisystem inflammatory syndrome (MIS) but present a high prevalence of symptomatic seasonal coronavirus infections. Aim We tested if prior infections by seasonal coronaviruses (HCoV) NL63, HKU1, 229E or OC43 as assessed by serology, provide cross-protective immunity against SARS-CoV-2 infection. Methods We set a cross-sectional observational multicentric study in pauci- or asymptomatic children hospitalised in Paris during the first wave for reasons other than COVID (hospitalised children (HOS), n = 739) plus children presenting with MIS (n = 36). SARS-CoV-2 antibodies directed against the nucleoprotein (N) and S1 and S2 domains of the spike (S) proteins were monitored by an in-house luciferase immunoprecipitation system assay. We randomly selected 69 SARS-CoV-2-seropositive patients (including 15 with MIS) and 115 matched SARS-CoV-2-seronegative patients (controls (CTL)). We measured antibodies against SARS-CoV-2 and HCoV as evidence for prior corresponding infections and assessed if SARS-CoV-2 prevalence of infection and levels of antibody responses were shaped by prior seasonal coronavirus infections. Results Prevalence of HCoV infections were similar in HOS, MIS and CTL groups. Antibody levels against HCoV were not significantly different in the three groups and were not related to the level of SARS-CoV-2 antibodies in the HOS and MIS groups. SARS-CoV-2 antibody profiles were different between HOS and MIS children. Conclusion Prior infection by seasonal coronaviruses, as assessed by serology, does not interfere with SARS-CoV-2 infection and related MIS in children.