Institut National Research Articles

Combining robust urine biomarkers to assess chronic kidney disease progression.

Urinary biomarkers may improve the prediction of chronic kidney disease (CKD) progression. Yet, data reporting the applicability of most commercial biomarker assays to the detection of their target analyte in urine together with an evaluation of their predictive performance are scarce. 30 commercial assays (ELISA) were tested for their ability to quantify the target analyte in urine using strict (FDA-approved) validation criteria. In an exploratory analysis, LASSO (Least Absolute Shrinkage and Selection Operator) logistic regression analysis was used to identify potentially complementary biomarkers predicting fast CKD progression, determined as the 51CrEDTA clearance-based measured glomerular filtration rate (mGFR) decline (>10% per year) in a subsample of 229 CKD patients (mean age, 61 years; 66% men; baseline mGFR, 38mL/min) from the NephroTest prospective cohort. Among the 30 assays, directed against 24 candidate biomarkers, encompassing different pathophysiological mechanisms of CKD progression, 16 assays fulfilled the FDA-approved criteria. LASSO logistic regressions identified a combination of five biomarkers including CCL2, EGF, KIM1, NGAL, and TGF-α that improved the prediction of fast mGFR decline compared to the kidney failure risk equation variables alone: age, gender, mGFR, and albuminuria. Mean area under the curves (AUC) estimated from 100 re-samples was higher in the model with than without these biomarkers, 0.722 (95% confidence interval 0.652-0.795) vs. 0.682 (0.614-0.748), respectively. Fully-adjusted odds-ratios (95% confidence interval) for fast progression were 1.87 (1.22, 2.98), 1.86 (1.23, 2.89), 0.43 (0.25, 0.70), 1.10 (0.71, 1.83), 0.55 (0.33, 0.89), and 2.99 (1.89, 5.01) for albumin, CCL2, EGF, KIM1, NGAL, and TGF-α, respectively. This study provides a rigorous validation of multiple assays for relevant urinary biomarkers of CKD progression which combination may improve the prediction of CKD progression. This work was supported by Institut National de la Santé et de la Recherche Médicale, Université de Paris, Assistance Publique Hôpitaux de Paris, Agence Nationale de la Recherche, MSDAVENIR, Pharma Research and Early Development Roche Laboratories (Basel, Switzerland), and Institut Roche de Recherche et Médecine Translationnelle (Paris, France).

#4724 MULTIPLE AIR POLLUTANT EXPOSURE AND RISK OF ALL-CAUSE MORTALITY IN DIALYSIS PATIENTS: A FRENCH REGISTRY-BASED NATIONWIDE STUDY

Abstract Background and Aims According to the Global Burden of Disease, mortality attributed to chronic kidney disease (CKD) is steadily increasing worldwide, with an estimated increase of more than 30% since 2005. Among the candidates mentioned to explain this inflation, air pollution is attracting more and more attention. Although the link between air pollution and the incidence of CKD and kidney failure seems increasingly clear, there is currently very little data regarding the potential effect of exposure to air pollutants on mortality in dialysis patients. Beyond the lack of data in the literature, their interpretation is hampered by the conventional analysis of air pollutants on an individual basis, whereas ambient pollution actually corresponds to a complex combination of multiple pollutant exposure. Composite spatial indices that account for multi-exposition have recently been developed and are now recognized as relevant indicators for global air exposure assessment. The main objectives of this project are to study the association of the level of multi-exposure to air pollutants with all-cause and cause-specific mortality in dialysis patients. Method We included all incident dialysis patients in France between January 1, 2012 and December 31, 2020, identified in the REIN registry. Annual mean levels of exposure to fine particulate matter (PM10, PM2.5) and nitrogen dioxide (NO2) were extracted over the entire study period based on the data from the French ‘Institut National de l’Environnement Industriel et des Risques (INERIS)’. A composite environmental score was created from the first component of a standardized, annualized principal component analysis of exposure levels to the three pollutants and estimated at the municipal level of each patient residency. This score was used as a continuous and categorical indicator (highest levels corresponding to the most exposed areas). The association between this score and all-cause mortality in dialysis patients was analyzed by multivariate Cox models considering comorbidities, modalities of dialysis start, socio-environmental factors (population density, social deprivation and distance to the nearest dialysis center), and the center effect. These analyses were declined according to the cause of death (all-cause, cardiovascular, infectious or cancer) and to different pre-dialysis exposure lags (1, 2 or 3 years). Interaction studies and subgroup analyses were performed according to age, gender and level of autonomy. Results A total of 90,373 patients were included in this study (64% men, median age 72 years) for a median follow-up of 46 months. Over the study period, 44,242 deaths were observed (20% of cardiovascular origin). The mean annual levels of each air pollutant exposure were 11.5 (± 2.5), 18.0 (± 2.5) and 16.8 (± 7.0) μg/m3 respectively for PM2.5, PM10 and NO2. For each point increment in the environmental score, we observed a linear 1.6% increase in the risk of all-cause mortality (HR = 1.016 [1.007-1.025] p < 0.001). Compared with the lowest exposure areas (Q1), patients residing in quartile 3 and 4 municipalities had an increased risk of all-cause death (HRQ2 = 1.00 [0.96-1.04] p = 0.99, HRQ3 = 1.06 [1.02-1.10] p = 0.005, and HRQ4 = 1.09 [1.05-1.13] p < 0.001 for quartiles 2, 3, and 4 of the environmental score respectively – see Figure). A significant interaction was observed with the level of autonomy of the patients, the risk of death associated with environmental exposure being higher in partially or totally dependent patients compared to fully autonomous ones (p for interaction = 0.006). These results were similar for deaths from cardiovascular or infectious causes and consistent regardless of exposure lag and each air pollutant taken individually. Conclusion In total, this is to our knowledge the first study describing an association between environmental multi-exposure and the risk of all-cause or cause-specific death in dialysis patients on a national scale. These results argue for intensified efforts to limit air pollution, particularly for the highly vulnerable dialysis patient population.

Pedestrian classification on transfer learning based deep convolutional neural network for partial occlusion handling

<span lang="EN-US">The investigation of a deep neural network for pedestrian classification using transfer learning methods is proposed in this study. The development of deep convolutional neural networks has significantly improved the autonomous driver assistance system for pedestrian classification. However, the presence of partially occluded parts and the appearance variation under complex scenes are still robust to challenge in the pedestrian detection system. To address this problem, we proposed six transfer learning models: end-to-end convolutional neural network (CNN) model, scratch-trained residual network (ResNet50) model, and four transfer learning models: visual geometry group 16 (VGG16), GoogLeNet (InceptionV3), ResNet50, and MobileNet. The performance of the pedestrian classification was evaluated using four publicly datasets: </span><em><span lang="EN-US">Institut National de Recherche en Sciences et Technologies du Numérique</span></em><span lang="EN-US"> (INRIA), Prince of Songkla University (PSU), CVC05, and Walailak University (WU) datasets. The experimental results show that six transfer learning models achieve classification accuracy of 65.2% (end-to-end CNN), 92.92% (scratch-trained ResNet50), 97.15% (pre-trained VGG16), 94.39% (pre-trained InceptionV3), 90.43% (pre-trained ResNet50), and 98.69% (pre-trained MobileNet) using data from Southern Thailand (PSU dataset). Further analysis reveals that the deeper the ConvNet architecture, the more specific information of features is provided. In addition, the deep ConvNet architecture can distinguish pedestrian occluded patterns while being trained with partially occluded parts of data samples.</span>

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Few quality of life (QoL) data are available for diffuse large B-cell lymphoma (DLBCL) patients during the first year of diagnosis. Due to the disease and treatment, patients can adapt to their condition and then change their criteria to assess QoL over time, resulting in a response shift (RS) effect. This study aims to provide QoL level for DLBCL patients at diagnosis and after 1 year, and to assess the occurrence of a RS effect. Methods: Data from DLBCL patients prospectively included in the French multicentric cohort REALYSA were used. QoL was collected at diagnosis and at 1 year using the EORTC QLQ-C30 and QLQ-NHL-HG29 (non-Hodgkin high-grade lymphoma) questionnaires. The recently validated QLQ-NHL-HG29 specific questionnaire assesses 5 symptomatic dimensions: symptom burden (SB), neuropathy (NP), physical condition/fatigue (PC), emotional impact (EI), worries/fears about health and functioning (WF). A score is generated per dimension on a 0 to 100 scale. Analyses were done on patients who received standard first-line immunochemotherapy regimen, with QoL questionnaire at diagnosis and at 1 year, and without relapse before 1 year questionnaire completion to avoid bias related to second line therapy. Scores were reported according to age, gender, performance status (PS) and disease stage. We examined the prevalence of clinically important problems/symptoms on QLQ-C30 scales at patient level using validated thresholds (Giesinger et al. J Clin Epidemiol. 2020). The potential occurrence of a RS effect was explored using the Oort procedure. Results: Between Nov 2018 and Dec 2021, 3116 patients were enrolled in REALYSA including 1198 DLBCL. Among 964 patients without relapse at 1 year, 523 had completed questionnaires at baseline and 1 year. For Global QoL, 57% of patients presented clinically important problems at baseline and 42% at 1 year. Regarding the QLQ-NHL-HG29, the mean PC score was 32 (SD 25) [PS 0–1 vs. 2: 29 (SD 24) vs. 47 (SD 25)] at baseline and 23 (SD 21) [PS 0–1 vs. 2: 22 (SD 20) vs. 27 (SD 22)] at 1 year; the mean NP score was 12 (SD 20) [PS 0–1 vs. 2: 11 (SD 19) vs. 16 (SD 26)] at baseline and 23 (SD 28) [PS 0–1 vs. 2: 23 (SD 27) vs. 24 (SD 29)] at 1 year. Among the QLQ-NHL-HG29, a RS effect was observed for NP, PC and WF. The highest effect was observed for NP (Figure 1), suggesting that there is no increase in NP level at 1 year compared to baseline (mean change of -1 points (SD 1)). If no RS effect was considered, it would have been concluded that the NP level had increased at 1 year compared to diagnosis (mean change of 12 points (SD 11)). The research was funded by: Institut National du Cancer (INCa, N°2021-130) Keyword: Aggressive B-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis.

The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis. For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524. The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%). The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma. Institut National du Cancer and Ligue Nationale Contre le Cancer.

A Twenty-Year Retrospective Analysis of Risk Assessment of Biomechanical Overload of the Upper Limbs in Multiple Occupational Settings: Comparison of Different Ergonomic Methods.

Several methods with which to assess the risk of biomechanical overload of the upper limb are described in the literature. We retrospectively analysed the results of the risk assessment of the biomechanical overload of the upper limb in multiple settings by comparing the application of the Washington State Standard, the threshold limit values (TLV) proposed by the American Conference of Governmental Industrial Hygienists (ACGIH), based on hand-activity levels (HAL) and normalised peak force (PF), the Occupational Repetitive Actions (OCRA) checklist, the Rapid Upper-Limb Assessment (RULA), and the Strain Index and Outil de Repérage et d'Evaluation des Gestes of INRS (Institut National de Recherche et de Sécurité). Overall, 771 workstations were analysed for a total of 2509 risk assessments. The absence of risk demonstrated for the Washington CZCL, used as the screening method, was in good agreement with the other methods, with the sole exception of the OCRA CL, which showed at-risk conditions in a higher percentage of workstations. Differences in the assessment of the frequency of actions were observed among the methods, while their assessments of strength appeared to be more uniform. However, the greatest discrepancies were observed in the assessment of posture. The use of multiple assessment methods ensures a more adequate analysis of biomechanical risk, allowing researchers to investigate the factors and segments in which different methods show different specificities.

Role of MR1-driven signals and amphiregulin on the recruitment and repair function of skin MAIT cells

Abstract Epithelial repair is crucial to reestablish adequate barrier integrity and function after tissue injury. In both mice and humans, MAIT (Mucosal associated invariant T) cells involvement in tissue repair is substantiated by their upregulation of tissue repair mediators following TCR-mediated activation. Additionally, in the absence of ɣδT cells, MAIT cells were shown to promote wound healing. By using both our congenic B6-MAIT CASTstrain (10× more MAIT cells than B6 mice) and a skin excision mouse model preventing epithelial contraction (mimicking the human repair process), we sought to uncover the underlying mechanisms of MAIT cell tissue repair function. Firstly, our scRNAseq analysis revealed that steady-state skin MAIT cells readily express a repair program. Additionally, we show that MAIT cells have a pro-repair function as their presence promotes keratinocyte proliferation, thereby accelerating healing. Using parabiosis, skin graft and the Kaede models, we found that, contrary to the resident ɣδT cells, MAIT cells are rapidly recruited into the inflamed skin. Parabiosis of MR1 +and MR1 −mice and MR1 −skin grafted onto MR1 +mice, showed that this recruitment was MR1-independent (MR1: antigen presenting molecule of MAIT cells). Instead, this recruitment relied on the chemokine receptor CXCR6 and its ligand CXCL16. Lastly, using conditional knock-out mice we demonstrated that the secretion by MAIT cells of the amphiregulin growth factor promotes skin wound healing. Overall, our study provides mechanistic insights into MAIT cell biology in the context of injury. Comprehension of these processes provides clues into the biology of related innate subsets and highlights potential new therapeutic avenues for wound healing. Institut National de la Santé et de la Recherche Médicale (OL) Institut Curie (OL) Agence Nationale de la Recherche Grant MAIT ANR-16-CE15-0020-01 (OL) Agence Nationale de la Recherche Grant MAITrepair ANR-20-CE15-0028-01 (OL) Agence Nationale de la Recherche ANR-10-IDEX-0001-02 PSL (OL) European Research Council (ERC-2019-AdG-885435) (OL) Fondation pour la Recherche Médicale, grant number FDT202106013036 (AdH)

Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome.

Genome-wide association studies (GWASs) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Our study aims to explore the shared genetic basis between these traits and investigate their impact on somatic environment of lung tumours. We performed genetic correlation, Mendelian randomisation (MR), and colocalisation analyses using the largest available GWASs summary statistics of LTL (N=464,716) and lung cancer (N=29,239 cases and 56,450 controls). Principal components analysis based on RNA-sequencing data was used to summarise gene expression profile in lung adenocarcinoma cases from TCGA (N=343). Although there was no genome-wide genetic correlation between LTL and lung cancer risk, longer LTL conferred an increased risk of lung cancer regardless of smoking status in the MR analyses, particularly for lung adenocarcinoma. Of the 144 LTL genetic instruments, 12 colocalised with lung adenocarcinoma risk and revealed novel susceptibility loci, including MPHOSPH6, PRPF6, and POLI. The polygenic risk score for LTL was associated with a specific gene expression profile (PC2) in lung adenocarcinoma tumours. The aspect of PC2 associated with longer LTL was also associated with being female, never smokers, and earlier tumour stages. PC2 was strongly associated with cell proliferation score and genomic features related to genome stability, including copy number changes and telomerase activity. This study identified an association between longer genetically predicted LTL and lung cancer and sheds light on the potential molecular mechanisms related to LTL in lung adenocarcinomas. Institut National du Cancer (GeniLuc2017-1-TABAC-03-CIRC-1-TABAC17-022), INTEGRAL/NIH (5U19CA203654-03), CRUK (C18281/A29019), and Agence Nationale pour la Recherche (ANR-10-INBS-09).

Impact of T-cell Receptor Status on Mutational Landscape and Outcome in T-ALL.

Impact of T-cell Receptor Status on Mutational Landscape and Outcome in T-ALL.

Deformation of Spartina patens and Spartina alterniflora stems under irregular wave action

ABSTRACT Physical modeling studies have endeavored to quantify the influence of plant biophysical parameters and hydrodynamics on wave-vegetation interactions and coastal protection. The accuracy with which such studies have characterized stem motion is limited by the predominant use of plant surrogates, and the few saltmarsh species considered in live vegetation studies. To address this, prototype-scale experiments were conducted in the outdoor Large Wave Canal of the Institut National de la Recherche Scientifique, Québec, in collaboration with the University of Ottawa and the National Research Council Canada, allowing novel characterization of live vegetation deformation under wave action. Two saltmarsh species were investigated (Spartina alterniflora, Spartina patens) under various irregular wave conditions (0.03 m< H s <0.28 m, T s 2.5, 10 s). Stem deformation was characterized using submerged cameras and bending angle tracking, coupled with wave height and velocity measurements. Significant differences in stem flexibility were observed between species, with S. alterniflora exhibiting more rigid stems (EI alterniflora =0.051 Nm2) than S. patens (EI patens =0.0015 Nm2; t-test; p<0.05). The two species consequexhibited different bending angles under similar hydrodynamic conditions, expected to influence their relative coastal protection capacity. These findings provide critical insight into the design of marsh construction or restoration for coastal protection.

Space-to-speed architecture supporting acceleration on VHR image processing

One of the major focuses in the remote sensing community is the rapid processing of deep neural networks (DNNs) on very high resolution (VHR) aerial images. Few studies have investigated the acceleration of training and prediction by optimizing the architecture of the DNN system rather than designing a lightweight DNN. Parallel processing using multiple graphics processing units (GPUs) increases VHR image processing performance. It drives extremely large and frequent data transfers (input/output(I/O)) from random access memory (RAM) to GPU memory. As a result, the system bus congestion causes the system to hang, resulting in long latency in training/predicting. In this paper, we evaluate the causes of long latency and propose a space-to-speed (S2S) DNN system to overcome the aforementioned challenges. A three-level memory system aiming to reduce data transfer during system operation is presented. Distribution optimization with parallel processing was used to accelerate the training. Training optimizations on VHR images (such as hot-zone searching and image/ground truth queues for data saving) were used to train the VHR images efficiently. Inference optimization was performed to speed up prediction in the release mode. To verify the efficiency of the proposed system, we used aerial image labeling from the Institut National de Recherche en Informatique et en Automatique (INRIA) and benchmarks from the Massachusetts Institute of Technology Aerial Imagery for Roof Segmentation (MITAIRS) to test the system performance and accuracy. Without the loss of accuracy, the S2S system improved prediction speed on the testing dataset by eight GPUs in a normal setting in both the INRIA dataset (from 534 to 72 s) and the MITAIRS dataset (818 to 120 s). With the prediction in half-float (using float-16 data), an 8-GPU parallel processing increased the speed to 38 s in the INRIA dataset and 83 s in the MITAIRS dataset. In a pressure test, our proposed system operated on 18,000 images with a size of 5000 × 5000 from 18.2 to 1.8 h with the prediction in full-float (using float-32 data) and 43 min with the prediction in half-float, increasing the speed by a factor of 9.78 and 25.3, respectively, when compared to system runs without optimization.

Socioeconomic inequalities in cancer mortality between and within countries in Europe: a population-based study.

Reducing socioeconomic inequalities in cancer is a priority for the public health agenda. A systematic assessment and benchmarking of socioeconomic inequalities in cancer across many countries and over time in Europe is not yet available. Census-linked, whole-of-population cancer-specific mortality data by socioeconomic position, as measured by education level, and sex were collected, harmonized, analysed, and compared across 18 countries during 1990-2015, in adults aged 40-79. We computed absolute and relative educational inequalities; temporal trends using estimated-annual-percentage-changes; the share of cancer mortality linked to educational inequalities. Everywhere in Europe, lower-educated individuals have higher mortality rates for nearly all cancer-types relative to their more highly-educated counterparts, particularly for tobacco/infection-related cancers [relative risk of lung cancer mortality for lower- versus higher-educated=2.4 (95% confidence intervals: 2.1-2.8) among men;=1.8 (95% confidence intervals: 1.5-2.1) among women]. However, the magnitude of inequalities varies greatly by country and over time, predominantly due to differences in cancer mortality among lower-educated groups, as for many cancer-types higher-educated have more similar (and lower) rates, irrespective of the country. Inequalities were generally greater in Baltic/Central/East-Europe and smaller in South-Europe, although among women large and rising inequalities were found in North-Europe (relative risk of all cancer mortality for lower- versus higher-educated ≥1.4 in Denmark, Norway, Sweden, Finland and the England/Wales). Among men, rate differences (per 100,000 person-years) in total-cancer mortality for lower-vs-higher-educated groups ranged from 110 (Sweden) to 559 (Czech Republic); among women from approximately null (Slovenia, Italy, Spain) to 176 (Denmark). Lung cancer was the largest contributor to inequalities in total-cancer mortality (between-country range: men, 29-61%; women, 10-56%). 32% of cancer deaths in men and 16% in women (but up to 46% and 24%, respectively in Baltic/Central/East-Europe) were associated with educational inequalities. Cancer mortality in Europe is largely driven by levels and trends of cancer mortality rates in lower-education groups. Even Nordic-countries, with a long-established tradition of equitable welfare and social justice policies, witness increases in cancer inequalities among women. These results call for a systematic measurement, monitoring and action upon the remarkable socioeconomic inequalities in cancer existing in Europe. This study was done as part of the LIFEPATH project, which has received financial support from the European Commission (Horizon 2020 grant number 633666), and the DEMETRIQ project, which received support from the European Commission (grant numbers FP7-CP-FP and 278511). SV and WN were supported by the French Institut National du Cancer (INCa) (Grant number 2018-116). PM was supported by the Academy of Finland (#308247, # 345219) and the European Research Council under the European Union's Horizon 2020 research and innovation programme (grant agreement No 101019329). The work by Mall Leinsalu was supported by the Estonian Research Council (grant PRG722).

Efficiency of Field Laboratories for Ebola Virus Disease Outbreak during Chronic Insecurity, Eastern Democratic Republic of the Congo, 2018–2020

Abstract During the 10th outbreak of Ebola virus disease in the Democratic Republic of the Congo, the Institut National de Recherche Biomédicale strategically positioned 13 decentralized field laboratories with dedicated equipment to quickly detect cases as the outbreak evolved. The laboratories were operated by national staff, who quickly handed over competencies and skills to local persons to successfully manage future outbreaks. Laboratories analyzed ≈230,000 Ebola diagnostic samples under stringent biosafety measures, documentation, and database management. Field laboratories diversified their activities (diagnosis, chemistry and hematology, survivor follow-up, and genomic sequencing) and shipped 127,993 samples from the field to a biorepository in Kinshasa under good conditions. Deploying decentralized and well-equipped laboratories run by local personnel in at-risk countries for Ebola virus disease outbreaks is an efficient response; all activities are quickly conducted in the field.

First report of citrus black spot disease caused by Phyllosticta citricarpa in Benin

In Benin, citrus production represents an important activity in the national economy and source of income for farmers. For a decade, the majority of orange orchards in Benin have been affected by a disease that is expressed by the appearance of spots on the fruits (Lokossou et al., 2009). A preliminary study conducted on farmers’ perception on the presence of this disease revealed positive answers from all 417 interviewed orchardists. In July 2021, 15 orchards were randomly selected for inspection in four orange production districts in Benin: Djidja (7°20’N, 1°56’E), Zakpota (7°15’N, 2°11’E), Lalo (6°56’N, 1°56’E) and Bopa (6°35’N, 1°57’E). Between 50 to 100% of the trees in the inspected orchards were affected by the disease. Disease symptoms consisted of numerous tiny to middle-sized dark brown to black spots, ranging in size from 3 to 10 mm in diameter. The tiny spots had a grey centre with a dark brown to black border surrounded by a green or yellow halo, depending on the maturity of the fruit. In cases of severe infection, the fruits were completely covered with black spots, and rot (Fig. 1). The leaves also had numerous black spots. In cases of less severe infection, symptoms were limited to the fruits. Four fruits per orchard, in total sixty fruits, showing black spots were randomly selected each of the inspected orchards. A fungus was isolated from the diseased orange fruits on potato dextrose agar medium. The fungus was identified as Phyllosticta citricarpa based on morphological and cultural characteristics. The fungus produced a slow mycelial growth with irregular edged colonies surrounded by a larger translucent zone of immersed clear mycelium (Fig. 2). The centre of the colonies was composed of grey aerial mycelium forming a plectenchymatous rind. The reverse had a very dark centre surrounded by grey and beige areas. Hard, black mass stromas appeared after seven to eight days and ripe pycnidia containing conidia after 10 to 14 days (Fig. 3). Conidia were 9.4 - 12.7 μm long and 5.0 - 8.5 μm wide, ellipsoid to obovoid with atruncate base, hyaline, guttulate, aseptate with a tiny apical mucoid and translucent layer appendage, 3–10 μm long and 1.5 μm wide (Fig. 4). These morphological features confirm the identity of the fungus as Phyllosticta citricarpa (Baayen et al., 2002). Koch's postulates were performed in the laboratory on 30 healthy ripe orange fruits, with two replicates, by injecting 5 μl of a suspension of 106 conidia/ml with a sterile medical needle approximately 2 mm deep in the albedo of fruit. On each fruit, 12 points were inoculated. Control fruits were inoculated with sterile needle and distilled water. Inoculated fruits were kept at room temperature (25 ±2°C). After 15 days, the inoculated fruits developed similar symptoms to those observed in the orange orchards while no symptoms were observed on the untreated fruits (Fig. 5). Phyllosticta citricarpa, was re-isolated from lesions developed on inoculated fruit. Phyllosticta citricarpa (syn. Guignardia citricarpa) has been found previously in Australia, in tropical and subtropical citrus-growing areas of Africa (Angola, Ghana, Kenya, Mozambique, Tunisia, Uganda, Namibia, South Africa, Zambia, Zimbabwe), the Americas (Brazil, Florida), and in Asia (China, India) (EFSA et al., 2020). This is the first report of Phyllosticta citricarpa causing citrus black spot in Benin. Management methods and strategies are being developed to control and limit the spread of the disease in the country. The authors thank the Partnership for Skills in Applied Sciences, Engineering and Technology (PASET) and Regional Scholarship and Innovation Funds (RSIF) programme, the Université Félix Houphouët-Boigny of Côte d'Ivoire, the Institut National des Recherches Agricoles du Bénin (INRAB), the African Centre of Excellence for Climate Change, Biodiversity and Sustainable Agriculture (CEA-CCBAD/Côte d'Ivoire) and the Laboratoire de Phytopathologie du Centre National de Spécialisation en Fruits et Légumes (CNS-FL) /INERA/Burkina-Faso for financial and technical support.

Efficiency of Field Laboratories for Ebola Virus Disease Outbreak during Chronic Insecurity, Eastern Democratic Republic of the Congo, 2018–2020

During the 10th outbreak of Ebola virus disease in the Democratic Republic of the Congo, the Institut National de Recherche Biomédicale strategically positioned 13 decentralized field laboratories with dedicated equipment to quickly detect cases as the outbreak evolved. The laboratories were operated by national staff, who quickly handed over competencies and skills to local persons to successfully manage future outbreaks. Laboratories analyzed ≈230,000 Ebola diagnostic samples under stringent biosafety measures, documentation, and database management. Field laboratories diversified their activities (diagnosis, chemistry and hematology, survivor follow-up, and genomic sequencing) and shipped 127,993 samples from the field to a biorepository in Kinshasa under good conditions. Deploying decentralized and well-equipped laboratories run by local personnel in at-risk countries for Ebola virus disease outbreaks is an efficient response; all activities are quickly conducted in the field.

Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative

Tracking progress and providing timely evidence is a fundamental step forward for countries to remain aligned with the targets set by WHO to eliminate cervical cancer as a public health problem (ie, to reduce the incidence of the disease below a threshold of 4 cases per 100 000 women-years). We aimed to assess the extent of global inequalities in cervical cancer incidence and mortality, based on The Global Cancer Observatory (GLOBOCAN) 2020 estimates, including geographical and socioeconomic development, and temporal aspects. For this analysis, we used the GLOBOCAN 2020 database to estimate the age-specific and age-standardised incidence and mortality rates of cervical cancer per 100 000 women-years for 185 countries or territories aggregated across the 20 UN-defined world regions, and by four-tier levels of the Human Development Index (HDI). Time trends (1988-2017) in incidence were extracted from the Cancer Incidence in Five Continents (CI5) plus database. Mortality estimates were obtained using the most recent national vital registration data from WHO. Globally in 2020, there were an estimated 604 127 cervical cancer cases and 341 831 deaths, with a corresponding age-standardised incidence of 13·3 cases per 100 000 women-years (95% CI 13·3-13·3) and mortality rate of 7·2 deaths per 100 000 women-years (95% CI 7·2-7·3). Cervical cancer incidence ranged from 2·2 (1·9-2·4) in Iraq to 84·6 (74·8-94·3) in Eswatini. Mortality rates ranged from 1·0 (0·8-1·2) in Switzerland to 55·7 (47·7-63·7) in Eswatini. Age-standardised incidence was highest in Malawi (67·9 [95% CI 65·7 -70·1]) and Zambia (65·5 [63·0-67·9]) in Africa, Bolivia (36·6 [35·0-38·2]) and Paraguay (34·1 [32·1-36·1]) in Latin America, Maldives (24·5 [17·0-32·0]) and Indonesia (24·4 [24·2-24·7]) in Asia, and Fiji (29·8 [24·7-35·0]) and Papua New Guinea (29·2 [27·3-31·0]) in Melanesia. A clear socioeconomic gradient exists in cervical cancer, with decreasing rates as HDI increased. Incidence was three times higher in countries with low HDI than countries with very high HDI, whereas mortality rates were six times higher in low HDI countries versus very high HDI countries. In 2020 estimates, a general decline in incidence was observed in most countries of the world with representative trend data, with incidence becoming stable at relatively low levels around 2005 in several high-income countries. By contrast, in the same period incidence increased in some countries in eastern Africa and eastern Europe. We observed different patterns of age-specific incidence between countries with well developed population-based screening and treatment services (eg, Sweden, Australia, and the UK) and countries with insufficient and opportunistic services (eg, Colombia, India, and Uganda). The burden of cervical cancer remains high in many parts of the world, and in most countries, the incidence and mortality of the disease remain much higher than the threshold set by the WHO initiative on cervical cancer elimination. We identified substantial geographical and socioeconomic inequalities in cervical cancer globally, with a clear gradient of increasing rates for countries with lower levels of human development. Our study provides timely evidence and impetus for future strategies that prioritise and accelerate progress towards the WHO elimination targets and, in so doing, address the marked variations in the global cervical cancer landscape today. French Institut National du Cancer, Horizon 2020 Framework Programme for Research and Innovation of the European Commission; and EU4Health Programme.

Editorial introductions.

Editorial introductions.

Estimates of global research productivity in primary ovarian insufficiency from 2000 to 2021: Bibliometric analysis.

Primary ovarian insufficiency (POI) is a heterogeneous disease with diverse clinical phenotypes and etiologies, which is defined as ovarian dysfunction under the age of 40 years. The global prevalence of POI is approximately about 1.1%, and it severely affects female fertility. Nevertheless, bibliometric analysis in this field is extremely limited. We aimed to visualize the research hotspots and trends of POI using bibliometric analysis and tried to predict the future development of this field. The original articles regarding POI were culled from the Web of Science Core Collection. Countries, institutions, journals, authors, and keywords in this field were visually analyzed by employing CiteSpace software and Microsoft Excel 2021 software. A total of 2,999 publications were included for further bibliometric analysis after screening the titles and abstracts stringently. The number of literature regarding POI significantly increased yearly. These publications come from 78 countries. The USA was dominant in the field of POI in terms of the number of publications (865), average citations per item (57.36), and h-index (112). The Institut National De La Sante Et De La Recherche Medicale Inserm is the most high-yield institution in this field with 351 publications. Fertility and Sterility ranked first with the highest number of publications (152), followed by Human Reproduction (138). According to the keyword cluster analysis from 2000 to 2021, the eight keyword clusters encountered frequently were apoptosis, osteoporosis, fertility preservation, mutation, fragile x syndrome, adrenal insufficiency, DNA repair, ovarian reserve. Keyword citation burst analysis revealed that whole-exome sequencing, ovarian tissue cryopreservation, and DNA repair had a citation burst until 2021. Great progress has been made in POI research over the past 20 years, which is widely researched but unevenly developed in the world. In terms of influence, the United States may be in the lead. The research hotspots in POI are mainly pathogenesis and treatment, including genetic mutation, hormone therapy, fertility preservation, and stem cell transplantation.

Third international challenge to model the medium- to long-range transport of radioxenon to four Comprehensive Nuclear-Test-Ban Treaty monitoring stations

In 2015 and 2016, atmospheric transport modeling challenges were conducted in the context of the Comprehensive Nuclear-Test-Ban Treaty (CTBT) verification, however, with a more limited scope with respect to emission inventories, simulation period and number of relevant samples (i.e., those above the Minimum Detectable Concentration (MDC)) involved. Therefore, a more comprehensive atmospheric transport modeling challenge was organized in 2019. Stack release data of Xe-133 were provided by the Institut National des Radioéléments/IRE (Belgium) and the Canadian Nuclear Laboratories/CNL (Canada) and accounted for in the simulations over a three (mandatory) or six (optional) months period. Best estimate emissions of additional facilities (radiopharmaceutical production and nuclear research facilities, commercial reactors or relevant research reactors) of the Northern Hemisphere were included as well. Model results were compared with observed atmospheric activity concentrations at four International Monitoring System (IMS) stations located in Europe and North America with overall considerable influence of IRE and/or CNL emissions for evaluation of the participants’ runs. Participants were prompted to work with controlled and harmonized model set-ups to make runs more comparable, but also to increase diversity. It was found that using the stack emissions of IRE and CNL with daily resolution does not lead to better results than disaggregating annual emissions of these two facilities taken from the literature if an overall score for all stations covering all valid observed samples is considered. A moderate benefit of roughly 10% is visible in statistical scores for samples influenced by IRE and/or CNL to at least 50% and there can be considerable benefit for individual samples. Effects of transport errors, not properly characterized remaining emitters and long IMS sampling times (12–24 h) undoubtedly are in contrast to and reduce the benefit of high-quality IRE and CNL stack data. Complementary best estimates for remaining emitters push the scores up by 18% compared to just considering IRE and CNL emissions alone. Despite the efforts undertaken the full multi-model ensemble built is highly redundant. An ensemble based on a few arbitrary runs is sufficient to model the Xe-133 background at the stations investigated. The effective ensemble size is below five. An optimized ensemble at each station has on average slightly higher skill compared to the full ensemble. However, the improvement (maximum of 20% and minimum of 3% in RMSE) in skill is likely being too small for being exploited for an independent period.

Notes on Contributors

Notes on Contributors