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One zoonotic infectious animal disease is brucellosis. The bacteria that cause brucellosis belong to the genus Brucella. Numerous animal and human species are affected by Brucellosis, with an estimated 500,000 human cases recorded annually worldwide. The occurrence of new areas of infection and the resurgence of infection in already infected areas indicate how dynamically Brucellosis is distributed throughout different geographic regions. Bacteria originate from the blood and are found in the reticuloendothelial system, the liver, the spleen, and numerous other locations, including the joints, kidneys, heart, and genital tract. Diagnosis of this disease can be done by Bacterial Isolation, Molecular tests, Modified acid-fast Stain, Rose Bengal Test (RBT), Milk Ring Test (MRT), Complement Fixation Test (CFT), Enzyme-Linked Immunosorbent Assay (ELISA), and Serum Agglutination Test (SAT). The primary sign of a B. abortus infection is infertility, which can result in abortion and the birth of a frail fetus that may go on to infect other animals. In humans, the main symptoms are acute febrile illness, with or without localization signs, and chronic infection. Female cattle have a greater risk of contracting Brucella disease. Human populations at high risk of contracting brucellosis include those who care for cattle, veterinarians, slaughterhouse employees, and butchers. Antibiotic treatment of brucellosis is often unsuccessful due to the intracellular survival of Brucella and its adaptability in macrophages. A 'One Health' strategy is necessary to control illnesses like brucellosis. [Open Vet J 2024; 14(5.000): 1081-1097]

Abstract The heterogeneity inherent in today’s biotherapeutics, especially as a result of heavy glycosylation, can affect a molecule’s safety and efficacy. Characterizing this heterogeneity is crucial for drug development and quality assessment, but existing methods are limited in their ability to analyze intact glycoproteins or other heterogeneous biotherapeutics. Here, we present an approach to the molecular assessment of biotherapeutics that uses proton-transfer charge-reduction with gas-phase fractionation to analyze intact heterogeneous and/or glycosylated proteins by mass spectrometry. The method provides a detailed landscape of the intact molecular weights present in biotherapeutic protein preparations in a single experiment. For glycoproteins in particular, the method may offer insights into glycan composition when coupled with a suitable bioinformatic strategy. We tested the approach on various biotherapeutic molecules, including Fc-fusion, VHH-fusion, and peptide-bound MHC class II complexes to demonstrate efficacy in measuring the proteoform-level diversity of biotherapeutics. Notably, we inferred the glycoform distribution for hundreds of molecular weights for the eight-times glycosylated fusion drug IL22-Fc, enabling correlations between glycoform sub-populations and the drug’s pharmacological properties. Our method is broadly applicable and provides a powerful tool to assess the molecular heterogeneity of emerging biotherapeutics.

Abstract The regressive evolution of independent lineages often results in convergent phenotypes. Several teleost groups display secondary loss of the stomach, and four gastric genes, atp4a, atp4b, pgc, and pga2 have been co-deleted in agastric (stomachless) fish. Analyses of genotypic convergence among agastric fishes showed that four genes, slc26a9, kcne2, cldn18a, and vsig1, were co-deleted or pseudogenized in most agastric fishes of the four major groups. kcne2 and vsig1 were also deleted or pseudogenized in the agastric monotreme echidna and platypus, respectively. In the stomachs of sticklebacks, these genes are expressed in gastric gland cells or surface epithelial cells. An ohnolog of cldn18 was retained in some agastric teleosts but exhibited an increased non-synonymous substitution when compared with gastric species. These results revealed novel convergent gene losses at multiple loci among the four major groups of agastric fish, as well as a single gene loss in the echidna and platypus.

Background: The problem, poultry is one of the most prominent sources of Campylobacter jejuni, which is also a major means of transmission to people. Campylobacter jejuni contamination in chicken meat comes from chicken faeces because it naturally exists in the intestine of chickens. Aim: The purpose of this study is to identify the antibiotic resistance genes and patterns of Campylobacter jejuni, which was found in hens in Pasuruan, Indonesia. Methods: The samples used in this study were 200 contents of the small intestine of broiler chickens from 40 farms in Pasuruan Regency. Enriched sample was streaked on the selective media of modified charcoal cefoperazone deoxycholate (mCCDA) containing the CCDA selective supplement. Antimicrobial susceptibility test utilizing the Kirby-Bauer Diffusion Test method in accordance with Clinical and Laboratory Standards Institute (CLSI) standards. The Polymerase Chain Reaction (PCR) method was used to detect the hipO, gyrA, blaOXA-61, and tetO genes, hipO is a gene encoding Campylobacter jejuni strain, while gyrA is a gene encoding fluoroquinolone resistance, blaOXA-61 encodes beta-lactam resistance, tetO encodes beta-lactam resistance. Results: The findings revealed a 14% (28/200) prevalence of Campylobacter jejuni. This isolates showed high resistance to enrofloxacin (92.9%). All isolates (100%) were susceptible to amoxicillin-clavulanate. PCR results showed that all Campylobacter jejuni isolates (100%) detected the gyrA gene, 96.7% detected the blaOXA-61 gene, and 50% detected the tetO gene. Conclusion: The findings of antimicrobial resistance resistance in high level from the small intestine of broiler chickens illustrates the potential threat to human health. To lessen the effects now and in the future, coordinated and suitable action is needed, as well as steps to guarantee the poultry industry's economic survival and public health insurance. [Open Vet J 2024; 14(3.000): 759-768]

Abstract Although retirement ages are rising in the United Kingdom and other countries, the average number of years people in England can expect to spend both healthy and work from age 50 (Healthy Working Life Expectancy; HWLE) is less than the number of years to the State Pension age. This study aimed to estimate HWLE with the presence and absence of selected health, socio-demographic, physical activity, and workplace factors relevant to stakeholders focusing on improving work participation. Data from 11,540 adults in the English Longitudinal Study of Ageing were analysed using a continuous time 3-state multi-state model. Age-adjusted hazard rate ratios (aHRR) were estimated for transitions between health and work states associated with individual and combinations of health, socio-demographic, and workplace factors. HWLE from age 50 was 3.3 years fewer on average for people with pain interference (6.54 years with 95% confidence interval [6.07, 7.01]) compared to those without (9.79 [9.50, 10.08]). Osteoarthritis and mental health problems were associated with 2.2 and 2.9 fewer healthy working years respectively (HWLE for people without osteoarthritis: 9.50 years [9.22, 9.79]; HWLE with osteoarthritis: 7.29 years [6.20, 8.39]; HWLE without mental health problems: 9.76 years [9.48, 10.05]; HWLE with mental health problems: 6.87 years [1.58, 12.15]). Obesity and physical inactivity were associated with 0.9 and 2.0 fewer healthy working years respectively (HWLE without obesity: 9.31 years [9.01, 9.62]; HWLE with obesity: 8.44 years [8.02, 8.86]; HWLE without physical inactivity: 9.62 years [9.32, 9.91]; HWLE with physical inactivity: 7.67 years [7.23, 8.12]). Workers without autonomy at work or with inadequate support at work were expected to lose 1.8 and 1.7 years respectively in work with good health from age 50 (HWLE for workers with autonomy: 9.50 years [9.20, 9.79]; HWLE for workers lacking autonomy: 7.67 years [7.22, 8.12]; HWLE for workers with support: 9.52 years [9.22, 9.82]; HWLE for workers with inadequate support: 7.86 years [7.22, 8.12]). This study identified demographic, health, physical activity, and workplace factors associated with lower HWLE and life expectancy at age 50. Identifying the extent of the impact on healthy working life highlights these factors as targets and the potential to mitigate against premature work exit is encouraging to policy-makers seeking to extend working life as well as people with musculoskeletal and mental health conditions and their employers. The HWLE gaps suggest that interventions are needed to promote the health, wellbeing and work outcomes of subpopulations with long-term health conditions.

Abstract Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML.

The declaration of a second Public Health Emergency of International Concern (PHEIC) for mpox in August 2024 underscores the urgent need for a comprehensive understanding of the evolving epidemiology [1] clinical manifestations, and zoonotic potential of this emerging threat [2]. This work delves into the intricate interplay between human and animal mpox infections, with a specific focus on the unique characteristics of various viral clades and their implications for individual and public health.There is a critical need to elucidate the factors driving multiple spillover events and the subsequent emergence of new clades better adapted to human-to-human transmission. We hypothesize that anthropogenic changes, including deforestation, urbanization, and climate change are facilitating increased human-to-animal contact, leading to more frequent zoonotic transmissions and viral adaptations. Our conceptual framework integrates One Health principles, evolutionary virology, and epidemiological modeling to investigate the demographic, clinical, and treatment differences among mpox clades in both humans and animals. We employ a mixed-methods approach, combining genomic analysis, clinical data review, and ecological surveys to construct a comprehensive picture of mpox's changing dynamics. The research questions explore the differences in epidemiological and clinical profiles among mpox clades and the factors that likely contribute to successful cross-species transmission and human adaptation.This manuscript introduces an updated Identify, Isolate, Inform (3I) Tool meticulously redesigned to significantly improve the early detection, containment, and reporting of mpox cases across diverse settings. By integrating clinical, virological, and ecological data, this work aims to lay the groundwork for enhanced risk assessment, targeted interventions, and global preparedness strategies in the face of this evolving zoonotic threat.

Measuring what people eat is a major methodological challenge. We developed and validated a new web-based method to record actual food supply data that would be less time consuming than the original method (i.e., food supply diary). Through the COD-Appro web application, participants can enter their food supplies by selecting a food item from a list based on items included in French food databases; thus automatically associated with nutrient composition and environmental impacts data. We recruited 102 participants who used COD-Appro during one month, among which 30 also used a classical paper-based food supply diary to be able to compare the two methods. A feedback questionnaire was completed by all the participants. The two methods showed no difference between the price and the quantity of food purchases when compared by food groups (n = 10) which confirms that the new method was robust compared to the original method. In addition, participants reported good usability of the COD-Appro web application and its use saved a considerable amount of time to the experimenters by integrating data entry and pairing with food databases (nutrient composition and environmental impacts) into the data collection step performed by the participants themselves. • Web-based food supply data collection • Association with nutrient composition and environmental impacts • External validity compared to original method (i.e., food supply diary)

Using the metaverse can impact how information is interacted with in educational settings. However, despite extensive research on the topic, there is still a lack of understanding of how learners perceive and experience this technology. To design learning experiences, designers must know the current landscape of metaverse implementation and digestion by student users. This article provides an overview of metaverse implementation examples to address this gap and then examines learners' perceptions of using the metaverse in education. Through a qualitative study, we aim to explore the potential advantages and obstacles of applying the metaverse to learning from an informal learning perspective, as perceived by learners. Compared to current implementation strategies, student feedback suggests a diversity of motivations and experiences in valuing the Edu-metaverse. Therefore, our study provides valuable insights into how the metaverse learning design can enhance learner engagement, interaction, and collaboration while identifying potential challenges and limitations. Ultimately, this research helps designers and educators better understand how metaverse technology can impact and improve learning experiences.

En France, le Ministère de la Transition Ecologique avec Vigicrues fournis une information sur le risque de crues à venir dans les prochaines 24 h (Vigilance Crue) sur plus de 20000km de cours d’eau. En complément de cette information, des prévisions de débits ou de hauteurs d’eau sont produites sur plus de 500 stations hydrométriques. Pour les besoins de la prévision des crues, PLATHYNES, une plateforme multi-modèles a été développée. L’article permettra de revenir sur l’origine de ce projet et détaillera ses trois principaux modèles distribués. Ils permettent sur le pourtour méditerranéen français mais aussi dans d’autres contextes hydroclimatiques de fournir des prévisions de crues lors d’épisodes pluvieux très intenses.Le mode global – semi-distribué de PLATHYNES sera également présenté, il permet notamment de créer des modèles simples de propagation débit-débit.Enfin dans le cadre de son plan stratégique, le réseau Vigicrues ambitionne de fournir sur les stations présentant les enjeux les plus importants, des prévisions plus fiables et avec une échéance d’au moins 24 h. En outre, une information de vigilance crues devra être publiée à terme, sur l’ensemble des cours d’eau de métropole. Pour atteindre ces objectifs ambitieux l’outil PLATHYNES de par sa polyvalence constitue un atout important.

Depuis sa création en 2005, le Service de Prévision des Crues Loire-Allier-Cher-Indre (SPC LACI) a réalisé de nombreux développements pour améliorer progressivement la prévision des crues et répondre ainsi aux besoins des gestionnaires de crise sur son territoire de compétence. Cette évolution s’est structurée selon différentes phases : les premières années ont été largement consacrées au développement des capacités des prévisions des crues et inondations avec le déploiement de différentes typologies de modèles pour répondre à des contextes hydrologiques spécifiques. Les modèles de prévision en place, l’estimation des incertitudes propres aux prévisions hydrologiques s’est ensuite naturellement imposée pour offrir des informations enrichies aux gestionnaires de crise dans leurs prises de décisions. Les prévisions ont alors été produites sous forme graphique, avec leurs intervalles de confiance associés et la diffusion progressive des cartes d’aléas d’inondations a permis une traduction concrète de ces prévisions de crue en termes d’impact sur le terrain. Toutes ces informations diffusées sont, depuis 2023, évaluées de manière régulière, en particulier après chaque évènement afin de contrôler leur qualité.

It is necessary to ensure security and community safety around High Voltage Transmission Poles (HVTP). Legislation requires a safety perimeter around HVTP and the High Voltage Lines (HVL) where no building and tree can be located. However, surveying thousands of kilometers of circuit is an expensive and challenging task that is currently performed by human inspection. Therefore, the use of automatic detection methods enables to facilitate the inspection is necessary to reduce time and cost. Convolutional Neural Network (CNN) is proposed in this work to detect, from Google Earth images, buildings and trees within the safety perimeter of HVTP. A dedicated 3 class (House, forest and HVTP) dataset of approximately 1 million tiles with a resolution of 0.09 m/pixel is created. Tiles size for trees and building classes is 64 × 64 pixels while for the HVTP 128 × 128 pixels is used. Three CNN models are built and optimized to classify each of these classes. Models validation shows that, except for houses where the accuracy is only 84 %, the other two classes have an accuracy of over 89 %. Moreover, by analyzing the classified HVTP, type can be identified. Finally, buildings and trees within the safety perimeter around the HVTP can be identified and displayed on the image demonstrating the usefulness of the tool.

Faculty development (FD) programs are critical for providing the knowledge and skills necessary to drive positive change in health professions education, but they take many forms to attain the program goals. The Macy Faculty Scholars Program (MFSP), created by the Josiah Macy Jr. Foundation (JMJF) in 2010, intends to develop participants as leaders, scholars, teachers, and mentors. After a decade of implementation, an external review committee conducted a program evaluation to determine how well the program met its intended goals and defined options for ongoing improvement.The committee selected Stufflebeam's CIPP (context, input, process, products) framework to guide the program evaluation. Context and input components were derived from the MFSP description and demographic data, respectively. Process and product components were obtained through a mixed-methods approach, utilizing both quantitative and qualitative data obtained from participant survey responses, and curriculum vitae (CV).The evaluation found participants responded favorably to the program and demonstrated an overall increase in academic productivity, most pronounced during the two years of the program. Mentorship, community of practice, and protected time were cited as major strengths. Areas for improvement included: enhancing the diversity of program participants, program leaders and mentors across multiple sociodemographic domains; leveraging technology to strengthen the MFSP community of practice; and improving flexibility of the program.The program evaluation results provide evidence supporting ongoing investment in faculty educators and summarizes key strengths and areas for improvement to inform future FD efforts for both the MFSP and other FD programs.

BackgroundThe HPTN 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was superior to tenofovir-disoproxil fumarate/emtricitabine for human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP). Integrase strand transfer inhibitor (INSTI) resistance-associated mutations (RAMs) were detected in some participants with HIV infection. We used a low viral load INSTI genotyping assay to evaluate the timing of emergence of INSTI RAMs and assessed whether HIV screening with a sensitive RNA assay would have detected HIV infection before INSTI resistance emerged.MethodsSingle-genome sequencing to detect INSTI RAMs was performed for samples with viral loads

In 2022, students at North American universities with third-dose COVID-19 vaccine mandates risk disenrolment if unvaccinated. To assess the appropriateness of booster mandates in this age group, we combine empirical risk-benefit assessment and ethical analysis. To prevent one COVID-19 hospitalisation over a 6-month period, we estimate that 31 207-42 836 young adults aged 18-29 years must receive a third mRNA vaccine. Booster mandates in young adults are expected to cause a net harm: per COVID-19 hospitalisation prevented, we anticipate at least 18.5 serious adverse events from mRNA vaccines, including 1.5-4.6 booster-associated myopericarditis cases in males (typically requiring hospitalisation). We also anticipate 1430-4626 cases of grade ≥3 reactogenicity interfering with daily activities (although typically not requiring hospitalisation). University booster mandates are unethical because they: (1) are not based on an updated (Omicron era) stratified risk-benefit assessment for this age group; (2) may result in a net harm to healthy young adults; (3) are not proportionate: expected harms are not outweighed by public health benefits given modest and transient effectiveness of vaccines against transmission; (4) violate the reciprocity principle because serious vaccine-related harms are not reliably compensated due to gaps in vaccine injury schemes; and (5) may result in wider social harms. We consider counterarguments including efforts to increase safety on campus but find these are fraught with limitations and little scientific support. Finally, we discuss the policy relevance of our analysis for primary series COVID-19 vaccine mandates.

Concern that synthetic food dyes may impact behavior in children prompted a review by the California Office of Environmental Health Hazard Assessment (OEHHA). OEHHA conducted a systematic review of the epidemiologic research on synthetic food dyes and neurobehavioral outcomes in children with or without identified behavioral disorders (particularly attention and activity). We also conducted a search of the animal toxicology literature to identify studies of neurobehavioral effects in laboratory animals exposed to synthetic food dyes. Finally, we conducted a hazard characterization of the potential neurobehavioral impacts of food dye consumption. We identified 27 clinical trials of children exposed to synthetic food dyes in this review, of which 25 were challenge studies. All studies used a cross-over design and most were double blinded and the cross-over design was randomized. Sixteen (64%) out of 25 challenge studies identified some evidence of a positive association, and in 13 (52%) the association was statistically significant. These studies support a relationship between food dye exposure and adverse behavioral outcomes in children. Animal toxicology literature provides additional support for effects on behavior. Together, the human clinical trials and animal toxicology literature support an association between synthetic food dyes and behavioral impacts in children. The current Food and Drug Administration (FDA) acceptable daily intakes are based on older studies that were not designed to assess the types of behavioral effects observed in children. For four dyes where adequate dose-response data from animal and human studies were available, comparisons of the effective doses in studies that measured behavioral or brain effects following exposure to synthetic food dyes indicate that the basis of the ADIs may not be adequate to protect neurobehavior in susceptible children. There is a need to re-evaluate exposure in children and for additional research to provide a more complete database for establishing ADIs protective of neurobehavioral effects.

Monkeypox 2022, a zoonotic virus similar to smallpox, presented as a rapidly escalating human outbreak with community transmission outside endemic regions of Africa. In just over one month of detection, confirmed cases escalated to over 3300, with reports of patients in at least 43 non-African nations. Mechanisms of transmission in animals and the reservoir host remain uncertain; spread from humans to wild or domestic animals risks the creation of new endemic zones. While initial cases were reported in men who have sex with men (MSM), monkeypox is not considered a sexually transmitted infection. Anyone with close contact with an infected person, aerosolized infectious material (e.g., from shaken bedsheets), or contact with fomites or infected animals is at risk. In humans, monkeypox typically presents with a non-specific prodromal phase followed by a classic rash with an incubation period of 5-21 days (usually 6-13 days). The prodrome may be subclinical, and the monkeypox virus may be transmissible from person-to-person before observed symptom onset. Most clinicians are unfamiliar with monkeypox. Information is rapidly evolving, producing an urgent need for immediate access to clear, concise, fact-based, and actionable information for frontline healthcare workers in prehospital, emergency departments/hospitals, and acute care/sexual transmitted infection clinics. This paper provides a novel Identify-Isolate-Inform (3I) Tool for the early detection and management of patients under investigation for monkeypox 2022. Patients are identified as potentially exposed or infected after an initial assessment of risk factors and signs/symptoms. Management of exposed patients includes consideration of quarantine and post-exposure prophylaxis with a smallpox vaccine. For infectious patients, providers must immediately don personal protective equipment and isolate patients. Healthcare workers must report suspected and confirmed cases in humans or animals to public health authorities. This innovative 3I Tool will assist emergency, primary care, and prehospital clinicians in effectively managing persons with suspected or confirmed monkeypox.

Background Renal cell carcinoma is the most common type of kidney cancer, comprising approximately 85% of all renal malignancies. Patients with advanced renal cell carcinoma are the focus of this National Institute for Health and Care Excellence multiple technology appraisal. A patient’s risk of disease progression depends on a number of prognostic risk factors; patients are categorised as having intermediate/poor risk or favourable risk of disease progression. Objectives The objectives of this multiple technology appraisal were to appraise the clinical effectiveness and cost-effectiveness of lenvatinib plus pembrolizumab versus relevant comparators listed in the final scope issued by the National Institute for Health and Care Excellence: sunitinib, pazopanib, tivozanib, cabozantinib and nivolumab plus ipilimumab. Methods The assessment group carried out clinical and economic systematic reviews and assessed the clinical and cost-effectiveness evidence submitted by Eisai, Hatfield, Hertfordshire, UK (the manufacturer of lenvatinib) and Merck Sharp & Dohme, Whitehouse Station, NJ, USA (the manufacturer of pembrolizumab). The assessment group carried out fixed-effects network meta-analyses using a Bayesian framework to generate evidence for clinical effectiveness. As convergence issues occurred due to sparse data, random-effects network meta-analysis results were unusable. The assessment group did not develop a de novo economic model, but instead modified the partitioned survival model provided by Merck Sharp & Dohme. Results The assessment group clinical systematic review identified one relevant randomised controlled trial (CLEAR trial). The CLEAR trial is a good-quality, phase III, multicentre, open-label trial that provided evidence for the efficacy and safety of lenvatinib plus pembrolizumab compared with sunitinib. The assessment group progression-free survival network meta-analysis results for all three risk groups should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons owing to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. The assessment group overall survival network meta-analysis results for the intermediate-/poor-risk subgroup suggested that there was a numerical, but not statistically significant, improvement in the overall survival for patients treated with lenvatinib plus pembrolizumab compared with patients treated with cabozantinib or nivolumab plus ipilimumab. Because of within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption, the assessment group overall survival network meta-analysis results for the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons. Only one cost-effectiveness study was included in the assessment group review of cost-effectiveness evidence. The study was limited to the all-risk population, undertaken from the perspective of the US healthcare system and included comparators that are not recommended by the National Institute for Health and Care Excellence for patients with untreated advanced renal cell carcinoma. Therefore, the extent to which resource use and results are generalisable to the NHS is unclear. The assessment group cost-effectiveness results from the modified partitioned survival model focused on the intermediate-/poor-risk and favourable-risk subgroups. The assessment group cost-effectiveness results, generated using list prices for all drugs, showed that, for all comparisons in the favourable-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated fewer benefits than all other treatments available to NHS patients. For the intermediate-/poor-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated more benefits than treatment with cabozantinib and nivolumab plus ipilimumab. Conclusions Good-quality clinical effectiveness evidence for the comparison of lenvatinib plus pembrolizumab with sunitinib is available from the CLEAR trial. For most of the assessment group Bayesian hazard ratio network meta-analysis comparisons, it is difficult to reach conclusions due to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. However, the data (clinical effectiveness and cost-effectiveness) used to populate the economic model are relevant to NHS clinical practice and can be used to inform National Institute for Health and Care Excellence decision-making. The assessment group cost-effectiveness results, generated using list prices for all drugs, show that lenvatinib plus pembrolizumab is less cost-effective than all other treatment options. Study registration This study is registered as PROSPERO CRD4202128587. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR134985) and is published in full in Health Technology Assessment; Vol. 28, No. 49. See the NIHR Funding and Awards website for further award information. Plain language summary What was the problem? Renal cell carcinoma is the most common type of kidney cancer. Several drug treatment options are available for NHS patients with advanced or metastatic disease, and the choice of treatment varies depending on a patient’s risk of disease progression. A new drug combination, lenvatinib plus pembrolizumab, may soon become available to treat NHS patients. This review explored whether treatment with lenvatinib plus pembrolizumab offered value for money to the NHS. What did we do? We reviewed the effectiveness of treatment with lenvatinib plus pembrolizumab versus other NHS treatment options. We also estimated the costs and benefits of treatment with lenvatinib plus pembrolizumab versus current NHS treatments for patients with higher and lower risks of disease progression. What did we find? Compared with current NHS treatments, treatment with lenvatinib plus pembrolizumab may increase the time that people with a higher risk of disease progression (i.e. worsening disease) were alive. However, for patients with a lower risk of disease progression, the available evidence is limited and only shows that treatment with lenvatinib plus pembrolizumab may prolong the time that patients have a stable level of disease. For all patients, compared to all current NHS treatments, treatment with lenvatinib plus pembrolizumab is very expensive. What does this mean? Compared with current NHS treatments for untreated renal cell carcinoma, using published prices (which do not include any discounts that are offered to the NHS), treatment with lenvatinib plus pembrolizumab may not provide good value for money to the NHS. Scientific summary Background Renal cell carcinoma (RCC) is the most common type of kidney cancer, comprising approximately 85% of all renal malignancies. Patients with advanced RCC (aRCC) have Stage 3 (locally advanced) or Stage 4 (metastatic) disease. A patient’s risk of disease progression depends on a number of prognostic risk factors. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is used in NHS clinical practice to categorise patients into one of two groups, namely favourable risk or intermediate/poor risk. This systematic review and cost-effectiveness analysis has been conducted to inform the following National Institute for Health and Care Excellence (NICE) multiple technology appraisal: lenvatinib with pembrolizumab for untreated aRCC (ID3760). In November 2021, the Medicines and Healthcare products Regulatory Agency approved the use of lenvatinib plus pembrolizumab as a treatment for all patients with untreated aRCC. Objectives The comparators listed in the final scope issued by NICE differ depending on the risk of disease progression. The objectives of this assessment were to appraise the clinical effectiveness and cost-effectiveness of lenvatinib plus pembrolizumab versus: cabozantinib and nivolumab plus ipilimumab in the intermediate-/poor-risk subgroup sunitinib, pazopanib and tivozanib in the favourable-risk subgroup sunitinib, pazopanib and tivozanib in the all-risk population. Clinical and economic systematic review methods The assessment group (AG) carried out a systematic review of clinical effectiveness evidence following the general principles outlined by the Centre for Reviews and Dissemination (CRD). The review was reported using the criteria recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Searches were conducted between 11 October 2021 and 22 November 2021 in accordance with the general principles recommended by the European Network for Health Technology Assessment. The protocol is registered with PROSPERO (registration number: CRD42021285879). The AG reviewed only randomised controlled trials (RCTs) and full economic analyses identified by the searches. However, the group also considered evidence provided by the manufacturers of lenvatinib (Eisai Ltd) and pembrolizumab (Merck Sharp & Dohme, Whitehouse Station, NJ, USA) provided in submissions to NICE; company submission (CS) reference lists were searched for relevant RCTs. In line with the final scope issued by NICE, the outcomes considered by the AG were overall survival (OS), progression-free survival (PFS), objective tumour response rate, adverse events (AEs), health-related quality of life (HRQoL), incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained. Clinical effectiveness results Direct clinical effectiveness evidence (CLEAR trial) The AG systematic review included one RCT, the CLEAR trial. The CLEAR trial was a good-quality, phase III, multicentre, open-label RCT (with an ongoing extension phase) that provided evidence for the comparison of the efficacy of lenvatinib plus pembrolizumab versus sunitinib. Results for all outcomes were assessed at the third interim analysis (August 2020, median OS follow-up of 26.6 months), that is the final data cut-off for PFS. The companies also presented OS results from an updated OS analysis (March 2021, median OS follow-up of approximately 33 months). At the time of the third interim analysis, the CLEAR trial hazard ratio (HR) results showed statistically significant improvements in PFS and objective tumour response rate for patients treated with lenvatinib plus pembrolizumab versus patients treated with sunitinib for the intermediate-/poor-risk subgroup, the favourable-risk subgroup and the all-risk population. The HR results from the updated OS analysis showed a statistically significant improvement for patients treated with lenvatinib plus pembrolizumab versus patients treated with sunitinib for the intermediate-/poor-risk subgroup and the all-risk population; there were too few events in the favourable-risk subgroup for robust OS conclusions to be drawn. Eisai carried out a treatment-switching analysis to test whether adjusting for the effect of subsequent treatments affected OS results. Results were generated only for the all-risk population and were marked as academic-in-confidence. Nearly all the patients in the CLEAR trial lenvatinib plus pembrolizumab and sunitinib arms experienced at least one all-grade AE, with more Grade ≥ 3 AEs reported in the lenvatinib plus pembrolizumab arm than in the sunitinib arm. The proportion of patients who discontinued treatment of either lenvatinib or pembrolizumab due to AEs was approximately twice as high as patients who discontinued treatment of sunitinib; the proportion of patients who withdrew treatment of both lenvatinib and pembrolizumab due to AEs was approximately the same as the proportion of patients who withdrew treatment with sunitinib. Health-related quality of life was measured using three tools, including the EuroQol-5 Dimensions, three-level version questionnaire. When compared with treatment with sunitinib, treatment with lenvatinib plus pembrolizumab did not result in any clinically meaningful differences (as measured by predefined minimally important differences) in HRQoL measured using any of the three tools. Indirect clinical effectiveness evidence To compare the effectiveness of lenvatinib plus pembrolizumab versus relevant comparators other than sunitinib, the AG carried out Bayesian HR network meta-analyses. It was decided not to undertake a flexible modelling approach for network meta-analysis (NMA), which relaxes the proportional hazards (PH) assumption, such as fractional polynomial network meta-analyses because interpretation of the estimates provided by these complex modelling techniques can be difficult and results are often not intuitive. While deviance information criterion (DIC) statistics provide an approach to compare the fit of different models, they do not provide information about whether a model is a good fit to the data or whether the estimates generated by the model, including projections of results beyond the follow-up times of trials included in the NMA, are clinically plausible. Furthermore, flexible models, which appear similar according to model fit (i.e. according to DIC statistics), may generate very different long-term survival estimates. The AG assessed the feasibility of conducting Bayesian HR NMAs for the three population risk groups (intermediate-/poor-risk subgroup, favourable-risk subgroup and all-risk population) for all outcomes listed in the final scope issued by NICE. However, due to limited data availability, it was not possible to carry out NMAs for all outcomes for all three patient risk groups. Further, as networks were sparse, it was only possible to generate results using fixed-effect NMAs. The AG PFS NMA results for the intermediate-/poor-risk subgroup, the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons because of within-trial PH violations or uncertainty regarding the validity of the PHs assumption. The AG OS NMA results for the intermediate-/poor-risk subgroup suggested that there was a numerical, but not statistically significant, improvement in the OS for patients treated with lenvatinib plus pembrolizumab compared with patients treated with cabozantinib or nivolumab plus ipilimumab. Because of within-trial PH violations or uncertainty regarding the validity of the PH assumption, the AG OS NMA results for the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons. The AG objective tumour response rate NMA results for the intermediate-/poor-risk subgroup suggested that, although treatment with lenvatinib plus pembrolizumab led to a statistically significant improvement in objective tumour response rate compared to treatment nivolumab plus ipilimumab, it did not lead to a statistically significant improvement in objective tumour response rate for the comparison of lenvatinib plus pembrolizumab versus cabozantinib. It was not possible to generate results for the IMDC/MSKCC (Memorial Sloan-Kettering Cancer Center) favourable-risk subgroup due to data limitations. The AG objective tumour response rate NMA results for the all-risk population suggest that treatment with lenvatinib plus pembrolizumab led to a statistically significant improvement in objective tumour response rate versus treatment with sunitinib and versus treatment with pazopanib. The AG Grade ≥ 3 AE NMA results for the intermediate-/poor-risk subgroup suggested that treatment with lenvatinib plus pembrolizumab led to statistically significantly more Grade ≥ 3 AEs versus treatment with cabozantinib. It was not possible to generate results for the IMDC/MSKCC favourable-risk subgroup. The AG Grade ≥ 3 AE NMA results for the all-risk population suggested that treatment with lenvatinib led to statistically significantly more Grade ≥ 3 AEs versus treatment with sunitinib and versus treatment with pazopanib. Economic systematic review results The AG systematic review identified one relevant cost-effectiveness study. This study compared the cost-effectiveness of lenvatinib plus pembrolizumab versus sunitinib (and vs. other treatments). However, the study was undertaken from the perspective of the US healthcare system and generated results only for the all-risk population and included comparators that are not recommended by NICE as treatment options for patients with aRCC. Therefore, the extent to which these results were generalisable to the NHS was unclear. Cost-effectiveness analysis methods The Eisai and Merck Sharp & Dohme CSs to NICE included partitioned survival models built in Microsoft Excel. The AG considered that results from both models could be used to inform decision-making but that, in some instances, the companies could have made more appropriate assumptions and parameter choices. The AG did not develop a de novo economic model; instead, it modified the model provided by Merck Sharp & Dohme [referred to as the Merck Sharp & Dohme/Assessment Group (MSD/AG) model]. Neither of the companies produced cost-effectiveness results for the comparison of lenvatinib plus pembrolizumab versus nivolumab plus ipilimumab (intermediate-/poor-risk subgroup) despite both models having the functionality for this comparison. Furthermore, Eisai did not generate any cost-effectiveness results for the favourable-risk subgroup. The MSD/AG model was populated with OS, PFS and time to treatment discontinuation (TTD) data from the CLEAR trial (lenvatinib plus pembrolizumab versus sunitinib for favourable-risk subgroup and the all-risk population). The AG PFS and OS NMA results were used to estimate effectiveness for the comparison of lenvatinib plus pembrolizumab versus cabozantinib and versus nivolumab plus ipilimumab for the intermediate-/poor-risk population. NICE appraisal committees have concluded that sunitinib and pazopanib are of equivalent effectiveness and that, at best, tivozanib may have a similar effect to sunitinib or pazopanib. These conclusions were based on all-risk population data; the AG has assumed that this assumption holds for the favourable-risk population. The most important changes made by the AG to the Merck Sharp & Dohme model were different choices for estimating PFS, OS and TTD for the intervention and comparator treatments and for modelling two lines, rather than one line, of subsequent treatment. Cost-effectiveness analysis results The AG cost-effectiveness results presented in this report were estimated using list prices. Also, the AG cost-effectiveness results generated using confidential discounted prices were supplied to NICE in a confidential appendix, but cannot be presented here. For the intermediate-/poor-risk subgroup, the AG base-case cost-effectiveness results suggested that treatment with lenvatinib plus pembrolizumab generated more QALYs versus treatment with cabozantinib and versus nivolumab plus ipilimumab, but at a greater overall cost than either of these two treatments. Using list prices, the incremental cost-effectiveness ratios per QALY gained for the comparison of lenvatinib plus pembrolizumab versus cabozantinib and versus nivolumab plus ipilimumab exceed £100,000. For the favourable-risk subgroup, the AG base-case cost-effectiveness results suggested that treatment with sunitinib generated more QALYs than treatment with lenvatinib plus pembrolizumab at a lower overall cost, that is treatment with lenvatinib plus pembrolizumab was dominated by treatment with sunitinib (and, using the assumption of equivalent effectiveness, by pazopanib and tivozanib). The AG carried out extensive one-way sensitivity analyses, scenario analyses and probabilistic sensitivity analyses. Results from these analyses demonstrate that the AG base-case cost-effectiveness results are robust. Clinical and cost-effectiveness conclusions Good-quality clinical effectiveness evidence for the comparison of lenvatinib plus pembrolizumab versus sunitinib was available from the CLEAR trial. For most of the AG Bayesian HR NMA comparisons, it was difficult to reach conclusions due to within-trial PH violations or uncertainty regarding the validity of the PHs assumption. However, the data (clinical effectiveness and cost-effectiveness) used to populate the MSD/AG model are relevant to NHS clinical practice and can be used to inform NICE decision-making. The all-risk population comprises patients with intermediate-/poor-risk and patients with favourable-risk disease. The AG cost-effectiveness analyses have focused on the two subgroups, and the AG cost-effectiveness results, generated using list prices for all drugs, show that lenvatinib plus pembrolizumab is less cost-effective than all other treatment options. Study registration This study is registered as PROSPERO CRD4202128587. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR134985) and is published in full in Health Technology Assessment; Vol. 28, No. 49. See the NIHR Funding and Awards website for further award information.

La méthode des Analogues est une adaptation statistique des prévisions météorologiques à l’échelle synoptique. Son principe peut s’énoncer clairement : à situations météorologiques semblables, les effets seront comparables. Les Services de Prévision des Crues (SPC) Alpes du Nord et Loire-Allier-Cher-Indre disposent, au sein de leur système de prévision, d’outils opérationnels directement issus des travaux de recherche : l’arrivée de cette approche dans la sphère du prévisionniste est la conclusion d’une riche histoire débutée à la fin des années 1960, ponctuées de nombreuses améliorations grâce à l’arrivée des réanalyses météorologiques, la définition de critères de similarité et de performance pertinents dans le contexte de la prévision probabiliste. Le réseau Vigicrues mène un projet visant à étendre la méthode à la France métropolitaine et à mettre en place une suite logicielle unique. Cela nécessite notamment de réduire le nombre de modèles d’analogie par la répartition des mailles SAFRAN en 30 groupes, de déterminer de nouveaux paramétrages optimaux, et d’adapter la suite logicielle AtmoSwing aux pratiques et aux contraintes opérationnelles des SPC. Ces prévisions sont complémentaires à la prévision d’ensemble Arome (PEARO) et leur arrivée ouvre de nouvelles perspectives de développement par le réseau Vigicrues.

BackgroundThe Canadian National Vaccine Safety (CANVAS) network conducted a multi-center, prospective vaccine safety study to collect safety data after dose 1 and 2 of COVID-19 vaccines and follow up safety information 7 months after dose 1.ObjectiveThis study aimed to describe and evaluate the recruitment methods used by CANVAS and the retention of participants by each modality.MethodsCANVAS deployed a multi-pronged recruitment approach to reach a larger sample, without in-person recruitment. Three primary recruitment strategies were used: passive recruitment, technology-assisted electronic invitation through the vaccine booking system (auto-invitation), or auto-registration through the vaccine registries (auto-enrollment).ResultsBetween December 2020 and April 2022, approximately 1.3 million vaccinated adults either self-enrolled or were auto-enrolled in CANVAS, representing about 5% of the vaccinated adult Canadian population. Approximately 1 million participants were auto-enrolled, 300,000 were recruited by auto-invitation, and 5,000 via passive recruitment. Overall survey completion rates for dose 1, dose 2 and the 7-month follow-up surveys were 51.7% (681,198 of 1,318,838), 54.3% (369,552 of 681,198), and 66.4% (452,076 of 681,198), respectively. Completion rates were lower among auto-enrolled participants compared to passively recruited or auto-invited participants who self-enrolled. However, auto-enrolled samples were much larger, which offset the lower completion rates.ConclusionOur data suggest that auto-enrollment provided an opportunity to reach and retain a larger number of individuals in the study compared to other recruitment modalities.

ABSTRACT Detection of HIV infection may be challenging in persons using long-acting cabotegravir (CAB-LA) pre-exposure prophylaxis (PrEP) due to viral suppression and reduced/delayed antibody production. We evaluated two point-of-care tests for detecting HIV infection in persons who received CAB-LA in the HPTN 083 trial. Samples were obtained from 12 participants who received CAB-LA and had delayed detection of HIV infection using HIV rapid tests and an antigen/antibody test (52 plasma samples; 18 dried blood spot [DBS] samples). Plasma samples were tested with the Xpert HIV-1 Viral Load XC test (Xpert VL-XC); DBS samples were tested with the total nucleic acid Xpert HIV-1 Qual XC test (Xpert Qual-XC). Results from these assays were compared to results from three reference, laboratory-based, plasma RNA assays (Aptima HIV-1 Qualitative assay [Aptima Qual]; Aptima HIV-1 Quant DX Assay [Aptima Quant]; cobas HIV-1/HIV-2 Qualitative Test [cobas]). HIV RNA was detected with all four plasma assays for all samples with viral loads (VLs) ≥ 200 copies/mL; the number of samples with VLs < 200 copies/mL with HIV RNA detected was: Xpert VL-XC: 19/26 (73.1%); Aptima Qual: 17/26 (65.4%); Aptima Quant: 17/26 (65.4%); and cobas: 12/21 (57.1%). The Xpert Qual-XC assay was positive for all DBS samples with VLs ≥ 200 copies/mL and 1/10 DBS with VLs < 200 copies/mL. The performance of the Xpert VL-XC assay was comparable to the reference assays for detecting HIV infection in these cases. The Xpert Qual-XC assay was less sensitive than plasma-based HIV RNA assays for detecting HIV in the setting of CAB-LA PrEP.IMPORTANCEHIV RNA assays can detect HIV infections earlier than HIV rapid tests or Ag/Ab tests in persons using CAB-LA PrEP. Earlier HIV diagnosis could allow for earlier treatment initiation and reduced risk of INSTI resistance. POC tests may help detect HIV infection before CAB-LA administration and may be more accessible than laboratory-based assays in some settings. In this study, the POC Xpert VL-XC assay detected HIV RNA in most samples from individuals who received CAB-LA PrEP and had delayed detection of HIV infection with HIV rapid tests and an Ag/Ab test. The performance of this assay was similar to laboratory-based HIV RNA assays in this cohort. The POC Xpert Qual-XC assay detects both HIV RNA and DNA, with a higher viral load cutoff for RNA detection. This assay was negative for most lower viral load samples and did not offer an advantage for HIV screening in persons using CAB-LA PrEP.

Congenital umbilical cord hernia is often misdiagnosed and easily confused with a small omphalocele. It is different from postnatally diagnosed umbilical hernias and is believed to arise from persistent physiological mid-gut herniation. Its incidence is estimated to be 1 in 5,000, although some articles reported the incidence rate of approximately 0.2%. It is very important to clearly diagnose these cases in the antenatal period so that the patients receive appropriate management postnatally and to decrease the stress in the parents as well. Umbilical cord hernias have not been associated with other chromosomal anomalies.

Our proposal for this special issue was inspired by the breadth of commemorations we were witnessing in the lead-up to September 11th, 2023, the 50th anniversary of the military coup that has cast a shadow over Chileans until today. Seeking to avoid repeating the question of where, how, and between whom European-Latin American solidarity takes and has taken place from its inception, we intended this special issue to go beyond the question of chronological memory and historiography to rethink the cyclical and reiterative nature of these solidarities rooted in the Cold War. From the unique vantage point of living with the third generation of Chile’s exile diaspora, we wanted to revisit the current-day vernaculars and practices of European-Latin American relations through concepts of translocal and transgenerational solidarity. Similarly, at a time when older categories of internationalism and anti-imperialism have taken on entirely new meanings for protest movements and social justice activism, adapted definitions of the vocabulary surrounding human rights, solidarity, and democracy play an increasingly central role in activism narratives and need to be more thoroughly scrutinised.

This article looks at the process of historical reinterpretation and anti-imperialist struggle around the Nicaragua mural in (former East) Berlin to demonstrate how internationalist solidarity does not unfold singularly but in a multi-layered, often contradictory manner. Since 2018, this mural has turned from an inconspicuous site into a place of contestation. On the one hand, for residents, the mural has transformed into a projection of rescuing and reinstating memory of the former GDR’s efforts of internationalist friendship and solidarity. On the other hand, it has become a site for political struggle for Nicaraguan exiles living in the area. Based on 14 months of ethnographic fieldwork and archival research in Nicaragua and Germany in 2018–2019 and 2023, this article complicates how memory practices shape everyday lives in Berlin for German and Nicaraguan residents alike. Their divergent interpretations of the mural’s meaning sheds light on the tensions of memory politics vis à vis political and historical reinterpretation and demonstrate the potential for the Nicaragua mural to place a magnifying glass over the anti-imperial politics of Berlin.

Across two studies we investigated the impact of instructor enthusiasm on student attentional engagement during an online undergraduate lecture, as well as their memory for lecture content and their motivation to watch additional lecture videos on the same topic (Study 2 only). In both studies participants were randomly assigned to watch a 22-min lecture, delivered with either high or low vocal enthusiasm by the instructor. Subjective ratings of instructor enthusiasm/energy confirmed that in both studies the manipulation of instructor enthusiasm was effective. More importantly, in both studies we found that students in the high enthusiasm condition were consistently more engaged over the course of the lecture compared to those in the low enthusiasm condition, and that overall, reports of engagement increased together with ratings of instructor enthusiasm. However, we found no evidence that instructor enthusiasm influenced quiz performance in either study. Nevertheless, Study 2 showed that those in the high enthusiasm condition were more motivated to watch the next lecture than those in the low enthusiasm condition. These findings make an important contribution to the study of online learning and indicate that instructor enthusiasm may be a viable strategy to increase student engagement and motivation in online courses.

Abstract Hybridization can provide evolutionary benefits (e.g., population resilience to climate change) through the introduction of adaptive alleles and increase of genetic diversity. Nevertheless, management strategies may be designed based only on the parental species within a hybrid zone, without considering the hybrids. This can lead to ineffective spatial management of species, which can directly harm population diversity and negatively impact food webs. Three species of rockfish (Brown Rockfish (Sebastes caurinus), Copper Rockfish (S. auriculatus), and Quillback Rockfish (S. maliger)) are known to hybridize within Puget Sound, Washington, but genetic data from these species are used to infer population structure in the entire genus, including in species that do not hybridize. The goal of this project was to estimate the hybridization rates within the region and determine the effect of hybridization on geographic patterns of genetic structure. We sequenced 290 Brown, Copper, and Quillback rockfish using restriction‐site associated DNA sequencing (RADseq) from four regions within and outside Puget Sound, Washington. We show that (i) hybridization within Puget Sound was asymmetrical, not recent, widespread among individuals, and relatively low level within the genome, (ii) hybridization affected population structure in Copper and Brown rockfish, but not in Quillback Rockfish and (iii) after taking hybridization into account we found limited directional dispersal in Brown and Copper rockfish, and evidence for two isolated populations in Quillback Rockfish. Our results suggest that rockfish population structure is species‐specific, dependent on the extent of hybridization, and cannot be inferred from one species to another despite similar life history.

Depuis 2014, le réseau Vigicrues a mis en place des outils et des méthodes pour estimer et expertiser l’incertitude associée à la prévision des crues. Les incertitudes liées à la modélisation hydrologique sont estimées par le logiciel OTAMIN, qui analyse statistiquement les écarts entre les observations et les débits simulés par les modèles à l’issue de leur calage. Un logiciel permettant l’expertise de scénarios hydrologiques avec incertitudes, l’EAO, a également été développé. Ces outils ont rendu possible la diffusion de prévisions expertisées assorties d’un intervalle d’incertitude (10–90%) dès 2017. Le projet stratégique du réseau Vigicrues prévoit de renforcer le service rendu sur les secteurs à fort enjeu. L’objectif est de publier des prévisions quantitatives assorties d’incertitudes à 24 heures d’échéance et avec un pas de temps suffisamment fin pour représenter la dynamique de la crue, y compris sur des cours d’eau à réaction rapide. Pour réaliser cet objectif, des évolutions sont nécessaires sur les outils et les pratiques opérationnelles, notamment par la construction de chaines de prévision forcées par des modèles d’ensemble météorologiques, l’amélioration de la quantification des autres sources d’incertitude et une réflexion sur le rôle du prévisionniste et la communication des incertitudes.

Abstract Kelvin probe force microscopy (KPFM) is a well‐established scanning probe technique, used to measure surface potential accurately; it has found extensive use in the study of a range of materials phenomena. In its conventional form, KPFM frustratingly precludes imaging samples or scenarios where large surface potential or surface potential gradients exist outside the typical ±10 V window. If the potential regime measurable via KPFM can be expanded, to enable precise and reliable metrology, through a high voltage KPFM (HV‐KPFM) adaptation, it can open up pathways toward a range of novel experiments, where the detection limit of regular KPFM has so far prevented the use of the technique. In this work, HV‐KPFM is realized and shown to be capable of measuring large surface potential and potential gradients with accuracy and precision. The technique is employed to study a range of materials (positive temperature coefficient of resistivity ceramics, charge storage fluoropolymers, and pyroelectrics) where accurate, spatially resolved mapping of surface potential within high voltage regime facilitates novel physical insight. The results demonstrate that HV‐KPFM can be used as an effective tool to fill in existing gaps in surface potential measurements while also opening routes for novel studies in materials physics.

Access to digital technology in the 21st century has led to the emergence of media multitasking (MMT), which involves attempting to engage with multiple streams of media at the same time. This behaviour, which is frequently considered to be a form of inattention, has become increasingly prevalent in educational settings, such as undergraduate lectures. The aim of the present study was to examine volitional media-multitasking (MMT) during an asynchronous online lecture by giving participants the opportunity to engage with a secondary, non-required media stream (i.e., the game of snake). Participants (n = 222) were randomly assigned to either an Active condition, in which they could play the snake game using the arrow keys; or a Passive condition, in which they could watch the snake game, but could not play it. In both conditions, participants could toggle the snake game on and off, using a keypress. MMT was indexed behaviourally by measuring the percentage of time participants had the secondary stream toggled on (i.e., snake time percentage), a method pioneered by Ralph et al. (2020), and subjectively by asking participants to what extent they engaged with other media while the lecture was playing. Following the lecture, participants completed a multiple-choice quiz and self-reported their level of MMT. Our behavioural measure (i.e., snake time percentage) indicated that participants spent significantly more time MMT in the Active condition than the Passive condition. However, there were no significant differences in self-reported MMT or quiz performance across conditions. Furthermore, correlations between both measures of MMT and quiz performance were non-significant. Thus, the present study found no performance decrement as a result of, or in association with, increased volitional MMT.

Les prévisions quantitatives réalisées par les services de prévision des crues (SPC) sont un outil de communication majeur pour le réseau Vigicrues. Sur la Loire, les prévisions sont quotidiennes et elles sont archivées depuis 2017 constituant une base de données suffisante pour analyser la fiabilité et la précision de ces données selon trois angles. L’analyse en fonction de la date de production confirme l’amélioration continue de la fiabilité de ces prévisions. La comparaison aux prévisions brutes issues de la modélisation souligne quant à elle l’apport positif de l’expertise des prévisionnistes. Enfin, l’analyse des prévisions réalisées pendant les crues ne montre pas de dégradation des résultats confirmant ainsi la pertinence des outils développés et des formations élaborées pour les prévisionnistes visant à leur fournir la meilleure information possible. Cependant, dans la partie estuarienne, des difficultés sont rencontrées pour réaliser des prévisions mettant en évidence la limite des outils et la nécessité d’en développer des nouveaux.

Non-communicable diseases (NCDs) pose a global health challenge, leading to substantial morbidity, mortality, and economic strain. Our review underscores the escalating incidence of NCDs worldwide and highlights the potential of regenerative agriculture (RA) products in mitigating these diseases. We also explore the efficacy of dietary interventions in NCD management and prevention, emphasizing the superiority of plant-based diets over those high in processed foods and red meat. Examining the role of the gut microbiome in various diseases, including liver disorders, allergies, metabolic syndrome, inflammatory bowel disease, and colon cancer, we find compelling evidence implicating its influence on disease development. Notably, dietary modifications can positively affect the gut microbiome, fostering a symbiotic relationship with the host and making this a critical strategy in disease prevention and treatment. Investigating agricultural practices, we identify parallels between soil/plant and human microbiome studies, suggesting a crucial link between soil health, plant- and animal-derived food quality, and human well-being. Conventional/Industrial agriculture (IA) practices, characterized in part by use of chemical inputs, have adverse effects on soil microbiome diversity, food quality, and ecosystems. In contrast, RA prioritizes soil health through natural processes, and includes avoiding synthetic inputs, crop rotation, and integrating livestock. Emerging evidence suggests that food from RA systems surpasses IA-produced food in quality and nutritional value. Recognizing the interconnection between human, plant, and soil microbiomes, promoting RA-produced foods emerges as a strategy to improve human health and environmental sustainability. By mitigating climate change impacts through carbon sequestration and water cycling, RA offers dual benefits for human and planetary health and well-being. Emphasizing the pivotal role of diet and agricultural practices in combating NCDs and addressing environmental concerns, the adoption of regional RA systems becomes imperative. Increasing RA integration into local food systems can enhance food quality, availability, and affordability while safeguarding human health and the planet's future.

For a UK based university faculty that delivers a bespoke Work Based suite of under and postgraduate programmes to a major South African client, the Equality, Diversity and Inclusion (EDI) agenda is important (Wall, 2013, 2017; Ferrández-Berrueco, Kekale, and Devins, 2016). Pre pandemic, EDI was about access to professionally relevant education that resulted in having an internationally recognised qualification where it previously had not existed, and a possible route to promotion. Early into the COVID pandemic, EDI became about continuity and contingency of the whole suite of programmes (Adnan and Anwar, 2020; Rapanata et al, 2020) when suddenly access to computer equipment and Wifi were impacted on by the global message 'STAY AT HOME'. The students were not in the workplace to access their work IT kit nor the online or resources part of their education and the lecturers could neither travel to South Africa or within it. This article discusses how the Programme Teams reached out to the continuing students to ascertain the significance and implications of their personal IT challenges.

Monkeypox 2022 exhibits unprecedented human-to-human transmission and presents with different clinical features than those observed in prior outbreaks. Previously endemic only to West and Central Africa, the monkeypox virus spread rapidly world-wide following confirmation of a case in the United Kingdom on May 7, 2022 of an individual that had traveled to Nigeria. Detection of cases with no travel history confirms on-going community spread. Emergency Medical Services (EMS) professionals will likely encounter patients suspected or confirmed to have monkeypox, previously a rare disease and therefore unfamiliar to most clinicians. Consequently, it is critical for EMS medical directors to immediately implement policies and procedures for EMS teams - including emergency medical dispatchers - to identify potential monkeypox cases. These must include direction on actions EMS professionals should take to protect themselves and others from virus transmission. Monkeypox 2022 may manifest more subtly than it has historically. Presentations include a subclinical prodrome and less dramatic skin lesions - potentially limited to genital or anal body regions - which can be easily confused with dermatologic manifestations of common sexually transmitted infections (STIs). While most readily spread by close contact with infectious skin lesions on a patient, it is also transmissible from fomites, such as bed sheets. Additionally, droplet transmission can occur, and the virus can be spread by aerosolization under certain conditions. The long incubation period could have profound negative consequences on EMS staffing if clinicians are exposed to monkeypox. This report summarizes crucial information needed for EMS professionals to understand and manage the monkeypox 2022 outbreak. It presents an innovative Identify-Isolate-Inform (3I) Tool for use by EMS policymakers, educators, and clinicians on the frontlines who may encounter monkeypox patients. Patients are identified as potentially exposed or infected after an initial assessment of risk factors with associated signs and symptoms. Prehospital workers must immediately don personal protective equipment (PPE) and isolate infectious patients. Also, EMS professionals must report exposures to their agency infection control officer and alert health authorities for non-transported patients. Prehospital professionals play a crucial role in emerging and re-emerging infectious disease mitigation. The monkeypox 2022 3I Tool includes knowledge essential for all clinicians, plus specific information to guide critical actions in the prehospital environment.

Loss-of-function mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome in males. Christianson syndrome involves endosome dysfunction leading to early cerebellar degeneration, as well as later-onset cortical and subcortical neurodegeneration, potentially including tau deposition as reported in post-mortem studies. In addition, there is reported evidence of modulation of amyloid-β levels in experimental models wherein NHE6 expression was targeted. We have recently shown that loss of NHE6 causes defects in endosome maturation and trafficking underlying lysosome deficiency in primary mouse neurons in vitro. For in vivo studies, rat models may have an advantage over mouse models for the study of neurodegeneration, as rat brain can demonstrate robust deposition of endogenously-expressed amyloid-β and tau in certain pathological states. Mouse models generally do not show the accumulation of insoluble, endogenously-expressed (non-transgenic) tau or amyloid-β. Therefore, to study neurodegeneration in Christianson syndrome and the possibility of amyloid-β and tau pathology, we generated an NHE6-null rat model of Christianson syndrome using CRISPR-Cas9 genome-editing. Here, we present the sequence of pathogenic events in neurodegenerating NHE6-null male rat brains across the lifespan. NHE6-null rats demonstrated an early and rapid loss of Purkinje cells in the cerebellum, as well as a more protracted neurodegenerative course in the cerebrum. In both the cerebellum and cerebrum, lysosome deficiency is an early pathogenic event, preceding autophagic dysfunction. Microglial and astrocyte activation also occur early. In the hippocampus and cortex, lysosome defects precede loss of pyramidal cells. Importantly, we subsequently observed biochemical and in situ evidence of both amyloid-β and tau aggregation in the aged NHE6-null hippocampus and cortex (but not in the cerebellum). Tau deposition is widely distributed, including cortical and subcortical distributions. Interestingly, we observed tau deposition in both neurons and glia, as has been reported in Christianson syndrome post-mortem studies previously. In summary, this experimental model is among very few examples of a genetically modified animal that exhibits neurodegeneration with deposition of endogenously-expressed amyloid-β and tau. This NHE6-null rat will serve as a new robust model for Christianson syndrome. Furthermore, these studies provide evidence for linkages between endolysosome dysfunction and neurodegeneration involving protein aggregations, including amyloid-β and tau. Therefore these studies may provide insight into mechanisms of more common neurodegenerative disorders, including Alzheimer's disease and related dementias.

Abstract Among 467 children under five hospitalized with community-acquired pneumonia, the prevalence of Haemophilus influenzae or Haemophilus haemolyticus was 60.8%, all cases were non-typable H. influenzae (NTHi) or H. haemolyticus. NTHi/H. haemolyticus PCR detection was associated with about twice the risk for severe disease. The results highlight the need for increased awareness and research efforts to investigate the role of NTHi/H. haemolyticus in severe CAP among children.

Abstract Household surveys give a precise estimate of poverty; however, surveys are costly and are fielded infrequently. We demonstrate the importance of jointly using multiple public and private sector data sources to estimate levels and changes in wealth for a large set of countries. We train models using 63,854 survey cluster locations across 59 countries, relying on data from satellites, Facebook Marketing information, and OpenStreetMaps. The model generalizes previous approaches to a wide set of countries. On average, across countries, the model explains 55% (min = 14%; max = 85%) of the variation in levels of wealth at the survey cluster level and 59% (min = 0%; max = 93%) of the variation at the district level, and the model explains 4% (min = 0%; max = 17%) and 6% (min = 0%; max = 26%) of the variation of changes in wealth at the cluster and district levels. Models perform best in lower-income countries and in countries with higher variance in wealth. Features from nighttime lights, OpenStreetMaps, and land cover data are most important in explaining levels of wealth, and features from nighttime lights are most important in explaining changes in wealth.

Abstract To quantify transplacental transmission of SARS-CoV-2 virus and antibody transfer in pregnant women and their newborns according to the gestational age at maternal infection. A prospective observational multicenter study including pregnant women with a positive RT-PCR or a positive serology for SARS-CoV-2 and compatible symptoms, from April to December 2020, in 11 French maternities. The study was designed to obtain a systematic collection of mother-infant dyad’s samples at birth. SARS-CoV-2 viral load was measured by RT-PCR. IgG and IgM antibodies against the SARS-CoV-2 spike protein were measured by enzyme-linked immunosorbent assay. Antibody concentrations and transplacental transfer ratios were analyzed according to the gestational age at maternal infection. The primary outcome was the rate of SARS CoV-2 materno-fetal transmission at birth. The secondary outcome was the quantification of materno-fetal antibody transfer. Maternal and neonatal outcomes at birth were additionally assessed. Among 165 dyads enrolled, one congenital infection was confirmed {n = 1 (0.63%) IC95% [0.02%; 3.48%]}. The average placental IgG antibody transfer ratio was 1.27 (IC 95% [0.69–2.89]). The transfer ratio increased with increasing time between the onset of maternal infection and delivery (P Value = 0.0001). Maternal and neonatal outcomes were reassuring. We confirmed the very low rate of SARS-CoV-2 transplacental transmission (

Anthrax is a zoonotic infectious disease caused by Bacillus anthracis. According to current knowledge, the disease originates in sub-Saharan Africa, especially Egypt and Mesopotamia. Laboratory tests involving direct staining or culture of samples taken from malignant pustules, sputum, blood, or patient discharge must be performed to establish a diagnosis. B. anthracis infection can enter the body through the skin, mouth, or nose. Human infection is usually caused by contact with infected animals or animal products. Anthrax causes a reduction in resource efficiency and decreases livestock productivity. B. anthracis spores are resistant to extreme temperatures, pressure, pH, drying, solvents, and ultraviolet light. The biological weapon of this disease may be fatal if it is designed to spread B. anthracis spores by aerosols. In the past, the treatment of human anthrax with penicillin at a high dose was the preferred method. The public can take several measures to prevent anthrax infection, such as purchasing and consuming meat that has been legally certified to have been slaughtered in a slaughterhouse, consuming healthy and properly cooked animal meat, and washing hands with antiseptic soap after handling, processing, and cooking animal products. This review aimed to describe the etiology, pathogenesis, mechanism of infection, epidemiology, diagnosis, clinical symptoms, transmission, risk factors, public health importance, economic impact, potential as a bio-warfare agent, treatment, and control of anthrax.