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The consumption of sausage worldwide increases every year; because of this increase, artisanal products have appeared and are intended to be perceived as natural and healthy. Obesity and cardiovascular diseases associated with consuming meat and meat derivatives have been estimated to be the leading cause of death in several countries. This study aimed to evaluate the nutritional quality, lipid content, and presence of saturated and unsaturated fatty acids, contributing to demonstrating the real nutritional value of artisanal sausages produced in Ecuador. Sausages from 10 factories in Ambato, Pelileo, and Píllaro, located in Tungurahua, Ecuador, were evaluated. The pH and acidity, color, proximal, sensory, microbiological, and lipid content were assessed. The pH and acidity showed a slight variation in all of the samples. Proximal analysis (moisture, protein, fat, and ash) established that the artisan sausages did not differ from the type of sausages reported in the literature. Microbiological analyses showed a good microbial quality, and there was no presence of Staphylococcus aureus , Enterobacteria , molds, or yeasts. The sensory attributes were similar for all of the sausages; the panelists did not notice any strange taste or odor. The lipid content showed that the artisanal sausages contained the highest percentage of palmitic, stearic, elaidic, and linolelaidic fatty acids. Unsaturated fatty acids were the most prevalent in all of the sausages collected from different locations. The results showed that the nutritional, microbiological, and sensory quality of the artisanal sausages did not show any parameter that would allow them to be classified as different or as having a better nutritional value.

The goal of tracing, testing, and quarantining contacts of infected individuals is to contain the spread of infectious diseases, a strategy widely used during the COVID-19 pandemic. However, limited research exists on the effectiveness of contact tracing, especially with regard to key performance indicators (KPIs), such as the proportion of cases arising from previously identified contacts. In our study, we analyzed contact tracing data from Belgium collected between September 2020 and December 2021 to assess the impact of contact tracing on SARS-CoV-2 transmission and understand its characteristics. Among confirmed cases involved in contact tracing in the Flemish and Brussels-Capital regions, 19.1% were previously identified as close contacts and were aware of prior exposure. These cases, referred to as 'known' to contact tracing operators, reported on average fewer close contacts compared to newly identified individuals (0.80 versus 1.05), resulting in fewer secondary cases (0.23 versus 0.28). Additionally, we calculated the secondary attack rate, representing infections per contact, which was on average lower for the 'known' cases (0.22 versus 0.25) between December 2020 and August 2021. These findings indicate the effectiveness of contact tracing in Belgium in reducing SARS-CoV-2 transmission. Although we were unable to quantify the exact number of prevented cases, our findings emphasize the importance of contact tracing as a public health measure. In addition, contact tracing data provide indications of potential shifts in transmission patterns among different age groups associated with emerging variants of concern and increasing vaccination rates., Competing Interests: Naima Hammami is an employee of the the Flemish Government’s Department of Care and Jorden Boone has been working as a consultant for this agency during the COVID-19 pandemic. Niel Hens declares that the Universities of Antwerp and Hasselt have received funding for advisory boards and research projects of MSD, GSK, JnJ, Pfizer outside the proposed work. Niel Hens has not received any personal remuneration related to this work. The other authors declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Kremer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We report the sequences of four complete genomes of parvovirus B19, extracted from human amniotic fluid specimens collected from pregnant women with abnormal ultrasound features in France. The genome sequences are 5,596 nucleotides long and include long terminal repeats. Several amino acid substitutions were observed in nonstructural protein (NS1)., Competing Interests: The authors declare no conflict of interest.

Numerous biomedical applications have been described for liver-humanized mouse models, such as in drug metabolism or drug-drug interaction (DDI) studies. However, the strong enlargement of the bile acid (BA) pool due to lack of recognition of murine intestine-derived fibroblast growth factor-15 by human hepatocytes and a resulting upregulation in the rate-controlling enzyme for BA synthesis, cytochrome P450 (CYP) 7A1, may pose a challenge in interpreting the results obtained from such mice. To address this challenge, the human fibroblast growth factor-19 (FGF19) gene was inserted into the Fah -/- , Rag2 -/- , Il2rg -/- NOD (FRGN) mouse model, allowing repopulation with human hepatocytes capable of responding to FGF19. While a decrease in CYP7A1 expression in human hepatocytes from humanized FRGN19 mice (huFRGN19) and a concomitant reduction in BA production was previously shown, a detailed analysis of the BA pool in these animals has not been elucidated. Furthermore, there are sparse data on the use of this model to assess potential clinical DDI. In the present work, the change in BA composition in huFRGN19 compared with huFRGN control animals was systematically evaluated, and the ability of the model to recapitulate a clinically described CYP3A4-mediated DDI was assessed. In addition to a massive reduction in the total amount of BA, FGF19 expression in huFRGN19 mice resulted in significant changes in the profile of various primary, secondary, and sulfated BAs in serum and feces. Moreover, as observed clinically, administration of the pregnane X receptor agonist rifampicin reduced the oral exposure of the CYP3A4 substrate triazolam. SIGNIFICANCE STATEMENT: Transgenic expression of FGF19 normalizes the unphysiologically high level of bile acids in a chimeric liver-humanized mouse model and leads to massive changes in bile acid composition. These adaptations could overcome one of the potential impediments in the use of these mouse models for drug-drug interaction studies., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Problem : High-quality communication improves patient satisfaction and clinical outcomes, yet formal communication training in residency is often minimal. Many studies on empathic communication show mixed results and are often hindered and skewed by brief study lengths, insufficiently and ambiguously defined concepts, and limited methods for objective measurements. Intervention : The FAN Curriculum is a unique communication curriculum, based on the conceptual frameworks of patient-centered communication, reflective practice, mindfulness, and attunement using the Facilitating Attuned Interactions (FAN) model. The first part of the FAN Curriculum was delivered as a 3-hour interactive workshop involving didactics, group discussion, and role play with pediatric residents. Residents then completed weekly self-reflections, a follow-up one-hour training to reinforce concepts, and five monthly mentor sessions, all emphasizing reflective practice. Context : This longitudinal, mixed-methods study examined the effects of the FAN Curriculum on residents' empathy levels and ability to communicate with parents in the clinical setting. The study was conducted at two urban, academic, medium-sized pediatric residency programs in Chicago between October 2016 and November 2017. First- and second-year pediatric residents whose continuity clinic site was located at their home institution participated. Residents received training in the use of the FAN Communication Tool using a delayed-start crossover study design. Impact : At five time points, residents and parents completed instruments validated for measuring physician empathy and mindfulness. Post-study interviews were conducted for one institution's residents and mentors and were evaluated using open and focused coding. Participants (n = 23) demonstrated a high degree of use of the FAN Communication Tool six months post-training and a significant rise in self-reported comfort with four of five FAN core processes. One parent-completed survey (Consultation and Relational Empathy, CARE) showed a statistically significant rise of 3.26% in resident relational empathy and collaboration after training (p = 0.02). In qualitative analysis of interviews, residents and mentors found the FAN Communication Tool beneficial, making clinic visits more efficient and collaborative. Both groups noted improvement in the residents' relationship-building skills; residents were able to use enhanced communication skills to better approach challenging encounters and work through parent concerns. Lessons Learned : Family-centered communication training can improve physician-perceived empathy and mindfulness. Effective communication for pediatric residents incorporates an empathic approach, and introduction to this formal curriculum supported their growth in connecting and engaging with children and parents. The FAN Curriculum may provide a useful method for improving resident communication skills with a positive impact on pediatricians' collaboration with patients and families.

Background: West Nile virus (WNV) and Usutu virus (USUV) are emerging arthropod-borne viruses (arboviruses) in Europe transmitted by Culex mosquitoes. In Belgium, it is currently unknown which Culex species are competent vectors for WNV or USUV and if these mosquitoes carry Wolbachia, an endosymbiotic bacterium that can block arbovirus transmission. The aims of our study were to measure the vector competence of Belgian Culex mosquitoes to WNV and USUV and determine if a naturally acquired Wolbachia infection can influence virus transmission., Methodology/principal Findings: Female Culex mosquitoes were captured from urban and peri-urban sites in Leuven, Belgium and offered an infectious bloodmeal containing WNV lineage 2, USUV European (EU) lineage 3, or USUV African (AF) lineage 3. Blood-fed females were incubated for 14 days at 25°C after which the body, head, and saliva were collected to measure infection, dissemination, and transmission rates as well as transmission efficiency. Mosquito species were identified by qRT-PCR or Sanger sequencing, the presence of infectious virus in mosquitoes was confirmed by plaque assays, and viral genome copies were quantified by qRT-PCR. Culex pipiens pipiens were able to transmit WNV (4.3% transmission efficiency, n = 2/47) but not USUV (EU lineage: n = 0/56; AF lineage: n = 0/37). In contrast, Culex modestus were able to transmit USUV (AF lineage: 20% transmission efficiency, n = 1/5) but not WNV (n = 0/6). We found that the presence or absence of Wolbachia was species-dependent and did not associate with virus transmission., Conclusions/significance: This is the first report that Belgian Culex mosquitoes can transmit both WNV and USUV, forewarning the risk of human transmission. More research is needed to understand the potential influence of Wolbachia on arbovirus transmission in Culex modestus mosquitoes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Soto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Detection dogs were trained to detect SARS-CoV-2 infection based on armpit sweat odor. Sweat samples were collected using cotton pads under the armpits of negative and positive human patients, confirmed by qPCR, for periods of 15-30 min. Multiple hospitals and organizations throughout Belgium participated in this study. The sweat samples were stored at -20°C prior to being used for training purposes. Six dogs were trained under controlled atmosphere conditions for 2-3 months. After training, a 7-day validation period was conducted to assess the dogs' performances. The detection dogs exhibited an overall sensitivity of 81%, specificity of 98%, and an accuracy of 95%. After validation, training continued for 3 months, during which the dogs' performances remained the same. Gas chromatography/mass spectrometry (GC/MS) analysis revealed a unique sweat scent associated with SARS-CoV-2 positive sweat samples. This scent consisted of a wide variety of volatiles, including breakdown compounds of antiviral fatty acids, skin proteins and neurotransmitters/hormones. An acceptability survey conducted in Belgium demonstrated an overall high acceptability and enthusiasm toward the use of detection dogs for SARS-CoV-2 detection. Compared to qPCR and previous canine studies, the detection dogs have good performances in detecting SARS-CoV-2 infection in humans, using frozen sweat samples from the armpits. As a result, they can be used as an accurate pre-screening tool in various field settings alongside the PCR test., Competing Interests: CC is the founder of DrArmpit BV. AA and AM are founders of Arome Science Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer A-LC is currently co-organizing a Research Topic with one of the authors DG., (Copyright © 2023 Callewaert, Pezavant, Vandaele, Meeus, Vankrunkelsven, Van Goethem, Plumacker, Misset, Darcis, Piret, De Vleeschouwer, Staelens, Van Varenbergh, Tombeur, Ottevaere, Montag, Vandecandelaere, Jonckheere, Vandekerckhove, Tobback, Wieers, Marot, Anseeuw, D’Hoore, Tuyls, De Tavernier, Catteeuw, Lotfi, Melnik, Aksenov, Grandjean, Stevens, Gasthuys and Guyot.)

Marine macroalgae (seaweeds) are important primary producers and foundation species in coastal ecosystems around the world. Seaweeds currently contribute to an estimated 51% of the global mariculture production, with a long-term growth rate of 6% per year, and an estimated market value of more than US$11.3 billion. Viral infections could have a substantial impact on the ecology and aquaculture of seaweeds, but surprisingly little is known about virus diversity in macroalgal hosts. Using metagenomic sequencing, we characterized viral communities associated with healthy and bleached specimens of the commercially important green seaweed Ulva . We identified 20 putative new and divergent viruses, of which the majority belonged to the Circular Rep-Encoding Single-Stranded (CRESS) DNA viruses [single-stranded (ss)DNA genomes], Durnavirales [double-stranded (ds)RNA], and Picornavirales (ssRNA). Other newly identified RNA viruses were related to the Ghabrivirales , the Mitoviridae , and the Tombusviridae . Bleached Ulva samples contained particularly high viral read numbers. While reads matching assembled CRESS DNA viruses and picorna-like viruses were nearly absent from the healthy Ulva samples (confirmed by qPCR), they were very abundant in the bleached specimens. Therefore, bleaching in Ulva could be caused by one or a combination of the identified viruses but may also be the result of another causative agent or abiotic stress, with the viruses simply proliferating in already unhealthy seaweed tissue. This study highlights how little we know about the diversity and ecology of seaweed viruses, especially in relation to the health and diseases of the algal host, and emphasizes the need to better characterize the algal virosphere. IMPORTANCE Green seaweeds of the genus Ulva are considered a model system to study microbial interactions with the algal host. Remarkably little is known, however, about viral communities associated with green seaweeds, especially in relation to the health of the host. In this study, we characterized the viral communities associated with healthy and bleached Ulva . Our findings revealed the presence of 20 putative novel viruses associated with Ulva , encompassing both DNA and RNA viruses. The majority of these viruses were found to be especially abundant in bleached Ulva specimens. This is the first step toward understanding the role of viruses in the ecology and aquaculture of this green seaweed.

Background: Burden of disease estimates have become important population health metrics over the past decade to measure losses in health. In Belgium, the disease burden caused by COVID-19 has not yet been estimated, although COVID-19 has emerged as one of the most important diseases. Therefore, the current study aims to estimate the direct COVID-19 burden in Belgium, observed despite policy interventions, during 2020 and 2021, and compare it to the burden from other causes., Methods: Disability-adjusted life years (DALYs) are the sum of Years Lived with Disability (YLDs) and Years of Life Lost (YLLs) due to disease. DALYs allow comparing the burden of disease between countries, diseases, and over time. We used the European Burden of Disease Network consensus disease model for COVID-19 to estimate DALYs related to COVID-19. Estimates of person-years for (a) acute non-fatal disease states were calculated from a compartmental model, using Belgian seroprevalence, social contact, hospital, and intensive care admission data, (b) deaths were sourced from the national COVID-19 mortality surveillance, and (c) chronic post-acute disease states were derived from a Belgian cohort study., Results: In 2020, the total number of COVID-19 related DALYs was estimated at 253,577 [252,541 - 254,739], which is higher than in 2021, when it was 139,281 [136,704 - 142,306]. The observed COVID-19 burden was largely borne by the elderly, and over 90% of the burden was attributable to premature mortality (i.e., YLLs). In younger people, morbidity (i.e., YLD) contributed relatively more to the DALYs, especially in 2021, when vaccination was rolled out. Morbidity was mainly attributable to long-lasting post-acute symptoms., Conclusion: COVID-19 had a substantial impact on population health in Belgium, especially in 2020, when COVID-19 would have been the main cause of disease burden if all other causes had maintained their 2019 level., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The release of vast quantities of sulfide from the sediment into the water column, known as a sulfidic event, has detrimental consequences on fish catches, including downstream effects on other linked element cycles. Despite being frequent occurrences in marine upwelling regions, our understanding of the factors that moderate sulfidic event formation and termination are still rudimentary. Here, we examined the biogeochemical and hydrodynamic conditions that underpinned the formation/termination of one of the largest sulfur plumes to be reported in the Peruvian upwelling zone. Consistent with previous research, we find that the sulfur-rich plume arose during the austral summer when anoxic conditions (i.e., oxygen and nitrate depletion) prevailed in waters overlying the upper shelf. Furthermore, the shelf sediments were organically charged and characterized by low iron-bound sulfur concentrations, further enabling the diffusion of benthic-generated sulfide into the water column. While these biogeochemical conditions provided a predicate to sulfidic event formation, we highlight that attenuations in local wind intensity served as an event trigger. Namely, interruptions in local wind speed constrained upwelling intensity, causing increased stratification over the upper shelf. Moreover, disturbances in local wind patterns likely placed additional constraints on wind-driven mesoscale eddy propagation, with feedback effects on coastal elemental sulfur plume (ESP) formation. We suggest ESP development occurs as a result of a complex interaction of biogeochemistry with regional hydrodynamics., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Flores et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The burrowing nematode Radopholus similis is considered a major problem of intensive banana cultivation. It can cause extensive root damage resulting in the toppling disease of banana, which means that plants fall to the ground. Soaking R. similis in double-stranded (ds) RNA of the nematode genes Rps13 , chitin synthase ( Chs-2 ), Unc-87 , Pat-10 or beta-1,4-endoglucanase ( Eng1a ) suppressed reproduction on carrot discs, from 2.8-fold ( Chs-2 ) to 7-fold ( Rps13 ). The East African Highland Banana cultivar Nakitembe was then transformed with constructs for expression of dsRNA against the same genes, and for each construct, 30 independent transformants were tested with nematode infection. Four months after transfer from in vitro culture to the greenhouse, the banana plants were transferred to a screenhouse and inoculated with 2000 nematodes per plant, and thirteen weeks later, they were analyzed for several parameters including plant growth, root necrosis and final nematode population. Plants with dsRNA constructs against the nematode genes were on average showing lower nematode multiplication and root damage than the nontransformed controls or the banana plants expressing dsRNA against the nonendogenous gene. In conclusion, RNAi seems to efficiently protect banana against damage caused by R. similis , opening perspectives to control this pest.

Background: Respiratory syncytial virus (RSV) infections are among the primary causes of death for children under 5 years of age worldwide. A notable challenge with many of the upcoming prophylactic interventions against RSV is their short duration of protection, making the age profile of key interest to the design of prevention strategies., Methods and Findings: We leverage the RSV data collected on cases, hospitalizations, and deaths in a systematic review in combination with flexible generalized additive mixed models (GAMMs) to characterize the age burden of RSV incidence, hospitalization, and hospital-based case fatality rate (hCFR). Due to the flexible nature of GAMMs, we estimate the peak, median, and mean incidence of infection to inform discussions on the ideal "window of protection" of prophylactic interventions. In a secondary analysis, we reestimate the burden of RSV in all low- and middle-income countries. The peak age of community-based incidence is 4.8 months, and the mean and median age of infection is 18.9 and 14.7 months, respectively. Estimating the age profile using the incidence coming from hospital-based studies yields a slightly younger age profile, in which the peak age of infection is 2.6 months and the mean and median age of infection are 15.8 and 11.6 months, respectively. More severe outcomes, such as hospitalization and in-hospital death have a younger age profile. Children under 6 months of age constitute 10% of the population under 5 years of age but bear 20% to 29% of cases, 28% to 39% of hospitalizations, and 38% to 50% of deaths. On an average year, we estimate 28.23 to 31.34 million cases of RSV, between 2.95 to 3.35 million hospitalizations, and 16,835 to 19,909 in-hospital deaths in low, lower- and upper middle-income countries. In addition, we estimate 17,254 to 23,875 deaths in the community, for a total of 34,114 to 46,485 deaths. Globally, evidence shows that community-based incidence may differ by World Bank Income Group, but not hospital-based incidence, probability of hospitalization, or the probability of in-hospital death (p ≤ 0.01, p = 1, p = 0.86, 0.63, respectively). Our study is limited mainly due to the sparsity of the data, especially for low-income countries (LICs). The lack of information for some populations makes detecting heterogeneity between income groups difficult, and differences in access to care may impact the reported burden., Conclusions: We have demonstrated an approach to synthesize information on RSV outcomes in a statistically principled manner, and we estimate that the age profile of RSV burden depends on whether information on incidence is collected in hospitals or in the community. Our results suggest that the ideal prophylactic strategy may require multiple products to avert the risk among preschool children., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: LW received grants from Research Foundation Flanders (FWO) during the conduct of the study and fees from Pfizer outside the submitted work for discussions on economic evaluation, for a total of <€3000 combined, fully paid directly to the University of Antwerp. PB reports a grant from the Respiratory Syncytial Virus Consortium in Europe (RESCEU), Innovative Medicines Initiative 2 of the European Commission, Joint Undertaking under grant agreement No 116019, during the conduct of the study; and outside the submitted work he reports grants from Pfizer, GSK, Merck and the Innovative Medicines Initiative 2 of the European Commission (N° 101034339 project PROMISE: Preparing for RSV immunisation and surveillance in Europe) as well as consultancy fees., (Copyright: © 2023 Antillón et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: During the COVID-19 pandemic, the CoMix study, a longitudinal behavioral survey, was designed to monitor social contacts and public awareness in multiple countries, including Belgium. As a longitudinal survey, it is vulnerable to participants' "survey fatigue", which may impact inferences., Methods: A negative binomial generalized additive model for location, scale, and shape (NBI GAMLSS) was adopted to estimate the number of contacts reported between age groups and to deal with under-reporting due to fatigue within the study. The dropout process was analyzed with first-order auto-regressive logistic regression to identify factors that influence dropout. Using the so-called next generation principle, we calculated the effect of under-reporting due to fatigue on estimating the reproduction number., Results: Fewer contacts were reported as people participated longer in the survey, which suggests under-reporting due to survey fatigue. Participant dropout is significantly affected by household size and age categories, but not significantly affected by the number of contacts reported in any of the two latest waves. This indicates covariate-dependent missing completely at random (MCAR) in the dropout pattern, when missing at random (MAR) is the alternative. However, we cannot rule out more complex mechanisms such as missing not at random (MNAR). Moreover, under-reporting due to fatigue is found to be consistent over time and implies a 15-30% reduction in both the number of contacts and the reproduction number ([Formula: see text]) ratio between correcting and not correcting for under-reporting. Lastly, we found that correcting for fatigue did not change the pattern of relative incidence between age groups also when considering age-specific heterogeneity in susceptibility and infectivity., Conclusions: CoMix data highlights the variability of contact patterns across age groups and time, revealing the mechanisms governing the spread/transmission of COVID-19/airborne diseases in the population. Although such longitudinal contact surveys are prone to the under-reporting due to participant fatigue and drop-out, we showed that these factors can be identified and corrected using NBI GAMLSS. This information can be used to improve the design of similar, future surveys., (© 2023. The Author(s).)

Normothermic regional perfusion (NRP) in controlled donation after the circulatory determination of death (cDCD) is a growing preservation technique for abdominal organs that coexists with the rapid recovery of lungs. We aimed to describe the outcomes of lung transplantation (LuTx) and liver transplantation (LiTx) when both grafts are simultaneously recovered from cDCD donors using NRP and compare them with grafts recovered from donation after brain death (DBD) donors. All LuTx and LiTx meeting these criteria during January 2015 to December 2020 in Spain were included in the study. Simultaneous recovery of lungs and livers was undertaken in 227 (17%) donors after cDCD with NRP and 1879 (21%) DBD donors (P < .001). Primary graft dysfunction grade-3 within the first 72 hours was similar in both LuTx groups (14.7% cDCD vs. 10.5% DBD; P = .139). LuTx survival at 1 and 3 years was 79.9% and 66.4% in cDCD vs. 81.9% and 69.7% in DBD (P = .403). The incidence of primary nonfunction and ischemic cholangiopathy was similar in both LiTx groups. Graft survival at 1 and 3 years was 89.7% and 80.8% in cDCD vs. 88.2% and 82.1% in DBD LiTx (P = .669). In conclusion, the simultaneous rapid recovery of lungs and preservation of abdominal organs with NRP in cDCD donors is feasible and offers similar outcomes in both LuTx and LiTx recipients to transplants using DBD grafts., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Lung cancer (LC) is one of the main causes of mortality in Brazil; geographic, cultural, socioeconomic and health access factors can affect the development of the disease. We explored the geospatial distribution of LC mortality, and associated factors, between 2015 and 2019, in Parana state, Brazil., Methods and Findings: We obtained mortality (from the Brazilian Health Informatics Department) and population rates (from the Brazilian Institute of Geography and Statistics [IBGE]) in people over 40 years old, accessibility of oncology centers by municipality, disease diagnosis rate (from Brazilian Ministry of Health), the tobacco production rate (IBGE) and Parana Municipal Performance Index (IPDM) (from Parana Institute for Economic and Social Development). Global Moran's Index and Local Indicators of Spatial Association were performed to evaluate the spatial distribution of LC mortality in Parana state. Ordinary Least Squares Regression and Geographically Weighted Regression were used to verify spatial association between LC mortality and socioeconomic indicators and health service coverage. A strong spatial autocorrelation of LC mortality was observed, with the detection of a large cluster of high LC mortality in the South of Parana state. Spatial regression analysis showed that all independent variables analyzed were directly related to LC mortality by municipality in Paraná., Conclusions: There is a disparity in the LC mortality in Parana state, and inequality of socioeconomic and accessibility to health care services could be associated with it. Our findings may help health managers to intensify actions in regions with vulnerability in the detection and treatment of LC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Dias Marques et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Compare the breast cancer mortality rate and the rate of mammograms with socioeconomic factors, in Brazilian´s Federative Units, during the period of 2015 to 2021. Methods: This is an ecological study, of a descriptive nature, which covers the 27 Brazilian federative units, using secondary data extracted from the DATASUS System. The information analyzed was mammography data, breast cancer mortality, demographic and economic data of the resident population and women over 20 years of age. Results: There is a direct relationship between mortality rate and mammograms rates in the Federative Units. The data obtained for Brazil presents a total of 133,048 deaths from breast cancer and 17,324,526 mammography exams in the period from 2015 to 2021. In other words, Brazil presents a standardized mortality rate value, 19.25 deaths per 100,000 women. Regarding the mammography rate, the value of the exam-specific mammography rate was 2,506.55 per 100,000 women. In relation to socioeconomic data by mortality rate group, higher mortality rates from breast cancer present higher rates in the variables: income rate by State (2,594.86), people with income (63.5), average percentage of women with more over 50 years old (29.5%), women with average years of education (6.64), white population (55.1%) and mammography exam rate (2873.20). When analysing the highest rates of mammography exam rates, higher rates are observed income rate by State (2,161.47), people with income (62.5%), average percentage of women over 50 years old (28.6%), women with an average number of years of education (5.8). Conclusion: Brazil has a high mortality rate due to breast cancer, when compared to other countries. The reasons are diverse, such as the modern, industrialized and populous lifestyle. The Federative Units with the highest mortality rate also have high rates of mammograms, that is, in the Federative Units with "better" sociodemographic conditions, the South and Southeast.

Objective: We identify factors related to SARS-CoV-2 infection linked to hospitalization, ICU admission, and mortality and develop clinical prediction rules., Methods: Retrospective cohort study of 380,081 patients with SARS-CoV-2 infection from March 1, 2020 to January 9, 2022, including a subsample of 46,402 patients who attended Emergency Departments (EDs) having data on vital signs. For derivation and external validation of the prediction rule, two different periods were considered: before and after emergence of the Omicron variant, respectively. Data collected included sociodemographic data, COVID-19 vaccination status, baseline comorbidities and treatments, other background data and vital signs at triage at EDs. The predictive models for the EDs and the whole samples were developed using multivariate logistic regression models using Lasso penalization., Results: In the multivariable models, common predictive factors of death among EDs patients were greater age; being male; having no vaccination, dementia; heart failure; liver and kidney disease; hemiplegia or paraplegia; coagulopathy; interstitial pulmonary disease; malignant tumors; use chronic systemic use of steroids, higher temperature, low O2 saturation and altered blood pressure-heart rate. The predictors of an adverse evolution were the same, with the exception of liver disease and the inclusion of cystic fibrosis. Similar predictors were found to be related to hospital admission, including liver disease, arterial hypertension, and basal prescription of immunosuppressants. Similarly, models for the whole sample, without vital signs, are presented., Conclusions: We propose risk scales, based on basic information, easily-calculable, high-predictive that also function with the current Omicron variant and may help manage such patients in primary, emergency, and hospital care., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Individuals with Down syndrome (DS) are more prone to develop severe respiratory tract infections. Although a RSV infection has a high clinical impact and severe outcome in individuals with DS, no vaccine nor effective therapeutics are available. Any research into infection pathophysiology or prophylactic and therapeutic antiviral strategies in the specific context of DS would greatly benefit this patient population, but currently such relevant animal models are lacking. This study aimed to develop and characterize the first mouse model of RSV infection in a DS-specific context. Ts65Dn mice and wild type littermates were inoculated with a bioluminescence imaging-enabled recombinant human RSV to longitudinally track viral replication in host cells throughout infection progression. This resulted in an active infection in the upper airways and lungs with similar viral load in Ts65Dn mice and euploid mice. Flow cytometric analysis of leukocytes in lungs and spleen demonstrated immune alterations with lower CD8+ T cells and B-cells in Ts65Dn mice. Overall, our study presents a novel DS-specific mouse model of hRSV infection and shows that potential in using the Ts65Dn preclinical model to study immune-specific responses of RSV in the context of DS and supports the need for models representing the pathological development.

Objectives: Model-based cost-effectiveness analyses on maternal vaccine (MV) and monoclonal antibody (mAb) interventions against respiratory syncytial virus (RSV) use context-specific data and produce varied results. Through model comparison, we aim to characterize RSV cost-effectiveness models and examine drivers for their outputs., Methods: We compared 3 static and 2 dynamic models using a common input parameter set for a hypothetical birth cohort of 100 000 infants. Year-round and seasonal programs were evaluated for MV and mAb interventions, using available evidence during the study period (eg, phase III MV and phase IIb mAb efficacy)., Results: Three static models estimated comparable medically attended (MA) cases averted versus no intervention (MV, 1019-1073; mAb, 5075-5487), with the year-round MV directly saving ∼€1 million medical and €0.3 million nonmedical costs, while gaining 4 to 5 discounted quality-adjusted life years (QALYs) annually in <1-year-olds, and mAb resulting in €4 million medical and €1.5 million nonmedical cost savings, and 21 to 25 discounted QALYs gained. In contrast, both dynamic models estimated fewer MA cases averted (MV, 402-752; mAb, 3362-4622); one showed an age shift of RSV cases, whereas the other one reported many non-MA symptomatic cases averted, especially by MV (2014). These differences can be explained by model types, assumptions on non-MA burden, and interventions' effectiveness over time., Conclusions: Our static and dynamic models produced overall similar hospitalization and death estimates, but also important differences, especially in non-MA cases averted. Despite the small QALY decrement per non-MA case, their larger number makes them influential for the costs per QALY gained of RSV interventions., (Copyright © 2023. Published by Elsevier Inc.)

Programmable genome integration of large, diverse DNA cargo without DNA repair of exposed DNA double-strand breaks remains an unsolved challenge in genome editing. We present programmable addition via site-specific targeting elements (PASTE), which uses a CRISPR-Cas9 nickase fused to both a reverse transcriptase and serine integrase for targeted genomic recruitment and integration of desired payloads. We demonstrate integration of sequences as large as ~36 kilobases at multiple genomic loci across three human cell lines, primary T cells and non-dividing primary human hepatocytes. To augment PASTE, we discovered 25,614 serine integrases and cognate attachment sites from metagenomes and engineered orthologs with higher activity and shorter recognition sequences for efficient programmable integration. PASTE has editing efficiencies similar to or exceeding those of homology-directed repair and non-homologous end joining-based methods, with activity in non-dividing cells and in vivo with fewer detectable off-target events. PASTE expands the capabilities of genome editing by allowing large, multiplexed gene insertion without reliance on DNA repair pathways., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Atherosclerosis evolves through dysregulated lipid metabolism interwoven with exaggerated inflammation. Previous work implicating the receptor for advanced glycation end products (RAGE) in atherosclerosis prompted us to explore if Diaphanous 1 (DIAPH1), which binds to the RAGE cytoplasmic domain and is important for RAGE signaling, contributes to these processes. We intercrossed atherosclerosis-prone Ldlr -/- mice with mice devoid of Diaph1 and fed them Western diet for 16 weeks. Compared to male Ldlr -/- mice, male Ldlr -/- Diaph1 -/- mice displayed significantly less atherosclerosis, in parallel with lower plasma concentrations of cholesterol and triglycerides. Female Ldlr -/- Diaph1 -/- mice displayed significantly less atherosclerosis compared to Ldlr -/- mice and demonstrated lower plasma concentrations of cholesterol, but not plasma triglycerides. Deletion of Diaph1 attenuated expression of genes regulating hepatic lipid metabolism, Acaca, Acacb, Gpat2, Lpin1, Lpin2 and Fasn, without effect on mRNA expression of upstream transcription factors Srebf1, Srebf2 or Mxlipl in male mice. We traced DIAPH1-dependent mechanisms to nuclear translocation of SREBP1 in a manner independent of carbohydrate- or insulin-regulated cues but, at least in part, through the actin cytoskeleton. This work unveils new regulators of atherosclerosis and lipid metabolism through DIAPH1., (© 2023. The Author(s).)

Background: Respiratory syncytial virus (RSV) imposes a substantial burden on pediatric hospital capacity in Europe. Promising prophylactic interventions against RSV including monoclonal antibodies (mAb) and maternal immunizations (MI) are close to licensure. Therefore, we aimed to evaluate the cost-effectiveness of potential mAb and MI interventions against RSV in infants, for six European countries., Methods: We used a static cohort model to compare costs and health effects of four intervention programs to no program and to each other: year-round MI, year-round mAb, seasonal mAb (October to April), and seasonal mAb plus a catch-up program in October. Input parameters were obtained from national registries and literature. Influential input parameters were identified with the expected value of partial perfect information and extensive scenario analyses (including the impact of interventions on wheezing and asthma)., Results: From the health care payer perspective, and at a price of €50 per dose (mAb and MI), seasonal mAb plus catch-up was cost-saving in Scotland, and cost-effective for willingness-to-pay (WTP) values ≥€20,000 (England, Finland) or €30,000 (Denmark) per quality adjusted life-year (QALY) gained for all scenarios considered, except when using ICD-10 based hospitalization data. For the Netherlands, seasonal mAb was preferred (WTP value: €30,000-€90,000) for most scenarios. For Veneto region (Italy), either seasonal mAb with or without catch-up or MI was preferred, depending on the scenario and WTP value. From a full societal perspective (including leisure time lost), the seasonal mAb plus catch-up program was cost-saving for all countries except the Netherlands., Conclusion: The choice between a MI or mAb program depends on the level and duration of protection, price, availability, and feasibility of such programs, which should be based on the latest available evidence. Future research should focus on measuring accurately age-specific RSV-attributable hospitalizations in very young children., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘PB reports grants from Respiratory Syncytial Virus Consortium in Europe (RESCEU), Innovative Medicines Initiative 2 of the European Commission, Joint Undertaking under grant agreement No 116,019 during the conduct of the study; and grants from Pfizer, GSK, Merck and European Commission IMI project PROMISE, outside the submitted work, but he has not received any personal fees or other personal benefits. LB’s institution, UMCU has received major funding (>€100,000 per industrial partner) for investigator initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD and MeMed Diagnostics. UMCU has received major funding for the RSV GOLD study from the Bill and Melinda Gates Foundation and major funding as part of the public private partnership IMI-funded projects (RESCEU and PROMISE). UMCU also has received major funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer and minor funding (€1,000–25,000 per industrial partner) for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna. TH declared consultancy fees from Sanofi and Janssen for Ad hoc advisory board meeting and honoraria for Lecture on the burden of RSV in children from Jassen and MSD, outside the submitted work. JvS’s institution, Nivel has received unrestricted research grants from WHO, Sanofi and the Foundation for Influenza Epidemiology for work outside the submitted work. CR declared consultancy fees for Ad hoc advisory board meeting and honoraria for Lecture from Seqirus, MSD, Sanofi, outside of the submitted work. ST was an employee of IVIDATA during the conduct of the study, and her employer received consultancy fees from Sanofi. All other authors report no potential conflicts.’, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Plasma apolipoprotein E levels were previously associated with the risk of developing Alzheimer's disease (AD), levels of cerebrospinal fluid AD biomarkers, cognition and imaging brain measures. Outside the brain, the liver is the primary source of apoE and liver transplantation studies have demonstrated that liver-derived apoE does not cross the blood-brain-barrier. How hepatic apoE may be implicated in behavioral and cognitive performance is not clear. In the current study, we behaviorally tested FRGN mice with humanized liver harboring the ε3/ε3 genotype (E3-human liver (HL)) and compared their behavioral and cognitive performance with that of age-matched ε3/ε3 targeted replacement (E3-TR) mice, the latter produces human apoE3 throughout the body whereas the E3-HL mice endogenously produce human apoE3 only in the liver. We also compared the liver weights and plasma apoE levels, and assessed whether plasma apoE levels were correlated with behavioral or cognitive measures in both models. E3-HL were more active but performed cognitively worse than E3-TR mice. E3-HL mice moved more in the open field containing objects, showed higher activity levels in the Y maze, showed higher activity levels during the baseline period in the fear conditioning test than E3-TR mice, and swam faster than E3-TR mice during training to locate the visible platform in the water maze. However, E3-HL mice showed reduced spatial memory retention in the water maze and reduced fear learning and contextual and cued fear memory than E3-TR mice. Liver weights were greater in E3-HL than E3-TR mice and sex-dependent only in the latter model. Plasma apoE3 levels were similar to those found in humans and comparable in female and male E3-TR mice but higher in female E3-HL mice. Finally, we found correlations between plasma apoE levels and behavioral and cognitive measures which were predominantly model-dependent. Our study demonstrates mouse-model dependent associations between plasma apoE levels, behavior and cognition in an 'AD-neutral' setting and suggests that a humanized liver might be sufficient to induce mouse behavioral and cognitive phenotypes., (© 2023. The Author(s).)

Tensor-network methods are used to perform a comparative study of the two-dimensional classical Heisenberg and RP^{2} models. We demonstrate that uniform matrix product states (MPSs) with explicit SO(3) symmetry can probe correlation lengths up to O(10^{3}) sites accurately, and we study the scaling of entanglement entropy and universal features of MPS entanglement spectra. For the Heisenberg model, we find no signs of a finite-temperature phase transition, supporting the scenario of asymptotic freedom. For the RP^{2} model we observe an abrupt onset of scaling behavior, consistent with hints of a finite-temperature phase transition reported in previous studies. A careful analysis of the softening of the correlation length divergence, the scaling of the entanglement entropy, and the MPS entanglement spectra shows that our results are inconsistent with true criticality, but are rather in agreement with the scenario of a crossover to a pseudocritical region which exhibits strong signatures of nematic quasi-long-range order at length scales below the true correlation length. Our results reveal a fundamental difference in scaling behavior between the Heisenberg and RP^{2} models: Whereas the emergence of scaling in the former shifts to zero temperature if the bond dimension is increased, it occurs at a finite bond-dimension independent crossover temperature in the latter.

Ungulate populations are increasing across Europe with important implications for forest plant communities. Concurrently, atmospheric nitrogen (N) deposition continues to eutrophicate forests, threatening many rare, often more nutrient-efficient, plant species. These pressures may critically interact to shape biodiversity as in grassland and tundra systems, yet any potential interactions in forests remain poorly understood. Here, we combined vegetation resurveys from 52 sites across 13 European countries to test how changes in ungulate herbivory and eutrophication drive long-term changes in forest understorey communities. Increases in herbivory were associated with elevated temporal species turnover, however, identities of winner and loser species depended on N levels. Under low levels of N-deposition, herbivory favored threatened and small-ranged species while reducing the proportion of non-native and nutrient-demanding species. Yet all these trends were reversed under high levels of N-deposition. Herbivores also reduced shrub cover, likely exacerbating N effects by increasing light levels in the understorey. Eutrophication levels may therefore determine whether herbivory acts as a catalyst for the "N time bomb" or as a conservation tool in temperate forests., (© 2022. The Author(s).)

Background: The increasing availability of data on social contact patterns and time use provides invaluable information for studying transmission dynamics of infectious diseases. Social contact data provide information on the interaction of people in a population whereas the value of time use data lies in the quantification of exposure patterns. Both have been used as proxies for transmission risks within in a population and the combination of both sources has led to investigate which contacts are more suitable to describe these transmission risks., Methods: We used social contact and time use data from 1707 participants from a survey conducted in Flanders, Belgium in 2010-2011. We calculated weighted exposure time and social contact matrices to analyze age- and gender-specific mixing patterns and to quantify behavioral changes by distance from home. We compared the value of both separate and combined data sources for explaining seroprevalence and incidence data on parvovirus-B19, Varicella-Zoster virus (VZV) and influenza like illnesses (ILI), respectively., Results: Assortative mixing and inter-generational interaction is more pronounced in the exposure matrix due to the high proportion of time spent at home. This pattern is less pronounced in the social contact matrix, which is more impacted by the reported contacts at school and work. The average number of contacts declined with distance. On the individual-level, we observed an increase in the number of contacts and the transmission potential by distance when travelling. We found that both social contact data and time use data provide a good match with the seroprevalence and incidence data at hand. When comparing the use of different combinations of both data sources, we found that the social contact matrix based on close contacts of at least 4 h appeared to be the best proxy for parvovirus-B19 transmission. Social contacts and exposure time were both on their own able to explain VZV seroprevalence data though combining both scored best. Compared with the contact approach, the time use approach provided the better fit to the ILI incidence data., Conclusions: Our work emphasises the common and complementary value of time use and social contact data for analysing mixing behavior and analysing infectious disease transmission. We derived spatial, temporal, age-, gender- and distance-specific mixing patterns, which are informative for future modelling studies., (© 2022. The Author(s).)

Viruses are the most abundant components of the human gut microbiome with a significant impact on health and disease. The effects of human immunodeficiency virus (HIV) infection on gut virome has been scarcely analysed. Several studies suggested that integrase strand transfers inhibitors (INSTIs) are associated with a healthier gut. Thus, the objective of this work was to evaluate the effects of HIV infection and INSTIs on gut virome composition. 26 non-HIV-infected volunteers, 15 naive HIV-infected patients and 15 INSTIs-treated HIV-infected patients were recruited and their gut virome composition was analysed using shotgun sequencing. Bacteriophages were the most abundant and diverse viruses present in gut. HIV infection was accompanied by a decrease in phage richness which was reverted after INSTIs-based treatment. β-diversity of phages revealed that samples from HIV-infected patients clustered separately from those belonging to the control group. Differential abundant analysis showed an increase in phages belonging to Caudoviricetes class in the naive group and a decrease of Malgrandaviricetes class phages in the INSTIs-treated group compared to the control group. Besides, it was observed that INSTIs-based treatment was not able to reverse the increase of lysogenic phages associated with HIV infection or to modify the decrease observed on the relative abundance of Proteobacteria-infecting phages. Our study describes for the first time the impact of HIV and INSTIs on gut virome and demonstrates that INSTIs-based treatments are able to partially restore gut dysbiosis at the viral level, which opens several opportunities for new studies focused on microbiota-based therapies., (© 2022. The Author(s).)

Background: The COVID-19 pandemic caused graduate medical education (GME) programs to pivot to virtual interviews (VIs) for recruitment and selection. This systematic review synthesizes the rapidly expanding evidence base on VIs, providing insights into preferred formats, strengths, and weaknesses., Methods: PubMed/MEDLINE, Scopus, ERIC, PsycINFO, MedEdPublish, and Google Scholar were searched from 1 January 2012 to 21 February 2022. Two authors independently screened titles, abstracts, full texts, performed data extraction, and assessed risk of bias using the Medical Education Research Quality Instrument. Findings were reported according to Best Evidence in Medical Education guidance., Results: One hundred ten studies were included. The majority (97%) were from North America. Fourteen were conducted before COVID-19 and 96 during the pandemic. Studies involved both medical students applying to residencies (61%) and residents applying to fellowships (39%). Surgical specialties were more represented than other specialties. Applicants preferred VI days that lasted 4-6 h, with three to five individual interviews (15-20 min each), with virtual tours and opportunities to connect with current faculty and trainees. Satisfaction with VIs was high, though both applicants and programs found VIs inferior to in-person interviews for assessing 'fit.' Confidence in ranking applicants and programs was decreased. Stakeholders universally noted significant cost and time savings with VIs, as well as equity gains and reduced carbon footprint due to eliminating travel., Conclusions: The use of VIs for GME recruitment and selection has accelerated rapidly. The findings of this review offer early insights that can guide future practice, policy, and research.

The emergence of West Nile virus and Usutu virus in Europe poses a significant risk to public health. In the absence of efficient antiviral therapy or vaccine candidates, the only strategy to control these arboviruses is to target the Culex (Diptera: Culicidae) mosquito vector. However, the selection pressure caused by exposure to insecticides for vector control or agricultural pest control can lead to insecticide resistance, thereby reducing the efficacy of insecticide-based vector control interventions. In Culex mosquitoes, two of the most common amino acid substitutions associated with insecticide resistance are the kdr L1014F in voltage gated sodium channels and G119S in acetylcholinesterase. In this study, Culex pipiens biotype pipiens, Culex torrentium, and Culex modestus were sampled from 2019 to 2021 in three distinct environmental habitats (urban, peri-urban, and agricultural) in and around the city of Leuven, Belgium. Individual mosquitoes were screened for two mutations resulting in L1014F and G119S amino acid substitutions. Both mutations were observed in Cx. pipiens and Cx. modestus but not in Cx. torrentium mosquitoes across the four collection sites. Furthermore, multi-resistance or cross-resistance in Cx. pipiens could be a threat in these areas, as both mutations were observed at low frequencies. These results provide the first report of kdr L1014F and ace-1 G119S resistance mutations in Cx. pipiens and Cx. modestus mosquitoes from Belgium, highlighting the importance of mosquito surveillance to design effective arbovirus outbreak control strategies., (© The Author(s) 2022. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent studies suggest that identification with all humanity (IWAH), apart from being related to universalistic values, could also be related to self-transcendent emotions (STE). In this scenario, the general objective of this cross-cultural longitudinal study is to examine the relationship between identification with proximate categories (i.e., community and country) and superordinate one (all humanity), and their association with positive self-oriented and STEs during a traumatic global phenomenon such as COVID-19 pandemics. Additionally, we explore variations regarding the patterns of those associations in different cultural contexts (Chile and Spain) and examine whether they change among two different time points (T1-T2). The total sample was composed of 403 participants, of whom 224 were residents in Chile ( M = 39.25, SD = 12.56; range 18-71 years; 49.6% women) and 179 were residents in Spain ( M = 36.35, SD = 12.12; range 18-68 years; 59.8% women). Data collection was carried out in September (T1) and November (T2) 2020, through online surveys administered via Survey Monkey ® platform. Overall, results show, as expected, greater identification with proximate categories rather than superordinate ones, and an association between STEs and IWAH, but also with national and community identification. IWAH, but not STEs decreased significantly (T1-T2) in both countries. Thereafter, these emotional and behavioral responses decline as a symptom of growing fatigue with the pandemic situation, and also reflect a shift from broader to more local concerns. Analysis regarding comparisons between countries indicated higher levels of identification with community and with all humanity in Spain and with country in Chile. The results are discussed in the context of new developments in studies on IWAH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wlodarczyk, Méndez, Cusi, Telletxea, Mendia, Briceño, Delgado, Balbontín, Lecaros and Páez.)

Whole-sporozoite (WSp) malaria vaccines induce protective immune responses in animal malaria models and in humans. A recent clinical trial with a WSp vaccine comprising genetically attenuated parasites (GAP) which arrest growth early in the liver (PfSPZ-GA1), showed that GAPs can be safely administered to humans and immunogenicity is comparable to radiation-attenuated PfSPZ Vaccine. GAPs that arrest late in the liver stage (LA-GAP) have potential for increased potency as shown in rodent malaria models. Here we describe the generation of four putative P. falciparum LA-GAPs, generated by CRISPR/Cas9-mediated gene deletion. One out of four gene-deletion mutants produced sporozoites in sufficient numbers for further preclinical evaluation. This mutant, PfΔmei2, lacking the mei2-like RNA gene, showed late liver growth arrest in human liver-chimeric mice with human erythrocytes, absence of unwanted genetic alterations and sensitivity to antimalarial drugs. These features of PfΔmei2 make it a promising vaccine candidate, supporting further clinical evaluation. PfΔmei2 (GA2) has passed regulatory approval for safety and efficacy testing in humans based on the findings reported in this study., (© 2022. The Author(s).)

Hedgehog diphtheric disease (HDD), an ulcerative skin disease with a high fatality rate, is an emerging threat to European hedgehogs (Erinaceus europaeus). We explored the potential role of a panel of zoonotic pathogens in the presumed multifactorial nature of HDD in 188 hedgehogs from 3 wildlife rescue centres in Belgium. As expected, and with a prevalence of 67% in 57 hedgehogs with skin lesions, characteristic of HDD, the occurrence of Corynebacterium ulcerans was strongly associated with the disease. Remarkably, with a prevalence of 42% in affected animals, infections with Borrelia burgdorferi sensu lato were 3.92 times more likely to be detected in HDD (95% confidence interval: 1.650-9.880; p = .0024). Overall, 40 hedgehogs tested positive for the B. burgdorferi sensu lato complex, including Borrelia afzelii (n = 30), Borrelia bavariensis (n = 7) and Borrelia spielmanii (n = 7). Other widely occurring pathogens included Salmonella (prevalence of 19%, with three pulsed-field gel electrophoresis profiles) and Leptospira sp. (prevalence of 11%, including Leptospira interrogans and Leptospira borgpetersenii), but these were not associated with the occurrence of HDD. These findings show that hedgehogs in Belgium represent a significant reservoir of multiple zoonotic bacteria, of which toxigenic C. ulcerans and B. burgdorferi sensu lato are associated with widespread hedgehog skin pathology and mortality., (© 2022 Wiley-VCH GmbH.)

Herein we report the impact of covalent modification (grafting), inducing lateral nanoconfinement conditions, on the self-assembly of a quinonoid zwitterion derivative into self-assembled molecular networks at the liquid/solid interface. At low concentrations where the compound does not show self-assembly behaviour on bare highly oriented pyrolytic graphite (HOPG), close-packed self-assembled structures are visualized by scanning tunneling microscopy on covalently modified HOPG. The size of the self-assembled domains decreases with increasing the density of grafted molecules, i.e. the molecules covalently bound to the surface. The dynamics of domains are captured with molecular resolution, revealing not only time-dependent growth and shrinkage processes but also the orientation conversion of assembled domains. Grafted pins play a key role in initiating the formation of on-surface molecular self-assembly and their stabilization, providing an elegant route to study various aspects of nucleation and growth processes of self-assembled molecular networks., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Mosquitoes are important vectors for many arboviruses. It is becoming increasingly clear that various symbiotic microorganisms (including bacteria and insect-specific viruses; ISVs) in mosquitoes have the potential to modulate the ability of mosquitoes to transmit arboviruses. In this study, we compared the bacteriome and virome (both eukaryotic viruses and bacteriophages) of female adult Aedes aegypti and Culex quinquefasciatus mosquitoes fed with sucrose/water, blood, or blood spiked with Zika virus (ZIKV) or West Nile virus (WNV), respectively. Furthermore, we investigated associations between the microbiota and vector competence. We show that the influence of arboviruses on the mosquito microbiome-and vice versa-is distinct for each combination of arbovirus/mosquito species. The presence of ZIKV resulted in a temporarily increased Aedes ISV diversity. However, this effect was distinct for different ISVs: some ISVs decreased following the blood meal (Aedes aegypti totivirus), whereas other ISVs increased only when the blood contained ZIKV (Guadeloupe mosquito virus). Also, the diversity of the Aedes bacteriome depended on the diet and the presence of ZIKV, with a lower diversity observed for mosquitoes receiving blood without ZIKV. In Cx. quinquefasciatus , some ISVs increased in WNV-infected mosquitoes (Guadeloupe Culex tymo-like virus). Particularly, the presence of Wenzhou sobemo-like virus 3 (WSLV3) was associated with the absence of infectious WNV in mosquito heads, suggesting that WSLV3 might affect vector competence for WNV. Distinct profiles of bacteriophages were identified in Culex mosquitoes depending on diet, despite the lack of clear changes in the bacteriome. Overall, our data demonstrate a complex three-way interaction among arboviruses, resident microbiota, and the host, which is distinct for different arbovirus-mosquito combinations. A better understanding of these interactions may lead to the identification of microbiota able to suppress the ability of arbovirus transmission to humans, and hence improved arbovirus control measures. IMPORTANCE In this study, we first utilized the single mosquito microbiome analysis, demonstrating a complex three-way interaction among arboviruses, resident microbiota, and the host, which is distinct for different arbovirus-mosquito combinations. Some of the previously described "core virus" increased in the mosquitos receiving viral blood meal, like Guadeloupe mosquito virus and Guadeloupe Culex tymo-like virus, suggesting their potential roles in ZIKV and WNV infection. Notably, Wenzhou sobemo-like virus 3 was associated with the absence of infectious WNV in heads of Culex mosquitoes, which might affect vector competence for WNV. A better understanding of these interactions will lead to the identification of microbiota able to suppress the ability of arbovirus transmission to humans, and hence improved arbovirus control measures.

Aims: Graft vascular disease (GVD), a clinically important and highly complex vascular occlusive disease, arises from the interplay of multiple cellular and molecular pathways. While occlusive intimal lesions are composed predominantly of smooth-muscle-like cells (SMLCs), the origin of these cells and the stimuli leading to their accumulation in GVD are uncertain. Macrophages have recently been identified as both potential drivers of intimal hyperplasia and precursors that undergo transdifferentiation to become SMLCs in non-transplant settings. Colony-stimulating factor-1 (CSF1) is a well-known regulator of macrophage development and differentiation, and prior preclinical studies have shown that lack of CSF1 limits GVD. We sought to identify the origins of SMLCs and of cells expressing the CSF1 receptor (CSF1R) in GVD, and to test the hypothesis that pharmacologic inhibition of CSF1 signalling would curtail both macrophage and SMLC activities and decrease vascular occlusion., Methods and Results: We used genetically modified mice and a vascular transplant model with minor antigen mismatch to assess cell origins. We found that neointimal SMLCs derive from both donor and recipient, and that transdifferentiation of macrophages to SMLC phenotype is minimal in this model. Cells expressing CSF1R in grafts were identified as recipient-derived myeloid cells of Cx3cr1 lineage, and these cells rarely expressed smooth muscle marker proteins. Blockade of CSF1R activity using the tyrosine kinase inhibitor PLX3397 limited the expression of genes associated with innate immunity and decreased levels of circulating monocytes and intimal macrophages. Importantly, PLX3397 attenuated the development of GVD in arterial allografts., Conclusion: These studies provide proof of concept for pharmacologic inhibition of the CSF1/CSF1R signalling pathway as a therapeutic strategy in GVD. Further preclinical testing of this pathway in GVD is warranted., Competing Interests: Conflict of interest: none declared., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of broadly immunodeficient chimeric mice respond to hypercaloric diets. As early as four weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatosis with ballooning degeneration selectively in the human graft, followed by pericellular fibrosis after eight weeks of hypercaloric feeding. Hepatocytes with the PNPLA3-148M variant, either from a homozygous 148M donor or overexpressed in a 148I donor background, developed microvesicular and severe steatosis with frequent ballooning degeneration, resulting in more active steatohepatitis than 148I hepatocytes. We conclude that PNPLA3-148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variant contributions to advanced fatty liver diseases., Competing Interests: Declaration of interests L.F., R.C., and M.G. have financial interest in Yecuris Corporation. All others declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Background: The coronavirus disease (COVID-19) pandemic has been a source of disruption, changing the face of medical education. In response to infection control measures at the University of California, San Diego, the hybrid in-person and recorded preclerkship curriculum was converted to a completely virtual format. The impact of this exclusive virtual teaching platform on the quality of trainee education is unknown., Objective: To determine the efficacy of a virtual course, relative to traditional hybrid in-person and recorded teaching, and to assess the impact of supplementary educational material on knowledge acquisition., Methods: A retrospective observational cohort study was performed to assess an introductory course, held mostly in person in 2019 versus completely virtual in 2020, for first-year medical students and second-year pharmacy students at the University of California, San Diego, School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences., Results: The midterm and final examination scores were similar for the hybrid and virtual courses. There was no association between the hours of recorded lectures watched and final examination scores for either course. In the 2019 in-person and recorded course, students who demonstrated consistent on-time use of practice quizzes scored statistically higher on the final examination ( P  = 0.0066). In the 2020 virtual course, students who downloaded quizzes regularly had statistically higher scores on the midterm examination ( P  < 0.0001)., Conclusion: The similar examination scores for the hybrid in-person and recorded and exclusively virtual courses suggest that the short-term knowledge acquired was equivalent, independent of the modality with which the content was delivered. Consistent on-time use of practice quizzes was associated with higher examination scores. Future studies are needed to assess the difference between a completely in-person versus virtual curriculum., (Copyright © 2022 by the American Thoracic Society.)

Superspreading events play an important role in the spread of several pathogens, such as SARS-CoV-2. While the basic reproduction number of the original Wuhan SARS-CoV-2 is estimated to be about 3 for Belgium, there is substantial inter-individual variation in the number of secondary cases each infected individual causes-with most infectious individuals generating no or only a few secondary cases, while about 20% of infectious individuals is responsible for 80% of new infections. Multiple factors contribute to the occurrence of superspreading events: heterogeneity in infectiousness, individual variations in susceptibility, differences in contact behavior, and the environment in which transmission takes place. While superspreading has been included in several infectious disease transmission models, research into the effects of different forms of superspreading on the spread of pathogens remains limited. To disentangle the effects of infectiousness-related heterogeneity on the one hand and contact-related heterogeneity on the other, we implemented both forms of superspreading in an individual-based model describing the transmission and spread of SARS-CoV-2 in a synthetic Belgian population. We considered its impact on viral spread as well as on epidemic resurgence after a period of social distancing. We found that the effects of superspreading driven by heterogeneity in infectiousness are different from the effects of superspreading driven by heterogeneity in contact behavior. On the one hand, a higher level of infectiousness-related heterogeneity results in a lower risk of an outbreak persisting following the introduction of one infected individual into the population. Outbreaks that did persist led to fewer total cases and were slower, with a lower peak which occurred at a later point in time, and a lower herd immunity threshold. Finally, the risk of resurgence of an outbreak following a period of lockdown decreased. On the other hand, when contact-related heterogeneity was high, this also led to fewer cases in total during persistent outbreaks, but caused outbreaks to be more explosive in regard to other aspects (such as higher peaks which occurred earlier, and a higher herd immunity threshold). Finally, the risk of resurgence of an outbreak following a period of lockdown increased. We found that these effects were conserved when testing combinations of infectiousness-related and contact-related heterogeneity., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: FV contributed to this work as a full time employee of the University of Antwerp. As of 21 March 2022, after his contributions to this work ended, FV is employed by the GSK group of companies.

The final quality of sheet and tube metal-formed components strongly depends on the tribology and friction conditions between the tools and the material to be formed. Furthermore, it has been recently demonstrated that friction is the numerical input parameter that has the biggest effect in the numerical models used for feasibility studies and process design. For these reasons, industrial dedicated software packages have introduced friction laws which are dependent on sliding velocity, contact pressure and sometimes strain suffered by the sheet, and currently, temperature dependency is being implemented as it has also a major effect on friction. In this work, three lubricants having different viscosity have been characterized using the tube-sliding test. The final aim of the study is to fit friction laws that are contact pressure and sliding velocity dependent for their use in tube hydroforming modeling. The tests performed at various contact pressures and velocities have demonstrated that viscosity has a major effect on friction. Experimental hydroforming tests using the three different lubricants have corroborated the importance of the lubricant in the final forming of a triangular shape. The measurement of the axial forces and the final principal strains of the formed tubes have shown the importance of using advanced friction laws to properly model the hydroforming process using the finite element modeling.

Background: Every winter, respiratory syncytial virus (RSV) disease results in thousands of cases in Norwegian children under 5 years of age. We aim to assess the RSV-related economic burden and the cost-effectiveness of upcoming RSV disease prevention strategies including year-round maternal immunization and year-round and seasonal monoclonal antibody (mAb) programs., Methods: Epidemiological and cost data were obtained from Norwegian national registries, while quality-adjusted life-years (QALYs) lost and intervention characteristics were extracted from literature and phase 3 clinical trials. A static model was used and uncertainty was accounted for probabilistically. Value of information was used to assess decision uncertainty. Extensive scenario analyses were conducted, including accounting for long-term consequences of RSV disease., Results: We estimate an annual average of 13 517 RSV cases and 1572 hospitalizations in children under 5, resulting in 79.6 million Norwegian kroner (~€8 million) treatment costs. At €51 per dose for all programs, a 4-month mAb program for neonates born in November to February is the cost-effective strategy for willingness to pay (WTP) values up to €40 000 per QALY gained. For higher WTP values, the longer 6-month mAb program that immunizes neonates from October to March becomes cost-effective. Sensitivity analyses show that year-round maternal immunization can become a cost-effective strategy if priced lower than mAb., Conclusions: Assuming the same pricing, seasonal mAb programs are cost-effective over year-round programs in Norway. The timing and duration of the cost-effective seasonal program are sensitive to the pattern of the RSV season in a country, so continued RSV surveillance data are essential., Competing Interests: Potential conflicts of interest. T. W. received funding for working on vaccines related to other diseases, varicella, and herpes zoster from MSD Norway, outside the submitted work. P. B. declared consultancy fees paid to the University of Antwerp from GSK and Pfizer on 2 occasions for discussions on economic evaluation (<€3000 in total), outside the submitted work. L. B. declares regular interaction with pharmaceutical and other industrial partners, but has not received personal fees or other personal benefits. University Medical Center Utrecht (UCMU) has received major funding (>€100,000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, Janssen, Pfizer, the Bill and Melinda Gates Foundation, and MeMed Diagnostics. UMCU has received major cash or in-kind funding as part of the public-private partnership Innovative Medicines Initiative–funded RESCEU project from GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi. UMCU has received major funding by Julius Clinical for participating in the INFORM study. M. J. is an affiliate member of RESCEU, but neither M. J. nor his research group has received any forms of pecuniary or other support from the pharmaceutical industry. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer's disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes neurodegeneration is unknown. Here we investigated the brains of Fah-/-, Rag2-/-, Il2rg-/- mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOEε4-associated risk of neurodegenerative disease., (© 2022. The Author(s).)

SARS-CoV-2 remains a worldwide emergency. While vaccines have been approved and are widely administered, there is an ongoing debate whether children should be vaccinated or prioritized for vaccination. Therefore, in order to mitigate the spread of more transmissible SARS-CoV-2 variants among children, the use of non-pharmaceutical interventions is still warranted. We investigate the impact of different testing strategies on the SARS-CoV-2 infection dynamics in a primary school environment, using an individual-based modelling approach. Specifically, we consider three testing strategies: (1) symptomatic isolation , where we test symptomatic individuals and isolate them when they test positive, (2) reactive screening , where a class is screened once one symptomatic individual was identified, and (3) repetitive screening , where the school in its entirety is screened on regular time intervals. Through this analysis, we demonstrate that repetitive testing strategies can significantly reduce the attack rate in schools, contrary to a reactive screening or a symptomatic isolation approach. However, when a repetitive testing strategy is in place, more cases will be detected and class and school closures are more easily triggered, leading to a higher number of school days lost per child. While maintaining the epidemic under control with a repetitive testing strategy, we show that absenteeism can be reduced by relaxing class and school closure thresholds., Competing Interests: AT, LW, VC, CK, CM, GD, PL No competing interests declared, NH Reviewing editor, eLife, (© 2022, Torneri et al.)

As end-users, employees appropriate technologies. Technology appropriation is generally conceived as a covert phenomenon. In particular, alternative ways and new purposes for which employees deploy technologies tend to remain hidden. Therefore, the potential of technologies as a source of organizational improvements may remain undisclosed. Continuous improvement (CI) programs, in contrast, are explicitly oriented at disclosing organizational improvements. In essence, CI programs encourage employees to openly discuss how to improve their work practices. Such continuous movements towards novel, often better, ways of working may be perfectly suited to bring the covert nature of technology appropriation into the open. Based on a case study on a personal digital assistant (PDA) in a Belgian nursing home with such a CI program in place, we document and analyze to what extent and why functionalities of the PDA were discussed and further developed. We distinguish between the functionalities that, upon implementation, intended to improve particular work practices, and those that surfaced after the technology had been introduced. To conclude, we point at employees' perceived usefulness of their work practices and their willingness to improve these, rather than only the technology itself, to further the debate on technology appropriation.

Industrial ammonia production without CO 2 emission and with low energy consumption is one of the technological grand challenges of this age. Current Haber-Bosch ammonia mass production processes work with a thermally activated iron catalyst needing high pressure. The need for large volumes of hydrogen gas and the continuous operation mode render electrification of Haber-Bosch plants difficult to achieve. Electrochemical solutions at low pressure and temperature are faced with the problematic inertness of the nitrogen molecule on electrodes. Direct reduction of N 2 to ammonia is only possible with very reactive chemicals such as lithium metal, the regeneration of which is energy intensive. Here, the attractiveness of an oxidative route for N 2 activation was presented. N 2 conversion to NO x in a plasma reactor followed by reduction with H 2 on a heterogeneous catalyst at low pressure could be an energy-efficient option for small-scale distributed ammonia production with renewable electricity and without intrinsic CO 2 footprint., (© 2022 Wiley-VCH GmbH.)

Carbonation of alkali activated materials is one of the main deteriorations affecting their durability. However, current understanding of the structural alteration of these materials exposed to an environment inducing carbonation at the nano/micro scale remains limited. This study examined the evolution of phase assemblages of alkali activated slag mortars subjected to accelerated carbonation (1% CO 2 , 60% relative humidity, up to 28 day carbonation) using XRD, FTIR and 29 Si, 27 Al, and 23 Na MAS NMR. Samples with three water to binder (w/b) ratios (0.35, 0.45, and 0.55) were investigated. The results show that the phase assemblages mainly consisted of C-A-S-H, a disordered remnant aluminosilicate binder, and a minor hydrotalcite as a secondary product. Upon carbonation, calcium carbonate is mainly formed as the vaterite polymorph, while no sodium carbonate is found after carbonation as commonly reported. Sodium acts primarily as a charge balancing ion without producing sodium carbonate as a final carbonation product in the 28-day carbonated materials. The C-A-S-H structure becomes more cross-linked due to the decalcification of this phase as evidenced by the appearance of Q 4 groups, which replace the Q 1 and Q 2 groups as observed in the 29 Si MAS NMR spectra, and the dominance of Al(IV) in 27 Al MAS NMR. Especially, unlike cementitious materials, the influence of w/b ratio on the crystalline phase formation and structure of C-A-S-H in the alkali activated mortars before and after carbonation is limited., (© 2022. The Author(s).)