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Relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains one of the leading causes of cancer mortality in children. We performed Hi-C, ATAC-seq, and RNA-seq on 12 matched diagnosis/relapse pediatric leukemia specimens to uncover dynamic structural variants (SVs) and 3D chromatin rewiring that may contribute to relapse. While translocations are assumed to occur early in leukemogenesis and be maintained throughout progression, we discovered novel, dynamic translocations and confirmed several fusion transcripts, suggesting functional and therapeutic relevance. Genome-wide chromatin remodeling was observed at all organizational levels: A/B compartments, TAD interactivity, and chromatin loops, including some loci shared by 25% of patients. Shared changes were found to drive the expression of genes/pathways previously implicated in resistance as well as novel therapeutic candidates, two of which (ATXN1 and MN1) we functionally validated. Overall, these results demonstrate chromatin reorganization under the selective pressure of therapy and offer the potential for discovery of novel therapeutic interventions., (© 2024. The Author(s).)

Objective: Liver cirrhosis is an increasing cause of morbidity and mortality worldwide with a heavy load on healthcare systems. We analysed the trends in hospitalisations for cirrhosis in Switzerland., Design: Cross-sectional study., Setting: Large nationwide inpatient database, years between 1998 and 2020., Participants: Hospitalisations for cirrhosis of adult patients were selected., Main Outcomes and Measures: Hospitalisations with either a primary diagnosis of cirrhosis or a cirrhosis-related primary diagnosis with a mandatory presence of cirrhosis as a secondary diagnosis were considered following the 10th revision of the International Statistical Classification of Diseases and Related Health Problems codes. Trends in demographic and clinical characteristics, in-hospital mortality and length of stay were analysed. Causes and costs of cirrhosis-related hospitalisations were available from 2012 onwards., Results: Cirrhosis-related hospitalisations increased from 1631 in 1998 to 4052 in 2020. Of the patients, 68.7% were men. Alcohol-related liver disease was the leading cause, increasing from 44.1% (95% CI, 42.4% to 45.9%) in 2012 to 47.9% (95% CI, 46.4% to 49.5%) in 2020. Assessed by exclusion of other coded causes, non-alcoholic fatty liver disease was the second cause at 42.7% (95% CI, 41.2% to 44.3%) in 2020. Hepatitis C virus-related cirrhosis decreased from 12.3% (95% CI, 11.2% to 13.5%) in 2012 to 3.2% (95% CI, 2.7% to 3.8%) in 2020. Median length of stay decreased from 11 to 8 days. Hospitalisations with an intensive care unit stay increased from 9.8% (95% CI, 8.4% to 11.4%) to 15.6% (95% CI, 14.5% to 16.8%). In-hospital mortality decreased from 12.1% (95% CI, 10.5% to 13.8%) to 9.7% (95% CI, 8.8% to 10.7%). Total costs increased from 54.4 million US$ (51.4 million €) in 2012 to 92.6 million US$ (87.5 million €) in 2020., Conclusions: Cirrhosis-related hospitalisations and related costs increased in Switzerland from 1998 to 2020 but in-hospital mortality decreased. Alcohol-related liver disease and non-alcoholic fatty liver disease were the most prevalent and preventable aetiologies of cirrhosis-related hospitalisations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The controlled expression of two or more proteins at a defined and stable ratio remains a substantial challenge, particularly in the bi- and multispecific antibody field. Achieving an optimal ratio of protein subunits can facilitate the assembly of multimeric proteins with high efficiency and minimize the production of by-products. In this study, we propose a solution based on alternative splicing, enabling the expression of a tunable and predefined ratio of two distinct polypeptide chains from the same pre-mRNA under the control of a single promoter. The pre-mRNA used in this study contains two open reading frames situated on separate exons. The first exon is flanked by two copies of the chicken troponin intron 4 (cTNT-I4) and is susceptible to excision from the pre-mRNA by means of alternative splicing. This specific design enables the modulation of the splice ratio by adjusting the strength of the splice acceptor. To illustrate this approach, we developed constructs expressing varying ratios of GFP and dsRED and extended their application to multimeric proteins such as monoclonal antibodies, achieving industrially relevant expression levels (>1 g/L) in a 14-day fed-batch process. The stability of the splice ratio was confirmed by droplet digital PCR in a stable pool cultivated over a 28-day period, while product quality was assessed via intact mass analysis, demonstrating absence of product-related impurities resulting from undesired splice events. Furthermore, we showcased the versatility of the construct by expressing two subunits of a bispecific antibody of the BEAT® type, which contains three distinct subunits in total.

Introduction: Patients with immune-mediated glomerular diseases are considered at high risk for severe COVID-19 outcomes. However, conclusive evidence for this patient population is scarce., Methods: We created a global registry and retrospectively collected clinical data of patients with COVID-19 and a previously diagnosed immune-mediated glomerular disease to characterize specific risk factors for severe COVID-19 outcomes., Results: Fifty-nine patients with a history of immune-mediated glomerular diseases were diagnosed with COVID-19 between 01.03.2020 and 31.08.2021. Over a mean follow-up period of 24.79 ± 18.89 days, ten patients (16.9%) developed acute kidney injury. Overall, 44.1% of patients were managed in an outpatient setting and therefore considered as having "non-severe" COVID-19, while 55.9% of patients had severe COVID-19 requiring hospitalization including worse outcomes. Comparing both groups, patients with severe COVID-19 were significantly older (53.55 ± 17.91 versus 39.77 ± 14.95 years, p = .003), had lower serum albumin levels at presentation (3.00 ± 0.80 g/dL versus 3.99 ± 0.68 g/dL, p = .016) and had a higher risk of developing acute kidney injury (27% versus 4%, p = .018). Male sex (p <.001) and ongoing intake of corticosteroids at presentation (p = .047) were also significantly associated with severe COVID-19 outcomes, while the overall use of ongoing immunosuppressive agents and glomerular disease remission status showed no significant association with the severity of COVID-19 (p = .430 and p = .326, respectively)., Conclusion: Older age, male sex, ongoing intake of corticosteroids and lower serum albumin levels at presentation were identified as risk factors for severe COVID-19 outcomes in patients with a history of various immune-mediated glomerular diseases., Competing Interests: PG received consulting fees from CLS Vifor and lecture fees from Otsuka Pharma GmbH. AK received grants from CSL Vifor and Otsuka, consulting fees from CSL Vifor, Otsuka, Walden Biosciences and Catalyst Biosciences, honoraria for lectures from CSL Vifor and Otsuka and support for attending meetings from CSL Vifor and Otsuka. DG received consulting fees from ChemoCentryx, Amgen, Otsuka, Aurinia Inc and GSK. BO reports receiving fees or research grants from CSL Vifor, Otsuka and Delta4. FA received consulting fees and honoraria for lectures from AstraZeneca. AB received consulting fees and honoraria for lectures from AstraZeneca, Bayer, ChemoCentryx, Fresenius, Merck/MSD, and Vifor and received payment for expert testimony from The Swedish National Board of Health and Welfare and chaired the Immunonephrology Working Group of ERA unpaid. VA received supporting attending meetings from Sanofi Genzyme, and reports board participations for Alnylam, Addmedica, AstraZeneca, Bayer and ViforPharma. KJ received consulting fees from GlaxoSmithKline, George Clinical, PMV Pharmaceuticals and Caliditas and honoraria for lectures from ASN and uptodate.com. MW received honoraria for lectures from Otsuka and participated on advisory boards for Otsuka, Delta4 and CSL Vifor. 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., (Copyright © 2023 Gauckler, Kesenheimer, Geetha, Odler, Eller, Laboux, Alberici, Zappa, Chebotareva, Moiseev, Bonilla, Jhaveri, Oniszczuk, Audard, Costa, Mastroianni-Kirsztajn, Bruchfeld, Muto, Windpessl, Mayer and Kronbichler.)

Epidemic Intelligence (EI) encompasses all activities related to early identification, verification, analysis, assessment, and investigation of health threats. It integrates an indicator-based (IBS) component using systematically collected surveillance data, and an event-based component (EBS), using non-official, non-verified, non-structured data from multiple sources. We described current EI practices in Europe by conducting a survey of national Public Health (PH) and Animal Health (AH) agencies. We included generic questions on the structure, mandate and scope of the institute, on the existence and coordination of EI activities, followed by a section where respondents provided a description of EI activities for three diseases out of seven disease models. Out of 81 gatekeeper agencies from 41 countries contacted, 34 agencies (42%) from 26 (63%) different countries responded, out of which, 32 conducted EI activities. Less than half (15/32; 47%) had teams dedicated to EI activities and 56% (18/34) had Standard Operating Procedures (SOPs) in place. On a national level, a combination of IBS and EBS was the most common data source. Most respondents monitored the epidemiological situation in bordering countries, the rest of Europe and the world. EI systems were heterogeneous across countries and diseases. National IBS activities strongly relied on mandatory laboratory-based surveillance systems. The collection, analysis and interpretation of IBS information was performed manually for most disease models. Depending on the disease, some respondents did not have any EBS activity. Most respondents conducted signal assessment manually through expert review. Cross-sectoral collaboration was heterogeneous. More than half of the responding institutes collaborated on various levels (data sharing, communication, etc.) with neighbouring countries and/or international structures, across most disease models. Our findings emphasise a notable engagement in EI activities across PH and AH institutes of Europe, but opportunities exist for better integration, standardisation, and automatization of these efforts. A strong reliance on traditional IBS and laboratory-based surveillance systems, emphasises the key role of in-country laboratories networks. EI activities may benefit particularly from investments in cross-border collaboration, the development of methods that can automatise signal assessment in both IBS and EBS data, as well as further investments in the collection of EBS data beyond scientific literature and mainstream media., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Cys 2 His 2 zinc finger (ZF) domains engineered to bind specific target sequences in the genome provide an effective strategy for programmable regulation of gene expression, with many potential therapeutic applications. However, the structurally intricate engagement of ZF domains with DNA has made their design challenging. Here we describe the screening of 49 billion protein-DNA interactions and the development of a deep-learning model, ZFDesign, that solves ZF design for any genomic target. ZFDesign is a modern machine learning method that models global and target-specific differences induced by a range of library environments and specifically takes into account compatibility of neighboring fingers using a novel hierarchical transformer architecture. We demonstrate the versatility of designed ZFs as nucleases as well as activators and repressors by seamless reprogramming of human transcription factors. These factors could be used to upregulate an allele of haploinsufficiency, downregulate a gain-of-function mutation or test the consequence of regulation of a single gene as opposed to the many genes that a transcription factor would normally influence., (© 2023. The Author(s).)

Introduction: Indoor residual spraying (IRS) and insecticide-treated bed nets (ITNs) are cornerstone malaria prevention methods in Madagascar. This retrospective observational study uses routine data to evaluate the impacts of IRS overall, sustained IRS exposure over multiple years and level of spray coverage (structures sprayed/found) in nine districts where non-pyrethroid IRS was deployed to complement standard pyrethroid ITNs from 2017 to 2020., Methods: Multilevel negative-binomial generalised linear models were fit to estimate the effects of IRS exposure overall, consecutive years of IRS exposure and spray coverage level on monthly all-ages population-adjusted malaria cases confirmed by rapid diagnostic test at the health facility level. The study period extended from July 2016 to June 2021. Facilities with missing data and non-geolocated communes were excluded. Facilities in IRS districts were matched with control facilities by propensity score analysis. Models were controlled for ITN survivorship, mass drug administration coverage, precipitation, enhanced vegetation index, seasonal effects and district. Predicted cases under a counterfactual no IRS scenario and number of cases averted by IRS were estimated using the fitted models., Results: Exposure to IRS overall reduced case incidence by an estimated 30.3% from 165.8 cases per 1000 population (95% CI=139.7 to 196.7) under a counterfactual no IRS scenario, to 114.3 (95% CI=96.5 to 135.3) over 12 months post-IRS campaign in nine districts. A third year of IRS reduced malaria cases 30.9% more than a first year (incidence rate ratio (IRR)=0.578, 95% CI=0.578 to 0.825, p<0.001) and 26.7% more than a second year (IRR=0.733, 95% CI=0.611 to 0.878, p=0.001). There was no significant difference between the first and second year (p>0.05). Coverage of 86%-90% was associated with a 19.7% reduction in incidence (IRR=0.803, 95% CI=0.690 to 0.934, p=0.005) compared with coverage ≤85%, although these results were not robust to sensitivity analysis., Conclusion: This study demonstrates that non-pyrethroid IRS appears to substantially reduce malaria incidence in Madagascar and that sustained implementation of IRS over three years confers additional benefits., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The Puumala virus (PUUV) is a hantavirus that causes hemorrhagic fever with renal syndrome. Studies showing an increased risk of lymphoid malignancies after hantavirus infection, together with the observation that PUUV infects B cells, motivated us to study the risk of lymphoid malignancies after PUUV infection., Methods: We linked data from the Finnish Cancer Registry and National Infectious Diseases Register for 2009-2019. We used a time-dependent Cox regression model to evaluate the hazard of the lymphoid malignancies grouped according to the HAEMACARE classification., Results: We identified 68 cases of lymphoid malignancies after PUUV infection among 16,075 PUUV-infected individuals during 61,114,826 person-years of observation. A total of 10 cases occurred within 3-<12 months and 38 within 1-<5 years after PUUV infection, and the risk of lymphoid malignancies increased with hazard ratios (HRs) of 2.0 (95% confidence interval [CI], 1.1-3.7) and 1.6 (95% CI, 1.2-2.3), respectively. The group of mature B cell neoplasms showed an increased risk 3-<12 months and 1-<5 years after PUUV infection, HR 2.2 (95% CI, 1.2-4.3) and HR 1.8 (95% CI, 1.3-2.5), respectively., Conclusion: PUUV infection is associated with lymphoid malignancies in the Finnish population, supporting the earlier studies. Further research is required to understand the pathophysiological mechanisms behind this association., Competing Interests: Declaration of competing interest TD works in Monitoring Outbreaks for Disease surveillance in a data science context (MOOD)/Horizon 2020 project, for which funding is received from the Finnish Institute for Health and Welfare and is a member of the executive board of MOOD Horizon 20202. TD also works on a project for vector-borne diseases and climate change in Finland (VECLIMIT), for which funding is received by the Finnish Institute for Health and Welfare from the Academy of Finland. JS owns stocks in a company (Genmab) that is involved in lymphoma drug development. EK reports a grant paid for their institution from the Finnish Society of Sciences and Letters for PUUV research outside of the submitted work., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

French Guiana (FG), a French overseas territory in South America, is susceptible to tropical diseases, including arboviruses. The tropical climate supports the proliferation and establishment of vectors, making it difficult to control transmission. In the last ten years, FG has experienced large outbreaks of imported arboviruses such as Chikungunya and Zika , as well as endemic arboviruses such as dengue, Yellow fever , and Oropouche virus. Epidemiological surveillance is challenging due to the differing distributions and behaviors of vectors. This article aims to summarize the current knowledge of these arboviruses in FG and discuss the challenges of arbovirus emergence and reemergence. Effective control measures are hampered by the nonspecific clinical presentation of these diseases, as well as the Aedes aegypti mosquito's resistance to insecticides. Despite the high seroprevalence of certain viruses, the possibility of new epidemics cannot be ruled out. Therefore, active epidemiological surveillance is needed to identify potential outbreaks, and an adequate sentinel surveillance system and broad virological diagnostic panel are being developed in FG to improve disease management.

Previous studies indicated that in some species phylogeographic patterns obtained in the analysis of nuclear and mitochondrial DNA (mtDNA) markers can be different. Such mitonuclear discordance can have important evolutionary and ecological consequences. In the present study, we aimed to check whether there was any discordance between mtDNA and nuclear DNA in the bank vole population in the contact zone of its two mtDNA lineages. We analysed the population genetic structure of bank voles using genome-wide genetic data (SNPs) and diversity of sequenced heart transcriptomes obtained from selected individuals from three populations inhabiting areas outside the contact zone. The SNP genetic structure of the populations confirmed the presence of at least two genetic clusters, and such division was concordant with the patterns obtained in the analysis of other genetic markers and functional genes. However, genome-wide SNP analyses revealed the more detailed structure of the studied population, consistent with more than two bank vole recolonisation waves, as recognised previously in the study area. We did not find any significant differences between individuals representing two separate mtDNA lineages of the species in functional genes coding for protein-forming complexes, which are involved in the process of cell respiration in mitochondria. We concluded that the contemporary genetic structure of the populations and the width of the contact zone were shaped by climatic and environmental factors rather than by genetic barriers. The studied populations were likely isolated in separate Last Glacial Maximum refugia for insufficient amount of time to develop significant genetic differentiation., (© 2023. The Author(s), under exclusive licence to The Genetics Society.)

Background: In case of high risk of lymph node invasion after endoscopic resection (ER) of superficial esophageal squamous cell carcinoma (SCC), adjuvant chemoradiotherapy (CRT) can be an alternative to surgery. We assessed long-term clinical outcomes of adjuvant therapy by CRT after non-curative ER for superficial SCC., Methods: We performed a retrospective multicenter study. From April 1999 to April 2018, all consecutive patients who underwent ER for SCC with tumor infiltration beyond the muscularis mucosae were included., Results: A total of 137 ER were analyzed. The overall nodal or metastatic recurrence-free survival rate at 5 years was 88% and specific recurrence-free survival rates at 5 years with and without adjuvant therapy were, respectively, 97.9% and 79.1% ( p = 0.011). Independent factors for nodal and/or distal metastatic recurrence were age (HR = 1.075, p = 0.031), Sm infiltration depth > 200 µm (HR = 4.129, p = 0.040), and the absence of adjuvant CRT or surgery (HR = 11.322, p = 0.029)., Conclusion: In this study, adjuvant therapy is associated with a higher recurrence-free survival rate at 5 years after non-curative ER. This result suggests this approach may be considered as an alternative to surgery in selected patients.

Context: There is a general health decline among farmers and the leading cause of death in this population remains cardiovascular (CV) diseases. The situation is similar in the Guianese general population, with a preoccupying increase in CV diseases. However, there are no data on farmers' health., Methods: A cross-sectional study analyzed data from the "Novembre Vert" action conducted in 2018 in French Guiana. Beneficiaries and farmers affiliated to the Mutualité Sociale Agricole who completed the survey were included. The objective was to assess their CV risk., Results: 603 farmers were included. The sex-ratio was 1.6 and the median age was 52. Over 70% of the participants had a Body Mass Index ≥ 25, with a greater risk of obesity in the female population. High blood pressure (HBP) affected 53.1% of farmers and 80.1% were diagnosed during screening. About 13.5% had diabetes. Overall, 27% of participants were at high or very high CV risk. CV risk was 3 times greater in men., Conclusion: HBP (53.1%), obesity (30.3%) and diabetes (13.5%) prevalence are particularly worrying and underline the importance of policies to reduce cardiovascular morbimortality among farmers.

Background: Despite experiencing the second-highest rate of HIV incidence in the United States, pre-exposure prophylaxis (PrEP) use remains low among Black women due, in part, to a lack of patients' awareness and providers' knowledge., Objective: Our goal was to design animated educational tools informed by patients and women's health providers to address these barriers, specifically for women at risk for HIV., Methods: Two animation storyboards about PrEP for women were created by academic stakeholders (eg, HIV clinical experts, educators, and HIV peer counselors), one for patients and one for providers. Four focus groups with community members from Baltimore, Maryland and four with women's health providers (eg, obstetrician/gynecologists, midwives, nurse practitioners, and peer counselors) at an academic center were conducted to discuss the storyboards. Transcripts were analyzed using conventional content analysis, and themes were incorporated into the final versions of the animations., Results: Academic stakeholders and 30 focus group participants (n=16 female community members and n=14 women's health providers) described important themes regarding PrEP. The themes most commonly discussed about the patient animation were understandability of side effects, HIV risk factors, messaging, PrEP access, and use confidence. Provider animation themes were indications for PrEP, side effects, and prescribing confidence., Conclusions: We created two PrEP animations focused on women. Stakeholder feedback highlighted the importance of ensuring the understandability and applicability of PrEP educational materials while including necessary information to facilitate use or prescribing confidence. Both community members and women's health providers reported greater use confidence after viewing the animations., (©Anna Marie Young, Timothee Fruhauf, Obianuju Okonkwo, Erin Gingher, Jenell Coleman. Originally published in JMIR Formative Research (https://formative.jmir.org), 08.07.2022.)

Background: Endoscopic papillectomy is a minimally invasive treatment for benign tumors of the ampulla of Vater or early ampullary carcinoma. However, reported recurrence rates are significant and risk factors for recurrence are unclear., Objective: The aims of this study were to evaluate the efficacy and safety of endoscopic papillectomy and to identify risk factors for recurrence and adverse events., Methods: All patients who underwent endoscopic papillectomy at five tertiary referral centers between January 2008 and December 2018 were included. Recurrence was defined as the detection of residue on one of the follow-up endoscopies. Treatment success was defined as the absence of tumor residue on the last follow-up endoscopy., Results: A total of 227 patients were included. The resections were en bloc in 64.8% of cases. The mean lesion size was 20 mm (range: 3-80) with lateral extension in 23.3% of cases. R0 resection was achieved in 45.3% of cases. The recurrence rate was 30.6%, and 60.7% of recurrences were successfully treated with additional endoscopic treatment. Finally, treatment success was achieved in 82.8% of patients with a median follow-up time of 22.3 months. R1 resection, intraductal invasion, and tumor size > 2 cm were associated with local recurrence. Adverse events occurred in 36.6% of patients and included pancreatitis (17.6%), post-procedural hemorrhage (11.0%), perforation (5.2%), and biliary stenosis (2.6%). The mortality rate was 0.9%., Conclusion: Endoscopic papillectomy is an effective and relatively well-tolerated treatment for localized ampullary tumors. In this series, R1 resection, intraductal invasion, and lesion size > 2 cm were associated with local recurrence., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Background: French Guiana is used as a drug trafficking pipeline of cocaine to Europe. The number of arrests for transporting cocaine in corpore has increased exponentially in recent years. Since 2010, Cayenne Hospital's emergency care unit has applied a medical management protocol system for body-packers. Our objective was to describe the epidemiology of body-packers and to evaluate medical management., Method: A retrospective descriptive study was performed among patients hospitalized in Cayenne Hospital for transporting cocaine in corpore between January 2010 and November 2015. In addition, a qualitative study including interviews of body-packers imprisoned in Rémire-Montjoly prison was conducted in April 2016., Result: A total of 282 patients were included in the study. The median age was 24 years and the sex ratio M/W was to 4/1. Among them, 3.5% showed signs of severity (9 with pre-existing condition and 1 with severe form). No surgery or deaths were reported. Ten endoscopies were performed because of the delay in evacuation without complications. Approximately 28% of patients had urinary screening, of which 60.7% were positive. The median length of stay was 1.8 days. Prolonged length of stay was significantly associated with the presence of gastrointestinal symptoms, hypoglycemia, or having swallowed a minimum of 10 pellets., Conclusion: This study led to a change in the management of body-packers in the hospital setting in Guiana. A computed tomography scan at discharge became more prevalent. Endoscopy has emerged as an effective and safe alternative to surgery. Despite the increase in the number of patients treated, it should be noted that there were few complications and no deaths in our cohort., Competing Interests: The authors declare no competing interests., (© 2022 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Background: The cause of the motor neuron (MN) death that drives terminal pathology in amyotrophic lateral sclerosis (ALS) remains unknown, and it is thought that the cellular environment of the MN may play a key role in MN survival. Several lines of evidence implicate vesicles in ALS, including that extracellular vesicles may carry toxic elements from astrocytes towards MNs, and that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. Because MN degeneration at the neuromuscular junction is a feature of ALS, and muscle is a vesicle-secretory tissue, we hypothesized that muscle vesicles may be involved in ALS pathology., Methods: Sporadic ALS patients were confirmed to be ALS according to El Escorial criteria and were genotyped to test for classic gene mutations associated with ALS, and physical function was assessed using the ALSFRS-R score. Muscle biopsies of either mildly affected deltoids of ALS patients (n = 27) or deltoids of aged-matched healthy subjects (n = 30) were used for extraction of muscle stem cells, to perform immunohistology, or for electron microscopy. Muscle stem cells were characterized by immunostaining, RT-qPCR, and transcriptomic analysis. Secreted muscle vesicles were characterized by proteomic analysis, Western blot, NanoSight, and electron microscopy. The effects of muscle vesicles isolated from the culture medium of ALS and healthy myotubes were tested on healthy human-derived iPSC MNs and on healthy human myotubes, with untreated cells used as controls., Results: An accumulation of multivesicular bodies was observed in muscle biopsies of sporadic ALS patients by immunostaining and electron microscopy. Study of muscle biopsies and biopsy-derived denervation-naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome-like vesicles and disruption of RNA-processing. Compared with vesicles from healthy control myotubes, when administered to healthy MNs the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA-processing proteins. The RNA-processing protein FUS and a majority of its binding partners were present in ALS muscle vesicles, and toxicity was dependent on the expression level of FUS in recipient cells. Toxicity to recipient MNs was abolished by anti-CD63 immuno-blocking of vesicle uptake., Conclusions: ALS muscle vesicles are shown to be toxic to MNs, which establishes the skeletal muscle as a potential source of vesicle-mediated toxicity in ALS., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: This translational study explores multi-tracer PET imaging for the non-invasive detection of the IDH1 mutation which is a positive prognostic factor in glioma., Methods: U87 human high-grade glioma (HGG) isogenic cell lines with or without the IDH1 mutation (CRISP/Cas9 method) were stereotactically grafted into rat brains, and examined, in vitro, in vivo and ex vivo. PET imaging sessions, with radiotracers specific for glycolytic metabolism ([ 18 F]FDG), amino acid metabolism ([ 18 F]FDopa), and inflammation ([ 18 F]DPA-714), were performed sequentially during 3-4 days. The in vitro radiotracer uptake was expressed as percent per million cells. For each radiotracer examined in vivo, static analyses included the maximal and mean tumor-to-background ratio (TBR max and TBR mean ) and metabolic tumor volume (MTV). Dynamic analyses included the distribution volume ratio (DVR) and the relative residence time (RRT) extracted from a reference Logan model. Ex vivo analyses consisted of immunological analyses., Results: In vitro, IDH1+ cells (i.e. cells expressing the IDH1 mutation) showed lower levels of [ 18 F]DPA-714 uptake compared to IDH1- cells (p < 0.01). These results were confirmed in vivo with lower [ 18 F]DPA-714 uptake in IDH+ tumors (3.90 versus 5.52 for TBR max , p = 0.03). Different values of [ 18 F]DPA-714 and [ 18 F] FDopa RRT (respectively 11.07 versus 22.33 and 2.69 versus - 1.81 for IDH+ and IDH- tumors, p < 0.02) were also observed between the two types of tumors. RRT [ 18 F]DPA-714 provided the best diagnostic performance to discriminate between the two cell lines (AUC of 100%, p < 0.01). Immuno-histological analyses revealed lower expression of Iba-1 and TSPO antibodies in IDH1+ tumors., Conclusions: [18F]DPA-714 and [18F] FDopa both correlate with the presence of the IDH1 mutation in HGG. These radiotracers are therefore good candidates for translational studies investigating their clinical applications in patients., (© 2022. The Author(s).)

Background: Transcatheter aortic valve implantation (TAVI) is nowadays the optimal therapeutic strategy in patients with severe aortic valve stenosis (AS). Consequently, percutaneous coronary intervention (PCI) of concomitant complex coronary artery disease (CAD) has increased in the last decade to optimize patients with severe AS before TAVI. Although the Impella ventricular assist device (Abiomed) was considered as a relative contraindication in patients with AS, its usage has demonstrated promising results in selected patients., Methods: All consecutive patients with severe AS who underwent staged approach with high-risk PCI of unprotected left main (ULM) using the Impella ventricular assist device before TAVI were retrospectively included. The primary endpoint was 30-day all-cause mortality, and secondary endpoints were peri-interventional mortality, vascular complication, and 30-day stroke rates. Due to the exploratory, observational intent of the study, no statistical analysis was performed., Results: Twenty-one consecutive patients (14 men; age, 80 ± 6 years; log EuroScore, 17 ± 7; SYNTAX score, 27 ± 10) were included. All patients (21/21) survived to 30-day follow-up exam. Three patients (14%) had PCI of ULM and TAVI at the same session. Eighteen patients (86%) underwent TAVI in a staged approach after previous PCI (10 ± 10 days). No patient suffered from stroke up to 30-day follow-up. One patient (5%) developed Valve Academic Research Consortium-2 major vascular complication after PCI. TAVI was successfully performed in all patients., Conclusion: Temporary hemodynamic support with the Impella device during staged approach with high-risk protected PCI appears to be safe and technically feasible in patients with severe AS before undergoing TAVI.

In this opinion article, we discuss the formatting of files from (plant) genotyping studies, in particular the formatting of (meta-) data in Variant Call Format (VCF) files. The flexibility of the VCF format specification facilitates its use as a generic interchange format across domains but can lead to inconsistency between files in the presentation of metadata. To enable fully autonomous machine actionable data flow, generic elements need to be further specified. We strongly support the merits of the FAIR principles and see the need to facilitate them also through technical implementation specifications. VCF files are an established standard for the exchange and publication of genotyping data. Other data formats are also used to capture variant call data (for example, the HapMap format and the gVCF format), but none currently have the reach of VCF. In VCF, only the sites of variation are described, whereas in gVCF, all positions are listed, and confidence values are also provided. For the sake of simplicity, we will only discuss VCF and our recommendations for its use. However, the part of the VCF standard relating to metadata (as opposed to the actual variant calls) defines a syntactic format but no vocabulary, unique identifier or recommended content. In practice, often only sparse (if any) descriptive metadata is included. When descriptive metadata is provided, proprietary metadata fields are frequently added that have not been agreed upon within the community which may limit long-term and comprehensive interoperability. To address this, we propose recommendations for supplying and encoding metadata, focusing on use cases from the plant sciences. We expect there to be overlap, but also divergence, with the needs of other domains., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Beier S et al.)

Single-cell RNA sequencing (scRNA-seq) is a powerful technique for dissecting the complexity of normal and diseased tissues, enabling characterization of cell diversity and heterogeneous phenotypic states in unprecedented detail. However, this technology has been underutilized for exploring the interactions between the host cell and viral pathogens in latently infected cells. Herein, we use scRNA-seq and single-molecule sensitivity fluorescent in situ hybridization (smFISH) technologies to investigate host single-cell transcriptome changes upon the reactivation of a human neurotropic virus, herpes simplex virus-1 (HSV-1). We identify the stress sensor growth arrest and DNA damage-inducible 45 beta (Gadd45b) as a critical antiviral host factor that regulates HSV-1 reactivation events in a subpopulation of latently infected primary neurons. We show that distinct subcellular localization of Gadd45b correlates with the viral late gene expression program, as well as the expression of the viral transcription factor, ICP4. We propose that a hallmark of a "successful" or "aborted" HSV-1 reactivation state in primary neurons is determined by a unique subcellular localization signature of the stress sensor Gadd45b., (© 2021 The Authors.)

BackgroundIn Finland, surveillance of tularaemia relies on laboratory-confirmed case notifications to the National infectious Diseases Register (NIDR).AimThe aim of the study was to assess the suitability and usefulness of clinical surveillance as an addition to laboratory notification to improve tularaemia surveillance in Finland.MethodsWe retrieved NIDR tularaemia surveillance and primary healthcare data on clinically diagnosed tularaemia cases in Finland between 2013 and 2019. We compared incidences, demographic distributions and seasonal trends between the two data sources.ResultsThe median annual incidence was 0.6 (range: 0.1-12.7) and 0.8 (range: 0.6-7.2) per 100,000 for NIDR notifications and primary healthcare notifications, respectively. Cases reported to NIDR were slightly older than cases reported to primary healthcare (median: 53 years vs 50 years, p = 0.04), but had similar sex distribution. Seasonal peaks differed between systems, both in magnitude and in timing. On average, primary healthcare notifications peaked 3 weeks before NIDR. However, peaks in NIDR were more pronounced, for example in 2017, monthly incidence per 100,000 of NIDR notifications peaked at 12.7 cases in September, while primary healthcare notifications peaked at 7.2 (1.8 ratio) in August.ConclusionsClinically diagnosed cases provide a valuable additional data source for surveillance of tularaemia in Finland. A primary healthcare-based system would allow for earlier detection of increasing incidences and thereby for early warning of outbreaks. This is crucial in order to implement targeted control and prevention measures as early as possible.

The ASCENT trial reports impressive results with a median overall survival (OS) increased from 6.7 months to 12.1 months with sacituzumab govitecan over single-agent chemotherapy, in metastatic triple negative breast cancer (TNBC) patients in second and subsequent line of therapy. We described design features in the ASCENT trial casting doubt on the extrapolation of the reported results to real world patients. First, the open-label design may exaggerate the effect of the experimental arm. Second, the choice of progression-free-survival (PFS) as a primary endpoint, debatable in metastatic TNBC, can lead to biases: early stopping rules may exaggerate efficacy results and informative censoring can bias PFS results interpretation. Third, the control arm was not a complete "physician's choice": it was restricted, preventing from using effective agents in this setting, and leading to a substandard control arm. Fourth and lastly, dose reduction and supportive care recommendations for the experimental drug were different between the trial protocol and the FDA labels, and favored the experimental arm as compared with the control arm. In conclusion, we described four design features in the ASCENT trial having the potential to favor the experimental arm or to penalize the control arm. It thus remains uncertain in which extent the reported outcomes will translate in the real world. Efforts should be made to avoid trial biases that will eventually prevent to conclude about their true impact in patients when applied broadly., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Many studies ask whether young or older males are better at acquiring mates. Even so, how age affects reproductive success is still poorly understood because male age and mating history are confounded in most studies: older males usually have more mating experience. To what extent does mating history rather than age explain variation in male mating success? And how do mating history and male age determine paternity when there is also postcopulatory sexual selection? Here, we experimentally manipulated the mating history of old and young males in the eastern mosquitofish (Gambusia holbrooki). We then recorded male mating behavior and share of paternity (1259 offspring from 232 potential sires) when they competed for mates and fertilizations. Old males, and males with no mating experience, spent significantly more time approaching females, and attempting to mate, than did young males and those with greater mating experience. Male age and mating history interacted to affect paternity: old males benefited from having previous mating experience, but young males did not. Our results highlight that the age-related changes in male reproductive traits and in paternity that have been described in many taxa may be partly attributable to male mating history and not simply to age itself., (© 2021 The Authors. Evolution © 2021 The Society for the Study of Evolution.)

Hypothesis: It is expected that low resolution (LR) NMR diffusometry enables (more) accurate water droplet size determination for solid-fat based water-in-oil (W/O) emulsions with (sub)-micron size water droplets in comparison to liquid-oil based W/O emulsions due to hindered extra-droplet water diffusion., Experiments: W/O emulsions with a volume-weighed mean diameter of about 1 µm and a solid fat content (SFC) ranging from 0% to 74% were produced. The aqueous phase contained the ionic marker tetraphenylphosphonium chloride (TPPCl). The water droplet size was estimated using LR and high resolution (HR) NMR diffusometry., Findings: HR-NMR diffusometry showed that the diffusion behavior of water and TPPCl was different, indicating water diffusion beyond the droplet's interfacial boundaries. From a certain SFC onwards, a slower echo decay was observed for the water molecules, thus decreasing the overestimation of the water droplet size in (sub)micron W/O emulsions. For those emulsions, the solid fat matrix is believed to hinder extra-droplet water diffusion, which is most likely to be related to the increased tortuosity of the diffusive path in the porous fat crystal network. Using LR-NMR, it can be verified whether the water echo attenuation is mono-exponential or bi-exponential by increasing the gradient pulse duration for the maximum gradient strength, which is more convenient for routine analysis compared to HR-NMR., 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 © 2021 Elsevier Inc. All rights reserved.)

The World Health Organization has presented their recommendations for energy expenditure to improve public health. Activity trackers do represent a modern solution for measuring physical activity, particularly in terms of steps/day and energy expended in physical activity (active energy expenditure). According to the manufacturer's instructions, these activity trackers can be placed on different body locations, mostly at the wrist and the hip, in an undifferentiated manner. The objective of this study was to compare the absolute error rate of active energy expenditure measured by a wrist-worn and hip-worn ActiGraph GT3X+ over a 24-h period in free-living conditions in young and older adults. Over the period of a 24-h period, 22 young adults and 22 older adults were asked to wear two ActiGraph GT3X+ at two different body locations recommended by the manufacturer, namely one around the wrist and one above the hip. Freedson algorithm was applied for data analysis. For both groups, the absolute error rate tended to decrease from 1,252 to 43% for older adults and from 408 to 46% for young participants with higher energy expenditure. Interestingly, for both young and older adults, the wrist-worn ActiGraph provided a significantly higher values of active energy expenditure (943 ± 264 cal/min) than the hip-worn (288 ± 181 cal/min). Taken together, these results suggest that caution is needed when using active energy expenditure as an activity tracker-based metric to quantify physical activity., 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 © 2021 Guediri, Robin, Lacroix, Aubourg, Vuillerme and Mandigout.)

We update our previous insights into COVID-19 vaccine acceptance and hesitancy in Finland. Vaccine acceptance increased from 64% (November/December 2020) to 74% (April 2021). However, there was a group of participants that were preferring to wait to get vaccinated ranging from 6% of over-64-years-olds to 29% of under-30-years-olds. The previously identified enablers convenience (below-50-years-olds), worry about severe disease and protection for oneself (above-50-years-olds) were no longer significantly associated with increased vaccine acceptance. Understanding barriers and enablers behind vaccine acceptance is decisive in ensuring a successful implementation of COVID-19 vaccination programs, which will be key to ending the pandemic.

Following spinal cord injury (SCI) for larval lampreys, descending axons of reticulospinal (RS) neurons regenerate, and locomotor function gradually recovers. In the present study, the electrophysiological properties of uninjured (left)-injured (right) pairs of large, identified RS neurons were compared following rostral, right spinal cord hemi-transections (HTs). First, changes in firing patterns of injured RS neurons began in as little as 2-3 days following injury, these changes were maximal at ~2-3 weeks (wks), and by 12-16 wks normal firing patterns were restored for the majority of neurons. Second, at ~2-3 wks following spinal cord HTs, injured RS neurons displayed several significant changes in properties compared to uninjured neurons: (a) more hyperpolarized V REST ; (b) longer membrane time constant and larger membrane capacitance; (c) increased voltage and current thresholds for action potentials (APs); (d) larger amplitudes and durations for APs; (e) higher slope for the repolarizing phase of APs; (f) virtual absence of some afterpotential components, including the slow afterhyperpolarization (sAHP); (g) altered, injury-type firing patterns; and (h) reduced average and peak firing (spiking) frequencies during applied depolarizing currents. These altered properties, referred to as the "injury phenotype", reduced excitability and spiking frequencies of injured RS neurons compared to uninjured neurons. Third, artificially injecting a current to add a sAHP waveform following APs for injured neurons or removing the sAHP following APs for uninjured neurons did not convert these neurons to normal firing patterns or injury-type firing patterns, respectively. Fourth, trigeminal sensory-evoked synaptic responses recorded from uninjured and injured pairs of RS neurons were not significantly different. Following SCI, injured lamprey RS neurons displayed several dramatic changes in their biophysical properties that are expected to reduce calcium influx and provide supportive intracellular conditions for axonal regeneration.

Conserved ATP-dependent chromatin remodelers establish and maintain genome-wide chromatin architectures of regulatory DNA during cellular lifespan, but the temporal interactions between remodelers and chromatin targets have been obscure. We performed live-cell single-molecule tracking for RSC, SWI/SNF, CHD1, ISW1, ISW2, and INO80 remodeling complexes in budding yeast and detected hyperkinetic behaviors for chromatin-bound molecules that frequently transition to the free state for all complexes. Chromatin-bound remodelers display notably higher diffusion than nucleosomal histones, and strikingly fast dissociation kinetics with 4-7 s mean residence times. These enhanced dynamics require ATP binding or hydrolysis by the catalytic ATPase, uncovering an additional function to its established role in nucleosome remodeling. Kinetic simulations show that multiple remodelers can repeatedly occupy the same promoter region on a timescale of minutes, implicating an unending 'tug-of-war' that controls a temporally shifting window of accessibility for the transcription initiation machinery., Competing Interests: JK, PV, VJ, SL, XT, KL, JS, CW No competing interests declared, QZ, LL LDL and QZ are listed as inventors on patents and patent applications whose value might be affected by publication. US Patent 9,933,417 and Patent Application 2021/0085805 describing azetidine-containing fluorophores and variant compositions (with inventors QZ, LDL, and TL) are assigned to HHMI. TL TL holds intellectual property rights related to Janelia Fluor dyes used in this publication. US Patent 9,933,417 and Patent Application 2021/0085805 describing azetidine-containing fluorophores and variant compositions (with inventors QZ, LDL, and TL) are assigned to HHMI., (© 2021, Kim et al.)

Background: Withdrawal dominates the contraceptive method mix in a geographical cluster of countries in South-Eastern Europe and Western Asia that have, in part, reached low fertility. This study examines the socio-demographic determinants associated with withdrawal use in Armenia, Albania, Jordan and Turkey that could explain withdrawal's persistence and inform contraceptive programs in these unique settings. Methods: Cross-sectional data on 31,569 married women 15 to 49 years were drawn from the Demographic and Health Surveys in Albania (2017-2018), Armenia (2015-2016), Jordan (2017-2018), and Turkey (2013). For each country, multinomial regression models estimating withdrawal use among all women and logistic regression models estimating withdrawal use among contraceptive users were used to evaluate the association with age, marital duration, parity, education, residence, and household wealth. Results: The socio-demographic determinants associated with withdrawal use varied by country among all women and among all contraceptive users. While these associations were not all significant for all four countries general trends included that women were more likely to use withdrawal than not use contraception, but less likely to use withdrawal than other methods with increasing parity, higher education, and greater household wealth. Measures of association are reported by country for each correlate. Conclusions: Despite the similar contraceptive mix in these four countries, no single set of factors was found to explain withdrawal's persistence. Withdrawal's prevalence in this geographical cluster may instead result from different balances of intertwined circumstances that include couples' fertility decisions, access to modern contraception and availability of abortion services., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Fruhauf T et al.)

Aim: To describe the epidemiological aspects, etiology and outcome of iatrogenic ureteral injury repair at the urology division of Souro Teaching Hospital of Bobo Dioulasso (Burkina-Faso)., Patients and Methods: This was a retrospective descriptive study of consecutive patients with iatrogenic ureteric injuries who were referred and managed in the urology division of Souro Sanou Teaching Hospital (Bobo-Dioulasso) from January 2012 to December 2017. Variables studied were age, the time at the diagnosis, the causative event, the method of repair, and the outcome of the management., Results: The mean age was 37.72±3.5 years coming from the rural population in most cases. The mean time at the diagnosis was 15 days. The injuries were due to gynecologic surgeries with hysterectomy (66%) and caesarian section (33%). Ureteric reimplantation with anti-reflux system was performed in seventeen patients. The rate of treatment success was 94% and the postoperative course was uneventful for all the patients., Conclusion: Iatrogenic ureteric lesions at the department of urology of Sanou Sourou teaching hospital of Bobo Dioulasso were mainly caused by gynecologic and obstetric surgeries like hysterectomy and caesarian section., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Ouattara et al.)

Background: Team-based and timely integrated palliative care is a gold standard of care in oncology, but issues concerning its optimal organization remain. Palliative Care in Day-Hospital (PCDH) could be one of the most efficient service model of palliative care to deliver interdisciplinary and multidimensional care addressing the complex supportive care needs of patients with advanced cancer. We hypothesize that, compared to conventional outpatient palliative care, PCDH allows the clinical benefits of palliative care to be enhanced., Methods/design: This study is a multicentre parallel group trial with stratified randomization. Patient management in PCDH will be compared to conventional outpatient palliative care. The inclusion criteria are advanced cancer patients referred to a palliative care team with an estimated life expectancy of more than 2 months and less than 1 year. The primary endpoint is health-related quality of life with deterioration-free survival based on the EORTC QLQ-C30 questionnaire. The secondary objectives are the following: increase in patient satisfaction with care using the EORTC PATSAT-C33 and OUT-PATSAT7 questionnaires, better understanding of the prognosis using the PTPQ questionnaire and advance care planning; decrease in the need for supportive care among relatives using the SCNS-P&C-F questionnaire, and reduction in end-of-life care aggressiveness. Patients will complete one to five questionnaires on a tablet before each monthly visit over 6 months and will be followed for 1 year. A qualitative study will take place, aiming to understand the specificity of palliative care management in PCDH. Cost-effectiveness, cost-utility and, an additional economic evaluation based on capability approach will be conducted from a societal point of view., Discussion: The first strength of this study is that it combines the main relevant outcomes assessing integrated palliative care; patient quality of life and satisfaction; discussion of the prognosis and advance care planning, family well-being and end-of-life care aggressiveness. The second strength of the study is that it is a mixed-method study associating a qualitative analysis of the specificity of PCDH organization, with a medical-economic study to analyse the cost of care., Trial Registration: Name of the registry: IDRCB 2019-A03116-51 Trial registration number: NCT04604873 Date of registration: October 27, 2020 URL of trial registry record.

Background: The COVID-19 pandemic has intensely changed the everyday lives of people worldwide. This study explores the forms and outcomes of coronavirus and COVID-19-related social stigma and the experiences of people who were home quarantined or isolated in Finland during the spring 2020. The findings of this study can be used to improve support for those quarantined or isolated and to develop strategies to reduce the stigma associated with coronavirus and COVID-19., Methods: The study is based on qualitative one-to-one interviews with households with at least two members and at least one PCR confirmed COVID-19 case. Recruitment took place via website or SMS messages sent to PCR confirmed cases in the capital area of Helsinki. Sampling was based on maximum variation to acquire different types of respondents. The framework of health stigma was used to develop question guides and analyze stigma. Quarantine and isolation experiences were explored through open-ended questions. The analysis was based on thematic analysis., Results: The study included 64 participants from 24 households. Perceived stigma among respondents was driven by fear and blame for infection, and it manifested in various ways leading to a reluctance to disclose their coronavirus status to others. Self-stigma developed from conflicting information and advice about coronavirus and COVID-19 led to difficulties interacting with others outside of the house and reluctance to meet people after quarantine and isolation. Quarantine and isolation experiences included uncertainty, health concerns, and boredom. Communication with others in similar situations was perceived vital, whereas discussions with family members about worries and fears related to coronavirus and COVID-19 was not preferred., Conclusions: This study shed light on the lives of those quarantined or isolated at home and provided a set of operational recommendations to minimize coronavirus and COVID-19-associated stigma and to reduce challenges faced by those in quarantine or isolation., Competing Interests: No authors have no competing interest.

Healthcare workers (HCWs) are at increased risk of both exposure and transmission of infectious disease. Two European Union (EU) directives state that health services are responsible for assessing their employees' potential exposure to infectious diseases and offering immunisation free of charge. We assessed current policy for immunisation of HCWs and the availability of vaccine coverage data in the Nordic countries by surveying national vaccination experts in Denmark, Finland, Iceland, Norway and Sweden, as well as Swedish county medical officers (CMOs). All national experts and 17 of 21 Swedish CMOs responded. All EU countries had transposed the European directives into national law, while Norway and Iceland had similar national legislation. Recommendations or guidelines were issued in Denmark, Finland, Iceland, Norway and 15 of 17 responding Swedish counties. The range of diseases covered differed by countries and Swedish counties. HCW vaccine coverage data were not systematically collected; incomplete estimates were only available for Finland and two Swedish counties. In conclusion, recommendations or guidelines exist in the Nordic countries, but their impact cannot be assessed, as vaccine uptake among HCWs is not currently measured. Systematic collection of data is a necessary step towards improving HCW immunisation policy and practice in the Nordic countries.

COVID-19 patients (n = 114) were included (55 patients with pneumonia (group P) and 59 without pneumonia (group NP). Patients in group P were older (69 (±17) years vs 46 (±16); p < 0.001) with a male predominance (58.2% vs 27.1%; p < 0.001). The symptoms which were statistically more frequents in patients with pneumonia were fever ≥ 38 °C (93% vs 70%; p = 0.002) and dyspnea (73% vs 22%; p < 0.001). Symptoms such as facial headache (42% vs 15%; p = 0.001), sore throat (39% vs 16%; p = 0.007), dysgeusia (61% vs 33%; p = 0.003), anosmia (63% vs 31%; p = 0.001) were statistically more frequents in patients without pneumonia., (Copyright © 2020 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

The H2A.Z histone variant, a genome-wide hallmark of permissive chromatin, is enriched near transcription start sites in all eukaryotes. H2A.Z is deposited by the SWR1 chromatin remodeler and evicted by unclear mechanisms. We tracked H2A.Z in living yeast at single-molecule resolution, and found that H2A.Z eviction is dependent on RNA Polymerase II (Pol II) and the Kin28/Cdk7 kinase, which phosphorylates Serine 5 of heptapeptide repeats on the carboxy-terminal domain of the largest Pol II subunit Rpb1. These findings link H2A.Z eviction to transcription initiation, promoter escape and early elongation activities of Pol II. Because passage of Pol II through +1 nucleosomes genome-wide would obligate H2A.Z turnover, we propose that global transcription at yeast promoters is responsible for eviction of H2A.Z. Such usage of yeast Pol II suggests a general mechanism coupling eukaryotic transcription to erasure of the H2A.Z epigenetic signal., Competing Interests: AR, VN, SL, JW, JK, XT, GM, EE, TN, VJ, BE, QZ, EL, LL, TL, CW No competing interests declared

Avian influenza and Newcastle disease viruses (AIV, NDV) are major pathogens of captive and wild birds worldwide. Wetlands and their associated bird communities, especially waterfowl and shorebirds, are known to play a central role in the epidemiology of these diseases as maintenance hosts. However, these viruses also circulate in places where these ecosystems and communities are uncommon, suggesting the involvement of other taxa in their epidemiological cycles. In the arid region of Abu Dhabi of the United Arab Emirates (UAE), both viruses are regularly detected, and represent a threat for local poultry and for the Houbara Bustard ( Chlamydotis macqueenii ) conservation breeding programs. To assess the presence, transmission, and maintenance of these viruses in such environments, 4,521 individuals from six resident and peridomestic wild bird species were sampled in the vicinity of two Houbara Bustard conservation breeding centers, and tested for AIV and NDV using real-time reverse transcriptase PCR and an enzyme-linked immunosorbent assay. A limited exposure to AIV was reflected in a virus prevalence below 0.4% and a serologic prevalence of 0.6%, and a moderate circulation of NDV was indicated by a virus prevalence of 0.9% and a serologic prevalence of 18.9% in the targeted peridomestic wild birds, suggesting different epidemiological roles for each taxa. Thus, some peridomestic species could actively participate in the epidemiological cycle of NDV in arid environments such as the UAE, challenging the conceptual epidemiologic framework centered on the involvement of waterfowl and shorebirds.

The relative roles that movement and proximity networks play in the spread of highly pathogenic avian influenza (HPAI) viruses are often unknown during an epidemic, preventing effective control. We used network analysis to explore the devastating epidemic of HPAI A(H5N8) among poultry, in particular ducks, in France during 2016-2017 and to estimate the likely contribution of live-duck movements. Approximately 0.2% of live-duck movements could have been responsible for between-farm transmission events, mostly early during the epidemic. Results also suggest a transmission risk of 35.5% when an infected holding moves flocks to another holding within 14 days before detection. Finally, we found that densely connected groups of holdings with sparse connections between groups overlapped farmer organizations, which represents important knowledge for surveillance design. This study highlights the importance of movement bans in zones affected by HPAI and of understanding transmission routes to develop appropriate HPAI control strategies.

Evolutionary adaptation is generally thought to occur through incremental mutational steps, but large mutational leaps can occur during its early stages. These are challenging to study in nature due to the difficulty of observing new genetic variants as they arise and spread, but characterizing their genomic dynamics is important for understanding factors favoring rapid adaptation. Here, we report genomic consequences of recent, adaptive song loss in a Hawaiian population of field crickets ( Teleogryllus oceanicus ). A discrete genetic variant, flatwing , appeared and spread approximately 15 years ago. Flatwing erases sound-producing veins on male wings. These silent flatwing males are protected from a lethal, eavesdropping parasitoid fly. We sequenced, assembled and annotated the cricket genome, produced a linkage map, and identified a flatwing quantitative trait locus covering a large region of the X chromosome. Gene expression profiling showed that flatwing is associated with extensive genome-wide effects on embryonic gene expression. We found that flatwing male crickets express feminized chemical pheromones. This male feminizing effect, on a different sexual signaling modality, is genetically associated with the flatwing genotype. Our findings suggest that the early stages of evolutionary adaptation to extreme pressures can be accompanied by greater genomic and phenotypic disruption than previously appreciated, and highlight how abrupt adaptation might involve suites of traits that arise through pleiotropy or genomic hitchhiking., (© 2019 The Authors. Evolution Letters published by Wiley Periodicals, Inc. on behalf of Society for the Study of Evolution (SSE) and European Society for Evolutionary Biology (ESEB).)