Search

Negative expectations can increase pain, but can they promote the development of central sensitization? This study used an inert treatment and verbal suggestions to induce expectations of increased high-frequency electrical stimulation (HFS)-induced pain and assessed their effects on pain ratings during HFS and HFS-induced pinprick hypersensitivity. Fifty healthy volunteers were randomly allocated to either a control group (N = 25) or a nocebo group (N = 25). Participants in both groups received a patch containing water on the right forearm. The nocebo group was told that the patch contained capsaicin that sensitized their skin, while the control group was told that the patch contained water that had no effect on skin sensitivity. Before and after patch attachment, single electrical stimuli were delivered to the area of the patch to measure the perceived intensity to these stimuli. After patch removal and after the participant rated expected pain and fear for HFS, HFS was delivered to the same skin site, followed by the assessment of pinprick sensitivity. The nocebo group rated the perceived intensity for the single electrical stimulus after removal of the patch as more intense compared with the control group, indicating that our manipulation worked. Yet, this effect did not transfer to expected pain for HFS, nor did it affect pain intensity ratings during HFS. HFS increased pinprick sensitivity but no group differences were found. Because of the lack of differences in expected pain and pain intensity ratings for HFS between groups, no firm conclusions can be drawn regarding their effect on pinprick hypersensitivity. PERSPECTIVE: This study shows that sham treatment combined with verbal suggestions induces a nocebo effect but does not necessarily change expectations and experience of upcoming pain., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

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.)

Background and Aims: The muscle retracting sign (MRS) can be present during endoscopic submucosal dissection (ESD) of macronodular colorectal lesions. The prevalence of MRS and its pathologic and clinical implications is unclear. This study evaluated the effect of MRS on the technical and clinical outcomes of ESD., Methods: All patients referred for ESD of protruding lesions or granular mixed lesions with >10 mm macronodule granular mixed laterally spreading tumors (LST-GMs) in 2 academic centers from January 2017 to October 2022 were prospectively included. Size of the macronodule was analyzed retrospectively. The primary outcome was the curative resection rate according to MRS status. Secondary outcomes were R0 resection, perforation, secondary surgery rate, and risk factors for MRS., Results: Of 694 lesions, 84 (12%) had MRS (MRS+). The curative resection rate was decreased by MRS (MRS+ 41.6% vs lesions without MRS [MRS-] 81.3%), whereas the perforation (MRS+ 22.6% vs MRS- 9.2%), submucosal cancer (MRS+ 34.9% vs MRS- 9.2%), and surgery (MRS+ 45.2% vs MRS- 6%) rates were increased. The R0 resection rate of MRS+ colonic lesions was lower than that of rectal lesions (53% vs 74.3%). In multivariate analysis, protruding lesions (odds ratio, 2.47; 95% confidence interval, 1.27-4.80) and macronodules >4 cm (odds ratio, 4.24; 95% confidence interval, 2.23-8.05) were risk factors for MRS., Conclusions: MRS reduces oncologic outcomes and increases the perforation rate. Consequently, procedures in the colon should be stopped if MRS is detected, and those in the rectum should be continued due to the morbidity of alternative therapy., Competing Interests: Disclosure The following authors disclosed financial relationships: J. Albouys: support for meeting from Amgen; consulting for Boston Scientific; remunerated lecture for Fujifilm; and ESD training for Erbe. M. Schaefer: Consultant for AbbVie; honoraria from Alfasigma, Boston Scientific, Duomed Endoscopy, Erbe Medical, Ferring, and Norgine; and meeting support from Boston Scientific, Cook, Cousin Endoscopy, Erbe, Ipsen, Janssen, Medtronic, Olympus, MSD, and Takeda R. Legros: training event for Pentax Medical, Fujifilm, Erbe, Olympus; and consulting for Boston Scientific. P. Leclercq: speaker fee and advisory board for Medtronic; speaker fee for Erbe; and travel grant from Olympus. M. Dahan: remunerated lecture for MSD; meeting support from Amgen; and training event for Fujifilm. A. Guyot: remunerated lecture for MSD. P. Carrier: consulting for AbbVie; support for meeting from Ipsen; and remunerated lecture for Gilead. V. Loustaud-Ratti: consulting for AbbVie and Gilead; and remunerated lecture for Ipsen. H. Lepetit: remunerated lecture for Fujifilm; and ESD training for Erbe. S. Geyl: remunerated lecture for AbbVie, Galapagos, and Ipsen; and support for meeting from Janssen and Takeda. T. Wallenhorst: training event for Fujifilm and Olympus; and support for meeting from AbbVie. M. Pioche: training event for Olympus, Fujifilm, and Viatris; and educational purposes for Boston Scientific, Olympus, Norgine, and AlfaSigma. J. Jacques: training event for Pentax Medical, Fujifilm, Erbe, and Olympus; and consulting for Boston Scientific. All other authors disclosed no financial relationships., (Copyright © 2024. Published by Elsevier Inc.)

Pathology diagnosis based on EEG signals and decoding brain activity holds immense importance in understanding neurological disorders. With the advancement of artificial intelligence methods and machine learning techniques, the potential for accurate data-driven diagnoses and effective treatments has grown significantly. However, applying machine learning algorithms to real-world datasets presents diverse challenges at multiple levels. The scarcity of labeled data, especially in low regime scenarios with limited availability of real patient cohorts due to high costs of recruitment, underscores the vital deployment of scaling and transfer learning techniques. In this study, we explore a real-world pathology classification task to highlight the effectiveness of data and model scaling and cross-dataset knowledge transfer. As such, we observe varying performance improvements through data scaling, indicating the need for careful evaluation and labeling. Additionally, we identify the challenges of possible negative transfer and emphasize the significance of some key components to overcome distribution shifts and potential spurious correlations and achieve positive transfer. We see improvement in the performance of the target model on the target (NMT) datasets by using the knowledge from the source dataset (TUAB) when a low amount of labeled data was available. Our findings demonstrated that a small and generic model (e.g. ShallowNet) performs well on a single dataset, however, a larger model (e.g. TCN) performs better in transfer learning when leveraging a larger and more diverse dataset., Competing Interests: Declaration of competing interest None Declared., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation., Significance: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027., (©2023 American Association for Cancer Research.)

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.

The diversity and utility of cinematic volume rendering (CVR) for medical image visualization have grown rapidly in recent years. At the same time, volume rendering on augmented and virtual reality systems is attracting greater interest with the advance of the WebXR standard. This paper introduces CVR extensions to the open-source visualization toolkit (vtk.js) that supports WebXR. This paper also summarizes two studies that were conducted to evaluate the speed and quality of various CVR techniques on a variety of medical data. This work is intended to provide the first open-source solution for CVR that can be used for in-browser rendering as well as for WebXR research and applications. This paper aims to help medical imaging researchers and developers make more informed decision when selecting CVR algorithms for their applications. Our software and this paper also provide a foundation for new research and product development at the intersection of medical imaging, web visualization, XR, and CVR.

Purpose: Incarcerated women are a vulnerable population in terms of sexual and reproductive health. In French Guiana, most incarcerated women come from unsafe environments and are incarcerated because of drug trafficking. Medical follow-up processes used in prison (medical assessment on arrival, and then two half-days per week upon request but without an obstetrician-gynecologist) does not allow for a thorough assessment of the impact of incarceration on women prisoners' health to take place. In the absence of data, the purpose of this study was to describe incarcerated women's experiences in relation to sexual and reproductive health., Design/methodology/approach: Semi-structured interviews were conducted among French-speaking adult women who had been incarcerated for at least four months in a French Guianan prison. Menstruation, contraception, pregnancy, abortion, sexually transmitted infections and sexuality were described by means of interpretative phenomenological analysis., Findings: A total of 14 women were interviewed. They suffered from menstrual cycle disorders, poor hygiene and menstrual insecurity. They appeared to have emotionally disinvested sexuality. However, intra-prison sexual activity existed for some (masturbation, conjugal prison visits, homosexual intercourse between fellow prisoners). Homosexual relations were a source of discrimination. Being pregnant while incarcerated was viewed negatively. A lack of knowledge about sexual and reproductive health and high-risk behaviors such as piercing and tattooing practices were widespread., Originality/value: Incarceration is a vulnerable time for women's sexual and reproductive health. Sexual activity exposes women to risks and discrimination that should be taken into account in a multidisciplinary approach adapted to the prison environment., (© Emerald Publishing Limited.)

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.)

Modeling biological neural networks has been a field opening to major advances in our understanding of the mechanisms governing the functioning of the brain in normal and pathological conditions. The emergence of real-time neuromorphic platforms has been leading to a rising significance of bio-hybrid experiments as part of the development of neuromorphic biomedical devices such as neuroprosthesis. To provide a new tool for the neurological disorder characterization, we design real-time single and multicompartmental Hodgkin-Huxley neurons on FPGA. These neurons allow biological neural network emulation featuring improved accuracy through compartment modeling and show integration in bio-hybrid system thanks to its real-time dynamics.

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.)

Objectives: The purpose of this retrospective observational study is to report author's experience in computed-tomography (CT)-guided percutaneous vertebroplasty (PV) of the cervicothoracic junction., Methods: The records of all consecutive patients treated by PV at levels C7, T1, T2, and T3 in a tertiary cancer center during year 2020 were extracted from the Institutional electronic archive. Following data were collected: demographics, indication for PV, procedure features, outcomes, and complications. Technical success was defined as when the trocar was placed into the vertebral body, allowing the injection of polymethyl-metacrylate (PMMA)., Results: Eleven patients were identified who received PV on 14 levels. Mean procedure duration was 57 ± 22 min (range [31-142]). A "trans-pedicular approach at the targeted level" was used in 1 vertebra (7%), a "costotransverse approach, at the targeted level" was used in 1 vertebra (7%), a "transpedicular approach via the level below" was used in 3 vertebrae (22%), and a "costotransverse approach via the level below" was used in 9 vertebrae (64%). Meantime to deploy each trocar was 20 ± 5 min (range [12-32]). Technical success was achieved in 14/14 (100%) of vertebrae. Mean postoperative hospitalization duration was 1.9 ± 1.7 days (range [1-11]). According to CIRSE classification, no adverse event occurred. PMMA leakage occurred in two patients; both remained asymptomatic., Conclusion: This study provides arguments in favor of safety and efficiency of CT-guided vertebroplasty of levels C7, T1, T2, and T3, for both trocar deployment and monitoring of the vertebral body filling during the PMMA injection., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

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.)

Competing Interests: The authors declare that they have no conflict of interest

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.)

Infectious diseases are a major burden to global economies, and public and animal health. To date, quantifying the spread of infectious diseases to inform policy making has traditionally relied on epidemiological data collected during epidemics. However, interest has grown in recent phylodynamic techniques to infer pathogen transmission dynamics from genetic data. Here, we provide examples of where this new discipline has enhanced disease management in public health and illustrate how it could be further applied in animal health. In particular, we describe how phylodynamics can address fundamental epidemiological questions, such as inferring key transmission parameters in animal populations and quantifying spillover events at the wildlife-livestock interface, and generate important insights for the design of more effective control strategies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. 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: Temporomandibular disorders (TMD) are characterised by complex symptomatology and their assessment can be enhanced using pain drawings (PD)., Objectives: To evaluate the location and extent of pain in people TMD using digital PD, and to explore their association with clinical features. Reliability of pain extent and pain location using PD was also assessed., Methods: Forty volunteers with TMD completed two consecutive digital PDs. Clinical features were captured from self-reported questionnaire. Additionally, secondary hyperalgesia was measured using the pressure pain threshold (PPT). The correlation between pain extent and clinical features was investigated using Spearman rank correlation coefficients. Reliability of pain extent was evaluated using intraclass correlation coefficient (ICC) and Bland-Altman plots. The Jaccard index was computed to assess the reliability of pain location., Results: Analysis of the PDs indicated that people with TMD commonly experience pain in other body regions including the neck, the shoulder and the low back. Except for PPT and pain catastrophising, all other clinical features were significantly correlated with pain extent. The ICCs of pain extent for all body charts were very high (ICCs 95% CI from 0.73 to 0.96), and Bland-Altman plots showed mean biases close to zero with narrow limits of agreement. The reliability of pain location was also supported by Jaccard index mean scores above 0.68., Conclusions: People with TMD showed widespread pain, and pain extent was associated with pain intensity, neck and headache-related disability, depression, anxiety, hyperventilation and central sensitivity. The reliability of measuring pain extent and pain location was confirmed., (© 2021 John Wiley & Sons Ltd.)

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.)