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The thermal scattering laws (TSL) take into account the crystalline structure and atomic motions of isotopes bound in materials. This paper presents the CINEL code, which was developed to generate temperature-dependent TSL for solid, liquid and free gas materials of interest for nuclear reactors. CINEL is able to calculate TSL from the phonon density of states (PDOS) of materials under the Gaussian-Incoherent approximations. The PDOS can be obtained by using theoretical approaches (e.g., ab initio density functional theory and molecular dynamics) or experimental results. In this work, the PDOS presented in the ENDF/BVIII.0 and NJOY-NCrystal libraries were used for numerical validation purposes. The CINEL results are in good agreement with those reported in these databases, even in the specific cases of TSL with the newly mixed elastic format. The coding flexibility offered by Python using the JupyterLab interface allowed to investigate limits of physical models reported in the literature, such as a four-site model for UO2, anharmonic behaviors of oxygen atoms bound in a Fm3m structure, texture in Zry4 samples and jump corrections in a roto-translational diffusion model for liquid water. The use of graphic processing units (GPU) is a necessity to perform calculations in a few minutes. The performances of the CINEL code is illustrated with the results obtained on actinide oxides having a Fm3m structure (UO2, ThO2, NpO2 and PuO2), low enriched fuel (UMo), cladding (Zry4) and moderators (H2O with a specific emphasis on ice).

Plastic pollution is a global environmental threat with potentially irreversible impacts on aquatic life, ecosystems, and human health. This study is a comprehensive assessment of the global apparel industry's contribution to plastic pollution. It includes plastic leakage of packaging and end-of-life apparel waste in addition to fiber emissions during apparel production and use. We estimate that the apparel industry generated 8.3 [4.8-12.3] million tons (Mt) of plastic pollution in 2019, corresponding to 14% [5.5%-30%] of the estimated 60 Mt from all sectors. In this study, we demonstrate that the main source of plastic pollution from the apparel supply chain is synthetic clothing as mismanaged waste either in the country of its original use or in the countries receiving used apparel exports. A fundamental transformation of the apparel economy towards a circular framework and decreased synthetic apparel consumption is needed to tackle apparel-related plastic pollution., (© 2024. The Author(s).)

Background: Epidemiological data reveal that 45% of persons with multiple sclerosis (PwMS) in France are more than 50 years. This population more than 50 is more susceptible to cancer, and this risk may be increased by frequent use of immunosuppressive drugs. Consequently, concerns have arisen about the potential increased risk of cancer in PwMS and how patients should be screened and managed in terms of cancer risk., Objective: To develop evidence-based recommendations to manage the coexistence of cancer and multiple sclerosis (MS)., Methods: The French Group for Recommendations in MS collected articles from PubMed and university databases covering the period January 1975 through June 2022. The RAND/UCLA method was employed to achieve formal consensus. MS experts comprehensively reviewed the full-text articles and developed the initial recommendations. A group of multidisciplinary health care specialists then validated the final proposal., Results: Five key questions were addressed, encompassing various topics such as cancer screening before or after initiating a disease-modifying therapy (DMT), appropriate management of MS in the context of cancer, recommended follow-up for cancer in patients receiving a DMT, and the potential reintroduction of a DMT after initial cancer treatment. A strong consensus was reached for all 31 recommendations., Conclusion: These recommendations propose a strategic approach to managing cancer risk in PwMS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: N. Collongues has received honoraria for consulting or presentation from Alexion, Biogen Idec, Bristol-Myers Squibb, Horizon Therapeutics, Merck Serono, Novartis, Roche, and Sanofi-Genzyme and is a member of the Editorial Board of the Journal de la Ligue Française contre la Sclérose en plaques and the Neurology and Therapy Journal. Françoise Durand-Dubief has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Biogen, BMS-Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Christine Lebrun Frenay has nothing to disclose. Géraldine Androdias has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme. Bertrand Audoin has nothing to disclose. Xavier Ayrignac has received consulting fees and lecturing fess, travel grants, and unconditional research support from Alexion, Biogen, Genzyme, Janssen, Merck Serono, Novartis, Roche, Sanofi Aventis, and Teva Pharma. Caroline Bensa has received consulting honoraria from Alexion, Sanofi, Merck, Biogen, BMS, and Novartis. Kevin Bigaut has received lecturing fees and travel grants from Biogen, Celgene-BMS, Novartis, Roche, and Sanofi-Genzyme. Julie Boucher has nothing to disclose. Bertrand Bourre serves on the scientific advisory board and has received funding for travel and honoraria from Alexion, Biogen, BMS, Horizon, Janssen, Merck, Novartis, Sanofi, and Roche. Clemence Boutiere has nothing to disclose. Pierre Branger has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, and Sanofi-Genzyme. C. Carra-Dalliere has received travel grants and/or consulting fees from Alexion, Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme. Jonathan Ciron has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Biogen, Novartis, Merck, Sanofi, Roche, Celgene-BMS, Alexion, and Horizon Therapeutics. Angelique Da Silva has received personal fees from Daichi and Leopharma. Gilles Defer has received personal fees from Biogen, Bristol-Myers Squibb, Merck Serono, Novartis, Sanofi-Genzyme, and Teva Pharmaceuticals. Sarah Demortière has nothing to disclose. Maxime Guillaume has received honoraria from Novartis, Merck, and Sanofi. Benjamin Hebant has nothing to disclose. Edouard Januel has nothing to disclose. Anne Kerbrat has nothing to disclose. Arnaud Kwiatkowski has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Biogen, Merck Serono, Novartis, Sanofi-Genzyme, Roche, and Teva. Emmanuelle Leray has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme. Elisabeth Maillart has received research support from Biogen and personal fees for lectures and serving on advisory boards from Biogen, Janssen, Merck, Novartis, Roche, Sanofi, and Teva. Guillaume Mathey has nothing to disclose. Xavier Moisset has received financial support from Allergan-Abbvie, Biogen, BMS, Grünenthal, Lilly, Lundbeck, Teva, Merck Serono, Novartis, Pfizer, Roche, and Sanofi-Genzyme and non-financial support from SOS Oxygène not related to the submitted work. Alexis Montcuquet has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Alexison, Biogen, Merck Serono, Novartis, Sanofi-Genzyme, Roche, and Teva. Nathalie Morel has nothing to disclose. Romain Marignier has received personal fees from Horizon Therapeutics, Alexion, Roche, and UCB; and nonfinancial support from Horizon Therapeutics, Merck, Biogen, and Roche. Chloe Pierret has nothing to disclose. Julie Pique has received travel grants and personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Teva, Biogen, Novartis, Merck, Sanofi-Genzyme, Roche, Celgene-BMS, and Alexion. Julien Poupart has nothing to disclose. Chloe Prunis has nothing to disclose. Eric Thouvenot has received personal fees from Actelion and Teva and grants from Biogen, Merck Serono, Novartis, and Roche. Thomas Roux has received personal compensation for consulting, speaking, or serving on a scientific advisory board from Alexion, Biogen, BMS-Celgene, Merck, Novartis, and Sanofi-Genzyme. Perrine Schmitt has nothing to disclose. Helene Zephir has nothing to disclose. Mikael Cohen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Ad Scientiam, Biogen, Merck, Sanofi-Genzyme, Roche, Celgene-BMS, Alexion, and Horizon Therapeutics.

The study of S100A9 in viral infections has seen increased interest since the COVID-19 pandemic. S100A8/A9 levels were found to be correlated with the severity of COVID-19 disease, cytokine storm, and changes in myeloid cell subsets. These data led to the hypothesis that S100A8/A9 proteins might play an active role in COVID-19 pathogenesis. This review explores the structures and functions of S100A8/9 and the current knowledge on the involvement of S100A8/A9 and its constituents in viral infections. The potential roles of S100A9 in SARS-CoV-2 infections are also discussed., (Copyright © 2024 by The American Association of Immunologists, Inc.)

CDK12 is a transcriptional cyclin-dependent kinase (CDK) that interacts with cyclin K to regulate different aspects of gene expression. The CDK12-cyclin K complex phosphorylates several substrates, including RNA polymerase II (Pol II), and thereby regulates transcription elongation, RNA splicing, as well as cleavage and polyadenylation. Because of its implication in cancer, including breast cancer and melanoma, multiple pharmacological inhibitors of CDK12 have been identified to date, including THZ531 and SR-4835. While both CDK12 inhibitors affect Poll II phosphorylation, we found that SR-4835 uniquely promotes cyclin K degradation via the proteasome. Using loss-of-function genetic screening, we found that SR-4835 cytotoxicity depends on a functional CUL4-RBX1-DDB1 ubiquitin ligase complex. Consistent with this, we show that DDB1 is required for cyclin K degradation, and that SR-4835 promotes DDB1 interaction with the CDK12-cyclin K complex. Docking studies and structure-activity relationship analyses of SR-4835 revealed the importance of the benzimidazole side-chain in molecular glue activity. Together, our results indicate that SR-4835 acts as a molecular glue that recruits the CDK12-cyclin K complex to the CUL4-RBX1-DDB1 ubiquitin ligase complex to target cyclin K for degradation., (© 2023. The Author(s).)

White matter is often severely affected after human ischaemic stroke. While animal studies have suggested that various factors may contribute to white matter structural damage after ischaemic stroke, the characterization of damaging processes to the affected hemisphere after human stroke remains poorly understood. Thus, the present study aims to thoroughly describe the longitudinal pattern of evolution of diffusion magnetic resonance imaging metrics in different parts of the ipsilesional white matter after stroke. We acquired diffusion and anatomical images in 17 patients who had suffered from a single left hemisphere ischaemic stroke, at 24-72 h, 8-14 days and 6 months post-stroke. For each patient, we created three regions of interest: (i) the white matter lesion; (ii) the perilesional white matter; and (iii) the remaining white matter of the left hemisphere. We extracted diffusion metrics (fractional anisotropy, mean, axial and radial diffusivities) for each region and conducted two-way repeated measures ANOVAs with stage post-stroke (acute, subacute and chronic) × regions of interest (white matter lesion, perilesional white matter and remaining white matter). Fractional anisotropy values stayed consistent across time-points, with significantly lower values in the white matter lesion compared to the perilesional white matter and remaining white matter tissue. Fractional anisotropy values of the perilesional white matter were also significantly lower than that of the remaining white matter. Mean, axial and radial diffusivities in the white matter lesion were all decreased in the acute stage compared to perilesional white matter and remaining white matter, but significantly increased in both the subacute and chronic stages. Significant increases in mean and radial diffusivities in the perilesional white matter were seen in the later stages of stroke. Our findings suggest that various physiological processes are at play in the acute, subacute and chronic stages following ischaemic stroke, with the infarct territory and perilesional white matter affected by ischaemia at different rates and to different extents throughout the stroke recovery stages. The examination of multiple diffusivity metrics may inform us about the mechanisms occurring at different time-points, i.e. focal swelling, axonal damage or myelin loss., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Few studies have investigated sustained B-cell depletion after long-term intravenous (IV) anti-CD20 B-cell depleting therapy (BCDT) in multiple sclerosis (MS) with respect to strict and/or minimal disease activity. The main objective of this study was to investigate how sustained B-cell depletion after BCDT influences clinical and radiological stability as defined by "no evidence of disease activity" (NEDA-3) and "minimal evidence of disease activity" (MEDA) status in MS patients at 12 and 18 months. Furthermore, we assessed the frequency of serious adverse events (SAE), and the influence of prior lymphocytopenia-inducing treatment (LIT) on lymphocyte subset counts and gammaglobulins in MS patients receiving long-term BCDT. We performed a retrospective, prospectively collected, study in a cohort of 192 MS patients of all clinical phenotypes treated by BCDT between January 2014 and September 2021. Overall, 84.2% and 96.9% of patients attained NEDA-3 and MEDA status at 18 months, respectively. Sustained CD19 + depletion was observed in 85.8% of patients at 18 months. No significant difference was observed when comparing patients achieving either NEDA-3 or MEDA at 18 months and sustained B-cell depletion. Compared to baseline levels, IgM and IgG levels on BCDT significantly decreased at 6 months and 30 months, respectively. Patients receiving LIT prior to BCDT showed significant CD4 + lymphocytopenia and lower IgG levels compared to non-LIT patients. Grade 3 or above SAEs were rare. As nearly all patients achieved MEDA at 18 months, we suggest tailoring IV BCDT after 18 months given the occurrence of lymphocytopenia, hypogammaglobulinemia, and SAE after this time point., (© 2023. The Author(s).)

The tumor-immune microenvironment (TIME) is a critical determinant of therapeutic response. However, the mechanisms regulating its modulation are not fully understood. HER2Δ16, an oncogenic splice variant of the HER2, has been implicated in breast cancer and other tumor types as a driver of tumorigenesis and metastasis. Nevertheless, the underlying mechanisms of HER2Δ16-mediated oncogenicity remain poorly understood. Here, we show that HER2∆16 expression is not exclusive to the clinically HER2+ subtype and associates with a poor clinical outcome in breast cancer. To understand how HER2 variants modulated the tumor microenvironment, we generated transgenic mouse models expressing either proto-oncogenic HER2 or HER2Δ16 in the mammary epithelium. We found that HER2∆16 tumors were immune cold, characterized by low immune infiltrate and an altered cytokine profile. Using an epithelial cell surface proteomic approach, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) as a functional regulator of the immune cold microenvironment. We generated a knock-in model of HER2Δ16 under the endogenous promoter to understand the role of Enpp1 in aggressive HER2+ breast cancer. Knockdown of Enpp1 in HER2Δ16-derived tumor cells resulted in decreased tumor growth, which correlated with increased T-cell infiltration. These findings suggest that HER2Δ16-dependent Enpp1 activation associates with aggressive HER2+ breast cancer through its immune modulatory function. Our study provides a better understanding of the mechanisms underlying HER2Δ16-mediated oncogenicity and highlights ENPP1 as a potential therapeutic target in aggressive HER2+ breast cancer., (©2023 American Association for Cancer Research.)

In vivo VHH discovery approaches have been limited by the lack of methodologies for camelid B cell interrogation. Here, we report a novel application of the Beacon® optofluidic platform to the discovery of heavy-chain-only antibodies by screening alpaca B cells. Methods for alpaca B cell enrichment, culture, IgG2/3 detection, and sequencing were developed and used to discover target-specific VHH from an alpaca immunized with prostate-specific membrane antigen (PSMA) or a second target. PSMA-specific hits were expressed as VHH-Fc and characterized using label-free techniques. Anti-PSMA IgG2/3 titer plateaued on day 153, when on-Beacon IgG2/3 secretion and target binding rates peaked. Of 13 recombinantly expressed VHH-Fc, all but one bound with nanomolar affinity, and five were successfully humanized. Repertoire sequencing uncovered additional variants within the clonal lineages of the validated hits. The establishment of this workflow extends the powerful Beacon technology to enable rapid VHH discovery directly from natural camelid immune repertoires., Competing Interests: M.B.S., J.B., A.B., A.D., J.G., V.K., K.P., F.G., J.W., R.K. and C.A.S. are or were employees of Twist Bioscience Corporation. The authors have applied for a patent on anti-PSMA antibodies and uses thereof., (© The Author(s) 2023. Published by Oxford University Press on behalf of Antibody Therapeutics. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To inform proactive management actions supporting community resilience to wildfires, we developed a new software package called FireLossRate . This package in R helps the user to compute wildfire impacts on residential structures at the Wildland Urban Interface (WUI). The package integrates spatial information about exposed structures, empirical equations that estimate the loss rate of structures affected by wildfires as a function of fireline intensity and distance from fire edge with fire growth modeling outputs from fire simulation software and burn probability models. FireLossRate helps to quantify and produce spatially explicit data on structural exposure and loss for single and multiple fires. The package automates post hoc analyses on simulations that include single or multiple wildfires and enables result mapping when combined with other packages available in R. In this paper, we describe the functionality of the FireLossRate package and introduce users to the interpretation of impact indicators of wildfires at the WUI. FireLossRate is available for download at https://github.com/LFCFireLab/FireLossRate.• FireLossRate allows the computation of wildfire impacts indicators on residential structures at the Wildland Urban Interface in support of community fire risk management., Competing Interests: 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., (Crown Copyright © 2023 Published by Elsevier B.V.)

How the genetic landscape governs a tumor's response to immunotherapy remains poorly understood. To assess the immune-modulatory capabilities of 573 genes associated with altered cytotoxicity in human cancers, here we perform CRISPR/Cas9 screens directly in mouse lung cancer models. We recover the known immune evasion factors Stat1 and Serpinb9 and identify the cancer testis antigen Adam2 as an immune modulator, whose expression is induced by Kras G12D and further elevated by immunotherapy. Using loss- and gain-of-function experiments, we show that ADAM2 functions as an oncogene by restraining interferon and TNF cytokine signaling causing reduced presentation of tumor-associated antigens. ADAM2 also restricts expression of the immune checkpoint inhibitors PDL1, LAG3, TIGIT and TIM3 in the tumor microenvironment, which might explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy in ADAM2 overexpressing tumors. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies., (© 2023. The Author(s).)

Background: Assessment of the safety of heartworm preventatives in dogs with pre-existing patent heartworm (Dirofilaria immitis) infections is necessary because rapid adult worm and microfilarial death can lead to severe clinical complications, including thromboembolism and anaphylactic shock in dogs. The aim of this study was to determine the clinical safety of Simparica Trio ® (sarolaner, pyrantel, moxidectin) in heartworm-infected dogs and the degree of microfilaricidal and adulticidal activity of three consecutive monthly treatments of Simparica Trio., Methods: Twenty-four laboratory Beagle dogs were implanted with 10 male and 10 female D. immitis (ZoeKY isolate), and once infection was patent, they were randomized equally among three groups to receive no treatment, 1× or 3× the maximum recommended label dose of Simparica Trio. Dogs in the treated groups received Simparica Trio on days 0, 28 and 56. In-life assessments included body weight, physical examinations, clinical observations, daily general health observations, a quantitative estimate of food consumption and blood collections for pharmacokinetic (PK) analysis, microfilariae (MF) counts and D. immitis antigen testing. At the end of the study the heart, lungs and pleural and peritoneal cavities were examined for adult D. immitis worms., Results: Simparica Trio was generally well tolerated. Emesis occurred at low frequency in all groups including control. Abnormal stool occurred occasionally in the 1× and 3× groups throughout the 3-month study. Fever (> 104 °F/40 °C) was recorded in one 1× and one 3× dog 1 day after the first dose and resolved by the following day. No severe hypersensitivity reactions occurred. The mean number of circulating microfilariae (MF) counts in the control group increased from 12,000/ml at study start (Day 0) to > 20,000/ml at Day 28 and remained > 20,000/ml for the duration of the study. The least squares means of circulating MF were reduced by 69.8% on Day 1 and 97.4% on Day 7 for the 1× group and remained at > 99% lower than the control group for the remainder of the study. Similarly, least squares means of circulating MF were reduced by 85.3% on Day 1 and 93.9% on Day 7 for the 3× group and remained > 98% lower than the control group for the remainder of the study. At the end of the study, the mean number of implanted adult worms recovered was < 10 per sex in all groups with 90%, 85% and 75% of live adult heartworms recovered in control, 1× and 3× treatment groups, respectively. Low numbers of dead adult worms were recovered in 1× and 3×, with none in control. Following each dose, the moxidectin and sarolaner AUC and C max had close to dose proportional increases., Conclusions: This study demonstrated that Simparica Trio (sarolaner, pyrantel, moxidectin) was well tolerated when administered to heartworm-positive dogs at 1× and 3× the maximum recommended dose at 28-day intervals for 3 consecutive months. Simparica Trio significantly reduced microfilaria counts in both treatment groups, without significant clinical consequences. At the doses administered, Simparica Trio had minor adulticidal activity but resulted in no clinical sequelae., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The hallmark of HIV-1 infection is the rapid dysregulation of immune functions. Recent investigations for biomarkers of such dysregulation in people living with HIV (PLWH) reveal a strong correlation between viral rebound and immune activation with an increased abundance of extracellular vesicles (EVs) enriched with microRNA-155. We propose that the activation of peripheral blood mononuclear cells (PBMCs) leads to an increased miR-155 expression and production of miR-155-rich extracellular vesicles (miR-155-rich EVs), which can exacerbate HIV-1 infection by promoting viral replication. PBMCs were incubated with either HIV-1 (NL4.3Balenv), a TLR-7/8 agonist, or TNF. EVs were harvested from the cell culture supernatant by differential centrifugation, and RT-qPCR quantified miR-155 in cells and derived EVs. The effect of miR-155-rich EVs on replication of HIV-1 in incubated PBMCs was then measured by viral RNA and DNA quantification. HIV-1, TLR7/8 agonist, and TNF each induced the release of miR-155-rich EVs by PBMCs. These miR-155-rich EVs increased viral replication in PBMCs infected in vitro. Infection with HIV-1 and inflammation promote the production of miR-155-rich EVs, enhancing viral replication. Such autocrine loops, therefore, could influence the course of HIV-1 infection by promoting viral replication.

Extracellular vesicles (EVs) and their cargo have been studied intensively as potential sources of biomarkers in HIV infection; however, their DNA content, particularly the mitochondrial portion (mtDNA), remains largely unexplored. It is well known that human immunodeficiency virus (HIV) infection and prolonged antiretroviral therapy (ART) lead to mitochondrial dysfunction and reduced mtDNA copy in cells and tissues. Moreover, mtDNA is a well-known damage-associated molecular pattern molecule that could potentially contribute to increased immune activation, oxidative stress, and inflammatory response. We investigated the mtDNA content of large and small plasma EVs in persons living with HIV (PLWH) and its implications for viral replication, ART use, and immune status. Venous blood was collected from 196 PLWH, ART-treated or ART-naïve (66 with ongoing viral replication, ≥20 copies/mL), and from 53 HIV-negative persons, all recruited at five HIV testing or treatment centers in Burkina Faso. Large and small plasma EVs were purified and counted, and mtDNA level was measured by RT-qPCR. Regardless of HIV status, mtDNA was more abundant in large than small EVs. It was more abundant in EVs of viremic than aviremic and control participants and tended to be more abundant in participants treated with Tenofovir compared with Zidovudine. When ART treatment was longer than six months and viremia was undetectable, no variation in EV mtDNA content versus CD4 and CD8 count or CD4/CD8 ratio was observed. However, mtDNA in large and small EVs decreased with years of HIV infection and ART. Our results highlight the impact of viral replication and ART on large and small EVs' mtDNA content. The mechanisms underlying the differential incorporation of mtDNA into EVs and their effects on the surrounding cells warrant further investigation., Competing Interests: The authors declare no conflict of interest.

Background: While Covid-19 monoclonal antibody therapies (Mab) have been available in the outpatient setting for over a year and a half, little is known about the impact of emerging variants and vaccinations on the effectiveness of Mab therapies. We sought to determine the effectiveness of Covid-19 Mab therapies during the first two waves of the pandemic in Los Angeles County and assess the impact of vaccines, variants, and other confounding factors., Methods and Findings: We retrospectively examined records for 2209 patients of with confirmed positive molecular SARS-CoV2 test either referred for outpatient Mab therapy or receiving Mab treatment in the emergency department (ED) between December 2020 and 2021. Our primary outcome was the combined 30-day incidence of ED visit, hospitalization, or death following the date of referral. Additionally, SARS-CoV2 isolates of hospitalized patients receiving Mabs were sequenced. The primary outcome was significantly reduced with combination therapy compared to bamlanivimab or no treatment (aHR 0·60; 95% CI ·37, ·99), with greater benefit in unvaccinated, moderate-to-high-risk patients (aHR ·39; 95% CI ·20, ·77). Significant associations with the primary outcome included history of lung disease (HR 7·13; 95% CI 5·12, 9·95), immunocompromised state (HR 6·59; 95% CI 2·91-14·94), and high social vulnerability (HR 2·29, 95% CI 1·56-3·36). Two predominant variants were noted during the period of observation: the Epsilon variant and the Delta variant., Conclusions: Only select monoclonal antibody therapies significantly reduced ED visits, hospitalizations, and death due to COVID-19 during. Vaccination diminished effectiveness of Mabs. Variant data and vaccination status should be considered when assessing the benefit of novel COVID-19 treatments., Competing Interests: No authors have competing interests., (Copyright: © 2022 Srinivasan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Xylanases can boost pulp bleachability in Elemental Chlorine Free (ECF) processes, but their industrial implementation for producing bleached kraft pulps is not straightforward. It requires enzymes to be active and stable at the extreme conditions of alkalinity and high temperature typical of this industrial process; most commercial enzymes are unable to withstand these conditions. In this work, a novel highly thermo and alkaline-tolerant xylanase from Pseudothermotoga thermarum was overproduced in E. coli and tested as a bleaching booster of hardwood kraft pulps to save chlorine dioxide (ClO 2 ) during ECF bleaching. The extremozyme-stage (EXZ) was carried out at 90 °C and pH 10.5 and optimised at lab scale on an industrial oxygen-delignified eucalyptus pulp, enabling us to save 15% ClO 2 to reach the mill brightness, and with no detrimental effect on paper properties. Then, the EXZ-assisted bleaching sequence was validated at pilot scale under industrial conditions, achieving 25% ClO 2 savings and reducing the generation of organochlorinated compounds (AOX) by 18%, while maintaining pulp quality and papermaking properties. Technology reproducibility was confirmed with another industrial kraft pulp from a mix of hardwoods. The new enzymatic technology constitutes a realistic step towards environmentally friendly production of kraft pulps through industrial integration of biotechnology.

Anecdotal reports and a small number of research studies suggest possible behavioral improvements in children with autism spectrum disorders (ASD) during a fever. However, previous studies rely largely on retrospective reports of this phenomenon. Establishing a robust association between fever and reduction of ASD-related symptoms would promote opportunities for the development of innovative therapeutic interventions for children with ASD. In the current study, prospective data were collected from 141 children with ASD and 103 typically developing (TD) controls using parent responses to an 11-item behavioral survey. Behaviors when no illness was present, during a fever, the week after a fever, and during non-febrile illnesses for TD and ASD children were compared. Profiles of cases in which caregivers reported consistent behavioral improvements during fever are described. Data indicated worsening social, emotional/behavioral, and somatic symptoms during a fever regardless of diagnosis, with children with ASD demonstrating greater worsening of behaviors during a fever than TD children. Only three out of 141 children with ASD demonstrated consistent behavioral improvements during a fever; these children had a range of cognitive and adaptive skills. Children with ASD had stronger negative responses to fever than TD children. These findings contradict previous literature suggesting behavioral improvements for children with ASD. While improvements may occur for some children, it does not appear to be a common phenomenon. Additional research is needed to elucidate the nature of behavioral improvements in the subset of children with ASD who may respond positively to fever., (© 2022 International Society for Autism Research and Wiley Periodicals LLC.)

Circadian rhythms play a critical role in regulating metabolism, including daily cycles of feeding/fasting. Glucokinase (GCK) is central for whole-body glucose homeostasis and oscillates according to a circadian clock. GCK activators (GKAs) effectively reduce hyperglycemia, but their use is also associated with hypoglycemia, hyperlipidemia, and hepatic steatosis. Given the circadian rhythmicity and natural postprandial activation of GCK, we hypothesized that GKA treatment would benefit from being timed specifically during feeding periods. Acute treatment of obese Zucker rats with the GKA AZD1656 robustly increased flux into all major metabolic pathways of glucose disposal, enhancing glucose elimination. Four weeks of continuous AZD1656 treatment of obese Zucker rats improved glycemic control; however, hepatic steatosis and inflammation manifested. In contrast, timing AZD1656 to feeding periods robustly reduced hepatic steatosis and inflammation in addition to improving glycemia, whereas treatment timed to fasting periods caused overall detrimental metabolic effects. Mechanistically, timing AZD1656 to feeding periods diverted newly synthesized lipid toward direct VLDL secretion rather than intrahepatic storage. In line with increased hepatic insulin signaling, timing AZD1656 to feeding resulted in robust activation of AKT, mTOR, and SREBP-1C after glucose loading, pathways known to regulate VLDL secretion and hepatic de novo lipogenesis. In conclusion, intermittent AZD1656 treatment timed to feeding periods promotes glucose disposal when needed the most, restores metabolic flexibility and hepatic insulin sensitivity, and thereby avoids hepatic steatosis. Thus, chronotherapeutic approaches may benefit the development of GKAs and other drugs acting on metabolic targets.

Objective: Cellular senescence, an irreversible proliferative cell arrest, is caused by excessive intracellular or extracellular stress/damage. Increased senescent cells have been identified in multiple tissues in different metabolic and other aging-related diseases. Recently, several human and mouse studies emphasized the involvement of senescence in development and progression of NAFLD. Hyperinsulinemia, seen in obesity, metabolic syndrome, and other conditions of insulin resistance, has been linked to senescence in adipocytes and neurons. Here, we investigate the possible direct role of chronic hyperinsulinemia in the development of senescence in human hepatocytes., Methods: Using fluorescence microscopy, immunoblotting, and gene expression, we tested senescence markers in human hepatocytes subjected to chronic hyperinsulinemia in vitro and validated the data in vivo by using liver-specific insulin receptor knockout (LIRKO) mice. The consequences of hyperinsulinemia were also studied in senescent hepatocytes following doxorubicin as a model of stress-induced senescence. Furthermore, the effects of senolytic agents in insulin- and doxorubicin-treated cells were analyzed., Results: Results showed that exposing the hepatocytes to prolonged hyperinsulinemia promotes the onset of senescence by increasing the expression of p53 and p21. It also further enhanced the senescent phenotype in already senescent hepatocytes. Addition of insulin signaling pathway inhibitors prevented the increase in cell senescence, supporting the direct contribution of insulin. Furthermore, LIRKO mice, in which insulin signaling in the liver is abolished due to deletion of the insulin receptor gene, showed no differences in senescence compared to their wild-type counterparts despite having marked hyperinsulinemia indicating these are receptor-mediated effects. In contrast, the persistent hyperinsulinemia in LIRKO mice enhanced senescence in white adipose tissue. In vitro, senolytic agents dasatinib and quercetin reduced the prosenescent effects of hyperinsulinemia in hepatocytes., Conclusion: Our findings demonstrate a direct link between chronic hyperinsulinemia and hepatocyte senescence. This effect can be blocked by reducing the levels of insulin receptors or administration of senolytic drugs, such as dasatinib and quercetin., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

The prevalence of obesity and metabolic diseases continues to rise, which has led to an increased interest in studying adipose tissue to elucidate underlying disease mechanisms. The use of genetic mouse models has been critical for understanding the role of specific genes for adipose tissue function and the tissue's impact on other organs. However, mouse adipose tissue displays key differences to human fat, which has led, in some cases, to the emergence of some confounding concepts in the adipose field. Such differences include the depot-specific characteristics of visceral and subcutaneous fat, and divergences in thermogenic fat phenotype between the species. Adipose tissue characteristics may therefore not always be directly compared between species, which is important to consider when setting up new studies or interpreting results. This mini review outlines our current knowledge about the cell biological differences between human and mouse adipocytes and fat depots, highlighting some examples where inadequate knowledge of species-specific differences can lead to confounding results, and presenting plausible anatomic explanations that may underlie the differences. The article thus provides critical insights and guidance for researchers working primarily with only human or mouse fat tissue, and may contribute to new ideas or concepts in the important and evolving field of adipose biology., Competing Interests: JB is an employee and shareholder of Evotec International. 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 © 2022 Börgeson, Boucher and Hagberg.)

Objective: To conduct a systematic review of studies that used registered dietitian nutritionists (RDNs) or registered nurses (RNs) to deliver pharmacological therapy using protocols for diabetes, dyslipidemia, or hypertension., Research Design and Methods: A database search of PubMed, the Cochrane Central Register of Controlled Trials, Ovid, and the Cumulative Index to Nursing and Allied Health Literature was conducted of literature published from 1 January 2000 to 31 December 2019., Results: Twenty studies met the inclusion criteria, representing randomized controlled trials (12), retrospective (1) and prospective cohort design studies (6), and time series (1). In all, the studies include 7,280 participants with a median study duration of 12 months (range 6-25 months). Fifteen studies were led by RNs alone, two by RDNs, and three by a combination of RDNs and RNs. All demonstrated improvements in A1C, blood pressure, or lipids. Thirteen studies provided a lifestyle behavior change component in addition to medication protocols., Conclusion: This systematic review provides evidence that RDN- and RN-led medication management using physician-approved protocols or treatment algorithms can lead to clinically significant improvements in diabetes, dyslipidemia, and hypertension management and is as good or better than usual care., (© 2022 by the American Diabetes Association.)

Managers designing infrastructure in fire-prone wildland areas require assessments of wildfire threat to quantify uncertainty due to future vegetation and climatic conditions. In this study, we combine wildfire simulation and forest landscape composition modeling to identify areas that would be highly susceptible to wildfire around a proposed conservation corridor in Québec, Canada. In this measure, managers have proposed raising the conductors of a new 735-kV hydroelectric powerline above the forest canopy within a wildlife connectivity corridor to mitigate the impacts to threatened boreal woodland caribou (Rangifer tarandus). Retention of coniferous vegetation, however, can increase the likelihood of an intense wildfire damaging powerline infrastructure. To assess the likelihood of high-intensity wildfires for the next 100 years, we evaluated three time periods (2020, 2070, 2120), three climate scenarios (observed, RCP 4.5, RCP 8.5), and four vegetation projections (static, no harvest, extensive harvesting, harvesting excluded in protected areas). Under present-day conditions, we found a lower probability of high-intensity wildfire within the corridor than in other parts of the study area, due to the protective influence of a nearby, poorly regenerated burned area. Wildfire probability will increase into the future, with strong, weather-induced inflation in the number of annual ignitions and wildfire spread potential. However, a conversion to less-flammable vegetation triggered by interactions between climate change and disturbance may attenuate this trend. By addressing the range of uncertainty of future conditions, we present a robust strategy to assist in decision-making about long-term risk management for both the proposed conservation measure and the powerline., (© 2022 Her Majesty the Queen in Right of Canada. Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America. Reproduced with the permission of the Minister of Natural Resources Canada.)

People living with HIV (PLWH), despite suppression of viral replication with antiretroviral therapy (ART), have high morbidity and mortality due to immune activation and chronic inflammation. Discovering new biomarkers of immune activation status under ART will be pertinent to improve PLWH quality of life when the majority will be treated. We stipulate that plasma large and small extracellular vesicle (EVs) and their microRNA content could be easily measured biomarkers to monitor immune activation in PLWH. Venous blood samples from n = 128 ART-treated PLWH with suppressed viral load (≤ 20 copies/mL) and n = 60 HIV-uninfected participants were collected at five testing or treatment centers of PLWH in Burkina Faso. Large and small plasma EVs were purified, counted, and the mature miRNAs miR-29a, miR-146a, and miR-155 were quantified by RT-qPCR. Diagnostic performances of large and small EVs miRNAs level were evaluated by receiver operating characteristic (ROC) curve analysis and principal component analysis (PCA). Among the EVs microRNA measured, only large EVs miR-155 copies distinguished PLWH with immune activation, with AUC of 0.75 for CD4/CD8 < 1 (95% CI: 0.58-0.91, P = 0.0212), and 0.77 for CD8 T cells ≥ 500/µL (95% CI: 0.63-0.92, P = 0.0096). In addition, PCA results suggest that large EVs miR-155 copies may be a biomarker of immune activation. Since miR-155 may influence immune cell function, its enrichment in large EV subpopulations could be a functional biomarker of immune activation in PLWH on ART. This measure could help to monitor and diagnose the immune activation with more accuracy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bazié, Boucher, Goyer, Traoré, Kania, Somé, Alary and Gilbert.)

Cellular senescence is a state of irreversible cell cycle arrest and has been shown to play a key role in many diseases, including metabolic diseases. To investigate the potential contribution of hepatocyte cellular senescence to the metabolic derangements associated with non-alcoholic steatohepatitis (NASH), we treated human hepatocyte cell lines HepG2 and IHH with the senescence-inducing drugs nutlin-3a, doxorubicin and etoposide. The senescence-associated markers p16, p21, p53 and beta galactosidase were induced upon drug treatment, and this was associated with increased lipid storage, increased expression of lipid transporters and the development of hepatic steatosis. Drug-induced senescence also led to increased glycogen content, and increased VLDL secretion from hepatocytes. Senescence was also associated with an increase in glucose and fatty acid oxidation capacity, while de novo lipogenesis was decreased. Surprisingly, cellular senescence caused an overall increase in insulin signaling in hepatocytes, with increased insulin-stimulated phosphorylation of IR, Akt, and MAPK. Together, these data indicate that hepatic senescence plays a causal role in the development of NASH pathogenesis, by modulating glucose and lipid metabolism, favoring steatosis. Our findings contribute to a better understanding of the mechanisms linking cellular senescence and fatty liver disease and support the development of new therapies targeting senescent cells for the treatment of NASH., Competing Interests: Authors TK, IA, JO and JB are or were shareholders and employed by Astrazeneca. JB is currently employed by and a shareholder of Evotec. 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 © 2022 Bonnet, Alexandersson, Baboota, Kroon, Oscarsson, Smith and Boucher.)

Objective: The present study aims to assess the relationship between quantitative measures of connected speech production and performance in confrontation naming in early post-stroke aphasia (8-14 days post-stroke). Method: We collected connected speech samples elicited by a picture description task and administered a confrontation naming task to 20 individuals with early post-stroke aphasia and 20 healthy controls. Transcriptions were made in compliance with the CHAT format guidelines. Several micro- (i.e. duration, total number of words, words per minute, mean length of utterances, ratio of open- to closed-class words and noun-to-verb ratio, VOC- D , repetitions, self-corrections, and phonological and semantic errors) and macrolinguistic (i.e. informativeness and efficiency) measures were extracted. Results: We provide evidence for the presence of impairments in an array of micro- and macrolinguistic measures of speech in individuals with early post-stroke aphasia. We show that in the patient group, confrontation naming abilities most strongly relate to informativeness in a picture description task. Conclusion: Our findings contribute to a better understanding of the relationship between performance in confrontation naming and in connected speech production in the first days after stroke onset and also suggest that discourse analysis may provide unique, possibly more complex information.

The role of hepatic cell senescence in human non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is not well understood. To examine this, we performed liver biopsies and extensive characterization of 58 individuals with or without NAFLD/NASH. Here, we show that hepatic cell senescence is strongly related to NAFLD/NASH severity, and machine learning analysis identified senescence markers, the BMP4 inhibitor Gremlin 1 in liver and visceral fat, and the amount of visceral adipose tissue as strong predictors. Studies in liver cell spheroids made from human stellate and hepatocyte cells show BMP4 to be anti-senescent, anti-steatotic, anti-inflammatory and anti-fibrotic, whereas Gremlin 1, which is particularly highly expressed in visceral fat in humans, is pro-senescent and antagonistic to BMP4. Both senescence and anti-senescence factors target the YAP/TAZ pathway, making this a likely regulator of senescence and its effects. We conclude that senescence is an important driver of human NAFLD/NASH and that BMP4 and Gremlin 1 are novel therapeutic targets., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Adipose tissue inflammation drives obesity-related cardiometabolic diseases. Enhancing endogenous resolution mechanisms through administration of lipoxin A 4 , a specialized pro-resolving lipid mediator, was shown to reduce adipose inflammation and subsequently protects against obesity-induced systemic disease in mice. Here, we demonstrate that lipoxins reduce inflammation in 3D-cultured human adipocytes and adipose tissue explants from obese patients. Approximately 50% of patients responded particularly well to lipoxins by reducing inflammatory cytokines and promoting an anti-inflammatory M2 macrophage phenotype. Responding patients were characterized by elevated systemic levels of C-reactive protein, which causes inflammation in cultured human adipocytes. Responders appeared more prone to producing anti-inflammatory oxylipins and displayed elevated prostaglandin D2 levels, which has been interlinked with transcription of lipoxin-generating enzymes. Using explant cultures, this study provides the first proof-of-concept evidence supporting the therapeutic potential of lipoxins in reducing human adipose tissue inflammation. Our data further indicate that lipoxin treatment may require a tailored personalized-medicine approach., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Changes in the cellular microRNA (miRNA) expression profile in response to HIV infection, replication or latency have been reported. Nevertheless, little is known concerning the abundance of miRNA in extracellular vesicles (EVs). In the search for a reliable predictor of viral rebound, we quantified the amount of miR-29a, miR-146a, and miR-155 in two types of plasma extracellular vesicles. Venous blood was collected from 235 ART-treated and ART-naive persons living with HIV (85 with ongoing viral replication, ≥20 copies/mL) and 60 HIV-negative participants at five HIV testing or treatment centers in Burkina Faso. Large and small plasma EVs were purified and counted, and mature miRNA miR-29a, miR-146a, and miR-155 were measured by RT-qPCR. Diagnostic performance of miRNA levels in large and small EVs was evaluated by a receiver operating characteristic curve analysis. The median duration of HIV infection was 36 months (IQR 14-117). The median duration of ART was 34 months (IQR 13-85). The virus was undetectable in 63.8% of these persons. In the others, viral load ranged from 108 to 33,978 copies/mL (median = 30,032). Large EVs were more abundant in viremic participants than aviremic. All three miRNAs were significantly more abundant in small EVs in persons with detectable HIV RNA, and their expression levels in copies per vesicle were a more reliable indicator of viral replication in ART-treated patients with low viremia (20-1000 copies/mL). HIV replication increased the production of large EVs more than small EVs. Combined with viral load measurement, quantifying EV-associated miRNA abundance relative to the number of vesicles provides a more reliable marker of the viral status. The expression level as copies per small vesicle could predict the viral rebound in ART-treated patients with undetectable viral loads.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to increase ketone bodies in patients with type 2 diabetes; however, the underlying mechanisms have not been fully elucidated. Here we examined the effect of the SGLT2 inhibitor dapagliflozin (1 mg/kg/day, formulated in a water, PEG400, ethanol, propylene glycol solution, 4 weeks) on lipid metabolism in obese Zucker rats. Fasting FFA metabolism was assessed in the anesthetized state using a [9,10- 3 H(N)]-palmitic acid tracer by estimating rates of plasma FFA appearance (R a ), whole-body FFA oxidation (R ox ), and nonoxidative disposal (R st ). In the liver, clearance (K β-ox ) and flux (R β-ox ) of FFA into β-oxidation were estimated using [9,10- 3 H]-(R)-bromopalmitate/[U- 14 C]palmitate tracers. As expected, dapagliflozin induced glycosuria and a robust antidiabetic effect; treatment reduced fasting plasma glucose and insulin, lowered glycated hemoglobin, and increased pancreatic insulin content compared with vehicle controls. Dapagliflozin also increased plasma FFA, R a , R ox , and R st with enhanced channeling toward oxidation versus storage. In the liver, there was also enhanced channeling of FFA to β-oxidation, with increased K β-ox , R β-ox and tissue acetyl-CoA, compared with controls. Finally, dapagliflozin increased hepatic HMG-CoA and plasma β-hydroxybutyrate, consistent with a specific enhancement of ketogenesis. Since ketogenesis has not been directly measured, we cannot exclude an additional contribution of impaired ketone body clearance to the ketosis. In conclusion, this study provides evidence that the dapagliflozin-induced increase in plasma ketone bodies is driven by the combined action of FFA mobilization from adipose tissue and diversion of hepatic FFA toward β-oxidation., Competing Interests: Conflict of interest All authors are or were employed by AstraZeneca and have shares in the company., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Allogeneic "off-the-shelf" (OTS) chimeric antigen receptor T cells (CAR-T cells) hold promise for more accessible CAR-T therapy. Here, we report a novel and simple way to make allogeneic OTS T cells targeting cancer. By engineering T cells with a bispecific T cell engager (BiTE), both TCRαβ and CD3ε expression on the T cell surface are dramatically reduced. BiTE-engineered T (BiTE-T) cells show reduced reaction to TCR stimulation in vitro and have low risk of graft-versus-host disease (GvHD) in vivo . BiTE-T cells down-regulated CD3ε/TCRαβ on bystander T cells by releasing BiTEs. BiTE-T cells produce much fewer cytokines and are comparable to CAR-T cells on anti-cancer efficacy in xenograft mouse models with pre-existing HLA-mismatched T cells. Co-expressing co-stimulatory factors or T cell-promoting cytokines enhanced BiTE-T cells. Our study suggests CD3ε engagement could be a new strategy for allogeneic T cell therapy worthy of further evaluation., Competing Interests: G.L. and M.L.D. are co-inventors of a patent related to the research. G.L. is the founder and holds equity in Immunebro Therapeutics, Inc., a company pursuing commercializing this technology., (© 2022 The Authors.)

The key role of B cells in the pathophysiology of multiple sclerosis (MS) is supported by the presence of oligoclonal bands in the cerebrospinal fluid, by the association of meningeal ectopic B cell follicles with demyelination, axonal loss and reduction of astrocytes, as well as by the high efficacy of B lymphocyte depletion in controlling inflammatory parameters of MS. Here, we use a spontaneous model of experimental autoimmune encephalomyelitis (EAE) to study the clonality of the B cell response targeting myelin oligodendrocyte glycoprotein (MOG). In particular, 94% of SJL/j mice expressing an I-A s : MOG 92-106 specific transgenic T cell receptor (TCR 1640 ) spontaneously develop a chronic paralytic EAE between the age of 60-500 days. The immune response is triggered by the microbiota in the gut-associated lymphoid tissue, while there is evidence that the maturation of the autoimmune demyelinating response might occur in the cervical lymph nodes owing to local brain drainage. Using MOG-protein-tetramers we tracked the autoantigen-specific B cells and localized their enrichment to the cervical lymph nodes and among the brain immune infiltrate. MOG-specific IgG1 antibodies were detected in the serum of diseased TCR 1640 mice and proved pathogenic upon adoptive transfer into disease-prone recipients. The ontogeny of the MOG-specific humoral response preceded disease onset coherent with their contribution to EAE initiation. This humoral response was, however, not sufficient for disease induction as MOG-antibodies could be detected at the age of 69 days in a model with an average age of onset of 197 days. To assess the MOG-specific B cell repertoire we FACS-sorted MOG-tetramer binding cells and clonally expand them in vitro to sequence the paratopes of the IgG heavy chain and kappa light chains. Despite the fragility of clonally expanding MOG-tetramer binding effector B cells, our results indicate the selection of a common CDR-3 clonotype among the Igk light chains derived from both disease-free and diseased TCR 1640 mice. Our study demonstrates the pre-clinical mobilization of the MOG-specific B cell response within the brain-draining cervical lymph nodes, and reiterates that MOG antibodies are a poor biomarker of disease onset and progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Salvador, Deramoudt, Leprêtre, Figeac, Guerrier, Boucher, Bas, Journiac, Peters, Mars and Zéphir.)

Background and Objectives: Acute optic neuritis (ON) is a classical presenting symptom of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and anti-MOG-associated disorders. The resulting visual impairment is variable and can be severe. Clinicians are in need of predictive biomarkers to optimize the management of acute ON. In this longitudinal study (IRMANO, NCT03651662), we evaluated the ability of optic nerve lesion length measured on MRI at the acute phase of ON to predict retinal neuro-axonal loss and visual impairment at a chronic stage., Methods: We conducted a longitudinal study (IRMANO, NCT03651662) of patients who presented a clinical episode of ON (≤8 weeks). All patients underwent a retinal optical coherence tomography (OCT) and a brain/optic nerve MRI, including 3D double-inversion recovery (DIR) sequence at the acute phase of ON and 12 months later. Primary outcomes were optic nerve DIR hypersignal lesion length, macular ganglion cell-inner plexiform layer (GCIPL) volume measured on OCT, and low-contrast monocular visual acuity (LCMVA)., Results: The study group included 51 patients (33 women, mean age of 32.4 years ± 7.9). We recruited patients with a clinically isolated syndrome (n = 20), a relapsing-remitting MS (n = 23), an isolated ON (n = 6), and a first clinical episode of NMOSD (n = 2). Optic nerve DIR hypersignal was observed in all but 1 symptomatic optic nerves. At inclusion, the mean optic nerve lesion length (in mm) was 12.35 ± 5.98. The mean GCIPL volume (in mm 3 ) significantly decreased between inclusion (1.90 ± 0.18) and M 12 (1.67 ± 0.21; p < 0.0001). Optic nerve lesion length at inclusion was significantly associated with GCIPL thinning (estimate ± SD; -0.012 ± 0.004; p = 0.0016) and LCMVA at M 12 (0.016 ± 0.003; p < 0.001). Optic nerve lesion length significantly increased at M 12 (15.76 ± 8.70; p = 0.0007). The increase in optic nerve lesion length was significantly associated with the GCIPL thinning between inclusion and M 12 (-0.012 ± 0.003; p = 0.0011)., Discussion: At the acute phase of ON, optic nerve lesion length is an imaging biomarker predictive of retinal neuro-axonal loss and chronic visual impairment, which can help to stratify future therapeutic strategies in acute ON., Classification of Evidence: This study provides Class I evidence that optic nerve lesion length measured on MRI during the acute phase of a first episode of ON is associated with long-term retinal neuro-axonal loss and visual impairment., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose: The main aim of this study is to provide French Canadian reference data for quantitative measures extracted from connected speech samples elicited by the Western Aphasia Battery-Revised picnic scene, a discourse task frequently used in clinical assessment of acquired language disorders., Method: Our sample consisted of 62 healthy French Canadian adults divided in two age groups: a 50- to 69-year-old group and a 70- to 90-year-old group., Results: High interrater reliability scores were obtained for most of the variables. Most connected speech variables did not demonstrate an age effect. However, the 70- to 90-year-old group produced more repetitions than the 50- to 69-year-old group and displayed reduced communication efficiency (number of information content units per minute)., Conclusion: These findings contribute to building a reference data set to analyze descriptive discourse production in clinical settings.

Background: The medical field causes significant environmental impact. Reduction of the primary care practice carbon footprint could contribute to decreasing global carbon emissions. This study aims to quantify the average carbon footprint of a primary care consultation, describe differences between primary care practices (best, worst and average performing) in western Switzerland and identify opportunities for mitigation., Methods: We conducted a retrospective carbon footprint analysis of ten private practices over the year 2018. We used life-cycle analysis to estimate carbon emissions of each sector, from manufacture to disposal, expressing results as CO 2 equivalents per average consultation and practice. We then modelled an average and theoretical best- case and worst-case practices. Collected data included invoices, medical and furniture inventories, heating and power supply, staff and patient transport, laboratory analyses (in/out-house) waste quantities and management costs., Results: An average medical consultation generated 4.8 kg of CO 2 eq and overall, an average practice produced 30 tons of CO 2 eq per year, with 45.7% for staff and patient transport and 29.8% for heating. Medical consumables produced 5.5% of CO 2 eq emissions, while in-house laboratory and X-rays contributed less than 1% each. Emergency analyses requiring courier transport caused 5.8% of all emissions. Support activities generated 82.6% of the total CO 2 eq. Simulation of best- and worst-case scenarios resulted in a ten-fold variation in CO 2 eq emissions., Conclusion: Optimizing structural and organisational aspects of practice work could have a major impact on the carbon footprint of primary care practices without large-scale changes in medical activities., (© 2021. The Author(s).)

Adipocytes exhibit different morphological and functional characteristics, depending on their anatomical location, developmental origin, and stimulus. While white adipocytes tend to accumulate energy as triglycerides, brown and beige adipocytes tend to direct carbon sources to fuel thermogenesis. White and beige adipocytes originate from common progenitor cells, which are distinct from brown adipocyte precursors. Having a method to study white vs. beige vs. brown adipocyte differentiation may help to unveil the mechanisms driving distinct adipogenic programs. Preadipocytes can be cultured and differentiated in vitro using a combination of compounds to stimulate adipogenesis. Here, we describe and compare protocols designed to stimulate adipocyte differentiation and induce brown/beige-like or white-like characteristics in differentiating adipocytes. The protocols consist in exposing murine preadipocytes to pharmacological stimuli aimed at triggering adipogenesis and inducing (or not) a thermogenic gene expression program. After 8 days of differentiation with a pro-browning cocktail, immortalized preadipocytes isolated from interscapular brown fat (9B cells) or inguinal white fat (9W cells) from the same mouse expressed higher levels of brown/beige adipocyte markers ( e.g., Ucp1 ) and pan-adipocyte differentiation markers ( e.g., Pparg, Cebpa and aP2 ) when compared to the same cells differentiated with a cocktail that lacked brown/beige adipogenic inducers ( i.e. , rosiglitazone, T3, and indomethacin). Consistent with a higher thermogenic potential of brown vs. beige adipocytes, differentiated 9B cells expressed higher Ucp1 levels than differentiated 9W cells. This simple protocol may help researchers to understand mechanisms of adipogenesis and how adipocytes become thermogenic., Competing Interests: Competing interestsThe authors declare no competing interests., (Copyright © 2021 The Authors; exclusive licensee Bio-protocol LLC.)

Despite heightened awareness of the detrimental impact of hate speech on social media platforms on affected communities and public discourse, there is little consensus on approaches to mitigate it. While content moderation-either by governments or social media companies-can curb online hostility, such policies may suppress valuable as well as illicit speech and might disperse rather than reduce hate speech. As an alternative strategy, an increasing number of international and nongovernmental organizations (I/NGOs) are employing counterspeech to confront and reduce online hate speech. Despite their growing popularity, there is scant experimental evidence on the effectiveness and design of counterspeech strategies (in the public domain). Modeling our interventions on current I/NGO practice, we randomly assign English-speaking Twitter users who have sent messages containing xenophobic (or racist) hate speech to one of three counterspeech strategies-empathy, warning of consequences, and humor-or a control group. Our intention-to-treat analysis of 1,350 Twitter users shows that empathy-based counterspeech messages can increase the retrospective deletion of xenophobic hate speech by 0.2 SD and reduce the prospective creation of xenophobic hate speech over a 4-wk follow-up period by 0.1 SD. We find, however, no consistent effects for strategies using humor or warning of consequences. Together, these results advance our understanding of the central role of empathy in reducing exclusionary behavior and inform the design of future counterspeech interventions., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Obesity is considered an important factor for many chronic diseases, including diabetes, cardiovascular disease and cancer. The expansion of adipose tissue in obesity is due to an increase in both adipocyte progenitor differentiation and mature adipocyte cell size. Adipocytes, however, are thought to be unable to divide or enter the cell cycle. We demonstrate that mature human adipocytes unexpectedly display a gene and protein signature indicative of an active cell cycle program. Adipocyte cell cycle progression associates with obesity and hyperinsulinemia, with a concomitant increase in cell size, nuclear size and nuclear DNA content. Chronic hyperinsulinemia in vitro or in humans, however, is associated with subsequent cell cycle exit, leading to a premature senescent transcriptomic and secretory profile in adipocytes. Premature senescence is rapidly becoming recognized as an important mediator of stress-induced tissue dysfunction. By demonstrating that adipocytes can activate a cell cycle program, we define a mechanism whereby mature human adipocytes senesce. We further show that by targeting the adipocyte cell cycle program using metformin, it is possible to influence adipocyte senescence and obesity-associated adipose tissue inflammation., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)