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Background Genetic predisposition to coronavirus disease 2019 (COVID-19) may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity. Aim To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity. Methods This retrospective case–control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the USA, Hungary and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8, rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection. Results In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls [11% vs. 19%, odds ratio (OR) 0.54 [0.41–0.72], P  < 0.0001]. Among inpatients with COVID-19 (n  = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n  = 187) (12% vs. 5%, OR 2.87 [1.42–5.78], P  = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, P  < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r  = 0.19, P  = 0.01) and maximum CRP (r  = 0.16, P  = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele. Conclusions In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7 MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of the high-expression CATT7 MIF allele, which occurs in 19% of the population, in different stages of COVID-19 infection. [ABSTRACT FROM AUTHOR]

During 19-21 June 2013 a heavy precipitation event affected southern Alberta and adjoining regions, leading to severe flood damage in numerous communities and resulting in the costliest natural disaster in Canadian history. This flood was caused by a combination of meteorological and hydrological factors, which are investigated from weather and climate perspectives with the fifth generation Canadian Regional Climate Model. Results show that the contribution of orographic ascent to precipitation was important, exceeding 30 % over the foothills of the Rocky Mountains. Another contributing factor was evapotranspiration from the land surface, which is found to have acted as an important moisture source and was likely enhanced by antecedent rainfall that increased soil moisture over the northern Great Plains. Event attribution analysis suggests that human induced greenhouse gas increases may also have contributed by causing evapotranspiration rates to be higher than they would have been under pre-industrial conditions. Frozen and snow-covered soils at high elevations are likely to have played an important role in generating record streamflows. Results point to a doubling of surface runoff due to the frozen conditions, while 25 % of the modelled runoff originated from snowmelt. The estimated return time of the 3-day precipitation event exceeds 50 years over a large region, and an increase in the occurrence of similar extreme precipitation events is projected by the end of the 21st century. Event attribution analysis suggests that greenhouse gas increases may have increased 1-day and 3-day return levels of May-June precipitation with respect to pre-industrial climate conditions. However, no anthropogenic influence can be detected for 1-day and 3-day surface runoff, as increases in extreme precipitation in the present-day climate are offset by decreased snow cover and lower frozen water content in soils during the May-June transition months, compared to pre-industrial climate. [ABSTRACT FROM AUTHOR]

Abstract: This paper gives the yearly 85Kr emissions of all known reprocessing facilities, which are the main sources of 85Kr in the atmosphere since 1945, for the years 1945 until 2000. According to this inventory 10,600PBq (Peta=1015) of 85Kr have been globally emitted from the year 1945 until the end of 2000. The global atmospheric inventory at the end of the year 2000 amounts to 4800PBq. These emissions have been incorporated into the ECHAM4 atmospheric general circulation model as point sources. Monthly mean model results are compared with measurements made at different locations and times. The influence of each source on the measured concentrations at various locations is studied. The calculated concentrations are found to give reasonably good agreement with the observations, indicating that the emission inventory is realistic. Although, at all northern hemispheric observation sites the model tends to slightly overestimate the concentrations. A possible reason for this overestimation can be found in model features (coarse resolution in time and space). The most prominent discrepancy that is consistently repeated at all northern hemispheric stations occurs in the early 1990s. This could most likely be related to an overestimate of sources. Possibly, the Russian emissions declined earlier than assumed in the current database. Another discrepancy between observations and simulations indicating an incompleteness of the release data is found at some southern hemispheric sites. The variability of their observations could only be explained by regional sources. However, several spikes occur after 1992 when no reprocessing facility is known to be in operation in the southern hemisphere. Production of isotopes for radiopharmaceuticals like technetium-99m from highly enriched uranium is the most likely explanation. [Copyright &y& Elsevier]

Background: Genetic predisposition to coronavirus disease 2019 (COVID-19) may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity., Aim: To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity., Methods: This retrospective case-control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the USA, Hungary and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8,rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection., Results: In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls [11% vs. 19%, odds ratio (OR) 0.54 [0.41-0.72], P < 0.0001]. Among inpatients with COVID-19 (n = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n = 187) (12% vs. 5%, OR 2.87 [1.42-5.78], P = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, P < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r = 0.19, P = 0.01) and maximum CRP (r = 0.16, P = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele., Conclusions: In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of the high-expression CATT7MIF allele, which occurs in 19% of the population, in different stages of COVID-19 infection., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes and are ubiquitously used for their anti-inflammatory properties. However, COX inhibition alone fails to explain numerous clinical outcomes of NSAID usage. Screening commonly used NSAIDs in primary human and murine myeloid cells demonstrated that NSAIDs could be differentiated by their ability to induce growth/differentiation factor 15 (GDF15), independent of COX specificity. Using genetic and pharmacologic approaches, NSAID-mediated GDF15 induction was dependent on the activation of nuclear factor erythroid 2-related factor 2 (NRF2) in myeloid cells. Sensing by Cysteine 151 of the NRF2 chaperone, Kelch-like ECH-associated protein 1 (KEAP1) was required for NSAID activation of NRF2 and subsequent anti-inflammatory effects both in vitro and in vivo. Myeloid-specific deletion of NRF2 abolished NSAID-mediated tissue protection in murine models of gout and endotoxemia. This highlights a noncanonical NRF2-dependent mechanism of action for the anti-inflammatory activity of a subset of commonly used NSAIDs., Competing Interests: Declaration of interests P.T., H.T., and H.H.L. were employees of NGM Biopharmaceuticals at the time this work was done and may hold stock or stock options in this company. All data are available in the main text or the supplementary materials., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Coronaviruses are a major health care threat to humankind. Currently, the host factors that contribute to limit disease severity in healthy young patients are not well defined. Interferons are key antiviral molecules, especially type I and type III interferons. The role of these interferons during coronavirus disease is a subject of debate. Here, using mice that are deficient in type I (IFNAR1 -/- ), type III (IFNLR1 -/- ), or both (IFNAR1/LR1 -/- ) interferon signaling pathways and murine-adapted coronavirus (MHV-A59) administered through the intranasal route, we define the role of interferons in coronavirus infection. We show that type I interferons play a major role in host survival in this model, while a minimal role of type III interferons was manifested only in the absence of type I interferons or during a lethal dose of coronavirus. IFNAR1 -/- and IFNAR1/LR1 -/- mice had an uncontrolled viral burden in the airways and lung and increased viral dissemination to other organs. The absence of only type III interferon signaling had no measurable difference in the viral load. The increased viral load in IFNAR1 -/- and IFNAR1/LR1 -/- mice was associated with increased tissue injury, especially evident in the lung and liver. Type I but not type III interferon treatment was able to promote survival if treated during early disease. Further, we show that type I interferon signaling in macrophages contributes to the beneficial effects during coronavirus infection in mice. IMPORTANCE The antiviral and pathological potential of type I and type III interferons during coronavirus infection remains poorly defined, and opposite findings have been reported. We report that both type I and type III interferons have anticoronaviral activities, but their potency and organ specificity differ. Type I interferon deficiency rendered the mice susceptible to even a sublethal murine coronavirus infection, while the type III interferon deficiency impaired survival only during a lethal infection or during a sublethal infection in the absence of type I interferon signaling. While treatment with both type I and III interferons promoted viral clearance in the airways and lung, only type I interferons promoted the viral clearance in the liver and improved host survival upon early treatment (12 h postinfection). This study demonstrates distinct roles and potency of type I and type III interferons and their therapeutic potential during coronavirus lung infection.

Metabolic programming is intricately linked to the anti-tumor properties of T cells. To study the metabolic pathways associated with increased anti-tumor T cell function, we utilized a metabolomics approach to characterize three different CD8 + T cell subsets with varying degrees of anti-tumor activity in murine models, of which IL-22-producing Tc22 cells displayed the most robust anti-tumor activity. Tc22s demonstrated upregulation of the pantothenate/coenzyme A (CoA) pathway and a requirement for oxidative phosphorylation (OXPHOS) for differentiation. Exogenous administration of CoA reprogrammed T cells to increase OXPHOS and adopt the CD8 + Tc22 phenotype independent of polarizing conditions via the transcription factors HIF-1α and the aryl hydrocarbon receptor (AhR). In murine tumor models, treatment of mice with the CoA precursor pantothenate enhanced the efficacy of anti-PDL1 antibody therapy. In patients with melanoma, pre-treatment plasma pantothenic acid levels were positively correlated with the response to anti-PD1 therapy. Collectively, our data demonstrate that pantothenate and its metabolite CoA drive T cell polarization, bioenergetics, and anti-tumor immunity., Competing Interests: Declaration of interests M.S.P., S.D.S., and P.S.O. have filed for a patent pertaining to this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Context: With pediatric obesity rates reaching epidemic scales across the United States, innovative research to identify key factors for successful implementation of obesity intervention programs is increasingly paramount. Project Healthy Attitudes Produces Positive Youth (HAPPY) is a family centered pediatric obesity prevention program targeting elementary age children and their families., Objectives: To determine whether Project HAPPY interventions emphasizing social networks were successful., Methods: This was a small scale evaluation of the Project HAPPY pilot program, conducted after school at a public elementary campus in Solano County, California. From April 2018 to May 2018, first year medical students from Touro University California College of Osteopathic Medicine served as "family navigators," guiding participants through a 5 week curriculum of didactic lessons, cooking demonstrations, and physical exercises. Eligibility requirements for Project HAPPY included basic English proficiency, confirmed enrollment of at least one child at the elementary school, and willingness to attend all study sessions. The primary outcome evaluated was a shift in attitude toward individual health. Changes in body mass index (BMI) and health behaviors were assessed as secondary outcomes. Outcomes were assessed through surveys and measurements of BMI completed during Session 1, Session 10, and 4, 6, and 8 month follow up sessions., Results: Initial study participants included seven families, consisting of elementary school students with their siblings and parents (n=27). Only four families (n=13) completed the entire 5 week intervention. Over the course of the study, survey results of participants' attitudes regarding health suggested a positive trend toward self efficacy, while BMI appeared stable or increased. Participants demonstrated retention of successful health behaviors up to 8 months after the end of the intervention through qualitative reports of being "more conscious of meals and what (they) are eating," "valu[ing their] nutrition on a daily basis," "play[ing] a lot outside and inside on the weekends," "carry[ing] a water bottle," and "cook(ing) a lot." A higher percentage of respondents in the final session compared selected the option "strongly agree" to each of the following statements: "I can be healthier if my family works together" (87.5% final session vs. 84.6% first session), "Drinking water makes me healthy" (87.5% final session vs. 84.6% first session), "Moving my body makes me healthy" (87.5% final session vs. 76.9% first session), "I reach my goals even when things get in my way" (62.5% final session vs. 46.2% first session), "Eating fruits and veggies make me healthy" (100% final session vs. 92.3% first session), "I can be healthy and enjoy my favorite foods" (87.5% final session vs. 66.7% first session), and "I can create a healthy balanced meal" (87.0% final session vs. 75.0% first session). Concrete data analysis was severely complicated by loss of study participants to follow up and incomplete data collection., Conclusions: Project HAPPY showed promising indications that should be further evaluated in studies of larger scale and longer duration., (© 2021 Madeline Bach et al., published by De Gruyter, Berlin/Boston.)

The intestine is a site of direct encounter with the external environment and must consequently balance barrier defense with nutrient uptake. To investigate how nutrient uptake is regulated in the small intestine, we tested the effect of diets with different macronutrient compositions on epithelial gene expression. We found that enzymes and transporters required for carbohydrate digestion and absorption were regulated by carbohydrate availability. The "on-demand" induction of this machinery required γδ T cells, which regulated this program through the suppression of interleukin-22 production by type 3 innate lymphoid cells. Nutrient availability altered the tissue localization and transcriptome of γδ T cells. Additionally, transcriptional responses to diet involved cellular remodeling of the epithelial compartment. Thus, this work identifies a role for γδ T cells in nutrient sensing., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

CD8 + T cells can be polarized into several different subsets as defined by the cytokines they produce and the transcription factors that govern their differentiation. Here, we identified the polarizing conditions to induce an IL22-producing CD8 + Tc22 subset, which is dependent on IL6 and the aryl hydrocarbon receptor transcription factor. Further characterization showed that this subset was highly cytolytic and expressed a distinct cytokine profile and transcriptome relative to other subsets. In addition, polarized Tc22 were able to control tumor growth as well as, if not better than, the traditional IFNγ-producing Tc1 subset. Tc22s were also found to infiltrate the tumors of human patients with ovarian cancer, comprising up to approximately 30% of expanded CD8 + tumor-infiltrating lymphocytes (TIL). Importantly, IL22 production in these CD8 + TILs correlated with improved recurrence-free survival. Given the antitumor properties of Tc22 cells, it may be prudent to polarize T cells to the Tc22 lineage when using chimeric antigen receptor (CAR)-T or T-cell receptor (TCR) transduction-based immunotherapies., (©2020 American Association for Cancer Research.)

Background: Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic, or postsynaptic. Causative mutations have been identified in 4 breeds including the Labrador Retriever, Jack Russell Terrier, Heideterrier, and Danish Pointing Dog., Hypothesis/objective: Clinical and genetic characterization of a neuromuscular disorder in Golden Retriever (GR) puppies., Animals: Four GR puppies from California were evaluated for generalized muscle weakness beginning at weaning. Biological specimens were collected from the affected puppies, and familial information was obtained. Blood or buccal swabs were obtained from 63 unaffected GRs., Methods: Complete physical, neurological, electrodiagnostic, and histological evaluations and biochemical quantification of muscle acetylcholine receptors were performed. Polymerase chain reaction was used to amplify the 17 exons of COLQ, and sequences were obtained by Sanger sequencing. Variant frequency was assessed in unrelated GRs and a public database., Results: Clinical, neurological, and electrodiagnostic evaluations confirmed a disorder of neuromuscular transmission in a GR family. Sequencing of all exons and splice sites of a primary candidate gene, COLQ, identified a point mutation that predicts an amino acid substitution (G294R). The primary COLQ transcript was absent from affected muscle samples. All affected puppies were homozygous for the mutation, which was not detected outside this GR family or in other breeds., Conclusions and Clinical Importance: We confirmed the diagnosis of a CMS in GR puppies and identified a novel COLQ mutation. The COLQ gene encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of skeletal muscle contraction by clearing acetylcholine at the neuromuscular junction. Clinicians and breeders should be aware of this CMS in GR puppies with an early onset of weakness., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Tumor osseous pseudoprogression (PP), defined as an imaging-based transient increase in tumor size following treatment, was recently described in patients with spinal metastases following stereotactic body radiation therapy. Distinguishing PP from true tumor progression is critical., Objective: To describe the incidence, time of onset, and time range of PP following stereotactic body radiation therapy in patients treated for spinal metastases from either prostate cancer (PC) or renal cell carcinoma (RCC), and associated predictive factors., Methods: A retrospective study was conducted on our institution's cancer database from 2009 to 2015. Selection was based on single level, no prior radiation or surgery, ≥2 follow-up spine magnetic resonance imaging (MRI), and metastases arising from either PC or RCC. Gross tumor volume was contoured on pre- and up to 5 posttreatment MRIs. Patients were sorted into groups depending on gross tumor volume response: PP, non-PP, or progressive disease. Clinical and dosimetric variables were compared using either Fisher's exact test or Kruskal-Wallis analyses., Results: Forty-three spinal segments from 31 patients were analyzed. RCC and PC patients showed similar incidence of PP (∼37%). Whether the primary was lytic or sclerotic was a significant predictive factor with more PP in the lytic group (P = .0208). There was a trend of earlier PP onset in RCC (within 6-18 mo) as compared to PC; however, PC segments showed more time-confined presentation of PP (9-12 mo)., Conclusion: There was a higher incidence of PP in lytic compared to sclerotic primary tumor type. PP in spinal metastatic sites may have variable presentations depending on the primary cancer., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Background: Simulation-based training (SBT) provides a safe environment and effective means to enhance skills development. Simulation-based curricula have been developed for a number of procedures, including gastrointestinal endoscopy. Gamification, which is the application of game-design principles to non-game contexts, is an instructional strategy with potential to enhance learning. No studies have investigated the effects of a comprehensive gamification curriculum on the acquisition of endoscopic skills among novice endoscopists., Methods and Analysis: Thirty-six novice endoscopists will be randomised to one of two endoscopy SBT curricula: (1) the Conventional Curriculum Group, in which participants will receive 6 hours of one-on-one simulation training augmented with expert feedback and interlaced with 4 hours of small group teaching on the theory of colonoscopy or (2) the Gamified Curriculum Group, in which participants will receive the same curriculum with integration of the following game-design elements: a leaderboard summarising participants' performance, game narrative, achievement badges and rewards for top performance. In line with a progressive learning approach, simulation training for participants will progress from low to high complexity simulators, starting with a bench-top model and then moving to the EndoVR virtual reality simulator. Performance will be assessed at three points: pretraining, immediately post-training and 4-6 weeks after training. Assessments will take place on the simulator at all three time points and transfer of skills will be assessed during two clinical colonoscopies 4-6 weeks post-training. Mixed factorial ANOVAs will be used to determine if there is a performance difference between the two groups during simulated and clinical assessments., Ethics and Dissemination: Ethical approval was obtained at St. Michael's Hospital. Results of this trial will be submitted for presentation at academic meetings and for publication in a peer-reviewed journal., Trial Registration Number: NCT03176251., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Memory CD8 + T cells (T mem ) are superior mediators of adoptive cell therapy (ACT) compared with effector CD8 + T cells (T eff ) due to increased persistence in vivo . Underpinning T mem survival is a shift in cellular metabolism away from aerobic glycolysis towards fatty acid oxidation (FAO). Here we investigated the impact of the peroxisome proliferator-activated receptor (PPAR) agonist GW501516 (GW), an agent known to boost FAO in other tissues, on CD8 + T-cell metabolism, function, and efficacy in a murine ACT model. Via activation of both PPARα and PPARδ/β, GW treatment increased expression of carnitine palmitoyl transferase 1a, the rate-limiting enzyme of FAO, in activated CD8 + T cells. Using a metabolomics approach, we demonstrated that GW increased the abundance of multiple different acylcarnitines, consistent with enhanced FAO. T cells activated in the presence of GW and inflammatory signals, either mature dendritic cells or IL12, also demonstrated enhanced production of IFNγ and expression of T-bet. Despite high expression of T-bet, a characteristic of short-lived effector cells, GW-treated cells demonstrated enhanced persistence in vivo and superior efficacy in a model of ACT. Collectively, these data identify combined PPARα and PPARδ/β agonists as attractive candidates for further studies and rapid translation into clinical trials of ACT. SIGNIFICANCE: Dual activation of peroxisome proliferator-activated receptors α and δ improves the efficacy of adoptive cell therapy by reprogramming T-cell metabolism and cytokine expression., (©2018 American Association for Cancer Research.)

A 10-year-old golden retriever dog was referred with a 24-h history of generalized seizures. Magnetic resonance imaging of the brain found no abnormalities on 3 mm transverse sections and the dog was subsequently humanely destroyed. Microscopically there was bilaterally symmetrical focal disorganization of cortical grey matter within the tips of the right and left suprasylvian gyri of the temporal cortex. The focal abnormal cortical lamination was characterized by loss of pyramidal neurons with abnormal, irregular, angular, remaining neurons occasionally forming clusters, surrounded by fibrillary astrogliosis and microgliosis and vascular proliferation. These histological findings are consistent with focal cortical dysplasia, a cerebral cortical malformation that causes seizures in people, but not reported previously in the dog., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Harrison (1918: J. Exp. Zool. 25: 413-461) described a developmental field as an "equipotential self-differentiating system." The present study was undertaken to address the question: To what extent can be pre-limb territory of a chick embryo be considered a developmental field? To what extent is the chick pre-limb territory an equipotential self-differentiating system? Two sets of experiments were undertaken to address these questions: (1) Whole and half limb territories were explanted to the celoma of host embryos, and (2) portions of the wing territories were extirpated. The wing exhibited the quality of self-differentiation after stage 12, in that the isolated wing territory, grafted to a host celom, could form limbs beginning at stage 12 (however, complete wings formed only from wing territories of stage 16 and older). On the other hand, the chick wing territory did not appear to exhibit equipotentiality. No posterior half limb graft formed normal limbs, and only in two exceptional cases did anterior half limb grafts form limbs. If part or all of the wing territory was removed from chick embryos, normal limbs formed in less than 15% of the cases after stage 15, in about 30% of the cases at stages 13 and 14, but in over half the cases at stages 10-12. Wound healing and reinitiation of limb potential may be responsible for the higher incidence of limb formation at the younger ages.