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Context Thyroid hormone (TH) is crucial for the adaptation to cold. Objective To evaluate the effect of hyperthyroidism on resting energy expenditure (REE), cold-induced thermogenesis (CIT) and changes in body composition and weight. Methods This was a prospective cohort study at the endocrine outpatient clinic of a tertiary referral center. Eighteen patients with overt hyperthyroidism were included. We measured REE during hyperthyroidism, after restoring euthyroid TH levels and after 3 months of normal thyroid function. In 14 of the 18 patients, energy expenditure (EE) was measured before and after a mild cold exposure of 2 hours and CIT was the difference between EEcold and EEwarm. Skin temperatures at 8 positions were recorded during the study visits. Body composition was assessed by dual X-ray absorption. Results Free thyroxine (fT4) and free triiodothyronine (fT3) decreased significantly over time (fT4, P = .0003; fT3, P = .0001). REE corrected for lean body mass (LBM) decreased from 42 ± 6.7 kcal/24 hour/kg LBM in the hyperthyroid to 33 ± 4.4 kcal/24 hour/kg LBM (–21%, P Conclusion CIT is not increased in patients with overt hyperthyroidism.

The web has become a dominant epistemic environment, influencing people's beliefs at a global scale. However, online epistemic environments are increasingly polluted, impairing societies' ability to coordinate effectively in the face of global crises. We argue that centralized platforms are a main source of epistemic pollution, and that healthier environments require redesigning how we collectively govern attention. Inspired by decentralization and open source software movements, we propose Open Source Attention, a socio-technical framework for "freeing" human attention from control by platforms, through a decentralized eco-system for creating, storing and querying stigmergic markers; the digital traces of human attention., Blue-sky ideas track of the 33rd ACM Conference on Hypertext and Social Media, Barcelona, 2022 (updated references)

Background Brown adipose tissue (BAT) is a thermogenic tissue which can generate heat in response to mild cold exposure. As it constitutes a promising target in the fight against obesity, we need reliable techniques to quantify its activity in response to therapeutic interventions. The current standard for the quantification of BAT activity is [18F]FDG PET/CT. Various sequences in magnetic resonance imaging (MRI), including those measuring its relative fat content (fat fraction), have been proposed and evaluated in small proof-of-principle studies, showing diverging results. Here, we systematically compare the predictive value of adipose tissue fat fraction measured by MRI to the results of [18F]FDG PET/CT. Methods We analyzed the diagnostic reliability of MRI measured fat fraction (FF) for the estimation of human BAT activity in two cohorts of healthy volunteers participating in two prospective clinical trials (NCT03189511, NCT03269747). In both cohorts, BAT activity was stimulated by mild cold exposure. In cohort 1, we performed [18F]FDG PET/MRI; in cohort 2, we used [18F]FDG PET/CT followed by MRI. Fat fraction was determined by 2-point Dixon and 6-point Dixon measurement, respectively. Fat fraction values were compared to SUVmean in the corresponding tissue depot by simple linear regression. Results In total, 33 male participants with a mean age of 23.9 years and a mean BMI of 22.8 kg/m2 were recruited. In 32 participants, active BAT was visible. On an intra-individual level, FF was significantly lower in high-SUV areas compared to low-SUV areas (cohort 1: p

ImportanceThe antiviral activity and efficacy of anti-SARS-CoV-2 monoclonal antibody (mAb) therapies to accelerate recovery from COVID-19 is important to define.ObjectiveTo determine safety and efficacy of the mAb bamlanivimab to reduce nasopharyngeal (NP) SARS-CoV-2 RNA levels and symptom duration.DesignACTIV-2/A5401 is a randomized, blinded, placebo-controlled platform trial. Two dose cohorts were enrolled between August 19 and November 17, 2020 for phase 2 evaluation: in the first, participants were randomized 1:1 to bamlanivimab 7000 mg versus placebo, and in the second to bamlanivimab 700 mg versus placebo. Randomization was stratified by time from symptom onset (≤ or >5 days) and risk of progression to severe COVID-19 (“higher” vs “lower”).SettingMulticenter trial conducted at U.S. sites.ParticipantsNon-hospitalized adults ≥18 years of age with positive SARS-CoV-2 antigen or nucleic acid test within 7 days, ≤10 days of COVID-19 symptoms, and with oxygen saturation ≥92% within 48 hours prior to study entry.InterventionSingle infusion of bamlanivimab (7000 or 700 mg) or placebo.Main Outcomes and MeasuresDetection of NP SARS-CoV-2 RNA at days 3, 7, 14, 21, and 28, time to improvement of all of 13 targeted COVID-19 symptoms by daily self-assessment through day 28, and grade 3 or higher treatment emergent adverse events (TEAEs) through day 28. Secondary measures included quantitative NP SARS-CoV-2 RNA, all-cause hospitalizations and deaths (composite), area under the curve of symptom scores from day 0 through day 28, plasma bamlanivimab concentrations, plasma and serum inflammatory biomarkers, and safety through week 24.ResultsNinety-four participants were enrolled to the 7000 mg cohort and 223 to the 700 mg cohort and initiated study intervention. The proportion meeting protocol criteria for “higher” risk for COVID-19 progression was 42% and 51% for the 7000 and 700 mg cohort, respectively. Median time from symptom onset at study entry for both cohorts was 6 days. There was no difference in the proportion with undetectable NP SARS-CoV-2 RNA at any post-treatment timepoints (risk ratio compared to placebo, 0.82-1.05 for 7000 mg dose [overall p=0.88] and 0.81-1.21 for 700 mg dose [overall p=0.49]), time to symptom improvement (median of 21 vs 18.5 days, p=0.97, for 7000 mg bamlanivimab vs placebo and 24 vs 20.5 days, p=0.08, for 700 mg bamlanivimab vs placebo), or grade 3+ TEAEs with either dose compared to placebo. Median NP SARS-CoV-2 RNA levels were lower at day 3 and C-reactive protein, ferritin, and fibrinogen levels significantly reduced at days 7 and 14 for bamlanivimab 700 mg compared to placebo, with similar trends observed for bamlanivimab 7000 mg. Viral decay modeling supported more rapid decay with bamlanivimab compared to placebo.Conclusions and RelevanceTreatment with bamlanivimab 7000 mg and 700 mg was safe and compared to placebo led to more rapid reductions in NP SARS-CoV-2 RNA and inflammatory biomarkers, but did not decrease time to symptom improvement. The clinical utility of mAbs for outcomes other than hospitalizations and deaths is uncertain.Trial RegistrationClinicalTrials.gov Identifier: NCT04518410KEY POINTSQuestionWhat is the safety and efficacy of bamlanivimab monoclonal antibody (mAb) treatment for mild to moderate COVID-19?FindingsIn this randomized, placebo-controlled phase 2 trial of 317 non-hospitalized adults with COVID-19, there was no relationship between symptoms or disease progression risk and nasopharyngeal (NP) virus shedding. Bamlanivimab was safe and reduced NP SARS-CoV-2 RNA levels and inflammatory biomarker levels more than placebo, but did not shorten symptom duration.MeaningNasal virus shedding was not associated with symptoms or baseline risk factors for severe COVID-19. Bamlanivimab, which has been associated with reduced hospitalizations in high-risk individuals, demonstrated antiviral activity with early post-treatment NP sampling but did not accelerate symptom improvement. The clinical utility of bamlanivimab for outcomes other than hospitalizations and deaths, including longer-term outcomes, is uncertain.

Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome in which affected individuals are prone to developing a wide spectrum of malignancies. LFS is caused by germline mutations in the TP53 tumour suppressor gene. LFS patients develop cancer significantly earlier than the general population and may experience multiple malignancies in their lifetime. Studies have indicated that environmental influences like radiation exposure and tobacco smoke may further increase cancer risk in LFS patients. Currently, there is no cure for LFS, and screening for early tumour detection is the standard of care for LFS patients. Recently, microbes have been found to be involved in cancer development, progression, and treatment responsiveness. Moreover, microbes have anti-tumourigenic properties that can be harnessed for therapeutic intervention. The interaction between microbes and cancer can be through contact-dependent, contact-independent, and/or immunological interactions. Profiling the microbiome in the context of cancer may provide prognostic and/or diagnostic options for patients. However, interactions between the microbiome and mutant p53 in LFS has not been studied to date. We induced dysbiosis using a combination of antibiotics in LFS mice harbouring the heterozygous Trp53 R172H mutation. Following 7 days of treatment, we challenged mice with subcutaneous injections of the MC38 colon adenocarcinoma cell line. We observed an increase in tumour volume in LFS mice treated with antibiotics; this change was not observed in p53 wildtype mice. These findings highlight potentially unique interactions between mutant p53 and the microbiome which influence tumour growth in the context of LFS. We also found that LFS mice treated with metformin have smaller tumours compared to untreated mice. A particular genus of bacteria, Faecalibaculum sp., was found to be upregulated in a cohort of metformin treated mice, and the abundance of this bacterium is inversely proportional to tumour volume. Zagato et al. have shown that Faecalibaculum rodentium has anti-tumourigenic properties through the production of short-chain fatty acid (SCFA). Altogether, these observations suggest that microbes may influence tumour growth in LFS mice. The study of interactions between the microbiome and mutant p53 and the influence of these interactions on cancer development in LFS may, with further study, provide avenues of prognostic and/or diagnostic interest. Differences in the microbiome in cancer-affected and cancer-free LFS patients may also introduce the possibility to exploit the microbiome for treatment and/or preventative purposes in these patients. Citation Format: Noel Wei Ong, Camilla Maria Giovino, Nicholas William Fischer, Pamela Psarianos, David Malkin. Investigating the interaction between the microbiome and mutant p53 in Li-Fraumeni Syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3047.

Background Brown adipose tissue (BAT) is a thermogenic tissue which can generate heat in response to mild cold exposure. As it constitutes a promising target in the fight against obesity, we need reliable techniques to quantify its activity in response to therapeutic interventions. The current standard for the quantification of BAT activity is [18F]FDG PET/CT. Various sequences in magnetic resonance imaging (MRI), including those measuring its relative fat content (fat fraction), have been proposed and evaluated in small proof-of-principle studies, showing diverging results. Here, we systematically compare the predictive value of adipose tissue fat fraction measured by MRI to the results of [18F]FDG PET/CT. Methods We analyzed the diagnostic reliability of MRI measured fat fraction (FF) for the estimation of human BAT activity in two cohorts of healthy volunteers participating in two prospective clinical trials (NCT03189511, NCT03269747). In both cohorts, BAT activity was stimulated by mild cold exposure. In cohort 1, we performed [18F]FDG PET/MRI; in cohort 2, we used [18F]FDG PET/CT followed by MRI. Fat fraction was determined by 2-point Dixon and 6-point Dixon measurement, respectively. Fat fraction values were compared to SUVmean in the corresponding tissue depot by simple linear regression. Results In total, 33 male participants with a mean age of 23.9 years and a mean BMI of 22.8 kg/m2 were recruited. In 32 participants, active BAT was visible. On an intra-individual level, FF was significantly lower in high-SUV areas compared to low-SUV areas (cohort 1: p

Submitted by Rosangela Silva (rosangela.silva3@unioeste.br) on 2019-01-08T14:04:31Z No. of bitstreams: 2 William Fischer da Silva Junior.pdf: 2849732 bytes, checksum: ce74b827359aa0cddccd384dff1ce011 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Made available in DSpace on 2019-01-08T14:04:31Z (GMT). No. of bitstreams: 2 William Fischer da Silva Junior.pdf: 2849732 bytes, checksum: ce74b827359aa0cddccd384dff1ce011 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-08-16 The theme investigated in this study is about the strategy and sustainability of the third sector, with the objective of investigating how management control systems can stimulate donations to the social causes of Civil Society Organizations (CSOs) from the gift theory perspective. The contribution, therefore, is focused on describing the interaction between effective management and the building of relationships and relationships with donors, which will provide better fundraising, promoting the sustainability of the organization. The theoretical framework deals with the Gift Theory, a social phenomenon that seeks to relate solidarity and alliance between people and groups, creating the cause and effect necessary for the durability of some relationships. On the systems of managerial control with emphasis in the approach of the model of the levers of control of Simons (1995), that favor the coordination and the control of the organizational processes. Also on fundraising with an inherent approach to the formulation of mobilization strategies. The methodology used will be descriptive with the consensus analysis and will be carried out in two non-profit entities of the municipality of Cascavel. The field of study entities are the Association of Parents and Friends of the Exceptional (APAE) and the Cascavelense Association of Friends of the Deaf (ACAS), and the data collection was done through questionnaires with closed questions and sent to the donors of both organizations. As a conclusion, the results ratified the initial proposals of this study and it was possible to understand that there is consensus among donors about donating time, financial resources and materials for social organizations. These, in turn, need to improve their management models in order to elicit the necessary stimulus for donations to be expanded. Finally, future research could address the main obstacles to management in non-profit organizations, contributing to their development of better corporate governance and a communication strategy with society that is able to attract and retain supporters as well as analyze the aspects related to its intangible assets. O tema investigado neste estudo versa sobre como o uso de sistemas de controle gerencial podem estimular as doações às causas sociais das Organizações da Sociedade Civil (OSC) sob a ótica da Teoria da Dádiva. Portanto, a contribuição centra-se em descrever a interação entre a administração eficaz e a construção de laços e relacionamentos com os doadores que proporcionará melhor captação de recursos, promovendo a sustentabilidade da organização. O referencial teórico discorre sobre a Teoria da Dádiva, fenômeno social que procura relacionar a solidariedade e a aliança entre pessoas e grupos, criando a causa e o efeito necessários para a durabilidade de algumas relações. Sobre os sistemas de controle gerencial com ênfase na abordagem do modelo das alavancas de controle de Simons (1995), que favorecem a coordenação e o controle dos processos organizacionais, e sobre a captação de recursos no intuito de uma abordagem inerente à formulação de estratégias de mobilização dos mesmos na dimensão relacional com base na Teoria da Dádiva. A metodologia utilizada será descritiva com a análise de consenso e será realizada em duas entidades sem fins lucrativos do município de Cascavel. As entidades campo de estudo são a Associação de Pais e Amigos dos Excepcionais (APAE) e a Associação Cascavelense de Amigos de Surdos (ACAS), sendo a coleta de dados realizada por meio de questionários com perguntas fechadas e encaminhados aos doadores de ambas as organizações. Como conclusão tem-se que os resultados ratificaram as proposições iniciais deste estudo e foi possível compreender que há consenso moderado e acentuado entre os doadores sobre doar tempo como voluntário, recursos financeiros e materiais para as organizações sociais. Estas, por sua vez, precisam aprimorar os seus modelos de gestão no intuito de provocar o estímulo necessário para que as doações sejam ampliadas. Por fim, futuras pesquisas poderiam tratar a respeito de apontar quais as principais deficiências na gestão das organizações sem fins lucrativos, contribuindo para que desenvolvam uma melhor governança corporativa e também uma estratégia de comunicação com a sociedade capaz de atrair e reter os seus doadores, bem como analisar os aspectos relacionados com os seus ativos intangíveis.

Background Hand hygiene (HH) is the single most important practice in the prevention of healthcare-associated infections (HAIs). However, HH is commonly suboptimal, with compliance often only 30–60%. In 2010, the Joint Commission Center for Transforming Healthcare launched the Targeted Solutions Tool (TST) for Hand Hygiene to aid institutions to increase HH compliance. After successfully deploying the TST at our medical center in 2015, we noted a remarkable improvement in overall HH. Unfortunately, improvements in HH across services were not uniform. Some services, like the environmental services (EVS), remained set in their old ways and continued to perform suboptimal HH. Methods We continued to engage staff using the TST model and just-in-time coaching (JITC) to encourage best HH practices. In addition, we often met with small groups for HH huddles, and reinforced the importance of EVS staff and their HH in helping to protect themselves and our patients, and reduce HAIs. Increasing EVS leadership commitment was key to further engage EVS staff and encourage better HH amongst EVS staff. Review of HH metrics was hard wired into the daily functions of the EVS department. Results Figure 1 shows EVS HH compliance from January 2014 through October 2017. This highlights the substantial progressive, albeit slow, improvement in EVS HH practices from a baseline of 40% to 60% to 80% over the course of nearly 4 years. Conclusion EVS HH rates remained suboptimal for prolonged periods. Initially the lack of leadership commitment and high staff turnover made training and engagement difficult. Continued interventions and use of just-in-time coaching proved to be effective to help improve compliance and better understand barriers to best practices. Connecting with EVS staff in small group huddles and the engagement of EVS leadership was key to success. Disclosures J. P. Parada, Merck: Speaker’s Bureau, Speaker honorarium.

A potential explanation of a fact is a hypothesis such that, if it were true, it would explain the fact in question. Let’s suppose that we become aware of a fact and some potential explanations thereof. Let’s also suppose that we would like to believe the truth. Given this aim, we can ask two questions. First, is it likely that one of these hypotheses is true? Second, given an affirmative answer to the first question, which one is it likely to be? Inference to the best explanation (IBE) offers answers to both questions. To the first, it says ‘Yes’—assuming that at least one of the hypotheses would, if true, provide a satisfactory explanation of the fact under consideration. To the second, it says that the hypothesis most likely to be true is the one that scores best on the explanatory virtues: conservatism, modesty, simplicity, generality, and predictive power. Many philosophers have argued against IBE’s answer to the first question. I am interested in an objection to its answer to the second. Many philosophers seem to think that it is unsustainable: they seem to think that even if we assume that one of the competing hypotheses is true, we should not think that IBE will help us to identify it. Or, more carefully, if these philosophers are doing what they appear to be doing—namely, offering critiques of IBE that don’t depend on assumptions about the field of competing hypotheses—then their claim is that IBE will not help us to identify the truth. I believe that this is mistaken: the argument for believing it assumes a model of IBE that we have no reason to accept.

International audience; As chartered by the Science Definition Team, the Mars 2020 mission addresses four primary objectives: A. Characterize the processes that formed and modified the geologic record within an astrobiologically relevant ancient environment, B. Perform astrobiologically relevant investigations to determine habitability, search for materials with biosignature presentation potential, and search for evidence of past life, C. Assemble a returnable cache of samples and D. Contribute to preparation for human exploration of Mars. The SuperCam instrument, selected for the Mars 2020 rover, as a suite of four instruments, provides nested and co-aligned remote investigations: Laser Induced Breakdown Spectroscopy (LIBS), Raman spectroscopy and time-resolved fluorescence (TRF), visible and near-infrared spectroscopy (VISIR), and high resolution color imaging (RMI). SuperCam appeals broadly to the four Mars 2020 objectives.In detail, SuperCam will perform:1. Microscale mineral identification by combining LIBS elemental and VISIR mineralogical spectroscopies, especially targeting secondary minerals2. Determine the sedimental stratigraphy through color imaging and LIBS and VISIR spectroscopy3. Search for organics and bio-signatures with LIBS and Raman spectroscopy4. Quantify the volatile content of the rocks by LIBS spectroscopy to determine the degree of aquaeous alteration5. Characterize the texture of the rocks by color imaging to determine their alteration processes6. Characterize the rocks' coatings by LIBS spectroscopy7. Characterize the soil and its potential for biosignature preservation8. Monitor the odd-oxygen atmospheric chemistry.To meet these goals SuperCam will perform LIBS spectroscopy on 0.5 mm spot up to 7-meter distance, perform Raman and time-resolved fluoresence up to 12-m distance with a 0.8 mrad angular resolution, a 100 ns time gating in the 534-850 nm spectral range, acquire VISIR spectra in the range 0.4-0.85 μm with a resolution of 0.35 nm, and in the IR range over 1.3-2.6 μm, rich in mineral signatures, with a resolution of 20 nm, and provide RGB images with an angular resolution of 40 μrad over a FOV of 20 mrad.We will present the science performances of SuperCam and the forecasted operation plans.

Prader–Willi syndrome (PWS) is due to loss of paternally expressed genes in the 15q11–q13 region generally from a paternal 15q11–q13 deletion. The proximal deletion breakpoint in the 15q11–q13 region occurs at one of two sites located within either of two large duplicons allowing for identification of two typical deletion subgroups. The larger type I (TI) deletion involving breakpoint 1 (BP1) is nearer to the centromere and located proximal to the microsatellite marker D15S1035, while the smaller type II (TII) deletion involves breakpoint 2 (BP2) and distal to D15S1035. Breakpoint 3 (BP3) is located at the distal end of the 15q11–q13 region and common to both typical deletion subgroups. Using high resolution aCGH, BP1 spanned a region from 18.683 to 20.220 Mb, BP2 from 20.812 to 21.357 Mb and BP3 from 25.941 to 27.286 Mb. The TI deletion ranged in size from 5.721 to 8.147 Mb (mean 6.583) and the type II deletion from 4.770 to 6.435 Mb (mean 5.330). A subset of the TI subjects showed larger deletions including the loss of at least three genes/transcripts (i.e., LOC283755, POTE5, OR4N4) in addition to the four genes between BP1 and BP2 (i.e., GCP5, CYFIP1, NIPA1, NIPA2). Interestingly, four PWS subjects had duplications of the 15q11 region in addition to the typical deletion. Furthermore, most PWS subjects had copy number variation (CNV) of 50 kb or larger in other chromosome regions; most common were deletions and duplications of 8p and 3q, previously recognized sites of CNV in the human genome. © 2008 Wiley-Liss, Inc.

Background: X-chromosome inactivation (XCI) is the mechanism by which gene dosage uniformity is achieved between female mammals with two X chromosomes and male mammals with a single X chromosome, and is thought to occur randomly. For molecular genetic testing, accessible tissues (eg blood) are commonly studied, but the relationship with inaccessible tissues (eg brain) is poorly understood. For accessible tissues to be informative for genetic analysis, a high degree of concordance of genetic findings among tissue types is required. Objective: To determine the relationship among multiple tissues within females at different ages (fetus to 82 years). M ethods: XCI patterns were analysed using the polymorphic androgen receptor ( AR ) gene assay. DNA was isolated from 26 different human females without history of malignancy, using 34 autopsy tissues representing the three embryonic germ layers. Results: 33 of the 280 tissue samples analysed from 13 of the 26 females showed skewed XCI values (>80:20%). Average XCI value was not significantly different among the tissues, but a trend for increasing XCI variability was observed with age in blood and other tissues studied (eg the SD for all tissues studied for the 0–2 years group was 9.9% compared with 14.8% in the >60 years group). We found a significant correlation (rs = 0.51, p = 0.035) between XCI values for blood and/or spleen and brain tissue, and in most other tissues representing the three embryonic germ layers. Conclusions: In our study, XCI data were comparable among accessible (eg blood) and inaccessible tissues (eg brain) in females at various ages, and may be useful for genetic testing. A trend was seen for greater XCI variability with increasing age, particularly in older women (>60 years).

The pattern of errors in reading isolated words was studied in two groups of children with respect, particularly, to reversals of letter sequence and letter orientation. One group (the Institute group) consisted of children 8 to 10 years old who had been diagnosed "dyslexic" according to medical and psychoeducational criteria. The other (the School group) included all the children in a second-year elementary school class (see Liberman, Shankweiler, Orlando, Harris and Berti, 1971) who fell into the lowest third on a standard test of reading achievement. Although the Institute children were somewhat poorer in word recognition than the backward readers selected purely on psychometric grounds, the groups did not differ significantly in the incidence of reversal errors. Also, for both groups, reversals represented a small proportion of the total number of reading errors. The performance of the two groups differed in two respects: in relation to directional bias in letter reversals and in the presence or absence of a significant correlation between letter-reversing and word-reversing tendencies. It was concluded from this that directional problems do not loom large in importance in most cases of reading backwardness, but may provide an additional source of difficulty for some dyslexic children. Other aspects of the error pattern were remarkably the same for both groups. The bulk of reading errors made by both groups reflect their common difficulties in phonemic segmentation of words in the lexicon, in phonetic recoding, and in mastery of the orthography--difficulties, in short, with linguistic characteristics of words rather than with their properties as visual patterns.

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