06-07 “The Economics of Inaction on Climate Change: A Sensitivity Analysis”

Economic models of climate change often take the problem seriously, but paradoxically conclude that the optimal policy is to do almost nothing about it. We explore this paradox as seen in the widely used DICE model. Three aspects of that model, involving the discount rate, the assumed benefits of moderate warming, and the treatment of the latest climate science, are sufficient to explain the timidity of the model's optimal policy recommendation. With modifications to those three points, DICE shows that the optimal policy is a much higher and rapidly rising marginal carbon price; that higher carbon price has a greater effect on physical measures of climate impacts. Our modifications exhibit nonlinear interactions; at least at low discount rates, there is synergy between individual changes to the model. At low discount rates, the inherent uncertainty about future damages looms larger in the analysis, rendering long-run economic modeling less useful. Our analysis highlights the sensitivity of the model to three debatable assumptions; it does not, and could not, lead to a more reliably “optimal” cost of carbon. Cost-effectiveness analysis, focusing on the generally shorter-term cost side of the problem, reduces the economic paradoxes of the long run, and may make a greater contribution than economic optimization modeling.

Disfluency in dialogue:an intentional signal from the speaker?

Disfluency is a characteristic feature of spontaneous human speech, commonly seen as a consequence of problems with production. However, the question remains open as to why speakers are disfluent: Is it a mechanical by-product of planning difficulty, or do speakers use disfluency in dialogue to manage listeners' expectations? To address this question, we present two experiments investigating the production of disfluency in monologue and dialogue situations. Dialogue affected the linguistic choices made by participants, who aligned on referring expressions by choosing less frequent names for ambiguous images where those names had previously been mentioned. However, participants were no more disfluent in dialogue than in monologue situations, and the distribution of types of disfluency used remained constant. Our evidence rules out at least a straightforward interpretation of the view that disfluencies are an intentional signal in dialogue. © 2012 Psychonomic Society, Inc

Loss of Expression and Promoter Methylation of SLIT2 Are Associated with Sessile Serrated Adenoma Formation.

Serrated adenomas form a distinct subtype of colorectal pre-malignant lesions that may progress to malignancy along a different molecular pathway than the conventional adenoma-carcinoma pathway. Previous studies have hypothesised that BRAF mutation and promoter hypermethylation plays a role, but the evidence for this is not robust. We aimed to carry out a whole-genome loss of heterozygosity analysis, followed by targeted promoter methylation and expression analysis to identify potential pathways in serrated adenomas. An initial panel of 9 sessile serrated adenomas (SSA) and one TSA were analysed using Illumina Goldengate HumanLinkage panel arrays to ascertain regions of loss of heterozygosity. This was verified via molecular inversion probe analysis and microsatellite analysis of a further 32 samples. Methylation analysis of genes of interest was carried out using methylation specific PCR (verified by pyrosequencing) and immunohistochemistry used to correlate loss of expression of genes of interest. All experiments used adenoma samples and normal tissue samples as control. SSA samples were found on whole-genome analysis to have consistent loss of heterozygosity at 4p15.1–4p15.31, which was not found in the sole TSA, adenomas, or normal tissues. Genes of interest in this region were PDCH7 and SLIT2, and combined MSP/IHC analysis of these genes revealed significant loss of SLIT2 expression associated with promoter methylation of SLIT2. Loss of expression of SLIT2 by promoter hypermethylation and loss of heterozygosity events is significantly associated with serrated adenoma development, and SLIT2 may represent a epimutated tumour suppressor gene according to the Knudson “two hit” hypothesis

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART) : a multicentre, prospective, randomised, open-label, blinded-endpoint trial

Funding Information: ISM reports research grants from Menarini, EMA, Sanofi, Health Data Research UK, the British Heart Foundation, and Innovative Medicines Initiative; institutional consultancy income from AstraZeneca outside the submitted work; and personal income from AstraZeneca and Amgen outside the submitted work. TMM reports grants from Menarini/Ipsen/Teijin and Merck Sharp & Dohme outside the submitted work, and personal income for consultancy from Novartis and AstraZeneca outside the submitted work, and is a trustee of the Scottish Heart Arterial Risk Prevention Society. AGB reports personal income from Novartis, Mylan, AstraZeneca, Bayer, Daiichi-Sankyo, Boehringer, Pfizer, Galderma, Zambon, and Novo-Nordisk outside the submitted work. ADS and the University of Dundee hold a European patent for the use of xanthine oxidase inhibitors in treating chest pain in angina pectoris. AW declares personal income for consultancy from AbbVie, Akcea, Albireo, Alexion, Allergan, Amarin, Apsara, Arena, Astellas, AstraZeneca, Autolus, Bayer, Biocryst, Biogen, Biomarin, Bristol Myers Squibb, Boehringer Ingelheim, Calico, Celgene, Chiesi, Daiichi Sankyo, Diurnal, Elsai, Eli Lilly, Ferring, Galapagos, Gedeon Richter, Gilead, GlaxoSmithKline, GW Pharma, Idorsia, Incyte, Intercept, Ionis, Ipsen, Janssen, Jazz, Jcyte, Kite Gilead, LEK, Leo Pharma, Les Laboratoires Servier, Lundbeck, Merck (Merck Sharp & Dohme), Merck-Serono, Mitenyi, Mundibiopharma, Mustang Bio, Mylan, Myovant, Norgine, Novartis, Novo Nordisk, Orchard, Paion, Pfizer, Pierre Fabre, PTC, RegenXBio, Rhythm, Sanofi, Santen, Sarepta, SeaGen, Shionogi, Sigmatec, SOBI, Takeda, Tanaya, UCB, and Vertex outside the submitted work. JST declares research funding from the UK National Institute for Health and Care Research (NIHR) and NHS England outside the submitted work and membership of a UK National Institute for Health and Care Excellence guideline committee on management of atrial fibrillation. All other authors declare no competing interests. Funding Information: This study was funded by the NIHR Health Technology Assessment programme (HTA 11/36/41 to ISM, IF, CJH, LW, ADS, AGB, AJA, AW, JST, and TMM). The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The study was supported by the Scottish Primary Care Research Network, Support for Science Scotland (Grampian, Highlands, Tayside, Fife, Forth Valley, Greater Glasgow and Clyde, Lothian, Ayrshire and Arran, Dumfries and Galloway, and Lanarkshire), and the NIHR Local Clinical Research Networks (East Midlands, West Midlands, Eastern, North Thames, Yorkshire and Humber, North East and North Cumbria, North West Coast, Kent, Surrey and Sussex, and South West Peninsula), which assisted with recruitment and other study activities. We thank Public Health Scotland and NHS Digital for providing data linkage. We thank all the participants, physicians, nurses, and other staff who participated in the ALL-HEART study. Funding Information: This study was funded by the NIHR Health Technology Assessment programme (HTA 11/36/41 to ISM, IF, CJH, LW, ADS, AGB, AJA, AW, JST, and TMM). The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The study was supported by the Scottish Primary Care Research Network, Support for Science Scotland (Grampian, Highlands, Tayside, Fife, Forth Valley, Greater Glasgow and Clyde, Lothian, Ayrshire and Arran, Dumfries and Galloway, and Lanarkshire), and the NIHR Local Clinical Research Networks (East Midlands, West Midlands, Eastern, North Thames, Yorkshire and Humber, North East and North Cumbria, North West Coast, Kent, Surrey and Sussex, and South West Peninsula), which assisted with recruitment and other study activities. We thank Public Health Scotland and NHS Digital for providing data linkage. We thank all the participants, physicians, nurses, and other staff who participated in the ALL-HEART study. Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licensePeer reviewedPublisher PD

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial

BACKGROUND: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. METHODS: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. FINDINGS: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89–1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87–1·20], p=0·77). INTERPRETATION: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. FUNDING: UK National Institute for Health and Care Research

Calibrating ADL-IADL scales to improve measurement accuracy and to extend the disability construct into the preclinical range: a systematic review

<p>Abstract</p> <p>Background</p> <p>Interest in measuring functional status among nondisabled older adults has increased in recent years. This is, in part, due to the notion that adults identified as 'high risk' for functional decline portray a state that is potentially easier to reverse than overt disability. Assessing relatively healthy older adults with traditional self-report measures (activities of daily living) has proven difficult because these instruments were initially developed for institutionalised older adults. Perhaps less evident, are problems associated with change scores and the potential for 'construct under-representation', which reflects the exclusion of important features of the construct (e.g., disability). Furthermore, establishing a formal hierarchy of functional status tells more than the typical simple summation of functional loss, and may have predictive value to the clinician monitoring older adults: if the sequence task difficulty is accelerated or out of order it may indicate the need for interventions.</p> <p>Methods</p> <p>This review identified studies that employed item response theory (IRT) to examine or revise functional status scales. IRT can be used to transform the ordinal nature of functional status scales to interval level data, which serves to increase diagnostic precision and sensitivity to clinical change. Furthermore, IRT can be used to rank items unequivocally along a hierarchy based on difficulty. It should be noted that this review is not concerned with contrasting IRT with more traditional classical test theory methodology.</p> <p>Results</p> <p>A systematic search of four databases (PubMed, Embase, CINAHL, and PsychInfo) resulted in the review of 2,192 manuscripts. Of these manuscripts, twelve met our inclusion/exclusion requirements and thus were targeted for further inspection.</p> <p>Conclusions</p> <p>Manuscripts presented in this review appear to summarise gerontology's best efforts to improve construct validity and content validity (i.e., ceiling effects) for scales measuring the early stages of activity restriction in community-dwelling older adults. Several scales in this review were exceptional at reducing ceiling effects, reducing gaps in coverage along the construct, as well as establishing a formal hierarchy of functional decline. These instrument modifications make it plausible to detect minor changes in difficulty for IADL items positioned at the edge of the disability continuum, which can be used to signal the onset of progressive type disability in older adults.</p

MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis, by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation (MTsat) and neurite orientation dispersion and density imaging (NODDI) diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 vs 0.57, difference 0.036, 95% CI 0.029 to 0.043, p &amp;lt; 0.001). Lesion volume (Spearman’s rho rs= 0.38, p &amp;lt; 0.001) and g-ratio (rs= 0.24 p &amp;lt; 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) (11/23 [48%] versus 2/15 [13%] p &amp;lt; 0.05). These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity, and help to identify individuals with a high degree of axonal damage at disease onset. York, Martin et al. simultaneously measured g-ratio and plasma neurofilament in 73 relapsing-remitting multiple sclerosis patients at diagnosis using advanced MRI and single molecule ELISA. They demonstrate that g-ratio of cerebral white matter lesions varies at diagnosis, and show that high g-ratio of lesions is associated with elevated plasma neurofilament

To which world regions does the valence–dominance model of social perception apply?

Over the past 10 years, Oosterhof and Todorov’s valence–dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov’s methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov’s original analysis strategy, the valence–dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence–dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution.C.L. was supported by the Vienna Science and Technology Fund (WWTF VRG13-007); L.M.D. was supported by ERC 647910 (KINSHIP); D.I.B. and N.I. received funding from CONICET, Argentina; L.K., F.K. and Á. Putz were supported by the European Social Fund (EFOP-3.6.1.-16-2016-00004; ‘Comprehensive Development for Implementing Smart Specialization Strategies at the University of Pécs’). K.U. and E. Vergauwe were supported by a grant from the Swiss National Science Foundation (PZ00P1_154911 to E. Vergauwe). T.G. is supported by the Social Sciences and Humanities Research Council of Canada (SSHRC). M.A.V. was supported by grants 2016-T1/SOC-1395 (Comunidad de Madrid) and PSI2017-85159-P (AEI/FEDER UE). K.B. was supported by a grant from the National Science Centre, Poland (number 2015/19/D/HS6/00641). J. Bonick and J.W.L. were supported by the Joep Lange Institute. G.B. was supported by the Slovak Research and Development Agency (APVV-17-0418). H.I.J. and E.S. were supported by a French National Research Agency ‘Investissements d’Avenir’ programme grant (ANR-15-IDEX-02). T.D.G. was supported by an Australian Government Research Training Program Scholarship. The Raipur Group is thankful to: (1) the University Grants Commission, New Delhi, India for the research grants received through its SAP-DRS (Phase-III) scheme sanctioned to the School of Studies in Life Science; and (2) the Center for Translational Chronobiology at the School of Studies in Life Science, PRSU, Raipur, India for providing logistical support. K. Ask was supported by a small grant from the Department of Psychology, University of Gothenburg. Y.Q. was supported by grants from the Beijing Natural Science Foundation (5184035) and CAS Key Laboratory of Behavioral Science, Institute of Psychology. N.A.C. was supported by the National Science Foundation Graduate Research Fellowship (R010138018). We acknowledge the following research assistants: J. Muriithi and J. Ngugi (United States International University Africa); E. Adamo, D. Cafaro, V. Ciambrone, F. Dolce and E. Tolomeo (Magna Græcia University of Catanzaro); E. De Stefano (University of Padova); S. A. Escobar Abadia (University of Lincoln); L. E. Grimstad (Norwegian School of Economics (NHH)); L. C. Zamora (Franklin and Marshall College); R. E. Liang and R. C. Lo (Universiti Tunku Abdul Rahman); A. Short and L. Allen (Massey University, New Zealand), A. Ateş, E. Güneş and S. Can Özdemir (Boğaziçi University); I. Pedersen and T. Roos (Åbo Akademi University); N. Paetz (Escuela de Comunicación Mónica Herrera); J. Green (University of Gothenburg); M. Krainz (University of Vienna, Austria); and B. Todorova (University of Vienna, Austria). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.https://www.nature.com/nathumbehav/am2023BiochemistryGeneticsMicrobiology and Plant Patholog

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children