Reasoning with comparative moral judgements: an argument for Moral Bayesianism

The paper discusses the notion of reasoning with comparative moral judgements (i.e judgements of the form “act a is morally superior to act b”) from the point of view of several meta-ethical positions. Using a simple formal result, it is argued that only a version of moral cognitivism that is committed to the claim that moral beliefs come in degrees can give a normatively plausible account of such reasoning. Some implications of accepting such a version of moral cognitivism are discussed

Acute synovitis and intra-articular methylprednisolone acetate in ponies

AbstractObjective: To determine how acute synovitis, with and without intra-articular methylprednisolone acetate (MPA), affect synthesis of proteoglycan, total protein, and collagen in articular cartilage and total protein synthesis in synovial membrane.Design: Synovitis was induced in 10 ponies by the injection of 0.5 ng lipopolysaccharide (LPS) into the left radiocarpal and midcarpal joints every 2 days for a total of four treatments. Synovitis was documented by clinical examination and synovial fluid analyses. Two days before euthanasia, MPA (0.1 mg/kg) was injected with the last dose of LPS into both the left and right radiocarpal and midcarpal joints of five of these ponies. Proteoglycan synthesis in articular cartilage explants from these joints was measured by incorporation of sodium [35S]sulfate. The size of the proteoglycan monomers and their aggregation with hyaluronan was assessed by size-exclusion chromatography. Protein synthesis in articular cartilage was measured by incorporation of [3H]proline and collagen synthesis by conversion of [3H]proline into [3H]hydroxyproline. Protein synthesis was measured in synovial membrane explants by incorporation of [35S]methionine.Results: Ponies developed carpal effusion and mild lameness accompanied by increased total nucleated cell count and total solids in synovial fluid in response to the LPS injections. Moderate to severe synovial membrane proliferation and inflammation were observed histopathologically in joints injected with LPS but no consistent light-microscopical changes were observed in the articular cartilage from these joints. Intra-articular MPA alone was associated with decreased proteoglycan synthesis and increased protein and collagen synthesis in the cartilage explants. Total protein synthesis by synovial membrane was also increased by MPA alone. In contrast, no differences in protein or proteoglycan synthesis were observed in explants from the joints with synovitis, with or without intra-articular MPA. Treatment with MPA, LPS, and LPS/MPA did not alter proteoglycan aggregate size, but LPS-induced synovitis resulted in an increase in the second largest population of monomers. MPA increased the synthesis of small proteoglycan monomers.Conclusion: Based on the methods used, acute synovitis prevented changes induced by intra-articular MPA alone. Results suggested that the effect of intra-articular MPA on joint metabolism was different between inflamed and normal joints. Experimental studies must consider the effect of inflammation, as well as the potential to introducein vitroculture artifacts when investigating the effect of intra-articular corticosteroids on chondrocyte function

Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling

Tissue inhibitor of metalloproteinases 1 (TIMP-1) is a matrix metalloproteinase (MMP)-independent regulator of growth and apoptosis in various cell types. The receptors and signaling pathways that are involved in the growth factor activities of TIMP-1, however, remain controversial. RNA interference of TIMP-1 has revealed that endogenous TIMP-1 suppresses the proliferation, metabolic activity, and osteogenic differentiation capacity of human mesenchymal stem cells (hMSCs). The knockdown of TIMP-1 in hMSCs activated the Wnt/β-catenin signaling pathway as indicated by the increased stability and nuclear localization of β-catenin in TIMP-1–deficient hMSCs. Moreover, TIMP-1 knockdown cells exhibited enhanced β-catenin transcriptional activity, determined by Wnt/β-catenin target gene expression analysis and a luciferase-based β-catenin– activated reporter assay. An analysis of a mutant form of TIMP-1 that cannot inhibit MMP indicated that the effect of TIMP-1 on β-catenin signaling is MMP independent. Furthermore, the binding of CD63 to TIMP-1 on the surface of hMSCs is essential for the TIMP-1–mediated effects on Wnt/β-catenin signaling. An array analysis of microRNAs (miRNAs) and transfection studies with specific miRNA inhibitors and mimics showed that let-7f miRNA is crucial for the regulation of β-catenin activity and osteogenic differentiation by TIMP-1. Let-7f was up-regulated in TIMP-1–depleted hMSCs and demonstrably reduced axin 2, an antagonist of β-catenin stability. Our results demonstrate that TIMP-1 is a direct regulator of hMSC functions and reveal a regulatory network in which let-7f modulates Wnt/β-catenin activity

Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome

Background: Placebo treatment can significantly influence subjective symptoms. However, it is widely believed that response to placebo requires concealment or deception. We tested whether open-label placebo (non-deceptive and non-concealed administration) is superior to a no-treatment control with matched patient-provider interactions in the treatment of irritable bowel syndrome (IBS). Methods: Two-group, randomized, controlled three week trial (August 2009-April 2010) conducted at a single academic center, involving 80 primarily female (70%) patients, mean age 47±18 with IBS diagnosed by Rome III criteria and with a score ≥150 on the IBS Symptom Severity Scale (IBS-SSS). Patients were randomized to either open-label placebo pills presented as “placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes” or no-treatment controls with the same quality of interaction with providers. The primary outcome was IBS Global Improvement Scale (IBS-GIS). Secondary measures were IBS Symptom Severity Scale (IBS-SSS), IBS Adequate Relief (IBS-AR) and IBS Quality of Life (IBS-QoL). Findings: Open-label placebo produced significantly higher mean (±SD) global improvement scores (IBS-GIS) at both 11-day midpoint (5.2±1.0 vs. 4.0±1.1, p<.001) and at 21-day endpoint (5.0±1.5 vs. 3.9±1.3, p = .002). Significant results were also observed at both time points for reduced symptom severity (IBS-SSS, p = .008 and p = .03) and adequate relief (IBS-AR, p = .02 and p = .03); and a trend favoring open-label placebo was observed for quality of life (IBS-QoL) at the 21-day endpoint (p = .08). Conclusion: Placebos administered without deception may be an effective treatment for IBS. Further research is warranted in IBS, and perhaps other conditions, to elucidate whether physicians can benefit patients using placebos consistent with informed consent. Trial Registration ClinicalTrials.gov NCT0101019

Preembryo Personhood: An Assessment of the President’s Council Arguments

The President’s Council on Bioethics has addressed the moral status of human preembryos in its reports on stem cell research and human therapeutic cloning. Although the Council has been criticized for being hand-picked to favor the right-to-life viewpoint concerning human preembryos, it has embraced the idea that the right-to-life position should be defended in secular terms. This is an important feature of the Council’s work, and it demonstrates a recognition of the need for genuine engagement between opposing sides in the debate over stem cell research. To promote this engagement, the Council has stated in secular terms several arguments for the personhood of human preembryos. This essay presents and critiques those arguments, and it concludes that they are unsuccessful. If the best arguments in support of the personhood of human preembryos have been presented by the Council, then there are no reasonable secular arguments in support of that view

Non-emphysematous chronic obstructive pulmonary disease is associated with diabetes mellitus

Abstract Background Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers. The utility of these clinical subtypes is unclear. However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant. The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients. Methods Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis. Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%. Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 < 5%). Results Out of 4197 COPD subjects, 1687 were classified as emphysema-predominant and 1817 as non-emphysematous; 693 had LAA-950 between 5–10% and were not categorized. Subjects with emphysema-predominant COPD were older (65.6 vs 60.6 years, p < 0.0001) with more severe COPD based on airflow obstruction (FEV1 44.5 vs 68.4%, p < 0.0001), greater exercise limitation (6-minute walk distance 1138 vs 1331 ft, p < 0.0001) and reduced quality of life (St. George’s Respiratory Questionnaire score 43 vs 31, p < 0.0001). Self-reported diabetes was more frequent in non-emphysematous COPD (OR 2.13, p < 0.001), which was also confirmed using a strict definition of diabetes based on medication use. The association between diabetes and non-emphysematous COPD was replicated in the ECLIPSE study. Conclusions Non-emphysematous COPD, defined by airflow obstruction with a paucity of emphysema on chest CT scan, is associated with an increased risk of diabetes. COPD patients without emphysema may warrant closer monitoring for diabetes, hypertension, and hyperlipidemia and vice versa. Trial registration Clinicaltrials.gov identifiers: COPDGene NCT00608764 , ECLIPSE NCT00292552 .http://deepblue.lib.umich.edu/bitstream/2027.42/109496/1/12890_2014_Article_599.pd

Interpreting and reporting ⁴⁰Ar/³⁹Ar geochronologic data

The ⁴⁰Ar/³⁹Ar dating method is among the most versatile of geochronometers, having the potential to date a broad variety of K-bearing materials spanning from the time of Earth’s formation into the historical realm. Measurements using modern noble-gas mass spectrometers are now producing ⁴⁰Ar/³⁹Ar dates with analytical uncertainties of ∼0.1%, thereby providing precise time constraints for a wide range of geologic and extraterrestrial processes. Analyses of increasingly smaller subsamples have revealed age dispersion in many materials, including some minerals used as neutron fluence monitors. Accordingly, interpretive strategies are evolving to address observed dispersion in dates from a single sample. Moreover, inferring a geologically meaningful “age” from a measured “date” or set of dates is dependent on the geological problem being addressed and the salient assumptions associated with each set of data. We highlight requirements for collateral information that will better constrain the interpretation of ⁴⁰Ar/³⁹Ar data sets, including those associated with single-crystal fusion analyses, incremental heating experiments, and in situ analyses of microsampled domains. To ensure the utility and viability of published results, we emphasize previous recommendations for reporting ⁴⁰Ar/³⁹Ar data and the related essential metadata, with the amendment that data conform to evolving standards of being findable, accessible, interoperable, and reusable (FAIR) by both humans and computers. Our examples provide guidance for the presentation and interpretation of ⁴⁰Ar/³⁹Ar dates to maximize their interdisciplinary usage, reproducibility, and longevity

Rapid in-country sequencing of whole virus genomes to inform rabies elimination programmes.

Genomic surveillance is an important aspect of contemporary disease management but has yet to be used routinely to monitor endemic disease transmission and control in low- and middle-income countries. Rabies is an almost invariably fatal viral disease that causes a large public health and economic burden in Asia and Africa, despite being entirely vaccine preventable. With policy efforts now directed towards achieving a global goal of zero dog-mediated human rabies deaths by 2030, establishing effective surveillance tools is critical. Genomic data can provide important and unique insights into rabies spread and persistence that can direct control efforts. However, capacity for genomic research in low- and middle-income countries is held back by limited laboratory infrastructure, cost, supply chains and other logistical challenges. Here we present and validate an end-to-end workflow to facilitate affordable whole genome sequencing for rabies surveillance utilising nanopore technology. We used this workflow in Kenya, Tanzania and the Philippines to generate rabies virus genomes in two to three days, reducing costs to approximately £60 per genome. This is over half the cost of metagenomic sequencing previously conducted for Tanzanian samples, which involved exporting samples to the UK and a three- to six-month lag time. Ongoing optimization of workflows are likely to reduce these costs further. We also present tools to support routine whole genome sequencing and interpretation for genomic surveillance. Moreover, combined with training workshops to empower scientists in-country, we show that local sequencing capacity can be readily established and sustainable, negating the common misperception that cutting-edge genomic research can only be conducted in high resource laboratories. More generally, we argue that the capacity to harness genomic data is a game-changer for endemic disease surveillance and should precipitate a new wave of researchers from low- and middle-income countries

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington\u27s Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington\u27s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington\u27s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression

A "nova classe média": repercussões psicossociais em famílias brasileiras

O presente artigo, em uma abordagem ensaística, tem como objetivo analisar efeitos psicossociais na constituição de modos de subjetivação e em famílias a partir da emergência daquilo que vem sendo nomeado de a "nova classe média brasileira". Para isto, primeiramente foi feita revisão bibliográfica de como a sociologia, economia e antropologia vem conceituando e caracterizando esta nova classe social, considerando que não há estudos acerca desse tema na Psicologia. A partir do diálogo com fontes midiáticas, buscou-se pensar como vem sendo operada a construção de um "estilo de vida" marcado pela tentativa de planejamento do futuro, consumo e meritocracia. Tais características mostram-se importantes formas de aproximação com a classe média tradicional. Por fim, buscou-se entender como famílias vêm vivenciando tais mudanças em seu cotidiano, organização e relações.</p