Discordance between the predictors of clinical and imaging remission in patients with early rheumatoid arthritis in clinical practice: implications for the use of ultrasound within a treatment to target strategy

Objective: To assess the prevalence, relationship between and predictors of clinical and imaging remission in early rheumatoid arthritis (RA), achieved with treat-to-target management in clinical practice. Methods: A prospective observational study was conducted in patients with new-onset RA. The treatment target was remission by disease activity score (DAS28-CRP<2.6). Twelve month outcomes included DAS28-CRP remission, DAS44-CRP remission, ACR/EULAR Boolean remission (BR) and absent or absent/minimal power Doppler activity (PDA) on ultrasound (US) of 26 joints (total PDA score=0 or ≤1, respectively). Logistic regression was conducted to identify baseline predictors of these outcomes. Results: Of 105 patients with complete 12-month data, the rate of DAS28-CRP remission was 43%, DAS44-CRP remission was 39%, BR was 14%, absent PDA was 40% and absent/minimal PDA was 57%. Amongst patients achieving clinical remission defined by DAS28-CRP, DAS44-CRP or BR, absence of PDA was observed in 42%, 44% and 40%, respectively; absent/minimal PDA was detected in 62%, 66% and 67%, respectively. On multivariable analysis, shorter symptom duration, male gender, fewer tender joints and lower disability were associated with the clinical remission definitions. Lack of osteoarthritis predicted absence of PDA and lower total baseline PDA predicted absent/minimal PDA. Conclusion: DAS28-CRP remission and absence of PDA were observed in almost half of patients, but less than a quarter achieved both. Achievement of BR was rare. The low agreement between any of the clinical and imaging outcomes and differences in their predictors highlight the complex interaction between symptoms and synovitis, with implications for treat-to-target management. Long-term follow-up should determine the most appropriate target

Measurement in Economics and Social Science

The paper discusses measurement, primarily in economics, from both analytical and historical perspectives. The historical section traces the commitment to ordinalism on the part of economic theorists from the doctrinal disputes between classical economics and marginalism, through the struggle of orthodox economics against socialism down to the cold-war alliance between mathematical social science and anti-communist ideology. In economics the commitment to ordinalism led to the separation of theory from the quantitative measures that are computed in practice: price and quantity indexes, consumer surplus and real national product. The commitment to ordinality entered political science, via Arrow’s ‘impossibility theorem’, effectively merging it with economics, and ensuring its sterility. How can a field that has as its central result the impossibility of democracy contribute to the design of democratic institutions? The analytical part of the paper deals with the quantitative measures mentioned above. I begin with the conceptual clarification that what these measures try to achieve is a restoration of the money metric that is lost when prices are variable. I conclude that there is only one measure that can be embedded in a satisfactory economic theory, free from unreasonable restrictions. It is the Törnqvist index as an approximation to its theoretical counterpart the Divisia index. The statistical agencies have at various times produced different measures for real national product and its components, as well as related concepts. I argue that all of these are flawed and that a single deflator should be used for the aggregate and the components. Ideally this should be a chained Törnqvist price index defined on aggregate consumption. The social sciences are split. The economic approach is abstract, focused on the assumption of rational and informed behavior, and tends to the political right. The sociological approach is empirical, stresses the non-rational aspects of human behavior and tends to the political left. I argue that the split is due to the fact that the empirical and theoretical traditions were never joined in the social sciences as they were in the natural sciences. I also argue that measurement can potentially help in healing this split

4-Hydroxyphenylpyruvate Dioxygenase (HPPD)-Inhibiting Herbicides: Past, Present, and Future

The 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicides are primarily used for weed control in corn, barley, oat, rice, sorghum, sugarcane, and wheat production fields in the United States. The objectives of this review were to summarize (1) the history of HPPD-inhibitor and their use in the United States, (2) HPPD-inhibitor resistant weeds, their mechanism of resistance, and management, (3) interaction of HPPD-inhibitor with other herbicides, and (4) the future of HPPD-inhibitor-resistant crops. As of 2022, three broadleaf weeds (Palmer amaranth, waterhemp, and wild radish) have evolved resistance to the HPPD-inhibitor. The predominance of metabolic resistance to HPPD-inhibitor was found in aforementioned three weed species. Management of HPPD-inhibitor-resistant weeds can be accomplished using alternate herbicides such as glyphosate, glufosinate, 2,4-D, or dicamba; however, metabolic resistance poses a serious challenge, as the weeds may be cross-resistant to other herbicide sites of action, leading to limited herbicide options. The HPPD-inhibitor is commonly applied with photosystem II (PS II)-inhibitor to increase efficacy and weed control spectrum. The synergism with HPPD-inhibitor arises from depletion of plastoquinones, which allows increased binding of PS II-inhibitor to the D1 protein. New HPPD-inhibitor from azole carboxamides class is in development and expected to be available in the near future. The HPPD-inhibitor-resistant crops have been developed through overexpression of a resistant bacterial HPPD enzyme in plants and the overexpression of transgenes for HPPD and a microbial gene that enhances the production of HPPD substrate. Isoxaflutole-resistant soybean is commercially available, and it is expected that soybean resistant to other HPPD-inhibitor such as mesotrione, stacked with resistance to other herbicides, will be available in the near future

Decay-accelerating factor expression in the rat kidney is restricted to the apical surface of podocytes

Decay-accelerating factor expression in the rat kidney is restricted to the apical surface of podocytes.BackgroundDecay-accelerating factor (DAF) has inhibitory activity toward complement C3 and C5 convertases. DAF is present in human glomeruli and on cultured human glomerular visceral epithelial cells (GEC). We studied the distribution and function of rat DAF.MethodsFunction-neutralizing antibodies (Abs) were raised against DAF. The distribution of DAF in vivo was determined by immunoelectron microscopy. Functional studies were performed in cultured GEC and following IV injection of anti-DAF Abs into rats.ResultsDAF was present exclusively on the apical surfaces of GEC, and was not present on the basal surfaces of GEC, nor other glomerular or kidney cells. DAF was functionally active on cultured GEC, and served to limit complement activation in concert with CD59, an inhibitor of C5b-9 formation. Upon injection into normal rats, anti-DAF F(ab′)2 Abs bound to GEC in vivo, yet there was no evidence for complement activation and animals did not develop abnormal albuminuria. Anti-megalin complement-activating IgG Abs were “planted” on GEC, which activated complement as evidenced by the presence of C3d on GEC. Attempts to inhibit DAF function with anti-DAF Abs did not affect the quantity of complement activation by these anti-megalin Abs, nor did it lead to development of abnormal albuminuria. In contrast, in the puromycin aminonucleoside model of GEC injury and proteinuria, anti-DAF Abs slowed the recovery from renal failure that occurs in this model.ConclusionIn cultured rat GEC, DAF is an effective complement regulator. In vivo, DAF is present on GEC apical surfaces. Yet, it appears that DAF is not essential to prevent complement activation from occurring under normal circumstances and in those cases in which complement-activating Abs are present on the basal surfaces of GEC in vivo. However, in proteinuric conditions, DAF appears to be protective to GEC

Structure-based optimization of potent, selective, and orally bioavailable CDK8 inhibitors discovered by high-throughput screening

The mediator complex-associated cyclin dependent kinase CDK8 regulates beta-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies

Fitness Cost Associated With Enhanced EPSPS Gene Copy Number and Glyphosate Resistance in an Amaranthus tuberculatus Population

The evolution of resistance to pesticides in agricultural systems provides an opportunity to study the fitness costs and benefits of novel adaptive traits. Here, we studied a population of Amaranthus tuberculatus (common waterhemp), which has evolved resistance to glyphosate. The growth and fitness of seed families with contrasting levels of glyphosate resistance was assessed in the absence of glyphosate to determine their ability to compete for resources under intra- and interspecific competition. We identified a positive correlation between the level of glyphosate resistance and gene copy number for the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) glyphosate target, thus identifying gene amplification as the mechanism of resistance within the population. Resistant A. tuberculatus plants were found to have a lower competitive response when compared to the susceptible phenotypes with 2.76 glyphosate resistant plants being required to have an equal competitive effect as a single susceptible plant. A growth trade-off was associated with the gene amplification mechanism under intra-phenotypic competition where 20 extra gene copies were associated with a 26.5 % reduction in dry biomass. Interestingly, this growth trade-off was mitigated when assessed under interspecific competition from maize

Adam Smith’s Green Thumb and Malthus’ Three Horsemen: Cautionary tales from classical political economy

This essay identifies a contradiction between the flourishing interest in the environmental economics of the classical period and a lack of critical parsing of the works of its leading representatives. Its focus is the work of Adam Smith and Thomas Malthus. It offers a critical analysis of their contribution to environmental thought and surveys the work of their contemporary devotees. It scrutinizes Smith's contribution to what Karl Polanyi termed the "economistic fallacy," as well as his defenses of class hierarchy, the "growth imperative" and consumerism. It subjects to critical appraisal Malthus's enthusiasm for private property and the market system, and his opposition to market regulation. While Malthus's principal attraction to ecological economists lies in his having allegedly broadened the scope of economics, and in his narrative of scarcity, this article shows that he, in fact, narrowed the scope of the discipline and conceptualized scarcity in a reified and pseudo-scientific way