Adalimumab dose tapering in patients with rheumatoid arthritis who are in long-standing clinical remission: results of the phase IV PREDICTRA study

Objective: To investigate the association between baseline disease activity and the occurrence of flares after adalimumab tapering or withdrawal in patients with rheumatoid arthritis (RA) in sustained remission. Methods: The PREDICTRA phase IV, randomised, double-blind (DB) study (ImPact of Residual Inflammation Detected via Imaging TEchniques, Drug Levels, and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) Patients) enrolled patients with RA receiving adalimumab 40 mg every other week who were in sustained remission ≥6 months. After a 4-week, open-label lead-in (OL-LI) period, patients were randomised 5:1 to DB adalimumab taper (every 3 weeks) or withdrawal (placebo) for 36 weeks. The primary endpoint was the association between DB baseline hand and wrist MRI-detected inflammation with flare occurrence. Results: Of 146 patients treated during the OL-LI period, 122 were randomised to taper (n=102) or withdrawal (n=20) arms. Patients had a mean 12.9 years of active disease and had received adalimumab for a mean of 5.4 years (mean 2.2 years in sustained remission). Overall, 37 (36%) and 9 (45%) patients experienced a flare in the taper and withdrawal arms, respectively (time to flare, 18.0 and 13.3 weeks). None of the DB baseline disease characteristics or adalimumab concentration was associated with flare occurrence after adalimumab tapering. Approximately half of the patients who flared regained clinical remission after 16 weeks of open-label rescue adalimumab. The safety profile was consistent with previous studies. Conclusions: Approximately one-third of patients who tapered adalimumab versus half who withdrew adalimumab experienced a flare within 36 weeks. Time to flare was numerically longer in the taper versus withdrawal arm. Baseline MRI inflammation was not associated with flare occurrence. Trial registration number: NCT02198651, EudraCT 2014-001114-26

Moderating effects of the relationship between offshore outsourcing and the export capability of firms

This paper analyzes the effect of offshore outsourcing on the export performance of firms, based on the theories of international business, the resource-based view of the firm and the transaction cost theory. Outsourcing can reduce production costs and increase flexibility. It can also provide new resources and market knowledge. However, the impact of offshore outsourcing depends on the resources and capabilities of firms to manage a network of foreign suppliers, and to absorb knowledge of foreign markets.   Using a database of about 1,000 manufacturing companies in Mexico in 2011, we found that offshore outsourcing increases the performance of exports. The effects are stronger in export markets from which the company also imports intermediate goods. The results also show that the size of the company, the organization of intra-firm imports and export experience moderate the effects of outsourcing in a positive way

Synthesis and Antiproliferative Activity of Sulfa-Michael Adducts and Thiochromenes Derived from Carbohydrates

The Michael addition reactions of carbohydrate-derived nitroalkenes with ethyl thioglycolate and 2-mercaptobenzyl alcohol were studied. Reactions were conducted under mild, solvent-free conditions with DABCO as a catalyst, affording the corresponding adducts in good yields. Furthermore, compounds resulting from the addition with 2-mercaptobenzyl alcohol were used as starting materials for the synthesis of chiral 3-nitro-2H-thiochromenes. For some of the compounds synthesized herein, the antioxidant and antiproliferative activities against a panel of human solid tumor cell lines were assayed and compared with those of carbohydrate-nitroalkene substrates.Junta de Extremadura GR15022Unión Europea FP7-REGPOT-2012-CT2012-31637-IMBRAI

The Global Alliance for Infections in Surgery: Defining a Model for Antimicrobial Stewardship-Results From an International Cross-Sectional Survey

BACKGROUND: Antimicrobial Stewardship Programs (ASPs) have been promoted to optimize antimicrobial usage and patient outcomes, and to reduce the emergence of antimicrobial-resistant organisms. However, the best strategies for an ASP are not definitively established and are likely to vary based on local culture, policy, and routine clinical practice, and probably limited resources in middle-income countries. The aim of this study is to evaluate structures and resources of antimicrobial stewardship teams (ASTs) in surgical departments from different regions of the world. METHODS: A cross-sectional web-based survey was conducted in 2016 on 173 physicians who participated in the AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections) project and on 658 international experts in the fields of ASPs, infection control, and infections in surgery. RESULTS: The response rate was 19.4%. One hundred fifty-six (98.7%) participants stated their hospital had a multidisciplinary AST. The median number of physicians working inside the team was five [interquartile range 4-6]. An infectious disease specialist, a microbiologist and an infection control specialist were, respectively, present in 80.1, 76.3, and 67.9% of the ASTs. A surgeon was a component in 59.0% of cases and was significantly more likely to be present in university hospitals (89.5%, p \u3c 0.05) compared to community teaching (83.3%) and community hospitals (66.7%). Protocols for pre-operative prophylaxis and for antimicrobial treatment of surgical infections were respectively implemented in 96.2 and 82.3% of the hospitals. The majority of the surgical departments implemented both persuasive and restrictive interventions (72.8%). The most common types of interventions in surgical departments were dissemination of educational materials (62.5%), expert approval (61.0%), audit and feedback (55.1%), educational outreach (53.7%), and compulsory order forms (51.5%). CONCLUSION: The survey showed a heterogeneous organization of ASPs worldwide, demonstrating the necessity of a multidisciplinary and collaborative approach in the battle against antimicrobial resistance in surgical infections, and the importance of educational efforts towards this goal

Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors

We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer’s agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC50 = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer’s disease through the cholinergic approach.Dirección General de Investigación de España. CTQ2016-78703-PJunta de Andalucía. FQM134Fondo Europeo de Desarrollo Regional (FEDER) y Consejo Nacional de Ciencia y Tecnología de México (CONACYT). CB-2015/257465Ministerio de Ciencia, Innovación y Universidades y Agencia Estatal de Investigación de España y Fondos FEDER de la Unión Europea (MCIU/AEI/FEDER). PGC2018-094503-B-C2

Dieta de herbívoros: técnica, importancia e implicaciones en el manejo de fauna silvestre

Objective: To review the contributions and implications of the microhistological technique in the management of wild herbivores and to provide recommendations for diet studies. Design/methodology/approach: A meta-analysis was carried out on diet subjects in wild cervids and bovines in North America, in order to know the approaches of diet studies in the management of these species. These works are described and discussed and recommendations are given to adequately perform the microhistological technique. Results: The microhistological technique is a fundamental tool in diet studies in wild herbivores. It has been used to evaluate the carrying capacity of species of hunting interest such as bighorn sheep. The use of sodium hypochlorite as a method of thinning has been questioned, however, it allows to identify cell structures efficiently, as long as the thinning time is not excessive. Dietary studies should be accompanied by an evaluation of forage availability. The stool collection must take place at least during the four seasons of the year and the number of samples must not be less than 50 samples per season. Limitations of the study/implications: The use of the microhistological technique assumes that all plant species have the same percentage of digestibility. However, it allows to determine the diet in fecal samples, which is indispensable in evaluations of carrying capacity for wild herbivores. Findings/Conclusions: The microhistological technique in the study of bighorn sheep using sodium hypochlorite has been an adequate method of thinning plant samples, to determine the availability of forage and in the determination of the diet are two aspects intimately linked for evaluations of habitat of this wild herbivore.Objetivo: Revisar los aportes e implicaciones de la técnica microhistológica en el manejo de herbívoros silvestres y brindar recomendaciones para realizar estudios de dieta.   Diseño/metodología/aproximación: Se realizó un meta-análisis en temas de dieta en cérvidos y bóvidos silvestres en Norteamérica, con la finalidad de conocer los enfoques de los estudios sobre dieta en el manejo de estas especies. Se describen estos trabajos, discuten, y brindan recomendaciones para realizar adecuadamente la técnica microhistológica. Resultados: La técnica microhistológica es una herramienta fundamental en estudios de dieta en herbívoros silvestres. Ha sido utilizada para evaluar la capacidad de carga de especies de interés cinegético como el borrego cimarrón. El uso de hipoclorito de sodio como método de aclareo ha sido cuestionado; sin embargo, permite identificar las estructuras celulares eficazmente, siempre y cuando el tiempo de aclareo no sea excesivo. Los estudios de dieta deben estar acompañados de una evaluación de disponibilidad de forraje. La recolecta de heces debe realizarse al menos durante las cuatro estaciones del año y número de muestras debe ser superior a 50 por estación. Limitaciones del estudio/implicaciones: El uso de la técnica microhistológica asume que todas las especies vegetales tienen el mismo porcentaje de digestibilidad. Permite determinar la dieta en muestras fecales, lo cual es indispensable en evaluaciones de capacidad de carga para herbívoros silvestres. Hallazgos/conclusiones: La técnica microhistológica en el estudio del borrego cimarrón usando el hipoclorito de sodio ha resultado un adecuado método de aclareo de muestras vegetales y determinar la disponibilidad de forraje y con ello definir la dieta, aspectos íntimamente ligados para evaluaciones de hábitat de este herbívoro silvestre

Economic analysis of alternative nutritional management of dual-purpose cow herds in central coastal Veracruz, Mexico

Market information was combined with predicted input–output relationships in an economic analysis of alternative nutritional management for dual-purpose member herds of the Genesis farmer organization of central coastal Veracruz, Mexico. Cow productivity outcomes for typical management and alternative feeding scenarios were obtained from structured sets of simulations in a companion study of productivity limitations and potentials using the Cornell Net Carbohydrate and Protein System model (Version 6.0). Partial budgeting methods and sensitivity analysis were used to identify economically viable alternatives based on expected change in milk income over feed cost (change in revenues from milk sales less change in feed costs). Herd owners in coastal Veracruz have large economic incentives, from $584 to$1,131 in predicted net margin, to increase milk sales by up to 74% across a three-lactation cow lifetime by improving diets based on good quality grass and legume forages. This increment is equal to, or exceeds, in value the total yield from at least one additional lactation per cow lifetime. Furthermore, marginal rates of return (change in milk income over feed costs divided by change in variable costs when alternative practices are used) of 3.3 ± 0.8 indicate clear economic incentives to remove fundamental productivity vulnerabilities due to chronic energy deficits and impeded growth of immature cows under typical management. Sensitivity analyses indicate that the economic outcomes are robust for a variety of market conditions

Long-term outcomes in patients with polyarticular juvenile idiopathic arthritis receiving adalimumab with or without methotrexate

Objectives Long-term safety and efficacy of adalimumab among patients with juvenile idiopathic arthritis (JIA) was evaluated through 6 years of treatment. Methods Children aged 4-17 years with polyarticular JIA were enrolled in a phase III, randomised-withdrawal, double-blind, placebo-controlled trial consisting of a 16-week open-label lead-in period, 32-week randomised double-blind period and 360-week long-term extension. Patients were stratified by baseline methotrexate use. Adverse events (AEs) were monitored, and efficacy assessments included JIA American College of Rheumatology (JIA ACR) 30%, 50%, 70% or 90% responses and the proportions of patients achieving 27-joint Juvenile Arthritis Disease Activity Score (JADAS27) low disease activity (LDA, = 6 continuous months) during the study. Attainment of JIA ACR 50 or higher and JADAS27 LDA or ID in the initial weeks were the best predictors of clinical remission. Mean JADAS27 decreased from baseline, 22.5 (n=170), to 2.5 (n=30) at week 312 (observed analysis). Conclusions Through 6 years of exposure, adalimumab was well tolerated with significant clinical response (up to clinical remission) and a relatively low retention rate

Limitations and potentials of dual-purpose cow herds in Central Coastal Veracruz, Mexico

Feed chemical and kinetic composition and animal performance information was used to evaluate productivity limitations and potentials of dual-purpose member herds of the Genesis farmer organization of central coastal Veracruz, Mexico. The Cornell Net Carbohydrate and Protein System model (Version 6.0) was systematically applied to specific groups of cows in structured simulations to establish probable input–output relationships for typical management, and to estimate probable outcomes from alternative management based on forage-based dietary improvements. Key herd vulnerabilities were pinpointed: chronic energy deficits among dry cows of all ages in late gestation and impeded growth for immature cows. Regardless of the forage season of calving, most cows, if not all, incur energy deficits in the final trimester of gestation; thus reducing the pool of tissue energy and constraining milking performance. Under typical management, cows are smaller and underweight for their age, which limits feed intake capacity, milk production and the probability of early postpartum return to ovarian cyclicity. The substitution of good-quality harvested forage for grazing increased predicted yields by about one-third over typical scenarios for underweight cows. When diets from first parturition properly supported growth and tissue repletion, milk production in second and third lactations was predicted to improve about 60%. Judiciously supplemented diets based on good quality grass and legume forages from first calving were predicted to further increase productivity by about 80% across a three-lactation cow lifetime. These dual-purpose herd owners have large incentives to increase sales income by implementing nutritional strategies like those considered in this study

β-Adrenergic Inhibition of Contractility in L6 Skeletal Muscle Cells

The β-adrenoceptors (β-ARs) control many cellular processes. Here, we show that β-ARs inhibit calcium depletion-induced cell contractility and subsequent cell detachment of L6 skeletal muscle cells. The mechanism underlying the cell detachment inhibition was studied by using a quantitative cell detachment assay. We demonstrate that cell detachment induced by depletion of extracellular calcium is due to myosin- and ROCK-dependent contractility. The β-AR inhibition of L6 skeletal muscle cell detachment was shown to be mediated by the β2-AR and increased cAMP but was surprisingly not dependent on the classical downstream effectors PKA or Epac, nor was it dependent on PKG, PI3K or PKC. However, inhibition of potassium channels blocks the β2-AR mediated effects. Furthermore, activation of potassium channels fully mimicked the results of β2-AR activation. In conclusion, we present a novel finding that β2-AR signaling inhibits contractility and thus cell detachment in L6 skeletal muscle cells by a cAMP and potassium channel dependent mechanism