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ObjectiveThis analysis evaluated efficacy and safety of filgotinib, a Janus-associated kinase 1-preferential inhibitor, in methotrexate (MTX)-naive patients with rheumatoid arthritis (RA) with multiple poor prognostic factors (PPFs).MethodsThis was a post hoc analysis of the phase III, randomised, double-blind, active-controlled, FINCH 3 study (clinicaltrials.gov NCT02886728). Patients received once-daily oral filgotinib 200 or 100 mg plus once-weekly oral MTX ≤20 mg (FIL200 + MTX and FIL100 + MTX), filgotinib 200 mg monotherapy (FIL200), or oral MTX monotherapy (MTX-mono) for up to 52 weeks. PPFs investigated were seropositivity for rheumatoid factor or anticyclic citrullinated peptide antibodies, high-sensitivity C reactive protein (CRP) ≥4 mg/L, Disease Activity Score in 28 joints with CRP (DAS28(CRP)) >5.1, and presence of erosions. Filgotinib efficacy and safety in patients with all four PPFs at baseline were explored versus MTX-mono within this subgroup and compared informally with the overall population.ResultsOf 1249 patients in FINCH 3, 510 (40.8%) had all PPFs. Efficacy of FIL200 + MTX among these patients was comparable to the overall population, with higher rates of 20%/50%/70% improvement from baseline by American College of Rheumatology criteria, DAS28(CRP) ConclusionFIL200 + MTX efficacy and safety in patients with multiple PPFs were similar to the overall population.

Plant-breeding programs are designed and operated over multiple cycles to systematically change the genetic makeup of plants to achieve improved trait performance for a Target Population of Environments (TPE). Within each cycle, selection applied to the standing genetic variation within a structured reference population of genotypes (RPG) is the primary mechanism by which breeding programs make the desired genetic changes. Selection operates to change the frequencies of the alleles of the genes controlling trait variation within the RPG. The structure of the RPG and the TPE has important implications for the design of optimal breeding strategies. The breeder’s equation, together with the quantitative genetic theory behind the equation, informs many of the principles for design of breeding programs. The breeder’s equation can take many forms depending on the details of the breeding strategy. Through the genetic changes achieved by selection, the cultivated varieties of crops (cultivars) are improved for use in agriculture. From a breeding perspective, selection for specific trait combinations requires a quantitative link between the effects of the alleles of the genes impacted by selection and the trait phenotypes of plants and their breeding value. This gene-to-phenotype link function provides the G2P map for one to many traits. For complex traits controlled by many genes, the infinitesimal model for trait genetic variation is the dominant G2P model of quantitative genetics. Here we consider motivations and potential benefits of using the hierarchical structure of crop models as CGM-G2P trait link functions in combination with the infinitesimal model for the design and optimization of selection in breeding programs.

Over the last decade, society witnessed the largest expansion of agricultural land planted with drought tolerant (DT) maize (Zea maysL.) Dedicated efforts to drought breeding led to development of DT maize. Here we show that after two decades of sustained breeding efforts the rate of crop improvement under drought is in the range 1.0-1.6% yr−1, which is higher than rates (0.7% yr−1) reported prior to drought breeding. Prediction technologies that leverage biological understanding and statistical learning to improve upon the quantitative genetics framework will further accelerate genetic gain. A review of published and unpublished analyses conducted on data including 138 breeding populations and 93 environments between 2009 and 2019 demonstrated an average prediction skill (r) improvement around 0.2. These methods applied to pre-commercial stages showed accuracies higher that current statistical approaches (0.85 vs. 0.70). Improvement in hybrid and management choice can increase water productivity. Digital gap analyses are applicable at field scale suggesting the possibility of transition from evaluating hybrids to designing genotype x management (GxM) technologies for target cropping systems in drought prone areas. Due to the biocomplexity of drought, research and development efforts should be sustained to advance knowledge and iteratively improve models.HighlightCrop improvement rate in maize increased after implementation of drought breeding efforts. Harnessing crop, quantitative genetics and gap models will enable the transition from genetic evaluation to crop design.

Plant breeding programs are designed and operated over multiple cycles to systematically change the genetic makeup of plants to achieve improved trait performance for a Target Population of Environments (TPE). Within each cycle, selection applied to the standing genetic variation within a structured reference population of genotypes (RPG) is the primary mechanism by which breeding programs make the desired genetic changes. Selection operates to change the frequencies of the alleles of the genes controlling trait variation within the RPG. The structure of the RPG and the TPE has important implications for the design of optimal breeding strategies. The breeder’s equation, together with the quantitative genetic theory behind the equation, informs many of the principles for design of breeding programs. The breeder’s equation can take many forms depending on the details of the breeding strategy. Through the genetic changes achieved by selection, the cultivated varieties of crops (cultivars) are improved for use in agriculture. From a breeding perspective, selection for specific trait combinations requires a quantitative link between the effects of the alleles of the genes impacted by selection and the trait phenotypes of plants and their breeding value. This gene-to-phenotype link function provides the G2P map for one to many traits. For complex traits controlled by many genes, the infinitesimal model for trait genetic variation is the dominant G2P model of quantitative genetics. Here we consider motivations and potential benefits of using the hierarchical structure of crop models as CGM-G2P trait link functions in combination with the infinitesimal model for the design and optimisation of selection in breeding programs.

Plants capture soil resources to produce the grains required to feed a growing population. Because plants capture water and nutrients through roots, it was proposed that changes in root systems architecture (RSA) underpin the three-fold increase in maize grain yield over the last century1,2,3,4. Within this framework, improvements in reproductive resilience due to selection are caused by increased water capture1. Here we show that both root architecture and yield have changed with decades of maize breeding, but not the water capture. Consistent with Darwinian agriculture5 theory, improved reproductive resilience6,7 enabled farmers increase the number of plants per unit land8,9,10, capture soil resources, and produced more dry matter and grain. Throughout the last century, selection operated to adapt roots to crowding, enabling reallocation of C from large root systems to the growing ear and the small roots of plants cultivated in high plant populations in modern agriculture.

Objective: Clinical trial results have shown that, in glucocorticoid-treated patients, treatment with denosumab 60 mg subcutaneously once every 6 months (Q6M) increased spine and hip bone mineral density (BMD) at month 12 significantly more than treatment with risedronate 5 mg orally once daily (QD). The present analysis was performed to compare efficacy and characterize safety through month 24. Methods: This phase III study enrolled men and women ≥18 years old who had received ≥7.5 mg daily prednisone or equivalent for

Context The effects of long-term exposure to denosumab in individuals with renal insufficiency are unknown. Objective This post hoc analysis evaluates the long-term safety and efficacy of denosumab in individuals with mild-to-moderate chronic kidney disease (CKD) (stages 2 and 3) using data from the pivotal phase 3, double-blind, 3-year FREEDOM (NCT00089791) and open-label, 7-year extension (NCT00523341) studies. Participants and Methods Women age 60 to 90 years with a bone mineral density (BMD) T-score of less than –2.5 to greater than –4.0 at the total hip or lumbar spine were randomly assigned 1:1 to receive denosumab 60 mg subcutaneously every 6 months (long-term arm) or placebo (cross-over arm) in FREEDOM; eligible participants could enroll in the extension to receive denosumab 60 mg subcutaneously every 6 months. Change in estimated glomerular filtration rate (eGFR) from study baseline and annualized rates of fracture and adverse events (AEs) were the main outcome measures. Results Most participants (1259/1969 [64%] long-term arm; 1173/1781 [66%] crossover arm) with baseline CKD stage 2 or 3 remained within the same CKD subgroup at study completion; less than 3% progressed to CKD stage 4. Participants in all eGFR subgroups showed similar, persistent BMD gains over time and a low incidence of fractures. The percentage of participants reporting serious AEs was similar among renal subgroups (normal, CKD stage 2, CKD stage 3a, CKD stage 3b) both for the long-term (54% vs 52% vs 57% vs 58%) and crossover (43% vs 42% vs 43% vs 68%) arms, except CKD stage 3b subgroup, crossover arm. Conclusion The safety and efficacy of denosumab did not differ among participants with mild to moderate CKD.

Background Filgotinib (FIL), an orally administered, potent, selective inhibitor of janus kinase 1 (JAK1), has shown good efficacy and was well tolerated for treatment of rheumatoid arthritis (RA). The objectives of this study were to compare efficacy and safety of FIL with and without methotrexate (MTX) in patients with RA who were naïve to MTX therapy. Methods This Phase 3, double-blind, active-controlled study randomised patients with moderately to severely active RA (2:1:1:2) to FIL 200mg daily+MTX, FIL 100mg+MTX, FIL 200mg (+placebo [PBO]), or MTX (+PBO) up to 52 weeks; results are through week 24. Primary endpoint was proportion achieving ACR20 response at week 24. Safety endpoints included adverse events types and rates. Results Of 1,252 randomised patients, 1,249 received study drug (416 FIL 200mg+MTX; 207 FIL 100mg+MTX; 210 FIL 200mg monotherapy; 416 MTX monotherapy) and were analysed; 1,130 completed week 24. Most (76.9%) were female; mean time since RA diagnosis was 2.2 years (median 0.4 years); mean (standard deviation [SD]) DAS28-CRP was 5.7 (1.0); and 35.9% were using oral steroids at baseline. At week 24, significantly more patients in the FIL 200mg+MTX (81.0%; P Conclusion The JAK1 inhibitor FIL in combination with MTX led to significant improvements in RA signs and symptoms, physical function, and patient-reported outcomes compared to MTX alone and was well tolerated in patients with early active RA naïve to MTX. Clinically meaningful response to FIL occurred as early as 2 weeks after treatment initiation. Disclosures N. McKay: None. D. van der Heijde: Corporate appointments; Director of Imaging Rheumatology bv. Consultancies; Consultant for AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda Pharmaceutical Company Ltd., UCB. R. Westhovens: Corporate appointments; Advisor for Celltrion and Galapagos/Gilead. Other; Advisor for Celltrion and Galapagos/Gilead. W.F.C. Rigby: Consultancies; Consultant for Gilead. D.W.T. Ching: Corporate appointments; Speaker for AbbVie. Member of speakers’ bureau; Speaker for AbbVie. B. Bartok: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. F. Matzkies: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Z. Yin: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. C. Tasset: Corporate appointments; Employee of Galapagos NV. J.S. Sundy: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. N. Mozaffarian: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. O.D. Messina: Honoraria; Received Honoraria from Pfizer, Amgen, and Americas Health Foundation (AHF). R.B.M. Landewé: Consultancies; Consultant for AbbVie, AstraZeneca, BMS, Galapagos, Pfizer, Eli Lilly, Novartis, and UCB. T. Atsumi: None. G.R. Burmester: Honoraria; Received Honoraria from AbbVie, Gilead, Eli Lilly, and Pfizer.

Genomic selection (GS) has revolutionized breeding strategies by predicting the rank performance of post-harvest traits via implementing genomic prediction (GP) models. However, predicting pre-harvest traits in unobserved environments might produce serious biases. In soybean, days to maturity (DTM) represents a crucial stage with a significant impact on yield potential; thus, genotypes must be carefully selected to ensure latitudinal adaptation in this photoperiod-sensitive crop species. This research assessed the use of daylength for predicting DTM in unobserved environments (CV00). A soybean dataset comprising 367 genotypes spanning nine families of the Soybean Nested Association Mapping Panel (SoyNAM) and tested in 11 environments (year-by-location combinations) was considered in this study. The proposed method (CB) returned a root-mean-square error (RMSE) of 5.2 days, a Pearson correlation (PC) of 0.66, and the predicted vs. observed difference in the environmental means (PODEM) ranged from −3.3 to 4.5 days; however, in the absence of daylength data, the conventional GP implementation produced an RMSE of 9 days, a PC of 0.66, and a PODEM range from −14.7 to 7.9 days. These results highlight the importance of dissecting phenotypic variability (G × E) based on photoperiod data and non-predictable environmental stimuli for improving the predictive ability and accuracy of DTM in soybeans.

Summary Economic evaluations are increasingly used to assess the value of health interventions, but variable quality and heterogeneity limit the use of these evaluations by decision-makers. These recommendations provide guidance for the design, conduct, and reporting of economic evaluations in osteoporosis to improve their transparency, comparability, and methodologic standards. Introduction This paper aims to provide recommendations for the conduct of economic evaluations in osteoporosis in order to improve their transparency, comparability, and methodologic standards. Methods A working group was convened by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis to make recommendations for the design, conduct, and reporting of economic evaluations in osteoporosis, to define an osteoporosis-specific reference case to serve a minimum standard for all economic analyses in osteoporosis, to discuss methodologic challenges and initiate a call for research. A literature review, a face-to-face meeting in New York City (including 11 experts), and a review/approval by a larger group of experts worldwide (including 23 experts in total) were conducted. Results Recommendations on the type of economic evaluation, methods for economic evaluation, modeling aspects, base-case analysis and population, excess mortality, fracture costs and disutility, treatment characteristics, and model validation were provided. Recommendations for reporting economic evaluations in osteoporosis were also made and an osteoporosis-specific checklist was designed that includes items to report when performing an economic evaluation in osteoporosis. Further, 12 minimum criteria for economic evaluations in osteoporosis were identified and 12 methodologic challenges and need for further research were discussed. Conclusion While the working group acknowledges challenges and the need for further research, these recommendations are intended to supplement general and national guidelines for economic evaluations, improve transparency, quality, and comparability of economic evaluations in osteoporosis, and maintain methodologic standards to increase their use by decision-makers.

A successful strategy for prediction of crop yield that accounts for the effects of genotype, environment and their interactions with management will create many opportunities for enhancing the productivity of agricultural systems. Crop growth models (CGMs) have a history of application for crop management decision support. Recently, whole genome prediction (WGP) methodologies have been developed and applied in breeding to enable prediction of crop traits for new genotypes, and thus increased the size of plant breeding programs without expanding expensive field testing. The integration of a CGM into the algorithm for WGP, referred to as CGM-WGP, has opened up the potential for prediction of G × E × M interactions for breeding and product placement applications. The main objectives of this study were to extend CGM-WGP methodology to train models using data from multiple environments, and to evaluate, using both synthetic and experimental data from a maize drought breeding program, whether CGM-WGP methodology can enable improved phenotypic prediction when G × E interactions are an important determinant of performance. The CGM-WGP methodology was improved by 1) reformulating the model as a Bayesian generalized linear hierarchical model, and 2) by sampling the posterior distribution using a Metropolis-within-Gibbs sampling algorithm. The increased efficiency of the algorithm enabled the use of multiple environments and larger populations than those used in previous studies. Synthetic datasets included three environments and an empirical dataset included two environments contrasting for drought stress pattern and intensity. The empirical dataset included four double haploid populations expressing different levels of G × E interaction. Collectively, the prediction accuracy results for the empirical study indicate there were realized advantages in prediction accuracy for yield, in both the water limited and the not water limited environments, from the modeling of the G × E interactions by the CGM-WGP methodology relative to the reference method BayesA. Similarly, the difference in CGM-WGP accuracy relative to BayesA increased with decreasing similarity between the environment types utilized for training and evaluating the predictions. The synthesis provided in this work that encompasses crop physiology and modeling, quantitative genetics, genomic prediction and breeding, should stimulate a cross disciplinary dialogue towards building the next generation of prediction methodologies.

Background Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis and is associated with an estimated annual fracture rate of 5%. We aimed to assess the efficacy and safety of denosumab compared with risedronate in glucocorticoid-induced osteoporosis. Methods We did a 24-month, double-blind, active-controlled, double-dummy, non-inferiority study at 79 centres in Europe, Latin America, Asia, and North America. Eligible patients were aged 18 years or older and were receiving glucocorticoids (>= 7.5 mg prednisone daily, or equivalent) for at least 3 months (glucocorticoid continuing) or less than 3 months (glucocorticoid initiating) before screening. Patients younger than 50 years needed to have a history of osteoporosis-related fracture; glucocorticoid-continuing patients aged 50 years or older needed a lumbar spine, total hip, or femoral neck bone mineral density T score of -2.0 or less, or -1.0 or less if they had a history of osteoporosis-related fracture. Participants were randomly assigned (1: 1) to either 60 mg subcutaneous denosumab every 6 months and oral placebo daily for 24 months, or 5 mg oral risedronate daily and subcutaneous placebo every 6 months for 24 months. Randomisation was stratified by sex within each subpopulation, and was done with an interactive voice-response system. Active drugs and corresponding placebos had identical packaging, labels, and appearance. The primary outcome was non-inferiority of denosumab to risedronate in terms of percentage change from baseline in lumbar spine bone mineral density at 12 months based on non-inferiority margins (-0.7 and -1.1 percentage points for the glucocorticoid-continuing and glucocorticoid-initiating subpopulations, respectively). Superiority was also assessed as a secondary outcome. The primary efficacy set included all randomly assigned participants who had a baseline and postbaseline lumbar spine bone mineral density measurement, and was analysed according to randomised treatment assignment. The safety analysis set included all randomly assigned participants who received at least one dose of investigational product, and was analysed by actual treatment received. This study is registered with ClinicalTrials.gov (NCT01575873) and is completed. Findings Between March 28, 2012, and June 30, 2015, 795 patients, 505 of whom were glucocorticoid continuing and 290 of whom were glucocorticoid initiating, were enrolled and randomly assigned (398 to denosumab, 397 to risedronate). Denosumab was both non-inferior and superior to risedronate at 12 months for effect on bone mineral density at the lumbar spine in both glucocorticoid-continuing (4.4% [95% CI 3.8-5.0] vs 2.3% [1.7-2.9]; p

Nitrogen (N) metabolism is a major research target for increasing productivity in crop plants. In maize (Zea mays L.), yield gain over the last few decades has been associated with increased N absorption and utilization efficiency (i.e. grain biomass per unit of N absorbed). However, a dynamical framework is still needed to unravel the role of internal processes such as uptake, allocation, and translocation of N in these adaptations. This study aimed to 1) characterize how genetic enhancement in N efficiency conceals changes in allocation and translocation of N, and 2) quantify internal fluxes behind grain N sources in two historical genotypes under high and low N supply. The genotypes 3394 and P1197, landmark hybrids representing key eras of genetic improvement (1990s and 2010s), were grown under high and low N supply in a two-year field study. Using stable isotope 15N labelling, post-silking nitrogen fluxes were modeled through Bayesian estimation by considering the external N (exogenous-N) and the pre-existing N (endogenous-N) supply across plant organs. Regardless of N availability, P1197 exhibited greater exogenous-N accumulated in leaves and cob-husks. This response was translated to a larger amount of N mobilized to grains (as endogenous-N) during grain-filling in this genotype. Furthermore, the enhanced N supply to leaves in P1197 was associated with increased post-silking carbon accumulation. The overall findings suggest that increased N utilization efficiency over time in maize genotypes was associated with an increased allocation of N to leaves and subsequent translocation to the grains.

Development of predictive algorithms accounting for uncertainty in processes underpinning the maize (Zea mays L.) yield response to nitrogen (N) are needed in order to provide new N fertilization guidelines. The aims of this study were to unravel the relative importance of crop management, soil, and weather factors on both the estimate and the size of uncertainty (as a risk magnitude assessment) of the main components of the maize yield response to N: i) yield without N fertilizer (B0); ii) yield at economic optimum N rate (YEONR); iii) EONR; and iv) the N fertilizer efficiency (NFE) at the EONR. Combining Bayesian statistics to fit the N response curves and a machine learning algorithm (extreme gradient boosting) to assess features importance on the predictability of the process, we analyzed data of 730 response curves from 481 site-years (4297 observations) in maize N rate fertilization studies conducted between 1999 and 2020 in the United States and Canada. The EONR was the most difficult attribute to predict, with an average uncertainty of 50 kg N ha−1, increasing towards low ( 200 kg N ha−1) EONR expected values. Crop management factors such as previous crop and irrigation contributed substantially (∼50%) to the estimation of B0, but minorly to other components of the maize yield response to N. Weather contributed about two-thirds of explained variance of the estimated values of YEONR, EONR, and NFE. Additionally, weather factors governed the uncertainty (72% to 81%) of all components of the N response process. Soil factors provided a consistent but limited (10% to 23%) contribution to explain both expected N response as well as its associated uncertainties. Efforts to improve N decision support tools should consider the uncertainty of models as a type of risk, potential in-season weather scenarios, and develop probabilistic frameworks for improving this data-driven decision-making process of N fertilization in maize crop.

Osteoporosis is an evolving disease which affects over 200 million people worldwide. Our recommendations are guidelines for its diagnosis, prevention and treatment, but they do not constitute standards for clinical decisions in individual cases. The physician must adapt them to individual special situations, incorporating personal factors that transcend the limits of these guidelines and are dependent on the knowledge and art of the practice of Medicine. These guidelines should be reviewed and updated periodically as new, better and more effective diagnostic and therapeutic tools become available

Background:Patients (pts) with rheumatoid arthritis (RA) with poor prognostic factors (PPF) are at risk for RA progression if disease activity is not rapidly controlled. In FINCH 3 (NCT02886728), filgotinib (FIL)—an oral, potent, selective JAK1 inhibitor—was effective relative to methotrexate monotherapy (MTX mono) in MTX-naïve patients with ≥1 PPF—erosions, seropositivity for rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP), or hsCRP ≥4 mg/L.1Objectives:This post hoc analysis examined FIL efficacy in FINCH 3 pts with multiple PPF.Methods:The global, phase 3, double-blind, active-controlled FINCH 3 study randomised MTX-naïve pts with moderately to severely active RA 2:1:1:2 to oral FIL 200 mg once daily + MTX ≤20 mg weekly, FIL 100 mg + MTX, FIL 200 mg mono, or PBO + MTX up to week (W)52. This subgroup analysis included pts with all 4 of the following PPF at baseline (PPF pts): erosions, seropositivity for RF or anti-CCP, hsCRP ≥4 mg/L, and DAS(28)CRP >5.1. Comparisons were not adjusted for multiplicity.Results:Of 1249 pts randomised and treated in FINCH 3, 510 had all 4 PPF. At baseline, relative to the overall FINCH 3 population, PPF pts had longer mean disease duration (2.4 vs 2.2 years); higher mean hsCRP (27.9 vs 17.5 mg/L), mTSS (17.9 vs 13.3), DAS28(CRP) (6.3 vs 5.7), HAQ-DI (1.76 vs 1.56), CDAI (44.3 vs 39.8), and SDAI (47.1 vs 41.5); and greater frequency of seropositivity for RF (90.6% vs 67.9%), anti-CCP (92.4% vs 68.5%), or both (82.9% vs 59.6%). Efficacy in PPF pts was comparable to data from all FINCH 3 pts (Table, Figures 1–2). PPF pts receiving FIL 200 mg with or without MTX vs MTX mono had higher frequencies of ACR20/50/70 response and greater improvement in HAQ-DI at W24; responses were numerically greater for FIL 200 mg + MTX vs FIL 100 mg + MTX or FIL 200 mg mono (Table) and were evident by W12 (data not shown). Radiographic progression at W24 was lower in PPF pts receiving FIL 200 mg + MTX or FIL 200 mg mono vs MTX mono (Figure 1). Proportions of PPF pts receiving FIL 200 mg with or without MTX who achieved DAS28(CRP) Table.Efficacy outcomes in patients with 4 PPF and all FINCH 3 patients at W24FIL 200 mg+ MTXFIL 100 mg+ MTXFIL 200 mg monoMTXmonoPPFAllPPFAllPPFAllPPFAlln1724168520787210166416ACR20, %85.5*81.0***83.580.2*81.678.174.771.4ACR50, %70.3***61.5***58.857.0**59.858.1**48.245.7ACR70, %54.1***43.8***37.640.1***43.7*40.0***28.326.0HAQ-DIa−1.2***−0.94***−1.0*−0.90**−1.0*−0.89*−0.9−0.79aMean change from baseline.*, p **, p ***, p FIL, filgotinib; mono, monotherapy; MTX, methotrexate; PPF, poor prognostic factors.Conclusion:FIL treatment provided rapid and deep disease control including higher rates of remission and other clinical outcomes, improved physical function, and less radiographic progression compared with MTX alone in MTX-naïve pts with RA with 4 PPF, a population at risk for severe progressive disease. In pts with 4 PPF, W24 remission rates following FIL 200 mg with or without MTX were higher vs MTX mono and numerically higher vs FIL 100 mg + MTX.References:[1]Westhovens et al.Ann Rheum Dis2019;78(Suppl2):259–60.Disclosure of Interests:Daniel Aletaha Grant/research support from: AbbVie, Novartis, Roche, Consultant of: AbbVie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme, Speakers bureau: AbbVie, Celgene, Lilly, Merck, Novartis, Pfizer, Sanofi Genzyme, UCB, Rene Westhovens Grant/research support from: Celltrion Inc, Galapagos, Gilead, Consultant of: Celltrion Inc, Galapagos, Gilead, Speakers bureau: Celltrion Inc, Galapagos, Gilead, Cecile Gaujoux-Viala Consultant of: AbbVie; Amgen; Bristol-Myers Squibb; Celgene; Gilead Sciences, Inc.; Janssen; Lilly; Medac; Merck-Serono; Mylan; Nordic Pharma; Novartis; Pfizer; Roche; Sandoz; Sanofi; UCB, Speakers bureau: AbbVie; Amgen; Bristol-Myers Squibb; Celgene; Gilead Sciences, Inc.; Janssen; Lilly; Medac; Merck-Serono; Mylan; Nordic Pharma; Novartis; Pfizer; Roche; Sandoz; Sanofi; UCB, Giovanni Adami: None declared, Alan Matsumoto Grant/research support from: AbbVie; BMS; Eli Lilly; Galapagos; Gilead Sciences, Inc.; GSK; Janssen; Novartis; Pfizer; Sanofi; UCB; Regeneron, Consultant of: AbbVie; Gilead Sciences, Inc.; GSK; Novartis, Paul Bird Consultant of: AbbVie, Celgene Corporation, Eli Lilly, Janssen, Novartis, Pfizer – advisor, Speakers bureau: AbbVie, Celgene Corporation, Eli Lilly, Janssen, Novartis, Pfizer, Osvaldo Messina Speakers bureau: Amgen; Americas Health Foundation; Pfizer, Maya H Buch Grant/research support from: Pfizer, Roche, and UCB, Consultant of: Pfizer; AbbVie; Eli Lilly; Gilead Sciences, Inc.; Merck-Serono; Sandoz; and Sanofi, Beatrix Bartok Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Zhaoyu Yin Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Ying Guo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Thijs Hendrikx Shareholder of: Galapagos (share/warrant holder), Employee of: Galapagos, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma

Introduction. An intimate relationship between osteoporosis and sarcopenia has been established. At present, there are few epidemiological studies about osteosarcopenia due to the recent use of this term, especially in Latin America. Objective. To study the association between osteoporosis and sarcopenia and determine the prevalence of osteosarcopenia in patients who attended a rheumatology center in Ecuador. Methods. A cross-sectional study was conducted in a population of patients who had a densitometric study. The diagnosis of sarcopenia was determined by the DXA standard gold test, screening, and conventional methods (bioimpedance, anthropometric measurements, SARC-F, muscle function, and gait test). Results. A total of 92 patients were studied. The median age was 66 ± 10, 90% females. Using the criteria of SMI, 65% had sarcopenia of which 9% had only sarcopenia and 56% had osteosarcopenia; 22% had only osteopenia/osteoporosis; and 13% none of these conditions. The prevalence of sarcopenia according to handgrip strength was 60%, gait speed 45%, and SARC-F score 40%. The prevalence of osteosarcopenia according to handgrip strength was 51%, gait speed 34%, and SARC-F score 32%. Osteoporosis was associated with a higher prevalence of sarcopenia using the criteria of SMI since 40% had sarcopenia in the normal DXA group, 64% in the osteopenia group, and 76% in the osteoporosis group (p=0.017). Of the women, 69% had sarcopenia compared to 33% of the men (p=0.034). The BMI was lower in the group with sarcopenia (25.1 ± 4.1 kg/m2) compared to the group without sarcopenia (29.4 ± 4.1 kg/m2, p<0.001). Patients with osteosarcopenia and sarcopenia had lower BMI, handgrip strength, ASM, SMI, and total-body skeletal muscle mass than those with osteopenia/osteoporosis or normal patients. Conclusion. 65% of the studied population had sarcopenia. It is clear that the prevalence of sarcopenia is higher in patients with greater loss of bone mass. Identifying pathways that affect both bone and muscle could facilitate the development of treatments that simultaneously improve osteoporosis and sarcopenia.

The competing demands of increasing grain yields to feed a growing population and decreasing nitrogen (N) fertilizer use and loss to the environment poses a grand challenge to farmers and society, and necessitates achieving improved N use efficiency (NUE) in cereal crops. Although selection for increased yield in maize has improved NUE over time, the present understanding of the physiological determinants of NUE and its key components hampers the design of more effective breeding strategies conducive to accelerating genetic gain for this trait. We show that maize NUE gains have been supported by more efficient allocation of N among plant organs during the grain filling period. Comparing seven maize hybrids commercialized between 1946 and 2015 from a single seed company in multiple N fertilizer treatments, we demonstrate that modern hybrids produced more grain per unit of accumulated N by more efficiently remobilizing N stored in stems than in leaves to support kernel growth. Increases in N fertilizer recovery and N harvest index at maturity were mirrored by a steady decrease in stem N allocation in this era study. These insights can inform future breeding strategies for continued NUE gains through improved conversion efficiency of accumulated plant N into grain yield.

Background In a study of patients initiating or continuing GC, 12 and 24 months gains in lumbar spine and total hip areal bone mineral density (aBMD) were greater with DMAb vs RIS.1,2 Objectives Evaluate the effects of DMAb vs RIS on cortical and trabecular bone. Methods Phase 3, double-blind, double-dummy, active-controlled study randomised women and men ≥18 years, receiving GC (≥7.5 mg prednisone daily or equivalent) for Results The substudy enrolled 111 subjects (57 DMAb, 54 RIS). DMAb was associated with significantly greater increases than RIS in cortical thickness, total volumetric BMD (vBMD) and cortical vBMD at the radius and tibia at 12 and 24 months, and in trabecular vBMD at the radius at 12 months and tibia at 24 months (Table). Change in cortical porosity did not differ between DMAb and RIS (Table). Percentage Change From Baseline and Treatment Difference in vBMD and Cortical Microarchitecture Conclusion Compared with RIS, DMAb was associated with sustained improvements in cortical bone structure, assessed by HR–pQCT of the radius and tibia. It remains to be confirmed whether increased cortical thickness with DMAb is associated with improved bone strength in GIOP. These results further support DMAb as a treatment for GC-treated patients at increased fracture risk. References [1] Saag KG, et al. Lancet Diabetes Endocrinol. 2018;6(6) [2] Saag KG, et al. Ann Rheum Dis. 2018;77 (Suppl 2) Acknowledgement This study was funded by Amgen Inc. Disclosure of Interests Piet Geusens Grant/research support from: Research support, consultant and/or speaker fees from: Pfizer, Abbott, Eli Lilly, Amgen, MSD, Roche, UCB, BMS, Novartis, Will-Pharma, Grant/research support from: Pfizer, Abbott, Lilly, Amgen, MSD, Will, Bio Minerals and Roche, Consultant for: Research support, consultant and/or speaker fees from: Pfizer, Abbott, Eli Lilly, Amgen, MSD, Roche, UCB, BMS, Novartis, Will-Pharma, Speakers bureau: Research support, consultant and/or speaker fees from: Pfizer, Abbott, Eli Lilly, Amgen, MSD, Roche, UCB, BMS, Novartis, Will-Pharma, Speakers bureau: Pfizer, Abbott, Lilly, Amgen, MSD, Will, Bio Minerals and Roche, Stefan Goemaere Grant/research support from: Grants/research funding from Amgen, UCB., Speakers bureau: Speakers’ bureau for Amgen., Nicola Pannacciulli Shareholder of: Amgen Inc. stockholder., Employee of: Amgen Inc. employee at the time of the study., Nancy Lane Consultant for: Samumed, LLC, Eric Lespessailles Grant/research support from: Grants/research support from Amgen, Eli Lily, MSD, UCB., Consultant for: Consultant for Amgen, Expanscience, Eli Lilly, MSD, UCB., Osvaldo Messina Consultant for: Consultant for Eli Lily, Amgen, Pfizer., Speakers bureau: Speakers’ bureau for Eli Lily, Amgen, Pfizer., Roland Chapurlat Grant/research support from: Grants/research support from Amgen, Roche-Chugai, MSD., Consultant for: Consultant for Amgen, UCB, Pfizer, Bristol-Myers Squibb, Sandoz, Radius., Speakers bureau: Speakers fees for Eli Lily, Pfizer, Abbvie, MSD, Janssen-Cilag., Xiang Yin Shareholder of: Amgen Inc. stockholder., Employee of: Amgen Inc. employee at the time of the study., Rachel Wagman Shareholder of: Amgen Inc. stockholder., Employee of: Amgen Inc. employee., Joop van den bergh Grant/research support from: Grants/research support from Eli Lily, Sanofi, Amgen.

In the published article the author name Maritza Vidal Wilman was processed incorrectly and now it has been rectified. The original article has been updated.

The introduction of winter canola (Brassica napus L.) into rotations with winter wheat (Triticum aestivum L.) in the United States (US) revealed economic and agronomic benefits as well as improved weed and pest control. Canola stand establishment during the fall and plant survival over the winter are critical to the success of this crop. The environment plays a key role influencing survival, but in-depth evaluation of meteorological factors has not been conducted. This research study aimed to: i) identify meteorological factors underpinning winter canola survival, ii) build probabilistic response models based on historical meteorological data for different severities of winter kill across the US, and iii) define areas of adaptation of current germplasm. A winter survival dataset was compiled from the National Winter Canola Variety Trials from 2003 until 2018 (190 site-years) and auxiliary meteorological data over the last 40 years. A regression tree analysis indicated that meteorological variables related to minimum temperature, fluctuating temperatures above and below 0°C, and windchill during the cold period were the main factors accounting for winter kill. Cold periods across all site-years were classified into three clusters: cold periods with high (96%), medium (70%), and low (28%) average plant winter survival. For 94 US sites, the probabilities of these conditions were calculated and summarized in a map that defined areas of adaptation: a large area south of 35° N latitude for the US was identified with greater potential for overwintering success. Based on the response under multiple meteorological conditions, four distinct genotype survival groups were identified (tolerant, semi-tolerant, semi-susceptible, and susceptible). Groups with a greater number of genotypes differ in the impact of meteorological conditions on survival for the medium cluster. In regions with more favorable conditions for overwintering success, farmers may be open to introducing this crop to diversify their farming system.

Hybrid biomaterials, combining naturally derived and synthetic materials, offer a tissue engineering platform that can provide initial mechanical support from a synthetic biomaterial, as well as a viable, bioactive substrate to support native cell infiltration and remodeling. The goal of this work was to develop a directional delivery system for bioactive molecules that can be coupled with a hybrid biomaterial. It was hypothesized that by using poly(propylene fumarate) as a scaffold to encapsulate PLGA microparticles, a tunable and directional release would be achieved from the intact scaffold into the bioactive substrate, pericardium. Release will occur as poly(lactic-co-glycolic acid) microparticles degrade hydrolytically into biocompatible molecules, leaving the PPF scaffold unchanged within the release time frame and able to mechanically support the pericardium substrate through remodeling. This study evaluated the degradation and strength of the composite polymer layer, and determined the release of ...

High throughput genotyping, phenotyping, and envirotyping applied within plant breeding multienvironment trials (METs) provide the data foundations for selection and tackling genotype x environment interactions (GEIs) through whole-genome prediction (WGP). Crop growth models (CGM) can be used to enable predictions for yield and other traits for different genotypes and environments within a MET if genetic variation for the influential traits and their responses to environmental variation can be incorporated into the CGM framework. Furthermore, such CGMs can be integrated with WGP to enable wholegenome prediction with crop growth models (CGM-WGP) through use of computational methods such as approximate Bayesian computation. We previously used simulated data sets to demonstrate proof of concept for application of the CGM-WGP methodology to plant breeding METs. Here the CGM-WGP methodology is applied to an empirical maize (Zea mays L.) drought MET data set to evaluate the steps involved in reduction to practice. Positive prediction accuracy was achieved for hybrid grain yield in two drought environments for a sample of doubled haploids (DHs) from a cross. This was achieved by including genetic variation for five component traits into the CGM to enable the CGM-WGP methodology. The five component traits were a priori considered to be important for yield variation among the maize hybrids in the two target drought environments included in the MET. Here, we discuss lessons learned while applying the CGM-WGP methodology to the empirical data set. We also identify areas for further research to improve prediction accuracy and to advance the CGM-WGP for a broader range of situations relevant to plant breeding.

Maize (Zea Mays L.) yield responsiveness to nitrogen (N) fertilization depends on the yield under non-limiting N supply as well as on the inherent productivity under zero N fertilizer (Y0). Understanding the driving factors and developing predictive algorithms for Y0 will enhance the optimization of N fertilization in maize. Using a random forest algorithm, we analyzed data from 679 maize N fertilization studies (1031 Y0 observations) conducted between 1999–2019 in the United States and Canada. Predictability of Y0 was assessed while identifying determinant factors such as soil, crop management, and weather. The inclusion of weather variables as predictors improved the model efficiency (ME) from 51 up to 64 %, and reduced the root mean square error (RMSE) from 2.5 to 2.0 Mg ha−1, 34 to 27 % in relative terms (RRMSE). The most relevant predictors of Y0 were previous crop, irrigation, and soil organic matter (SOM), while the most influential weather data was linked to the radiation per unit of thermal time (Q quotient) around flowering and spring precipitations. The crop rotation effect resulted in Alfalfa (Medicago sativa L.) as the previous crop with the highest Y0 level (IQR = 11.5–15.0 Mg ha−1) as compared to annual legumes (IQR = 5.6–10.0 Mg ha−1) and other previous crops (IQR = 3.6–7.8 Mg ha−1). The Q quotient around flowering positively affected Y0, while spring precipitations and extreme temperature events during grain filling showed a negative association to Y0. Overall, these results reinforce the concept that yields are controlled not only by soil N supply but also by factors modifying plant demand and ability to capture N. Lastly, we foresee a promising future for the use of machine learning to address both prediction and interpretation of maize yield to obtain more reliable N guidelines.

Background:Infectious diseases are increased in patients with rheumatic disorders; vaccination improves morbidity and mortalityObjectives:The aim of this study was to describe the frequency of vaccination in patients with rheumatic disorders and to compare the results with those obtained in 2009 and 2013 in a similar population. We also identified factors leading to lack of vaccination and patients beliefs on vaccines.Methods:Multicentric cross sectional study in patients with autoinmune diseases from external rheumatology offices. Evaluation of vaccination status and patients´ knowledge about vaccines were studied. A comparative analysis was carried out with the series registered in 2009 and 2013 in a similar population.Results:179 patients (158 female, 88.3% and 21 male, 11.7%) were evaluated. Median age was 52 years. Main pathologies were: Rheumatoid Arthritis 65.9% (n:118), Systemic Lupus Erythematosus 11.7% (n:21), Systemic Sclerosis 3.9% (7), Sjogren Syndrome n = 3.4% (n:6), other diseases 15% (n: 27). Median disease duration: 8.87 years. Ninety three percent of patients (n:167) were taking inmunomodulators and 36.8% (n: 66) were using oral corticosteroids (20mg/day or less); 26,8% patients (n: 48) were receiving biological therapies. Vaccination frequency in the population was: Influenza 82% (147); 13-valent conjugate pneumococcal 69.3% (124), 23-valent pneumococcal 64.2% (115) and hepatitis B 62% (111). Comparative with 2009 and 2013 series there was an increase in the rate of vaccinated patients: influenza (82% vs. 39,1% and 74,2% respectively), antineumococcal (64% vs. 17% and 29%) and hepatitis B (62% vs. 6,7% and 26,7%).Reasons for non-vaccination were absence of medical indication (41% of patients for hepatitis B; 32% for 23-valent pneumococcal; 38% for 13-valent pneumococcal and 34% for influenza).139 patients (77, 7%) knew the benefits of vaccines, 164 (91, 6%) thought vaccines are useful; 134 (74,9%) reported that vaccines may decrease dying probability, 155 (86,5%) thought that vaccines are effective to prevent diseases and 149 patients (83,2%) believed that they prevent serious infections. 71 patients (39%) believed that vaccines can lead to serious consequences and 99 (55,3%) that they are more likely to acquire infections than the rest of the population.Conclusion:Frequency of vaccination has increased since 2009 but there is still misinformation regarding vaccines risks and benefits. Promotion and information is essential to improve adherence.References:[1]2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Furer V, et al. Ann Rheum Dis 2020;79:39–52[2] Vaccines and Disease-Modifying Antirheumatic Drugs: Practical Implications for the Rheumatologist. Friedman MA et al. Rheum Dis Clin North Am. 2017 Feb; 43 (1):1-13.[3] Recommendations and barriers to vaccination in systemic lupus erythematosus. Garg M et al. Autoimmun Rev. 2018 Oct; 17 (10):990-1001.[4] Comparison of national clinical practice guidelines and recommendations on vaccination of adult patients with autoimmune rheumatic diseases. Papadopoulou D. et al. Rheumatol Int. 2014 Feb;34 (2):151-63.[5] Guías de recomendaciones de prevención de infecciones en pacientes que reciben modificadores de la respuesta biológica. Jordán R. Et al. Rev Arg Reumatol. 2014; 25 (2): 08-26.Disclosure of Interests:Malena Viola: None declared, Alejandro Benitez: None declared, Cecilia Garbarino: None declared, Gonzalo Rodriguez: None declared, Federico Benavidez: None declared, Claudia Peon: None declared, Eliana Soledad Blanco: None declared, Hernan Molina: None declared, Gimena Gómez: None declared, griselda redondo: None declared, Maria DeLaVega: None declared, Dario Mata: None declared, Augusto Riopedre: None declared, Osvaldo Messina Speakers bureau: Amgen; Americas Health Foundation; Pfizer

Background:Filgotinib (FIL) is a potent, selective JAK 1 inhibitor. FINCH 3 assessed FIL efficacy and safety in methotrexate (MTX)-naïve patients (pts) with rheumatoid arthritis (RA); week (W)24 primary outcome results were previously presented.1Objectives:To report FINCH 3 (NCT02886728) results through W52.Methods:This global, phase 3, double-blind, active-controlled study randomised MTX-naïve pts with moderately to severely active RA 2:1:1:2 to oral FIL 200 mg once daily + MTX ≤20 mg weekly, FIL 100 mg + MTX, FIL 200 mg monotherapy (mono) + placebo (PBO), or PBO + MTX up to W52. Comparisons at W52 were not adjusted for multiplicity. Safety was assessed from adverse events and laboratory abnormalities.Results:Of 1249 treated pts, 975 received study drug through W52. FIL efficacy was sustained up to W52. Treatment with FIL + MTX or FIL mono increased proportions of pts achieving ACR20/50/70 and clinical disease remission by DAS28(CRP) Figure). Safety was consistent with W24 data (Table 2).Table 1.Efficacy outcomes at week 52FIL 200 mg + MTX (n = 416)FIL 100 mg + MTX (n = 207)FIL 200 mg(n = 210)MTX(n = 416)ACR20, %75.0***73.4**74.8***61.8ACR50, %62.3***59.4**61.4**48.3ACR70, %47.8***40.1*45.2***29.8mTSSa0.21***0.27*0.23**0.74HAQ-DIb−1.00***−0.97−0.95*−0.88aLeast-squares mean change from baseline.bMean change from baseline.*, p **, p ***, p FIL, filgotinib; mTSS, van der Heijde modified total Sharp score; MTX, methotrexate.Table 2.Safety outcomes through week 52Event, n (%)FIL 200 mg + MTX(n = 416)FIL 100 mg + MTX(n = 207)FIL 200 mg(n = 210)MTX(n = 416)All AEs318 (76.4)164 (79.2)143 (68.1)305 (73.3)Serious AEs26 (6.3)13 (6.3)17 (8.1)28 (6.7)Infection148 (35.6)76 (36.7)75 (35.7)157 (37.7)Serious infection5 (1.2)3 (1.4)5 (2.4)8 (1.9)Herpes zoster6 (1.4)3 (1.4)4 (1.9)4 (1.0)VTE0004 (1.0)MACE (adjudicated)4 (1.0)1 (0.5)2 (1.0)2 (0.5)Malignancya1 (0.2)004 (1.0)NMSC2 (0.5)001 (0.2)Death3 (0.7)b1 (0.5)c00aExcluding NMSC.b1 lupus cardiomyopathy, 1 atypical interstitial pneumonia, 1 non–treatment-emergent cardiovascular death.cDissecting cerebral and vertebral aneurysm.AE, adverse event; FIL, filgotinib; MACE, major adverse cardiovascular event; MTX, methotrexate; NMSC, nonmelanoma skin cancer; VTE, venous thromboembolism.Conclusion:Efficacy of FIL 200 mg + MTX, FIL 100 mg + MTX, and FIL 200 mg mono was sustained through W52, with faster onset1and consistently numerically greater efficacy for FIL 200 vs 100 mg. No new safety signals were observed.References:[1]Westhovens, et al.Ann Rheum Dis.2019;78(Suppl2):259–60.Disclosure of Interests:Rene Westhovens Grant/research support from: Celltrion Inc, Galapagos, Gilead, Consultant of: Celltrion Inc, Galapagos, Gilead, Speakers bureau: Celltrion Inc, Galapagos, Gilead, William Rigby Consultant of: Gilead Sciences, Inc., Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Daniel Ching Grant/research support from: AbbVie, Gilead Sciences, Inc., Pfizer, Sanofi, Consultant of: AbbVie, Pfizer, Speakers bureau: AbbVie, William Stohl Grant/research support from: GlaxoSmithKline, Consultant of: Janssen Research & Development, Jonathan Kay Grant/research support from: Gilead Sciences, Inc., Pfizer, Novartis Pharmaceuticals Corporation, Consultant of: Alvotech Suisse AG; Arena Pharmaceuticals, Inc.; Boehringer Ingelheim GmbH; Celltrion Healthcare Co. Ltd.; Merck Sharp & Dohme Corp.; Mylan Inc.; Novartis AG; Samsung Bioepis; Sandoz, Inc; UCB, Inc., Arvind Chopra Grant/research support from: Zydus Pharamceutical Ltd India, Beatrix Bartok Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Franziska Matzkies Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Zhaoyu Yin Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Ying Guo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Chantal Tasset Shareholder of: Galapagos (share/warrant holder), Employee of: Galapagos, John Sundy Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Angelika Jahreis Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Neelufar Mozaffarian Shareholder of: Gilead, Employee of: Gilead, Osvaldo Messina Speakers bureau: Amgen; Americas Health Foundation; Pfizer, Robert B.M. Landewé Consultant of: AbbVie; AstraZeneca; Bristol-Myers Squibb; Eli Lilly & Co.; Galapagos NV; Novartis; Pfizer; UCB Pharma, Tatsuya Atsumi Grant/research support from: Eli Lily Japan K.K., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb Co., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Consultant of: Gilead Sciences, Inc., Eli Lilly Japan K.K., UCB Japan Co. Ltd., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Speakers bureau: Eli Lilly Japan K.K., UCB Japan Co. Ltd., Bristol-Myers Squibb Co., AbbVie Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma

Reproductive failure under drought in maize (Zea mays) is a major cause of instability in global food systems. While there has been extensive research on maize reproductive physiology, it has not been formalized in mathematical form to enable the study and prediction of emergent phenotypes, physiological epistasis and pleiotropy. We developed a quantitative synthesis organized as a dynamical model for cohorting of reproductive structures along the ear while accounting for carbon and water supply and demand balances. The model can simulate the dynamics of silk initiation, elongation, fertilization and kernel growth, and can generate well-known emergent phenotypes such as the relationship between plant growth, anthesis-silking interval, kernel number and yield, as well as ear phenotypes under drought (e.g. tip kernel abortion). Simulation of field experiments with controlled drought conditions showed that predictions tracked well the observed response of yield and yield components to timing of water deficit. This framework represents a significant improvement from previous approaches to simulate reproductive physiology in maize. We envisage opportunities for this predictive capacity to advance our understanding of maize reproductive biology by informing experimentation, supporting breeding and increasing productivity in maize.

Late-season fertilizer N applications in maize (Zea mays L.) is a tactical agronomic practice that seeks to improve the synchrony between plant N demand and soil N supply. While this management practice can increase yield and limit unintended environmental impacts, a quantitative synthesis of the effects of late N applications on grain yield and resource use efficiency is lacking. A meta-analysis was conducted to identify patterns of yield response to late-N fertilization (post tenth-leaf, V10) across site-years studies. The goals of this study were to: 1) quantify the effect of late-season N fertilization on maize yield; and 2) identify an indicator for decision support of late-N fertilization. Published and unpublished sources from 1983 until 2018 were included in the meta-analysis (14 studies; n = 625 treatment means). Early-season (EN, ≈ 100% of fertilizer applied prior to the sixth-leaf, V6) and late-season (LN, 28% of N uptake at maturity occurring after silking) was positively related with yield increases for LN (+577 kg ha−1), and the contrast in REN between LN and EN was 0.04 kg kg−1. Environments prone to a greater N uptake during reproductive stages are proposed to be more suitable for late N applications. Prediction algorithms to inform tactical N management that can both increase productivity and sustainability could be developed provided adequate links between late-season N uptake and growing-season indicators could be established.

Background Osteoporosis is a common disorder affecting populations worldwide. In Latin America, an aging population combined with limited health care resources result in osteoporosis quickly becoming a condition of considerable magnitude with disproportionate morbidity and mortality. Aim To review the current state of prevention, diagnosis, and treatment of osteoporosis in Latin America and to develop strategies and recommendations that may be adopted in the region, an expert panel of clinicians and scientists was assembled to develop a consensus statement outlining future directions. Method The panel conducted a comprehensive literature review of publications mainly related to osteoporosis in Latin America, and at an in-person meeting developed a consensus position to address the relevant issues. Results The epidemiology, burden, diagnosis, and treatment of osteoporosis in the region were discussed with particular attention to issues unique to the region. A series of recommendations were developed encompassing virtually all aspects of the disease, including improved public and health professional awareness, better diagnostic processes, improved access to care, and greater engagement by health policy makers, government, and a wide variety of private organizations. Conclusions The panel concluded that a comprehensive approach to osteoporosis prevention and treatment in Latin America is urgently needed.

Background Denosumab 60 mg subcutaneously Q6M increased spine and hip BMD significantly more than risedronate 5 mg orally QD at 12 months in glucocorticoid-treated subjects (as previously reported¹). Objectives This analysis compared the BMD effects of denosumab vs risedronate and further characterised denosumab safety in this population at 24 months. Methods This phase 3, randomised, double-blind, double-dummy study enrolled adults≥18 years receiving ≥7.5 mg daily prednisone (or equivalent) for Results Of 795 randomised subjects, 590 (74.2%) completed the 24 month study (glucocorticoid-initiating: 109/145 denosumab, 117/145 risedronate; glucocorticoid-continuing: 186/253 denosumab, 178/252 risedronate). Denosumab was superior to risedronate for increases from baseline in LS and TH BMD at all timepoints assessed through 24 months in each subpopulation (figure 1). Adverse events, serious adverse events (including infection), and fractures were similar between groups. Conclusions In conclusion, denosumab was superior to risedronate for increases in spine and hip BMD through 24 months. The overall safety profile was similar between groups. Denosumab may offer a valuable osteoporosis treatment option for patients receiving glucocorticoids. Reference [1] Saag K, Wagman RB, Geusens P, et al. Effect of denosumab compared with risedronate in glucocorticoid-treated individuals: Results from the 12-month primary analysis of a randomized, double-blind, active-controlled study. Ann Rheum Dis2017:76(Suppl 2):54. Acknowledgements This study was funded by Amgen Inc. Jonathan Latham (PharmaScribe, LLC) and Lisa Humphries (Amgen Inc.) provided medical writing support. Disclosure of Interest K. Saag Grant/research support from: Amgen, Merck, Consultant for: Amgen, Lilly, Merck, Radius, N. Pannacciulli Shareholder of: Amgen, Employee of: Amgen, P. Geusens Grant/research support from: Abbott, Amgen, BMS, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, UCB, Will-Pharma, Consultant for: Amgen, Lilly, J. Adachi Grant/research support from: Amgen, Consultant for: Amgen, Employee of: McMaster University, Speakers bureau: Amgen, O. Messina: None declared, J. Morales-Torres Consultant for: Amgen, Speakers bureau: Amgen, R. Emkey Speakers bureau: Amgen, P. Butler Shareholder of: Amgen, Employee of: Amgen, X. Yin Shareholder of: Amgen, Employee of: Amgen, W. Lems Consultant for: Amgen, Eli Lilly, Merck, Speakers bureau: Amgen, Eli Lilly, Merck

Temperature and vapor pressure deficit (VPD) are two important environmental factors influencing stomatal conductance and transpiration. A limited transpiration rate (TRlim) trait expressed under high VPD has been shown to offer an approach to increase crop yield in water-limited areas. The benefit of the TRlim trait is that it lowers the effective VPD under which plants lose water and so conserves soil water to support crop growth for use during drought periods later in the growing season. Previous studies at moderate temperatures (32 degrees C and lower) identified 12 maize (Zea mays L.) hybrids that express the TRlim trait. A critical question is whether the TRlim trait is also expressed by these hybrids under temperatures up to 38 degrees C, which are relevant in environments where maize may be grown. Five hybrids failed to express the TRlim trait at 38 degrees C but seven hybrids had sustained expression of the trait at 38 degrees C. The loss of expression of the TRlim response in the five hybrids was found to occur in the very narrow range of temperature increase from 36 to 38 degrees C. The genetic differences in water use among these maize hybrids could be useful in selecting hybrids that are especially well adapted for temperature conditions in a targeted production area.

Yield loss due to water deficit is ubiquitous in maize (Zea mays L.) production environments in the United States. The impact of water deficits on yield depends on the cropping system management and physiological characteristics of the hybrid. Genotypic diversity among maize hybrids in the transpiration response to vapor pressure deficit (VPD) indicates that a limited-transpiration trait may contribute to improved drought tolerance and yield in maize. By limiting transpiration at VPD above a VPD threshold, this trait can increase both daily transpiration efficiency and water availability for lateseason use. Reduced water use, however, may compromise yield potential. The complexity associated with genotype X environment X management interactions can be explored in a quantitative assessment using a simulation model. A simulation study was conducted to assess the likely effect of genotypic variation in limited-transpiration rate on yield performance of maize at a regional scale in the United States. We demonstrated that the limited-transpiration trait can result in improved maize performance in drought-prone environments and that the impact of the trait on maize productivity varies with geography, environment type, expression of the trait, and plant density. The largest average yield increase was simulated for drought-prone environments (135 g m(-2)), while a small yield penalty was simulated for environments where water was not limiting (-33 g m(-2)). Outcomes from this simulation study help interpret the ubiquitous nature of variation for the limited-transpiration trait in maize germplasm and provide insights into the plausible role of the trait in past and future maize genetic improvement.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. It is characterized by demyelination of neurons and loss of neuronal axons and oligodendrocytes. In MS, auto-reactive T cells and B cells cross the blood-brain barrier (BBB), causing perivenous demyelinating lesions that form multiple discrete inflammatory demyelinated plaques located primarily in the white matter. In chronic MS, cortical demyelination and progressive axonal transections develop. Treatment for MS can be stratified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs aim to decrease circulating immune cells or to prevent these cells from crossing the BBB and reduce the inflammatory response. There are currently 10 DMTs approved for the relapsing forms of MS; these vary with regard to their efficacy, route and frequency of administration, adverse effects, and toxicity profile. Better drug delivery systems are being developed in order to decrease adverse effects, increase drug efficacy, and increase patient compliance through the direct targeting of pathologic cells. Here, we address the uses and benefits of advanced drug delivery systems, including nanoparticles, microparticles, fusion antibodies, and liposomal formulations. By altering the properties of therapeutic particles and enhancing targeting, breakthrough drug delivery technologies potentially applicable to multiple disease treatments may rapidly emerge.

Although there have been many evaluations of the Federal Reserve’s Greenbook forecasts, we analyze them in a different dimension. We examine the revisions of these forecasts in the context of fixed event predictions to determine how new information is incorporated in the forecasting process. This analysis permits us to determine if there was an inefficient use of information in the sense that the forecast revision has predictive power for the forecast error. Research on forecast smoothing suggests that we might find a positive relationship between the forecast error and the forecast revision. Although we do find for some variables and horizons the Fed’s forecast errors are predictable from its forecast revisions, there is no evidence of forecast smoothing. Instead the revisions sometimes have a negative relationship with the forecast error, suggesting in these cases that the Fed may be over-responsive to new information.

Maize (Zea mays L.) is among the most important grains contributing to global food security. Eighty years of genetic gain for yield of maize under both favorable and unfavorable stress-prone drought conditions have been documented for the US Corn Belt, yet maize remains vulnerable to drought conditions, especially at the critical developmental stage of flowering. Optimum AQUAmax (Dupont Pioneer) maize hybrids were developed for increased grain yield under drought and favorable conditions in the US Corn Belt. Following the initial commercial launch in 2011, a large on-farm data set has been accumulated (10,731 locations) comparing a large sample of the AQUAmax hybrids (78 hybrids) to a large sample of industry-leading hybrids (4287 hybrids) used by growers throughout the US Corn Belt. Following 3 yr (2011-2013) of on-farm industry-scale testing, the AQUAmax hybrids were on average 6.5% higher yielding under water-limited conditions (2006 locations) and 1.9% higher yielding under favorable growing conditions (8725 locations). In a complementary study, 3 yr (2010-2012) of hybrid-by-management-by-environment evaluation under water-limited conditions (14 locations) indicated that the AQUAmax hybrids had greater yield at higher plant populations when compared to non-AQUAmax hybrids. The combined results from research (2008-2010) and on-farm (2011-2013) testing throughout the US Corn Belt over the 6-yr period from 2008 to 2013 indicate that the AQUAmax hybrids offer farmers greater yield stability under water-limited conditions with no yield penalty when the water limitations are relieved and growing conditions are favorable.

Genotype × environment interaction explains a proportion of variation for crop yield performance often higher than the genotypic effect, becoming a major impediment to genetic progress. In this study, a crop model of yield determination in combination with three-mode principal component analysis (PCA) was used to analyze genotype × environment × attribute interaction. A full diallel of six maize (Zea mays L.) inbred lines was grown in 10 environments in Argentina. The first environment component associated with the common genotype and attribute pattern across environments revealed that the main numerical determinant of plant grain yield (PGY) was kernel weight and not kernel number per plant (KNP). The second environment component established the importance of genotype × year interaction for anthesis-silking interval (ASI), KNP, and PGY when water deficit prevailed during the critical period of yield determination and revealed a lack of association between ASI and ear growth rate during this period. The three-mode PCA described the specific patterns of hybrid performance across environments, revealing physiological processes that separate inbred lines that contribute to drought tolerance, but at the expense of limiting PGY under well-watered conditions. The use of a crop growth model allowed interpretation of the effects of environment conditions on main physiological determinants of grain yield, exposing the effects of water supply/demand ratio as a possible driver of differential performance of inbred lines. Fil: Munaro, Eugenia. DuPont Pioneer; Estados Unidos Fil: De la Vega, Abelardo J.. DuPont Pioneer; España Fil: D'andrea, Karina Elizabeth. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Producción Vegetal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Messina, Carlos D.. DuPont Pioneer; Estados Unidos Fil: Otegui, Maria Elena. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Producción Vegetal; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Norte. Estación Experimental Agropecuaria Pergamino; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

A plant trait to minimize the impact of drought on crop yield is limited-transpiration rate (TR) under high ambient vapor pressure deficit (VPD) so that soil water is conserved to sustain grain fill. Variation among maize (Zea mays L) hybrids has been identified for the existence of the limited-TR trait at high atmospheric VPD, and the VPD at which TR becomes limited. Further, it has been shown that the TR limitation at high VPD is related to plant hydraulic conductance, which may be due to differences in aquaporin expression. This paper reports studies to relate the TR response of 21 maize hybrids to treatment of leaves and intact plants with cycloheximide (CHX) and four aquaporin inhibitors: silver (AgNO3), gold (HAuCl4), zinc (ZnCl2), and mercury (HgCl2). There was no discrimination among hybrids based on treatment with Hg or CHX. Segregation between hybrids for response to increasing VPD corresponded with differences in leaf response to Ag and Au treatment and intact plant response to Zn. The highest correlation (r = 0.90) between VPD breakpoint and TR response to inhibitor was with Ag treatment of leaves. These results indicate that Ag may be an effective initial screen for expression of the limited-TR trait under high VPD. (C) 2014 Elsevier B.V. All rights reserved.

Understanding transient phases that evolve during solidification can be critical to phase selection and the resulting microstructure of an alloy. However, the nature of high-temperature metastable phases makes them difficult to study with conventional techniques. The authors combine a tunnel-diode oscillator, electrostatic levitator, and x-ray diffraction for contactless precision measurement of magnetic transitions during the freezing of Fe-B, an industrially important material. This technique will prove invaluable for studying high-temperature magnetism in challenging systems.

SummaryAge-specific intervention and assessment thresholds were developed for seven Latin American countries. The inter-vention threshold ranged from 1.2% (Ecuador) to 27.5% (Argentina) at the age of 50 and 90 years, respectively. In the LatinAmerican countries, FRAX offers a substantial advance for the detection of subjects at high fracture risk.IntroductionIntervention thresholds are proposed using the Fracture Risk Assessment (FRAX) tool. We recommended their useto calculate the ten-year probability of fragility fracture (FF) in both, men and women with or without the inclusion of bonemineral density (BMD). The purpose of this study is to compute FRAX-based intervention and BMD assessment thresholds forseven Latin American countries in men and women≥40 years.MethodsThe intervention threshold (IT) was set at a 10-year probability of a major osteoporotic fracture (MOF) equivalent to awoman with a prior FF and a body mass index (BMI) equal to 25.0 kg/m2without BMD or other clinical risk factors. The lowerassessment threshold was set at a 10-year probability of a MOF in women with BMI equal to 25.0 kg/m2, no previous fracture andno clinical risk factors. The upper assessment threshold was set at 1.2 times the IT.ResultsFor the seven LA countries, the age-specific IT varied from 1.5 to 27.5% in Argentina, 3.8 to 25.2% in Brazil, 1.6 up to20.0% in Chile, 0.6 to 10.2% in Colombia, 0.9 up to 13.6% in Ecuador, 2.6 to 20.0% in Mexico, and 0.7 up to 22.0% inVenezuela at the age of 40 and 90 years, respectively.ConclusionsIn the LA countries, FRAX-based IT offers a substantial advance for the detection of men and women at highfracture risk, particularly in the elderly. The heterogeneity of IT between the LA countries indicates that country-specific FRAXmodels are appropriate rather than a global LA model.

We present two recent cases of toddlers who developed malignant cerebellar edema subsequent to accidental ingestion of prescription opioids. Both children presented acute neurological decline, hydrocephalus, and tonsillar herniation requiring emergent ventricular drain placement, suboccipital craniectomy, and partial cerebellectomy. Together with several other reports, these cases suggest the existence of an uncommon yet severe syndrome of acute opioid-induced malignant cerebellar edema. We hypothesize that the condition results from a combination of primary opioid receptor-mediated changes in neuronal metabolism that are exacerbated by secondary hypoxic insult. If recognized promptly, this syndrome can be treated with emergent neurosurgical intervention with good clinical outcomes. These cases also illustrate the unintended consequences and innocent victims of the spiraling prescription opioid epidemic, which will likely increase in prevalence. Recognition of this syndrome by clinicians is thus critical.

Objective.To define whether Amerindian genetic ancestry correlates with clinical and therapeutic variables in admixed individuals with rheumatoid arthritis (RA) from Latin America.Methods.Patients with RA (n = 1347) and healthy controls (n = 1012) from Argentina, Mexico, Chile, and Peru were included. Samples were genotyped for the Immunochip v1 using the Illumina platform. Clinical data were obtained through interviews or the clinical history.Results.Percentage of Amerindian ancestry was comparable between cases and controls. Morning stiffness (p < 0.0001, OR 0.05), rheumatoid factor (RF; p < 0.0001, OR 0.22), radiographic changes (p < 0.0001, OR 0.05), and higher number of criteria were associated with lower Amerindian ancestry after Bonferroni correction. Higher Amerindian ancestry correlated only with weight loss (pBonferroni < 0.0001, OR 2.85). Increased Amerindian ancestry correlated with higher doses of azathioprine (p < 0.0001, OR 163.6) and sulfasalazine (p < 0.0001, OR 48.6), and inversely with methotrexate (p = 0.001, OR 0.35), leflunomide (p = 0.001, OR 0.16), and nonsteroidal antiinflammatory drugs (pBonferroni = 0.001, OR 0.37). Only the presence of RF and weight loss were modified after confounders adjustment.Conclusion.Amerindian ancestry protects against most major clinical criteria of RA, but regarding the association of RF with increased European ancestry, age, sex, and smoking are modifiers. Ancestry also correlates with the therapeutic profiles.

Background Glucocorticoid (GC)-induced osteoporosis (GIOP) remains the most common secondary cause of osteoporosis. Despite approved therapies, many subjects do not receive GIOP prevention or treatment. There is increased RANKL and decreased osteoprotegerin (OPG) expression in patients with GIOP. Denosumab (DMAb) is a monoclonal antibody to RANKL. This study was designed to assess the safety and efficacy of DMAb compared with risedronate (RIS) in GC-treated individuals, in whom treatment guidelines advocate a GIOP intervention. Objectives The primary objective was to demonstrate, in separate GC-continuing (GC-C) and GC-initiating (GC-I) subpopulations, that DMAb was not inferior to RIS with respect to percentage change from baseline (%Δ) in lumbar spine (LS) bone mineral density (BMD) at 12 months. Secondary objectives were to assess superiority of DMAb over RIS with respect to %Δ in LS and total hip (TH) BMD at 12 months. Methods This was a phase 3, randomized, double-blind, double-dummy, active-controlled study to evaluate DMAb vs. RIS in GC-treated individuals for 24 months. Eligible subjects were women and men ≥18 yrs receiving GC therapy at a dose ≥7.5 mg prednisone daily or its equivalent for ≥3 months or Results A total of 795 subjects (505 GC-C and 290 GC-I) enrolled in the study. Baseline characteristics were balanced between treatment groups (Table). Non-inferiority and superiority with DMAb were demonstrated for both the GC-C and GC-I subpopulations, as indicated by significantly greater BMD gains compared with RIS at the LS and TH in both subpopulations (Figure). The incidences of adverse events (AEs) and serious AEs, including serious AEs of infection, as well as fracture, were similar between treatment groups and consistent with the known safety profile of DMAb. Conclusions DMAb significantly increased BMD more than RIS at the spine and hip at 12 months. The overall safety profile was similar between treatment groups. DMAb has the potential to become another treatment option for patients newly initiating or continuing GC who are at risk for fracture. Acknowledgements The study was funded by Amgen. C Desborough (Amgen [Europe] GmbH) provided editorial support. Disclosure of Interest K. Saag Grant/research support from: Amgen, Merck, Consultant for: Amgen, Merck, Radius, R. B. Wagman Shareholder of: Amgen, Employee of: Amgen, P. Geusens Grant/research support from: Pfizer, Abbott, Lilly, Amgen, MSD, Will, Roche, UCB, BMS, Novartis, J. Adachi Grant/research support from: Amgen, Eli Lilly, Merck, Pfizer, Consultant for: Amgen, Eli Lilly, Merck, International Osteoporosis Foundation, Speakers bureau: Amgen, Eli Lilly, O. Messina Grant/research support from: Amgen, GSK, R. Emkey Speakers bureau: Amgen, R. Chapurlat Grant/research support from: Amgen, Merck, Chugai, Consultant for: Amgen, Eli Lilly, BMS, AbbVie, Pfizer, Chugai, UCB, N. Daizadeh Shareholder of: Amgen, Employee of: Amgen, N. Pannacciulli Shareholder of: Amgen, Employee of: Amgen, W. Lems Grant/research support from: Eli Lilly, Amgen, MSD, Novartis.

INTRODUCTION: Rheumatoid arthritis (RA) is a common systemic autoimmune disease of unknown cause, characterized by a chronic, symmetric, and progressive inflammatory polyarthritis. One of the most deleterious effects induced by the chronic inflammation of RA is bone loss. During the last 15 years, the better knowledge of the cytokine network involved in RA allowed the development of potent inhibitors of the inflammatory process classified as biological DMARDs. These new drugs are very effective in the inhibition of inflammation, but there are only few studies regarding their role in bone protection. The principal aim of this review was to show the evidence of the principal biologic therapies and bone loss in RA, focusing on their effects on bone mineral density, bone turnover markers, and fragility fractures.METHODS: Using the PICOST methodology, two coauthors (PC, LM-S) conducted the search using the following MESH terms: rheumatoid arthritis, osteoporosis, clinical trials, TNF- antagonists, infliximab, adalimumab, etanercept, certolizumab, golimumab, IL-6 antagonists, IL-1 antagonists, abatacept, tocilizumab, rituximab, bone mineral density, bone markers, and fractures. The search was conducted electronically and manually from the following databases: Medline and Science Direct. The search period included articles from 2003 to 2015. The selection included only original adult human research written in English. Titles were retrieved and the same two authors independently selected the relevant studies for a full text. The retrieved selected studies were also reviewed completing the search for relevant articles. The first search included 904 titles from which 253 titles were selected. The agreement on the selection among researchers resulted in a Kappa statistic of 0.95 (p < 0.000). Only 248 abstracts evaluated were included in the acronym PICOST. The final selection included only 28 studies, derived from the systematic search. Additionally, a manual search in the bibliography of the selected articles was made and included into the text and into the section of "small molecules of new agents."CONCLUSION: Treatment with biologic drugs is associated with the decrease in bone loss. Studies with anti-TNF blocking agents show preservation or increase in spine and hip BMD and also a better profile of bone markers. Most of these studies were performed with infliximab. Only three epidemiological studies analyzed the effect on fractures after anti-TNF blocking agent's treatment. IL-6 blocking agents also showed improvement in localized bone loss not seen with anti-TNF agents. There are a few studies with rituximab and abatacept. Although several studies reported favorable actions of biologic therapies on bone protection, there are still unmet needs for studies regarding their actions on the risk of bone fractures.

Background Endovascular interventions are increasing; however, there are little data regarding outcomes of complex interventions involving the below-knee popliteal/P3 artery. This study evaluated the short-term and long-term results and predictors of success of below-knee popliteal artery endovascular interventions. Methods This was a retrospective review of a prospectively maintained endovascular lower extremity database of all patients with below-knee popliteal interventions from 2004 to 2012. Patient demographics, angiographic findings, interventions, primary and secondary patency, limb loss, and mortality were recorded. Analysis was performed using Kaplan-Meier life-table and multivariate analysis, with P Results There were 221 patients (56% male) with below-knee popliteal/P3 artery lesions. Mean age was 73 ± 11.2 years. Claudication was present in 22% and critical limb ischemia (CLI) in 78%. Mean lesion length was 10 ± 8.5 cm, with 45% having total occlusions. Treatment included percutaneous transluminal angioplasty (PTA) with or without a stent (47%), atherectomy (ATH) with or without PTA/stent (52%), and stenting with PTA and ATH (3%). Complications included embolization (0.4%), hematoma (2.7%), pseudoaneurysm (1.3%), and dissection (7%). Freedom from restenosis (peak systolic velocity ratio >2.4) was 65% at 1 year. Independent predictors of restenosis were CLI (hazard risk [HR], 4.4; 95% confidence interval [CI], 1.9-9.9) and stenting combined with PTA and ATH (HR, 2.7; 95% CI, 1.01-7.4). Primary assisted and secondary patencies were 95% and 85% at 1 year. ATH with PTA had lower short-term restenosis in diabetic patients compared with nondiabetic patients (95% vs 78% at 4 months). Limb loss was 18% at 4 years. Mortality was 24% at 4 years. Statin use was protective against primary restenosis (HR, 0.39; 95% CI, 0.23-0.67) and death (HR, 0.5; 95% CI, 0.28-1.0). Conclusions Endovascular intervention for lesions involving the below-knee popliteal artery is a safe and effective therapy for claudication and CLI. Diabetic patients benefit most from ATH with PTA. Statin use is protective against restenosis and mortality and should be the standard of care in patients undergoing peripheral endovascular interventions.

Limited transpiration rate (TR) under high vapor pressure deficit (VPD) conditions has been proposed as a desirable trait for crop yield improvement. The limited-TR trait has been identified in several single-cross maize hybrids, and among these hybrids, a range in the VPD breakpoint for limited TR was identified. It was hypothesized that the variation in the VPD breakpoint was due to differences in hydraulic conductance in their roots or leaves, or both. Therefore, the objective of this study was to compare relative hydraulic conductance in the roots and leaves across the maize hybrids expressing the VPD breakpoint. It was found that the VPD of the breakpoint was correlated with each of three indices of hydraulic conductance. That is, low VPD breakpoint was associated with low hydraulic conductance in both leaves and roots indicating a common, underlying limiting mechanism in these two tissues. It was hypothesized that expression of similar aquaporin populations influencing hydraulic flow across membranes in the roots and leaves may account for the consistency in results across the indices of hydraulic conductance.

Germplasm, genetics, phenotyping, and selection, combined with a clear definition of product targets, are the foundation of successful hybrid maize breeding. Breeding maize hybrids with superior yield for the drought-prone regions of the US corn-belt involves integration of multiple drought-specific technologies together with all of the other technology components that comprise a successful maize hybrid breeding programme. Managed-environment technologies are used to enable scaling of precision phenotyping in appropriate drought environmental conditions to breeding programme level. Genomics and other molecular technologies are used to study trait genetic architecture. Genetic prediction methodology was used to breed for improved yield performance for drought-prone environments. This was enabled by combining precision phenotyping for drought performance with genetic understanding of the traits contributing to successful hybrids in the target drought-prone environments and the availability of molecular markers distributed across the maize genome. Advances in crop growth modelling methodology are being used to evaluate the integrated effects of multiple traits for their combined effects and evaluate drought hybrid product concepts and guide their development and evaluation. Results to date, lessons learned, and future opportunities for further improving the drought tolerance of maize for the US corn-belt are discussed.