Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study

Objectives The interleukin-6 receptor (IL-6R) blocker tocilizumab (TCZ) reduces inflammatory disease activity in rheumatoid arthritis (RA) but elevates lipid concentrations in some patients. We aimed to characterise the impact of IL-6R inhibition on established and novel risk factors in active RA. Methods Randomised, multicentre, two-part, phase III trial (24-week double-blind, 80-week open-label), MEASURE, evaluated lipid and lipoprotein levels, high-density lipoprotein (HDL) particle composition, markers of coagulation, thrombosis and vascular function by pulse wave velocity (PWV) in 132 patients with RA who received TCZ or placebo. Results Median total-cholesterol, low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels increased in TCZ versus placebo recipients by week 12 (12.6% vs 1.7%, 28.1% vs 2.2%, 10.6% vs −1.9%, respectively; all p&#60;0.01). There were no significant differences in mean small LDL, mean oxidised LDL or total HDL-C concentrations. However, HDL-associated serum amyloid A content decreased in TCZ recipients. TCZ also induced reductions (&#60;30%) in secretory phospholipase A2-IIA, lipoprotein(a), fibrinogen and D-dimers and elevation of paraoxonase (all p&#60;0.0001 vs placebo). The ApoB/ApoA1 ratio remained stable over time in both groups. PWV decreases were greater with placebo than TCZ at 12 weeks (adjusted mean difference 0.79 m/s (95% CI 0.22 to 1.35; p=0.0067)). Conclusions These data provide the first detailed evidence for the modulation of lipoprotein particles and other surrogates of vascular risk with IL-6R inhibition. When compared with placebo, TCZ induced elevations in LDL-C but altered HDL particles towards an anti-inflammatory composition and favourably modified most, but not all, measured vascular risk surrogates. The net effect of such changes for cardiovascular risk requires determination.</p

Data Provisioning for the Object Modeling System (OMS)

The Object Modelling System (OMS) platform supports initiatives to build or re - factor agro - environmental models and deploy them in different business contexts as model services on cloud computing platforms. Whether traditional desktop, client - server, or emerging cloud deployments, success especially at the enterprise level relies on stable and efficient data provisioning to the models. In this paper we describe recent experience and trends with tools and services to supply data for model inputs. Solutions range from simple pre - processing tools to data services deployed to cloud platforms. Also, systematic, sustained data stewardship and alignment with standards organizations impart stability to data provisioning efforts

Children\u27s Behavioral Traits and Risk of Injury: Analyses from a Case-Control Study of Agricultural Households

Problem: Children on family agricultural operations have high risk of injury. The association between children\u27s behavioral traits and their risk of injury is not well understood. Method: Data from the Regional Rural Injury Study-II were used to assess behavioral risk factors for injury to children ages six to \u3c20 years. A total of 379 injury events (cases) and 1,562 randomly selected controls were identified. Adjusted odds ratios (OR) and 95% confidence intervals (CI), calculated using logistic regression, were used to estimate injury risk in reference to behavioral traits. Results: Injury risks were greater for children with high levels of depressive symptoms (OR=1.9, CI=1.0-3.7) and aggression (OR=1.6, CI=0.9-2.7), and low levels of careful/cautious behavior (OR=1.8, CI=1.1-2.9). Children with low levels of self-regulation had reduced risks (OR=0.4, CI=0.2-0.8). Discussion: Results suggest that children\u27s behaviors affect their risk of agricultural injury. Additional research could elucidate mechanisms and inform interventions. Impact on industry: The development of multifaceted, sustainable approaches for prevention is necessary for this unique population. These findings suggest a need for interventions that incorporate specific behavior-related risk factors in the context of family farms and ranches

An Exploratory Investigation on the Invasiveness of Environmental Modeling Frameworks

Environmental modeling frameworks provide an array of useful features that model developers can harness when implementing models. Each framework differs in how it provides features to a model developer via its Application Programming Interface (API). Environmental modelers harness framework features by calling and interfacing with the framework API. As modelers write model code, they make framework-specific function calls and use framework specific data types for achieving the functionality of the model. As a result of this development approach, model code becomes coupled with and dependent on a specific modeling framework. Coupling to a specific framework makes migration to other frameworks and reuse of the code outside the original framework more difficult. This complicates collaboration between model developers wishing to share model code that ma y have been developed in a variety of languages and frameworks. This paper provides initial results of an exploratory investigation on the invasiveness of environmental modeling frameworks. Invasiveness is defined as th e coupling between application (i.e., model) and framework code used to implement the model. By comparing the implementation of an environmental model across several modeling frameworks, we aim to better understand the consequences of framework design. How frameworks present functionality to modelers through APIs can lead to consequences with respect to model development, model maintenance, reuse of model code, and ultimately collaboration among model developers. By measuring framework invasiveness, we hope to provide environmental modeling framework developers and environmental modelers with valuable in formation to assist in future development efforts. Eight implementations (six framework-based) of Thornthwaite, a simple water balance model, were made in a variety of environmental modeling frameworks and languages. A set of software metrics were proposed and applied to measure invasiveness between model implementation code and framework code. The metrics produced a rank ordering of invasiveness for the framework-based implementations of Thornthwaite. We compared model invasiveness results with several popular software metrics including size in lines of code (LOC), cyclomatic complexity, and object oriented coupling. To investigate software quality implications of framework invasiveness we checked for relationships between the Chidamber and Kemerer (1994) object oriented software metrics and our framework invasiveness measures. For the six framework-based implementations of Thornthwaite we found a five-fold variation in code size (LOC). We observed up to a seven-fold variation in total cyclomatic complexity, and a two to three-fold variation in object oriented coupling. For the model implementations we found that total size, total complexity, and total coupling all had a significant positive correlation. The raw count version of our invasiveness measures correlated with application size (LOC), total cyclomatic complexity, total efferent coupling (fan out) and total afferent coupling (fan in). Large size, complexity, and high levels of coupling between units (classes, modules) in a software system are often cited in software engineering as causes of high maintenance costs due to poor understandability and flexibility of the code. This study provides initial results but further investigation is desired to evaluate the utility of our invasiveness measurement approach as well as the software quality implications of framework invasiveness

Environmental Modeling Framework Invasiveness: Analysis and Implications

Environmental modeling frameworks support scientific model development by providing an Application Programming Interface (API) which model developers use to implement models. This paper presents results of an investigation on the framework invasiveness of environmental modeling frameworks. Invasiveness is defined as the quantity of dependencies between model code and the modeling framework. This research investigates relationships between invasiveness and the quality of modeling code. Additionally, we investigate the relationship between invasiveness and two common framework designs (lightweight vs. heavyweight). Five metrics to measure framework invasiveness were proposed and applied to measure invasiveness between model and framework code of several implementations of Thornthwaite and the Precipitation-Runoff Modeling System (PRMS), two hydrological models. Framework invasiveness measurements were compared with existing software metrics including size (lines of code), cyclomatic complexity, and object-oriented coupling with generally positive correlations being found. We found that models with lower framework invasiveness tended to be smaller, less complex, and have lower coupling. In addition, the lightweight framework implementations of the Thornthwaite and PRMS models were less invasive than the heavyweight framework model implementations. Our initial results suggest that framework invasiveness is undesirable for model code quality and that lightweight frameworks may help reduce invasiveness

Pharmacological Targeting of Native CatSper Channels Reveals a Required Role in Maintenance of Sperm Hyperactivation

The four sperm-specific CatSper ion channel proteins are required for hyperactivated motility and male fertility, and for Ca2+ entry evoked by alkaline depolarization. In the absence of external Ca2+, Na+ carries current through CatSper channels in voltage-clamped sperm. Here we show that CatSper channel activity can be monitored optically with the [Na+]i-reporting probe SBFI in populations of intact sperm. Removal of external Ca2+ increases SBFI signals in wild-type but not CatSper2-null sperm. The rate of the indicated rise of [Na+]i is greater for sperm alkalinized with NH4Cl than for sperm acidified with propionic acid, reflecting the alkaline-promoted signature property of CatSper currents. In contrast, the [Na+]i rise is slowed by candidate CatSper blocker HC-056456 (IC50 ∼3 µM). HC-056456 similarly slows the rise of [Ca2+]i that is evoked by alkaline depolarization and reported by fura-2. HC-056456 also selectively and reversibly decreased CatSper currents recorded from patch-clamped sperm. HC-056456 does not prevent activation of motility by HCO3− but does prevent the development of hyperactivated motility by capacitating incubations, thus producing a phenocopy of the CatSper-null sperm. When applied to hyperactivated sperm, HC-056456 causes a rapid, reversible loss of flagellar waveform asymmetry, similar to the loss that occurs when Ca2+ entry through the CatSper channel is terminated by removal of external Ca2+. Thus, open CatSper channels and entry of external Ca2+ through them sustains hyperactivated motility. These results indicate that pharmacological targeting of the CatSper channel may impose a selective late-stage block to fertility, and that high-throughput screening with an optical reporter of CatSper channel activity may identify additional selective blockers with potential for male-directed contraception

Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia

Antiapoptotic BCL2 family members have been implicated in the pathogenesis of acute myelogenous leukemia (AML), but the functional significance and relative importance of individual proteins (e.g., BCL2, BCL-XL, and myeloid cell leukemia 1 [MCL1]) remain poorly understood. Here, we examined the expression of BCL2, BCL-XL, and MCL1 in primary human hematopoietic subsets and leukemic blasts from AML patients and found that MCL1 transcripts were consistently expressed at high levels in all samples tested. Consistent with this, Mcl1 protein was also highly expressed in myeloid leukemic blasts in a mouse Myc-induced model of AML. We used this model to test the hypothesis that Mcl1 facilitates AML development by allowing myeloid progenitor cells to evade Myc-induced cell death. Indeed, activation of Myc for 7 days in vivo substantially increased myeloid lineage cell numbers, whereas hematopoietic stem, progenitor, and B-lineage cells were depleted. Furthermore, Mcl1 haploinsufficiency abrogated AML development. In addition, deletion of a single allele of Mcl1 from fully transformed AML cells substantially prolonged the survival of transplanted mice. Conversely, the rapid lethality of disease was restored by coexpression of Bcl2 and Myc in Mcl1-haploinsufficient cells. Together, these data demonstrate a critical and dose-dependent role for Mcl1 in AML pathogenesis in mice and suggest that MCL1 may be a promising therapeutic target in patients with de novo AML

Identification of Bone Marrow Cell Subpopulations Associated With Improved Functional Outcomes in Patients With Chronic Left Ventricular Dysfunction: An Embedded Cohort Evaluation of the FOCUS-CCTRN Trial

In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4(+) BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy-even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials

The effect of lengthening contractions on neuromuscular junction structure in adult and old mice

Skeletal muscles of old mice demonstrate a profound inability to regenerate fully following damage. Such a failure could be catastrophic to older individuals where muscle loss is already evident. Degeneration and regeneration of muscle fibres following contraction-induced injury in adult and old mice are well characterised, but little is known about the accompanying changes in motor neurons and neuromuscular junctions (NMJs) following this form of injury although defective re-innervation of muscle following contraction-induced damage has been proposed to play a role in sarcopenia. This study visualised and quantified structural changes to motor neurons and NMJs in Extensor digitorum longus (EDL) muscles of adult and old Thy1-YFP transgenic mice during regeneration following contraction-induced muscle damage. Data demonstrated that the damaging contraction protocol resulted in substantial initial disruption to NMJs in muscles of adult mice, which was reversed entirely within 28 days following damage. In contrast, in quiescent muscles of old mice, ∼15 % of muscle fibres were denervated and ∼80 % of NMJs showed disruption. This proportion of denervated and partially denervated fibres remained unchanged following recovery from contraction-induced damage in muscles of old mice although ∼25 % of muscle fibres were completely lost by 28 days post-contractions. Thus, in old mice, the failure to restore full muscle force generation that occurs following damage does not appear to be due to any further deficit in the percentage of disrupted NMJs, but appears to be due, at least in part, to the complete loss of muscle fibres following damag