A re-examination of the BEST Trial using composite outcomes, including emergency department visits

Objectives: The influence of choice of endpoint on trial size, duration, and interpretation of results was examined in patients with heart failure who were enrolled in BEST (Beta-blocker Evaluation of Survival Trial). Background: The choice of endpoints in heart failure trials has evolved over the past 3 decades. Methods: In the BEST trial, we used Cox regression analysis to examine the effect of bucindolol on the current standard composite of cardiovascular death or heart failure hospitalization (CVD/HFH) compared with the original primary mortality endpoint and the expanded composite that included emergency department (ED) visits. We also undertook an analysis of recurrent events primarily using the Lin, Wei, Ying, and Yang model. Results: Overall, 448 (33%) patients on placebo and 411 (30%) patients on bucindolol died (hazard ratio [HR]: 0.90; 95% confidence interval [CI]: 0.78 to 1.02; p = 0.11). A total of 730 (54%) patients experienced CVD/HFH on placebo and 624 (46%) on bucindolol (HR: 0.80; 95% CI: 0.72 to 0.89; p < 0.001). Adding ED visits increased these numbers to 768 (57%) and 668 (49%), respectively (HR: 0.81; 95% CI: 0.73 to 0.90; p < 0.001). A total of 568 (42%) patients on placebo experienced HFH compared with 476 (35%) patients on bucindolol (HR: 0.78; 95% CI: 0.69 to 0.89; p < 0.001), with a total of 1,333 and 1,124 admissions, respectively. With the same statistical assumptions, using the composite endpoint instead of all-cause mortality would have reduced the trial size by 40% and follow-up duration by 69%. The rate ratio for recurrent events (CVD/HFH) was 0.83 (95% CI: 0.73 to 0.94; p = 0.003). Conclusions: Choice of endpoint has major implications for trial size and duration, as well as interpretation of results. The value of broader composite endpoints and inclusion of recurrent events needs further investigation. (Beta Blocker Evaluation in Survival Trial [BEST]; NCT00000560

Improved representation of underwater light field and its impact on ecosystem dynamics: a study in the North Sea

Understanding ecosystem state on the North-West European (NWE) Shelf is of major im18 portance for both economy and climate research. The purpose of this work is to advance our modelling of in-water optics on the NWE Shelf, with important implications for how we model primary productivity, as well as for assimilation of water-leaving radiances. We implement a stand-alone bio-optical module into the existing coupled physical-biogeo-chemical model configuration. The advantage of the bio-optical module, when compared to the pre-existing light scheme is that it resolves the underwater light spectrally and distinguishes between direct and diffuse downwelling streams. The changed underwater light compares better with both satellite and in-situ observations. The module lowered the underwater Photosynthetically Active Radiation, decreasing the simulated primary productivity, but overall the improved underwater light had relatively limited impact on the phyto plankton seasonal dynamics. We showed that the model skill in representing phytoplankton seasonal cycle (e.g phytoplankton bloom) can be substantially improved either by assimilation of satellite Phytoplankton Functional Type (PFT) chlorophyll, or by assimilating a novel PFT absorption product. Assimilation of the two PFT products yields similar results, with an important difference in the PFT community structure. Both assimilative runs lead to lower plankton biomass and increase the nutrient concentrations. We discuss some future directions on how to improve our model skill in biogeochemistry without using as similation, e.g. by improving nutrient forcing, re-tuning the model parameters and using the bio-optical module to provide a two-way physical-biogeochemical coupling, improving the consistency between model physical and biogeochemical components

Photonic crystal resonator integrated in a microfluidic system

We report on a novel optofluidic system consisting of a silica-based 1D photonic crystal, integrated planar waveguides and electrically insulated fluidic channels. An array of pillars in a microfluidic channel designed for electrochromatography is used as a resonator for on-column label-free refractive index detection. The resonator was fabricated in a silicon oxynitride platform, to support electroosmotic flow, and operated at 1.55 microns. Different aqueous solutions of ethanol with refractive indices ranging from n = 1.3330 to 1.3616 were pumped into the column/resonator and the transmission spectra were recorded. Linear shifts of the resonant wavelengths yielded a maximum sensitivity of 480 nm/RIU and a minimum difference of 0.007 RIU was measured

Bone marrow-derived and peritoneal macrophages have different inflammatory response to oxLDL and M1/M2 marker expression:implications for atherosclerosis research

Macrophages are heterogeneous and can polarize into specific subsets, e.g. pro-inflammatory M1-like and re-modelling M2-like macrophages. To determine if peritoneal macrophages (PEMs) or bone marrow derived macrophages (BMDMs) resembled aortic macrophages from ApoE−/− mice, their M1/M2 phenotype, inflammatory status, and lipid metabolism signatures were compared. oxLDL accumulation was similar in PEMs and BMDMs. On protein expression level, BMDMs showed an M2-like CD206(high)CD11c(low) profile, while cholesterol loading led to enhanced CD11c expression and reduced MCP-1 secretion. In contrast, PEMs expressed low levels of CD206 and CD11c, and responded to cholesterol loading by increasing CD11c expression and MCP-1 secretion. mRNA expression of M1/M2 markers was higher in PEMS than BMDMs, while lipid metabolism genes were similarly expressed. Whole aorta flow cytometry showed an accumulation of M2-like CD206(high)CD11c(low) macrophages in advanced versus early atherosclerotic disease in ApoE−/− mice. In isolated lesions, mRNA levels of the M2 markers Socs2, CD206, Retnla, and IL4 were downregulated with increasing disease severity. Likewise, mRNA expression of lipid metabolism genes (SREBP2, ACSL1, SRB1, DGAT1, and cpt1a) was decreased in advanced versus early lesions. In conclusion, PEMs and BMDMs are phenotypically distinct and differ from macrophages in lesions with respect to expression of M1/M2 markers and lipid metabolism genes

Major Cardiac Events in Patients and Relatives With Hereditary Hypertrophic Cardiomyopathy

BackgroundLittle evidence is available on the disease expression in relatives of index patients with hypertrophic cardiomyopathy (HCM). This information has important implications for family screening programs, genetic counseling, and management of affected families.ObjectivesThe purpose of this study was to investigate the disease expression and penetrance in relatives of index patients carrying pathogenic/likely pathogenic (P/LP) variants in recognized HCM genes.MethodsA total of 453 consecutive and unrelated HCM index patients underwent clinical and genetic investigations. A total of 903 relatives of genotype-positive index patients were invited for clinical investigations and genetic testing. Penetrance, disease expression, and incidence rates of major adverse cardiac events (MACEs) were investigated in individuals carrying P/LP variants.ResultsForty percent (183/453) of index patients carried a P/LP variant. Eighty-four percent (757/903) of all relatives of index patients with P/LP variants were available for the investigation, of whom 54% (407/757) carried a P/LP variant. The penetrance of HCM among relatives was 39% (160/407). Relatives with HCM and index patients were diagnosed at a similar age (43 ± 18 years vs 46 ± 15 years; P = 0.11). There were no differences in clinical characteristics or incidence rates of MACE during 8 years of follow-up.ConclusionsThe disease expression of HCM among index patients and affected relatives carrying P/LP variants in recognized disease genes was similar, with an equal risk of experiencing MACE. These findings provide evidence to support family screening and follow-up of genotype-positive HCM families to improve management and diminish the number of adverse disease complications among relatives

Liquid-infiltrated photonic crystals - enhanced light-matter interactions for lab-on-a-chip applications

Optical techniques are finding widespread use in analytical chemistry for chemical and bio-chemical analysis. During the past decade, there has been an increasing emphasis on miniaturization of chemical analysis systems and naturally this has stimulated a large effort in integrating microfluidics and optics in lab-on-a-chip microsystems. This development is partly defining the emerging field of optofluidics. Scaling analysis and experiments have demonstrated the advantage of micro-scale devices over their macroscopic counterparts for a number of chemical applications. However, from an optical point of view, miniaturized devices suffer dramatically from the reduced optical path compared to macroscale experiments, e.g. in a cuvette. Obviously, the reduced optical path complicates the application of optical techniques in lab-on-a-chip systems. In this paper we theoretically discuss how a strongly dispersive photonic crystal environment may be used to enhance the light-matter interactions, thus potentially compensating for the reduced optical path in lab-on-a-chip systems. Combining electromagnetic perturbation theory with full-wave electromagnetic simulations we address the prospects for achieving slow-light enhancement of Beer-Lambert-Bouguer absorption, photonic band-gap based refractometry, and high-Q cavity sensing.Comment: Invited paper accepted for the "Optofluidics" special issue to appear in Microfluidics and Nanofluidics (ed. Prof. David Erickson). 11 pages including 8 figure

Towards a multi-platform assimilative system for North Sea biogeochemistry

Oceanography has entered an era of new observing platforms, such as biogeochemical-Argo floats and gliders, some of which will provide three-dimensional maps of essential ecosystem variables on the North-West European (NWE) Shelf. In a foreseeable future operational centers will use multi-platform assimilation to integrate those valuable data into ecosystem reanalysis and forecast systems. Here we address some important questions related to glider biogeochemical data assimilation (DA) and introduce multi-platform DA in a preoperational model of the NWE Shelf sea ecosystem. We test the impact of the different multi-platform system components (glider vs. satellite, physical vs. biogeochemical) on the simulated biogeochemical variables. To characterize the model performance, we focus on the period around the phytoplankton spring bloom, since the bloom is a major ecosystem driver on the NWE Shelf. We found that the timing and magnitude of the phytoplankton bloom is insensitive to the physical DA, which is explained in the study. To correct the simulated phytoplankton bloom one needs to assimilate chlorophyll observations from glider or satellite Ocean Color (OC) into the model. Although outperformed by the glider chlorophyll assimilation, we show that OC assimilation has mostly desirable impact on the sub-surface chlorophyll. Since the OC assimilation updates chlorophyll only in the mixed layer, the impact on the sub-surface chlorophyll is the result of the model dynamical response to the assimilation. We demonstrate that the multi-platform assimilation combines the advantages of its components and always performs comparably to its best performing component

Evaluation of the influence of kyphosis and scoliosis on intervertebral disc extrusion in French bulldogs

Although thoracic vertebral malformations with kyphosis and scoliosis are often considered incidental findings on diagnostic imaging studies of screw-tailed brachycephalic breeds, they have been suggested to interfere with spinal biomechanics and intervertebral disc degeneration. It is however unknown if an abnormal spinal curvature also predisposes dogs to develop clinically relevant intervertebral disc herniations. The aim of this study was to evaluate if the occurrence of thoracic vertebral malformations, kyphosis or scoliosis would be associated with a higher prevalence of cervical or thoracolumbar intervertebral disc extrusion in French bulldogs