567 research outputs found
Recent Chinese Legislation Assisting Foreign Investors to Solve Their Hard Currency Problem: Import Substitution and Other Options
Heritability patterns in hand osteoarthritis: the role of osteophytes
Abstract Introduction The objective of the present study was to assess heritability of clinical and radiographic features of hand osteoarthritis (OA) in affected patients and their siblings. Methods A convenience sample of patients with clinical and radiographic hand OA and their siblings were evaluated by examination and radiography. Radiographs were scored for hand OA features by radiographic atlas. The heritability of hand OA phenotypes was assessed for clinical and radiographic measures based on anatomic locations and radiographic characteristics. Phenotypic data were transformed to reduce non-normality, if necessary. A variance components approach was used to calculate heritability. Results One hundred and thirty-six probands with hand OA and their sibling(s) were enrolled. By anatomic location, the highest heritability was seen with involvement of the first interphalangeal joint (h 2 = 0.63, P = 0.00004), the first carpometacarpal joint (h 2 = 0.38, P = 0.01), the distal interphalangeal joints (h 2 = 0.36, P = 0.02), and the proximal interphalangeal joints (h 2 = 0.30, P = 0.03) with osteophytes. The number and severity of joints with osteophyte involvement was heritable overall (h 2 = 0.38, P = 0.008 for number and h 2 = 0.35, P = 0.01 for severity) and for all interphalangeal joints (h 2 = 0.42, P = 0.004 and h 2 = 0.33, P = 0.02). The severity of carpometacarpal joint involvement was also heritable (h 2 = 0.53, P = 0.0006). Similar results were obtained when the analysis was limited to the Caucasian sample. Conclusions In a population with clinical and radiographic hand OA and their siblings, the presence of osteophytes was the most sensitive biomarker for hand OA heritability. Significant heritability was detected for anatomic phenotypes by joint location, severity of joint involvement with osteophytes as well as for overall number and degree of hand OA involvement. These findings are in agreement with the strong genetic predisposition for hand OA reported by others. The results support phenotyping based on severity of osteophytes and a joint-specific approach. More specific phenotypes may hold greater promise in the study of genetics in hand OA
Using Biomarkers to Inform Cumulative Risk Assessment
BACKGROUND: Biomarkers are considered the method of choice for determining exposure to environmental contaminants and relating such exposures to health outcomes. However, the association between many biomarkers and outcome is not direct because of variability in sensitivity and susceptibility in the individual. OBJECTIVES: We explore the relationship between environmental exposures and health outcomes as mitigated by differential susceptibility in individuals or populations and address the question “Can biomarkers enable us to understand and quantify better the population burden of disease and health effects attributable to environmental exposures?” METHODS: We use a case–study approach to develop the thesis that biomarkers offer a pathway to disaggregation of health effects into specific, if multiple, risk factors. We offer the point of view that a series or array of biomarkers, including biomarkers of exposure, biomarkers of susceptibility, and biomarkers of effect, used in concert offer the best means by which to effect this disaggregation. We commence our discussion by developing the characteristics of an ideal biomarker, then give some examples of commonly used biomarkers to show the strengths and weaknesses of current usage. We follow this by more detailed case-study assessment outlining the state-of-the-science in specific cases. We complete our work with recommendations regarding the future use of biomarkers and areas for continued development. CONCLUSIONS: The case studies provide examples of when and how biomarkers can be used to infer the source and magnitude of exposure among a set of competing sources and pathways. The answer to this question is chemical specific and relates to how well the biomarker matches the characteristics of an “ideal” biomarker–in particular ease of collection and persistence. The use of biomarkers in combination provides a better opportunity to disaggregate both source and pathway contributions
Spag17 Deficiency Results in Skeletal Malformations and Bone Abnormalities
Height is the result of many growth and development processes. Most of the genes associated with height are known to play a role in skeletal development. Single-nucleotide polymorphisms in the SPAG17 gene have been associated with human height. However, it is not clear how this gene influences linear growth. Here we show that a targeted mutation in Spag17 leads to skeletal malformations. Hind limb length in mutants was significantly shorter than in wild-type mice. Studies revealed differences in maturation of femur and tibia suggesting alterations in limb patterning. Morphometric studies showed increased bone formation evidenced by increased trabecular bone area and the ratio of bone area to total area, leading to reductions in the ratio of marrow area/total area in the femur. Micro-CTs and von Kossa staining demonstrated increased mineral in the femur. Moreover, osteocalcin and osterix were more highly expressed in mutant mice than in wild-type mice femurs. These data suggest that femur bone shortening may be due to premature ossification. On the other hand, tibias appear to be shorter due to a delay in cartilage and bone development. Morphometric studies showed reduction in growth plate and bone formation. These defects did not affect bone mineralization, although the volume of primary bone and levels of osteocalcin and osterix were higher. Other skeletal malformations were observed including fused sternebrae, reduced mineralization in the skull, medial and metacarpal phalanges. Primary cilia from chondrocytes, osteoblasts, and embryonic fibroblasts (MEFs) isolated from knockout mice were shorter and fewer cells had primary cilia in comparison to cells from wild-type mice. In addition, Spag17 knockdown in wild-type MEFs by Spag17 siRNA duplex reproduced the shorter primary cilia phenotype. Our findings disclosed unexpected functions for Spag17 in the regulation of skeletal growth and mineralization, perhaps because of its role in primary cilia of chondrocytes and osteoblasts
Reverberation Mapping of the Kepler-Field AGN KA1858+4850
KA1858+4850 is a narrow-line Seyfert 1 galaxy at redshift 0.078 and is among
the brightest active galaxies monitored by the Kepler mission. We have carried
out a reverberation mapping campaign designed to measure the broad-line region
size and estimate the mass of the black hole in this galaxy. We obtained 74
epochs of spectroscopic data using the Kast Spectrograph at the Lick 3-m
telescope from February to November of 2012, and obtained complementary V-band
images from five other ground-based telescopes. We measured the H-beta light
curve lag with respect to the V-band continuum light curve using both
cross-correlation techniques (CCF) and continuum light curve variability
modeling with the JAVELIN method, and found rest-frame lags of lag_CCF = 13.53
(+2.03, -2.32) days and lag_JAVELIN = 13.15 (+1.08, -1.00) days. The H-beta
root-mean-square line profile has a width of sigma_line = 770 +/- 49 km/s.
Combining these two results and assuming a virial scale factor of f = 5.13, we
obtained a virial estimate of M_BH = 8.06 (+1.59, -1.72) x 10^6 M_sun for the
mass of the central black hole and an Eddington ratio of L/L_Edd ~ 0.2. We also
obtained consistent but slightly shorter emission-line lags with respect to the
Kepler light curve. Thanks to the Kepler mission, the light curve of
KA1858+4850 has among the highest cadences and signal-to-noise ratios ever
measured for an active galactic nucleus; thus, our black hole mass measurement
will serve as a reference point for relations between black hole mass and
continuum variability characteristics in active galactic nuclei
Virtual Exploration of Safe Entry Zones in the Brainstem: Comprehensive Definition and Analysis of the Operative Approach
Background
Detailed and accurate understanding of intrinsic brainstem anatomy and the inter-relationship between its internal tracts and nuclei and external landmarks is of paramount importance for safe and effective brainstem surgery. Using anatomical models can be an important step in sharpening such understanding.
Objective
To show the applicability of our developed virtual 3D model in depicting the safe entry zones (SEZs) to the brainstem.
Methods
Accurate 3D virtual models of brainstem elements were created using high-resolution magnetic resonance imaging and computed tomography to depict brainstem SEZs.
Results
All the described SEZs to different aspects of the brainstem were successfully depicted using our 3D virtual models.
Conclusions
The virtual models provide an immersive experience of brainstem anatomy, allowing users to understand the intricacies of the microdissection that is necessary to appropriately traverse the brainstem nuclei and tracts toward a particular target. The models provide an unparalleled learning environment for illustrating SEZs into the brainstem that can be used for training and research
Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients
To characterize effects of alemtuzumab treatment on measures of disability improvement in patients with relapsing-remitting multiple sclerosis (RRMS) with inadequate response (≥1 relapse) to prior therapy.
Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II, a 2-year randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial, compared efficacy and safety of alemtuzumab 12 mg with subcutaneous interferon-β-1a (SC IFN-β-1a) 44 μg in patients with RRMS. Prespecified and post hoc disability outcomes based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Sloan low-contrast letter acuity (SLCLA) are reported, focusing on improvement of preexisting disability in addition to slowing of disability accumulation.
Alemtuzumab-treated patients were more likely than SC IFN-β-1a-treated patients to show improvement in EDSS scores ( < 0.0001) on all 7 functional systems. Significantly more alemtuzumab patients demonstrated 6-month confirmed disability improvement. The likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than SC IFN-β-1a ( = 0.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores ( = 0.0014) and MSFC + SLCLA composite scores ( = 0.0097) than SC IFN-β-1a-treated patients.
In patients with RRMS and inadequate response to prior disease-modifying therapies, alemtuzumab provides greater benefits than SC IFN-β-1a across several disability outcomes, reflecting improvement of preexisting disabilities.
This study provides Class I evidence (based on rater blinding and a balance in baseline characteristics between arms) that alemtuzumab modifies disability measures favorably compared with SC IFN-β-1a.Sanofi Genzyme, Bayer HealthCare Pharmaceutical
Context processing in older adults: Evidence for a theory relating cognitive control to neurobiology in healthy aging.
Safety and efficacy of pembrolizumab in combination with acalabrutinib in advanced head and neck squamous cell carcinoma: Phase 2 proof-of-concept study
PURPOSE: Programmed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton\u27s tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti-PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC.
PATIENTS AND METHODS: Patients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival.
RESULTS: Seventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3-4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4-6.8] months in the combination arm and 1.7 (95% CI, 1.4-4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size.
CONCLUSIONS: Despite lack of clinical efficacy, immune subset analyses suggest that there are additive effects of this combination; however, the associated toxicity limits the feasibility of combination treatment with pembrolizumab and acalabrutinib in patients with recurrent or metastatic HNSCC
Quantum Cognitive Modeling: New Applications and Systems Research Directions
Expanding the benefits of quantum computing to new domains remains a
challenging task. Quantum applications are concentrated in only a few domains,
and driven by these few, the quantum stack is limited in supporting the
development or execution demands of new applications. In this work, we address
this problem by identifying both a new application domain, and new directions
to shape the quantum stack. We introduce computational cognitive models as a
new class of quantum applications. Such models have been crucial in
understanding and replicating human intelligence, and our work connects them
with quantum computing for the first time. Next, we analyze these applications
to make the case for redesigning the quantum stack for programmability and
better performance. Among the research opportunities we uncover, we study two
simple ideas of quantum cloud scheduling using data from gate-based and
annealing-based quantum computers. On the respective systems, these ideas can
enable parallel execution, and improve throughput. Our work is a contribution
towards realizing versatile quantum systems that can broaden the impact of
quantum computing on science and society
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