Block-copolymer assisted fabrication of anisotropic plasmonic nanostructures.
The anisotropic nanostructures of noble metals are of great interest for plasmonic applications, due to the possibility of tuning the localized surface plasmon resonance (LSPR) across the UV-visible-near infrared (UV-vis-NIR) without sacrificing the linewidth, as well as achieving larger local field enhancement. Here, we report a simple and promising fabrication method of anisotropic gold nanostructures film using polystyrene-b-poly(2vinylpyridine) (PS-b-P2VP) block copolymers (BCPs) as a template. In this approach, PS-b-P2VP spherical micelles were first synthesized as a template, followed by selective deposition of an Au precursor inside the P2VP core of the micelles, using an ethanol solution of Au salt. Subsequently, heat treatment of the precursor deposited BCP films followed by the removal of the BCP template produced anisotropic gold nanostructures of various shapes, such as octahedron, decahedron, tetrahedron, triangles, and triangular prism. A temperature and time dependent study during heat treatment shows the formation of clusters at a higher temperature. Furthermore, measurements of the ensemble extinction spectra of the anisotropic Au nanoparticle films showed two broad distinct LSPR peaks; one in the visible range (∼660 nm), and the other in the NIR range (∼875 nm). The electrodynamic simulation showed that octahedron and decahedron nanoparticles are responsible for the LSPR response in the visible; whereas the triangular shapes are responsible for the LSPR response in the NIR. Our work is expected to open up a new direction for the synthesis of anisotropic nanostructures of noble metals, that can be utilized to tune the LSPR response across the UV-vis-NIR range, using a simple BCP template-based method.


The impact of free-time activities on sleep, recovery and well-being.
We compared the effects of different types of free-time activity on subjective and objective indices of sleep, recovery and well-being in an experimental field study. Twelve participants spent four consecutive evenings after work in each of three conditions: pursuing quiet leisure activities at home; undertaking active leisure pursuits; doing additional work. Ratings of rest and recuperation, and of satisfaction, were lowest in the additional work condition. There were few other differences between conditions. However, being satisfied with one's evening activities (regardless of which experimental condition was being undertaken) was associated with improved subsequent sleep (self-reported). Evening activities involving lower mental effort were also associated with better-rated sleep, as well as improved recuperation and fatigue the next day. It is concluded that the nature of activity per se may be less important than (1) whether the activity accords with individual preference and (2) the cumulative demands of daytime and evening activities.


Synaptic structure quantification in cultured neurons.
Behavioral problems (e.g., learning and memory) following developmental exposure to toxicants suggests that dysregulation of the process of synapse formation and function may occur. The ability to assess these changes is thus of value. This unit describes a method to investigate toxicant-induced changes to synaptic structure formation in primary hippocampal neurons using immunocytochemical labeling of the pre- and post-synaptic markers synaptophysin and PSD-95, confocal imaging, and three-dimensional object analysis. Protocols for the long-term culturing of primary hippocampal neurons and of primary cortical astrocytes, as well as their co-culture, are included. While the described methods focus on how astrocytes influence synapse formation and how toxicants may interfere in this process, modifications to the experimental plan can easily be implemented. This would allow for the investigation of the effects of toxicants after treating neurons alone, or both astrocytes and neurons in co-culture. With the common endpoint of synapse structure formation, differences between varying treatment paradigms can expand the understanding of the influence of particular toxicants on these diverse cell types and provide insight into potential mechanisms of effect and the contributions of each to synapse formation.


IL32 is progressively expressed in mycosis fungoides independent of helper T-cell 2 and helper T-cell 9 polarization.
Mycosis fungoides, the most common type of cutaneous T-cell lymphoma (CTCL), is characterized by a helper T-cell 2 (Th2) skewing with a mature CD4(+) memory T-cell phenotype. Using skin samples from patients with mycosis fungoides (n = 21), healthy volunteers (n = 17), and individuals with atopic dermatitis (n = 17) and psoriasis (n = 9), we found IL32 mRNA expression significantly higher in mycosis fungoides samples than in samples from benign inflammatory skin diseases, and its expression increases with disease progression. By IHC and immunofluorescence, we confirmed IL32 protein expression in many CD3(+)CD4(+) T cells and some epidermotropic T cells in mycosis fungoides lesions. MyLa cells (a mycosis fungoides cell line) express IL32, which, in turn, could promote cellular proliferation and viability in a dose-dependent fashion. IL32-treated MyLa and CTCL HH cells upregulated cell proliferation and survival genes. Of the major "polarizing" T-cell cytokines, only IFNγ mRNA increases with mycosis fungoides progression and positively correlates with IL32 mRNA expression. Th2 cytokines do not positively correlate with IL32 mRNA expression or mycosis fungoides progression. Furthermore, by flow cytometry, IL32 production by circulating activated T cells in healthy individuals was found in both IFNγ(+) and IFNγ(-) cells but not in IL4(+) or IL13(+) cells. In conclusion, we have identified IL32(+) cells as the likely tumor cells in mycosis fungoides, and demonstrated that IL32 mRNA expression increases with mycosis fungoides progression and is significantly higher than mRNA expression in other skin diseases, and that some IL32(+) T cells are independent from the defined Th subsets. Thus, IL32 may play a unique role in mycosis fungoides progression as an autocrine cytokine.


Enhancement of mitochondrial energy metabolism by melatonin promotes vascularized skeletal muscle regeneration in a volumetric muscle loss model.
Volumetric muscle loss (VML) is a condition that results in the extensive loss of 20 % or more of skeletal muscle due to trauma or tumor ablation, leading to severe functional impairment and permanent disability. The current surgical interventions have limited functional regeneration of skeletal muscle due to the compromised self-repair mechanism. Melatonin has been reported to protect skeletal muscle from exercise-induced oxidative damage and holds great potential to treat muscle diseases. In this study, we hypothesize that melatonin can enhance myoblast differentiation and promote effective recovery of skeletal muscle following VML. In vitro administration of melatonin resulted in a significant enhancement of myogenesis in C2C12 myoblast cells, as evidenced by the up-regulation of myogenic marker genes in a dose-dependent manner. Further experiments revealed that silent information of regulator type 3 (SIRT3) played a critical role in the melatonin-enhanced myoblast differentiation through enhancement of mitochondrial energy metabolism and activation of mitochondrial antioxidant enzymes such as superoxide dismutase 2 (SOD2). Silencing of Sirt3 completely abrogated the protective effect of melatonin on the mitochondrial function of myoblasts, evidenced by the increased reactive oxygen species, decreased adenosine triphosphate production, and down-regulated myoblast-specific marker gene expression. In order to attain a protracted and consistent release, liposome-encapsuled melatonin was integrated into gelatin methacryloyl hydrogel (GelMA-Lipo@MT). The implantation of GelMA-Lipo@MT into a tibialis anterior muscle defect in a VML model effectively stimulated the formation of myofibers and new blood vessels in situ, while concurrently inhibiting fibrotic collagen deposition. The findings of this study indicate that the incorporation of melatonin with GelMA hydrogel has facilitated the de novo vascularized skeletal muscle regeneration by augmenting mitochondrial energy metabolism. This represents a promising approach for the development of skeletal muscle tissue engineering, which could be utilized for the treatment of VML and other severe muscle injuries.


Homogeneous liquid-liquid extraction of neodymium(III) by choline hexafluoroacetylacetonate in the ionic liquid choline bis(trifluoromethylsulfonyl)imide.
The ionic liquid choline bis(trifluoromethylsulfonyl)imide, [Chol][Tf2N], was used for the extraction of neodymium(III), in combination with choline hexafluoroacetylacetonate, [Chol][hfac], as the extractant. The binary mixture of [Chol][Tf2N] and water shows temperature-dependent phase behavior, with an upper critical solution temperature of 72 °C. A novel extraction technique, homogeneous liquid-liquid extraction (HLLE), was applied to this solvent system. HLLE is based on the use of thermomorphic solvent mixtures and has the advantage of forming a homogeneous phase during mixing. Extraction is not kinetically hindered by an interface and the extraction equilibrium is reached faster than in the case of heterogeneous mixing in conventional solvent extraction. Several extraction parameters were studied for the extraction of neodymium(III) with [Chol][hfac]: temperature, pH, extractant concentration and loading of the ionic liquid phase. A speciation study was performed to determine the stoichiometry of the extracted neodymium(III) complex and a plausible extraction mechanism is proposed. Neodymium is extracted as a tetrakis hexafluoroacetylacetonate complex with one choline cation as counter ion. The crystal structure of the extracted complex showed the presence of a coordination bond between the choline counter ion and the neodymium(III) center, resulting in a coordination number of nine. The stripping of the loaded neodymium and the influence of acid and extractant concentrations on the phase behavior of the [Chol][Tf2N]-H2O system were investigated.


Variation among the Dmanisi hominins: Multiple taxa or one species?
There is continuing controversy over the number of taxa documented by the Dmanisi hominins. Variation may reflect age and sex differences within a single population. Alternatively, two (or more) distinct species may be present. Our null hypothesis states that just one population is represented at the site. We assess the likely sources of variation in endocranial capacity, craniofacial and mandibular morphology, and the expression of characters related to aging and sex dimorphism. We use the coefficient of variation and a modified version of Levene's test for equal variances to compare trait variation at Dmanisi with that in fossil hominins and modern Homo sapiens from Africa. Skull 5 presents a low, massive vault, and a muzzle-like lower face. Other individuals have larger brains and more globular vaults. Despite such variation, the five crania share numerous features. All of the mandibles possess marginal tubercles, mandibular tori, and a distinctive patterning of mental foramina. Relative variation at Dmanisi is comparable to that in selected reference groups. Further growth anticipated in Skull 3, age-related remodeling affecting the D2600 mandible, pathology, and sex dimorphism can account for much of the interindividual variation observed. The preponderance of evidence supports our null hypothesis. Sources of the variation within ancient Homo assemblages remain poorly understood. Skull 5 is a very robust male, with a brain smaller than that of both a juvenile (Skull 3) and a probable female (Skull 2). Skull 1 has the largest brain, but cranial superstructures do not clearly mark this individual as male or female. It is likely that the Dmanisi hominins represent a single paleospecies of Homo displaying a pattern of sex dimorphism not seen in living hominids.


Markers Associated with COVID-19 Susceptibility, Resistance, and Severity.
In December 2019, the latest member of the coronavirus family, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan, China, leading to the outbreak of an unusual viral pneumonia known as coronavirus disease 2019 (COVID-19). COVID-19 was then declared as a pandemic in March 2020 by the World Health Organization (WHO). The initial mortality rate of COVID-19 declared by WHO was 2%; however, this rate has increased to 3.4% as of 3 March 2020. People of all ages can be infected with SARS-CoV-2, but those aged 60 or above and those with underlying medical conditions are more prone to develop severe symptoms that may lead to death. Patients with severe infection usually experience a hyper pro-inflammatory immune reaction (i.e., cytokine storm) causing acute respiratory distress syndrome (ARDS), which has been shown to be the leading cause of death in COVID-19 patients. However, the factors associated with COVID-19 susceptibility, resistance and severity remain poorly understood. In this review, we thoroughly explore the correlation between various host, viral and environmental markers, and SARS-CoV-2 in terms of susceptibility and severity.


Subclinical cardiac stiffness is associated with arterial stiffness in healthy young nulligravid women: Potential links to preeclampsia.
Preeclampsia is an independent risk factor for subsequent cardiovascular disease and diastolic dysfunction and has been linked to arterial stiffness. We hypothesized that arterial stiffness would be associated with echocardiographic markers of diastolic dysfunction in healthy nulligravid women. 31 healthy nulligravid women underwent assessment of peripheral arterial stiffness via aorto-femoral pulse wave velocity, popliteal distensibility and β stiffness measures as well as hemodynamic response to volume challenge. 22 underwent cardiac assessment via conventional and stress echocardiography with a focus on diastolic function utilizing tissue/pulse wave Doppler imaging and 3D speckle tracking. Bivariate associations between variables were evaluated using correlation coefficients (Pearson r) and Student's t-tests. No participants had echocardiographic values meeting criteria for overt diastolic dysfunction. Baseline global circumferential strain was significantly correlated with distensibility and β stiffness (n = 18, r = -0.61, p = 0.007, n = 18, r = 0.56, p = 0.01). Peak deceleration time was correlated with βstiffness (n = 9; r = 0.80, p = 0.01). Pulse wave velocity was not significantly correlated with cardiac measures (p > 0.05). Family history of a first or second degree relative with myocardial infarction or hypertension was associated with decreased popliteal artery distensibility (p = 0.02 and p = 0.03, respectively). In healthy nulligravid women there is evidence that markers of decreased left ventricular relaxation are associated with increased peripheral vascular stiffness as is a family history of myocardial infarction or hypertension. These findings raise the possibility that the diastolic dysfunction and arterial stiffness observed in the setting of preeclampsia are driven by underlying properties present prior to pregnancy and contribute to lifetime cardiovascular risk.


Neuropsychological performance in persons with chronic fatigue syndrome: results from a population-based study.
To examine the neuropsychological function characterized in subjects with chronic fatigue syndrome (CFS) at the same time controlling for relevant confounding factors. CFS is associated with symptoms of neuropsychological dysfunction. Objective measures of neuropsychological performance have yielded inconsistent results possibly due to sample selection bias, diagnostic heterogeneity, comorbid psychiatric disorders, and medication usage. CFS subjects (n = 58) and well controls (n = 104) from a population-based sample were evaluated, using standardized symptom severity criteria. Subjects who had major psychiatric disorders or took medications known to influence cognition were excluded. Neuropsychological function was measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Compared with controls, CFS subjects exhibited significant decreases in motor speed as measured in the simple and five-choice movement segments of the CANTAB reaction time task. CFS subjects also exhibited alterations in working memory as manifested by a less efficient search strategy on the spatial working memory task, fewer % correct responses on the spatial recognition task, and prolonged latency to a correct response on the pattern recognition task. A significantly higher percentage of CFS subjects versus controls exhibited evidence of neuropsychological impairment (defined by performance 1 standard deviation below the CANTAB normative mean) in tasks of motor speed and spatial working memory. Impairment in CFS subjects versus control subjects ranged from 20% versus 4.8% in five-choice movement time (p = .002) to 27.8% versus 10.6% in search strategy on the spatial working memory task (p = .006). These results confirm and quantify alterations in motor speed and working memory in CFS subjects independent of comorbid psychiatric disease and medication usage.


Paraoxonase-1 (PON-1) genotype and activity and in vivo oxidized plasma low-density lipoprotein in Type II diabetes.
The HDL (high-density lipoprotein)-associated enzyme PON (paraoxonase)-1 protects LDL (low-density lipoprotein) from oxidative modification in vitro, although it is unknown if this anti-atherogenic action occurs in vivo. In a cross-sectional study of 58 Type II diabetic subjects and 50 controls, we examined the fasting plasma LDL basal conjugated diene concentration [a direct measurement of circulating oxLDL (oxidatively modified LDL)], lipoprotein particle size by NMR spectroscopy, PON-1 polymorphisms (coding region polymorphisms Q192R and L55M, and gene promoter polymorphisms -108C/T and -162G/A), PON activity (with paraoxon or phenyl acetate as the substrates) and dietary antioxidant intake. Plasma oxLDL concentrations were higher in Type II diabetic patients (males, P = 0.048; females, P = 0.009) and unrelated to NMR lipoprotein size, PON-1 polymorphisms or PON activity (with paraoxon as the substrate) in any group. In men with Type II diabetes, however, there was a direct relationship between oxLDL concentrations and PON activity (with phenyl acetate as the substrate; r = 0.611, P = 0.0001) and an atherogenic NMR lipid profile in those who were PON-1 55LL homozygotes. Circulating oxLDL concentrations in vivo were unrelated to PON-1 genotypes or activity, except in male Type II diabetics where there was a direct association between PON activity (with phenyl acetate as the substrate) and oxLDL levels. These in vivo data contrast with in vitro data, and may be due to confounding by dietary fat intake. Male Type II diabetic subjects with PON-1 55LL homozygosity have an atherogenic NMR lipid profile independent of LDL oxidation. These data do not support an in vivo action of PON on LDL oxidation.


Variability and diversity of nasopharyngeal microbiota in children: a metagenomic analysis.
The nasopharynx is the ecological niche for many commensal bacteria and for potential respiratory or invasive pathogens like Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. Disturbance of a balanced nasopharyngeal (NP) microbiome might be involved in the onset of symptomatic infections with these pathogens, which occurs primarily in fall and winter. It is unknown whether seasonal infection patterns are associated with concomitant changes in NP microbiota. As young children are generally prone to respiratory and invasive infections, we characterized the NP microbiota of 96 healthy children by barcoded pyrosequencing of the V5-V6 hypervariable region of the 16S-rRNA gene, and compared microbiota composition between children sampled in winter/fall with children sampled in spring. The approximately 1,000,000 sequences generated represented 13 taxonomic phyla and approximately 250 species-level phyla types (OTUs). The 5 most predominant phyla were Proteobacteria (64%), Firmicutes (21%), Bacteroidetes (11%), Actinobacteria (3%) and Fusobacteria (1,4%) with Moraxella, Haemophilus, Streptococcus, Flavobacteria, Dolosigranulum, Corynebacterium and Neisseria as predominant genera. The inter-individual variability was that high that on OTU level a core microbiome could not be defined. Microbiota profiles varied strongly with season, with in fall/winter a predominance of Proteobacteria (relative abundance (% of all sequences): 75% versus 51% in spring) and Fusobacteria (absolute abundance (% of children): 14% versus 2% in spring), and in spring a predominance of Bacteroidetes (relative abundance: 19% versus 3% in fall/winter, absolute abundance: 91% versus 54% in fall/winter), and Firmicutes. The latter increase is mainly due to (Brevi)bacillus and Lactobacillus species (absolute abundance: 96% versus 10% in fall/winter) which are like Bacteroidetes species generally related to healthy ecosystems. The observed seasonal effects could not be attributed to recent antibiotics or viral co-infection.The NP microbiota of young children is highly diverse and appears different between seasons. These differences seem independent of antibiotic use or viral co-infection.


Laminin and optic nerve regeneration in the goldfish.
Previous work from our laboratory had shown that goldfish retinal fragments explanted onto a polylysine substratum 1 to 2 weeks following optic nerve crush exhibit a striking clockwise pattern of neuritic outgrowth. In the present study, however, when the basal lamina component laminin was used as a substratum, neurites grew out as uncurved spokes, were less fasciculated, and had an increased rate of elongation. When laminin was combined with polylysine in the substratum, the degree of fasciculation and rate of elongation were similar to those seen on laminin alone, whereas the tendency for clockwise outgrowth was even more pronounced than that observed with polylysine alone. These results suggest that regenerating neurites have an affinity for laminin. Using an antibody to murine Engelbreth-Holm-Swarm sarcoma laminin, which cross-reacted with basal lamina in goldfish tissue sections, we studied the histochemical distribution of laminin in the goldfish visual system. Immunoperoxidase staining for laminin showed a characteristic scalloped pattern of staining in cross-sections of optic nerve bundles. Following optic nerve crush, the reaction product became much more diffuse and intense, especially distal to the crush site. When the retinal ganglion cell bodies were eliminated by removing the eye, the degenerating optic nerve stump still showed the intensive staining. We interpret these results to indicate that optic nerve glia are responsible in large part for the formation of laminin. Taken together, these in vivo and in vitro findings suggest that laminin plays a role in nerve regeneration in the goldfish central nervous system.


Craniofacial growth and SITAR growth curve analysis.
SITAR (SuperImposition by Translation And Rotation) is a shape invariant growth curve model that effectively summarizes somatic growth in puberty. To apply the SITAR model to longitudinal mandibular growth data to clarify its suitability to facial growth analysis. 2D-cephalometric data on two mandibular measurements (AP: articulare-pogonion; CP: condylion-pogonion) were selected from the Denver Growth Study, consisting of longitudinal records (age range: 7.9-19.0 years) of females (sample size N: 21; number of radiographs n: 154) and males (N: 18; n: 137). The SITAR mixed effects model estimated, for each measurement and gender separately, a mean growth curve versus chronological age, along with mean age at peak velocity (APV) and peak velocity (PV), plus subject-specific random effects for PV and mean size. The models were also fitted versus Greulich-Pyle bone age. In males, mean APV occurred at 14.6 years (AP) and 14.4 years (CP), with mean PV 3.1 mm/year (AP) and 3.3 mm/year (CP). In females, APV occurred at 11.6 years (AP and CP), with mean PV 2.3 mm/year (AP) and 2.4 mm/year (CP). The models explained 95-96 per cent of the cross-sectional variance for males and 92-93 per cent for females. The random effects demonstrated standard deviations (SDs) in size of 5.6 mm for males and 3.9 mm for females, and SDs for PV between 0.3 and 0.5 mm/year. The bone age results were similar. The SITAR model is a useful tool to analyse epidemiological craniofacial growth based on cephalometric data and provides an array of information on pubertal mandibular growth and its variance in a concise manner.


Preschool performance of children with normal intelligence who were very low-birth-weight infants.
Children who were very low-birth-weight infants (less than 1,500 g), beneficiaries of modern neonatal intensive care, are now of school age. To evaluate their school performance 80 children born in 1976 who had very low-birth-weight (mean birth weight 1.2 kg, mean gestational age 30 weeks) were examined at age 5 years. Sixty-five children were neurologically intact and had normal IQ (greater than or equal to 85) on the Stanford-Binet; five children were neurologically abnormal and ten had IQ below 85. Of the 65 children with normal intelligence and no neurologic impairments, 46 were single births and enrolled in preschool. These 46 children were matched by race, sex, and family background with classmate control children who had been born at full term. Outcome measurements included the Slosson Intelligence Test, the Woodcock-Johnson Psycho-Educational Battery (including subscales of Picture Vocabulary, Spatial Relations, Memory for Sentences, Visual Auditory Learning, Quantitative Concepts, and Blending) and the Beery Developmental Test of Visual-Motor Integration. No significant differences in IQ were found between children who were very low-birth-weight infants and control children; however, children who were very low-birth-weight infants performed significantly less well on the Spatial Relations subtest of the Woodcock-Johnson and on the Visual-Motor Integration test. Similar results were found for nine sets of twins and their control children. Recognition of these perceptual and visual-motor problems may permit appropriate early remedial intervention and prevent the compounding of these difficulties.


Periodontal disease in chronic kidney disease and end-stage renal disease patients: a review.
Periodontal disease is a chronic inflammatory disorder and being so it has been associated with accelerated atherosclerosis and malnutrition. Cardiovascular diseases are the leading cause of mortality in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients [National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases: Annual Data Report, 2010]. A recent scientific statement released by the American Heart Association [Lockhart et al.: Circulation 2012;125:2520-2544] claims that, even though evidence exists to believe that periodontal interventions result in a reduction in systemic inflammation and endothelial dysfunction, there is little evidence that those interventions prevent atherosclerotic vascular disease or modify the outcomes. In this review, we discuss the periodontal findings and their association with an increased prevalence of inflammatory markers and cardiovascular mortality in ESRD patients and CKD.


Diabetes Care in Nigeria.
Diabetes is a noncommunicable disease that has attained great significance in the sub-Saharan region, with Nigeria being the most affected. Many persons with the condition suffer a reduced life expectancy and quality of life. Diabetes places an extra burden on the individuals and families affected, especially for the majority of patients unable to access quality health care. To describe the elements of diabetes management in Nigeria, areas for improvement, and proposed strategies to optimize care. A systematic literature search was performed on diabetes in Nigeria. Local and nonindexed literature, PubMed, and Google Scholar were used to source information on the subject. Diabetes-related morbidity and mortality continue to increase due to population expansion, urban migration, declining physical activity, and dietary factors. The organization of diabetes care is poorly coordinated, especially at the primary and secondary tiers of the public health care system, with consequent poor outcomes. Thus life expectancy (just about 50 years), which is low in the region, is further reduced by the double jeopardy of communicable (eg, tuberculosis, HIV/AIDS, and malaria) and noncommunicable diseases, such as diabetes and its closely related comorbidity, hypertension. The way forward is to improve maternal and child care, promote screening of at-risk populations, and develop strategies for primary prevention and early intervention to optimize glycemic control. Greater commitment to health care by the government and nongovernmental organizations and greater awareness by Nigerians should facilitate the desired improvements in disease prevention and glycemic control in those who are already affected.


Large-Voltage Tuning of Dzyaloshinskii-Moriya Interactions: A Route toward Dynamic Control of Skyrmion Chirality.
Electric control of magnetism is a prerequisite for efficient and low-power spintronic devices. More specifically, in heavy metal-ferromagnet-insulator heterostructures, voltage gating has been shown to locally and dynamically tune magnetic properties such as interface anisotropy and saturation magnetization. However, its effect on interfacial Dzyaloshinskii-Moriya Interaction (DMI), which is crucial for the stability of magnetic skyrmions, has been challenging to achieve and has not been reported yet for ultrathin films. Here, we demonstrate a 130% variation of DMI with electric field in Ta/FeCoB/TaO x trilayer through Brillouin Light Spectroscopy (BLS). Using polar magneto-optical Kerr-effect microscopy, we further show a monotonic variation of DMI and skyrmionic bubble size with electric field with an unprecedented efficiency. We anticipate through our observations that a sign reversal of DMI with an electric field is possible, leading to a chirality switch. This dynamic manipulation of DMI establishes an additional degree of control to engineer programmable skyrmion-based memory or logic devices.


Suppressed translation and ULK1 degradation as potential mechanisms of autophagy limitation under prolonged starvation.
Macroautophagy/autophagy is a well-organized process of intracellular degradation, which is rapidly activated under starvation conditions. Recent data demonstrate a transcriptional upregulation of several autophagy genes as a mechanism that controls autophagy in response to starvation. Here we report that despite the significant upregulation of mRNA of the essential autophagy initiation gene ULK1, its protein level is rapidly reduced under starvation. Although both autophagic and proteasomal systems contribute to the degradation of ULK1, under prolonged nitrogen deprivation, its level was still reduced in ATG7 knockout cells, and only initially stabilized in cells treated with the lysosomal or proteasomal inhibitors. We demonstrate that under starvation, protein translation is rapidly diminished and, similar to treatments with the proteosynthesis inhibitors cycloheximide or anisomycin, is associated with a significant reduction of ULK1. Furthermore, it was found that inhibition of the mitochondrial respiratory complexes or the mitochondrial ATP synthase function that could also take place in the absence of substrates, promote upregulation of ULK1 mRNA and protein expression in an AMPK-dependent manner in U1810 lung cancer cells growing in complete culture medium. These inhibitors could also drastically increase the ULK1 protein in U1810 cells with knockout of ATG13, where the ULK1 expression is significantly diminished. However, such upregulation of ULK1 protein is negligible under starvation conditions, further signifying the contribution of translation and suggesting that transcriptional upregulation of ULK1 protein will be diminished under such conditions. Thus, we propose a model where inhibition of protein translation, together with the degradation systems, limit autophagy during starvation.


Citrullination of central nervous system proteins during the development of experimental autoimmune encephalomyelitis.
Immunization of mammals with central nervous system (CNS)-derived proteins or peptides induces experimental autoimmune encephalomyelitis (EAE), a disease resembling the human autoimmune disease multiple sclerosis (MS). Both diseases are accompanied by destruction of a part of the of the myelin sheaths, which surround neurites in the CNS. Previous studies in MS have described alterations in the citrullination of myelin basic protein, one of the main protein constituents of the myelin sheath. Here, we show that, also during the development of EAE in mice, hypercitrullination occurs in the areas of the spinal cord that show the highest degree of inflammation and that myelin basic protein and glial fibrillary acidic protein are among the hypercitrullinated proteins. We conclude that hypercitrullination of myelin proteins in the CNS is a common phenomenon in demyelinating disease. Hypercitrullination may cause conformational changes in proteins, so the affected proteins may be involved in the pathogenesis of CNS autoimmune disease by acting as autoreactive T-cell epitopes. This is the first report in which hypercitrullination of CNS proteins in EAE is described and in which proteins other than myelin basic protein are reported to be citrullinated during autoimmune-mediated CNS inflammation.


Nurse Managers' Experiences With Electronic Health Records in Quality Monitoring.
Little is known about how hospital-based nurse managers use electronic health records (EHR) to monitor nurse-sensitive quality measures, or about how they learn to do so. This article describes the role of nurse managers in quality monitoring, their experience in using the EHR to monitor nurse-sensitive quality measures, and their related training. A convenience sample of nurse managers and directors (n = 28) was recruited to participate in semistructured interviews. The resulting data were analyzed, using content analysis. This study revealed 3 components of the nurse manager's quality-monitoring role: monitoring documentation, monitoring practice, and performing investigations. Facilitators for accessing EHR information included ease of navigation, timeliness and accessibility of reports, and usefulness of EHR tools. Participants described a range of formal and informal approaches to learning how to access information for quality monitoring in general and for the EHR specifically. The findings provide direction for further exploration of the EHR structures and processes needed to support nurse managers' information needs and quality-monitoring training.


Two-dimensional type-II Dirac fermions in layered oxides.
Relativistic massless Dirac fermions can be probed with high-energy physics experiments, but appear also as low-energy quasi-particle excitations in electronic band structures. In condensed matter systems, their massless nature can be protected by crystal symmetries. Classification of such symmetry-protected relativistic band degeneracies has been fruitful, although many of the predicted quasi-particles still await their experimental discovery. Here we reveal, using angle-resolved photoemission spectroscopy, the existence of two-dimensional type-II Dirac fermions in the high-temperature superconductor La1.77Sr0.23CuO4. The Dirac point, constituting the crossing of [Formula: see text] and [Formula: see text] bands, is found approximately one electronvolt below the Fermi level (EF) and is protected by mirror symmetry. If spin-orbit coupling is considered, the Dirac point degeneracy is lifted and the bands acquire a topologically non-trivial character. In certain nickelate systems, band structure calculations suggest that the same type-II Dirac fermions can be realised near EF.


Prospective evaluation of low-dose ketoconazole plus hydrocortisone in docetaxel pre-treated castration-resistant prostate cancer patients.
Ketoconazole is a well-known CYP17-targeted systemic treatment for castration-resistant prostate cancer (CRPC). However, most of the published data has been in the pre-chemotherapy setting; its efficacy in the post-chemotherapy setting has not been as widely described. Chemotherapy-naïve patients treated with attenuated doses of ketoconazole (200-300 mg three times daily) had PSA response rate (>50% decline) of 21-62%. We hypothesized that low-dose ketoconazole would likewise possess efficacy and tolerability in the CRPC post-chemotherapy state. Men with CRPC and performance status 0-3, adequate organ function and who had received prior docetaxel were treated with low-dose ketoconazole (200 mg orally three times daily) and hydrocortisone (20 mg PO qAM and 10 mg PO qPM) until disease progression. Primary endpoint was PSA response rate (>50% reduction from baseline) where a rate of 25% was to be considered promising for further study (versus a null rate of <5%); 25 patients were required. Secondary endpoints included PSA response >30% from baseline, progression-free survival (PFS), duration of stable disease and evaluation of adverse events (AEs). Thirty patients were accrued with median age of 72 years (range 55-86) and median pre-treatment PSA of 73 ng ml(-1) (range 7-11,420). Twenty-nine patients were evaluable for response and toxicity. PSA response (>50% reduction) was seen in 48% of patients; PSA response (>30% reduction) was seen in 59%. Median PFS was 138 days; median duration of stable disease was 123 days. Twelve patients experienced grade 3 or 4 AEs. Of the 17 grade 3 AEs, only 3 were attributed to treatment. None of the two grade 4 AEs were considered related to treatment. In docetaxel pre-treated CRPC patients, low-dose ketoconazole and hydrocortisone is a well-tolerated, relatively inexpensive and clinically active treatment option. PSA response to low-dose ketoconazole appears historically comparable to that of abiraterone in this patient context. A prospective, randomized study of available post-chemotherapy options is warranted to assess comparative efficacy.


Measurement of digitalis-like compound in plasma: application in studies of essential hypertension.
A digitalis-like compound was detected in human plasma by tritiated ouabain competition binding to the sodium pump. The study comprised analyses of plasma extracts from 17 normal controls, 17 normotensive subjects with one or both parents hypertensive, and 16 patients with untreated essential hypertension. In two thirds of the untreated hypertensive and several of the normotensive subjects with a family history of hypertension the potency of the digitalis-like compound, as measured by its interference with ouabain binding, was significantly greater than in the controls. In the untreated hypertensive patients the potency of the compound was significantly correlated with the urinary sodium output. Measurement of this salt-related, digitalis-like compound may be useful in clinical studies of hypertension.


Triple therapy at discharge from internal medicine wards in heart failure patients with reduced ejection fraction: results from an observational study.
Guidelines recommend triple therapy (TT) with ACE inhibitors or ARBs, beta-blockers and mineralcorticoid receptor antagonists in symptomatic heart failure patients with ejection fraction <35 % (HFrEF). Nevertheless, many patients remain untreated. This study was aimed to evaluate the use of TT in HFrEF patients discharged from internal medicine wards of Tuscany, Italy. We analyzed the database of a multicenter observational study which included 770 patients consecutively hospitalized for HF in 32out of 36 Internal Medicine Units of Tuscany, Italy. The value of ejection fraction was available in 490 of the 725 patients discharged alive. Of the 117 patients with HFrEF, only 46 (39.3%) were on TT at discharge while 71 (60.7%) were not. In the latter group we observed a significantly greater percentage of patients with cognitive deficit (25.3% vs 10.8%, p=0.05). In the same group there was a slightly greater percentage of patients with hypertension (61.9% vs 58.6%), diabetes (43.6% vs 36.9%), GFR<60 ml/min (74.6% vs 67.3%), anemia (52.1% vs 45.6%) and atrial fibrillation (40.8% vs 34.7%), but the differences were not statistically significant. These results indicate that TT is underutilized in internal medicine wards of Tuscany. Untreated patients had a greater rate of cognitive deficit and were probably sicker, more complex and fragile.


Contributors to beat-to-beat stroke volume variability during acute mental stress in healthy volunteers.
Acute mental stress elicits sympathetic activation, increasing heart rate and shortening the QT interval, but it is unknown whether this activation translates to stroke volume (SV) changes. Multivariate power spectral decomposition was used to assess the influence of heart rate and QT variabilities on SV variability at rest and during acute mental stress. Acute mental stress elicits mild but statistically significant increase in SV variability. Heart rate variability contributes almost one third of SV variability, while the contribution of QT variability is below 3%. In conclusion, although heart rate variability appears to contribute directly to increase in SV variability during acute mental stress, most of SV variability is attributed to sources independent of heart rate and QT variabilities.Clinical Relevance-Acute mental stress elicits small fluctuations in stroke volume in healthy volunteers. Its significance for clinical populations remains to be established.


Hypersensitivity reactions to HIV therapy.
Many drugs used for the treatment of HIV disease (including the associated opportunistic infections) can cause drug hypersensitivity reactions, which vary in severity, clinical manifestations and frequency. These reactions are not only seen with the older compounds, but also with the newer more recently introduced drugs. The pathogenesis is unclear in most cases, but there is increasing evidence to support that many of these are mediated through a combination of immunologic and genetic factors through the major histocompatibility complex (MHC). Genetic predisposition to the occurrence of these allergic reactions has been shown for some of the drugs, notably abacavir hypersensitivity which is strongly associated with the class I MHC allele, HLA-B*5701. Testing before the prescription of abacavir has been shown to be of clinical utility, has resulted in a change in the drug label, is now recommended in clinical guidelines and is practiced in most Western countries. For most other drugs, however, there are no good methods of prevention, and clinical monitoring with appropriate (usually supportive and symptomatic) treatment is required. There is a need to undertake further research in this area to increase our understanding of the mechanisms, which may lead to better preventive strategies through the development of predictive genetic biomarkers or through guiding the design of drugs less likely to cause these types of adverse drug reactions.


Integrated genome-wide DNA copy number and expression analysis identifies distinct mechanisms of primary chemoresistance in ovarian carcinomas.
A significant number of women with serous ovarian cancer are intrinsically refractory to platinum-based treatment. We analyzed somatic DNA copy number variation and gene expression data to identify key mechanisms associated with primary resistance in advanced-stage serous cancers. Genome-wide copy number variation was measured in 118 ovarian tumors using high-resolution oligonucleotide microarrays. A well-defined subset of 85 advanced-stage serous tumors was then used to relate copy number variation to primary resistance to treatment. The discovery-based approach was complemented by quantitative-PCR copy number analysis of 12 candidate genes as independent validation of previously reported associations with clinical outcome. Likely copy number variation targets and tumor molecular subtypes were further characterized by gene expression profiling. Amplification of 19q12, containing cyclin E (CCNE1), and 20q11.22-q13.12, mapping immediately adjacent to the steroid receptor coactivator NCOA3, was significantly associated with poor response to primary treatment. Other genes previously associated with copy number variation and clinical outcome in ovarian cancer were not associated with primary treatment resistance. Chemoresistant tumors with high CCNE1 copy number and protein expression were associated with increased cellular proliferation but so too was a subset of treatment-responsive patients, suggesting a cell-cycle independent role for CCNE1 in modulating chemoresponse. Patients with a poor clinical outcome without CCNE1 amplification overexpressed genes involved in extracellular matrix deposition. We have identified two distinct mechanisms of primary treatment failure in serous ovarian cancer, involving CCNE1 amplification and enhanced extracellular matrix deposition. CCNE1 copy number is validated as a dominant marker of patient outcome in ovarian cancer.


Nanometric morphological variation of zinc oxide crystals using organic molecules with carboxy and sulfonic groups.
The morphological variation of wurtzite-type zinc oxide (ZnO) grown on a substrate in basic aqueous solutions was investigated using a wide variety of organic molecules with carboxy and sulfonic groups. The effect of the organic molecules on the nanometric morphology was classified into several categories. Hexagonal plates exhibiting the (001) planes were obtained by a planarizing effect with the addition of citric, tartaric, and maleic acids, although acetic, salicylic, fumaric, and succinic acids exhibited no effects on the morphology. The production of nanograins was observed by a miniaturizing effect with the addition of a polymeric molecule with carboxy groups and an anionic surfactant with a sulfonic group. Mosaic structures composed of granular crystals and bundles consisting of fibrils elongated in a direction toward the c-axis were produced by the addition of bulky dye molecules having benzene rings and carboxy or sulfonic groups. The influence of the organic molecules was related to the number of the functional groups and the stereochemical structure. The findings of this study suggest that the adsorbability of the organic molecules depending on the chemical structure to the specific crystal faces is essential for the variation of the nanometric morphology.


The generalist disciplines in American medicine one hundred years following the Flexner Report: a case study of unintended consequences and some proposals for post-Flexnerian reform.
Abraham Flexner's analysis of U.S. medical education at the turn of the 20th century transformed the processes of student selection and instruction, the roles and responsibilities of faculty members, and the provision of resources to support medical education. Flexner's report also led to the nearly universal adoption of the academic medical center as the focal point of medical school teaching, research, and clinical activities. In this article, the authors describe the effects of the dissemination of this model and how the subsequent introduction of public funding for research and patient care transformed academic health centers and altered the composition of the physician workforce, resulting in the proliferation of specialties. They also describe how these workforce changes, along with the evolution of health care financing during the late 20th century, have led to a system that affords the most scientifically advanced and potentially efficacious care in the world, yet so profoundly fails to ensure affordability and equitable access and quality, that the system is no longer sustainable. The authors propose that both health care system reform and medical education reform are needed now to restore economic viability and moral integrity, and that a key element of this process will be to rebalance the generalist and specialist composition of the physician workforce. They conclude by suggesting that post-Flexnerian reform of medical education should include broadening the scope of criteria used to select medical students and reshaping the curriculum to address the evolving needs of patient care during the 21st century.


The economic impact of Staphylococcus aureus infection in New York City hospitals.
We modeled estimates of the incidence, deaths, and direct medical costs of Staphylococcus aureus infections in hospitalized patients in the New York City metropolitan area in 1995 by using hospital discharge data collected by the New York State Department of Health and standard sources for the costs of health care. We also examined the relative impact of methicillin-resistant versus -sensitive strains of S. aureus and of community-acquired versus nosocomial infections. S. aureus-associated hospitalizations resulted in approximately twice the length of stay, deaths, and medical costs of typical hospitalizations; methicillin-resistant and -sensitive infections had similar direct medical costs, but resistant infections caused more deaths (21% versus 8%). Community-acquired and nosocomial infections had similar death rates, but community-acquired infections appeared to have increased direct medical costs per patient ($35,300 versus $28,800). The results of our study indicate that reducing the incidence of methicillin-resistant and -sensitive nosocomial infections would reduce the societal costs of S. aureus infection.


Development and Validation of the School Refusal Evaluation Scale for Adolescents.
School refusal (SR) is considered as a clinical form of emotionally based school absenteeism related to the experience of strong negative emotions when attending school. However, there are no psychometrically sound measures specifically designed to assess SR. The aim of the present research was to develop and validate a multidimensional self-report measure of SR: the SChool REfusal EvaluatioN Scale (SCREEN) for adolescents. Two studies were performed to develop this scale. Study 1 used content analysis on 42 semi-directed interviews to identify and organize the indicators of SR and to generate items. The item pool was then reviewed by experts to construct a pilot scale. Study 2 examined the psychometric properties of this pilot scale of the SCREEN in a community sample of 649 French adolescents (age: 10-16 years) and a clinical sample of 31 adolescents. The initial SCREEN structure was identified via exploratory factor analysis, and the resultant model was validated using confirmatory factor analysis. In its final version (an 18-item, four-factor measurement model), the SCREEN reliably measures four interrelated aspects of SR. Data suggest good reliability and validity of scores on this SR measure. Results of the receiver operating characteristic (ROC) curve analysis indicated good accuracy of the SCREEN (sensitivity = .94 and specificity = .88). The SCREEN offers a new and valid measure to assess SR in research and clinical settings.


Modelling of human leucyl aminopeptidases for in silico off target binding analysis of potential Plasmodium falciparum leucine aminopeptidase (PfA-M17) specific inhibitors.
Malaria is one of the most widespread infectious diseases in the world. Emergence of multi-drug resistant Plasmodium strains makes it crucial to identify new classes of compounds for anti-malarial therapy. Novel anti-malarial compounds from natural sources (Gomphostema niveum) as well as synthetic chemicals (5-aminolevulinic acid) have been reported in recent patents. Plasmodium falciparum leucyl aminopeptidase (PfA-M17) is a validated target for antimalarial drug development. However, known aminopeptidase inhibitors beset with the problem of non-specificity. Therefore, 3D structural models of PfA-M17 human homologs, Leucine aminopeptidase3 (hLAP3) and probable leucine aminopeptidase (hNPEPL1) were predicted for molecular docking based screening of potential inhibitors for their off target activity. Comparison of IC50 and docking scores of highly active hLAP3 inhibitors shows good correlation (r(2)≈ 0.8). Further, docking analysis with potential PfA-M17 inhibitor Compound-X (identified through virtual screening) shows much higher binding affinity towards PfA-M17 (docking score -11.44) than hLAP3 (docking score -4.26) and hNPEPL1 (docking score -5.08). This lead compound, Compound-X can act as a scaffold for further increasing PfA-M17 binding affinity and hLAP3 and hNPEPL1 3D structure models will be useful for screening of PfA-M17 specific inhibitors.


The Extended Starling principle needs clinical validation.
The Revised (or "Extended") Starling principle is based on highly controlled laboratory-based frog and rodent experiments and remains a hypothesis awaiting clinical validation. A key point is that the endothelial glycocalyx layer moves the oncotic gradient from being between the plasma and the interstitium to between the plasma and a virtually protein-free space between the glycocalyx and the endothelial cell membrane, which dramatically changes the prerequisites for fluid absorption from tissue to plasma. However, many experimental and clinical observations in humans agree poorly with the new microcirculatory proposals. The most troubling aspect of the explanation regarding the role of the glycocalyx in the Revised Starling principle is the effective reabsorption of fluid by skeletal muscle when the capillary filtration pressure is acutely reduced. Other issues include the plasma volume effects of hypertonic saline, iso-oncotic and hyper-oncotic albumin, fluid distribution during cardio-pulmonary bypass, and the virtually identical capillary leakage of plasma and albumin despite marked inflammation found in our fluid therapy studies. The Revised Starling principle deals mainly with steady-state conditions, but the circulatory system is highly dynamic. Second to second vasomotion is always operational and must be considered to understand what we observe in humans.


Effects of intrinsic strain on the structural stability and mechanical properties of phosphorene nanotubes.
Using molecular dynamics simulations, we explore the structural stability and mechanical integrity of phosphorene nanotubes (PNTs), where the intrinsic strain in the tubular PNT structure plays an important role. It is proposed that the atomic structure of larger-diameter armchair PNTs (armPNTs) can remain stable at a higher temperature, but the high intrinsic strain in the hoop direction renders zigzag PNTs less favorable. The mechanical properties of PNTs, including Young's modulus and fracture strength, are sensitive to the diameter, showing a size-dependence. A simple model is proposed to express Young's modulus as a function of the intrinsic axial strain, which in turn depends on the diameter of the PNTs. In addition, the compressive buckling of armPNTs is length-dependent, and instability modes transitioning from column buckling to shell buckling are observed as the ratio of the diameter/length increases.


Oscillatory EEG Signatures of Affective Processes during Interaction with Adaptive Computer Systems.
Affect monitoring is being discussed as a novel strategy to make adaptive systems more user-oriented. Basic knowledge about oscillatory processes and functional connectivity underlying affect during naturalistic human-computer interactions (HCI) is, however, scarce. This study assessed local oscillatory power entrainment and distributed functional connectivity in a close-to-naturalistic HCI-paradigm. Sixteen participants interacted with a simulated assistance system which deliberately evoked positive (supporting goal-achievement) and negative (impeding goal-achievement) affective reactions. Electroencephalography (EEG) was used to examine the reactivity of the cortical system during the interaction by studying both event-related (de-)synchronization (ERD/ERS) and event-related functional coupling of cortical networks towards system-initiated assistance. Significantly higher α-band and β-band ERD in centro-parietal and parieto-occipital regions and β-band ERD in bi-lateral fronto-central regions were observed during impeding system behavior. Supportive system behavior activated significantly higher γ-band ERS in bi-hemispheric parietal-occipital regions. This was accompanied by functional coupling of remote β-band and γ-band activity in the medial frontal, left fronto-central and parietal regions, respectively. Our findings identify oscillatory signatures of positive and negative affective processes as reactions to system-initiated assistance. The findings contribute to the development of EEG-based neuroadaptive assistance loops by suggesting a non-obtrusive method for monitoring affect in HCI.


Case Report: C-Reactive Protein Apheresis in a Patient With COVID-19 and Fulminant CRP Increase.
Plasma levels of C-reactive protein (CRP), induced by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) triggering COVID-19, can rise surprisingly high. The increase of the CRP concentration as well as a certain threshold concentration of CRP are indicative of clinical deterioration to artificial ventilation. In COVID-19, virus-induced lung injury and the subsequent massive onset of inflammation often drives pulmonary fibrosis. Fibrosis of the lung usually proceeds as sequela to a severe course of COVID-19 and its consequences only show months later. CRP-mediated complement- and macrophage activation is suspected to be the main driver of pulmonary fibrosis and subsequent organ failure in COVID-19. Recently, CRP apheresis was introduced to selectively remove CRP from human blood plasma. A 53-year-old, SARS-CoV-2 positive, male patient with the risk factor diabetes type 2 was referred with dyspnea, fever and fulminant increase of CRP. The patient's lungs already showed a pattern enhancement as an early sign of incipient pneumonia. The oxygen saturation of the blood was ≤ 89%. CRP apheresis using the selective CRP adsorber (PentraSorb® CRP) was started immediately. CRP apheresis was performed via peripheral venous access on 4 successive days. CRP concentrations before CRP apheresis ranged from 47 to 133 mg/l. The removal of CRP was very effective with up to 79% depletion within one apheresis session and 1.2 to 2.14 plasma volumes were processed in each session. No apheresis-associated side effects were observed. It was at no point necessary to transfer the patient to the Intensive Care Unit or to intubate him due to respiratory failure. 10 days after the first positive SARS-CoV-2 test, CRP levels stayed below 20 mg/l and the patient no longer exhibited fever. Fourteen days after the first positive SARS-CoV-2 test, the lungs showed no sign of pneumonia on X-ray. This is the first report on CRP apheresis in an early COVID-19 patient with fulminant CRP increase. Despite a poor prognosis due to his diabetes and biomarker profile, the patient was not ventilated, and the onset of pneumonia was reverted.


Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results.
A sequential approach including bortezomib induction, intermediate-dose melphalan, and autologous stem cell transplantation (ASCT), followed by lenalidomide consolidation-maintenance, has been evaluated. Efficacy and safety data have been analyzed on intention-to-treat and results updated. Newly diagnosed myeloma patients 65 to 75 years of age (n = 102) received 4 cycles of bortezomib-pegylated liposomal doxorubicin-dexamethasone, tandem melphalan (100 mg/m(2)) followed by ASCT (MEL100-ASCT), 4 cycles of lenalidomide-prednisone consolidation (LP), and lenalidomide maintenance (L) until disease progression. The complete response (CR) rate was 33% after MEL100-ASCT, 48% after LP and 53% after L maintenance. After a median follow-up of 66 months, median time-to-progression (TTP) was 55 months and median progression-free survival 48 months. Median overall survival (OS) was not reached, 5-year OS was 63%. In CR patients, median TTP was 70 months and 5-year OS was 83%. Median survival from relapse was 28 months. Death related to adverse events (AEs) occurred in 8/102 patients during induction or transplantation. Rate of death related to AEs was higher in patients ≥70 years compared with younger (5/26 vs 3/76, P = .024). Bortezomib-induction followed by ASCT and lenalidomide consolidation-maintenance is a valuable option for elderly myeloma patients, with the greatest benefit in those younger than 70 years of age.


Exploring determinants of surrogate decision-maker confidence: an example from the ICU.
This article is an exploratory data analysis of the determinants of confidence in a surrogate decision maker who has been asked to permit an intensive care unit (ICU) patient's participation in genetic research. We pursue the difference between surrogates' and patients' confidence that the surrogate can accurately represent the patient's wishes. The article also explores whether greater confidence leads to greater agreement between patients and surrogates. Our data come from a survey conducted in three hospital ICUs. We interviewed 445 surrogates and 214 patients. The only thing that influences patients' confidence in their surrogate's decision is whether they had prior discussions with him or her; however, there are more influences operating on the surrogate's self-confidence. More confident surrogates are more likely to match their patients' wishes. Patients are more likely to agree to research participation than their surrogates would allow. The surrogates whose response did not match as closely were less trusting of the hospital staff, were less likely to allow patient participation if there were no direct benefits to the patient, had given less thought about the way genetic research is conducted, and were much less likely to have a person in their life who they would trust to make decisions for them if they were incapacitated.


Evaluation of one-step luminescent cyanoacrylate fuming.
One-step luminescent cyanoacrylates have recently been introduced as an alternative to the conventional cyanoacrylate fuming methods. These new techniques do not require the application of a luminescent post-treatment in order to enhance cyanoacrylate-developed fingermarks. In this study, three one-step polymer cyanoacrylates: CN Yellow Crystals (Aneval Inc.), PolyCyano UV (Foster+Freeman Ltd.) and PECA Multiband (BVDA), and one monomer cyanoacrylate: Lumikit™ (Crime Scene Technology), were evaluated against a conventional two-step cyanoacrylate fuming method (Cyanobloom (Foster+Freeman Ltd.) with rhodamine 6G stain). The manufacturers' recommended conditions or conditions compatible with the MVC™ 1000/D (Foster+Freeman Ltd.) were assessed with fingermarks aged for up to 8 weeks on non-porous and semi-porous substrates. Under white light, Cyanobloom generally gave better development than the one-step treatments across the substrates. Similarly when viewed under the respective luminescent conditions, Cyanobloom with rhodamine 6G stain resulted in improved contrast against the one-step treatments except on polystyrene, where PolyCyano UV and PECA Multiband gave better visualisation. Rhodamine 6G post-treatment of one-step samples did not significantly enhance the contrast of any of the one-step treatments against Cyanobloom/rhodamine 6G-treated samples.


Evolution of intrinsic growth rate: metabolic costs drive trade-offs between growth and swimming performance in Menidia menidia.
There is strong evidence that genetic capacity for growth evolves toward an optimum rather than an absolute maximum. This implies that fast growth has a cost and that trade-offs occur between growth and other life-history traits, but the fundamental mechanisms are poorly understood. Previous work on the Atlantic silverside fish Menidia menidia has demonstrated a trade-off between growth and swimming performance. We hypothesize that the trade-off derives from the competing metabolic demands associated with growth and swimming activity. We tested this by measuring standard metabolic rate (M(STD)), maximum sustainable metabolic rate (M(ACT)) and metabolic scope of laboratory-reared silversides originating from two geographically distinct populations with well-documented differences in genetic capacity for growth. The fast-growth genotype had a significantly greater M(STD) than the slow-growth genotype, but a similar MACT when swum to near exhaustion. The scope for activity of the fast-growth genotype was lower than that of the slow-growth genotype. Furthermore, the fast-growth genotype eats larger meals, thereby incurring a greater postprandial oxygen demand. We conclude that a metabolic trade-off occurs between growth and other metabolic demands and that this trade-off provides a general mechanism underlying the evolution of growth rate.


[A model of a long functioning drainage catheter].
The model of a long functioning tube was used in 98 patients with abscesses, phlegmons, suppurating hematomas and diffuse purulent peritonitis. The tube had a purifying device in its lumen as a small bead used for permanent destruction of the fibrin clot in the tube lumen in the postoperative period. It allowed maintenance of its patency for the limitless duration. The tube in the purulent cavity had the through direction, i.e. its both ends were brought onto the skin surface. The duration of treatment of patients with purulent diffuse peritonitis was from 18 to 23 days, with the suppurating process of soft tissues--from 12 to 18 days. There were no complications associated with using the model of the tube.


Advances and challenges in neuroimaging studies on the effects of serotonergic hallucinogens: Contributions of the resting brain.
The effects of hallucinogenic drugs on the human brain have been studied since the earliest days of neuroimaging in the 1990s. However, approaches are often hard to compare and results are heterogeneous. In this chapter, we summarize studies investigating the effects of hallucinogens on the resting brain, with a special emphasis on replicability and limitations. In previous studies, similarities were observed between psilocybin, LSD, and ayahuasca, with respect to decreases in cerebral blood flow and increases in global functional connectivity in the precuneus and thalamus. Additionally, LSD consistently decreased functional connectivity within distinct resting state networks. Little convergence was observed for connectivity between networks and for blood flow in other brain regions. Although these studies are limited by small sample sizes and might be biased by unspecific drug effects on physiological parameters and the vascular system, current results indicate that neuroimaging could be a useful tool to elucidate the neuronal correlates of hallucinogenic effects.


No sustained increase in zooarchaeological evidence for carnivory after the appearance of Homo erectus.
The appearance of Homo erectus shortly after 2.0 Ma is widely considered a turning point in human dietary evolution, with increased consumption of animal tissues driving the evolution of larger brain and body size and a reorganization of the gut. An increase in the size and number of zooarchaeological assemblages after the appearance of H. erectus is often offered as a central piece of archaeological evidence for increased carnivory in this species, but this characterization has yet to be subject to detailed scrutiny. Any widespread dietary shift leading to the acquisition of key traits in H. erectus should be persistent in the zooarchaeological record through time and can only be convincingly demonstrated by a broad-scale analysis that transcends individual sites or localities. Here, we present a quantitative synthesis of the zooarchaeological record of eastern Africa from 2.6 to 1.2 Ma. We show that several proxies for the prevalence of hominin carnivory are all strongly related to how well the fossil record has been sampled, which constrains the zooarchaeological visibility of hominin carnivory. When correcting for sampling effort, there is no sustained increase in the amount of evidence for hominin carnivory between 2.6 and 1.2 Ma. Our observations undercut evolutionary narratives linking anatomical and behavioral traits to increased meat consumption in H. erectus, suggesting that other factors are likely responsible for the appearance of its human-like traits.


Transient polarized radiative transfer in cloud layers: numerical simulation of imaging lidar returns.
In this paper, we investigate the time-dependent backscattering halo of a pulsed light beam in a layer of scattering medium. We start from numerical simulations of polarized radiative transfer in the layer, which immediately reveals the effect under investigation. Then we analyze time-dependent structure of the light field using the simulation results. From the radiation field, we extract two principal components, immediately forming the halo structure. For each diffuse and ballistic component, we use the proper theoretical model, yielding a convenient analytic description of the time-dependent behavior of the radiation field. From the theory developed by us, we derive a simple numerical criterion of visibility of the halo. Finally, we validate our theory against Monte Carlo radiative transfer simulations. Thus, we propose a quantitative explanation of the studied effect.


Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition that primarily affects the motor system and shares many features with frontotemporal dementia (FTD). Evidence suggests that ALS is a 'dying-back' disease, with peripheral denervation and axonal degeneration occurring before loss of motor neuron cell bodies. Distal to a nerve injury, a similar pattern of axonal degeneration can be seen, which is mediated by an active axon destruction mechanism called Wallerian degeneration. Sterile alpha and TIR motif-containing 1 (Sarm1) is a key gene in the Wallerian pathway and its deletion provides long-term protection against both Wallerian degeneration and Wallerian-like, non-injury induced axonopathy, a retrograde degenerative process that occurs in many neurodegenerative diseases where axonal transport is impaired. Here, we explored whether Sarm1 signalling could be a therapeutic target for ALS by deleting Sarm1 from a mouse model of ALS-FTD, a TDP-43Q331K, YFP-H double transgenic mouse. Sarm1 deletion attenuated motor axon degeneration and neuromuscular junction denervation. Motor neuron cell bodies were also significantly protected. Deletion of Sarm1 also attenuated loss of layer V pyramidal neuronal dendritic spines in the primary motor cortex. Structural MRI identified the entorhinal cortex as the most significantly atrophic region, and histological studies confirmed a greater loss of neurons in the entorhinal cortex than in the motor cortex, suggesting a prominent FTD-like pattern of neurodegeneration in this transgenic mouse model. Despite the reduction in neuronal degeneration, Sarm1 deletion did not attenuate age-related behavioural deficits caused by TDP-43Q331K. However, Sarm1 deletion was associated with a significant increase in the viability of male TDP-43Q331K mice, suggesting a detrimental role of Wallerian-like pathways in the earliest stages of TDP-43Q331K-mediated neurodegeneration. Collectively, these results indicate that anti-SARM1 strategies have therapeutic potential in ALS-FTD.


Thoracoscopy in perspective.
The indications for thoracoscopy are undiagnosed pleural disease effusions of tumors; when tissue specificity is important for future treatment and adequate tissue is needed for estrogen binding studies; undiagnosed pleuropulmonary disease; biopsy of pulmonary lesions undiagnosed by other means; mediastinal masses, particularly in children; hilar masses; preoperative screening preliminary to thoracotomy for resection in malignant disease, particularly those with effusions; in spontaneous pneumothorax, to define the abnormality and indicate the need for thoracotomy; for postresection space problems; trauma, and, of course, for intrapleural pneumonolysis.


Lifestyle Inequalities: Explaining Socioeconomic Differences in Preventive Practices of Clinically Overweight Women After Menopause.
Excess weight and menopause are two major factors increasing aging women's vulnerability to chronic diseases. However, social position and socioeconomic status have also been identified as major determinants influencing both health behaviors and the development of such diseases. This study focuses on the socioeconomic variations of behavioral risk factors of chronic diseases in aging women. By drawing on Bourdieu's sociocultural theory of practice, 40 semistructured interviews were conducted to investigate preventive health practices of clinically overweight, postmenopausal women from contrasting socioeconomic classes living in Canada. Findings emphasize class-based differences with respect to long-term health and preventive practices according to three major themes: priority to long-term time horizons, attention given to risk factors of diseases, and control over future health. Health care providers should strive to work in concert with all subgroups of women to better understand their values, worldviews, and needs to decrease health inequalities after menopause.


Detection of P300 waves in single trials by the wavelet transform (WT).
The P300 response is conventionally obtained by averaging the responses to the task-relevant (target) stimuli of the oddball paradigm. However, it is well known that cognitive ERP components show a high variability due to changes of cognitive state during an experimental session. With simple tasks such changes may not be demonstrable by the conventional method of averaging the sweeps chosen according to task-relevance. Therefore, the present work employed a response-based classification procedure to choose the trials containing the P300 component from the whole set of sweeps of an auditory oddball paradigm. For this purpose, the most significant response property reflecting the P300 wave was identified by using the wavelet transform (WT). The application of a 5 octave quadratic B-spline-WT on single sweeps yielded discrete coefficients in each octave with an appropriate time resolution for each frequency range. The main feature indicating a P300 response was the positivity of the 4th delta (0.5-4 Hz) coefficient (310-430 ms) after stimulus onset. The average of selected single sweeps from the whole set of data according to this criterion yielded more enhanced P300 waves compared with the average of the target responses, and the average of the remaining sweeps showed a significantly smaller positivity in the P300 latency range compared with the average of the non-target responses. The combination of sweeps classified according to the task-based and response-based criteria differed significantly. This suggests an influence of changes in cognitive state on the presence of the P300 wave which cannot be assessed by task performance alone.


In vivo detection of metabolic changes in a mouse model of scrapie using nuclear magnetic resonance spectroscopy.
In vivo proton nuclear magnetic resonance (NMR) spectroscopy studies of scrapie in a mouse model have shown the appearance of an abnormal peak in the brain early in the incubation period. This abnormal peak was detected weeks before the detection of a protease-resistant form of a membrane protein and vacuolar histopathology in vitro, and several months before clinical signs, and the signal increased in intensity as the disease progressed. In the chronic stage of the disease, a reduction in N-acetyl aspartate levels was observed using in vivo and in vitro proton NMR spectroscopy.


An analysis of action of intercostal muscles in human upper rib cage.
The actions of the intercostal and paraspinal muscles in stabilizing the human upper rib cage have been analyzed using a geometrically realistic mathematical model of the first six ribs, vertebrae, and associated musculature. The model suggests roles of the deep layers of erector spinae in stabilizing the vertebral column so that it can support the loads placed upon it by the ribs under physiological load. If we assume that the tension exerted by an intercostal muscle is proportional to its local thickness, the model predicts that the observed distribution of intercostal thickness is close to that which minimizes the stresses in ribs when the model is subjected to peak physiological load. The observed shape of the ribs are optimal to withstand the calculated pattern of loading along their length. These calculations raise the hypothesis that the arrangement of intercostal musculature and rib geometry result in an optimally light rib cage, which is capable of withstanding the loads placed upon it. The analysis of the mechanics of the entire model indicates that the geometrical simplifications made in Hamberger's model are not valid when applied to the rib cage.


Comparison of arterial and capillary blood glucose with the use of the Accu-Chek III.
Glucose monitoring is a widely-used procedure in caring for critically ill patients. The determination of a blood glucose using arterial blood has not been approved with the use of glucose meters. After comparing the data from 75 subjects using the parameters established by the American Diabetes Association, arterial blood proved to be an accurate indicator of a subject's blood glucose level. The benefits enjoyed by both the patients and nursing staff establish a convincing reason to incorporate this procedure into current nursing practice. This article will describe the sample, method and results used to affect change in clinical practice.


Heat-related cardiovascular morbidity and mortality in Switzerland: a clinical perspective.
Previous studies found increased cardiovascular mortality during hot days, while emergency hospital admissions were decreasing. We explored potential underlying reasons by analysing clinically similar cardiovascular disease groups taking into account primary, underlying and immediate causes of death. We assessed associations of daytime maximum temperature in relation to cardiovascular deaths and emergency hospital admissions between 1998 and 2016 in Switzerland. We applied conditional quasi-Poisson models with non-linear distributed lag functions to estimate relative risks (RRs) of daily cardiovascular mortality and morbidity for temperature increases from the median (22°C) to the 98th percentile (32°C) of the warm season temperature distribution with 10 days of lag. Cardiovascular mortality (n = 163,856) increased for total cardiovascular disease (RR 1.13, 95% confidence interval [CI] 1.08-1.19) and the disease groups hypertension (1.18, 1.02-1.38), arrhythmia (1.29, 1.08-1.55), heart failure (1.22, 1.05-1.43) and stroke of unknown origin (1.20, 1.02-1.4). In contrast, emergency hospital admissions (n = 447,577) decreased for total cardiovascular disease (0.91, 0.88-0.94), hypertension (0.72, 0.64-0.81), heart failure (0.83, 0.76-0.9) and myocardial infarction (0.88, 0.82-0.95). Opposing heat effects were most pronounced for disease groups associated with diuretic and antihypertensive drug use, with the age group ≥75 years at highest risk. Volume depletion and vasodilation from heat stress plausibly explain the risk reduction of heat-related emergency hospital admissions for hypertension and heart failure. Since primary cause of death mostly refers to the underlying chronic disease, the seemingly paradoxical heat-related mortality increase can plausibly be explained by an exacerbation of heat effects by antihypertensive and diuretic drugs. Clinical guidelines should consider recommending strict therapy monitoring of such medication during heatwaves, particularly in the elderly.


Discordance in nuchal translucency measurements in monochorionic diamniotic twins as predictor of twin-to-twin transfusion syndrome.
Discordance in nuchal translucency measurements in monochorionic diamniotic twin pregnancies was assessed as predictor of Twin-to-Twin Transfusion Syndrome. A total of 61 monochorionic diamniotic twins were enrolled. Nuchal translucency (NT) and crown-rump-length (CRL) discordance was calculated as the percentage of delta NT and CRL (absolute difference NT/CRL fetus 1 and fetus 2) of the largest measurement, and correlated with subsequent development of Twin-to-Twin Transfusion Syndrome. Twin-to-Twin Transfusion Syndrome developed in 14/61 (23%) of cases. A NT discordance of 20% or more best predicted Twin-to-Twin Transfusion Syndrome development, with a sensitivity of 64% and a specificity of 78%. We found a positive predictive value of 50% and negative predicted value of 86% for Twin-to-Twin Transfusion Syndrome development if NT discordance was 20% or more. NT discordance of more than 20% in monochorionic diamniotic twins is associated with an increased risk for subsequent development of Twin-to-Twin Transfusion Syndrome, and with earlier presentation of symptoms.


[The communication of the diagnosis of schizophrenia. Focus group findings on psychiatrists' point of view].
Evidence from the literature show that patients affected by psychosis rarely are informed about their diagnosis and/or involved in the decision making process regarding the therapeutic program. The aim of the present study is to investigate psychiatrists' clinical experiences, beliefs and attitudes towards communicating the diagnosis to patients affected by psychosis. Three focus groups were conducted with 28 psychiatrists of different levels of expertise (10 senior psychiatrists and 18 psychiatrists in training), all working at the South-Verona Community-based Mental Health Service. The group discussions were audiotaped and transcribed. The authors derived different thematic categories which were used by two raters to classify all contributions of the psychiatrists. The main themes of interest which emerged were: experience with the communication of the diagnosis of psychosis and main communication strategies used; obstacles and personal difficulties in giving such information. In the psychiatric setting the disclosure of the diagnosis of psychosis implies different clinical and ethical issues and is felt as highly problematic. These findings suggest a need of psychiatrists to involve the psychotic patient in the information giving process in order to learn his/her informative needs which are the starting point for individually tailored information. The authors have no potential conflict of interest related to the subject of the paper.


A 1.9 A crystal structure of the HDV ribozyme precleavage suggests both Lewis acid and general acid mechanisms contribute to phosphodiester cleavage.
The hepatitis delta virus (HDV) ribozyme and HDV-like ribozymes are self-cleaving RNAs found throughout all kingdoms of life. These RNAs fold into a double-nested pseudoknot structure and cleave RNA, yielding 2',3'-cyclic phosphate and 5'-hydroxyl termini. The active site nucleotide C75 has a pK(a) shifted >2 pH units toward neutrality and has been implicated as a general acid/base in the cleavage reaction. An active site Mg(2+) ion that helps activate the 2'-hydroxyl for nucleophilic attack has been characterized biochemically; however, this ion has not been visualized in any previous structures. To create a snapshot of the ribozyme in a state poised for catalysis, we have crystallized and determined the structure of the HDV ribozyme bound to an inhibitor RNA containing a deoxynucleotide at the cleavage site. This structure includes the wild-type C75 nucleotide and Mg(2+) ions, both of which are required for maximal ribozyme activity. This structure suggests that the position of C75 does not change during the cleavage reaction. A partially hydrated Mg(2+) ion is also found within the active site where it interacts with a newly resolved G.U reverse wobble. Although the inhibitor exhibits crystallographic disorder, we modeled the ribozyme-substrate complex using the conformation of the inhibitor strand observed in the hammerhead ribozyme. This model suggests that the pro-R(P) oxygen of the scissile phosphate and the 2'-hydroxyl nucleophile are inner-sphere ligands to the active site Mg(2+) ion. Thus, the HDV ribozyme may use a combination of metal ion Lewis acid and nucleobase general acid strategies to effect RNA cleavage.


The PcACE1 transcription factor from Phanerochaete chrysosporium contains a Cys- and Ser-rich transactivation domain.
Transcription factor Ace1 from Saccharomyces cerevisiae regulates the expression of target genes when the copper concentration reaches 200 ìÌ levels. We are studying the ortholog of Ace1 from fungus Phanerochaete chrysosporium PcACE1, isolated by complementation in yeast. In this report we show the localization of the transactivation region of PcACE1. Different PcACE1 fragments were ligated in frame to the GAL4 DNA-binding domain by site-directed mutagenesis in a suitable yeast expression vector. Transformation of an appropriate Saccharomyces cerevisiae strain was used as host. This strain contains the fusion GAL1:lacZ in its genome under the control of promoter sequences recognized by GAL4. Finally, we measured â-galactosidase activity in each yeast clone. The activation of the reporter gene is proportional to the transactivation capacity of the transcription factor PcACE1. The results obtained indicate that PcACE1 transactivation domain is located in the carboxy terminal half and contains an array of cysteines in the form of Cys-X-Cys and Cys-X2-Cys and a 60% of Ser. Therefore, these results show that this type of Cys motif can function as transcription activating domain not only in transcription factors that respond to minimal copper concentrations but also in those that respond to high copper concentrations. This is the first transactivation domain reported in a basidiomycete fungus.


Role of Ryanodine Type 2 Receptors in Elementary Ca2+ Signaling in Arteries and Vascular Adaptive Responses.
Background Hypertension is the major risk factor for cardiovascular disease, the most common cause of death worldwide. Resistance arteries are capable of adapting their diameter independently in response to pressure and flow-associated shear stress. Ryanodine receptors (RyRs) are major Ca2+-release channels in the sarcoplasmic reticulum membrane of myocytes that contribute to the regulation of contractility. Vascular smooth muscle cells exhibit 3 different RyR isoforms (RyR1, RyR2, and RyR3), but the impact of individual RyR isoforms on adaptive vascular responses is largely unknown. Herein, we generated tamoxifen-inducible smooth muscle cell-specific RyR2-deficient mice and tested the hypothesis that vascular smooth muscle cell RyR2s play a specific role in elementary Ca2+ signaling and adaptive vascular responses to vascular pressure and/or flow. Methods and Results Targeted deletion of the Ryr2 gene resulted in a complete loss of sarcoplasmic reticulum-mediated Ca2+-release events and associated Ca2+-activated, large-conductance K+ channel currents in peripheral arteries, leading to increased myogenic tone and systemic blood pressure. In the absence of RyR2, the pulmonary artery pressure response to sustained hypoxia was enhanced, but flow-dependent effects, including blood flow recovery in ischemic hind limbs, were unaffected. Conclusions Our results establish that RyR2-mediated Ca2+-release events in VSCM s specifically regulate myogenic tone (systemic circulation) and arterial adaptation in response to changes in pressure (hypoxic lung model), but not flow. They further suggest that vascular smooth muscle cell-expressed RyR2 deserves scrutiny as a therapeutic target for the treatment of vascular responses in hypertension and chronic vascular diseases.


Suppressive and facilitatory spatial interactions in foveal vision: foveal crowding is simple contrast masking.
Spatial interactions are a critical and ubiquitous feature of spatial vision. These interactions may be inhibitory (reducing sensitivity as occurs in crowding) or facilitatory (enhancing sensitivity). In this work, we had four goals. 1. To test the hypothesis that foveal crowding depends on target size by measuring the extent of crowding for novel targets that were limited in their spatial frequency content. We used a large range of target sizes and spatial frequencies. 2. To assess whether the critical spatial frequency model (Hess, Dakin, & Kapoor, 2000) provides a general model for foveal crowding. To test this model, we measured crowding for a direction-identification task that did not require judging the orientation of the gap. 3. To test the hypothesis that foveal crowding is simply contrast masking by remote flanks we measured and compared crowding in a direction-identification experiment with masking by remote flanks in a detection experiment. In each of the experiments, our targets and flanks were composed of Gabor features, thus allowing us to control the feature contrast, spatial frequency, and orientation. 4. To assess the relationship between suppressive and facilitatory spatial interactions in foveal vision. Our results show that (1) foveal crowding is proportional to feature size over the more than 50-fold range of target sizes that we examined. Over this large range, foveal crowding is scale invariant. Our results also show it is the size of the envelope (SD) rather than the carrier (SF) that determines the extent of crowding in the fovea. 2. Crowding that occurs in the direction-identification task is quite similar to crowding where orientation information is available. Thus we conclude that the critical spatial frequency model does not provide a general explanation for foveal crowding. 3. Threshold elevation for crowding is similar to threshold elevation for masking as predicted by our test-pedestal model. Thus we conclude that foveal crowding is simple contrast masking. 4. Based on our comparison of threshold changes in crowding and masking, we conclude that in foveal vision, the suppressive spatial interactions due to nearby flanks are similar in the two tasks. However, the facilitatory interactions are quite different. In the crowding task, we find very little evidence for facilitation by flankers, whereas in the detection task, we find strong facilitation. We suggest that facilitation of detection by remote flanks may be, at least in part, a consequence of uncertainty reduction.


Twelve-month post-treatment parameters are superior in predicting hepatocellular carcinoma in patients with chronic hepatitis B.
There are currently several prediction models for hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) receiving oral antiviral therapy. However, most models are based on pre-treatment clinical parameters. The current study aimed to develop a novel and practical prediction model for HCC by using both pre- and post-treatment parameters in this population. We included two treatment-naïve CHB cohorts who were initiated on oral antiviral therapies: the derivation cohort (n = 1480, Korea prospective SAINT cohort) and the validation cohort (n = 426, the US retrospective Stanford Bay cohort). We employed logistic regression, decision tree, lasso regression, support vector machine and random forest algorithms to develop the HCC prediction model and selected the most optimal method. We evaluated both pre-treatment and the 12-month clinical parameters on-treatment and found the 12-month on-treatment values to have superior HCC prediction performance. The lasso logistic regression algorithm using the presence of cirrhosis at baseline and alpha-foetoprotein and platelet at 12 months showed the best performance (AUROC = 0.843 in the derivation cohort. The model performed well in the external validation cohort (AUROC = 0.844) and better than other existing prediction models including the APA, PAGE-B and GAG models (AUROC = 0.769 to 0.818). We provided a simple-to-use HCC prediction model based on presence of cirrhosis at baseline and two objective laboratory markers (AFP and platelets) measured 12 months after antiviral initiation. The model is highly accurate with excellent validation in an external cohort from a different country (AUROC 0.844) (Clinical trial number: KCT0003487).


Biomechanical and histological evaluation of the application of biodegradable poly-L-lactic cushion to the plate internal fixation for bone fracture healing.
Internal plate fixation of fracture can provide favorable mechanical environment for fracture fragments. However, osteoporosis under the plate is often found, and refracture may occur after the plate is removed. There are two different opinions about the bone loss beneath the plate: first is the stress shielding effect brought by the rigid fixation, and the second is the insufficient blood supply of the bone caused by the placement of the plate. In this paper, we tried to achieve a favorable condition for the fracture healing by inserting a kind of biodegradable cushion, through which the stress shielding effect and the interruption of the bone blood supply could be relieved at the same time. Animal models of internal fixation for tibia diaphyseal fracture with the placement of the poly-l-lactic (PLLA) cushion between the plate and the bone were established; a series of in vitro investigations and finite element (FE) analysis were performed to evaluate the effect of this new internal fixation system. During both the initial and 50% healing periods, the extent of stress shielding of the fracture zone decreased due to the use of the PLLA cushion. Especially for the 50% healing stage, the insertion of the PLLA cushion on alleviating the stress shielding of the bone tissue between the inner two screws directly under the plate is more apparent than that at the initial healing period. Meanwhile, radiological and histological coloration results demonstrated sooner callus growth and better trabecular rearrangement of the fracture zone in the PLLA group with the degradation of the PLLA cushion during the healing periods. This study showed that the use of the PLLA cushion at the initial period did not impair the stability of the whole system, which provides a favorable mechanical environment for the following fracture healing. On the other hand, its superiorities on alleviating stress shielding effect and interruption with the blood supply of the bone tissue beneath the plate contributed to the favorable fracture healing conditions in PLLA group with the degradation of the materials.


Biosimilars and the European experience: implications for the United States.
Biologics are medicines derived from a biological source. Their high prices and rapid uptake have raised hopes that with the gradual expiration of patents on the first generations of biologics, the advent of lower-cost follow-on products known as biosimilars will help "bend the cost curve." Although biosimilars have been available since 2006 within the European Union and are expected to save $15-$44 billion by 2020, the Food and Drug Administration (FDA) has yet to finalize the necessary regulatory processes for their approval in the United States. The European experience suggests, however, that once these are in place, the US biosimilar market may well emerge as bimodal: Initially, modestly discounted biosimilars deemed noninterchangeable with the original products will compete to become the initial treatment of choice in new patients. Subsequently, a second market may be anticipated for those products able to meet the FDA's higher standard for "interchangeability." In that market, discounts may be more dramatic.


Relations between cuticular hydrocarbon (HC) polymorphism, resistance against desiccation and breeding temperature; a model for HC evolution in D. melanogaster and D. simulans.
D. simulans and D. melanogaster present two types of polymorphism in their cuticular hydrocarbon (HC) composition. Especially both sexes of D. simulans, and D. melanogaster males display 7-tricosene (7T) as the major compound type [7T]s and [7T]m, or 7-pentacosene (7P) [7P]s and [7P]m. D. melanogaster females display 7,11-heptacosadiene (7,11HD) as the major compound: [7,11HD]m, or 5,9-heptacosadiene (5,9HD): [5,9HD]m. The [7P]s, [7P]m and [5,9HD]m are mainly present in central Africa. A significant correlation was found between latitude and the proportion of compounds with 23 and 25 carbon atoms, especially 7T and 7P in both sexes of D. melanogaster. [7P]m type of D. melanogaster, characterized with an excess of C25 compounds, presents a higher resistance against desiccation than [7T]m type, where C23 compounds are more abundant. These differences can be correlated with calculated HC fusion temperatures. Moreover, increasing the breeding temperature from 18 to 29 degrees C induces in D. melanogaster males an increase in 25C compounds and a decrease in 23C compounds, but the opposite effect in D. simulans. A mathematical model of biosynthesis, based on kinetics of elongation and decarboxylation enzymes, suggests that a simple variation of the efficiency of an elongation enzyme may account for the differences observed between the [7T]m and [7P]m types of D. melanogaster and [7T]s and [7P]s types D. simulans. Finally on the basis of the geographical distribution of the HC types of both Drosophila species, an evolutionary dispersal pathway is proposed and discussed in relation to the environment and reproductive behavior.