Epidemiology, Staging, and Management of Multiple Myeloma.
Multiple myeloma (MM) is a plasma cell disorder that is on the rise throughout the world, especially in the US, Australia, and Western Europe. In the US, MM accounts for almost 2% of cancer diagnoses and over 2% of cancer deaths (more than double the global proportion). Incidence has risen by 126% globally and over 40% in the US since 1990, while global mortality has risen by 94% and US mortality has fallen by 18%. The 5 year survival in the US has more than doubled over the past decades with the introduction of new targeted therapies and transplant techniques. Risk factors for MM include age (average age of diagnosis is 69), race (African Americans are over double as likely to be diagnosed), sex (men are at a 1.5× risk), and family history. Diagnosis includes serum or urine electrophoresis and free light-chain assay but requires bone marrow biopsy. It is distinguished from smoldering myeloma and monoclonal gammopathy of undetermined significance by a high (>3 g/dL) level of M-protein (monoclonal light chains) and the presence of CRAB (Hypercalcemia, Renal failure, Anemia, Bone pain) symptoms, which include hypercalcemia, renal failure, anemia, and bone pain, suggesting an end-organ damage. International staging system staging involves beta 2 microglobulin and albumin levels, while the revised system considers prognostic factors such as lactate dehydrogenase levels and chromosomal abnormalities. Front-line management includes induction regimen, maintenance therapy and hematopoietic cell transplantation for eligible patients and bisphosphonates or bone-stimulating agents for the prevention of skeletal events. Treatment for relapsed disease includes newly approved monoclonal antibodies like the CD38-targeting daratumumab, proteasome inhibitors, immunomodulating agents, and investigational therapies such as B cell maturation antigen Chimeric antigen receptor T cells.


Effect of addition of bevacizumab to chemoradiotherapy in newly diagnosed stage IVB cervical cancer: a single institution experience in Korea.
The aim of this study was to compare the clinical outcomes of chemoradiotherapy with or without bevacizumab in patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer. 41 patients with stage IVB cervical cancer who underwent chemoradiotherapy between August 2015 and December 2017 were retrospectively analyzed. This study included 11 patients who received bevacizumab before or after radiotherapy (group A) and 30 patients who received conventional chemoradiotherapy without bevacizumab (group B). We excluded the following patients: those with dual primary cancers; those whose pathologic diagnosis was neither squamous cell carcinoma nor adenocarcinoma; those who did not undergo radiotherapy; or those from whom follow-up data could not be collected. We analyzed the treatment responses, toxicities, progression-free survival, and overall survival rates. A total of 41 patients were included in the analysis. The median follow-up was 19 months (range 3-108). The response rates at 3 months after treatment were 90.9% in group A and 83.3% in group B (p=0.54). After completing all treatments, the complete response rates were 81.8% in group A and 47% in group B (p=0.04). Grade ≥3 gastrointestinal toxicities, including bleeding, fistula, perforation, and obstruction, were more frequent in group A (54.5%) than in group B (6.7%) (p=0.003). The 12 month progression-free survival and overall survival rates were similar in both arms (12 month progression-free survival: 45.5% vs 46.7%, respectively, p=0.22; 12 month overall survival: 81.8% vs 72.9%, respectively, p=0.57). Patients with node-only metastasis had better 12 month progression-free survival in group B than in group A (59.1% vs 42.9%, respectively, p=0.04). However, the responses to both treatments did not differ in patients with organ metastasis. Bevacizumab for stage IVB cervical cancer is associated with higher complete response rates. However, patients treated with bevacizumab experienced more bowel toxicities. Bevacizumab did not improve progression-free survival among patients with node-only metastasis.


Standards for plasma and serum proteomics in early cancer detection: a needs assessment report from the national institute of standards and technology--National Cancer Institute Standards, Methods, Assays, Reagents and Technologies Workshop, August 18-19, 2005.
NIST and the National Cancer Institute cosponsored a workshop on August 18-19, 2005, to examine needs for reference materials for early cancer detection. This meeting focused on standards, methods, assays, reagents, and technologies. Needs for plasma and serum proteomics, DNA methylation, and specimen reference collections were discussed, and recommendations from participants were solicited. This report summarizes the discussion and recommendations for proteomics reference materials.


The affinity of newly synthesized proteoglycan for hyaluronic acid can be enhanced by exposure to mild alkali.
The affinities for hyaluronic acid of newly synthesized proteoglycan from post-confluent rabbit chondrocyte cultures and purified bovine proteoglycan monomer were compared. In mixtures prepared at pH 6.8 the newly synthesized proteoglycan had the lower affinity; however, in mixtures incubated at pH 8.5 for 24 h before addition of hyaluronic acid, the newly synthesized proteoglycan exhibited a markedly higher affinity than the bovine monomer. The results suggest that proteoglycan secreted without associated link protein [Plaas, Sandy & Muir (1983) Biochem. J. 214, 855-864] has a low affinity for hyaluronate and that this may be increased during subsequent extracellular processing.


The importance of HT-ADME in drug discovery.
The inaugural meeting of the Boston Society High-Throughput Absorption, Distribution, Metabolism and Excretion (HT-ADME) Conference was held in Cambridge, MA (USA). The theme was 'The Importance of HT-ADME in Drug Discovery' and the organizers of the conference stressed the importance of incorporating audience participation and discussion in the field. The conference hosted 65 attendees and 16 presentations, which was a good size to achieve the goal of active participation while maintaining focus on HT-ADME. The speakers provided broad coverage of HT-ADME within the drug discovery arena, while remembering that the overall goal in drug discovery is identifying potential drug candidates to move forward into development.


[Role of Ca(2+)-activated potassium channels with high-conductivity in hypoxic preconditioning and posthypoxic hyperexcitability in CA1 hippocampal neurons in vitro].
The role of highly conductive Ca(2+)-activated potassium channels (BK(Ca)-channels) of rat hippocampal CA1 neurons in the processes induced by repeated episodes of brief hypoxia was investigated. A specific blocker of BK(Ca)-channels iberiotoxin (10-20 nM) tended to decrease the efficiency of hypoxia in depressing the amplitude of population spikes during hypoxic episode. Iberiotoxin significantly abolished both the preconditioning effect of hypoxic episodes and the posthypoxic hyperexcitability of pyramidal neurons. It is suggested that BK(Ca)-channels play an important role in the mechanisms of such forms of neuroplasticity as rapid hypoxic preconditioning and posthypoxic hyperexcitability in hippocampal CA1 neurons.


Characterization of amino acid profiles of culture media via pre-column 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate derivatization and ultra performance liquid chromatography.
The AccQ.Tag™ method, as a well-established protocol for amino acid analysis combining derivatization procedure, dedicated HPLC separation and fluorescence detection, was properly transferred and accordingly optimized for the application on ultra performance liquid chromatography (UPLC™) and UV detection. Capitalizing on sub-2 μm particles, this newly established UV-UPLC™ technique facilitated efficient chromatographic separation of 21 amino acid derivatives within 12 min. In addition, UPLC™ demonstrated significant improvements due to superior performance and reduced run times compared with the former 35 min of the original HPLC protocol. Using UV instead of fluorescence detection, amino acid quantification after pre-column derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) yielded appropriate sensitivities within the low pmol range with corresponding detection limits varying from 0.11 to 0.57 pmol per injection. Moreover, the UPLC™ method was applied to characterize changes in the free (FAA) as well as total amino acid (TAA) profiles specific to culture media at three distinctive stages of fermentation: fresh medium, fermentation broth after cell mass production prior to induction and after product expression at the end of fermentation. Amino acid profiles intrinsic to the fresh, sterilized medium indicated free, hence more bioavailable, amino acids at a FAA/TAA ratio of 40%, whereas ongoing fermentation implied a rather specific, successive decline in selective FAA concentrations. Thereby, the most distinctive variations in FAAs were highlighted by aspartic acid, serine and threonine, each exhibiting an almost complete uptake from the culture media (-96% to -99%), with remaining FAA/TAA ratios of 1%, 8%, and 1%, respectively. This indeed may indicate limitations and shortages within the nutrient broth. Thus, amino acid monitoring utilizing high-throughput chromatography, such as UPLC™, can be considered as a valuable tool to facilitate rapid adjustments of fermentation broths and to optimize culture media to specific requirements.


Asian Pacific Society of Cardiology Consensus Recommendations on Dyslipidaemia.
The prevalence of dyslipidaemia has been increasing in the Asia-Pacific region and this is attributed to dietary changes and decreasing physical activity. While there has been substantial progress in dyslipidaemia therapy, its management in the region is hindered by limitations in awareness, adherence and healthcare costs. The Asian Pacific Society of Cardiology (APSC) developed these consensus recommendations to address the need for a unified approach to managing dyslipidaemia. These recommendations are intended to guide general cardiologists and internists in the assessment and treatment of dyslipidaemia and are hoped to pave the way for improving screening, early diagnosis and treatment. The APSC expert panel reviewed and appraised the evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Consensus recommendations were developed, which were then put to an online vote. The resulting consensus recommendations tackle contemporary issues in the management of dyslipidaemia, familial hypercholesterolaemia and lipoprotein(a) in the Asia-Pacific region.


Synaptic and Nonsynaptic Localization of Benzodiazepine/GABAA Receptor/Cl- Channel Complex Using Monoclonal Antibodies in the Dorsal Lateral Geniculate Nucleus of the Cat.
The two monoclonal antibodies, bd-17 and bd-24, are specific for beta- and alpha-subunits of the GABAA/benzodiazepine receptor/chloride channel complex respectively. An abundance of both subunits has been revealed in the visual thalamus of the cat by light microscopic immunocytochemistry using these antibodies. The alpha-subunit specific antibody and electron microscopy were used to determine the subcellular distribution of immunoreactivity with respect to specific cell classes in the dorsal lateral geniculate nucleus. Immunoreactivity was always associated with membranes and the degree of immunoreactivity varied greatly between different types of cell as defined by: (i) immunoreactivity for GABA; (ii) soma area; (iii) presence or absence of cytoplasmic laminated bodies (CLB). GABA negative neurons with the smallest soma area showed the strongest immunoreactivity, mainly in the endoplasmic reticulum and also on the somatic plasma membrane. Cytoplasmic laminated bodies could be found in the majority of these neurons. Large GABA negative cells without CLBs were strongly immunoreactive on the plasma membrane of the soma and dendrites, but showed scant if any intracellular immunoreactivity. GABA-positive cells showed weak intracellular immunoreactivity but negligible if any immunoreactivity at the somatic and proximal dendritic plasma membrane. A similar reaction pattern was found in GABA negative cells which contained no CLBs and which constituted a medium sized cell population. It is suggested that the degree of intracellular receptor immunoreactivity is positively correlated with receptor turnover. The dendrites of projection cells, particularly outside the glomeruli, showed strong immunoreactivity on the plasma membrane. The synaptic junctions formed by many boutons (F terminals) establishing symmetrical synapses with dendrites of relay cells were immunopositive, but no immunoreactivity could be detected at the synapses established by the presynaptic dendrites of the local interneurons. Many axo-somatic F1 junctions were also immunoreactive. However, immunoreactivity for the receptor/channel complex was also widely distribution on nonsynaptic plasma membranes of somata and dendrites. Thus GABA may act at both synaptic and non-synaptic sites. Furthermore, the correlation of immunoreactivity for the GABAA receptor complex with previously published properties of physiologically identified cells suggests that the strongly immunoreactive, small, GABA negative cells with CLBs might correspond to the 'lagged' X-type cells, and the large GABA negative receptor outlined cells without CLBs might correspond to some of the Y-type neurons.


Sympathetic ganglionic blockade masks beneficial effect of isoflurane on histologic outcome from near-complete forebrain ischemia in the rat.
Isoflurane-anesthetized rats have better outcome from global cerebral ischemia than rats anesthetized with fentanyl and nitrous oxide. The authors wanted to determine whether circulating catecholamine concentrations depend on the anesthetic agent and whether sympathetic ganglionic blockade affects anesthetic-mediated differences in outcome from near-complete forebrain ischemia. For two different experiments, normothermic Sprague-Dawley rats that had fasted were assigned to one of four groups and subjected to 10 min of 30 mm Hg mean arterial pressure and bilateral carotid occlusion. Rats were anesthetized with 1.4% isoflurane or fentanyl (25 microg x kg(-1) x h(-1)) and 70% nitrous oxide, with or without preischemic trimethaphan (2.5 mg given intravenously). In experiment 1, arterial plasma catecholamine concentrations were measured before, at 2 and 8 min during, and after ischemia (n = 5-8). In experiment 2, animals (n = 15) underwent histologic analysis 5 days after ischemia. In experiment 1, intraischemic increases in plasma norepinephrine and epinephrine levels were 28 and 12 times greater in the fentanyl-nitrous oxide group than in the isoflurane group (P<0.01). Trimethaphan blocked all changes in plasma catecholamine concentrations (P<0.02). In experiment 2, isoflurane reduced the mean +/- SD percentage of dead hippocampal CA1 neurons compared with fentanyl-nitrous oxide (43+/-22% vs. 87+/-10%; P<0.001). Trimethaphan abolished the beneficial effects of isoflurane (91+/-6%; P<0.001). Similar observations were made in the cortex. Isoflurane attenuated the peripheral sympathetic response to ischemia and improved histologic outcome compared with fentanyl and nitrous oxide. This outcome benefit was reversed by sympathetic ganglionic blockade. The beneficial effects of isoflurane may result from a neuroprotective influence of an intermediate sympathetic response that is abolished by trimethaphan.


ODE, RDE and SDE models of cell cycle dynamics and clustering in yeast.
Biologists have long observed periodic-like oxygen consumption oscillations in yeast populations under certain conditions, and several unsatisfactory explanations for this phenomenon have been proposed. These 'autonomous oscillations' have often appeared with periods that are nearly integer divisors of the calculated doubling time of the culture. We hypothesize that these oscillations could be caused by a form of cell cycle synchronization that we call clustering. We develop some novel ordinary differential equation models of the cell cycle. For these models, and for random and stochastic perturbations, we give both rigorous proofs and simulations showing that both positive and negative growth rate feedback within the cell cycle are possible agents that can cause clustering of populations within the cell cycle. It occurs for a variety of models and for a broad selection of parameter values. These results suggest that the clustering phenomenon is robust and is likely to be observed in nature. Since there are necessarily an integer number of clusters, clustering would lead to periodic-like behaviour with periods that are nearly integer divisors of the period of the cell cycle. Related experiments have shown conclusively that cell cycle clustering occurs in some oscillating yeast cultures.


Incremental communication for multilayer neural networks: error analysis.
Artificial neural networks (ANNs) involve a large amount of internode communications. To reduce the communication cost as well as the time of learning process in ANNs, we earlier proposed (1995) an incremental internode communication method. In the incremental communication method, instead of communicating the full magnitude of the output value of a node, only the increment or decrement to its previous value is sent to a communication link. In this paper, the effects of the limited precision incremental communication method on the convergence behavior and performance of multilayer neural networks are investigated. The nonlinear aspects of representing the incremental values with reduced (limited) precision for the commonly used error backpropagation training algorithm are analyzed. It is shown that the nonlinear effect of small perturbations in the input(s)/output of a node does not cause instability. The analysis is supported by simulation studies of two problems. The simulation results demonstrate that the limited precision errors are bounded and do not seriously affect the convergence of multilayer neural networks.


The Plastic Age: River Pollution in China from Crop Production and Urbanization.
Many rivers are polluted with macro (>5 mm)- and microplastics (<5 mm). We assess plastic pollution in rivers from crop production and urbanization in 395 Chinese sub-basins. We develop and evaluate an integrated model (MARINA-Plastics model, China-1.0) that considers plastics in crop production (plastic films from mulching and greenhouses, diffuse sources), sewage systems (point sources), and mismanaged solid waste (diffuse source). Model results indicated that 716 kton of plastics entered Chinese rivers in 2015. Macroplastics in rivers account for 85% of the total amount of plastics (in mass). Around 71% of this total plastic is from about one-fifth of the basin area. These sub-basins are located in central and eastern China, and they are densely populated with intensive agricultural activities. Agricultural plastic films contribute 20% to plastics in Chinese rivers. Moreover, 65% of plastics are from mismanaged waste in urban and rural areas. Sewage is responsible for the majority of microplastics in rivers. Our study could support the design of plastic pollution control policies and thus contribute to green development in China and elsewhere.


Observation of atomic diffusion at twin-modified grain boundaries in copper.
Grain boundaries affect the migration of atoms and electrons in polycrystalline solids, thus influencing many of the mechanical and electrical properties. By introducing nanometer-scale twin defects into copper grains, we show that we can change the grain-boundary structure and atomic-diffusion behavior along the boundary. Using in situ ultrahigh-vacuum and high-resolution transmission electron microscopy, we observed electromigration-induced atomic diffusion in the twin-modified grain boundaries. The triple point where a twin boundary meets a grain boundary was found to slow down grain-boundary and surface electromigration by one order of magnitude. We propose that this occurs because of the incubation time of nucleation of a new step at the triple points. The long incubation time slows down the overall rate of atomic transport.


Extendability of proper holomorphic mappings and global analytic hypoellipticity of the partial differential-Neumann problem.
IN THIS COMMUNICATION, THE PROOF OF THE FOLLOWING THEOREM IS SKETCHED: If D(1) is a bounded domain in C(n) with real analytic boundary whose partial differential-Neumann problem is globally real analytic hypoelliptic and f is a proper holomorphic mapping of D(1) onto a second bounded domain D(2) in C(n) with real analytic boundary, then the mapping f extends to be holomorphic in a neighborhood of D(1). The proof relies on a transformation formula for the Bergman projection under proper holomorphic mappings.


[Incompatibility properties of pKMR plasmids determining antibiotic resistance and the capacity to produce colonization antigen].
pKMR207-1, pKMR208-1, pKMR209, pKMR210 and pKMR212 plasmids controlling simultaneously antibiotic resistance and capacity for synthesis of the colonization antigen were detected in wild strains of E. coli of various serotypes. The properties of compatibility of plasmids pKMR to each other and their attitude to the known incompatibility groups were studied. It was shown that pKMR207-1, pKMR208-1, pKMR210 and pKMR212 plasmids were incompatible. These plasmids had the incompatibility properties with respect to R388 (Inc FI) plasmid and probably belonged to the incompatibility group Inc. FI. pKMR209 plasmid was compatible with pKMR207-1, pKMR208-1, pKMR210 and pKMR212 plasmids and belonged to another incompatibility group.


Visually guided reaching for food in binocularly deprived cats.
Four visually deprived cats and four controls were tested in reaching for food from a cage. In each trial the animals in the groups responded immediately after unscreening the cage. However, in reaction time of forelimb extension the deprived group showed proportionally fewer responses with shorter reaction time than the control group.


Health literacy, numeracy, and graphical literacy among veterans in primary care and their effect on shared decision making and trust in physicians.
Studies reveal high levels of inadequate health literacy and numeracy in African Americans and older veterans. The authors aimed to investigate the distribution of health literacy, numeracy, and graph literacy in these populations. They conducted a cross-sectional survey of veterans receiving outpatient care and measured health literacy, numeracy, graph literacy, shared decision making, and trust in physicians. In addition, the authors compared subgroups of veterans using analyses of covariance. Participants were 502 veterans (22-82 years). Low, marginal, and adequate health literacy were found in, respectively, 29%, 26%, and 45% of the veterans. The authors found a significant main effect of race qualified by an age and race interaction. Inadequate health literacy was more common in African Americans than in Whites. Younger African Americans had lower health literacy (p <.001), graph literacy (p <.001), and numeracy (p <.001) than did Whites, even after the authors adjusted for covariates. Older and younger participants did not differ in health literacy, objective numeracy, or graph literacy after adjustment. The authors found no health literacy or age-related differences regarding preferences for shared decision making. African Americans expressed dissatisfaction with their current role in decision making (p =.03). Older participants trusted their physicians more than younger participants (p =.01). In conclusion, African Americans may be at a disadvantage when reviewing patient education materials, potentially affecting health care outcomes.


Monitoring Bone Density Using Microwave Tomography of Human Legs: A Numerical Feasibility Study.
A major cause of bone mass loss worldwide is osteoporosis. X-ray is considered to be the gold-standard technique to diagnose this disease. However, there is currently a need for an alternative modality due to the ionizing radiations used in X-rays. In this vein, we conducted a numerical study herein to investigate the feasibility of using microwave tomography (MWT) to detect bone density variations that are correlated to variations in the complex relative permittivity within the reconstructed images. This study was performed using an in-house finite-element method contrast source inversion algorithm (FEM-CSI). Three anatomically-realistic human leg models based on magnetic resonance imaging reconstructions were created. Each model represents a leg with a distinct fat layer thickness; thus, the three models are for legs with thin, medium, and thick fat layers. In addition to using conventional matching media in the numerical study, the use of commercially available and cheap ultrasound gel was evaluated prior to bone image analysis. The inversion algorithm successfully localized bones in the thin and medium fat scenarios. In addition, bone volume variations were found to be inversely proportional to their relative permittivity in the reconstructed images with the root mean square error as low as 2.54. The observations found in this study suggest MWT as a promising bone imaging modality owing to its safe and non-ionizing radiations used in imaging objects with high quality.


[Trend in the prevalence of mental disorders in population of big industrial center under conditions of social and economic changes].
The prevalence and incidence rates of mental disorders in outpatient contingent were analyzed during 1985-1995 years. Their dynamics was examined in terms of nosology, sex, age and social aspects. The dependence was observed between the prevalence and incidence rates and the conditions of financial support of psychiatric departments, social and economic situation in the country, pecullarities of organization and resources of psychiatric services.


An integrated proteomics analysis of bone tissues in response to mechanical stimulation.
Bone cells can sense physical forces and convert mechanical stimulation conditions into biochemical signals that lead to expression of mechanically sensitive genes and proteins. However, it is still poorly understood how genes and proteins in bone cells are orchestrated to respond to mechanical stimulations. In this research, we applied integrated proteomics, statistical, and network biology techniques to study proteome-level changes to bone tissue cells in response to two different conditions, normal loading and fatigue loading. We harvested ulna midshafts and isolated proteins from the control, loaded, and fatigue loaded Rats. Using a label-free liquid chromatography tandem mass spectrometry (LC-MS/MS) experimental proteomics technique, we derived a comprehensive list of 1,058 proteins that are differentially expressed among normal loading, fatigue loading, and controls. By carefully developing protein selection filters and statistical models, we were able to identify 42 proteins representing 21 Rat genes that were significantly associated with bone cells' response to quantitative changes between normal loading and fatigue loading conditions. We further applied network biology techniques by building a fatigue loading activated protein-protein interaction subnetwork involving 9 of the human-homolog counterpart of the 21 rat genes in a large connected network component. Our study shows that the combination of decreased anti-apoptotic factor, Raf1, and increased pro-apoptotic factor, PDCD8, results in significant increase in the number of apoptotic osteocytes following fatigue loading. We believe controlling osteoblast differentiation/proliferation and osteocyte apoptosis could be promising directions for developing future therapeutic solutions for related bone diseases.


Molecular cytogenetic characterization of a wheat - Leymus mollis 3D(3Ns) substitution line with resistance to leaf rust.
Leymus mollis (Trin.) Pilger (NsNsXmXm, 2n = 28), a wild relative of common wheat, possesses many potentially valuable traits that could be transferred to common wheat during breeding programs. In this study, the karyotypic constitution of a wheat - L. mollis 3D(3Ns#1) disomic substitution line isolated from the F5 progeny of octoploid Tritileymus M842-16 × Triticum durum cv. D4286, which was designated as 10DM57, was determined using genomic in situ hybridization (GISH), fluorescent in situ hybridization (FISH), SSR markers, and EST-STS markers. Screening of mitosis and meiosis showed that 10DM57 had a chromosome karyotype of 2n = 42 = 21II. GISH indicated that 10DM57 was a line with 40 chromosomes from wheat and two of the Ns chromosomes from L. mollis, which formed a ring bivalent in pollen mother cells at metaphase I. FISH analysis showed that the chromosome 3D may be replaced by 3Ns#1 in 10DM57. DNA markers, including SSR and EST-STS primers, showed that the pair of wheat chromosome 3D in 10DM57 was substituted by the pair of chromosome 3Ns#1 from L. mollis. Evaluation of the agronomic traits showed that, compared with its common wheat relative 7182, 10DM57 was resistant to leaf rust while the spike length and number of spikes per plant were improved significantly, which correlated with a higher wheat yield. The new germplasm, 10DM57, could be exploited as an intermediate material in wheat genetic and breeding programs.


Long-term prognostic value of stress myocardial perfusion echocardiography in patients with coronary artery disease: a meta-analysis.
To evaluate the prognostic value of myocardial perfusion (MP) imaging during contrast stress echocardiography (cSE) in patients with known or suspected coronary artery disease (CAD). A search in PubMed, Embase databases, and the Cochrane library was conducted through May 2019. The Cochran Q statistic and the I2 statistic were used to assess heterogeneity, and the results were analysed by RevMan V5.3 and Stata V15.1 software. Twelve studies (seven dipyridamole and five exercise/dobutamine) without evidence of patient overlap (same institution publishing results over a similar time period) enrolling 5953 subjects (47% female, 8-80 months of follow-up) were included in the analysis. In all studies, total adverse cardiovascular events were defined as either cardiac death, non-fatal myocardial infarction (NFMI), or need for urgent revascularization. Hazard ratios (HRs) revealed that a MP abnormality [pooled HR 4.75; 95% confidence interval (CI) 2.47-9.14] was a higher independent predictor of total events than abnormal wall motion (WM, pooled HR 2.39; 95% CI 1.58-3.61) and resting left ventricular ejection fraction (LVEF, pooled HR 1.92; 95% CI 1.44-2.55) with significant subgroup differences (P = 0.002 compared with abnormal WM and 0.01 compared with abnormal LVEF). Abnormal MP was associated with higher risks for death [Risk ratio (RR) 5.24; 95% CI 2.91-9.43], NFMI (RR 3.09; 95% CI 1.84-5.21), and need for coronary revascularization (RR 16.44; 95% CI 6.14-43.99). MP analysis during stress echocardiography is an effective prognostic tool in patients with known or suspected CAD and provides incremental value over LVEF and WM in predicting clinical outcomes.


Moral agency, moral worth and the question of double standards in medical research in developing countries.
International regulations governing medical research, healthcare and medical practice, are, obviously, meant to be guidelines and not detailed procedural rules of thumb that can be applied unreflectively without any danger of doing moral wrong. Moreover, such regulations are meant to apply internationally, and no set of straight-jacketed rules of thumb can conceivably apply to all societies and communities of the world, extremely diverse and differently situated as they are. The mark of a good international guideline or regulation, in my view, is that it should provide a clear principle of action that applies equally to all global communities and societies without seeking to foist the particular or momentary moral dilemmas, quandaries, obsessions and preoccupations of some on all. In this paper, I propose to argue that, because moral obligations are obligations only from the point of view of a particular moral agent, we should avoid making the peculiar problems of any particular moral agent(s) the obsessive concern of all moral agents, and that we need, in particular, to make appropriate distinctions between the ethics of developed world research in the developing world, collaborative or cooperative research between the developed and developing worlds, developed world research in the developed world and developing world research in the developing world. A consequence of looking at things this way is that, while it should be clear that there are ethical concerns, imperatives and obligations at all levels, different standards may and, in fact, cannot but be applied in different contexts at different levels, without resorting to the use of double standards, which can never be morally justified. Finally, I venture to propose a formula for a solemn pledge of moral integrity and noble intent, from the perspective of the agent, that is to say, the investigator, sponsor and funder of any research, to complement and balance the widely accepted informed consent requirement, from the perspective of the patient, the subject of any biomedical research.


Diuretic uptitration with half dose combined ACEI + ARB better decreases proteinuria than combined ACEI + ARB uptitration.
Residual proteinuria is a strong modifiable risk factor for renal failure progression. We previously showed that the antiproteinuric effect of combined half doses of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) is increased by raising diuretic dosage. Methods. We tested whether uptitration of loop diuretics on top of combined half doses of ACEI and ARB would better decrease proteinuria than uptitration to combined full doses of ACEI and ARB in a randomized, crossover, three periods of 6-week controlled study. Eighteen patients with stable proteinuria over 1 g/day with combined ramipril at 5 mg/day and valsartan at 80 mg/day in addition to conventional antihypertensive treatments were randomized to receive combined ramipril at 5 mg/day and valsartan at 80 mg/day, or combined ramipril at 10 mg/day and valsartan at 160 mg/day, or combined ramipril at 5 mg/day, valsartan at 80 mg/day and increased furosemide dosage in random order. The primary end point was the mean urinary protein/creatinine ratio in two 24-hour urine collections at the end of the three treatment periods. Secondary end points included mean 24-hour proteinuria, home systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP) and estimated glomerular filtration rate (eGFR) levels. The geometric mean urinary protein/creatinine ratio was lower with combined ramipril at 5 mg/day, valsartan at 80 mg/day and increased furosemide dosage compared to combined ramipril at 5 mg/day and valsartan at 80 mg/day, but also to combined ramipril at 10 mg/day and valsartan at 160 mg/day. These differences remained significant after adjustment for SBP, DBP or MAP and 24-hour natriuresis but not after adjustment on eGFR. Diuretic dosage uptitration did not increase the number of home systolic blood pressure measurements below 100 mmHg, but led to a statistically significant increase in the number of symptomatic hypotension episodes. A cautious uptitration of loop diuretic dosage in addition to combined half doses of ACEI and ARB better decrease proteinuria in patients with CKD and high residual proteinuria than uptitration to full dose of combined ACEI and ARB. This antiproteinuric effect of diuretics was partly explained by an eGFR decrease, suggesting the contribution of haemodynamic modifications, whose safety on the long term still need to be addressed.


Microwave-assisted aqueous synthesis of highly luminescent carboxymethyl chitosan-coated CdTe/CdS quantum dots as fluorescent probe for live cell imaging.
This paper describes the development of a simplified and rapid method for the aqueous synthesis of quantum dots (QDs) with CdTe cores and gradient CdS external shells (CdTe/CdS QDs) aided by microwave irradiation. Several synthesis parameters, such as molar ratio of reagents, pH, reaction temperature, and reaction time, were studied in details. Under the optimized conditions, highly effective CdTe/CdS QDs could be synthesized in aqueous phase in only 15 min. In order to improve the biocompatibility of the CdTe/CdS QDs, these QDs were then interacted with carboxymethyl chitosan (CMC) so as they could be used as fluorescent probes in the aqueous phase. With the incorporation of CMC, the stability of modified QDs was found to have improved significantly (from 4 months to more than 10 months at room temperature). The photoluminescence quantum yield (PLQY) of the modified QDs could reach 75%, other parameters include a full width at half maximum of the emission (FWHM) spectrum as 40 ~ 60 nm, and an average size, estimated from electron microscopic images, as 3.5 nm. As fluorescent probes, these modified QDs were successfully used for imaging live Madin-Darby canine kidney (MDCK) cells, in which the preliminary results indicated that these modified QDs demonstrated good biocompatibility and showed promising applications for bio-labeling and imaging.


The Alps as barrier to dispersal in cold-adapted freshwater fishes? Phylogeographic history and taxonomic status of the bullhead in the Adriatic freshwater drainage.
The freshwater faunas of the Italian peninsula are isolated from the rest of Europe by the geographic barrier of the Alps and consequently have developed many endemic forms and contain few non-endemic species. However, some 'non-endemics' may either represent recent invaders of the Adriatic basin or cryptic endemic species. To test these two hypotheses against each other, we studied the origin and phylogenetic relationships of bullheads, cold adapted freshwater fishes of the genus Cottus, from both sides of the Alps and Dinaric Mountains. From the Adriatic basin, Cottus ferrugineus () was described as an endemic species, but the present analyses of sequences of the complete mitochondrial control region of 146 individuals from 43 localities showed no major differentiation between bullheads from both sides of the Alps. The very low diversification between representatives across the Alps suggests active transfers of haplotypes across this geographic barrier from the glacial cycles up to recent times. The transfers are most likely based on stream capture, since the cold-adapted bullhead is able to colonise the highest stretches of the water courses. No other freshwater fish in Europe is known to have experienced such an extensive gene flow across the highest European Mountains. In contrast, the Dinaric Mountains seem to have been a much more effective barrier between the Danube and the Adriatics. Our data reject the hypothesis of C. ferrugineus as an endemic species in the whole Adriatic drainage.


Autophagy in Diabetic Retinopathy.
Autophagy is an important homeostatic cellular process encompassing a number of consecutive steps indispensable for degrading and recycling cytoplasmic materials. Basically autophagy is an adaptive response that under stressful conditions guarantees the physiological turnover of senescent and impaired organelles and, thus, controls cell fate by various cross-talk signals. Diabetic retinopathy (DR) is a serious microvascular complication of diabetes and accounts for 5% of all blindness. Although, various metabolic disorders have been linked with the onset of DR, due to the complex character of this multi-factorial disease, a connection between any particular defect and DR becomes speculative. Diabetes increases inflammation, advanced glycation end products (AGEs) and oxidative stress in the retina and its capillary cells. Particularly, a great number of evidences suggest a mutual connection between oxidative stress and other major metabolic abnormalities implicated in the development of DR. In addition, the intricate networks between autophagy and apoptosis establish the degree of cellular apoptosis and the progression of DR. Growing data underline the crucial role of reactive oxygen species (ROS) in the activation of autophagy. Depending on their delicate balance both redox signaling and autophagy, being detrimental or beneficial, retain opposing effects. The molecular mechanisms of autophagy are very complex and involve many signaling pathways cooperating at various steps. This review summarizes recent advances of the possible molecular mechanisms in autophagic process that are involved in pathophysiology of DR. In-depth analysis on the molecular mechanisms leading to autophagy in the retinal pigment epithelial (RPE) will be helpful to plan new therapies aimed at preventing or improving the progression of DR.


FoxO6 inhibits cell proliferation in lung carcinoma through up-regulation of USP7.
Emerging evidence has suggested that misregulation of oncogenes and/or tumor suppressors has a crucial role in the development of lung carcinoma. The present study demonstrated that the expression levels of forkhead box O6 (FOXO6) were downregulated in lung cancer tissue samples, as compared with those in adjacent normal tissue. Overexpression of FOXO6 inhibited the proliferation of A549 human lung cancer cells, whereas knockdown of endogenous FOXO6 expression enhanced cell proliferation. Furthermore, ectopic FOXO6 expression induced the expression of ubiquitin-specific-processing protease 7 (USP7). As a result of this regulation, FOXO6 overexpression led to an elevation of p53 protein expression levels in A549 cells. In conclusion, the results of the present study indicated that the FOXO6/USP7 molecular network has an important role in the regulation of lung cancer development.


Safety and feasibility of magnetic seizure therapy (MST) in major depression: randomized within-subject comparison with electroconvulsive therapy.
Magnetic seizure therapy (MST) is a novel means of performing convulsive therapy using rapidly alternating strong magnetic fields. MST offers greater control of intracerebral current intensity than is possible with electroconvulsive therapy (ECT). These features may result in a superior cognitive side effect profile for MST, while possibly retaining the efficacy of ECT. The objective of this study was to determine whether MST and ECT differ in seizure characteristics, and acute objective and subjective cognitive side effects. A total of 10 inpatients in a major depressive episode referred for ECT were enrolled in this randomized, within-subject, double-masked trial. Seizure threshold was determined with MST and ECT in the first two sessions of a course of convulsive therapy, with order randomized. The remaining two sessions consisted of suprathreshold stimulation with MST and ECT. A neuropsychological battery and side effect rating scale were administered by a masked rater before and after each session. Tonic-clonic seizures were elicited with MST in all patients. Compared to ECT, MST seizures had shorter duration, lower ictal EEG amplitude, and less postictal suppression. Patients had fewer subjective side effects and recovered orientation more quickly with MST than ECT. MST was also superior to ECT on measures of attention, retrograde amnesia, and category fluency. Magnetic seizure induction in patients with depression is feasible, and appears to have a superior acute side effect profile than ECT. Future research will be needed to establish whether MST has antidepressant efficacy.


Cancer-associated carbohydrate antigens as potential biomarkers for hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common human malignancies. Therefore, developing the early, high-sensitivity diagnostic biomarkers to prevent HCC is urgently needed. Serum a-fetoprotein (AFP), the clinical biomarker in current use, is elevated in only ~60% of patients with HCC; therefore, identification of additional biomarkers is expected to have a significant impact on public health. In this study, we used glycan microarray analysis to explore the potential diagnostic value of several cancer-associated carbohydrate antigens (CACAs) as biomarkers for HCC. We used glycan microarray analysis with 58 different glycan analogs for quantitative comparison of 593 human serum samples (293 HCC samples; 133 chronic hepatitis B virus (HBV) infection samples, 134 chronic hepatitis C virus (HCV) infection samples, and 33 healthy donor samples) to explore the diagnostic possibility of serum antibody changes as biomarkers for HCC. Serum concentrations of anti-disialosyl galactosyl globoside (DSGG), anti-fucosyl GM1 and anti-Gb2 were significantly higher in patients with HCC than in chronic HBV infection individuals not in chronic HCV infection patients. Overall, in our study population, the biomarker candidates DSGG, fucosyl GM1 and Gb2 of CACAs achieved better predictive sensitivity than AFP. We identified potential biomarkers suitable for early detection of HCC. Glycan microarray analysis provides a powerful tool for high-sensitivity and high-throughput detection of serum antibodies against CACAs, which may be valuable serum biomarkers for the early detection of persons at high risk for HCC.


Lichen planopilaris is characterized by immune privilege collapse of the hair follicle's epithelial stem cell niche.
Lichen planopilaris (LPP) is a chronic inflammatory disease of unknown pathogenesis that leads to permanent hair loss. Whilst destruction of epithelial hair follicle stem cells (eHFSCs) that reside in an immunologically protected niche of the HF epithelium, the bulge, is a likely key event in LPP pathogenesis, this remains to be demonstrated. We have tested the hypotheses that bulge immune privilege (IP) collapse and inflammation-induced eHFSC death are key components in the pathogenesis of LPP. Biopsies of lesional and non-lesional scalp skin from adult LPP patients (n = 42) were analysed by quantitative (immuno)histomorphometry, real-time quantitative polymerase chain reaction (qRT-PCR), laser capture microdissection and microarray analysis, or skin organ culture. At both the protein and transcriptional level, lesional LPP HFs showed evidence for bulge IP collapse (ie increased expression of MHC class I and II, β2microglobulin; reduced TGFβ2 and CD200 expression). This was accompanied by a Th1-biased cytotoxic T cell response (ie increased CD8(+) GranzymeB(+) T cells and CD123(+) plasmacytoid dendritic cells, with increased CXCR3 expression) and increased expression of interferon-inducible chemokines (CXCL9/10/11). Interestingly, lesional LPP eHFSCs showed both increased proliferation and apoptosis in situ. Microarray analysis revealed a loss of eHFSC signatures and increased expression of T cell activation/binding markers in active LPP, while bulge PPARγ transcription was unaltered compared to non-lesional LPP HFs. In organ culture of non-lesional LPP skin, interferon-γ (IFNγ) induced bulge IP collapse. LPP is an excellent model disease for studying and preventing immune destruction of human epithelial stem cells in situ. These novel findings raise the possibility that LPP represents an autoimmune disease in whose pathogenesis IFNγ-induced bulge IP collapse plays an important role. Therapeutically, bulge IP protection/restoration may help to better manage this highly treatment-resistant cicatricial alopecia.


Survival Comparison between Melanoma Patients Treated with Patient-Specific Dendritic Cell Vaccines and Other Immunotherapies Based on Extent of Disease at the Time of Treatment.
Encouraging survival was observed in single arm and randomized phase 2 trials of patient-specific dendritic cell vaccines presenting autologous tumor antigens from autologous cancer cells that were derived from surgically resected metastases whose cells were self-renewing in vitro. Based on most advanced clinical stage and extent of tumor at the time of treatment, survival was best in patients classified as recurrent stage 3 without measurable disease. Next best was in stage 4 without measurable disease, and the worst survival was for measurable stage 4 disease. In this study, the survival of these patients was compared to the best contemporary controls that were gleaned from the clinical trial literature. The most comparable controls typically were from clinical trials testing other immunotherapy approaches. Even though contemporary controls typically had better prognostic features, median and/or long-term survival was consistently better in patients treated with this dendritic cell vaccine, except when compared to anti-programmed death molecule 1 (anti-PD-1). The clinical benefit of this patient-specific vaccine appears superior to a number of other immunotherapy approaches, but it is more complex to deliver than anti-PD-1 while equally effective. However, there is a strong rationale for combining such a product with anti-PD-1 in the treatment of patients with metastatic melanoma.


Incidence and Duration of Continuously Measured Oxygen Desaturation During Emergency Department Intubation.
Desaturation during intubation has been associated with serious complications, including dysrhythmias, hemodynamic decompensation, hypoxic brain injury, and cardiac arrest. We seek to determine the incidence and duration of oxygen desaturation during emergency department (ED) rapid sequence intubation. This study included adult rapid sequence intubation cases conducted between September 2011 and July 2012 in an urban, academic, Level I trauma center ED. We obtained continuous vital signs with BedMasterEX data acquisition software. Start and completion times of rapid sequence intubation originated from nursing records. We defined oxygen desaturation as (1) cases exhibiting SpO2 reduction to less than 90% if the starting SpO2 was greater than or equal to 90%, or (2) a further reduction in SpO2 in cases in which starting SpO2 was less than 90%. We used multivariable logistic regression to predict oxygen desaturation during rapid sequence intubation. During the study period, there were 265 rapid sequence intubation cases. The study excluded 99 cases for failure of electronic data acquisition, inadequate documentation, or poor SpO2 waveform during rapid sequence intubation, and excluded cases managed by anesthesia providers, leaving 166 patients in the analysis. After preoxygenation, starting SpO2 was greater than 93% in 124 of 166 cases (75%) and SpO2 was less than 93% in the remaining 46 cases. Oxygen desaturation occurred in 59 patients (35.5%). The median duration of desaturation was 80 seconds (interquartile range 40, 155). Multivariable analysis demonstrated that oxygen desaturation was associated with preintubation SpO2 less than 93% (odds ratio [OR] 5.1; 95% confidence interval (CI) 2.3 to 11.0), multiple intubation attempts (>1 attempt) (OR 3.4; 95% CI 1.4 to 6.1), and rapid sequence intubation duration greater than 3 minutes (OR 2.7; 95% CI 1.2 to 6.1). In this series, 1 in 3 patients undergoing ED rapid sequence intubation experienced oxygen desaturation for a median duration of 80 seconds. Preintubation saturation less than 93%, multiple intubation attempts, and prolonged intubation time are independently associated with oxygen desaturation. Clinicians should use strategies to prevent oxygen desaturation during ED rapid sequence intubation.


Concepts and controversies of juvenile myoclonic epilepsy: still an enigmatic epilepsy.
Juvenile myoclonic epilepsy (JME) is a clinically and genetically heterogenous, generalized epilepsy syndrome usually starting in adolescence. An age-related, predominantly frontocortical-subcortical network dysfunction is likely to be the substrate of bilateral myoclonic seizures occurring at full consciousness within hours after awakening, which are the clinical hallmark of JME. Although essential features of JME were recognized by Herpin more than 140 years ago, it is still an enigmatic epilepsy syndrome in many ways; advanced imaging techniques reveal multi-focal abnormalities in this paradigmatic generalized epilepsy syndrome; clinical studies reveal a major role of genetics in etiology, but the underlying molecular changes are likely to be highly heterogeneous; many JME patients have psycho-social issues, even though their intelligence is normal; antiepileptic drugs (AEDs), notably valproic acid, achieve seizure remission in two thirds of patients, but more patients seem to relapse after stopping AEDs than in any other epilepsy syndrome. This pessimistic outlook has been challenged in recent population-based studies and needs to be assessed in randomized AED withdrawal trials. This review summarizes recent focus neuroimaging, genetic, and behavioral aspects of JME and re-appraises the entrenched view that remission off AEDs is exceptionally rare in JME.


Renal expression of two 'thyroid-specific' genes: thyrotropin receptor and thyroglobulin.
Numerous renal abnormalities accompany thyroid disease, most of which have been ascribed to the effects of thyroid hormone on renal metabolism. In the present report, we investigate the renal expression of the nominally thyroid-specific proteins, thyroid-stimulating hormone (TSH) receptor (TSHR) and thyroglobulin (Tg), as potential links between renal and thyroid function. The expression of TSHR has been identified in several extrathyroidal tissues, but its presence in the kidney remains controversial. We have used reverse-transcriptase polymerase chain reaction and DNA sequencing to demonstrate the presence of TSHR transcript in human and mouse kidney, in a primary culture of human kidney, and in a green monkey kidney epithelioid cell line. Furthermore, human kidney cells responded to TSH with a 2.5- fold increase in intracellular cyclic adenosine monophosphate, suggesting the presence of functional TSHR protein. Comparison of renal expression of TSHR in a bovine growth hormone transgenic mouse model of progressive glomerulosclerosis with control mice suggested increased TSHR transcript in the renal cortex of transgenic animals. TSHR transcript was also detected in mouse mesangial cells in vitro which responded to TSH with significant increases in the formation of three-dimensional hillhocks. Polymerase chain reaction also confirmed the presence of Tg transcript in human and mouse kidneys and in mouse mesangial cells, but no effect of either TSH or cyclic adenosine monophosphate on Tg transcript levels could be discerned. Immunofluorescent staining with a monoclonal anti-Tg antibody identified positive staining in the cytoplasm of mesangial cells. These data suggest that the kidney is capable of expressing the thyroid-specific genes, TSHR and Tg, which could conceivably mediate effects of thyroid disease in the kidney.


[Effect of pyocyanin on the intensity of KMnO4-induced protein chemiluminescence].
Pyocyanin being added to protein solutions influenced the intensity of the subsequent chemiluminescence caused by KMnO4. The amplitude of chemiluminescence for albumin, peptone and peroxidase decreased by 38, 39 and 42%, respectively. Pyocyanin had only a minor effect on the chemiluminescence of alcohol dehydrogenase; it decreased the intensity of the reaction by 7%. The reaction of chemiluminescence for cytochrome c and lysozyme did not change in the presence of pyocyanin.


Art therapy with the frail elderly.
The use of art engages frail oder persons in a unique way. Art therapists recognize the creative source in the elderly and strive to involve them in the creative process. The art therapist combines the media of the visual artist with assistance in art skills to enable the older person to make meaningful expressions of emotion despite deteriorating functional ability. Supportive and therapeutic art interventions augment the skills and assets that many older persons retain. Effective art therapy sessions may be brought to older persons in their homes or in the day programs they attend. Through art therapy, the frail elderly learn new ways to express and interpret life situations, to communicate perspectives and respond to the difficulties before them.


S-nitrosylated S100A8: novel anti-inflammatory properties.
S100A8 and S100A9, highly expressed by neutrophils, activated macrophages, and microvascular endothelial cells, are secreted during inflammatory processes. Our earlier studies showed S100A8 to be an avid scavenger of oxidants, and, together with its dependence on IL-10 for expression in macrophages, we postulated that this protein has a protective role. S-nitrosylation is an important posttranslational modification that regulates NO transport, cell signaling, and homeostasis. Relatively few proteins are targets of S-nitrosylation. To date, no inflammation-associated proteins with NO-shuttling capacity have been identified. We used HPLC and mass spectrometry to show that S100A8 and S100A9 were readily S-nitrosylated by NO donors. S-nitrosylated S100A8 (S100A8-SNO) was the preferred nitrosylated product. No S-nitrosylation occurred when the single Cys residue in S100A8 was mutated to Ala. S100A8-SNO in human neutrophils treated with NO donors was confirmed by the biotin switch assay. The stable adduct transnitrosylated hemoglobin, indicating a role in NO transport. S100A8-SNO suppressed mast cell activation by compound 48/80; intravital microscopy was used to demonstrate suppression of leukocyte adhesion and extravasation triggered by compound 48/80 in the rat mesenteric microcirculation. Although S100A8 is induced in macrophages by LPS or IFN-gamma, the combination, which activates inducible NO synthase, did not induce S100A8. Thus, the antimicrobial functions of NO generated under these circumstances would not be compromised by S100A8. Our results suggest that S100A8-SNO may regulate leukocyte-endothelial cell interactions in the microcirculation, and suppression of mast cell-mediated inflammation represents an additional anti-inflammatory property for S100A8.


Optimizing Transcutaneous Oxygen Measurement Sites on Humans.
This study utilizes an optical method of transcutaneous oxygen sensing that has the potential to revolutionize at-home care. This technique is based on quenching the luminescence of a platinum porphyrin film. Since oxygen quenches luminescence, its lifetime is further measured to assess the partial pressure of transcutaneous oxygen diffusing through the skin. Unlike conventional transcutaneous oxygen monitors that use electrochemical sensors, the luminescence-based sensor allows the use of dry electrodes that do not require heating and reduce the risk of accidental skin irritations or burns. These properties not only improve patient safety but also allow the creation of miniature wearable transcutaneous oxygen sensors for continuous and accurate remote respiratory monitoring. To this end, it is critical to assess the efficiency of the wearable sensor by determining the optimal location for its placement on the body. Depending on the location on the body, physiological factors such as blood flow rate and skin thickness affect dermal perfusion of transcutaneous oxygen. In this work, four healthy volunteers participated in subject testing. We assessed each participant at the following locations: thumb, top of the wrist, forearm, thigh, and shin. All locations consistently reported accurate and reliable data. Among them, the thumb demonstrated shorter settling times and the most uniform luminescence lifetime values.


SPARC Expression Did Not Predict Efficacy of nab-Paclitaxel plus Gemcitabine or Gemcitabine Alone for Metastatic Pancreatic Cancer in an Exploratory Analysis of the Phase III MPACT Trial.
nab-Paclitaxel plus gemcitabine was superior to gemcitabine alone for patients with metastatic pancreatic cancer (MPC) in the phase III MPACT trial. This study evaluated the association of secreted protein acidic and rich in cysteine (SPARC) levels with efficacy as an exploratory endpoint. Patients with previously untreated MPC (N = 861) received nab-paclitaxel plus gemcitabine or gemcitabine alone. Baseline SPARC level was measured in the tumor stroma and epithelia (archival biopsies) and plasma. Experiments were performed in pancreatic cancer mouse models in which SPARC was intact or deleted. SPARC was measured in the tumor stroma of 256 patients (30%), the tumor epithelia of 301 patients (35%), and plasma of 343 patients (40%). Stroma-evaluable samples were from metastases (71%), from the pancreas (11%), or of unidentifiable origin (insufficient tissue to determine; 17%). For all patients, stromal SPARC level [high (n = 71) vs. low (n = 185)] was not associated with overall survival (OS; HR, 1.019; P = 0.903); multivariate analysis confirmed this lack of association. There was no association between stromal SPARC level and OS in either treatment arm. Neither tumor epithelial SPARC nor plasma SPARC was associated with OS. Results from a SPARC knockout mouse model treated with nab-paclitaxel plus gemcitabine revealed no correlation between SPARC expression and tumor progression or treatment efficacy. SPARC levels were not associated with efficacy in patients with MPC. This exploratory analysis does not support making treatment decisions regarding nab-paclitaxel plus gemcitabine or gemcitabine alone in MPC based on SPARC expression.


Previous infection protects house finches from re-infection with St. Louis encephalitis virus.
Antibody titers against St. Louis encephalitis virus (SLE) measured by a plaque reduction neutralization test (PRNT) decreased rapidly in house finches (Capodacus mexicanus) after initial infection, whereas antibodies measured by enzyme immunoassay (EIA) remained detectable in all birds for the length of the experiment, indicating long-term persistence and greater assay sensitivity of the EIA. After 52 wk, birds were challenged by subcutaneous inoculation with the same strain of SLE virus. Virus was not detected for 1-4 d postchallenge in blood samples tested by plaque assay and RT-PCR or by xenodiagnosis in Culex tarsalis fed concurrently and then held for 11 d at 26 degrees C. Virus was detected by all three methods in control birds infected concurrently for the first time. Challenge with SLE produced a rapid and marked ananmestic rise in both neutralizing and EIA antibody titers that exceeded the primary response in the same birds or in concurrently inoculated control birds. At necropsy 4 wk postchallenge, 3 of 7 challenged and 1 of 2 positive control birds were chronically infected, with viral RNA detected by RT-PCR in brain, spleen, lung, and/or kidney tissues. Our results indicated that persistence of protective antibody prevents reinfection during the following season and may prevent the recrudescence of infectious virus in chronically infected birds.


Evaluation of the implementation of an integrated primary care network for prevention and management of cardiometabolic risk in Montréal.
The goal of this project is to evaluate the implementation of an integrated and interdisciplinary program for prevention and management of cardiometabolic risk (PCMR). The intervention is based on the Chronic Care Model. The study will evaluate the implementation of the PCMR in 6 of the 12 health and social services centres (CSSS) in Montréal, and the effects of the PCMR on patients and the practice of their primary care physicians up to 40 months following implementation, as well as the sustainability of the program. Objectives are: 1-to evaluate the effects of the PCMR and their persistence on patients registered in the program and the practice of their primary care physicians, by implementation site and degree of exposure to the program; 2-to assess the degree of implementation of PCMR in each CSSS territory and identify related contextual factors; 3-to establish the relationships between the effects observed, the degree of PCMR implementation and the related contextual factors; 4-to assess the impact of the PCMR on strengthening local services networks. The evaluation will use a mixed design that includes two complementary research strategies. The first strategy is similar to a quasi-experimental "before-after" design, based on a quantitative approach; it will look at the program's effects and their variations among the six territories. The effects analysis will use data from a clinical database and from questionnaires completed by participating patients and physicians. Over 3000 patients will be recruited. The second strategy corresponds to a multiple case study approach, where each of the six CSSS constitutes a case. With this strategy, qualitative methods will set out the context of implementation using data from semi-structured interviews with program managers. The quantitative data will be analyzed using linear or multilevel models complemented with an interpretive approach to qualitative data analysis. Our study will identify contextual factors associated with the effectiveness, successful implementation and sustainability of such a program. The contextual information will enable us to extrapolate our results to other contexts with similar conditions. ClinicalTrials.gov: NCT01326130.


Factors related to self-concept of elderly residing in a retirement center.
The purpose of this study was to explore the self-concept of elderly adults residing in retirement centers as well as its relationship to other variables, including function of activities of daily living (ADL), subjective well being, etc. Selected demographic attributes (sex, age, years of education etc.) were also examined for their relationship to self-concept. The subjects were a convenience sample of people aged 65 or older who were recruited from a retirement center in the south of Taiwan (N = 42), and a control group of elderly living with their family (N = 33). The Tennessee Self-Concept Scale (TSCS) was used to measure self-concept. The Multidimensional Functional Assessment Questionnaire- Chinese Version (MFAQ) was applied to measure the function of activities of daily living. A total of 37 subjects from the retirement center group and 28 subjects from the home group completed these questionnaires. The data were analyzed using SPSS/PC software version 10.0. After multiple linear regression analysis, the results showed that the elderly residing in the retirement center had significantly lower Personal Self and Family Self scores. The variables of ADL, sex and subjective well-being had effects on the total self-concept. Female elderly individuals also revealed significant higher scores than males in the subscales of Moral- Ethical, Family Self, Social Self, Identity, Satisfaction Self. These results suggest we should design appropriate programs to increase elderly people's interaction with others and establish new social networks for them which may enhance a sense of positive self-concept.


Suitability of different containers for the sampling and storage of biogas and biomethane for the determination of the trace-level impurities--A review.
The traceable and accurate measurement of biogas impurities is essential in order to robustly assess compliance with the specifications for biomethane being developed by CEN/TC408. An essential part of any procedure aiming to determinate the content of impurities is the sampling and the transfer of the sample to the laboratory. Key issues are the suitability of the sample container and minimising the losses of impurities during the sampling and analysis process. In this paper, we review the state-of-the-art in biogas sampling with the focus on trace impurities. Most of the vessel suitability studies reviewed focused on raw biogas. Many parameters need to be studied when assessing the suitability of vessels for sampling and storage, among them, permeation through the walls, leaks through the valves or physical leaks, sorption losses and adsorption effects to the vessel walls, chemical reactions and the expected initial concentration level. The majority of these studies looked at siloxanes, for which sampling bags, canisters, impingers and sorbents have been reported to be fit-for-purpose in most cases, albeit with some limitations. We conclude that the optimum method requires a combination of different vessels to cover the wide range of impurities commonly found in biogas, which have a wide range of boiling points, polarities, water solubilities, and reactivities. The effects from all the parts of the sampling line must be considered and precautions must be undertaken to minimize these effects. More practical suitability tests, preferably using traceable reference gas mixtures, are needed to understand the influence of the containers and the sampling line on sample properties and to reduce the uncertainty of the measurement.


Ruptured aneurysm of the sinus of Valsalva.
The objective of the present study was to assess the value of imaging techniques in the diagnosis of ruptured aneurysm of sinus of Valsalva (RASV). 38 patients were included in the study. 30 were male and 8 female. Their age ranged from 7 to 55 years (mean 25.8 years). Echocardiographic and doppler studies were done in all cases and 20 patients underwent catheterization and angiography. Two patients were asymptomatic, 20 (53%) had acute onset of symptoms and in the remaining 16 (42%) patients symptoms developed gradually. Twenty two (58%) patients were in NYHA functional class III or IV when first seen. Predominant symptoms were dyspnea (79%), palpitation (55%) and chest pain (52%). A continuous machinery murmur was detected in all the patients with associated thrill in 34 patients. Right coronary sinus (RCS) was the most common sinus involved (89%) followed by the noncoronary sinus (NCS) which was involved in 11% of patients. None of the patients in our series had aneurysm of the left coronary sinus. Twenty eight of the 34 RCS aneurysms ruptured into the right ventricular outflow tract (RVOT), 4 into right ventricular cavity (RVC), one into right atrium (RA) and one dissected into the ventricular septum and subsequently ruptured into the left ventricle. Of the 4 NCS aneurysms, 2 ruptured into RVC, one into RA and one into both the RA and RVC. Associated ventricular septal defect (VSD) was found in 10 (26%) patients and all of these patients had RCS aneurysm that ruptured into the RVOT. Aortic regurgitation (AR) was detected in 16 (42%) cases. Discrete subaortic stenosis was detected in one patient who also had associated VSD and AR. Vegetation of the aortic valve was detected in one patient who had RCS aneurysm. Twelve patients (11 male and one female) underwent surgical correction, 10 with and 2 without prior catheterization. Localization of the involved sinus, site of rupture and associated cardiac lesions by echocardiography and doppler study were found accurate at surgery and/or angiography in 22 cases of our series. Imaging techniques, thus appeared to be reliable tools for the diagnosis of RASV.


A 12-year study of menarcheal age.
Data on menarcheal age were collected on girls admitted to the University College of Swansea over a 12-year period. It appears that the downward trend in menarcheal age ceased in girls born about 1946 (the 1965 student intake) and that an upward swing may have since occurred. This change in the secular trend is not due to the association of menarcheal age with family size or of position in sibship, or to changes in the regional composition of the student intake. The well established effect of physique remains, but there is no effect of socio-economic status as assessed by the Registrar-General's classification of the father's occupation.


Interleukin-17 may be a valuable serum tumor marker in patients with colorectal carcinoma.
The promotion of tumor growth is due to a combination of several mechanisms, including angiogenesis and the abundance of cell-derived inflammatory cytokines. The aim of this study was to investigate the serum levels of interleukin 17 (IL-17) and the expression of p53 and Vascular Endothelial Growth Factor (VEGF), in order to determine the relationship between these markers and serum IL-17 levels in patients with colorectal carcinoma. Serum levels of the proinflammatory cytokine IL-17 in patients with colorectal carcinoma (CRC) (n=40) and in a healthy group (n=37) were analysed by ELISA. Surgically resected specimens of 59 colorectal carcinomas were studied by immunohistochemical staining for VEGF and p53. Analyses by ELISA showed significantly higher IL-17 serum levels in patients with colorectal carcinoma than in control subjects (IL-17; mean 128.52+/-47.62 pg/ml vs. mean 101.91+/-22.46 pg/ml; p=0.022). We also found an inverse correlation between p53 expression and the level of IL-17 in the serum of patients with CRC. In fact, the serum concentration of IL-17 was significantly higher in patients who did not express p53 (p=0.023). There was no significant correlation between the expression of p53 and VEGF. However, concomitant expression of VEGF and p53 showed a significant correlation with the histological and nuclear grade of the carcinoma. The data presented in our study indicate that IL-17 might act as a valuable tumor marker in patients with CRC and that combined analysis of p53 and VEGF expression might provide additional information about tumor features.


White blood cell differential fluorescence abnormal scattergram: A useful indicator for early detection of malarial parasite.
Undiagnosed malarial infectionis associated with significant mortality and morbidity. Laboratory investigations leading to rapid, accurate and timely diagnosis of malaria is still a challenge. This study was done to assess the utility of abnormal White blood cell differential fluorescence (WDF) scattergram for diagnosis of malaria. Our aim was to study the utility of WDF scattergram for early detection of malarial parasite. All EDTA anti-coagulated blood samples received in laboratory during a period from Dec 2019 to May 2020 were analyzed on anautomated hematology analyzer, Sysmex XN 1000. All abnormal WDF scattergrams pertaining to plasmodium specie were critically evaluated and recorded. Review of Leishman-stained peripheral smears as well as immune-chromatographic assay by rapid test devices (RTD) was done. Accordingly, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for detection of malaria by abnormal scattergram were calculated. Out of total 1, 26,000of samples analyzed, abnormal WDF scattergrams were detected in 96 cases. Amongst these, 95.8% (92) were positive for MP on Leishman-stained peripheral smear as well as on ICT with a p-value of 0.05. WDF scattergram abnormalities typical of malaria showed a sensitivity of 80% and specificity of 93.26%. Positive predictive value of 95.8% whereas negative predictive value of 99.9% was detected. Significant findings of hemolysis, platelet clumps, nucleated RBCS (NRBCs) and RBC agglutination were noted in cases (n=4) with abnormal WDF scattergram negative for malaria on peripheral smear. Interpretation of abnormal WDF scattergram not only increases the early detection rate for malarial parasite but isa strong indicator for presence of hemolysis, RBC agglutination, platelet clumps and leucoerythroblastic blood picture as well.


Auditory streaming and bistability paradigm extended to a dynamic environment.
We explore stream segregation with temporally modulated acoustic features using behavioral experiments and modelling. The auditory streaming paradigm in which alternating high- A and low-frequency tones B appear in a repeating ABA-pattern, has been shown to be perceptually bistable for extended presentations (order of minutes). For a fixed, repeating stimulus, perception spontaneously changes (switches) at random times, every 2-15 s, between an integrated interpretation with a galloping rhythm and segregated streams. Streaming in a natural auditory environment requires segregation of auditory objects with features that evolve over time. With the relatively idealized ABA-triplet paradigm, we explore perceptual switching in a non-static environment by considering slowly and periodically varying stimulus features. Our previously published model captures the dynamics of auditory bistability and predicts here how perceptual switches are entrained, tightly locked to the rising and falling phase of modulation. In psychoacoustic experiments we find that entrainment depends on both the period of modulation and the intrinsic switch characteristics of individual listeners. The extended auditory streaming paradigm with slowly modulated stimulus features presented here will be of significant interest for future imaging and neurophysiology experiments by reducing the need for subjective perceptual reports of ongoing perception.


Successful endovascular therapy for cerebral venous sinus thrombosis accompanied by heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication of heparin exposure. A limited number of studies have reported cerebral venous sinus thrombosis accompanied by heparin-induced thrombocytopenia. Here, we present a case of successful endovascular therapy (EVT) without periprocedural heparinization in this situation. A 47-year-old woman taking an oral contraceptive was admitted to our hospital with severe headache to be diagnosed as cerebral venous sinus thrombosis. Initially, she got improved by medical treatment with intravenous unfractionated heparin. However, she rapidly developed disturbance of consciousness and right hemiplegia due to cerebral venous sinus thrombosis accompanied by heparin-induced thrombocytopenia on the 14th hospital day. She underwent emergent EVT by immediate conversion of anticoagulation from heparin to argatroban. Despite a large clot burden, sufficient recanalization and anterograde venous drainage were re-established by combined EVT including aspiration, balloon sinoplasty, and local thrombolysis with urokinase infusion. She got improved immediately after the intervention and discharged home without any neurological sequelae after two months. This unique case of cerebral venous sinus thrombosis worsened by occurrence of heparin-induced thrombocytopenia during the treatment finally resulted in excellent outcome highlights effectiveness of emergent endovascular intervention for critical cerebral venous sinus thrombosis resistant to initial medical treatment and of immediate establishment of effective anticoagulant strategy for both of heparin-induced thrombocytopenia and cerebral venous sinus thrombosis. Neuroendovascular therapy for cerebral venous sinus thrombosis using alternative argatroban to heparin for periprocedural anticoagulation might be safe and feasible.


Single-step electrospun TiO2-Au hybrid electrodes for high selectivity photoelectrocatalytic glutathione bioanalysis.
Understanding the fundamentals of photoelectrocatalytic (PEC) biomolecular oxidation benefits the development of next-generation PEC biosensors. In this work, single-step electrospun titanium-di-oxide-gold (TiO2-Au) hybrid nanofibers (HNF) are reported as being a potential candidate for PEC glutathione (GSH) bioanalysis. The chemical environment of TiO2 and TiO2-Au HNFs were studied with X-ray photoelectron spectroscopy and found to have a strong electronic interaction between TiO2 and the Au nanoparticles (NPs). The PEC measurements revealed that the intramolecular backbone hydrogen bonding of GSH molecules predominantly contributes highly active Au-GSH bio-nano interfaces, which facilitate the PEC oxidation rate of GSH and thus enhance the photocurrent. Furthermore, the Au NPs present act as auxiliary electron transport channels resulting in enhanced charge collection at the external circuit. As a result, the TiO2-Au electrode generated a two-fold higher photocurrent density of ∼84.4 μA cm-2 in the presence of 0.5 mM GSH, where the pristine TiO2 NFs displayed only a negligible influence. Likewise, the TiO2-Au HNF electrode showed a higher sensitivity of 0.002 mM and a wide linear detection range between 0.022 mM and 0.7 mM, with a superior selectivity towards GSH bioanalysis over ascorbic acid and glucose at -0.33 V (versus silver/silver chloride) than that obtained with pristine TiO2. The implications of these findings towards the development of a next-generation PEC biosensor are discussed.


Effects of long-term administration of carprofen on healing of a tibial osteotomy in dogs.
To evaluate effects of long-term administration of carprofen on healing of a tibial osteotomy in dogs. 12 healthy female Beagles. A mid-diaphyseal transverse osteotomy (stabilized with an intramedullary pin) of the right tibia was performed in each dog. The carprofen group (n = 6 dogs) received carprofen (2.2 mg/kg, PO, q 12 h) for 120 days; the control group (6) received no treatment. Bone healing and change in callus area were assessed radiographically over time. Dogs were euthanized 120 days after surgery, and tibiae were evaluated biomechanically and histologically. The osteotomy line was not evident in the control group on radiographs obtained 120 days after surgery. In contrast, the osteotomy line was still evident in the carprofen group. Callus area was significantly less in the carprofen group, compared with the area in the control group, at 20, 30, and 60 days after surgery. At 120 days after surgery, stiffness, elastic modulus, and flexural rigidity in the carprofen group were significantly lower than corresponding values in the control group. Furthermore, histologic evaluation revealed that the cartilage area within the callus in the carprofen group was significantly greater than that in the control group. Long-term administration of carprofen appeared to inhibit bone healing in dogs that underwent tibial osteotomy. We recommend caution for carprofen administration when treating fractures that have delays in healing associated with a reduction in osteogenesis as well as fractures associated with diseases that predispose animals to delays of osseous repair.


Dietary Habits of Type 2 Diabetes Patients: Variety and Frequency of Food Intake.
The objective of the present study was to observe the dietary patterns and food frequencies of type 2 diabetes patients attending the clinics of the Family Practice Center of the University of Sri Jayewardenepura, located in a highly urbanized area in Sri Lanka. An interviewer administered questionnaire based cross-sectional study was conducted among randomly selected 100 type 2 diabetes patients [age 35-70 years; mean age 55 ± 9 (males = 44; females = 56)]. The data were analyzed by SPSS version 18.0 software. Vegetables, fatty foods, and poultry consumption were in accordance with the national guidelines. A significant percentage (45.5%) consumed rice mixed meals for all three meals and only 67% consumed fruits at least once a day. Majority (71%) consumed full-cream milk and sugar intake (77%) was in accordance with the guidelines. Noncaloric sweetener usage was nonexistent. Daily green leafy vegetable intake and the quantity consumed were inadequate to obtain beneficial effects. From the study population, 44% [females 50%; males 36%] of the patients were either overweight or obese. However, only 60% of those patients accepted that they were either overweight or obese. Only 14% exercised daily while 69% never exercised. Study revealed the importance of educating patients with type 2 diabetes on dietary changes and more importantly the involvement in regular physical exercises.


The proteomic response of cheliped myofibril tissue in the eurythermal porcelain crab Petrolisthes cinctipes to heat shock following acclimation to daily temperature fluctuations.
The porcelain crab Petrolisthes cinctipes lives under rocks and in mussel beds in the mid-intertidal zone where it experiences immersion during high tide and saturating humid conditions in air during low tide, which can increase habitat temperature by up to 20°C. To identify the biochemical changes affected by increasing temperature fluctuations and subsequent heat shock, we acclimated P. cinctipes for 30 days to one of three temperature regimes: (1) constant 10°C, (2) daily temperature fluctuations between 10 and 20°C (5 h up-ramp to 20°C, 1 h down-ramp to 10°C) and (3) 10-30°C (up-ramp to 30°C). After acclimation, animals were exposed to either 10°C or a 30°C heat shock to analyze the proteomic changes in claw muscle tissue. Following acclimation to 10-30°C (measured at 10°C), enolase and ATP synthase increased in abundance. Following heat shock, isoforms of arginine kinase and glycolytic enzymes such as aldolase, triose phosphate isomerase and glyceraldehyde 3-phosphate dehydrogenase increased across all acclimation regimes. Full-length isoforms of hemocyanin increased abundance following acclimation to 10-30°C, but hemocyanin fragments increased after heat shock following constant 10°C and fluctuating 10-20°C, possibly playing a role as antimicrobial peptides. Following constant 10°C and fluctuating 10-20°C, paramyosin and myosin heavy chain type-B increased in abundance, respectively, whereas myosin light and heavy chain decreased with heat shock. Actin-binding proteins, which stabilize actin filaments (filamin and tropomyosin), increased during heat shock following 10-30°C; however, actin severing and depolymerization proteins (gelsolin and cofilin) increased during heat shock following 10-20°C, possibly promoting muscle fiber restructuring. RAF kinase inhibitor protein and prostaglandin reductase increased during heat shock following constant 10°C and fluctuating 10-20°C, possibly inhibiting an immune response during heat shock. The results suggest that ATP supply, muscle fiber restructuring and immune responses are all affected by temperature fluctuations and subsequent acute heat shock in muscle tissue. Furthermore, although heat shock after acclimation to constant 10°C and fluctuating 10-30°C showed the greatest effects on the proteome, moderately fluctuating temperatures (10-20°C) broadened the temperature range over which claw muscle was able to respond to an acute heat shock with limited changes in the muscle proteome.


The 2020 update of the CEAP classification system and reporting standards.
The CEAP (Clinical-Etiology-Anatomy-Pathophysiology) classification is an internationally accepted standard for describing patients with chronic venous disorders and it has been used for reporting clinical research findings in scientific journals. Developed in 1993, updated in 1996, and revised in 2004, CEAP is a classification system based on clinical manifestations of chronic venous disorders, on current understanding of the etiology, the involved anatomy, and the underlying venous pathology. As the evidence related to these aspects of venous disorders, and specifically of chronic venous diseases (CVD, C2-C6) continue to develop, the CEAP classification needs periodic analysis and revisions. In May of 2017, the American Venous Forum created a CEAP Task Force and charged it to critically analyze the current classification system and recommend revisions, where needed. Guided by four basic principles (preservation of the reproducibility of CEAP, compatibility with prior versions, evidence-based, and practical for clinical use), the Task Force has adopted the revised Delphi process and made several changes. These changes include adding Corona phlebectatica as the C4c clinical subclass, introducing the modifier "r" for recurrent varicose veins and recurrent venous ulcers, and replacing numeric descriptions of the venous segments by their common abbreviations. This report describes all these revisions and the rationale for making these changes.


Video clip assessment of a salivary gland ultrasound scoring system in Sjögren's syndrome using consensual definitions: an OMERACT ultrasound working group reliability exercise.
To develop ultrasound (US) definitions and a US novel scoring system for major salivary gland (SG) lesions in patients with primary Sjögren's syndrome (pSS) and to test their intrareader and inter-reader reliability using US video clips. Twenty-five rheumatologists were subjected to a three-round, web-based Delphi process in order to agree on (1) definitions and scanning procedure of salivary gland ultrasonography (SGUS): parotid, submandibular and sublingual glands (PG, SMG and SLG); (2) definitions for the elementary SGUS lesions in patients with Sjögren's syndrome; (3) scoring system for grading changes. The experts rated the statements on a 1-5 Likert scale. In the second step, SGUS video clips of patients with pSS and non-pSS sicca cases were collected containing various spectrums of disease severity followed by an intrareader and inter-reader reliability exercise. Each video clip was evaluated according to the agreed definitions. Consensual definitions were developed after three Delphi rounds. Among the three selected SGs, US assessment of PGs and SMGs was agreed on. Agreement was reached to score only greyscale lesions and to focus on anechoic/hypoechoic foci in a semiquantitative matter or, if not possible on a qualitatively (present/absent) evaluation of fatty or fibrous lesions. Intrareader reliability for detecting and scoring these lesions was excellent (Cohen's kappa 0.81) and inter-reader reliability was good (Light's kappa 0.66). New definitions for developing a novel semiquantitative US score in patients with pSS were developed and tested on video clips. Inter-reader and intrareader reliabilities were good and excellent, respectively.


Strengthening the health workforce and rolling out universal health coverage: the need for policy analysis.
This article opens a debate about how to think about moving forward with the emerging twin movements of human resources for health (HRH) and universal health coverage (UHC). There is sufficient evidence to warrant these movements, but actors and the policy process significantly affect which policies are adopted and how they are implemented. How exactly this occurs in low- and middle-income countries (LMICs) is not very well understood. Furthermore, it is not clear whether actors will mobilize for or against the emergent HRH and UHC agendas. Policy analysis should help illuminate potential strategies to account for multiple interests and divergent values in volatile stakeholder environments. We argue that not only should the movement for UHC be paired with current efforts to address the human resources crisis, but also, for both to succeed, we need to know more about how health policy works in LMICs.


[Cytomorphological diagnosis of sarcoidosis in patients with lesions of the peripheral lymph nodes and respiratory organs].
In sarcoidosis, the cytomorphologic pattern of aspirates shows a predominant progressive inflammation without exudative reaction and caseous necrosis, round granulomas with signs of polymorphism with the presence of mononuclear elements, giant cells by the "foreign body" type and development of pronounced fibrosis.


[Sentinel lymph node diagnosis in prostatic carcinoma: II. Biokinetics and dosimetry of 99mTc-Nanocolloid after intraprostatic injection].
To visualise the sentinel lymph nodes (SLNs) of the prostate we injected the radiotracer into the parenchyma of the prostate. The activity was deposited in liver, spleen, bone marrow, urinary bladder and regional lymphatic system. The aim of this work is to determine biokinetical data and to estimate radiation doses to the patient. The patients with prostate cancer received a sonographically controlled, transrectal administration of 99mTc-Nanocoll, injected directly into both prostate lobes. In 10 randomly selected patients radionuclide distribution and its time course was determined via regions of interest (ROIs) over prostate, urinary bladder, liver, spleen and the lymph nodes. The uptake in the SLNs was estimated from gamma probe measurements at the surgically removed nodes. To compare tumour positive with tumour free lymph nodes according to SLN-uptake and SLN-localisation we evaluated 108 lymph nodes out of 24 patients with tumour positive SLN. For calculating the effective dose according to ICRP 60 of the patients we used the MIRD-method and the Mirdose 3.1 software. The average uptake of separate organs was: bladder content 24%, liver 25.5%, spleen 2%, sum of SLN 0.5%. An average of 9% of the applied activity remained in the prostate. The residual activity was mainly accumulated in bone marrow and blood. Occasionally a weak activity enrichment in intestinal tract and kidneys could be recognized. The effective dose to the patient was estimated to 7.6 microSv/MBq. The radioactivity uptake of the SLN varied in several orders of magnitude between 0.006% and 0.6%. The probability of SLN-metastasis was found to be independent from tracer uptake in the lymph node. The radioactivity uptake of the SLNs in distinct lymph node regions showed no significant differences. The radiotracer is transferred out of the prostate via blood flow, by direct transfer via the urethra into the bladder and by lymphatic transport. Injecting a total activity of 200 MBq leads to a mean effective dose of 1.5 mSv. It is not recommended to use the tracer uptake in lymph nodes as the only criterion to characterize SLNs.


Comparing deep learning architectures for sentiment analysis on drug reviews.
Since the turn of the century, as millions of user's opinions are available on the web, sentiment analysis has become one of the most fruitful research fields in Natural Language Processing (NLP). Research on sentiment analysis has covered a wide range of domains such as economy, polity, and medicine, among others. In the pharmaceutical field, automatic analysis of online user reviews allows for the analysis of large amounts of user's opinions and to obtain relevant information about the effectiveness and side effects of drugs, which could be used to improve pharmacovigilance systems. Throughout the years, approaches for sentiment analysis have progressed from simple rules to advanced machine learning techniques such as deep learning, which has become an emerging technology in many NLP tasks. Sentiment analysis is not oblivious to this success, and several systems based on deep learning have recently demonstrated their superiority over former methods, achieving state-of-the-art results on standard sentiment analysis datasets. However, prior work shows that very few attempts have been made to apply deep learning to sentiment analysis of drug reviews. We present a benchmark comparison of various deep learning architectures such as Convolutional Neural Networks (CNN) and Long short-term memory (LSTM) recurrent neural networks. We propose several combinations of these models and also study the effect of different pre-trained word embedding models. As transformers have revolutionized the NLP field achieving state-of-art results for many NLP tasks, we also explore Bidirectional Encoder Representations from Transformers (BERT) with a Bi-LSTM for the sentiment analysis of drug reviews. Our experiments show that the usage of BERT obtains the best results, but with a very high training time. On the other hand, CNN achieves acceptable results while requiring less training time.


Mixture models for cancer survival analysis: application to population-based data with covariates.
The interest in estimating the probability of cure has been increasing in cancer survival analysis as the curability of many cancer diseases is becoming a reality. Mixture survival models provide a way of modelling time to death when cure is possible, simultaneously estimating death hazard of fatal cases and the proportion of cured case. In this paper we propose an application of a parametric mixture model to relative survival rates of colon cancer patients from the Finnish population-based cancer registry, and including major survival determinants as explicative covariates. Disentangling survival into two different components greatly facilitates the analysis and the interpretation of the role of prognostic factors on survival patterns. For example, age plays a different role in determining, from one side, the probability of cure, and, from the other side, the life expectancy of fatal cases. The results support the hypothesis that observed survival trends are really due to a real prognostic gain for more recently diagnosed patients.


Immunopathogenesis of HCV-related endocrine manifestations in chronic hepatitis and mixed cryoglobulinemia.
Hepatitis C Virus (HCV) is known to be responsible for both hepatic and extrahepatic diseases (HCV-related extrahepatic diseases = HCV-EHDs). The most important systemic HCV-EHDs are mixed cryoglobulinemia and lymphoproliferative disorders, while the most frequent and clinically important endocrine HCV-EHDs are thyroid disorders and type 2 diabetes mellitus (T2D). From a meta-analysis of the literature a significant association between HCV infection and thyroid autoimmunity and hypothyroidism has been reported. A high prevalence of thyroid cancer has been reported, too. Furthermore, several clinical epidemiologic studies have reported that HCV infection is associated to T2D. Many studies have linked Th1 immune response with HCV infection, thyroid autoimmunity, or diabetes. These findings suggest that a possible common immunological Th1 pattern could be the pathophysiological base of the association of HCV-EHDs, with thyroid autoimmunity and T2D. In fact, HCV infection of thyrocytes or beta-cells may act by upregulating CXCL10 secretion in these cells that is responsible for Th1 lymphocyte recruitment. Th1 response leads to increased IFNgamma and TNFalpha production that in turn stimulates CXCL10 secretion by the target cells, thus perpetuating the immune cascade. This process may lead to the appearance of thyroid autoimmune disorders or T2D in genetically predisposed subjects.


Gold nanosponges: green synthesis, characterization, and cytotoxicity.
A simply approach for the synthesis of Au nanostructures in tea infusions at room temperature is developed. By controlling the concentrations of tea infusions, Au nanostructures in various shapes and sizes have been prepared. From 1 x (original concentration) and 0.01 x (100 times diluted) tea infusions, 52.2 +/- 8.1 nm Au nanosponges (T-Au NSs) and 23 +/- 2 nm spherical Au nanoparticles (T-Au NPs) were prepared. The phytochemicals present on the surface of T-Au NSs were proved by surface-assisted laser desorption/ionization mass spectrometry, Fourier transform infrared spectrometry and capillary electrophoresis coupled with UV detection. The energy-dispersive X-ray spectroscopy and powder X-ray diffraction data reveal pure crystalline structures of the T-Au NSs. The dark field scattering images observe that the T-Au NSs have significant affinity toward HeLa cells. The cytotoxicity of T-Au NSs on HeLa cells is through caspase-3 activation.