Phenotypic differences in genetically identical organisms: the epigenetic perspective.
Human monozygotic twins and other genetically identical organisms are almost always strikingly similar in appearance, yet they are often discordant for important phenotypes including complex diseases. Such variation among organisms with virtually identical chromosomal DNA sequences has largely been attributed to the effects of environment. Environmental factors can have a strong effect on some phenotypes, but evidence from both animal and human experiments suggests that the impact of environment has been overstated and that our views on the causes of phenotypic differences in genetically identical organisms require revision. New theoretical and experimental opportunities arise if epigenetic factors are considered as part of the molecular control of phenotype. Epigenetic mechanisms may explain paradoxical findings in twin and inbred animal studies when phenotypic differences occur in the absence of observable environmental differences and also when environmental differences do not significantly increase the degree of phenotypic variation.


Antibiotic Resistance in Agricultural Soil and Crops Associated to the Application of Cow Manure-Derived Amendments From Conventional and Organic Livestock Farms.
The application of organic amendments to agricultural soil can enhance crop yield, while improving the physicochemical and biological properties of the recipient soils. However, the use of manure-derived amendments as fertilizers entails environmental risks, such as the contamination of soil and crops with antibiotic residues, antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs). In order to delve into these risks, we applied dairy cow manure-derived amendments (slurry, fresh manure, aged manure), obtained from a conventional and an organic farm, to soil. Subsequently, lettuce and wheat plants were grown in the amended soils. After harvest, the abundance of 95 ARGs and MGE-genes from the amended soils and plants were determined by high-throughput qPCR. The structure of soil prokaryotic communities was determined by 16S rRNA amplicon sequencing and qPCR. The absolute abundance of ARGs and MGE-genes differed between treatments (amended vs. unamended), origins of amendment (conventional vs. organic), and types of amendment (slurry vs. fresh manure vs. aged manure). Regarding ARG-absolute abundances in the amendments themselves, higher values were usually found in slurry vs. fresh or aged manure. These abundances were generally higher in soil than in plant samples, and higher in wheat grain than in lettuce plants. Lettuce plants fertilized with conventional amendments showed higher absolute abundances of tetracycline resistance genes, compared to those amended with organic amendments. No single treatment could be identified as the best or worst treatment regarding the risk of antibiotic resistance in soil and plant samples. Within the same treatment, the resistome risk differed between the amendment, the amended soil and, finally, the crop. In other words, according to our data, the resistome risk in manure-amended crops cannot be directly inferred from the analysis of the amendments themselves. We concluded that, depending on the specific question under study, the analysis of the resistome risk should specifically focus on the amendment, the amended soil or the crop.


Why national eHealth programs need dead philosophers: Wittgensteinian reflections on policymakers' reluctance to learn from history.
Policymakers seeking to introduce expensive national eHealth programs would be advised to study lessons from elsewhere. But these lessons are unclear, partly because a paradigm war (controlled experiment versus interpretive case study) is raging. England's $20.6 billion National Programme for Information Technology (NPfIT) ran from 2003 to 2010, but its overall success was limited. Although case study evaluations were published, policymakers appeared to overlook many of their recommendations and persisted with some of the NPfIT's most criticized components and implementation methods. In this reflective analysis, illustrated by a case fragment from the NPfIT, we apply ideas from Ludwig Wittgenstein's postanalytic philosophy to justify the place of the "n of 1" case study and consider why those in charge of national eHealth programs appear reluctant to learn from such studies. National eHealth programs unfold as they do partly because no one fully understands what is going on. They fail when this lack of understanding becomes critical to the programs' mission. Detailed analyses of the fortunes of individual programs, articulated in such a way as to illuminate the contextualized talk and action ("language games") of multiple stakeholders, offer unique and important insights. Such accounts, portrayals rather than models, deliver neither statistical generalization (as with experiments) nor theoretical generalization (as with multisite case comparisons or realist evaluations). But they do provide the facility for heuristic generalization (i.e., to achieve a clearer understanding of what is going on), thereby enabling more productive debate about eHealth programs' complex, interdependent social practices. A national eHealth program is best conceptualized not as a blueprint and implementation plan for a state-of-the-art technical system but as a series of overlapping, conflicting, and mutually misunderstood language games that combine to produce a situation of ambiguity, paradox, incompleteness, and confusion. But going beyond technical "solutions" and engaging with these language games would clash with the bounded rationality that policymakers typically employ to make their eHealth programs manageable. This may explain their limited and contained response to the nuanced messages of in-depth case study reports. The complexity of contemporary health care, combined with the multiple stakeholders in large technology initiatives, means that national eHealth programs require considerably more thinking through than has sometimes occurred. We need fewer grand plans and more learning communities. The onus, therefore, is on academics to develop ways of drawing judiciously on the richness of case studies to inform and influence eHealth policy, which necessarily occurs in a simplified decision environment.


On the depths and shapes of the freshest kilometer-scale simple craters on the lunar maria: A new crater shape model.
Recent work on the shapes of small, simple impact craters on the Moon has shown that the parabolic ideal does not well represent the vast majority of these craters. They are hyperbolic in shape and usually resemble a cone more than a parabola. A parabolic shape also does not fit the most commonly held archetype for simple craters in general (Linné), which is also hyperbolic. In addition, Linné itself may not be the best model for fresh simple craters, in terms of cross-sectional shape, although shape data to compare it to have heretofore been lacking. Here, the "free shadowfront method" for determining the shapes of simple craters is used to measure 64 fresh simple craters on five lunar maria to test both assumptions. Laser altimetry cross sections, available for many of the craters measured herein, are used to complement and spot-check the shadow measurement results, and thereby demonstrate the efficacy of the free shadowfront method. A new shape model is established, and two craters that better fit this model than Linné are identified. These are located at 24.45° N/328.12° E and 31.35° N/296.46° E and have diameters of 1.40 and 2.73 km, respectively. An apparent dichotomy between fresh simple craters smaller than 2.5 km and those larger than this is observed. Flat floors are found to be ubiquitous among the larger craters, but rare and small in extent in smaller ones. A slide in one crater which appears to be an incipient flat floor suggests a major mode of formation for these flat floors.


The efficacy and safety of the novel long-acting β2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial.
Vilanterol (GW642444M) (VI) is a novel, inhaled, long-acting β(2) agonist with inherent 24-h activity under development as a once-daily combination therapy with an inhaled corticosteroid for COPD and asthma. This study assessed the dose response, efficacy, and safety of VI at doses of 3 to 50 μg in patients with moderate to severe COPD. Six hundred two patients (intent-to-treat) were randomized (double-blind) to VI 3, 6.25, 12.5, 25, or 50 μg or placebo once daily for 28 days. The primary end point was change from baseline in trough FEV1 at the end of the 28-day treatment period. Secondary end points included 0- to 24-h weighted mean FEV(1) on days 1 and 28 and time to increases of ≥ 100 mL or ≥ 12% from baseline FEV(1) on day 1. Safety assessments included adverse events, vital signs, ECG assessment, and clinical laboratory tests. VI once daily for 28 days significantly improved trough FEV(1) in a dose-dependent manner vs placebo. Clinically relevant treatment differences of ≥ 130 mL in trough and 0- to 24-h weighted mean FEV(1) were observed with VI 25- and 50-μg doses vs placebo. All doses of VI were associated with a low incidence of treatment-related adverse events/serious adverse events, with no suggestion of effects on BP, pulse rate, QT intervals corrected for heart rate calculated by Fridericia formula, or blood glucose and potassium levels. VI 25 and 50 μg once daily provided both statistically and clinically relevant 24-h improvements in lung function in patients with COPD compared with placebo. All doses of VI had a safety and tolerability profile similar to placebo.


Are proteins ideal mixtures of amino acids? Analysis of energy parameter sets.
Various existing derivations of the effective potentials of mean force for the two-body interactions between amino acid side chains in proteins are reviewed and compared to each other. The differences between different parameter sets can be traced to the reference state used to define the zero of energy. Depending on the reference state, the transfer free energy or other pseudo-one-body contributions can be present to various extents in two-body parameter sets. It is, however, possible to compare various derivations directly by concentrating on the "excess" energy-a term that describes the difference between a real protein and an ideal solution of amino acids. Furthermore, the number of protein structures available for analysis allows one to check the consistency of the derivation and the errors by comparing parameters derived from various subsets of the whole database. It is shown that pair interaction preferences are very consistent throughout the database. Independently derived parameter sets have correlation coefficients on the order of 0.8, with the mean difference between equivalent entries of 0.1 kT. Also, the low-quality (low resolution, little or no refinement) structures show similar regularities. There are, however, large differences between interaction parameters derived on the basis of crystallographic structures and structures obtained by the NMR refinement. The origin of the latter difference is not yet understood.


Acetylcholine receptor gating in a zebrafish model for slow-channel syndrome.
Slow-channel syndrome (SCS) is an autosomal-dominant disease resulting from mutations in muscle acetylcholine (ACh) receptor subunits. The associated fatigue and muscle degeneration are proposed to result from prolonged synaptic responses that overload intracellular calcium. Single-channel studies on reconstituted receptors bearing human mutations indicate that the prolonged responses result from an increase in receptor open duration and, in some cases, increased sensitivity to ACh. We show that both of these aberrant receptor properties are recapitulated in heterozygotic zebrafish bearing an L258P mutation in the α subunit, thus affording the unique opportunity to compare the single-channel properties of mutant receptors to the synaptic currents in vivo. Whole-cell recordings revealed synaptic currents that decayed along a multiexponential time course, reflecting receptors containing mixtures of wild-type and mutant α subunits. Treatment with quinidine, an open-channel blocker used to treat the human disorder, restored fast synaptic current kinetics and the ability to swim. Quinidine block also revealed that mutant receptors generate a large steady-state current in the absence of ACh. The spontaneous openings reflected a destabilization of the closed state, leading to an apparent increase in the sensitivity of these receptors to ACh. The effective block by quinidine on synaptic currents as well as nonliganded openings points to dual sources for the calcium-dependent myopathy in certain forms of SCS.


The 18 Household Food Security Survey items provide valid food security classifications for adults and children in the Caribbean.
We tested the properties of the 18 Household Food Security Survey (HFSS) items, and the validity of the resulting food security classifications, in an English-speaking middle-income country. Survey of primary school children in Trinidad and Tobago. Parents completed the HFSS. Responses were analysed for the 10 adult-referenced items and the eight child-referenced items. Item response theory models were fitted. Item calibrations and subject scores from a one-parameter logistic (1PL) model were compared with those from either two-parameter logistic model (2PL) or a model for differential item functioning (DIF) by ethnicity. There were 5219 eligible with 3858 (74%) completing at least one food security item. Adult item calibrations (standard error) in the 1PL model ranged from -4.082 (0.019) for the 'worried food would run out' item to 3.023 (0.042) for 'adults often do not eat for a whole day'. Child item calibrations ranged from -3.715 (0.025) for 'relied on a few kinds of low cost food' to 3.088 (0.039) for 'child didn't eat for a whole day'. Fitting either a 2PL model, which allowed discrimination parameters to vary between items, or a differential item functioning model, which allowed item calibrations to vary between ethnic groups, had little influence on interpretation. The classification based on the adult-referenced items showed that there were 19% of respondents who were food insecure without hunger, 10% food insecure with moderate hunger and 6% food insecure with severe hunger. The classification based on the child-referenced items showed that there were 23% of children who were food insecure without hunger and 9% food insecure with hunger. In both children and adults food insecurity showed a strong, graded association with lower monthly household income (P < 0.001). These results support the use of 18 HFSS items to classify food security status of adults or children in an English-speaking country where food insecurity and hunger are more frequent overall than in the US.


The effect of cryotherapy on oral mucosa: a study in healthy volunteers.
Oral cryotherapy causes local vasoconstriction, which reduces blood flow and reduces the cytotoxic damage to the oral mucosa, has been shown to reduce oral mucositis after intense cytostatic treatment. The main object of this study was to investigate the effect of oral cryotherapy on the temperature in the oral mucosa, the level of proinflammatory cytokine interleukin-6 (IL-6) in saliva and the effect on blood pressure in healthy volunteers, before and after 1 h of cooling the oral cavity with crushed ice. Twelve healthy volunteers [mean age 32.4 (SD 13.2) (20-56) years] were treated with oral cryotherapy in the form of crushed ice. Temperature measurements were performed in the oral mucosa using infrared thermograph following a flowchart protocol. Blood pressure (BP) was measured with a sphygmomanometer. Saliva was analysed for inflammatory cytokine IL-6, using an enzyme-linked immunosorbent assay (ELISA). All participants fulfilled the cooling session. The temperature in the oral cavity decreased significantly (mean 12.9 °C, p < .002). The systolic BP was marginally but significantly higher after cooling (~5 mmHg, p = .019). We could not detect any differences in cytokine IL-6 levels before and after oral cooling. We conclude that cryotherapy during 1 h lowers the mucosal temperature as much as ~12.9 °C, which explains the significant protective effect against mucosal damage by cytostatic drugs. The cooling caused no increase in IL-6 levels. Systemic blood pressure was marginally increased.


[Endoscopic removal of calculi from the choledochus. Are there debatable questions in this problem?].
The article generalizes experience (1986-1991) in the treatment of 246 patients with choledocholithiasis with the performance of endoscopic papillosphincterotomy. Most patients (61%) were over 60 years of age, many had serious concomitant diseases. Among patients with occlusion of the bile ducts, 53.6% had obstructive purulent cholangitis, 53.6% had acute biliary pancreatitis, and 30.9% had acute cholecystitis. Typical as well as atypical cannulation EPST was applied. To exclude an X-ray load on the patient and doctor, the orifices of the terminal part of the common bile duct and of the main pancreatic duct were identified in most patients by an elaborated method of cannulation with aspiration control without preliminary contrast X-ray examination. After EPST the concrements were removed completely in 194 and partly in 52 patients. Complications occurred in 35 patients (bleeding in 5, acute pancreatitis in 8, acute cholangitis in 6, acute cholecystitis in 8, perforation of the duodenum in 1, and wedging of Dormia's basket in 8 patients. Eight patients died after EPST from unresolved purulent cholangitis and multiple cholangitic abscesses of the liver. The long-term results were studied in follow-up periods of 12 months to 7 years. Recurrent cholelithiasis was encountered in 2 patients. On the basis of the accumulated experience we believe EPST to be the method of choice in the management of: residual and recurrent choledocholithiasis, patients with cholecystocholedocholithiasis and operation risk factors, patients with acute biliary pancreatitis and acute obstructive cholangitis.


Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells.
Acquired resistance to cisplatin treatment is a caveat when treating patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Ceramide increases in response to chemotherapy, leading to proliferation arrest and apoptosis. However, a tumour stress activation of glucosylceramide synthase (GCS) follows to eliminate ceramide by formation of glycosphingolipids (GSLs) such as globotriaosylceramide (Gb3), the functional receptor of verotoxin-1. Ceramide elimination enhances cell proliferation and apoptosis blockade, thus stimulating tumor progression. GSLs transactivate multidrug resistance 1/P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1) expression which further prevents ceramide accumulation and stimulates drug efflux. We investigated the expression of Gb3, MDR1 and MRP1 in NSCLC and MPM cells with acquired cisplatin resistance, and if GCS activity or MDR1 pump inhibitors would reduce their expression and reverse cisplatin-resistance. Cell surface expression of Gb3, MDR1 and MRP1 and intracellular expression of MDR1 and MRP1 was analyzed by flow cytometry and confocal microscopy on P31 MPM and H1299 NSCLC cells and subline cells with acquired cisplatin resistance. The effect of GCS inhibitor PPMP and MDR1 pump inhibitor cyclosporin A for 72h on expression and cisplatin cytotoxicity was tested. The cisplatin-resistant cells expressed increased cell surface Gb3. Cell surface Gb3 expression of resistant cells was annihilated by PPMP whereas cyclosporin A decreased Gb3 and MDR1 expression in H1299 cells. No decrease of MDR1 by PPMP was noted in using flow cytometry, whereas a decrease of MDR1 in H1299 and H1299res was indicated with confocal microscopy. No certain co-localization of Gb3 and MDR1 was noted. PPMP, but not cyclosporin A, potentiated cisplatin cytotoxicity in all cells. Cell surface Gb3 expression is a likely tumour biomarker for acquired cisplatin resistance of NSCLC and MPM cells. Tumour cell resistance to MDR1 inhibitors of cell surface MDR1 and Gb3 could explain the aggressiveness of NSCLC and MPM. Therapy with GCS activity inhibitors or toxin targeting of the Gb3 receptor may substantially reduce acquired cisplatin drug resistance of NSCLC and MPM cells.


Robust Variable and Interaction Selection for Logistic Regression and General Index Models.
Under the logistic regression framework, we propose a forward-backward method, SODA, for variable selection with both main and quadratic interaction terms. In the forward stage, SODA adds in predictors that have significant overall effects, whereas in the backward stage SODA removes unimportant terms to optimize the extended Bayesian Information Criterion (EBIC). Compared with existing methods for variable selection in quadratic discriminant analysis, SODA can deal with high-dimensional data in which the number of predictors is much larger than the sample size and does not require the joint normality assumption on predictors, leading to much enhanced robustness. We further extend SODA to conduct variable selection and model fitting for general index models. Compared with existing variable selection methods based on the Sliced Inverse Regression (SIR) (Li, 1991), SODA requires neither linearity nor constant variance condition and is thus more robust. Our theoretical analysis establishes the variable-selection consistency of SODA under high-dimensional settings, and our simulation studies as well as real-data applications demonstrate superior performances of SODA in dealing with non-Gaussian design matrices in both logistic and general index models.


The mentalizing network orchestrates the impact of parochial altruism on social norm enforcement.
Parochial altruism--a preference for altruistic behavior towards ingroup members and mistrust or hostility towards outgroup members--is a pervasive feature in human society and strongly shapes the enforcement of social norms. Since the uniqueness of human society critically depends on the enforcement of norms, the understanding of the neural circuitry of the impact of parochial altruism on social norm enforcement is key, but unexplored. To fill this gap, we measured brain activity with functional magnetic resonance imaging (fMRI) while subjects had the opportunity to punish ingroup members and outgroup members for violating social norms. Findings revealed that subjects' strong punishment of defecting outgroup members is associated with increased activity in a functionally connected network involved in sanction-related decisions (right orbitofrontal gyrus, right lateral prefrontal cortex, right dorsal caudatus). Moreover, the stronger the connectivity in this network, the more outgroup members are punished. In contrast, the much weaker punishment of ingroup members who committed the very same norm violation is associated with increased activity and connectivity in the mentalizing-network (dorsomedial prefrontal cortex, bilateral temporo-parietal junction), as if subjects tried to understand or justify ingroup members' behavior. Finally, connectivity analyses between the two networks suggest that the mentalizing-network modulates punishment by affecting the activity in the right orbitofrontal gyrus and right lateral prefrontal cortex, notably in the same areas showing enhanced activity and connectivity whenever third-parties strongly punished defecting outgroup members.


Engineering the substrate specificity and reactivity of a heme protein: creation of an ascorbate binding site in cytochrome c peroxidase.
The binding of substrates to heme enzymes has been widely assumed to occur at the so-called delta-heme edge. Recently, however, a number of examples have appeared in which substrate binding at an alternative site, the gamma-heme edge, is also possible. In previous work [Sharp et al. (2003) Nat. Struct. Biol. 10, 303-307], we showed that binding of ascorbate to ascorbate peroxidase occurred at the gamma-heme edge. Here, we show that the closely related cytochrome c peroxidase enzyme can duplicate the substrate binding properties of ascorbate peroxidase through the introduction of relatively modest structural changes at Tyr36 and Asn184. Hence, crystallographic data for the Y36A/N184R/W191F triple variant of cytochrome c peroxidase shows ascorbate bound to the gamma-heme edge, with hydrogen bonds to the heme propionate and Arg184. In parallel mechanistic studies in variants incorporating the W191F mutation, we show that a transient porphyrin pi-cation radical in Compound I of cytochrome c peroxidase, analogous to that observed in ascorbate peroxidase, is competent for ascorbate oxidation but that under steady state conditions this intermediate decays too rapidly to sustain efficient turnover of ascorbate. The results are discussed in terms of our more general understanding of substrate oxidation across other heme proteins, and the emerging role of the heme propionates at the gamma-heme edge.


Low vibration high numerical aperture automated variable temperature Raman microscope.
Raman micro-spectroscopy is well suited for studying a variety of properties and has been applied to a wide range of areas. Combined with tuneable temperature, Raman spectra can offer even more insights into the properties of materials. However, previous designs of variable temperature Raman microscopes have made it extremely challenging to measure samples with low signal levels due to thermal and positional instabilities as well as low collection efficiencies. Thus contemporary Raman microscope has found limited applicability to probing the subtle physics involved in phase transitions and hysteresis. This paper describes a new design of a closed-cycle, Raman microscope with full polarization rotation. High collection efficiency, thermal stability, and mechanical stability are ensured by both deliberate optical, cryogenic, and mechanical design. Measurements on two samples, Bi2Se3 and V2O3, which are challenging due to low thermal conductivities, low signal levels, and/or hysteretic effects, are measured with previously undemonstrated temperature resolution.


Path analysis of the chronicity of depression using the comprehensive developmental model framework.
Background Depressive disorder is recognized as recurrent or chronic in the majority of affected individuals; but literature is not consistent about determinants of the disorder course. Aims To analyse the relationships between familial, personal and environmental characteristics in different life phases and their effects on the chronicity of depression in a population-based sample. Methods It was a longitudinal panel study with three waves (W1-W3) for 651 adult men and women with diagnosis of minor/major depression or dysthymia at W1 of the Swedish PART (mental health, work and relations) study. Risk factors and co-morbidities were assessed with questionnaires. The main outcome was an episode of minor/major depression or dysthymia at 10-12 years of follow-up (W3). Liability for depressive episodes was determined using exploratory structural equation modelling (SEM), following a path approach with step-wise specification searches. Results Most of the risk factors determined, directly or indirectly, depression severity at W3. Somatic trait anxiety, partner loss and other negative life events at W1, depressive symptoms at W2, and life difficulties and other dependent life events at W3 had direct effects on the outcome. Conclusions SEM model revealed complex and intertwined psychopathological pathways leading to chronicity of depression, given previous episodes, which could be assembled in two main mechanisms: a depressive-internalizing path and an adversity path comprised of life events. Pathways are simpler than those of depression occurrence, emphasizing the relevance of personality factors as depression determinants, and excluding disability levels, co-morbidities and social support. These novel findings need to be replicated in future studies.


Common carp insulin-like growth factor-I gene: complete nucleotide sequence and functional characterization of the 5'-flanking region.
Insulin-like growth factor-I (IGF-I) plays an important role in the growth and development of fish. To understand the molecular mechanism which controls the transcription of the IGF-I gene in common carp, we have cloned and completely sequenced the IGF-I gene and the 5'-flanking region from a local tropical fish, the common carp (Cyprinus carpio), and characterized its promoter activity by transfection into human embryonic kidney (293GHR) cells which express the human growth hormone (GH) receptor. The common carp gene is the smallest IGF-I gene known so far, spanning approximately 13 kb, and is consisted of five exons and four introns. The sequence of the gene is consistent with the single type of IGF-I cDNA that we have isolated previously from a common carp liver cDNA library. The expression pattern of IGF-I is similar between juvenile carp and adult carp. While liver was found to be the major site of IGF-I gene expression in common carp, the expression levels in other tissues are relatively low. Like many other IGF-I gene promoters, there are no apparent TATA box and CCAAT box upstream of the transcription initiation site. However, sequence analysis of the common carp IGF-I promoter region identified several consensus liver-enriched transcription factor binding sites, including HNF-1alpha, HNF-3beta, C/EBP, and one STAT5. We have analyzed the promoter activity of the 5'-flanking region of the common carp IGF-I gene by performing luciferase reporter assays in transfected 293GHR cells. Addition of human GH to the transfected cells led to an increased expression of the reporter gene, indicating that the cloned genomic fragment possessed promoter activity. This was confirmed by the lack of promoter activity of a construct in which the putative promoter was cloned in a reverse orientation upstream of the reporter gene. The liver-specific transcription factor, hepatic nuclear factor (HNF)-1alpha, was also found to be involved in the regulation of the common carp IGF-I transcription. Transfection results from a set of deletion mutants helped to map the locations of the responsive elements on the promoter responsible for the GH effect and for the interaction with HNF-1alpha. These observations provide information for delineating the transcriptional regulation of IGF-I gene expression in common carp.


The correlation between ATLS and junior doctors' anatomical knowledge of central venous catheter insertion at a major trauma centre in South Africa.
To review the ability of junior doctors (JDs) in identifying the correct anatomical site for central venous catheterization (CVC) and whether prior Advanced Trauma Life Support (ATLS) training influences this. We performed a prospective, observational study using a structured survey and asked a group of JDs (postgraduate year 1 [PGY1] or year 2 [PGY2]) to indicate on a photograph the exact site for CVC insertion via the internal jugular (IJV) and the subclavian (SCV) approach. This study was conducted in a large metropolitan university hospital in South Africa. A total of 139 JDs were included. Forty-four per cent (61/139) were males and the mean age was 25 years. There were 90 PGY1s (65%) and 49 PGY2s (35%). Overall, 32% (45/139) were able to identify the correct insertion site for the IJV approach and 60% (84/139) for the SCV approach. Of the 90 PGY1s, 34% (31/90) correctly identified the insertion site for the IJV approach and 59% (53/90) for the SCV approach. Of the 49 PGY2s, 29% (14/49) correctly identified the insertion site for the IJV approach and 63% (31/49) for the SCV approach. No significant difference between PGY1 and 2 were identified. Those with ATLS provider training were significantly more likely to identify the correct site for the IJV approaches [OR=4.3, p=0.001]. This was marginally statistically significant (i.e. p>0.05 but <0.1) for the SCV approach. The majority of JDs do not have sufficient anatomical knowledge to identify the correct insertion site CVCs. Those who had undergone ATLS training were more likely to be able to identify the correct insertion site.


Resting heart rate and the risk of heart failure in healthy adults: the Rotterdam Study.
An elevated resting heart rate is associated with rehospitalization for heart failure and is a modifiable risk factor in heart failure patients. We aimed to examine the association between resting heart rate and incident heart failure in a population-based cohort study of healthy adults without pre-existing overt heart disease. We studied 4768 men and women aged ≥55 years from the population-based Rotterdam Study. We excluded participants with prevalent heart failure, coronary heart disease, pacemaker, atrial fibrillation, atrioventricular block, and those using β-blockers or calcium channel blockers. We used extended Cox models allowing for time-dependent variation of resting heart rate along follow-up. During a median of 14.6 years of follow-up, 656 participants developed heart failure. The risk of heart failure was higher in men with higher resting heart rate. For each increment of 10 beats per minute, the multivariable adjusted hazard ratios in men were 1.16 (95% confidence interval, 1.05-1.28; P=0.005) in the time-fixed heart rate model and 1.13 (95% confidence interval, 1.02-1.25; P=0.017) in the time-dependent heart rate model. The association could not be demonstrated in women (P for interaction=0.004). Censoring participants for incident coronary heart disease or using time-dependent models to account for the use of β-blockers or calcium channel blockers during follow-up did not alter the results. Baseline or persistent higher resting heart rate is an independent risk factor for the development of heart failure in healthy older men in the general population.


Risk of lung cancer associated with domestic use of coal in Xuanwei, China: retrospective cohort study.
To estimate the risk of lung cancer associated with the use of different types of coal for household cooking and heating. Xuanwei County, Yunnan Province, China. Retrospective cohort study (follow-up 1976-96) comparing mortality from lung cancer between lifelong users of "smoky coal" (bituminous) and "smokeless coal" (anthracite). 27,310 individuals using smoky coal and 9962 individuals using smokeless coal during their entire life. Primary outcomes were absolute and relative risk of death from lung cancer among users of different types of coal. Unadjusted survival analysis was used to estimate the absolute risk of lung cancer, while Cox regression models compared mortality hazards for lung cancer between smoky and smokeless coal users. Lung cancer mortality was substantially higher among users of smoky coal than users of smokeless coal. The absolute risks of lung cancer death before 70 years of age for men and women using smoky coal were 18% and 20%, respectively, compared with less than 0.5% among smokeless coal users of both sexes. Lung cancer alone accounted for about 40% of all deaths before age 60 among individuals using smoky coal. Compared with smokeless coal, use of smoky coal was associated with an increased risk of lung cancer death (for men, hazard ratio 36 (95% confidence interval 20 to 65); for women, 99 (37 to 266)). In Xuanwei, the domestic use of smoky coal is associated with a substantial increase in the absolute lifetime risk of developing lung cancer and is likely to represent one of the strongest effects of environmental pollution reported for cancer risk. Use of less carcinogenic types of coal could translate to a substantial reduction of lung cancer risk.


Familial placement and relations of Rehmannia and Triaenophora (Scrophulariaceae s.l.) inferred from five gene regions.
Accurate classification systems based on evolution are imperative for biological investigations. The recent explosion of molecular phylogenetics has resulted in a much improved classification of angiosperms. More than five phylogenetic lineages have been recognized from Scrophulariaceae sensu lato since the family was determined to be polyphyletic; however, questions remain about the genera that have not been assigned to one of the segregate families of Scrophulariaceae s.l. Rehmannia Liboschitz and Triaenophora Solereder are such genera with uncertain familial placement. There also is debate whether Triaenophora should be segregated from Rehmannia. To evaluate the phylogenetic relations between Rehmannia and Triaenophora, to find their closest relatives, and to verify their familial placement, we conducted phylogenetic analyses of the sequences of one nuclear DNA (ITS) region and four chloroplast DNA gene regions (trnL-F, rps16, rbcL, and rps2) individually and combined. The analyses showed that Rehmannia and Triaenophora are each strongly supported as monophyletic and together are sister to Orobanchaceae. This relation was corroborated by phytochemical and morphological data. Based on these data, we suggest that Rehmannia and Triaenophora represent the second nonparasitic branch sister to the remainder of Orobanchaceae (including Lindenbergia).


Progress and challenges for abiotic stress proteomics of crop plants.
Plants are continually challenged to recognize and respond to adverse changes in their environment to avoid detrimental effects on growth and development. Understanding the mechanisms that crop plants employ to resist and tolerate abiotic stress is of considerable interest for designing agriculture breeding strategies to ensure sustainable productivity. The application of proteomics technologies to advance our knowledge in crop plant abiotic stress tolerance has increased dramatically in the past few years as evidenced by the large amount of publications in this area. This is attributed to advances in various technology platforms associated with MS-based techniques as well as the accessibility of proteomics units to a wider plant research community. This review summarizes the work which has been reported for major crop plants and evaluates the findings in context of the approaches that are widely employed with the aim to encourage broadening the strategies used to increase coverage of the proteome.


The x-ray crystal structure of mannose-binding lectin-associated serine proteinase-3 reveals the structural basis for enzyme inactivity associated with the Carnevale, Mingarelli, Malpuech, and Michels (3MC) syndrome.
The mannose-binding lectin associated-protease-3 (MASP-3) is a member of the lectin pathway of the complement system, a key component of human innate and active immunity. Mutations in MASP-3 have recently been found to be associated with Carnevale, Mingarelli, Malpuech, and Michels (3MC) syndrome, a severe developmental disorder manifested by cleft palate, intellectual disability, and skeletal abnormalities. However, the molecular basis for MASP-3 function remains to be understood. Here we characterize the substrate specificity of MASP-3 by screening against a combinatorial peptide substrate library. Through this approach, we successfully identified a peptide substrate that was 20-fold more efficiently cleaved than any other identified to date. Furthermore, we demonstrated that mutant forms of the enzyme associated with 3MC syndrome were completely inactive against this substrate. To address the structural basis for this defect, we determined the 2.6-Å structure of the zymogen form of the G666E mutant of MASP-3. These data reveal that the mutation disrupts the active site and perturbs the position of the catalytic serine residue. Together, these insights into the function of MASP-3 reveal how a mutation in this enzyme causes it to be inactive and thus contribute to the 3MC syndrome.


Effectiveness of long-term treatment with SGLT2 inhibitors: real-world evidence from a specialized diabetes center.
Diabetes is a progressive disease needing multiple drugs for achieving and maintaining good glycemic control. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) is a novel class of anti-diabetic agent which offers several beneficial effects. However, the long-term effectiveness in clinical practice and safety data of SGLT2 inhibitors is limited, especially in Asian patients. To better understand the effectiveness of SGLT2i in clinical practice, we conducted a retrospective evaluation of patients with diabetes on SGLT2i. This retrospective observational study uses data of patients with diabetes who had been prescribed SGLT2i and continued to use at least 6 months at Theptarin Hospital, Bangkok. The characteristics of patients, changes in glycemic control and body weight at 3, 6, 12, 18, 24 months and the last follow-up were evaluated. A total of 189 patients with diabetes (females 50.3%, mean age 59.9 ± 12.3 years, T2DM 97.3%, duration of diabetes 16.3 ± 9.2 years, baseline BMI 29.9 ± 6.1 kg/m2, baseline HbA1c 8.8 ± 1.6%) were prescribed SGLT2i during the study period. At the time of first SGLT2i prescription, 80.4% used three or more other anti-diabetic agents concomitantly and 34.6% used insulin concomitantly. 151 patients who continue to use at least 6 months were included in analysis. At the last follow-up (median time 16 months), overall median HbA1c reduction and weight reduction were 1.0% and 1.5 kg, respectively. While glycemic control could maintain up to 18 months, weight loss gradually rebounded after the first 6 months and then backed to baseline body weight at 18 months (78.2 ± 18.0 kg vs. 78.0 ± 17.8, p value = 0.324). The incidence of adverse drug reactions of special interest (polyuria, volume depletion-related events, urinary tract infection, genital infection, and hypoglycemia) was 2.1, 1.6, 2.1, 2.6, and 7.9%, respectively. This real-world study confirmed long-term durability of glycemic control with SGLT2i in not only monotherapy, but also add-on studies with other oral anti-diabetic drugs and/or insulin treatment. However, weight loss became evident early after 6 weeks then reached slightly rebounds after 24 weeks until the end of follow-up. Further studies should be done towards a better understanding of treatment with SGLT2i in routine clinical practice.


Multi-meter fiber-delivery and pulse self-compression of milli-Joule femtosecond laser and fiber-aided laser-micromachining.
We report on damage-free fiber-guidance of milli-Joule energy-level and 600-femtosecond laser pulses into hypocycloid core-contour Kagome hollow-core photonic crystal fibers. Up to 10 meter-long fibers were used to successfully deliver Yb-laser pulses in robustly single-mode fashion. Different pulse propagation regimes were demonstrated by simply changing the fiber dispersion and gas. Self-compression to ~50 fs, and intensity-level nearing petawatt/cm(2) were achieved. Finally, free focusing-optics laser-micromachining was also demonstrated on different materials.


Age-dependent alterations in Ca2+ homeostasis: role of TRPV5 and TRPV6.
Aging is associated with alterations in Ca2+ homeostasis, which predisposes elder people to hyperparathyroidism and osteoporosis. Intestinal Ca2+ absorption decreases with aging and, in particular, active transport of Ca2+ by the duodenum. In addition, there are age-related changes in renal Ca2+ handling. To examine age-related changes in expression of the renal and intestinal epithelial Ca2+ channels, control (TRPV5+/+) and TRPV5 knockout (TRPV5-/-) mice aged 10, 30, and 52 wk were studied. Aging of TRPV5(+/+) mice resulted in a tendency toward increased renal Ca2+ excretion and significantly decreased intestinal Ca2+ absorption, which was accompanied by reduced expression of TRPV5 and TRPV6, respectively, despite increased serum 1,25(OH)2D3 levels. Similarly, in TRPV5-/- mice the existing renal Ca2+ loss was more pronounced in elder animals, whereas the compensatory intestinal Ca2+ absorption and TRPV6 expression declined with aging. In both mice strains, aging resulted in a resistance to 1,25(OH)2D3 and diminished renal vitamin D receptor mRNA levels, whereas serum Ca2+ levels remained constant. Furthermore, 52-wk-old TRPV5-/- mice showed severe hyperparathyroidism, whereas PTH levels in elder TRPV5+/+ mice remained normal. In 52-wk-old TRPV5-/- mice, serum osteocalcin levels were increased in accordance with the elevated PTH levels, suggesting an increased bone turnover in these mice. In conclusion, downregulation of TRPV5 and TRPV6 is likely involved in the impaired Ca2+ (re)absorption during aging. Moreover, TRPV5-/- mice likely develop age-related hyperparathyroidism and osteoporotic characteristics before TRPV5+/+ mice, demonstrating the importance of the epithelial Ca2+ channels in Ca2+ homeostasis.


Blood transfusion for preventing stroke in people with sickle cell disease.
Sickle cell disease is a common inherited haemoglobin disorder. The abnormal haemoglobin causes distortion of red blood cells, anaemia, vaso-occlusion and dysfunction in virtually any organ system in the body. Stroke occurs in around 10% of children with sickle cell anaemia, and recurrences after a first stroke are likely. Chronic blood transfusion regimes are often used in an attempt to dilute the sickled red blood cells, thus reducing the risk of vaso-occlusion and stroke. However, the side-effects of such regimens can be severe. To assess the relative risks and benefits of chronic blood transfusion regimes in patients with sickle cell disease to prevent a first stroke or further strokes. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group specialist register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Date of the most recent search of the Group's specialised register: July 2001 All those randomised or quasi-randomised controlled trials in which blood transfusion as a preventative measure for stroke in patients with sickle cell disease are compared to an alternative treatment or to no treatment. Both reviewers independently assessed trial quality and extracted data from the study included. One trial was identified by the initial search and this met the inclusion criteria for the review. The trial compared a chronic transfusion regime to maintain sickle haemoglobin at less than 30% with standard care in 130 children with sickle cell disease who were judged to be at high risk of a first stroke through transcranial doppler ultrasonography. Eleven children in the standard care group suffered a stroke during the trial, compared to only one in the transfusion group. Because of this 92% relative risk reduction, the trial was terminated 16 months early. It had been planned that all patients would be treated for 30 months, but median follow-up only 21.1 months. However, a high rate of complications such as iron overload, alloimmunisation and transfusion reactions were seen in the children who were receiving transfusions. No randomised controlled trials were identified which investigated use of transfusion for preventing recurrence of stroke. While the included study demonstrated a significantly reduced risk of stroke in patients receiving regular blood transfusions, the degree of risk must be balanced against the burden of a chronic transfusion regime. Further research is required to establish the use of transfusion in preventing secondary stroke, the age, or length of time after an event, at which transfusion can safely be stopped, and to further define risk factors for stroke in order to reduce the chance of unnecessarily putting children onto a chronic transfusion regime.


Bridging spinal cord injuries.
One strategy for spinal cord injury repair is to make cellular bridges that support axon regeneration. However, the bridging cells often fail to integrate with host tissue and may lead to increased pain sensitivity. Recent work has tested bridging with two forms of progenitor-derived astrocyte. One type integrates, suppresses scar formation and promotes axon regeneration, whereas another very similar type, reported in Journal of Biology, does not support regeneration and increases pain sensitivity.


Skills training groups for men with ADHD in compulsory care due to substance use disorder: a feasibility study.
Dialectical behavior therapy (DBT)-based skills training has been developed and previously evaluated for adults with ADHD in a psychiatric outpatient context. The aim of the present study was to evaluate the feasibility of DBT-based skills training as a voluntary intervention for men with ADHD in compulsory care due to severe substance abuse. Forty sufficiently detoxified men with ADHD in compulsory care due to life-threatening substance use disorder (SUD) were included in DBT-based skills training groups. Self- and staff-rating scales were administered before and after the treatment. The refusal rate was 42.9 %. Of those who started the DBT-based skills training, 70 % completed the treatment (attendance at ≥75 % of the sessions). The treatment acceptability was good. Both ADHD and psychiatric symptoms decreased from pre- to post-intervention in self-ratings, but not in staff ratings. The patients reported improved general well-being. The correlation between self- and staff ratings was poor. Motivation for voluntary nonpharmacological treatment was low in a compulsory care context. However, the results indicate that a DBT-based skills training program for adults with ADHD may be feasible for some patients with ADHD in combination with SUD in compulsory care, provided that considerable resources are allocated with adjustments to the target group and compulsory care context.


Comparison between web-based and paper versions of a self-administered anthropometric questionnaire.
Online data collection could advantageously replace paper-and-pencil questionnaires in epidemiological studies by reducing the logistic burden, the cost and the duration of data processing. However, there is a need for studies comparing these new instruments to traditional ones. Our objective was to compare the web-based version of the NutriNet-Santé self-administered anthropometric questionnaire to the paper-based version. The questionnaire included 17 questions divided into subquestions (55 variables in all) dealing with height, weight, hip and waist circumferences, weight history, restrictive diet and weight self-perception. Both versions of the questionnaire were filled out by 147 volunteers (paper version first, N = 76, or web-based version first, N = 71) participating in the SU.VI.MAX ("Supplémentation en VItamines Minéraux et AntioXydants") cohort (age-range: 49-75 years; men: 46.3%). At the end of the test, subjects filled in a "satisfaction" questionnaire giving their opinions and feelings about each version. Agreement was assessed by intraclass correlation coefficients (ICCs) and kappas. We also quantified the number of errors inherent in the paper version. Agreement between the two versions was high. ICCs ranged from 0.86 to 1.00. Kappas ranged from 0.69 to 1.00 for comparable variables. A total of 82 data entry mistakes (1.5% of total entries), 60 missing values (1.1%), 57 inconsistent values (1.1%) and 3 abnormal values (0.1%) were counted in the paper version (non-existent in the web-based version due to integrated controls). The web-based version was preferred by 92.2% of users. In conclusion, the quality of information provided by the web-based anthropometric questionnaire used in the NutriNet-Santé Study was equal to, or better than, that of the paper version, with substantial logistic and cost advantages.


Genetics of resistance to HIV infection: Role of co-receptors and co-receptor ligands.
Susceptibility to HIV infection and AIDS progression is variable among individuals and populations, and in part genetically determined. Genetic variants of genes encoding HIV co-receptors and their chemokine ligands have been described, and some of these variants were associated with resistance to HIV infection and/or disease progression. We review here the reported data regarding the variants of the CCR5, CCR2, CX3CR1, MIP-1alpha/CCL3, MIP-1beta/CCL4, RANTES/CCL5 and SDF-1/CXCL12 genes. The Delta32 deletion mutant of CCR5, resulting in a non-functional receptor not reaching the cell surface, is unambiguously associated with strong, although incomplete, resistance to HIV infection for homozygotes, and retarded progression for heterozygotes. Specific haplotypes encompassing the CCR5 and CCR2 loci, and the copy number of the CCL3L1 gene, have also been convincingly correlated with delayed progression. For other gene variants, involving CXCL12/SDF-1 and CX3CR1, conclusive evidence for their relevance in the frame of HIV susceptibility is still lacking.


Optical coherence tomography in gastroenterology: a review and future outlook.
Optical coherence tomography (OCT) is an imaging technique optically analogous to ultrasound that can generate depth-resolved images with micrometer-scale resolution. Advances in fiber optics and miniaturized actuation technologies allow OCT imaging of the human body and further expand OCT utilization in applications including but not limited to cardiology and gastroenterology. This review article provides an overview of current OCT development and its clinical utility in the gastrointestinal tract, including disease detection/differentiation and endoscopic therapy guidance, as well as a discussion of its future applications.


Size-Dependent Neurotoxicity of Aluminum Oxide Particles: a Comparison Between Nano- and Micrometer Size on the Basis of Mitochondrial Oxidative Damage.
Aluminum nanoparticles (AlNPs) are among the most abundantly produced nanosized particles in the market. There is limited information about the potential harmful effects of aluminum oxide due to its particle size on human health. Considering the toxic effects of Al on brain as its target tissue, in this study, the toxicity of nanoparticles, microparticles, and ionic forms of Al on rat brain and isolated mitochondria was evaluated. Sixty male Wistar rats were divided into ten groups (six rats each), in which group I was the control, and the other groups were administered different doses of Al nanoparticles, Al microparticles (AlMP), and Al ionic forms (2, 4, and 8 mg/kg, i.p.) for 28 days. After 24 h, the animals were killed, brain tissue was separated, the mitochondrial fraction was isolated, and oxidative stress markers were measured. Also, mitochondrial function was assayed by MTT test. The results showed that all forms of Al particles induced ROS formation, lipid peroxidation, protein oxidation, glutathione depletion, mitochondrial dysfunction, and gait abnormalities in a dose-dependent manner. In addition, Al particles decreased mitochondrial membrane potential. These data indicated that oxidative stress might contribute to the toxicity effects of Al. Comparison of oxidative stress markers between all forms of Al revealed that the toxic effect of AlNP on brain tissue was substantially more than that caused by AlMP and bulk form. This study showed more neurotoxicity of AlNPs compared to other forms on brain oxidative damage that probably is due to more penetration into the brain.


The Natural History of Postconcussion Recovery Among High School Athletes.
Evaluate postconcussive symptom reporting and recovery. Public high school. Unmatched controls (n = 760); students who sustained a sports-related concussion (n = 77); matched controls (gender, grade, sport) (n = 77). Prospective longitudinal cohort study. Immediate Postconcussion Assessment and Cognitive Testing. At baseline, athletes who went on to sustain concussions were more likely than unmatched controls to be younger (P = .02), male (P = .001), and participate in different sports (P < .0001) such as football (concussed = 52%, unmatched controls = 20%). Differences were also noted regarding a previous history of concussion (P = .045; concussed athletes = 26%; unmatched control athletes = 16%) and lifetime number of concussions (P = .05). At baseline, those whose sustained concussions during the study period were more likely than matched controls to report numbness (P = .01) and concentration problems (P = .01) and more likely than unmatched controls to report dizziness (P = .02), sensitivity to light (P = .01), sensitivity to noise (P = .002), and numbness (P = .02). However, when data were reanalyzed and those with a previous history of concussion were removed, differences between those who sustained concussions during the study period and matched controls were no longer significant; when compared to unmatched controls, sensitivity to light (P = .01) and vision problems (P = .04) remained significant. Among those who sustained concussions, median time to recovery was 6 days (95% confidence interval: 4-9), and 71 out of 77 (92%) recovered by the fourth postinjury evaluation (median: 20 days postinjury). Course and time frame of recovery were variable. Data also suggest that a previous history of concussion may be contributing to baseline symptom reporting and highlight the potential enduring impact of history of concussion on sensorimotor function. However, further research as to whether preinjury measures of sensorimotor function may increase understanding regarding concussion risk is warranted.


The association between mental health nursing and hospital admissions for people with serious mental illness: a protocol for a systematic review.
Relapse in individuals with severe mental illness (SMI) is a frequent occurrence and can add considerably to the burden of disease. As such, relapse prevention is an essential therapeutic outcome for people with SMI. Mental health nurses (MHNs) are well placed to support individuals with SMI and to prevent relapse; notwithstanding, there has been no synthesis of the evidence to date to determine whether MHNs prevent relapse in this population. Electronic databases will be systemically searched for observational studies and clinical trials that report the association between mental health nursing and the hospitalisation of persons living with an SMI. The search will be supplemented by reference checking and a search of the grey literature. The primary outcome of interest will be hospital admission rate. Screening of articles, data extraction and critical appraisal will be undertaken by two reviewers, independently, with a third reviewer consulted should disagreement occur between reviewers. The quality of studies will be assessed using the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool and the Cochrane Collaboration risk of bias tool. Depending on the number of studies and level of heterogeneity, the evidence may be synthesised using meta-analysis or narrative synthesis. This review will explore for the first time the clinical potential of mental health nursing in preventing relapse in persons with SMI. The findings of this review will serve to inform future research and education in this area. The evidence may also help inform future policy, including decisions regarding future mental health workforce development and planning. PROSPERO CRD42017058694 .


Exploring uncertainty in the calibration of the molecular clock.
Calibration is a critical step in every molecular clock analysis but it has been the least considered. Bayesian approaches to divergence time estimation make it possible to incorporate the uncertainty in the degree to which fossil evidence approximates the true time of divergence. We explored the impact of different approaches in expressing this relationship, using arthropod phylogeny as an example for which we established novel calibrations. We demonstrate that the parameters distinguishing calibration densities have a major impact upon the prior and posterior of the divergence times, and it is critically important that users evaluate the joint prior distribution of divergence times used by their dating programmes. We illustrate a procedure for deriving calibration densities in Bayesian divergence dating through the use of soft maximum constraints.


A self-reported survey on the confidence levels and motivation of New South Wales practice nurses on conducting advance-care planning (ACP) initiatives in the general-practice setting.
Nurses are well positioned to initiate and conduct advance-care planning (ACP) conversations; however, there has been limited research on practice nurses performing this role in Australia. The aim of the present study was to understand the beliefs, attitudes, perceptions, confidence, training and educational needs of New South Wales practice nurses with regards to involvement in ACP. A cross-sectional online survey was conducted in August to October 2014. Nurses were recruited through nursing organisations and Medicare Locals. There were 147 completed surveys (n=147). Participants were mostly female registered nurses, with a median age of 50, and 6 years of practice-nurse experience. Practice nurses were generally positive towards their involvement in ACP and believed it would be beneficial for the community. Their confidence in initiating ACP increased as their familiarity with patients increased. They showed a high level of interest in participating in training and education in ACP. Barriers to their involvement in ACP included the lack of a good documentation system, limited patient-education resources and unclear source of remuneration. Nurses were also concerned over legalities of ACP, ethical considerations and their understanding of end-of-life care options. Nevertheless, they were highly receptive of integrating ACP discussions and were willing to enhance their skills. These findings uncover a need for further training and development of practice nurses for ACP discussions.


Biodistribution of the radiophamarceutical sodium pertechnetate (Na99mTcO4) after massive small bowel resection in rats.
To evaluate the biodistribution of sodium pertecnetate (Na(99m)TcO(4)) in organs and tissues, the morphometry of remnant intestinal mucosa and ponderal evolution in rats subjected to massive resection of the small intestine. Twenty-one Wistar rats were randomly divided into three groups of 7 animals each. The short bowel (SB) group was subjected to massive resection of the small intestine; the control group (C) rats were not operated on, and soft intestinal handling was performed in sham rats. The animals were weighed weekly. On the 30th postoperative day, 0.l mL of Na(99m)TcO(4), with mean activity of 0.66 MBq was injected intravenously into the orbital plexus. After 30 minutes, the rats were killed with an overdose of anesthetic, and fragments of the liver, spleen, pancreas, stomach, duodenum, small intestine, thyroid, lung, heart, kidney, bladder, muscle, femur and brain were harvested. The biopsies were washed with 0.9% NaCl.,The radioactivity was counted using Gama Counter Wizard 1470, PerkinElmer. The percentage of radioactivity per gram of tissue (%ATI/g) was calculated. Biopsies of the remaining jejunum were analysed by HE staining to obtain mucosal thickness. Analysis of variance (ANOVA) and the Tukey test for multiple comparisons were used, considering p<0.05 as significant. There were no significant differences in %ATI/g of the Na(99m)TcO(4) in the organs of the groups studied (p>0.05). An increase in the weight of the SB rats was observed after the second postoperative week. The jejunal mucosal thickness of the SB rats was significantly greater than that of C and sham rats (p<0.05). In rats with experimentally-produced short bowel syndrome, an adaptive response by the intestinal mucosa reduced weight loss. The biodistribution of Na(99m)TcO(4) was not affected by massive intestinal resection, suggesting that short bowel syndrome is not the cause of misleading interpretation, if an examination using this radiopharmaceutical is indicated.


Canine leishmaniosis. Modulation of macrophage/lymphocyte interactions by L. infantum.
Canine leishmaniosis, caused by Leishmania infantum, is a systemic disease with variable clinical signs and a progressive evolution. This disease is characterized by impaired T cell-mediated immune response, which has been associated with disease chronicity and high mortality. Protective immunity against leishmaniosis is thought to be mediated by T cell and cytokine production. The T cell activation requires a primary signal delivered by the major histocompatibility complex (MHC) molecules present on the surface of antigen presenting cells, and a non-specific signal generated by co-stimulatory molecules. To characterize canine immune responses in the presence of L. infantum parasites or their antigens, in vitro cell cultures of canine macrophages and lymphocytes were established, and the macrophages presenting MHC class II molecules were evaluated as well as the expression of IL-12 and CD80-86 co-stimulatory molecules and nitric oxide production. The results showed for the first time the up-regulation of MHC class II molecules on the surface in canine peripheral blood monocyte-derived macrophages during L. infantum infection in the presence of lymphocytes. In addition, a lack of co-stimulatory expression and a reduced release of nitric oxide were observed, suggesting a loss of T cell function and consequently an inactivation of the macrophage oxidative burst which, in turn, favors the survival of Leishmania. These results constitute a new contribution for the understanding of the interactions between L. infantum and the canine immune system.


Obesity in South Africa: the South African demographic and health survey.
To ascertain the anthropometric profile and determinants of obesity in South Africans who participated in the Demographic and Health Survey in 1998. A sample of 13,089 men and women (age, > or =15 years) were randomly selected and then stratified by province and urban and nonurban areas. Height, weight, mid-upper arm circumference, and waist and hip circumference were measured. Body mass index (BMI) was used as an indicator of obesity, and the waist/hip ratio (WHR) was used as an indicator of abdominal obesity. Multivariate regression identified sociodemographic predictors of BMI and waist circumference in the data. Mean BMI values for men and women were 22.9 kg/m(2) and 27.1 kg/m(2), respectively. For men, 29.2% were overweight or obese (> or =25 kg/m(2)) and 9.2% had abdominal obesity (WHR > or =1.0), whereas 56.6% of women were overweight or obese and 42% had abdominal obesity (WHR >0.85). Underweight (BMI <18.5 kg/m(2)) was found in 12.2% of men and 5.6% of women. For men, 19% of the variation of BMI and 34% of the variation in waist circumference could be explained by age, level of education, population group, and area of residence. For women, these variables explained 16% of the variation of BMI and 24% of the variation in waist circumference. Obesity increased with age, and higher levels of obesity were found in urban African women. Overnutrition is prevalent among adult South Africans, particularly women. Determinants of overnutrition include age, level of education, ethnicity, and area of residence.


Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients.
Cancer cell death can be perceived as immunogenic by the host only when malignant cells emit immunostimulatory signals (so-called "damage-associated molecular patterns," DAMPs), as they die in the context of failing adaptive responses to stress. Accumulating preclinical and clinical evidence indicates that the capacity of immunogenic cell death to (re-)activate an anticancer immune response is key to the success of various chemo- and radiotherapeutic regimens. Malignant blasts from patients with acute myeloid leukemia (AML) exposed multiple DAMPs, including calreticulin (CRT), heat-shock protein 70 (HSP70), and HSP90 on their plasma membrane irrespective of treatment. In these patients, high levels of surface-exposed CRT correlated with an increased proportion of natural killer cells and effector memory CD4+ and CD8+ T cells in the periphery. Moreover, CRT exposure on the plasma membrane of malignant blasts positively correlated with the frequency of circulating T cells specific for leukemia-associated antigens, indicating that ecto-CRT favors the initiation of anticancer immunity in patients with AML. Finally, although the levels of ecto-HSP70, ecto-HSP90, and ecto-CRT were all associated with improved relapse-free survival, only CRT exposure significantly correlated with superior overall survival. Thus, CRT exposure represents a novel powerful prognostic biomarker for patients with AML, reflecting the activation of a clinically relevant AML-specific immune response.


The geometrical learning of binary neural networks.
In this paper, the learning algorithm called expand-and-truncate learning (ETL) is proposed to train multilayer binary neural networks (BNN) with guaranteed convergence for any binary-to-binary mapping. The most significant contribution of this paper is the development of a learning algorithm for three-layer BNN which guarantees the convergence, automatically determining a required number of neurons in the hidden layer. Furthermore, the learning speed of the proposed ETL algorithm is much faster than that of backpropagation learning algorithm in a binary field. Neurons in the proposed BNN employ a hard-limiter activation function, with only integer weights and integer thresholds. Therefore, this will greatly facilitate actual hardware implementation of the proposed BNN using currently available digital VLSI technology.


Speciation of indium(iii) chloro complexes in the solvent extraction process from chloride aqueous solutions to ionic liquids.
Most metal extraction studies focus on the kinetics, the maximum loading and the extraction equilibrium, while structural information on the extracted complexes has been limited. This paper concerns the nature of the indium(iii) chloride complexes, present in the organic and aqueous phase during the solvent extraction of indium(iii) from an aqueous HCl solution by undiluted ionic liquids Cyphos® IL 101 and Aliquat® 336. In an aqueous HCl solution (0-12 M), indium(iii) exists as octahedral mixed complexes, [In(H2O)6-nCln]3-n (0 ≤ n ≤ 6). EXAFS and 115In NMR were used to characterize these species. The stoichiometric composition of the extracted complexes, which is estimated from viscosity and maximum loading studies and confirmed by EXAFS, is unaffected by the HCl concentration in the aqueous phase. Indium(iii) is present in the ionic liquid phase as the tetrahedral [InCl4]- complex. Based on the speciation results an extraction mechanism is proposed.


Evaluation of 2D-/3D-Feet-Detection Methods for Semi-Autonomous Powered Wheelchair Navigation.
Powered wheelchairs have enhanced the mobility and quality of life of people with special needs. The next step in the development of powered wheelchairs is to incorporate sensors and electronic systems for new control applications and capabilities to improve their usability and the safety of their operation, such as obstacle avoidance or autonomous driving. However, autonomous powered wheelchairs require safe navigation in different environments and scenarios, making their development complex. In our research, we propose, instead, to develop contactless control for powered wheelchairs where the position of the caregiver is used as a control reference. Hence, we used a depth camera to recognize the caregiver and measure at the same time their relative distance from the powered wheelchair. In this paper, we compared two different approaches for real-time object recognition using a 3DHOG hand-crafted object descriptor based on a 3D extension of the histogram of oriented gradients (HOG) and a convolutional neural network based on YOLOv4-Tiny. To evaluate both approaches, we constructed Miun-Feet-a custom dataset of images of labeled caregiver's feet in different scenarios, with backgrounds, objects, and lighting conditions. The experimental results showed that the YOLOv4-Tiny approach outperformed 3DHOG in all the analyzed cases. In addition, the results showed that the recognition accuracy was not improved using the depth channel, enabling the use of a monocular RGB camera only instead of a depth camera and reducing the computational cost and heat dissipation limitations. Hence, the paper proposes an additional method to compute the caregiver's distance and angle from the Powered Wheelchair (PW) using only the RGB data. This work shows that it is feasible to use the location of the caregiver's feet as a control signal for the control of a powered wheelchair and that it is possible to use a monocular RGB camera to compute their relative positions.


Positive feedbacks in the fire dynamic of closed canopy tropical forests
The incidence and importance of fire in the Amazon have increased substantially during the past decade, but the effects of this disturbance force are still poorly understood. The forest fire dynamics in two regions of the eastern Amazon were studied. Accidental fires have affected nearly 50 percent of the remaining forests and have caused more deforestation than has intentional clearing in recent years. Forest fires create positive feedbacks in future fire susceptibility, fuel loading, and fire intensity. Unless current land use and fire use practices are changed, fire has the potential to transform large areas of tropical forest into scrub or savanna.


Insulin-like growth factors in endometrioid adenocarcinoma: correlation with clinico-pathological features and estrogen receptor expression.
Endometrial carcinoma is a common malignancy of female genital tract. Insulin-like growth factor is known to elicit estrogen-induced mitogenic activity and anti-apoptotic effect in endometrial tissues. The retrospective study investigated the expression of insulin-like growth factors, estrogen receptors and their associations in endometrioid adenocarcinoma (EAC) from 80 EAC patients in immunohistochemistry, and 58 EAC patients and 42 control patients in quantitative RT-PCR. The Pearson correlation analysis was used to analyze their correlations with clinic-pathological parameters. Our results showed that insulin-like growth factor-1 and insulin-like growth factor-2 mRNA levels were higher in tumor tissues and tumor-adjacent tissues than those in control cells, and were inversely correlated with the malignancy of the tumor with a positive correlation with ERα and ERβ expression. Insulin-like growth factor-1R protein expression was correlated with clinical stage, and insulin-like growth factor-2R protein expression was inversely correlated with histological grade. Insulin-like growth factor system plays an important role in estrogen-induced endometrial carcinogenesis, and overexpression of insulin-like growth factor-1R in the advanced endometrioid adenocarcinoma is not estrogen-dependent.


A better approach to medical malpractice claims? The University of Michigan experience.
The root causes of medical malpractice claims are deeper and closer to home than most in the medical community care to admit. The University of Michigan Health System's experience suggests that a response by the medical community more directly aimed at what drives patients to call lawyers would more effectively reduce claims, without compromising meritorious defenses. More importantly, honest assessments of medical care give rise to clinical improvements that reduce patient injuries. Using a true case example, this article compares the traditional approach to claims with what is being done at the University of Michigan. The case example illustrates how an honest, principle-driven approach to claims is better for all those involved-the patient, the healthcare providers, the institution, future patients, and even the lawyers.


The Challenges for Labour Market Policy during the COVID-19 Pandemic.
The COVID-19 pandemic is having a dramatic economic impact in most countries. In the UK, it has led to sharp falls in labour demand in many sectors of the economy and to initial acute labour shortages in other sectors. Much more than in a typical downturn, the current crisis is not simply a general slowdown in economic activity but also a radical short-term shift in the mix of economic activities - of which an unknown, but possibly significant, amount will be persistent. The initial policy response has focused on cushioning the blow to families' finances and allowing the majority of workers and firms to resume their original activities once the crisis subsides. These are crucial priorities. But there should also be a focus on reallocating some workers, either temporarily if working in shut-down sectors or permanently by facilitating transitions to sectors and jobs offering better prospects and facing labour shortages. The phasing-out of the furlough subsidies, which is projected to happen in Autumn 2020, brings this into even sharper focus since the alternative for many workers will be unemployment. Active labour market policy will need to be front and centre.


Joint lavage for osteoarthritis of the knee.
Osteoarthritis is the most common form of joint disorder and a leading cause of pain and physical disability. Observational studies suggested a benefit for joint lavage, but recent, sham-controlled trials yielded conflicting results, suggesting joint lavage not to be effective. To compare joint lavage with sham intervention, placebo or non-intervention control in terms of effects on pain, function and safety outcomes in patients with knee osteoarthritis. We searched CENTRAL, MEDLINE, EMBASE, and CINAHL up to 3 August 2009, checked conference proceedings, reference lists, and contacted authors. We included studies if they were randomised or quasi-randomised trials that compared arthroscopic and non-arthroscopic joint lavage with a control intervention in patients with osteoarthritis of the knee. We did not apply any language restrictions. Two independent review authors extracted data using standardised forms. We contacted investigators to obtain missing outcome information. We calculated standardised mean differences (SMDs) for pain and function, and risk ratios for safety outcomes. We combined trials using inverse-variance random-effects meta-analysis. We included seven trials with 567 patients. Three trials examined arthroscopic joint lavage, two non-arthroscopic joint lavage and two tidal irrigation. The methodological quality and the quality of reporting was poor and we identified a moderate to large degree of heterogeneity among the trials (I(2) = 65%). We found little evidence for a benefit of joint lavage in terms of pain relief at three months (SMD -0.11, 95% CI -0.42 to 0.21), corresponding to a difference in pain scores between joint lavage and control of 0.3 cm on a 10-cm visual analogue scale (VAS). Results for improvement in function at three months were similar (SMD -0.10, 95% CI -0.30 to 0.11), corresponding to a difference in function scores between joint lavage and control of 0.2 cm on a WOMAC disability sub-scale from 0 to 10. For pain, estimates of effect sizes varied to some degree depending on the type of lavage, but this variation was likely to be explained by differences in the credibility of control interventions: trials using sham interventions to closely mimic the process of joint lavage showed a null-effect. Reporting on adverse events and drop out rates was unsatisfactory, and we were unable to draw conclusions for these secondary outcomes. Joint lavage does not result in a relevant benefit for patients with knee osteoarthritis in terms of pain relief or improvement of function.


Numb Isoforms Deregulation in Medulloblastoma and Role of p66 Isoform in Cancer and Neural Stem Cells.
Numb is an intracellular protein with multiple functions. The two prevalent isoforms, Numb p66 and Numb p72, are regulators of differentiation and proliferation in neuronal development. Additionally, Numb functions as cell fate determinant of stem cells and cancer stem cells and its abnormal expression has been described in several types of cancer. Involvement of deregulated Numb expression has been described in the malignant childhood brain tumor medulloblastoma, while Numb isoforms in these tumors and in cancer stem-like cells derived from them, have not been studied to date. Here we show that medulloblastoma stem-like cells and cerebellar neuronal stem cells (NSCs) express Numb p66 where its expression tampers stemness features. Furthermore, medulloblastoma samples evaluated in this study express decreased levels of Numb p66 while overexpressed Numb p72 compared with normal tissues. Our results uncover different roles for the two major Numb isoforms examined in medulloblastoma and a critical role for Numb p66 in regulating stem-like cells and NSCs maintenance.


Vegetable Organosulfur Compounds and their Health Promoting Effects.
Trends in modern pharmaceutical science show an increase in demand for new drugs and diet supplements derived from natural products, while during the last decades, great research is conducted regarding the natural compounds and their medicinal and bioactive properties. Organosulfur compounds are present in many plants and their bioactive properties have been used in folk and traditional medicine throughout the centuries. Not until recently, modern science confirmed and revealed the chemical compounds that are responsible for these properties, the chemistry involved in their biosynthesis and the main mechanisms of action. In the present review, the organosulfur compounds of vegetable origin and their health effects are presented, focusing on the chemical composition of their main compounds, their biosynthesis and the mechanisms involved in their health effects. Sulfur compound sources presented include mainly vegetable species belonging to Allium genus and Brassicaceae family. Organosulfur compounds of vegetable sources are very important in human diet, and their regular consumption has a beneficial contribution to health and well-being. Moreover, their medicinal properties and therapeutic effects have been described thousands of years ago, while they constitute an important ingredient in traditional medicines and preparations. However, not until recently, the mechanisms of action of organosulfur compounds have started to unravel, with promising results for further exploitation of these significant bioactive compounds in drug development and novel nutraceutical products. This review reveals the numerous biological activities of organosulfur compounds of vegetable origin, while it also presents the results of recent clinical studies and trials.


Molecular Classification of Gastric Adenocarcinoma.
As one of the leading causes of cancer-related deaths, gastric cancer (GC) has gained more and more attention. Although most GCs are adenocarcinomas, they have considerable heterogeneity among patients. Thus, appropriate classification and individualized treatment of GCs is essential. The traditional morphology-based classification systems including the World Health Organization (WHO) classification and the Lauren's classification have a limited utility in guiding clinical treatment due to the molecular heterogeneity of GC. Classifications based on molecular features become important. Recent years, molecular methods such as next-generation sequencing (NGS) including deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, whole-exome sequencing, copy number variation analysis and DNA methylation arrays have been used to classify the GC into molecular subtypes which can convey more detailed information of tumor than histopathological characteristics. In this review, we described the current molecular classifications of GC including the intrinsic subtypes, Lei subtypes, The Cancer Genome Atlas (TCGA) subtypes, Asian Cancer Research Group (ACRG) subtypes, and some other additional classifications.


Crystal structure of the lectin from Dioclea grandiflora complexed with core trimannoside of asparagine-linked carbohydrates.
The seed lectin from Dioclea grandiflora (DGL) has recently been shown to possess high affinity for 3, 6-di-O-(alpha-D-mannopyranosyl)-alpha-D-mannopyranose, the core trimannoside of asparagine-linked carbohydrates, but lower affinity for biantennary complex carbohydrates. In the previous paper, the thermodynamics of DGL binding to deoxy analogs of the core trimannoside and to a biantennary complex carbohydrate were determined by isothermal titration microcalorimetry. The data suggest that DGL recognizes specific hydroxyl groups of the trimannoside similar to that of the jack bean lectin concanavalin A (ConA) (Gupta, D. Dam, T. K., Oscarson, S., and Brewer, C. F. (1997) J. Biol. Chem. 272, 6388-6392). However, the thermodynamics of DGL binding to certain deoxy analogs and to the complex carbohydrate are different from that of ConA. In the present paper, the x-ray crystal structure of DGL complexed to the core trimannoside was determined to a resolution of 2.6 A. The overall structure of the DGL complex is similar to the structure of the ConA-trimannoside complex (Naismith, J. H., and Field, R. A. (1996) J. Biol. Chem. 271, 972-976). The location and conformation of the bound trimannoside as well as its hydrogen-bonding interactions in both complexes are nearly identical. However, differences exist in the location of two loops outside of the respective binding sites containing residues 114-125 and 222-227. The latter residues affect the location of a network of hydrogen-bonded water molecules that interact with the trisaccharide. Differences in the arrangement of ordered water molecules in the binding site and/or protein conformational differences outside of the binding site may account for the differences in the thermodynamics of binding of the two lectins to deoxy analogs of the trimannoside. Molecular modeling studies suggest how DGL discriminates against binding the biantennary complex carbohydrate relative to ConA.


Percolation, renormalization, and quantum computing with nondeterministic gates.
We apply a notion of static renormalization to the preparation of entangled states for quantum computing, exploiting ideas from percolation theory. Such a strategy yields a novel way to cope with the randomness of nondeterministic quantum gates. This is most relevant in the context of optical architectures, where probabilistic gates are common, and cold atoms in optical lattices, where hole defects occur. We demonstrate how to efficiently construct cluster states without the need for rerouting, thereby avoiding a massive amount of conditional dynamics; we furthermore show that except for a single layer of gates during the preparation, all subsequent operations can be shifted to the final adapted single-qubit measurements. Remarkably, cluster state preparation is achieved using essentially the same scaling in resources as if deterministic gates were available.


Renin is not synthesized by cardiac and extrarenal vascular tissues. A review of experimental evidence.
A comprehensive review of physiological and molecular biological evidence refutes claims for synthesis of renin by cardiac and vascular tissues. Cardiovascular tissue renin completely disappears after binephrectomy. Residual putative reninlike activity, where investigated, has had the characteristics of lysosomal acid proteases. Occasional reports of renin or renin mRNA in vascular and cardiac tissues can be ascribed to failure to remove the kidneys 24 hours beforehand, overloading of detection systems, problems with stringency in identification, and illegitimate transcripts after more than 25 cycles of polymerase chain reaction. Others, using more stringent criteria, have failed to detect cardiac and vascular renin mRNA. Accordingly, a growing number of investigators have concluded that the kidneys are the only source of cardiovascular tissue renin. Although prorenin is secreted from extrarenal tissues as well as from the kidneys, there is no evidence that it is ever converted to renin in the circulation. The kidney is the only tissue with known capacity to convert prorenin to renin and to secrete active renin into the circulation. Accordingly, renin of renal origin determines plasma and hence, extracellular fluid renin levels. In these loci, angiotensin (Ang) I, formed by renin cleavage of circulating and interstitial fluid angiotensinogen, is in turn cleaved by angiotensin converting enzyme, located in plasma and extracellular fluids and on the luminal surface of pulmonary and systemic vascular endothelial cells, to Ang II, which perfuses and bathes the heart and vasculature. Consistent with this model, plasma renin and angiotensin and the antihypertensive action of renin inhibitors, converting enzyme inhibitor, or Ang II antagonists all disappear after binephrectomy. Thus, the plasma renin level, via Ang II formation, determines renin system vasoconstrictor activity, the antihypertensive potential of anti-renin system drugs, and the risk of heart attack in hypertensive patients. This analysis redirects renin research to renal mechanisms that create the plasma renin level, to renal prorenin biosynthesis and its processing to renin, and to their regulated secretion, extracellular distribution, and possible binding to by target tissues. In this context, it is still possible that changes in circulating and interstitial renin substrate or available converting enzyme might exert subtle modulating influences on Ang II formation. However, this analysis redefines the importance of plasma renin measurements to assess clinical situations, because plasma renin is the only known initiator driving the cardiovascular renin-angiotensin system, and its strength can be measured.


Electrocardiographic features of immune checkpoint inhibitor associated myocarditis.
Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis. From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested. Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39). The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.


Diabetes mellitus and gestational diabetes, active and reserve component service members and dependents, 2008-2018.
During 2008-2018, a total of 12,582 active component service members received incident diagnoses of any diabetes mellitus (DM), for a crude overall incidence rate of 84.8 per 100,000 person-years. More than four-fifths of incident cases were type 2 DM. The overall rates of this form of DM among Asian/Pacific Islander and non-Hispanic black active and reserve component service members were 1.5 or more times the rates among their respective counterparts in other race/ethnicity groups. Crude annual rates of type 2 DM diagnoses among active and reserve component members peaked in 2010 and then decreased to their lowest points in 2018. From 2010 through 2018, decreases in rates of incident type 2 DM diagnoses were observed among active and reserve component members in all subgroups examined (sex, age, race/ethnicity, service), with the greatest slopes of decline seen among service members aged 40 years or older, Asian/Pacific Islanders, and Army members. During 2008-2018, total counts of incident diagnoses of type 2 DM among Military Health System (MHS) dependents decreased by 66.0%, from 29,625 to 10,066. The overall crude prevalence of gestational DM ranged from 7.3% among active component service women to 8.4% among female MHS dependents. Comparisons to data from U.S. civilian populations are made when appropriate.


Melatonin Treatment Improves Mesenchymal Stem Cells Therapy by Preserving Stemness during Long-term In Vitro Expansion.
Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro passaging leads to stemness loss of MSCs, resulting in failure of MSCs therapy. Here, we report a melatonin-based strategy to improve cell therapy of in vitro cultured MSCs. Among four small molecules with anti-aging and stem cell-protection properties (rapamycin, resveratrol, quercetin and melatonin), colony forming, proliferation, and osteogenic differentiation assay showed that melatonin was the most efficient to preserve self-renewal and differentiation properties of rat bone marrow MSCs (BMMSCs) after long-term passaging. Functional assays confirmed melatonin treatment did not affect the colony forming, proliferation and osteogenic differentiation of BMMSCs cultured for 1 or 4 passages, but largely prevented the decline of self-renew and differentiation capacity of BMMSCs cultured for 15 passages in vitro. Furthermore, heterotopic osteogenesis assay, critical size calvarial defects repair assay, osteoporosis treatment and experimental colitis therapy assay strongly certified that melatonin preserved the therapeutic effect of long-term passaged BMMSCs on bone regeneration and immunotherapy in vivo. Mechanistically, melatonin functioned by activating antioxidant defense system, inhibiting the pathway of cell senescence, and preserving the expression of gene governing the stemness. Taken together, our findings showed that melatonin treatment efficiently prevented the dysfunction and therapeutic failure of BMMSCs after long-term passaging, providing a practical strategy to improve the application of BMMSCs in tissue engineering and cytotherapy.


HIV latency in isolated patient CD4+ T cells may be due to blocks in HIV transcriptional elongation, completion, and splicing.
Latently infected CD4+ T cells are the main barrier to complete clearance of HIV infection, but it is unclear what mechanisms govern latent HIV infection in vivo. To address this question, we developed a new panel of reverse transcription droplet digital polymerase chain reaction (RT-ddPCR) assays specific for different HIV transcripts that define distinct blocks to transcription. We applied this panel of assays to CD4+ T cells freshly isolated from HIV-infected patients on suppressive antiretroviral therapy (ART) to quantify the degree to which different mechanisms inhibit HIV transcription. In addition, we measured the degree to which these transcriptional blocks could be reversed ex vivo by T cell activation (using anti-CD3/CD28 antibodies) or latency-reversing agents. We found that the main reversible block to HIV RNA transcription was not inhibition of transcriptional initiation but rather a series of blocks to proximal elongation, distal transcription/polyadenylation (completion), and multiple splicing. Cell dilution experiments suggested that these mechanisms operated in most of the HIV-infected CD4+ T cells examined. Latency-reversing agents exerted differential effects on the three blocks to HIV transcription, suggesting that these blocks may be governed by different mechanisms.


Relationship between silicosis and smoking.
An evaluation of the relationship between silicosis and smoking is important in exploring the etiology of silicosis, and the relationship could have an impact on studies dealing with silicosis and lung cancer. Data addressing this relationship were found in studies designed explicitly to evaluate this association and studies that explored other questions. Studies based on compensation registers were excluded. Smoking data and methods varied across the studies considered. Of the 13 studies, 3 supported the hypothesis that smoking was positively associated with silicosis, 8 provided limited support (most included subpopulations showing positive associations), and 1 did not support the hypothesis. The only autopsy study suggested an inverse association. It is unclear whether the generally positive results indicate that smoking predisposes to silicosis or that nonspecific radiographic appearances from smoking were interpreted as silicosis in some studies. A positive association between radiographic silicosis and smoking would bias studies of silicosis and lung cancer, especially those lacking smoking data.