Interventions for post-stroke fatigue.
Post-stroke fatigue (PSF) is a common and distressing problem after stroke. The best ways to prevent or treat PSF are uncertain. Several different interventions can be argued to have a rational basis. To determine whether, among people with stroke, any intervention reduces the proportion of people with fatigue, fatigue severity, or both; and to determine the effect of intervention on health-related quality of life, disability, dependency and death, and whether such intervention is cost effective. We searched the Cochrane Stroke Group Trials Register (last searched May 2014), Cochrane Central Register of Controlled Trials (The Cochrane Library, 2014, Issue 4), MEDLINE (1950 to May 2014), EMBASE (1980 to May 2014), CINAHL (1982 to May 2014), AMED (1985 to May 2014), PsycINFO (1967 to May 2014), Digital Dissertations (1861 to May 2014), British Nursing Index (1985 to May 2014), PEDro (searched May 2014) and PsycBITE (searched May 2014). We also searched four ongoing trials registries, scanned reference lists, performed citation tracking of included trials and contacted experts. Two review authors independently scrutinised all titles and abstracts and excluded obviously irrelevant studies. We obtained the full texts for potentially relevant studies and three review authors independently applied the inclusion criteria. We included randomised controlled trials (RCTs) that compared an intervention with a control, or compared different interventions for PSF. Two review authors independently extracted data and assessed risk of bias for each included trial. The primary outcomes were severity of fatigue, or proportion of people with fatigue after treatment. We performed separate analyses for trials investigating efficacy in treating PSF, trials investigating efficacy in preventing PSF and trials not primarily investigating efficacy in PSF but which reported fatigue as an outcome. We pooled results from trials that had a control arm. For trials that compared different potentially active interventions without a control arm, we performed analyses for individual trials without pooling.We calculated standardised mean difference (SMD) as the effect size for continuous outcomes and risk ratio (RR) for dichotomous outcomes. We pooled the results using a random-effects model and assessed heterogeneity using the I(2) statistic. We performed separate subgroup analyses for pharmacological and non-pharmacological interventions. We also performed sensitivity analyses to assess the influence of methodological quality. We retrieved 12,490 citations, obtained full texts for 58 studies and included 12 trials (three from the 2008 search and nine from the 2014 search) with 703 participants. Eight trials primarily investigated the efficacy in treating PSF, of which six trials with seven comparisons provided data suitable for meta-analysis (five pharmacological interventions: fluoxetine, enerion, (-)-OSU6162, citicoline and a combination of Chinese herbs; and two non-pharmacological interventions: a fatigue education programme and a mindfulness-based stress reduction programme). The fatigue severity was lower in the intervention groups than in the control groups (244 participants, pooled SMD -1.07, 95% confidence interval (CI) -1.93 to -0.21), with significant heterogeneity between trials (I(2) = 87%, degrees of freedom (df) = 6, P value < 0.00001). The beneficial effect was not seen in trials that had used adequate allocation concealment (two trials, 89 participants, SMD -0.38, 95% CI -0.80 to 0.04) or trials that had used adequate blinding of outcome assessors (four trials, 198 participants, SMD -1.10, 95% CI -2.31 to 0.11).No trial primarily investigated the efficacy in preventing PSF.Four trials (248 participants) did not primarily investigate the efficacy on fatigue but other symptoms after stroke. None of these interventions showed any benefit on reducing PSF, which included tirilazad mesylate, continuous positive airway pressure for sleep apnoea, antidepressants and a self management programme for recovery from chronic diseases. There was insufficient evidence on the efficacy of any intervention to treat or prevent fatigue after stroke. Trials to date have been small and heterogeneous, and some have had a high risk of bias. Some of the interventions described were feasible in people with stroke, but their efficacy should be investigated in RCTs with a more robust study design and adequate sample sizes.


Meningococcal disease: clinical presentation and sequelae.
The clinical spectrum of invasive meningococcal disease is diverse with meningitis and/or septicaemia being the commonest modes of presentation. The severity of manifestations of meningococcal infection ranges from bacteraemia, associated with mild non-specific symptoms, to fulminant sepsis with multiorgan failure and death in approximately 10-15% of cases. Localised infections (such as conjunctivitis or septic arthritis) as well as chronic disease may be the sole clinical manifestations but can also lead to disseminated fulminant disease. Among survivors, disabling long-term sequelae can complicate meningococcal disease and result in potentially devastating effects on the quality of life of survivors, most of whom are infants, children and adolescents. The only rational approach to the prevention of meningococcal disease and the associated human suffering is through vaccination.


Deterministic aperiodic arrays of metal nanoparticles for surface-enhanced Raman scattering (SERS).
Deterministic Aperiodic (DA) arrays of gold (Au) nanoparticles are proposed as a novel approach for the engineering of reproducible surface enhanced Raman scattering (SERS) substrates. A set of DA and periodic arrays of cylindrical and triangular Au nanoparticles with diameters ranging between 50-110 nm and inter-particle separations between 25-100 nm were fabricated by e-beam lithography on quartz substrates. Using a molecular monolayer of pMA (p-mercaptoaniline) as a Raman reporter, we show that higher values of SERS enhancement factors can be achieved in DA structures compared to their periodic counterparts, and discuss the specific scaling rules of DA arrays with different morphologies. Electromagnetic field calculations based on the semi-analytical generalized Mie theory (GMT) fully support our findings and demonstrate the importance of morphology-dependent diffractive coupling (long-range interactions) for the engineering of the SERS response of DA arrays. Finally, we discuss optimization strategies based on the control of particles sizes and shapes, and we demonstrate that spatially-averaged SERS enhancement factors of the order of approximately 10(7) can be reproducibly obtained using DA arrays of Au nano-triangles. The ability to rigorously design lithographically fabricated DA arrays of metal nanoparticles enables the optimization and control of highly localized plasmonic fields for a variety of chip-scale devices, such as more reproducible SERS substrates, label-free bio-sensors and non-linear elements for nano-plasmonics.


Nanopore Sensing of Protein Folding.
Single-molecule studies of protein folding hold keys to unveiling protein folding pathways and elusive intermediate folding states-attractive pharmaceutical targets. Although conventional single-molecule approaches can detect folding intermediates, they presently lack throughput and require elaborate labeling. Here, we theoretically show that measurements of ionic current through a nanopore containing a protein can report on the protein's folding state. Our all-atom molecular dynamics (MD) simulations show that the unfolding of a protein lowers the nanopore ionic current, an effect that originates from the reduction of ion mobility in proximity to a protein. Using a theoretical model, we show that the average change in ionic current produced by a folding-unfolding transition is detectable despite the orientational and conformational heterogeneity of the folded and unfolded states. By analyzing millisecond-long all-atom MD simulations of multiple protein transitions, we show that a nanopore ionic current recording can detect folding-unfolding transitions in real time and report on the structure of folding intermediates.


Sulfur-containing bimetallic metal organic frameworks with multi-fold helix as anode of lithium ion batteries.
We utilise the dual synthesis strategy in terms of bimetallic inorganic building blocks and sulfur containing organic ligand. A novel sulfur-containing bimetallic metal organic framework (Fe2Co-TPDC) with two types of 4-fold meso-helical structures has been successfully synthesized. Benefitting from the uniform distribution of active sulfur sites and the structural stability of the mixed-metallic method, Fe2Co-TPDC can efficiently prevent a shuttle behavior of sulfur and endow a commendable specific capacity. As far as we know, this is the first time that a sulfur-containing bimetallic crystalline MOF with helical structure and prominent specific capacity and remarkable cycling stability has served as an electrode material for LIBs.


Analysis of immune-related ESTs and differential expression analysis of few important genes in lines of rohu (Labeo rohita) selected for resistance and susceptibility to Aeromonas hydrophila infection.
A total of 137,629 contigs generated via de novo transcriptome assembly from resistant and susceptible lines of rohu (first generation) raised against aeromoniasis were further analyzed in terms of defence-related genes. Out of 1,939 contigs showing homology to genes involved in immune processes, 1,866 were further categorised into different functional subgroups. Comparative analysis revealed five genes for the first time in any carp species out of which apolipoprotein h, septin 4 isoform 3 and septin isoform cra_c were identified for the first time in fish. Differential expression analysis of ten genes viz., heat shock proteins (Hsps) (Hsp30, Hsp70 and Hsp90), serum lectin isoform 1 (SLI1), linker histone H1M (LHH1M), NAD(P)H quinone 1 (NQO1), zona pellucida 2 (ZP2) and three unknown genes that were highly up-expressed in first generation resistant line fish from mRNA-seq coverage data, was carried out using susceptible and resistant individuals of the second generation selected populations in eight different tissues viz. liver, kidney, intestine, gill, brain, spleen, skin and muscle using qPCR. Significant up-regulation in Hsp90, NQO1, C_116914 and C_22454 in specific tissues of resistant line and variable expression in Hsp30 and LHH1M genes in different tissues of both lines were noticed. The expression of Hsp70 was lower in many tissues of the resistant line than in susceptible line rohu. The expression of ZP2, SLI1 and C_94589 genes was not significantly different in terms of fold difference between the two lines. Differentially expressed genes need further characterisation to explore their role in resistance to Aeromonas hydrophila infection in rohu.


Monitoring the oxygen transfer efficiency of full-scale aeration systems: investigation method and experimental results.
This paper reports the results of a series of off-gas tests aimed at monitoring the evolution of the oxygen transfer efficiency in an urban wastewater treatment plant (3,500 population equivalent) located in Tuscany (Italy). The tests were conducted over a 2-year period starting with the testing of the aeration system. It was found that in the absence of membrane-panel cleaning operations, the oxygen transfer efficiency under standard conditions in process water (αSOTE) dropped from 18 to 9.5% in 2 years. This gives rise to a 40% increase in the wastewater treatment plant annual energy costs. The on-site chemical cleaning of the diffusers allowed for an almost total recovery of the transfer efficiency (αSOTE equal to 16%). The use of the off-gas method for monitoring the oxygen transfer efficiency over time is therefore essential for enabling correct planning of the cleaning operations of the diffusers and for cutting the energy consumption and operating costs of the aeration system.


Lymph nodes cytology in HIV seropositive cases with haematological alterations.
Lymphadenopathy and haematological alterations are the earliest manifestations with other associated opportunistic infections and malignancies. Hence, there is a need for simple investigations like fine needle aspiration cytology (FNAC) for evaluation of HIV lymphadenopathy and a haemogram to interpret the haematological alterations. This study was undertaken to analyze the cytological patterns of lymph node lesions in HIV/AIDS patients, to compare with available clinico-pathological and haematological parameters to segregate lymphadenopathy cases for further evaluation. In the present study, 129 HIV seropositive patients were included. Lymph node aspirates were stained routinely with hematoxylin and eosin and Ziehl-Neelsen (Z-N) stains. Special stains and cultures were done in selected patients. Peripheral smears were taken from all the patients and CD4 counts were recorded. Tuberculous lymphadenitis was further categorized. Acid fast bacilli (AFB) grading was done on Z-N positive smears. Each lesion was compared with CD4 counts, WHO clinical staging and haematological picture. Cytological diagnosis in 129 patients included tuberculous (n=54, 41.9%), reactive lymphadenopathy (n=46, 35.6%), suppurative (n=16, 12.4%) lymphadenitis, non-Hodgkin's lymphoma (n=4, 3.1%), and Hodgkin's lymphoma, secondary deposits, other granulomatous lesions, and cryptoccocal lymphadenitis in one patient each. The predominant cytomorphological pattern in tuberculous lymphadenitis was caseous necrosis + epithelioid granuloma formation (51.85%). Grade 2+ Z-N grading was noted in 62.96 per cent of AFB positive smears. CD4 counts showed a descending pattern with progression of WHO clinical staging. Cytopenia was more common in WHO clinical stage IV disease. Lymph node cytology was found to be a useful tool for segregating lymphadenopathy cases for further evaluation and for identification of opportunistic infections, neoplastic and non-neoplastic lesions. Comparison of lymph node lesions with CD4 counts, WHO clinical staging, haematological alterations and AFB grading reflects immunity, stage of disease and disease activity aiding better treatment.


HHLA2 is expressed in pancreatic and ampullary cancers and increased expression is associated with better post-surgical prognosis.
HHLA2 is a recently discovered member of the B7-family of immune checkpoint molecules with limited expression in normal tissues but overexpression in several types of cancer. The aim was to determine the expression, prevalence and biological relevance of HHLA2 protein expression in two closely related human cancer types, namely pancreatic cancer and ampullary cancer. HHLA2 expression levels were retrospectively determined by immunohistochemistry in tissue micro-arrays of surgically resected tumours of 122 pancreatic cancer patients and 72 patients with ampullary cancer of the pancreato-biliary subtype. HHLA2 was expressed at variable levels by tumour cells in 67% of pancreatic tumours and 93% of ampullary tumours. In the combined cohort high tumoural HHLA2 expression levels were significantly associated with delayed cancer recurrence and improved post-operative cancer-specific survival. The association of HHLA2 expression with cancer-specific survival and recurrence was statistically significant for the pancreatic cancer subgroup while a similar trend was found for the ampullary cancer subgroup. In multivariable analysis together with clinicopathologic characteristics, higher HHLA2 expression was an independent predictor of cancer-specific survival. The wide expression of HHLA2 in tumour cells and its association with cancer recurrence and patient survival suggest that HHLA2 represents a relevant immune checkpoint molecule in pancreatic and ampullary cancers.


Decreased Hepcidin Levels Are Associated with Low Steady-state Hemoglobin in Children With Sickle Cell Disease in Tanzania.
The contribution of hepcidin as a regulator of iron metabolism & erythropoiesis on the severity of anemia in sickle cell disease (SCD) remains poorly characterized, especially in Sub-Saharan African populations. The aims of the study were to determine if hepcidin is associated with severity of steady-state anemia in SCD and to investigate factors associated with hepcidin and anemia in SCD. Archived samples from 199 Tanzanian children, 56% boys aged 3-18 with laboratory-confirmed SCD were analysed based on recorded averaged steady-state hemoglobin (ASSH) quartiles (lowest vs. highest). Univariable and multivariable logistic regression was used to assess associations with ASSH quartiles. In univariable analysis, hepcidin <5·5 ng/mL was associated with increased odds of being in the lowest ASSH quartile (OR 2·20; 95%CI 1·2-3·93) but which was limited to girls (OR 4·85, 95%CI 1·79-13·09, p = .046 for interaction). In multivariable analyses including either reticulocyte percentage or erythropoietin, lower hepcidin remained significantly associated with lowest ASSH quartile, although the hepcidin-sex interaction no longer reached statistical significance. No associations with ASSH quartile were observed for markers of inflammation, hemolysis or potential iron markers except for microcytosis, associated with higher ASSH, but which was confounded by reticulocyte percentage and alpha-thalassaemia status. Hepcidin is lower in more severely anaemic children with SCD independent of inflammation or markers of erythropoiesis. Funding sources include The Wellcome Trust (080025, 095009, 094780 & 070114), MRC-UK (MC-A760-5QX00), NIHR Oxford Biomedical Research Centre, and the Bill and Melinda Gates Foundation ("Hepcidin and Iron in Global Health", OPP1055865).


High incidence of childhood pneumonia at high altitudes in Pakistan: a longitudinal cohort study.
To determine the incidence of pneumonia and severe pneumonia among children living at high altitudes in Pakistan. A longitudinal cohort study was conducted in which 99 female government health workers in Punial and Ishkoman valleys (Ghizer district, Northern Areas of Pakistan) enrolled children at home, conducted home visits every 2 weeks and actively referred sick children to 15 health centres. Health centre staff used Integrated Management of Childhood Illness criteria to screen all sick children aged 2-35 months and identify those with pneumonia or severe pneumonia. Community health workers enrolled 5204 eligible children at home and followed them over a 14-month period, ending on 31 December 2002. Health centre staff identified 1397 cases of pneumonia and 377 of severe pneumonia in enrolled children aged 2-35 months. Among children reported with pneumonia, 28% had multiple episodes. Incidence rates per 100 child-years of observation were 29.9 for pneumonia and 8.1 for severe pneumonia. Factors associated with a high incidence of pneumonia were younger age, male gender and living at high altitude. Pneumonia incidence rates in the Northern Areas of Pakistan are much higher than rates reported at lower altitudes in the country and are similar to those in high-altitude settings in other developing countries. More studies are needed to determine the causes of pneumonia in these high-mountain communities. However, early introduction of the vaccines that are known to prevent pneumonia should be considered.


[Simulating measles and rubella elimination levels according to social stratification and interaction].
The study was aimed at comparing measles and rubella disease elimination levels in a homogeneous and heterogeneous population according to socioeconomic status with interactions amongst low- and high-income individuals and diversity in the average number of contacts amongst them. Effective reproductive rate simulations were deduced from a susceptibleinfected- recovered (SIR) mathematical model according to different immunisation rates using measles (1980 and 2005) and rubella (1998 and 2005) incidence data from Latin-America and the Caribbean. Low- and high-income individuals' social interaction and their average number of contacts were analysed by bipartite random network analysis. MAPLE 12 (Maplesoft Inc, Ontario Canada) software was used for making the simulations. The progress made in eliminating both diseases between both periods of time was reproduced in the socially-homogeneous population. Measles (2005) would be eliminated in high- and low-income groups; however, it would only be achieved in rubella (2005) if there were a high immunity rate amongst the low-income group. If the average number of contacts were varied, then rubella would not be eliminated, even with a 95 % immunity rate. Monitoring the elimination level in diseases like measles and rubella requires that socio-economic status be considered as well as the population's interaction pattern. Special attention should be paid to communities having diversity in their average number of contacts occurring in confined spaces such as displaced communities, prisons, educational establishments, or hospitals.


Differential effect of biochar upon reduction-induced mobility and bioavailability of arsenate and chromate.
Heavy metals such as chromium (Cr) and arsenic (As) occur in ionic form in soil, with chromate [Cr(VI)] and arsenate As(V) being the most pre-dominant forms. The application of biochar to Cr(VI) and As(V) spiked and field contaminated soils was evaluated on the reduction processes [(Cr(VI) to Cr(III)] and [As(V) to As(III))], and subsequent mobility and bioavailability of both As(V) and Cr(VI). The assays used in this study included leaching, soil microbial activity and XPS techniques. The reduction rate of As(V) was lower than that of Cr(VI) with and without biochar addition, however, supplementation with biochar enhanced the reduction process of As(V). Leaching experiments indicated Cr(VI) was more mobile than As(V). Addition of biochar reversed the effect by reducing the mobility of Cr and increasing that of As. The presence of Cr and As in both spiked and contaminated soils reduced microbial activity, but with the addition of biochar to these soils, the microbial activity increased in the Cr(VI) contaminated soils, while it was further decreased with As(V) contaminated soils. The addition of biochar was effective in mitigating Cr toxicity by reducing Cr(VI) to Cr(III). In contrast, the conversion process of As(V) to As(III) hastened by biochar was not favourable, as As(III) is more toxic in soils. Overall, the presence of functional groups on biochar promotes reduction by providing the electrons required for reduction processes to occur as determined by XPS data.


Health-related correlates of psychological well-being among girls and boys 6-8 years of age: The Physical Activity and Nutrition in Children study.
Due to limited knowledge on the differences in the correlates of psychological well-being (PSWB) between girls and boys, we compared the correlates of PSWB between primary school girls and boys. A population sample of 412 children participated in the Physical Activity and Nutrition in Children study. Parents completed a questionnaire that included 19 questions on the components of PSWB, and a PSWB score was computed. We assessed correlates of PSWB, including physical activity, sedentary behaviour, cardiorespiratory fitness, diet quality, body fat content, sleep duration, sleep disordered breathing, prevalent diseases and parental characteristics. We used logistic regression to analyse the risk of being in the lowest third of the PSWB scores. Low parental education was associated with increased risk (odds ratio (OR) 2.34, P = 0.039) and high cardiorespiratory fitness with decreased risk (OR 0.26, P = 0.006) of poor PSWB in girls. At least 2 h of screen-based sedentary behaviour per day (OR 1.93, P = 0.037), daily parental smoking (OR 2.10, P = 0.034) and sleep disordered breathing (OR 4.24, P = 0.003) were related to increased risk of poor PSWB in boys. There are large differences in the correlates of PSWB between girls and boys. Most of these correlates are modifiable and related to the health behaviour of children and their parents.


Detection and identification of sub-nanogram levels of protein in a nanoLC-trypsin-MS system.
Proteomic workflows involving liquid-based protein separations are an alternative to gel-based protein analysis, however the trypsin digestion procedure is usually difficult to implement, particularly when processing low abundance proteins from capillary column effluent. To convert the protein to peptides for the purpose of identification, current protocols require several sample handling steps, and sample losses become an issue. In this study, we present an improved system that conducts reversed-phase protein chromatography and rapid on-line tryptic digestion requiring sub-nanogram quantities of protein. This system employs a novel mirror-gradient concept that allows for dynamic titration of the column effluent to create optimal conditions for real-time tryptic digestion. The purpose behind this development was to improve the limits of detection of the online concept, to support flow-based alternatives to gel-based proteomics and to simplify the characterization of low abundance proteins. Using test mixtures of proteins, we show that peptide mass fingerprinting with high sequence representation can be easily achieved at the 20 fmol level, with detection limits down to 5 fmol (85 pg myoglobin). Limits of identification using standard data-dependent MS/MS experiments are as low as 10 fmol. These results suggest that the nanoLC-trypsin-MS/MS system could represent an alternative to the conventional "1D-gel to MS" proteomic strategy.


Silencing of hypoxia-inducible factor-1β induces anti-tumor effects in hepatoma cell lines under tumor hypoxia.
Dimerization of hypoxia-inducible factor-1 beta (HIF-1β) [aryl hydrocarbon receptor nuclear translocator (ARNT)] with HIF-1α is involved in various aspects of cancer biology, including proliferation and survival under hypoxic conditions. We investigated the in vitro mechanism by which silencing of HIF-1β leads to the suppression of tumor cell growth and cellular functions. Various hepatocellular carcinoma (HCC) cell lines (Huh-7, Hep3B, and HepG2) were transfected with small interfering RNA (siRNA) against HIF-1β (siHIF-1β) and cultured under hypoxic conditions (1% O2 for 24 h). The expression levels of HIF-1β, HIF-1α, and growth factors were examined by immunoblotting. Tumor growth was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and tumor activity was measured by terminal deoxynucleotidyl transferase dUTP nick end labeling, tumor cell invasion, and migration assays. Under hypoxic conditions, silencing of HIF-1β expression suppressed tumor cell growth and regulated the expression of tumor growth-related factors, such as vascular endothelial growth factor, epidermal growth factor, and hepatocyte growth factor. Suppression of tumor cell invasion and migration was also demonstrated in HIF-1β-silenced HCC cell lines. Silencing of HIF-1β expression may induce anti-tumor effects under hypoxic conditions in HCC cell lines.


Entrainment of cerebellar purkinje cells with directional AC electric fields in anesthetized rats.
Transcranial electrical stimulation (tES) shows promise to treat neurological disorders. Knowledge of how the orthogonal components of the electric field (E-field) alter neuronal activity is required for strategic placement of transcranial electrodes. Yet, essentially no information exists on this relationship for mammalian cerebellum in vivo, despite the cerebellum being a target for clinical tES studies. To characterize how cerebellar Purkinje cell (PC) activity varies with the intensity, frequency, and direction of applied AC and DC E-fields. Extracellular recordings were obtained from vermis lobule 7 PCs in anesthetized rats. AC (2-100 Hz) or DC E-fields were generated in a range of intensities (0.75-30 mV/mm) in three orthogonal directions. Field-evoked PC simple spike activity was characterized in terms of firing rate modulation and phase-locking as a function of these parameters. t-tests were used for statistical comparisons. The effect of applied E-fields was direction and intensity dependent, with rostrocaudally directed fields causing stronger modulations than dorsoventral fields and mediolaterally directed ones causing little to no effect, on average. The directionality dependent modulation suggests that PC is the primary cell type affected the most by electric stimulation, and this effect was probably given rise by a large dendritic tree and a soma. AC stimulation entrained activity in a frequency dependent manner, with stronger phase-locking to the stimulus cycle at higher frequencies. DC fields produced a modulation consisting of strong transients at current onset and offset with an intervening plateau. Orientation of the exogenous E-field critically determines the modulation depth of cerebellar cortical output. With properly oriented fields, PC simple spike activity can strongly be entrained by AC fields, overriding the spontaneous firing pattern.


Axitinib in metastatic renal cell carcinoma: results of a pharmacokinetic and pharmacodynamic analysis.
Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second-line therapy for advanced renal cell carcinoma (RCC). Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated. Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients with other solid tumors in 17 trials, the disposition of axitinib was best described by a 2-compartment model with first-order absorption and a lag time, with estimated mean systemic clearance (CL) of 14.6 L/h and central volume of distribution (V(c)) of 47.3 L. Of 12 covariates tested, age over 60 years and Japanese ethnicity were associated with decreased CL, whereas V(c) increased with body weight. However, the magnitude of predicted changes in exposure based on these covariates does not warrant dose adjustments. Multivariate Cox proportional hazard regression and logistic regression analyses showed that higher exposure and diastolic blood pressure were independently associated with longer progression-free and overall survivals and higher probability of partial response in metastatic RCC patients. These findings support axitinib dose titration to increase plasma exposure in patients who tolerate axitinib, and also demonstrate diastolic blood pressure as a potential marker of efficacy.


Impaired Endothelial Glycocalyx Predicts Adverse Outcome in Subjects Without Overt Cardiovascular Disease: a 6-Year Follow-up Study.
We investigated whether disturbance of glycocalyx integrity is related with increased cardiovascular risk. In 600 healthy subjects, we measured perfused boundary region (PBR), a marker of glycocalyx integrity, in sublingual microvessels with diameter ranging 5-25 µm using a dedicated camera (Sideview Darkfield Imaging). Increased PBR indicates reduced glycocalyx thickness. We prospectively monitored the occurrence of cardiovascular events (MACE-death, myocardial infarction, and stroke) during a 6-year follow-up. Fifty-seven MACE were documented. Increased values of PBR5-25 predicted higher risk for MACE in a model including sex, age, hyperlipidemia, diabetes, hypertension, smoking, family history of coronary disease, treatment with ACEi/ARBs, or lipid-lowering agents (hazard ratio (HR), 6.44, p = 0.011; net reclassification improvement (NRI), 28%; C-statistic: 0.761). PBR5-25 was an independent and additive predictor of outcome when added in a model including the European Heart SCORE, diabetes, family history of CAD, and medication (HR, 4.71; NRI: 39.7%, C-statistic from 0.653 to 0.693; p < 0.01).Glycocalyx integrity is an independent and additive predictor to risk factors for MACE at 6-year follow-up in individuals without cardiovascular disease. ClinicalTrials.govIdentifier:NCT04646252. PBR5-25 was an independent and additive predictor of adverse cardiovascular events in a model including the European Heart SCORE, diabetes, family history of coronary disease, and medication (HR: 4.71, NRI: 39.7%, C-statistic from 0.653 to 0.693; p < 0.01, NRI:37.9%).


Establishment and characterization of a highly tumorigenic African American prostate cancer cell line, E006AA-hT.
Genuine racial differences in prostate cancer (PCa) biology have been considered among the potential reasons to explain PCa disparities. There is no animal model to represent all aspects of human PCa and, more specifically, to be used for PCa disparity research. The lack of a spontaneously transformed in vitro cell-based model system has been a significant impediment to investigating and understanding potential molecular mechanisms, and the hormonal, genetic, and epigenetic factors underlying the biological and clinical aggressiveness of PCa in African American (AA) men. In this study, we established and characterized the E006AA-hT cell line as a highly tumorigenic subline of the previously characterized primary AA-PCa cell line, E006AA. Extensive characterization of the E006AA-hT cell line was accomplished using cytodifferentiation and prostate-specific markers, spectral karyotyping, cell line authentication assays, cell proliferation and migration assays, and in vitro tumorigenesis assays. Spectral karyotyping of E006AA-hT showed a hypertriploid chromosome complement and shared cytogenetic changes similar to its parental cells such as diploid X, absence of Y-chromosomes, numerical gains in chromosomes 5,6,8,10,17,20,21, and marker chromosomes of unknown origin. In addition, E006AA-hT also presented numerous clonal and structural aberrations such as insertion, deletion, duplication, and translocations in chromosomes 1-5, 8, 9, 11, 13, 14, 17, and 18. The E006AA-hT cell line was shown to be highly tumorigenic and produced tumors at an accelerated growth rate in both athymic nude and triple-deficient SCID mice. Silencing the mutated androgen receptor (AR-599 Ser>Gly) did not affect proliferation (loss-of-function), but decreased migration (gain-of-function) in E006AA-hT and its parental cell type. These data support that AR-point mutations may lead simultaneously to different "loss-of-function" and "gain-of-function" phenotypes in PCa cells. E006AA-Par and its subline as the only available spontaneously transformed low- and highly-tumorigenic primary AA-PCa cell lines could be used for basic and translational research aimed in supporting prostate cancer disparity research.


Downstream Effect of Ramping Neuronal Activity through Synapses with Short-Term Plasticity.
Ramping neuronal activity refers to spiking activity with a rate that increases quasi-linearly over time. It has been observed in multiple cortical areas and is correlated with evidence accumulation processes or timing. In this work, we investigated the downstream effect of ramping neuronal activity through synapses that display short-term facilitation (STF) or depression (STD). We obtained an analytical result for a synapse driven by deterministic linear ramping input that exhibits pure STF or STD and numerically investigated the general case when a synapse displays both STF and STD. We show that the analytical deterministic solution gives an accurate description of the averaging synaptic activation of many inputs converging onto a postsynaptic neuron, even when fluctuations in the ramping input are strong. Activation of a synapse with STF shows an initial cubical increase with time, followed by a linear ramping similar to a synapse without STF. Activation of a synapse with STD grows in time to a maximum before falling and reaching a plateau, and this steady state is independent of the slope of the ramping input. For a synapse displaying both STF and STD, an increase in the depression time constant from a value much smaller than the facilitation time constant τ(F) to a value much larger than τ(F) leads to a transition from facilitation dominance to depression dominance. Therefore, our work provides insights into the impact of ramping neuronal activity on downstream neurons through synapses that display short-term plasticity. In a perceptual decision-making process, ramping activity has been observed in the parietal and prefrontal cortices, with a slope that decreases with task difficulty. Our work predicts that neurons downstream from such a decision circuit could instead display a firing plateau independent of the task difficulty, provided that the synaptic connection is endowed with short-term depression.


Reduced expression of Dicer associated with poor prognosis in lung cancer patients.
Emerging evidence suggests that microRNA, which are well-conserved, abundant and small regulatory RNA, may be involved in the pathogenesis of human cancers. We recently reported that expression of let-7 was frequently reduced in lung cancers, and that reduced let-7 expression was significantly associated with shorter patient survival. Two members of the double-stranded RNA-specific endonuclease family, Dicer and Drosha, convert precursor forms of microRNA into their mature forms using a stepwise process. In the present study, we examined expression levels of these genes in 67 non-small cell lung cancer cases, and found for the first time that Dicer expression levels were reduced in a fraction of lung cancers with a significant prognostic impact on the survival of surgically treated cases. It should be noted that multivariate COX regression analysis showed that the prognostic impact of Dicer (P=0.001) appears to be independent of disease stage (P=0.001), while logistic regression analysis demonstrated that the higher incidence of reduced Dicer expression in poorly differentiated tumors remained significant even after correction for other parameters (P=0.02). Given the fundamental and multiple biological roles of Dicer in various cellular processes, our results suggest the involvement of reduced Dicer expression in the development of lung cancers, thus warranting further investigations of the underlying mechanisms, which can be expected to enhance understanding of the molecular pathogenesis of this fatal cancer.


Children and young people's participation in developing interventions in health and well-being: a scoping review.
Greater interest is being shown in participatory approaches, especially in research on interventions that concern children and young people's health and well-being. Although participatory approaches have user involvement in common, they differ in terms of the explicit guidance on how to actually involve and engage children and young people in health research. The aim of this scoping review was to systematically map recent research involving children and young people in the development of interventions targeting issues of health and well-being. An interpretative scoping literature review based on: a scientific literature search in (health and social science) databases, reference lists, a manual search in key journals and contact with existing networks was conducted. A total of 4458 references were identified through the literature search, of which 41 studies published between 2000 and 2017 were included in the review. The target population was children and young people under 25 years old. Level of participation was categorized according to Shier's Pathways to Participation Model. The review showed that participatory approaches were most often used in the development of interventions in school settings and in community and healthcare settings and on issues concerning support in lifestyle or in managing illness or disease. The level of participation varied from children and young people taking part just as active informants, through stages of greater participation both in quantitative and qualitative terms, to children and young people becoming an active agent involved as a co-researcher where the research process was shaped by views of a higher level of mutuality. Most of the studies were categorised at a medium level and only three studies were judged to involve the children and young people at the highest level. This scoping review showed that work remains in enabling children and young people to influence the development of interventions targeting health and well-being. In relation to level of sustainability in the interventions, it is relevant that goals, strategies and processes are formulated by those who can gain from the interventions. Participatory approaches aiming for a higher level of participation where children and young people work together with the researchers in partnerships are thus warranted.


A Comparative View on Sex Differentiation and Gametogenesis Genes in Lungfish and Coelacanths.
Gonadal sex differentiation and reproduction are the keys to the perpetuation of favorable gene combinations and positively selected traits. In vertebrates, several gonad development features that differentiate tetrapods and fishes are likely to be, at least in part, related to the water-to-land transition. The collection of information from basal sarcopterygians, coelacanths, and lungfishes, is crucial to improve our understanding of the molecular evolution of pathways involved in reproductive functions, since these organisms are generally regarded as "living fossils" and as the direct ancestors of tetrapods. Here, we report for the first time the characterization of >50 genes related to sex differentiation and gametogenesis in Latimeria menadoensis and Protopterus annectens. Although the expression profiles of most genes is consistent with the intermediate position of basal sarcopterygians between actinopterygian fish and tetrapods, their phylogenetic placement and presence/absence patterns often reveal a closer affinity to the tetrapod orthologs. On the other hand, particular genes, for example, the male gonad factor gsdf (Gonadal Soma-Derived Factor), provide examples of ancestral traits shared with actinopterygians, which disappeared in the tetrapod lineage.


IMRT using simultaneously integrated boost (SIB) in head and neck cancer patients.
Preliminary very encouraging clinical results of intensity modulated radiation therapy (IMRT) in Head Neck Cancer (HNC) are available from several large centers. Tumor control rates seem to be kept at least at the level of conventional three-dimensional radiation therapy; the benefit of normal tissue preservation with IMRT is proven for salivary function. There is still only limited experience with IMRT using simultaneously integrated boost (SIB-IMRT) in the head and neck region in terms of normal tissue response.The aim of this work was (1) to establish tumor response in HNC patients treated with SIB-IMRT, and (2) to assess tissue tolerance following different SIB-IMRT schedules. Between 1/2002 and 12/2004, 115 HNC patients have been curatively treated with IMRT. 70% received definitive IMRT (dIMRT), 30% were postoperatively irradiated. In 78% concomitant chemotherapy was given. SIB radiation schedules with 5-6 x 2 Gy/week to 60-70 Gy, 5 x 2.2 Gy/week to 66-68.2 Gy (according to the RTOG protocol H-0022), or 5 x 2.11 Gy/week to 69.6 Gy were used. After mean 18 months (10-44), 77% of patients were alive with no disease. Actuarial 2-year local, nodal, and distant disease free survival was 77%, 87%, and 78%, respectively. 10% were alive with disease, 10% died of disease. 20/21 locoregional failures occurred inside the high dose area. Mean tumor volume was significantly larger in locally failed (63 cc) vs controlled tumors (32 cc, p <0.01), and in definitive (43 cc) vs postoperative IMRT (25 cc, p <0.05); the locoregional failure rate was twofold higher in definitively irradiated patients. Acute reactions were mild to moderate and limited to the boost area, the persisting grade 3/4 late toxicity rate was low with 6%. The two grade 4 reactions (dysphagia, laryngeal fibrosis) were observed following the SIB schedule with 2.2 Gy per session. SIB-IMRT in HNC using 2.0, 2.11 or 2.2 Gy per session is highly effective and safe with respect to tumor response and tolerance. SIB with 2.2 Gy is not recommended for large tumors involving laryngeal structures.


In vivo measurement of lipofuscin in Stargardt's disease--Fundus flavimaculatus.
Several histopathologic studies have concluded that Stargardt's disease (Fundus flavimaculatus) is associated with abnormally high levels of lipofuscin-like material in the retinal pigment epithelium. The purpose of this study was to determine whether this material has the same fluorescence characteristics as lipofuscin in vivo and whether noninvasive measurements identify a significant elevation in this material. Five patients with autosomal recessive Stargardt's disease were included in this study, as were 45 healthy controls. All patients had the angiographic dark choroid sign. The intensity and emission spectra of lipofuscin fluorescence were measured by noninvasive fundus spectrophotometry at 7 degrees temporal to the fovea. The fluorescence intensities in the five patients with Stargardt's disease were significantly higher (P < 0.0001) than those observed in normal subjects of the same age. The emission spectra in the patients are similar in shape to those measured in normals, but flecks appear to shift the spectra toward shorter wavelengths. The spectral characteristics of the fluorophore observed in patients with Stargardt's disease are consistent with those of retinal pigment epithelial lipofuscin. These patients have abnormally high levels of lipofuscin, confirming previous histopathologic observations. Noninvasive retinal pigment epithelial lipofuscin measurements may be a useful adjunct in the diagnosis of Stargardt's disease.-F. flavimaculatus.


Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study.
Phosphodiesterase type 5 inhibitors are widely used to treat erectile dysfunction. Preliminary data have suggested phosphodiesterase type 5 inhibitor efficacy in men with lower urinary tract symptoms associated with clinical benign prostatic hyperplasia. After a 4-week placebo run-in period 1,058 men with benign prostatic hyperplasia lower urinary tract symptoms were randomly allocated to receive 12-week, once daily treatment with placebo or tadalafil (2.5, 5, 10 or 20 mg). The International Prostate Symptom Score least squares mean change from baseline to end point was significantly improved for 2.5 (-3.9, p = 0.015), 5 (-4.9, p <0.001), 10 (-5.2, p <0.001) and 20 mg (-5.2, p <0.001) tadalafil compared to placebo (-2.3). International Prostate Symptom Score improvements at 4, 8 and 12 weeks were significant for all tadalafil doses and they demonstrated a dose-response relationship. Tadalafil (2.5 mg) significantly improved the International Prostate Symptom Score obstructive subscore and the International Index of Erectile Function-Erectile Function domain, the latter in sexually active men with a history of erectile dysfunction. Statistically significant improvements were noted for 5, 10 and 20 mg tadalafil compared to placebo, as assessed by the International Prostate Symptom Score irritative and obstructive subscores, International Prostate Symptom Score Quality of Life, Benign Prostatic Hyperplasia Impact Index (nonsignificant for 10 mg), Global Assessment Question and International Index of Erectile Function-Erectile Function domain. No statistically significant effect of treatment compared to placebo was noted for peak flow at any tadalafil dose. Treatment emergent adverse events were infrequent in all tadalafil groups. Once daily tadalafil demonstrated clinically meaningful and statistically significant efficacy and it was well tolerated in men with benign prostatic hyperplasia lower urinary tract symptoms. Of the doses studied 5 mg tadalafil appeared to provide a positive risk-benefit profile.


First Report and Comparative Study of Steinernema surkhetense (Rhabditida: Steinernematidae) and its Symbiont Bacteria from Subcontinental India.
Two populations (CS19 and CS20) of entomopathogenic nematodes were isolated from the soils of vegetable fields from Bijnor district, India. Based on morphological, morphometrical, and molecular studies, the nematodes were identified as Steinernema surkhetense. This work represents the first report of this species in India. The infective juveniles (IJs) showed morphometrical and morphological differences, with the original description based on longer IJs size. The IJs of the Indian isolates possess six ridges in their lateral field instead of eight reported in the original description. The analysis of ITS-rDNA sequences revealed nucleotide differences at 345, 608, and 920 positions in aligned data. No difference was observed in D2-D3 domain. The S. surkhetense COI gene was studied for the first time as well as the molecular characterization of their Xenorhabdus symbiont using the sequences of recA and gyrB genes revealing Xenorhabdus stockiae as its symbiont. These data, together with the finding of X. stockiae, suggest that this bacterium is widespread among South Asian nematodes from the "carpocapsae" group. Virulence of both isolates was tested on Spodoptera litura. The strain CS19 was capable to kill the larvae with 31.78 IJs at 72 hr, whereas CS20 needed 67.7 IJs.


One-year outcomes after rapid-deployment aortic valve replacement.
The goals of rapid-deployment aortic valve replacement include facilitation of minimally invasive surgery and reduced aortic crossclamp time. We report the short-term outcomes of a series of 493 patients undergoing rapid-deployment aortic valve replacement with the EDWARDS INTUITY valve system (Edwards Lifesciences, LLC, Irvine, Calif). Assessing Standard oF Care and Clinical Outcomes UsiNg the EDWARDS INTUITY VAlve SysTem in a European multI-center, Active, pOst-market surveillaNce Study was a prospective, multicenter (n = 26) European registry designed to evaluate the safety and performance of the valve system. During rapid-deployment aortic valve replacement, device technical success and crossclamp time were assessed. Procedural outcomes, hemodynamic performance, and various adverse events and clinical outcomes were evaluated up to 2 years. Between 2012 and 2014, 493 of 517 enrolled patients successfully received implants with the study valve (95.4% technical success). Mean crossclamp times for 163 full sternotomies, 128 mini-upper sternotomies, and 36 right anterior thoracotomies isolated aortic valve replacements were 47.3, 52.0, and 73.3 minutes, respectively. Mean follow-up was 1.8 years, with 870 total patient-years of follow-up. Mean effective orifice area increased from 0.72 (baseline) to 1.88 cm2, and mean pressure gradient decreased from 47.6 to 9.6 mm Hg (1 year). Mean effective orifice area index increased (0.39-1.01 cm2/m2), and 28 of 287 patients (9.8%) exhibited severe prosthesis-patient mismatch at 1 year. After 1 year, 68.1% and 21.7% of patients were in New York Heart Association class I and II, respectively. Freedom from death, major bleeding, major perivalvular leak, reoperation, and device explant at 1 year were 0.935, 0.939, 0.976, 0.975, and 0.983, respectively. These results demonstrate commendable safety and performance of the test valve system over the short term in a broad European setting.


Procreative sex in infertile couples: the decay of pleasure?
Infertility represents a major challenge to the emotional balance and sexual life of couples, with long-lasting and gender-specific effects. The objective of this study is to explore personality features of infertile patients and detect possible sexual disorders in couples undergoing infertility treatment. In this prospective study 60 infertile couples and 52 fertile control couples were asked to complete standardized and validated questionnaires: the Adjective Check List (ACL) to enquire about personality features and the Female Sexual Function Index (FSFI) or the International Index of Erectile Function (IIEF) to assess sexual functioning of female and male partners. The study population was divided into 3 groups: Group A (N = 30, recently diagnosed infertile couples) Group B (N = 30, infertile couples already undergoing Intrauterine Insemination) and Group C (N = 52, fertile control group). Infertile patients did not display any distinguishing personality features. Regarding sexual function, men of all the three groups scored higher in both questionnaires (sexual satisfaction, desire and orgasm) than their female partners. Comparing results between groups, Group A male partners obtained lower scores in all the subscales. Women belonging to Group A and Group B showed an impairment of sexual arousal, satisfaction, lubrification and orgasm when compared to fertile controls. Even if at the very first stages of infertility treatment no personality disturbances can be detected, the couples' sexual life is already impaired with different sexual disorders according to gender.


Vitamin D insufficiency in North America.
Vitamin D insufficiency is a term that has been used to describe the finding of biochemical evidence of deficiency, without obvious clinical signs or symptoms, such as rickets or osteomalacia. The condition is most commonly diagnosed by a serum 25-hydroxyvitamin D below 40 nmol/L (16 microg/L). This paper reviews North American studies addressing the prevalence of the problem, and the growing body of evidence that vitamin D insufficiency predisposes individuals to poor bone and muscle health. The term insufficiency is somewhat misleading, as patients with this condition are really just part of the spectrum of vitamin D deficiency. If the more generous definition of this condition is used (serum 25-hydroxyvitamin D < 80 nmol/L), a much larger proportion of the population has the problem. The response to vitamin D supplementation in clinical trials suggests current recommendations for dietary intake of this vitamin are too low and that a higher adequate intake should be recommended.


Locoregional Therapies of Cholangiocarcinoma.
Cholangiocarcinoma (CC) is the second most primary liver malignancy with increasing incidence in Western countries. Currently, surgical R0 resection is regarded as the only potentially curative treatment. The results of systemic chemotherapy and best supportive care (BSC) in patients with metastatic disease are often disappointing in regard to toxicity, oncologic efficacy, and overall survival. In current practice, the use of different locoregional therapies is increasingly more accepted. A review of the literature on locoregional therapies for intrahepatic cholangiocarcinoma (ICC) was undertaken. There are no prospective randomized controlled trials. For localized ICC, either primary or recurrent, radiofrequency ablation (RFA) is by far the most commonly used thermal ablation modality. Thereby, a systematic review and meta-analysis reports major complication in 3.8% as well as 1-, 3-, and 5-year overall survival rates of 82, 47, and 24%, respectively. In selected patients (e.g. with a tumor diameter of ≤3 cm), oncologic efficacy and survival after RFA are comparable with surgical resection. For diffuse ICC, different transarterial therapies, either chemotherapy-based (hepatic artery infusion (HAI), transarterial chemoembolization (TACE)) or radiotherapy-based (transarterial radioembolization (TARE)), show extremely promising results. With regard to controlled trials (transarterial therapy versus systemic chemotherapy, BSC or no treatment), tumor control is virtually always better for transarterial therapies and very often accompanied by a dramatic survival benefit and improvement of quality of life. Of note, the latter is the case not only for patients without extrahepatic metastatic disease but also for those with liver-dominant extrahepatic metastatic disease. There are other locoregional therapies such as microwave ablation, irreversible electroporation, and chemosaturation; however, the current data support their use only in controlled trials or as last-line therapy. Dedicated locoregional therapies are commonly used for primary and recurrent ICC as well as liver-only and liver-dominant extrahepatic metastatic disease. Currently, the best evidence and most promising results are available for RFA, HAI, TACE, and TARE. In cohort studies, the overall survival rates are similar to those obtained with surgery or systemic therapies. Prospective randomized controlled trials are warranted to compare safety and efficacy between different surgical, interventional, and systemic therapies, as well as their combinations.


The psychological correlates of distinct neural states occurring during wakeful rest.
When unoccupied by an explicit external task, humans engage in a wide range of different types of self-generated thinking. These are often unrelated to the immediate environment and have unique psychological features. Although contemporary perspectives on ongoing thought recognise the heterogeneity of these self-generated states, we lack both a clear understanding of how to classify the specific states, and how they can be mapped empirically. In the current study, we capitalise on advances in machine learning that allow continuous neural data to be divided into a set of distinct temporally re-occurring patterns, or states. We applied this technique to a large set of resting state data in which we also acquired retrospective descriptions of the participants' experiences during the scan. We found that two of the identified states were predictive of patterns of thinking at rest. One state highlighted a pattern of neural activity commonly seen during demanding tasks, and the time individuals spent in this state was associated with descriptions of experience focused on problem solving in the future. A second state was associated with patterns of activity that are commonly seen under less demanding conditions, and the time spent in it was linked to reports of intrusive thoughts about the past. Finally, we found that these two neural states tended to fall at either end of a neural hierarchy that is thought to reflect the brain's response to cognitive demands. Together, these results demonstrate that approaches which take advantage of time-varying changes in neural function can play an important role in understanding the repertoire of self-generated states. Moreover, they establish that important features of self-generated ongoing experience are related to variation along a similar vein to those seen when the brain responds to cognitive task demands.


Azurophilic granules of human neutrophilic leukocytes are deficient in lysosome-associated membrane proteins but retain the mannose 6-phosphate recognition marker.
During granulocyte differentiation in the bone marrow (BM), neutrophilic leukocyte precursors synthesize large amounts of lysosomal enzymes. These enzymes are sequestered into azurophilic storage granules until used days later for digestion of phagocytized microorganisms after leukocyte emigration to inflamed tissues. This azurophil granule population has previously been defined as a primary lysosome, i.e., a membrane-bound organelle containing acid hydrolases that have not entered into a digestive event. In this study, azurophil granules were purified and shown to contain large amounts of mannose 6-phosphate-containing glycoproteins (Man 6-P GP) but little lysosome-associated membrane proteins (LAMP). In addition, the fine structural localization of Man 6-P GP and LAMP was investigated at various stages of maturation in human BM and blood. Man 6-P GP were present within the azurophilic granules at all stages of maturation and in typical multivesicular bodies (MVB) as well as in multilaminar compartments (MLC), identified by their content of concentric arrays of internal membranes. LAMP was absent in all identified granule populations, but was consistently found in the membranes of vesicles, MVB, and MLC. The latter compartment has not been previously described in this cell type. In conclusion, the azurophilic granules, which contain an abundance of lysosomal enzymes and Man 6-P GP, lack the LAMP glycoproteins. By current criteria, they therefore cannot be classified as lysosomes, but rather may have the functional characteristics of a regulated secretory granule. Rather, the true lysosomes of the resting neutrophil are probably the MVB and MLC. Finally, the typical "dense bodies" or mature lysosomes described in other cells are not present in resting neutrophils.


Neural signature of developmental coordination disorder in the structural connectome independent of comorbid autism.
Children with autism spectrum disorders (ASD) often exhibit motor clumsiness (Developmental Coordination Disorder, DCD), i.e. they struggle with everyday tasks that require motor coordination like dressing, self-care, and participating in sport and leisure activities. Previous studies in these neurodevelopmental disorders have demonstrated functional abnormalities and alterations of white matter microstructural integrity in specific brain regions. These findings suggest that the global organization of brain networks is affected in DCD and ASD and support the hypothesis of a 'dys-connectivity syndrome' from a network perspective. No studies have compared the structural covariance networks between ASD and DCD in order to look for the signature of DCD independent of comorbid autism. Here, we aimed to address the question of whether abnormal connectivity in DCD overlaps that seen in autism or comorbid DCD-autism. Using graph theoretical analysis, we investigated differences in global and regional topological properties of structural brain networks in 53 children: 8 ASD children with DCD (DCD+ASD), 15 ASD children without DCD (ASD), 11 with DCD only, and 19 typically developing (TD) children. We constructed separate structural correlation networks based on cortical thickness derived from Freesurfer. The children were assessed on the Movement-ABC and the Beery Test of Visual Motor Integration. Behavioral results demonstrated that the DCD group and DCD+ASD group scored on average poorer than the TD and ASD groups on various motor measures. Furthermore, although the brain networks of all groups exhibited small-world properties, the topological architecture of the networks was significantly altered in children with ASD compared with DCD and TD. ASD children showed increased normalized path length and higher values of clustering coefficient. Also, paralimbic regions exhibited nodal clustering coefficient alterations in singular disorders. These changes were disorder-specific, and included alterations in clustering coefficient in the isthmus of the right cingulate gyrus and the pars orbitalis of the right inferior frontal gyrus in ASD children, and DCD-related increases in the lateral orbitofrontal cortex. Children meeting criteria for both DCD and ASD exhibited topological changes that were more widespread from those seen in children with only DCD, i.e. children with DCD+ASD showed alterations of clustering coefficient in (para)limbic regions, primary areas, and association areas. The DCD+ASD group showed changes in clustering coefficient in the left association cortex relative to the ASD group. Finally, the DCD+ASD group shared ASD-specific abnormalities in the pars orbitalis of right inferior frontal gyrus, which was hypothesized to reflect atypical emotional-cognitive processing. Our results provide evidence that DCD and ASD are neurodevelopmental disorders with a low degree of overlap in abnormalities in connectivity. The co-occurrence of DCD+ASD was also associated with a distinct topological pattern, highlighting the unique neural signature of comorbid neurodevelopmental disorders.


Phenylbutyrate increases pyruvate dehydrogenase complex activity in cells harboring a variety of defects.
Deficiency of pyruvate dehydrogenase complex (PDHC) is the most common genetic disorder leading to lactic acidosis. PDHC deficiency is genetically heterogenous and most patients have defects in the X-linked E1-α gene but defects in the other components of the complex encoded by PDHB, PDHX, DLAT, DLD genes or in the regulatory enzyme encoded by PDP1 have also been found. Phenylbutyrate enhances PDHC enzymatic activity in vitro and in vivo by increasing the proportion of unphosphorylated enzyme through inhibition of pyruvate dehydrogenase kinases and thus, has potential for therapy of patients with PDHC deficiency. In the present study, we investigated response to phenylbutyrate of multiple cell lines harboring all known gene defects resulting in PDHC deficiency. Fibroblasts of patients with PDHC deficiency were studied for their enzyme activity at baseline and following phenylbutyrate incubation. Drug responses were correlated with genotypes and protein levels by Western blotting. Large deletions affecting PDHA1 that result in lack of detectable protein were unresponsive to phenylbutyrate, whereas increased PDHC activity was detected in most fibroblasts harboring PDHA1 missense mutations. Mutations affecting the R349-α residue were directed to proteasome degradation and were consistently unresponsive to short-time drug incubation but longer incubation resulted in increased levels of enzyme activity and protein that may be due to an additional effect of phenylbutyrate as a molecular chaperone. PDHC enzyme activity was enhanced by phenylbutyrate in cells harboring missense mutations in PDHB, PDHX, DLAT, DLD, and PDP1 genes. In the prospect of a clinical trial, the results of this study may allow prediction of in vivo response in patients with PDHC deficiency harboring a wide spectrum of molecular defects.


A bibliometric analysis in the fields of preventive medicine, occupational and environmental medicine, epidemiology, and public health.
Research in the fields of Preventive Medicine, Occupational/Environmental Medicine, Epidemiology and Public Health play an important role in the advancement of knowledge. In order to map the research production around the world we performed a bibliometric analysis in the above fields. All articles published by different world regions in the above mentioned scientific fields and cited in the Journal Citation Reports (JCR) database of the Institute for Scientific Information (ISI) during the period 1995 and 2003, were evaluated. The research production of different world regions was adjusted for: a) the gross domestic product in 1995 US dollars, and b) the population size of each region. A total of 48,861 articles were retrieved and categorized. The USA led the research production in all three subcategories. The percentage of articles published by USA researchers was 43%, 44% and 61% in the Preventive Medicine, Epidemiology, and Public Health subcategories, respectively. Canada and Western Europe shared the second position in the first two subcategories, while Oceania researchers ranked second in the field of Public Health. USA researchers maintain a leadership position in the production of scientific articles in the fields of Preventive Medicine, Occupational/Environmental Medicine and Epidemiology, at a level similar to other scientific disciplines, while USA contribution to science in the field of Public Health is by all means outstanding. Less developed regions would need to support their researchers in the above fields in order to improve scientific production and advancement of knowledge in their countries.


Extrusion Bioprinting of Shear-Thinning Gelatin Methacryloyl Bioinks.
Bioprinting is an emerging technique for the fabrication of 3D cell-laden constructs. However, the progress for generating a 3D complex physiological microenvironment has been hampered by a lack of advanced cell-responsive bioinks that enable bioprinting with high structural fidelity, particularly in the case of extrusion-based bioprinting. Herein, this paper reports a novel strategy to directly bioprint cell-laden gelatin methacryloyl (GelMA) constructs using bioinks of GelMA physical gels (GPGs) achieved through a simple cooling process. Attributed to their shear-thinning and self-healing properties, the GPG bioinks can retain the shape and form integral structures after deposition, allowing for subsequent UV crosslinking for permanent stabilization. This paper shows the structural fidelity by bioprinting various 3D structures that are typically challenging to fabricate using conventional bioinks under extrusion modes. Moreover, the use of the GPG bioinks enables direct bioprinting of highly porous and soft constructs at relatively low concentrations (down to 3%) of GelMA. It is also demonstrated that the bioprinted constructs not only permit cell survival but also enhance cell proliferation as well as spreading at lower concentrations of the GPG bioinks. It is believed that such a strategy of bioprinting will provide many opportunities in convenient fabrication of 3D cell-laden constructs for applications in tissue engineering, regenerative medicine, and pharmaceutical screening.


Voices from the Field: Supporting the Educational Needs of Cytotechnologists.
Sustaining a well-trained, competitive, and marketable cytotechnology workforce is a major goal of the American Society of Cytopathology/American Society for Clinical Pathology Workgroup Focusing on Emerging Roles in Cytopathology (ASC/ASCP Workgroup). This article describes the data collection initiatives performed by the Workgroup to confirm cytotechnologist (CT) perceived educational needs to keep pace with emerging practice changes in the workplace. In response to data collected, the Workgroup created Advanced Cytopathology Education (ACE)da unique, innovative educational resource designed to fulfill this need. Data collection efforts included annual needs assessment surveys to gauge CT participants' preferred topics and learning modalities. These data were used to design and prioritize ACE topics. Program evaluations were also administered to evaluate participants' perceptions of program quality and effectiveness at meeting their educational needs. Research findings reveal CT education needs to align with emerging practice areas as reported in other Workgroup data collection efforts. The incorporation of new entry-level competencies in cytotechnology training programs prepares new CT graduates, but there is no standardized mechanism for formal, robust, and recognized ongoing education for other practicing CTs. This article highlights the educational endeavors carried out by the Workgroup in fulfilling the educational needs of practicing CTs as communicated through various data collection efforts. As CT responsibilities evolve, ASC and Workgroup efforts will continue to focus on providing educational support for current practicing CTs who need training in emerging practice areas.


Design principles of a microtubule polymerase.
Stu2/XMAP215 microtubule polymerases use multiple tubulin-binding TOG domains and a lattice-binding basic region to processively promote faster elongation. How the domain composition and organization of these proteins dictate polymerase activity, end localization, and processivity is unknown. We show that polymerase activity does not require different kinds of TOGs, nor are there strict requirements for how the TOGs are linked. We identify an unexpected antagonism between the tubulin-binding TOGs and the lattice-binding basic region: lattice binding by the basic region is weak when at least two TOGs engage tubulins, strong when TOGs are empty. End-localization of Stu2 requires unpolymerized tubulin, at least two TOGs, and polymerase competence. We propose a 'ratcheting' model for processivity: transfer of tubulin from TOGs to the lattice activates the basic region, retaining the polymerase at the end for subsequent rounds of tubulin binding and incorporation. These results clarify design principles of the polymerase.


Macrophage-B Cell Interactions in the Inverted Porcine Lymph Node and Their Response to Porcine Reproductive and Respiratory Syndrome Virus.
Swine lymph nodes (LN) present an inverted structure compared to mouse and human, with the afferent lymph diffusing from the center to the periphery. This structure, also observed in close and distant species such as dolphins, hippopotamus, rhinoceros, and elephants, is poorly described, nor are the LN macrophage populations and their relationship with B cell follicles. B cell maturation occurs mainly in LN B cell follicles with the help of LN macrophage populations endowed with different antigen delivery capacities. We identified three macrophage populations that we localized in the inverted LN spatial organization. This allowed us to ascribe porcine LN MΦ to their murine counterparts: subcapsular sinus MΦ, medullary cord MΦ and medullary sinus MΦ. We identified the different intra and extrafollicular stages of LN B cells maturation and explored the interaction of MΦ, drained antigen and follicular B cells. The porcine reproductive and respiratory syndrome virus (PRRSV) is a major porcine pathogen that infects tissue macrophages (MΦ). PRRSV is persistent in the secondary lymphoid tissues and induces a delay in neutralizing antibodies appearance. We observed PRRSV interaction with two LN MΦ populations, of which one interacts closely with centroblasts. We observed BCL6 up-regulation in centroblast upon PRRSV infection, leading to new hypothesis on PRRSV inhibition of B cell maturation. This seminal study of porcine LN will permit fruitful comparison with murine and human LN for a better understanding of normal and inverted LN development and functioning.


Influence of exocrine and endocrine pancreatic function on intestinal brush border enaymatic activities.
Digestive enzymatic activities (disaccharidases, alkaline phosphatase, peptide hydrolases) have been determined in the mucosa of 14 patients with chronic pancreatitis. All had an abnormal secretin-pancreozymin test. Four patients had insulin-dependent diabetes mellitus, four a pathological glucose tolerance test. Nine patients had steatorrhoea. Maltase, sucrase, and alkaline phosphatase activity was significantly elevated in patients with exocrine pancreatic insufficiency, whereas those of lactase, trehalase, and peptide hydrolase were normal. Patients with steatorrhoea had higher maltase and sucrase activity than those without steatorrhoea, whereas decreased glucose tolerance had no effect on brush border enzymatic activity. It is suggested thatdecreased exocrine rather than decreased endocrine pancreatic function is responsible for the increase in intestinal disaccharidase and alkaline phosphatase activity, possible by the influence of pacreatic enzymes on the turnover of brush border enzymes from the luminal side of the mucosal membranes or by direct hormonal stimulation though cholecystokinin.


Protein structure determination using metagenome sequence data.
Despite decades of work by structural biologists, there are still ~5200 protein families with unknown structure outside the range of comparative modeling. We show that Rosetta structure prediction guided by residue-residue contacts inferred from evolutionary information can accurately model proteins that belong to large families and that metagenome sequence data more than triple the number of protein families with sufficient sequences for accurate modeling. We then integrate metagenome data, contact-based structure matching, and Rosetta structure calculations to generate models for 614 protein families with currently unknown structures; 206 are membrane proteins and 137 have folds not represented in the Protein Data Bank. This approach provides the representative models for large protein families originally envisioned as the goal of the Protein Structure Initiative at a fraction of the cost.


Outdoor dissolution of detonation residues of three insensitive munitions (IM) formulations.
We seek to understand the environmental fate of three new insensitive munitions, explosive formulations developed to reduce the incidence of unintended detonations. To this end, we measured the size distribution of residues from low order detonations of IMX 101, IMX 104, and PAX 21-filled munitions and are studying how these three formulations weather and dissolve outdoors. The largest pieces collected from the detonations were centimeter-sized and we studied 12 of these in the outdoors test. We found that the particles break easily and that the dissolution of 2,4-dinitroanisole (DNAN) is quasi-linear as a function of water volume. DNAN is the matrix and the least soluble major constituent of the three formulations. We used DNAN's linear dissolution rate to estimate the life span of the pieces. Particles ranging in mass from 0.3 to 3.5 g will completely dissolve in 3-21 years given 100 cm y(-1) precipitation rates.


Characterization of a "silencer" in yeast: a DNA sequence with properties opposite to those of a transcriptional enhancer.
The mating type of yeast is determined by the allele, either a or alpha, at the MAT locus. Two other loci, HML and HMR, contain complete copies of the alpha and a genes, respectively, which are not expressed. The four SIR gene products are required in trans for repression of the silent loci, as are cis-acting sites on either side of HML and HMR, about 1000 bp from the mating-type promoters. We demonstrate that one of these cis-acting sequences, HMRE, is able to switch off at least two nonmating-type promoters. In common with enhancers, it is able to function in either orientation, relatively independently of its position with respect to the regulated promoter, and can act on promoters 2600 bp away. However since HMRE represses, rather than enhances, transcription we have called it a "silencer" sequence.


Severe hyposmia distinguishes neuropathologically confirmed dementia with Lewy bodies from Alzheimer's disease dementia.
Many subjects with neuropathologically-confirmed dementia with Lewy bodies (DLB) are never diagnosed during life, instead being categorized as Alzheimer's disease dementia (ADD) or unspecified dementia. Unrecognized DLB therefore is a critical impediment to clinical studies and treatment trials of both ADD and DLB. There are studies that suggest that olfactory function tests may be able to distinguish DLB from ADD, but few of these had neuropathological confirmation of diagnosis. We compared University of Pennsylvania Smell Identification Test (UPSIT) results in 257 subjects that went on to autopsy and neuropathological examination. Consensus clinicopathological diagnostic criteria were used to define ADD and DLB, as well as Parkinson's disease with dementia (PDD), with (PDD+AD) or without (PDD-AD) concurrent AD; a group with ADD and Lewy body disease (LBD) not meeting criteria for DLB (ADLB) and a clinically normal control group were also included. The subjects with DLB, PDD+AD and PDD-AD all had lower (one-way ANOVA p < 0.0001, pairwise Bonferroni p < 0.05) first and mean UPSIT scores than the ADD, ADLB or control groups. For DLB subjects with first and mean UPSIT scores less than 20 and 17, respectively, Firth logistic regression analysis, adjusted for age, gender and mean MMSE score, conferred statistically significant odds ratios of 17.5 and 18.0 for the diagnosis, vs ADD. For other group comparisons (PDD+AD and PDD-AD vs ADD) and UPSIT cutoffs of 17, the same analyses resulted in odds ratios ranging from 16.3 to 31.6 (p < 0.0001). To our knowledge, this is the largest study to date comparing olfactory function in subjects with neuropathologically-confirmed LBD and ADD. Olfactory function testing may be a convenient and inexpensive strategy for enriching dementia studies or clinical trials with DLB subjects, or conversely, reducing the inclusion of DLB subjects in ADD studies or trials.


Impact of pneumococcal conjugate vaccine on infections caused by antibiotic-resistant Streptococcus pneumoniae.
Studies have shown that vaccination with seven-valent pneumococcal conjugate vaccine (PCV7) results in a decline in nasopharyngeal carriage of penicillin-resistant Streptococcus pneumoniae, in carriage of vaccine-type pneumococci, and in replacement by non-vaccine serotypes. Vaccines can reduce pneumococcal resistance in vaccinated and unvaccinated populations by reducing the carriage of antibiotic-resistant serotypes, which protects the vaccinated population and prevents spread of disease to others, and by decreasing antibiotic resistance through overall reduction in antibiotic use. However, while reducing the level of vaccine serotypes and drug-resistant serotypes in the nasopharynx, PCV7 also causes non-vaccine pneumococci replacement. The impact of serotype replacement on disease is not clearly understood. Pelton et al. surveyed two communities shortly after the introduction of the PCV7 immunization programme and found that while colonization with vaccine serotypes declined from 22% to 2% from 2000 to 2003, prevalence of non-vaccine serotypes increased from 7% to 16%. Although penicillin-resistant colonizing S. pneumoniae isolates initially declined, penicillin-intermediate isolates increased 2 years following PCV7 introduction. The change was primarily accounted for by an increase in penicillin-intermediate serotype 19A. Serotype 19A is the only serotype not affected by PCV7 that is prevalent worldwide, clinically important, and highly multidrug-resistant. A study by Hicks et al. established serotype 19A as the predominant post-PCV7 cause of invasive pneumococcal disease (IPD) in children and the elderly. An increase in IPD rates caused by antibiotic-resistant serotype 19A isolates can also occur without vaccination; reports indicate increases in regions characterized by extensive antibiotic use, underscoring the importance of strategies to contain antibiotic resistance.


Early-phase development of cancer prevention agents: challenges and opportunities.
Chemoprevention is the administration of agents (drugs, biologics, dietary supplements, or nutrients) to reduce the risk of developing cancer or prevent the recurrence of cancer. The National Cancer Institute, Division of Cancer Prevention (NCI, DCP), is a major sponsor of cancer preventive preclinical and clinical research. As such, it has developed a comprehensive drug development program specifically designed to meet the requirements needed for cancer preventive drugs to achieve initial regulatory approval. Clinical development of cancer prevention agents presents unique challenges that are not encountered with most cancer therapeutic agents. To meet these challenges, NCI, DCP has implemented new approaches and programs, including phase 0 clinical trial designs and microdose studies. In addition, the PREVENT Cancer Program was recently implemented by NCI, DCP to offer a formalized structure for moving drugs forward in the prevention pipeline using a continue/not continue decision process. Likewise, DCP has implemented a Clinical Trials Consortium to further develop these agents. These and other approaches will be discussed in this commentary.


Awareness Regarding Causes of Infertility Among Out-patients at a Tertiary Care Hospital in Karachi, Pakistan.
Infertility is the inability of a couple to achieve pregnancy within 12 months of sexual intercourse without the use of contraceptives. The Pakistani population, belonging to a low-middle income country, has a high prevalence of infertility due to a low knowledge and awareness regarding its causes, and lack of healthcare-seeking behavior for this medical issue. The prevalence of infertility in Pakistan is reported as 22%, with primary infertility accounting for 4% of the total cases. This leads to psychological trauma among women as societal norms equate infertility with failure on a personal, emotional, and social level. In this study, we aimed to assess among this population the general awareness regarding infertility and its causes; and identify any key knowledge gaps pertaining to the subject. A cross-sectional study was carried out between June 2019 and November 2019, at a public hospital (Civil Hospital Karachi) in Karachi, Pakistan. Convenience sampling technique was used to collect data from adult participants (older than 18 years) via an interview-administered questionnaire. The questionnaire was based on the Cardiff Fertility Knowledge Scale (CFKS) and assessed the knowledge regarding causes of infertility such as smoking, healthy lifestyle, contraceptives, genital tract infections among others. We also determined the association between socio-demographic variables with mean knowledge scores. Data were analyzed using Statistical Package for Social Sciences (SPSS), version 20.0. The majority of the participants were married (n=342, 68.8%) and more than half were unemployed (n=259, 52.1%). Approximately, two-quarters (n=250, 50.3%) did not believe that equal proportions of males and females contribute to infertility. The mean knowledge score of our study population was 12.95 ± 2.48 points. An overwhelming proportion of the participants (n=326, 65.6%) falsely believed that the usage of the intra-uterine device contributes to infertility. Additionally, more than half of the responders (n=278, 55.9%) incorrectly believed that a male achieving erection is an indication of fertility. Education (p=0.019), vehicle ownership (p=0.018), and marital status (p=0.031) were the only demographic factors that showed significant differences with mean knowledge scores. Awareness regarding the causes of infertility among the general population was found to be inadequate. Emphasis on targeted fertility education, in association with general public awareness programs regarding its causes and risk factors may help mitigate this problem by potentially reducing the prevalence of this condition, and increasing the number of affected individuals who seek medical care in a timely fashion.


Child bicyclist injuries: are we obtaining enough information in the emergency department chart?
The purpose of this study was to assess the range of information relevant to bicyclist injury research that is available on routinely completed emergency department medical records. A retrospective chart review of emergency department medical records was conducted on children who were injured as bicyclists and treated at an urban level I pediatric trauma center. A range of variables relevant to bicyclist injury research and prevention was developed and organized according to the Haddon matrix. Routinely completed free text emergency department medical records were assessed for the presence of each of the targeted elements. In addition, medical records of seriously injured patients (for whom a more structured medical record is routinely used) were compared to free form records of less seriously injured patients to identify differences in documentation that may be related to the structure of the medical record. Information related to previous medical history (96% of records), diagnosis (89%), documentation of pre-hospital care (82%), and child traumatic contact points (81%) were documented in the majority of medical records. Information relevant to prevention efforts was less commonly documented: identification of motor vehicle/object involved in crash (58%), the precipitating event (24%), the location of the crash (23%), and documentation of helmet use (23%). Records of seriously injured patients demonstrated significantly higher documentation rates for pre-hospital care and child traumatic contact points, and significantly lower documentation rates for previous medical history, child kinematics, main body parts impacted, and location of injury event. Routinely completed free text emergency department medical records contain limited information that could be used by injury researchers in effective surveillance. In particular information relating to the circumstances of the crash event that might be used to design or target prevention efforts is typically lacking. Routine use of more structured medical records has the potential to improve documentation of key information.


Low-dose adjunctive cilostazol in patients with complex lesions undergoing percutaneous coronary intervention.
Patients with complex coronary lesions undergoing percutaneous coronary intervention (PCI) have more major adverse cardiac events (MACE) than do those with simpler cases. Therefore, intensive antiplatelet therapy might be needed in these patients. A total of 127 patients with complex lesions undergoing PCI in the Second Hospital of Tianjin Medical University from October 2012 to April 2014 were randomized to receive either dual (aspirin plus clopidogrel, DAPT, n = 66), or triple antiplatelet therapy (aspirin plus clopidogrel plus cilostazol; TAPT, n = 61). Patients in the TAPT group received low-dose cilostazol (100 mg loading, followed with 50 mg twice per day) for 3-6 months. The primary endpoint was composite MACE. The complex coronary target lesions were defined as at least one of the following: left main disease; severe 3-vessel disease; chronic total occlusion lesions; true bifurcation lesion; ostial lesions; severe calcified lesions; and highly thrombotic lesions. The two groups had similar baseline clinical and angiographic characteristics. One-year clinical outcomes showed that the TAPT group had significantly lower incidences of myocardial infarction (1.6% vs 13.6%, P = 0.018) and MACE (1.6% vs 16.7%, P = 0.004) than DAPT group. The DAPT group had two cases of stent thrombosis, while the TAPT group did not. Furthermore, adjunctive low-dose cilostazol didn't significantly increase the incidence of bleeding events (26.2% vs 19.7%, P = 0.381) regardless of major (4.9% vs 4.5%, P = 0.921) or minor (21.3% vs 15.2%, P = 0.368) bleeding events. In conclusion, low-dose adjunctive cilostazol seems superior to dual antiplatelet therapy in reducing recurrent ischemic events in patients with complex coronary lesions and the two test groups have a similar incidence of bleeding events.


Psychometric evaluation and predictive validity of Ryff's psychological well-being items in a UK birth cohort sample of women.
Investigations of the structure of psychological well-being items are useful for advancing knowledge of what dimensions define psychological well-being in practice. Ryff has proposed a multidimensional model of psychological well-being and her questionnaire items are widely used but their latent structure and factorial validity remains contentious. We applied latent variable models for factor analysis of ordinal/categorical data to a 42-item version of Ryff's psychological well-being scales administered to women aged 52 in a UK birth cohort study (n = 1,179). Construct (predictive) validity was examined against a measure of mental health recorded one year later. Inter-factor correlations among four of the first-order psychological well-being constructs were sufficiently high (> 0.80) to warrant a parsimonious representation as a second-order general well-being dimension. Method factors for questions reflecting positive and negative item content, orthogonal to the construct factors and assumed independent of each other, improved model fit by removing nuisance variance. Predictive validity correlations between psychological well-being and a multidimensional measure of psychological distress were dominated by the contribution of environmental mastery, in keeping with earlier findings from cross-sectional studies that have correlated well-being and severity of depression. Our preferred model included a single second-order factor, loaded by four of the six first-order factors, two method factors, and two more distinct first-order factors. Psychological well-being is negatively associated with dimensions of mental health. Further investigation of precision of measurement across the health continuum is required.


A retrospective study of past graduates of a residential life skills program for youth with physical disabilities.
Young people with physical disabilities experience issues regarding employment, schooling, independent living and establishing meaningful personal relationships. A lack of life skills has been recognized as an important factor contributing to this lag. The Independence Program (TIP) is a short-term residential life skills program that aims to equip youth with the foundational life skills required to assume adult roles. This study retrospectively examined the achievements, skills acquired and program attributions of youth and young adults who took part in this three-week immersive teen independence program over a 20-year period. A total of 162 past graduates were invited to take part, with 78 doing so (a 48% response rate). These past graduates completed an online survey assessing objective outcomes such as employment and independent living; subjective outcomes such as feeling in control and living meaningful lives; and reflections on skills acquired, opportunities experienced and attributions to TIP. The majority of respondents were female (71%), had a diagnosis of cerebral palsy (55%) and ranged from 20 to 35 years of age (92%). Despite a range of outcomes related to the achievement of adult roles, high levels of life satisfaction and overall quality of life were reported. Nearly every respondent reported using the skills they learned at the program in their lives afterwards and a high percentage attributed the acquisition and consolidation of core life skills to participating in this intensive immersive program. Although causality cannot be assumed, respondents reflected very positively on the opportunities provided by TIP to develop their independent living and life skills, extend their social networks and understand their strengths and weaknesses. Such findings validate the importance of targeted skill development to assist young people with physical disabilities in attaining their life goals and encourage focused investigations of key features in program design.


New evidence for an extra-hepatic role of N-acetylglucosaminyltransferase III in the progression of diethylnitrosamine-induced liver tumors in mice.
N-acetylglucosaminyltransferase III (GlcNAc-TIII) is encoded by the Mgat3 gene and catalyzes the addition of the bisecting GlcNAc to the core of N-glycans. Mice lacking GlcNAc-TIII due to the insertion mutation Mgat3tmlPst (termed Mgat3neo), exhibit retarded progression of liver tumors induced by diethylnitrosamine (DEN; M. Bhaumik et al, Cancer Res., 58: 2881-2887, 1998). This phenotype seemed to be due to a reduction, in activity or amount, of a circulating glycoprotein(s) that enhances DEN-induced liver tumor progression. Here, we provide new evidence to support this hypothesis. First, we show that mice with a deletion mutation of the Mgat3 gene coding exon (Mgat3tmlJxm, termed Mgat3delta) also exhibit retarded progression of DEN-induced liver tumors. At 7 months there was a significant decrease in liver weight (approximately 27%; P < 0.01), reflecting reduced tumor burden in Mgat3delta/delta mice. In addition, tumors were generally fewer and smaller, and histological changes were less severe in Mgat3delta/delta livers. Therefore, tumor progression is retarded in mice with two different null mutations in the Mgat3 gene. Second, we show that the development of DEN-induced tumors is unaltered by high levels of GlcNAc-TIII in the liver of transgenic mice. The Mgat3 gene coding exon under the control of the major urinary protein (MUP) promoter was used to generate transgenic mice that express GlcNAc-TIII in liver. Following DEN injection and phenobarbitol treatment, however, no significant differences were observed between MUP/Mgat3 transgenic and control mice in either tumor numbers or liver weight. The combined data provide strong evidence that retarded progression of tumors in mice lacking GlcNAc-TIII is due to the absence of the bisecting GlcNAc residue on N-glycans of a circulating glycoprotein(s) from a tissue other than liver.


Rapid use of high-sensitive cardiac troponin I for ruling-in and ruling-out of acute myocardial infarction (RACING-MI): study protocol.
The European Society of Cardiology has suggested an accelerated algorithm for ruling-in and ruling-out myocardial infarction (MI) with high-sensitive cardiac troponin (hs-cTn) measured at admission (0 hour) and after 1 hour (1 hour) as an alternative to standard measurements at 0 hour and 3 hours. However, the 0 hour/1 hour algorithm has only been tested in a limited amount of patient cohorts and not for all hs-cTn assays. Moreover, it is unknown if MI can be ruled-out faster than 1 hour. In this single-centre, clinical trial, we will investigate whether MI safely can be ruled-in or ruled-out after 30 min and 1 hour. Patients with chest pain suggestive of MI admitted to the emergency department will be subjected to hs-cTn measurements at the following time points: 0 hour, 30 min, 1 hour and 3 hours. Chest pain characteristics will be recorded. In total, 1000 patients with all four blood samples will be included. The diagnostic algorithms will be derived based on the first 500 patients and validated in the subsequent 500 patients. The primary endpoint is the negative predictive value of the 0 hour/30 min and the 0 hour/1 hour algorithms. Secondary endpoints include positive predictive value, sensitivity and specificity. Results will be compared with the standard 0 hour/3 hour algorithm. Oral and written informed consent will be obtained from all patients. The trial is approved by The Regional Committee on Health Research Ethics and the Danish Data Protection Agency. Data will be disseminated and submitted to peer-reviewed scientific journals and meetings irrespective of study outcome. NCT03634384.