Myofibroblast-derived PDGF-BB promotes Hedgehog survival signaling in cholangiocarcinoma cells.
Cholangiocarcinoma (CCA) cells paradoxically express the death ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and, therefore, are dependent upon potent survival signals to circumvent TRAIL cytotoxicity. CCAs are also highly desmoplastic cancers with a tumor microenvironment rich in myofibroblasts (MFBs). Herein, we examine a role for MFB-derived CCA survival signals. We employed human KMCH-1, KMBC, HuCCT-1, TFK-1, and Mz-ChA-1 CCA cells, as well as human primary hepatic stellate and myofibroblastic LX-2 cells, for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. Coculturing CCA cells with myofibroblastic human primary hepatic stellate cells or LX-2 cells significantly decreased TRAIL-induced apoptosis in CCA cells, a cytoprotective effect abrogated by neutralizing platelet-derived growth factor (PDGF)-BB antiserum. Cytoprotection by PDGF-BB was dependent upon Hedgehog (Hh) signaling, because it was abolished by the smoothened (SMO; the transducer of Hh signaling) inhibitor, cyclopamine. PDGF-BB induced cyclic adenosine monophosphate-dependent protein kinase-dependent trafficking of SMO to the plasma membrane, resulting in glioma-associated oncogene (GLI)2 nuclear translocation and activation of a consensus GLI reporter gene-based luciferase assay. A genome-wide messenger RNA expression analysis identified 67 target genes to be commonly up- (50 genes) or down-regulated (17 genes) by both Sonic hedgehog and PDGF-BB in a cyclopamine-dependent manner in CCA cells. Finally, in a rodent CCA in vivo model, cyclopamine administration increased apoptosis in CCA cells, resulting in tumor suppression. MFB-derived PDGF-BB protects CCA cells from TRAIL cytotoxicity by a Hh-signaling-dependent process. These results have therapeutical implications for the treatment of human CCA.


Deceitful red-flag: angina secondary to iron deficiency anaemia as a presenting complaint for underlying malignancy.
A 73-year-old man with an 8-week history of angina underwent an exercise tolerance test at the rapid access clinic, which indicated inducible ischaemia and he was subsequently referred for angiogram. His angiogram demonstrated no coronary pathology. It was later discovered that bloods taken on the day of the procedure showed a haemoglobin of 54 g/L (130-180 g/L). His haemoglobin used to book the angiogram 3 months before was 143 g/L. Following angiogram, a mass was identified in the right iliac fossa and CT scan confirmed a caecal tumour. The patient ultimately underwent a curative right hemicolectomy as an outpatient. The case is a reminder of the importance of basic preangiogram investigations, in particularly a full blood count, to rule-out angina secondary to anaemia through a low haemoglobin. Most importantly, it also questions when the appropriate time is for these investigations to be carried out, prior to coronary angiography.


Monitoring the price and affordability of foods and diets globally.
Food prices and food affordability are important determinants of food choices, obesity and non-communicable diseases. As governments around the world consider policies to promote the consumption of healthier foods, data on the relative price and affordability of foods, with a particular focus on the difference between 'less healthy' and 'healthy' foods and diets, are urgently needed. This paper briefly reviews past and current approaches to monitoring food prices, and identifies key issues affecting the development of practical tools and methods for food price data collection, analysis and reporting. A step-wise monitoring framework, including measurement indicators, is proposed. 'Minimal' data collection will assess the differential price of 'healthy' and 'less healthy' foods; 'expanded' monitoring will assess the differential price of 'healthy' and 'less healthy' diets; and the 'optimal' approach will also monitor food affordability, by taking into account household income. The monitoring of the price and affordability of 'healthy' and 'less healthy' foods and diets globally will provide robust data and benchmarks to inform economic and fiscal policy responses. Given the range of methodological, cultural and logistical challenges in this area, it is imperative that all aspects of the proposed monitoring framework are tested rigorously before implementation.


Apoptosis-associated proteins and the development of oral squamous cell carcinoma.
Expression of apoptosis-associated proteins was evaluated in premalignant and malignant oral epithelial lesions, to test the hypothesis that protein regulation of apoptosis may be altered in the development of oral squamous cell carcinoma. Ninety archived paraffin-embedded specimens from 25 patients (two or more sequential biopsies each) and eight control specimens were evaluated in immunohistochemically stained sections for tumor suppressor protein p53, p53 binding protein mdm-2, and apoptosis regulatory proteins Bcl-2, Bcl-X, Bax, and Bak. The initial histologic diagnosis for 17/25 patients was either focal keratosis, mild dysplasia, or moderate dysplasia; the initial diagnosis for the remaining eight patients ranged from severe dysplasia to moderately differentiated squamous cell carcinoma. Thirty of 90 specimens showed positive p53 expression, nine of which were dysplasias. In patients with one or more lesions displaying p53 expression, there was increased intensity of staining with disease progression. Bak was expressed in 57/90 specimens, including 27 dysplasias of various grades. There was also a significantly increased intensity of Bak staining with disease progression, which did not appear to be dependent upon p53 status. Bcl-X was expressed in 73/90 specimens, with staining displayed earlier in premalignant lesions than either p53 or Bak. Ten of 90 specimens were positive for Bcl-2 (all were dysplasias or carcinomas), and only 2/90 specimens were positive for Bax. Eleven of 90 specimens were positive for mdm-2; six of which were also positive for p53. These data show that apoptosis-associated proteins are altered in variable patterns in both premalignant and malignant oral epithelial lesions. p53 and especially Bak and Bcl-X are expressed early; Bax is largely absent; and Bcl-2 and mdm-2 show sporadic expression in the development of oral premalignant and malignant disease.


Exopolysaccharide production by lactose-hydrolyzing bacteria isolated from traditionally fermented milk.
With increasing consumer demands for safer, healthier and more natural products, bacterially produced exopolysaccharides (EPSs) are becoming a viable option as an additive in designer-type foods. Fresh milk samples from cattle and sheep were collected from informal settlements in South Africa. After a three day incubation period at 25 degrees C, 550 bacterial strains were isolated and evaluated for EPS production from lactose as sole carbon source. Strains producing EPS on lactose were identified to species level with 16S rRNA gene sequencing and encompass 11 Gram-positive and 6 Gram-negative bacteria. EPS production was assigned for the first time to members of the species Staphylococcus hominis and Enterococcus lactis, and also to apparently novel species of the genera Sphingomonas and Acinetobacter. The polymers consisted mainly out of galactose and glucose, while a few isolates also incorporated rhamnose. Isolates produced diverse biopolymers as seen by significant differences in monomer ratios.


Management of Botrytis Fruit Rot in Annual Winter Strawberry Using Captan, Thiram, and Iprodione.
The management of Botrytis fruit rot on annual strawberry by fungicides was evaluated in Florida during the 1995-96, 1996-97, and 1997-98 seasons. Weekly applications of captan or thiram, bloom applications of iprodione applied twice during each of two peak flowering periods, and weekly applications of captan combined with iprodione bloom applications were evaluated. Significant treatment effects (P ≤ 0.05) on the incidence of Botrytis fruit rot were detected for the early, late, and whole-season periods each season. Weekly applications of captan or thiram controlled Botrytis fruit rot, reducing disease incidence by more than 41% compared to the untreated control. These treatments also affected marketable yield during two seasons, with a 42 to 127% increase in yield compared to the control. Weekly fungicide applications did not reduce the incidence of Botrytis fruit rot until at least the fourth week of harvest, 9 to 10 weeks after applications began. Bloom applications of iprodione alone reduced the incidence of Botrytis fruit rot during the second peak bloom period, and the reductions in incidence occurred 1 to 3 weeks after the start of bloom applications. This suggests that iprodione applications control infections at flowering or early stages of fruit development. However, early-season bloom applications did not reduce the incidence of Botrytis fruit rot. The control of Botrytis fruit rot by weekly captan applications was not improved by the addition of iprodione bloom applications. These data suggest that early-season fungicide applications for the control of Botrytis fruit rot in annual winter strawberry are of limited efficacy, and that bloom applications of Botryticides such as iprodione should be focused on the second peak bloom period.


Interactions between phytochemical components of Sutherlandia frutescens and the antiretroviral, atazanavir in vitro: implications for absorption and metabolism.
African traditional medicinal plants, such as Sutherlandia frutescens have the potential to interact pharmacokinetically with the protease inhibitor class of antiretrovirals, thereby impacting on their safety and efficacy. The effects of extracts and phytochemical components of Sutherlandia frutescens, on the in vitro absorption and metabolism of the protease inhibitor, atazanavir were thus investigated. Aqueous and methanolic extracts of Sutherlandia frutescens were prepared by freeze-drying of hot water and methanol decoctions of Sutherlandia frutescens plant material respectively, whilst crude triterpenoid glycoside and flavonol glycoside fractions were isolated by solvent extraction and subsequent column chromatography. Atazanavir was quantitated in the absence or presence of these compounds as well as commercially available purported constituents of Sutherlandia frutescens, namely, L-canavanine, L-GABA and D-pinitol, after a one hour co-incubation in Caco-2 cell monolayers and human liver microsomes. The triterpenoid and flavonol glycoside fractions were found to be present in the aqueous and methanolic extracts of Sutherlandia frutescens and were shown to contain the sutherlandiosides and sutherlandins known to be present in Sutherlandia frutescens. The aqueous extract and D-pinitol significantly reduced atazanavir accumulation by Caco-2 cells, implying a decrease in atazanavir absorption, whilst the opposite was true for the triterpenoid glycoside fraction. Both the aqueous and methanolic extracts inhibited atazanavir metabolism in human liver microsomes, whilst enhanced atazanavir metabolism was exhibited by the triterpenoid glycoside fraction. The extracts and phytochemical components of Sutherlandia frutescens influenced the accumulation of atazanavir by Caco-2 cells and also affected ATV metabolism in human liver microsomes. These interactions may have important implications on the absorption and metabolism and thus the overall oral bioavailability of atazanavir.


Fast phage detection and quantification: An optical density-based approach.
Since 1959 with the proposal of Double Agar Layer (DAL) method for phage detection and quantification, many sophisticated methods have emerged meanwhile. However, many of them are either too complex/expensive or insensitive to replace routine utilization of DAL method in clinical, environmental and industrial environments. For that purpose, we have explored an alternative method for the detection and quantification of bacteriophages that fulfills the criteria of being rapid, simple and inexpensive. In this paper we have developed a method based on the analysis of optical density kinetics in bacterial cultures exposed to phage-containing samples. Although the decrease in optical density caused by cell lysis was one of the first observable consequences of the effect of viral infection in bacterial cultures, the potential of the method for the assessment of phage abundance has never been fully exploited. In this work we carry out a detailed study of optical density kinetics in phage-infected bacterial cultures, as a function of both, phage abundance and initial concentration of the host organisms. In total, 90 different combinations of bacteria/phage concentrations have been used. The data obtained provide valuable information about sensitivity ranges, duration of the assay, percentages of inhibition and type of lysing behavior for each phage concentration. The method described can detect, as few as 10 phage particles per assay volume after a phage incubation period of 3.5h. The duration of the assay can be shortened to 45min at the expense of losing sensitivity and increasing the limit of detection to 108 pfu/ml. Despite using non-sophisticated technology, the method described has shown sensitivity and response time comparable to other high-end methods. The simplicity of the technology and of the analytical steps involved, make the system susceptible of miniaturization and automation for high-throughput applications which can be implemented in routine analysis in many environments.


S100B and the influence of seasonal variation.
Background A blood test for S100B can be used to rule out intracranial complications after minor head injury and thereby reduce the need for computed tomography (CT) examinations. The aim of this study was to investigate the clinical importance of a possible influence of seasonal variation on S100B. Methods The individual seasonal variation of S100B in 69 healthy volunteers living at latitudes with extremely variable seasonal exposure to sunlight was investigated. Results The mean serum concentration of S100B was 13% higher in August than in February, but however, not statistically significant (p = 0.068). A good agreement between summer and winter S100B values was confirmed by Bland-Altman analysis and a significant correlation (r = 0.317, p = 0.008) was shown between summer and winter S100B values. Conclusion This study did not show any clinical importance of seasonal variation of S100B that may influence the decision of CT scanning patients with head injuries.


Our surgical heritage: the role of the Department of Paediatric Surgery in the development of paediatric surgery in Cape Town, in Africa, and around the world.
The Department of Paediatric Surgery at the University of Cape Town has made a remarkable contribution to the academic body of knowledge of Paediatric Surgery both in South Africa and around the world. It has played a key role in the development of the specialty in South Africa and through the South African diaspora has trained many paediatric surgeons who have made their mark internationally. More recently it has become a major focus of teaching and training for African paediatric surgeons. This article traces this legacy through its origins in the early 1920s to its current prominent position in the world paediatric surgical community.


Microvascular destruction identifies murine allografts that cannot be rescued from airway fibrosis.
Small airway fibrosis (bronchiolitis obliterans syndrome) is the primary obstacle to long-term survival following lung transplantation. Here, we show the importance of functional microvasculature in the prevention of epithelial loss and fibrosis due to rejection and for the first time, relate allograft microvascular injury and loss of tissue perfusion to immunotherapy-resistant rejection. To explore the role of alloimmune rejection and airway ischemia in the development of fibroproliferation, we used a murine orthotopic tracheal transplant model. We determined that transplants were reperfused by connection of recipient vessels to donor vessels at the surgical anastomosis site. Microcirculation through the newly formed vascular anastomoses appeared partially dependent on VEGFR2 and CXCR2 pathways. In the absence of immunosuppression, the microvasculature in rejecting allografts exhibited vascular complement deposition, diminished endothelial CD31 expression, and absent perfusion prior to the onset of fibroproliferation. Rejecting grafts with extensive endothelial cell injury were refractory to immunotherapy. After early microvascular loss, neovascularization was eventually observed in the membranous trachea, indicating a reestablishment of graft perfusion in established fibrosis. One implication of this study is that bronchial artery revascularization at the time of lung transplantation may decrease the risk of subsequent airway fibrosis.


Antioxidant potential properties of mushroom extract (Agaricus bisporus) against aluminum-induced neurotoxicity in rat brain.
Aluminum (Al) is an environmental toxin that induces oxidative stress in neuronal cells. Mushroom cultivar extract (MCE) acted as a potent antioxidant agent and protects against cellular oxidative stress in human cultured neuronal cells. This study aimed to investigate the neuroprotective effect of MCE against Al-induced neurotoxicity in rat brain. Forty Sprague-Dawley rats were divided into 4 groups (10 rats per group), control group, MCE-fed group, Al-administered group and MCE/Al-treated group. Animals were continuously fed ad-libitum their specific diets for 4 weeks. At the end of the experiment, all rats were sacrificed and the brain tissues were homogenized and examined for biochemical measurements of neurocellular oxidative stress indices [glutathione (GSH), Total Antioxidant Capacity (TAC), antioxidant enzymes and oxidized dichlorofluorescein (DCF)]. Al-administration caused inhibition of antioxidant enzymes and a significant decrease in GSH and TAC levels, meanwhile it positively increased cellular oxidized DCF level, as well as Al concentration in brain tissues. Feeding animals with MCE had completely offset the Al-induced oxidative stress and significantly restrict the Al accumulation in brain tissues of Al-administered rats. The results obtained suggest that MCE acted as a potent dietary antioxidant and protects against Al-mediated neurotoxicity, by abrogating neuronal oxidative stress.


Direct visualization of sulfur cathodes: new insights into Li-S batteries via operando X-ray based methods.
As the need for the development of "beyond lithium" ion battery technologies continuous unabated, lithium sulfur batteries have attracted widespread attention due to their very high theoretical energy density of 2,600 Wh kg-1. However, despite much effort, the detailed reaction mechanism remains poorly understood. In this study, we have combined operando X-ray diffraction and X-ray microscopy along with X-ray tomography, to visualize the evolution of both the morphology and crystal structure of the materials during the entire battery cycling (discharging/charging) process. The dissolution and reformation of sulfur clusters is clearly observed during cycling. In addition, we demonstrate, for the first time, the critical role of current density and temperature in determining the size of both the resulting sulfur clusters and Li2S particles. This study provides new insights about promising avenues for the continued development of lithium sulfur batteries, which we believe may lead to their broad deployment and application.


Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial.
Type 2 diabetes mellitus (T2DM) is characterized by systemic metabolic abnormalities and the development of micro- and macrovascular complications, resulting in a shortened life expectancy. A recent cardiovascular (CV) safety trial, the EMPA-REG OUTCOME trial, showed that empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, markedly reduced CV death and all-cause mortality and hospitalization for heart failure in patients with T2DM and established CV disease (CVD). SGLT2 inhibitors are known to not only decrease plasma glucose levels, but also favorably modulate a wide range of metabolic and hemodynamic disorders related to CV pathways. Although some experimental studies revealed a beneficial effect of SGLT2 inhibitors on atherosclerosis, there is a paucity of clinical data showing that they can slow the progression of atherosclerosis in patients with T2DM. Therefore, the EMBLEM trial was designed to investigate whether empagliflozin treatment can improve endothelial function, which plays a pivotal role in the pathogenesis of atherosclerosis, in patients with T2DM and established CVD. The EMBLEM trial is an ongoing, prospective, multicenter, placebo-controlled double-blind randomized, investigator-initiated clinical trial in Japan. A total of 110 participants with T2DM (HbA1c range 6.0-10.0%) and with established CVD will be randomized (1:1) to receive either empagliflozin 10 mg once daily or a placebo. The primary endpoint of the trial is change in the reactive hyperemia (RH)-peripheral arterial tonometry-derived RH index at 24 weeks from baseline. For comparison of treatment effects between the treatment groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for the following allocation factors: HbA1c (<7.0 or ≥7.0%), age (<65 or ≥65 years), systolic blood pressure (<140 or ≥140 mmHg), and current smoking status (nonsmoker or smoker). Key secondary endpoints include the change from baseline for other vascular-related markers such as arterial stiffness, sympathetic nervous activity, and parameters of cardiac and renal function. Importantly, serious adverse effects independently on the causal relationship to the trial drugs and protocol will be also evaluated throughout the trial period. EMBLEM is the first trial to assess the effect of empagliflozin on endothelial function in patients with T2DM and established CVD. Additionally, mechanisms associating empagliflozin-mediated actions with endothelial function and other CV markers will be evaluated. Thus, the trial is designed to elucidate potential mechanisms by which empagliflozin protects CV systems and improves CV outcomes. Trial registration Unique Trial Number, UMIN000024502 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000028197 ).


The burden of knowing: balancing benefits and barriers in HIV testing decisions. a qualitative study from Zambia.
Client-initiated HIV counselling and testing has been scaled up in many African countries, in the form of voluntary counselling and testing (VCT). Test rates have remained low, with HIV-related stigma being an important barrier to HIV testing. This study explored HIV testing decisions in one rural and one urban district in Zambia with high HIV prevalence and available antiretroviral treatment. Data were collected through 17 in-depth interviews and two focus group discussions with individuals and 10 in-depth interviews with counsellors. Interpretive description methodology was employed to analyse the data. 'To know your status' was found to be a highly charged concept yielding strong barriers against HIV testing. VCT was perceived as a diagnostic device and a gateway to treatment for the severely ill. Known benefits of prevention and early treatment were outweighed by a perceived burden of knowing your HIV status related to stigma and fear. The manner in which the VCT services were organised added to this burden. This study draws on social stigma theory to enhance the understanding of the continuity of HIV related stigma in the presence of ART, and argues that the burden of knowing an HIV status and the related reluctance to get HIV tested can be understood both as a form of label-avoidance and as strong expressions of the still powerful embodied memories of suffering and death among non-curable AIDS patients over the last decades. Hope lies in the emerging signs of a reduction in HIV related stigma experienced by those who had been tested for HIV. Further research into innovative HIV testing service designs that do not add to the burden of knowing is needed.


Lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer: A systematic review .
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer, which accounts for 20 - 25% of cases of breast cancers, is highly aggressive. Due to cardiotoxicity and increasing resistance associated with trastuzumab, the first-line treatment, there is a need for effective second-line therapies in treating HER2-positive breast cancer. In this context, there has been increasing interest in the combination of lapatinib plus capecitabine. The aim of this systematic review was to assess the efficacy of lapatinib plus capecitabine for HER2-positive breast cancer after progression with trastuzumab therapy, in comparison with capecitabine monotherapy and other agents such as vinorelbine and trastuzumab emtansine. We performed a keyword search in five electronic databases (OVID MEDLINE, the Cochrane Library, Web of Science, SCOPUS, and CINAHL; January 2010 to April 2017) for trials in patients with HER2-positive breast cancer that has progressed on trastuzumab. After screening, the relevant studies were assessed for their methodological quality (including selection bias, randomization, control for confounders, and blinding) by two reviewers independently. A total of 50 studies were identified; only 6 of those met the inclusion criteria and were analyzed. Five received a weak rating on the quality assessment tool, and none could be considered as being of high scientific quality after taking the risk of bias and other confounding variables into account. The studies demonstrated that lapatinib plus capecitabine is effective in extending median overall (OS) and progression-free survival (PFS) outcomes, achieving OS of 37.6 - 108.7 weeks and PFS of 21.1 - 30 weeks across studies. However, median OS and PFS for trastuzumab emtansine therapy were found to be considerably better (133.9 weeks and 41.6 weeks, respectively) than for lapatinib plus capecitabine. The results suggest that the combination of lapatinib plus capecitabine can improve PFS and OS in patients with HER2-positive breast cancer that has progressed on trastuzumab. However, it appears that trastuzumab emtansine provides better treatment outcomes in this context. .


In vitro and in vivo characterization of three Cellvibrio japonicus glycoside hydrolase family 5 members reveals potent xyloglucan backbone-cleaving functions.
Xyloglucan (XyG) is a ubiquitous and fundamental polysaccharide of plant cell walls. Due to its structural complexity, XyG requires a combination of backbone-cleaving and sidechain-debranching enzymes for complete deconstruction into its component monosaccharides. The soil saprophyte Cellvibrio japonicus has emerged as a genetically tractable model system to study biomass saccharification, in part due to its innate capacity to utilize a wide range of plant polysaccharides for growth. Whereas the downstream debranching enzymes of the xyloglucan utilization system of C. japonicus have been functionally characterized, the requisite backbone-cleaving endo-xyloglucanases were unresolved. Combined bioinformatic and transcriptomic analyses implicated three glycoside hydrolase family 5 subfamily 4 (GH5_4) members, with distinct modular organization, as potential keystone endo-xyloglucanases in C. japonicus. Detailed biochemical and enzymatic characterization of the GH5_4 modules of all three recombinant proteins confirmed particularly high specificities for the XyG polysaccharide versus a panel of other cell wall glycans, including mixed-linkage beta-glucan and cellulose. Moreover, product analysis demonstrated that all three enzymes generated XyG oligosaccharides required for subsequent saccharification by known exo-glycosidases. Crystallographic analysis of GH5D, which was the only GH5_4 member specifically and highly upregulated during growth on XyG, in free, product-complex, and active-site affinity-labelled forms revealed the molecular basis for the exquisite XyG specificity among these GH5_4 enzymes. Strikingly, exhaustive reverse-genetic analysis of all three GH5_4 members and a previously biochemically characterized GH74 member failed to reveal a growth defect, thereby indicating functional compensation in vivo, both among members of this cohort and by other, yet unidentified, xyloglucanases in C. japonicus. Our systems-based analysis indicates distinct substrate-sensing (GH74, GH5E, GH5F) and attack-mounting (GH5D) functions for the endo-xyloglucanases characterized here. Through a multi-faceted, molecular systems-based approach, this study provides a new insight into the saccharification pathway of xyloglucan utilization system of C. japonicus. The detailed structural-functional characterization of three distinct GH5_4 endo-xyloglucanases will inform future bioinformatic predictions across species, and provides new CAZymes with defined specificity that may be harnessed in industrial and other biotechnological applications.


Sleep patterns in high school and university students: a longitudinal study.
We performed a longitudinal study to investigate whether changes in social zeitgebers and age alter sleep patterns in students during the transition from high school to university. Actimetry was performed on 24 high-school students (mean age+/-SD: 18.4+/-0.9 yrs; 12 females) for two weeks. Recordings were repeated in the same subjects 5 yrs later when they were university students. The sleep period duration and its center, the mid-sleep time, and total sleep time were estimated by actimetry. Actigraphic total sleep time was similar when in high school and at the university on school days (6.31+/-0.47 vs. 6.45+/-0.80 h, p = ns) and longer on leisure days by 1.10+/-1.10 h (p < 0.0001 vs. school days) when in high school, but not at the university. Compared to the high school situation, the mid-sleep time was delayed when at the university on school days (03:11+/-0.6 vs. 03:55+/-0.7 h, p < 0.0001), but not on leisure days. Individual mid-sleep times on school and leisure days when in high school were significantly correlated with the corresponding values 5 yrs later when at the university (r = 0.58 and r = 0.55, p < 0.05, respectively). The large differences in total sleep time between school and leisure days when students attended high school and the delayed mid-sleep time on school days when students attended university are consistent with a circadian phase shift due to changes in class schedules, other zeitgebers, and lifestyle preferences. Age-related changes may also have occurred, although some individuality of the sleep pattern was maintained during the 5 yr study span. These findings have important implications for optimizing school and work schedules in students of different age and level of education.


TMT Labeling for the Masses: A Robust and Cost-efficient, In-solution Labeling Approach.
Isobaric stable isotope labeling using, for example, tandem mass tags (TMTs) is increasingly being applied for large-scale proteomic studies. Experiments focusing on proteoform analysis in drug time course or perturbation studies or in large patient cohorts greatly benefit from the reproducible quantification of single peptides across samples. However, such studies often require labeling of hundreds of micrograms of peptides such that the cost for labeling reagents represents a major contribution to the overall cost of an experiment. Here, we describe and evaluate a robust and cost-effective protocol for TMT labeling that reduces the quantity of required labeling reagent by a factor of eight and achieves complete labeling. Under- and overlabeling of peptides derived from complex digests of tissues and cell lines were systematically evaluated using peptide quantities of between 12.5 and 800 μg and TMT-to-peptide ratios (wt/wt) ranging from 8:1 to 1:2 at different TMT and peptide concentrations. When reaction volumes were reduced to maintain TMT and peptide concentrations of at least 10 mm and 2 g/l, respectively, TMT-to-peptide ratios as low as 1:1 (wt/wt) resulted in labeling efficiencies of > 99% and excellent intra- and interlaboratory reproducibility. The utility of the optimized protocol was further demonstrated in a deep-scale proteome and phosphoproteome analysis of patient-derived xenograft tumor tissue benchmarked against the labeling procedure recommended by the TMT vendor. Finally, we discuss the impact of labeling reaction parameters for N-hydroxysuccinimide ester-based chemistry and provide guidance on adopting efficient labeling protocols for different peptide quantities.


Efficient gradient calibration based on diffusion MRI.
To propose a method for calibrating gradient systems and correcting gradient nonlinearities based on diffusion MRI measurements. The gradient scaling in x, y, and z were first offset by up to 5% from precalibrated values to simulate a poorly calibrated system. Diffusion MRI data were acquired in a phantom filled with cyclooctane, and corrections for gradient scaling errors and nonlinearity were determined. The calibration was assessed with diffusion tensor imaging and independently validated with high resolution anatomical MRI of a second structured phantom. The errors in apparent diffusion coefficients along orthogonal axes ranged from -9.2% ± 0.4% to + 8.8% ± 0.7% before calibration and -0.5% ± 0.4% to + 0.8% ± 0.3% after calibration. Concurrently, fractional anisotropy decreased from 0.14 ± 0.03 to 0.03 ± 0.01. Errors in geometric measurements in x, y and z ranged from -5.5% to + 4.5% precalibration and were likewise reduced to -0.97% to + 0.23% postcalibration. Image distortions from gradient nonlinearity were markedly reduced. Periodic gradient calibration is an integral part of quality assurance in MRI. The proposed approach is both accurate and efficient, can be setup with readily available materials, and improves accuracy in both anatomical and diffusion MRI to within ±1%. Magn Reson Med 77:170-179, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.


Single-Molecule Sequencing (PacBio) of the Staphylococcus capitis NRCS-A Clone Reveals the Basis of Multidrug Resistance and Adaptation to the Neonatal Intensive Care Unit Environment.
The multi-resistant Staphylococcus capitis clone NRCS-A has recently been described as a major pathogen causing nosocomial, late-onset sepsis (LOS) in preterm neonates worldwide. NRCS-A representatives exhibit an atypical antibiotic resistance profile. Here, the complete closed genome (chromosomal and plasmid sequences) of NRCS-A prototype strain CR01 and the draft genomes of three other clinical NRCS-A strains from Australia, Belgium and the United Kingdom are annotated and compared to available non-NRCS-A S. capitis genomes. Our goal was to delineate the uniqueness of the NRCS-A clone with respect to antibiotic resistance, virulence factors and mobile genetic elements. We identified 6 antimicrobial resistance genes, all carried by mobile genetic elements. Previously described virulence genes present in the NRCS-A genomes are shared with the six non-NRCS-A S. capitis genomes. Overall, 63 genes are specific to the NRCS-A lineage, including 28 genes located in the methicillin-resistance cassette SCCmec. Among the 35 remaining genes, 25 are of unknown function, and 9 correspond to an additional type I restriction modification system (n = 3), a cytosine methylation operon (n = 2), and a cluster of genes related to the biosynthesis of teichoic acids (n = 4). Interestingly, a tenth gene corresponds to a resistance determinant for nisin (nsr gene), a bacteriocin secreted by potential NRCS-A strain niche competitors in the gut microbiota. The genomic characteristics presented here emphasize the contribution of mobile genetic elements to the emergence of multidrug resistance in the S. capitis NRCS-A clone. No NRCS-A-specific known virulence determinant was detected, which does not support a role for virulence as a driving force of NRCS-A emergence in NICUs worldwide. However, the presence of a nisin resistance determinant on the NRCS-A chromosome, but not in other S. capitis strains and most coagulase-negative representatives, might confer a competitive advantage to NRCS-A strains during the early steps of gut colonization in neonates. This suggests that the striking adaptation of NRCS-A to the NICU environment might be related to its specific antimicrobial resistance and also to a possible enhanced ability to challenge competing bacteria in its ecological niche.


Fire Performance of Heavyweight Self-Compacting Concrete and Heavyweight High Strength Concrete.
In this study, the fresh and hardened state properties of heavyweight self-compacting concrete (HWSCC) and heavyweight high strength concrete (HWHSC) containing heavyweight magnetite aggregate with 50, 75, and 100% replacement ratio, and their performance at elevated temperatures were explored experimentally. For fresh-state properties, the flowability and passing ability of HWSCCs were assessed by using slump flow, T500 mm, and J-ring tests. Hardened-state properties including hardened density, compressive strength, and modulus of elasticity were evaluated after 28 days of mixing. High-temperature tests were also performed to study the mass loss, spalling of HWSCC and HWHSC, and residual mechanical properties at 100, 300, 600 and 900 °C with a heating rate of 5 °C/min. Ultimately, by using the experimental data, rational numerical models were established to predict the compressive strength and modulus of elasticity of HWSCC at elevated temperatures. The results of the flowability and passing ability revealed that the addition of magnetite aggregate would not deteriorate the workability of HWSCCs and they retained their self-compacting characteristics. Based on the hardened densities, only self-compacting concrete (SCC) with 100% magnetite content, and high strength concrete (HSC) with 75 and 100% magnetite aggregate can be considered as HWC. For both the compressive strength and elastic modulus, decreasing trends were observed by introducing magnetite aggregate to SCC and HSC at an ambient temperature. Mass loss and spalling evaluations showed severe crack propagation for SCC without magnetite aggregate while SCCs containing magnetite aggregate preserved up to 900 °C. Nevertheless, the mass loss of SCCs containing 75 and 100% magnetite content were higher than that of SCC without magnetite. Due to the pressure build-up, HSCs with and without magnetite showed explosive spalling at high temperatures. The residual mechanical properties analysis indicated that the highest retention of the compressive strength and modulus of elasticity after exposure to elevated temperatures belonged to HWSCC with 100% magnetite content.


Prospective comparison of the HEP score and 4Ts score for the diagnosis of heparin-induced thrombocytopenia.
The HIT Expert Probability (HEP) score compared favorably with the 4Ts score in a retrospective study. We assessed the diagnostic accuracy of the HEP score compared with the 4Ts score in a prospective cohort of 310 patients with suspected heparin-induced thrombocytopenia (HIT). A member of the clinical team calculated the HEP score and 4Ts score. An independent panel adjudicated HIT status based on a clinical summary as well as the results of HIT laboratory testing. The prevalence of HIT in the study population was 14.7%. At a cutoff of ≥3, the HEP score was 95.3% sensitive (95% confidence interval [CI], 84.2-99.4) and 35.7% specific (95% CI, 29.8-42.0) for HIT. A 4Ts score of ≥4 had a sensitivity of 97.7% (95% CI, 86.2-99.8) and specificity of 32.9% (95% CI, 27.2-39.1). The areas under the receiver operating characteristic (ROC) curves (AUCs) for the HEP score and 4Ts score were similar (0.81 [95% CI, 0.74-0.87] vs 0.76 [95% CI, 0.69-0.83]; P = .12). The HEP score exhibited a significantly higher AUC than the 4Ts score in patients in the intensive care unit (ICU) (0.86 vs 0.79; P = .03). Among trainee scorers, the HEP score performed significantly better than the 4Ts score (AUC, 0.80 vs 0.73; P = .03). Our data suggest that either the 4Ts score or the HEP score may be used in clinical practice. The HEP score may be preferable in ICU patients and among less experienced clinicians.


Influence of multi-cycle loading on the structure and mechanics of marine mussel plaques.
The proteinaceous byssal plaque-thread structures created by marine mussels exhibit extraordinary load-bearing capability. Although the nanoscopic protein interactions that support interfacial adhesion are increasingly understood, major mechanistic questions about how mussel plaques maintain toughness on supramolecular scales remain unanswered. This study explores the mechanical properties of whole mussel plaques subjected to repetitive loading cycles, with varied recovery times. Mechanical measurements were complemented with scanning electron microscopy to investigate strain-induced structural changes after yield. Multicyclic loading of plaques decreases their low-strain stiffness and introduces irreversible, strain-dependent plastic damage within the plaque microstructure. However, strain history does not compromise critical strength or maximum extension compared with plaques monotonically loaded to failure. These results suggest that a multiplicity of force transfer mechanisms between the thread and plaque-substrate interface allow the plaque-thread structure to accommodate a wide range of extensions as it continues to bear load. This improved understanding of the mussel system at micron-to-millimeter lengthscales offers strategies for including similar fail-safe mechanisms in the design of soft, tough and resilient synthetic structures.


The Unrealised Potential for Predicting Pregnancy Complications in Women with Gestational Diabetes: A Systematic Review and Critical Appraisal.
Gestational diabetes (GDM) increases the risk of pregnancy complications. However, these risks are not the same for all affected women and may be mediated by inter-related factors including ethnicity, body mass index and gestational weight gain. This study was conducted to identify, compare, and critically appraise prognostic prediction models for pregnancy complications in women with gestational diabetes (GDM). A systematic review of prognostic prediction models for pregnancy complications in women with GDM was conducted. Critical appraisal was conducted using the prediction model risk of bias assessment tool (PROBAST). Five prediction modelling studies were identified, from which ten prognostic models primarily intended to predict pregnancy complications related to GDM were developed. While the composition of the pregnancy complications predicted varied, the delivery of a large-for-gestational age neonate was the subject of prediction in four studies, either alone or as a component of a composite outcome. Glycaemic measures and body mass index were selected as predictors in four studies. Model evaluation was limited to internal validation in four studies and not reported in the fifth. Performance was inadequately reported with no useful measures of calibration nor formal evaluation of clinical usefulness. Critical appraisal using PROBAST revealed that all studies were subject to a high risk of bias overall driven by methodologic limitations in statistical analysis. This review demonstrates the potential for prediction models to provide an individualised absolute risk of pregnancy complications for women affected by GDM. However, at present, a lack of external validation and high risk of bias limit clinical application. Future model development and validation should utilise the latest methodological advances in prediction modelling to achieve the evolution required to create a useful clinical tool. Such a tool may enhance clinical decision-making and support a risk-stratified approach to the management of GDM. Systematic review registration: PROSPERO CRD42019115223.


Binocular combination of phase and contrast explained by a gain-control and gain-enhancement model.
We investigated suprathreshold binocular combination, measuring both the perceived phase and perceived contrast of a cyclopean sine wave. We used a paradigm adapted from Ding and Sperling (2006, 2007) to measure the perceived phase by indicating the apparent location (phase) of the dark trough in the horizontal cyclopean sine wave relative to a black horizontal reference line, and we used the same stimuli to measure perceived contrast by matching the binocular combined contrast to a standard contrast presented to one eye. We found that under normal viewing conditions (high contrast and long stimulus duration), perceived contrast is constant, independent of the interocular contrast ratio and the interocular phase difference, while the perceived phase shifts smoothly from one eye to the other eye depending on the contrast ratios. However, at low contrasts and short stimulus durations, binocular combination is more linear and contrast summation is phase-dependent. To account for phase-dependent contrast summation, we incorporated a fusion remapping mechanism into our model, using disparity energy to shift the monocular phases towards the cyclopean phase in order to align the two eyes' images through motor/sensory fusion. The Ding-Sperling model with motor/sensory fusion mechanism gives a reasonable account of the phase dependence of binocular contrast combination and can account for either the perceived phase or the perceived contrast of a cyclopean sine wave separately; however it requires different model parameters for the two. However, when fit to both phase and contrast data simultaneously, the Ding-Sperling model fails. Incorporating interocular gain enhancement into the model results in a significant improvement in fitting both phase and contrast data simultaneously, successfully accounting for both linear summation at low contrast energy and strong nonlinearity at high contrast energy.


Role of topical application of gentamicin containing collagen implants in cardiac surgery.
Sternal wound infections (SWI) continue to be a major cause of concern after cardiac surgery. It leads to prolonged hospital stay and increased morbidity, mortality and increased hospital costs. Prophylactic systemic antibiotics have been used to prevent surgical site infection (SSI). However, prolonged postoperative use of systemic antibiotics can lead to emergence of resistant organisms. Gentamycin Containing Collagen Implants (GCCI) when used during sternotomy closure produces high local antibiotic concentrations in the wound with a low serum concentration. There is evidence that the concentration of gentamicin in the mediastinal fluid reaches levels high enough to be effective against bacteria that are considered resistant to gentamycin and other antibiotics.However, questions have been raised about the safety and efficacy of GCCI. There were concerns whether GCCI can lead to systemic absorption with renal impairment and whether use of topical antibiotics can lead to emergence of antimicrobial resistance.We, hereby, review the literature on GCCI (Collatamp) and take the opportunity to appraise the scientific community about their role in cardiac surgery. Several recent studies have supported their clinical effectiveness. They should be used in dry condition and should not be soaked in saline even for a short period prior to use. However, for GCCI to become part of routine practice in cardiac surgery further large randomised studies are required. As the incidence of sternal wound infection is low in the specialty of cardiac surgery, for any study to be sufficiently powered to address this issue, multicenter studies might be the way forward.Based on the evidence presented in this manuscript it is recommended GCCI (Collatamp) can be a cost effective adjunct for prevention of sternal wound infection. They can also be used for treatment of Deep Sternal Wound Infection.


Invasive cervical tumors with high and low HPV titer represent molecular subgroups with different disease etiology.
Invasive cervical cancer (ICC) with very low titer of high-risk human papillomavirus (HPV) has worse clinical outcome than cases with high titer, indicating a difference in molecular etiology. Fresh-frozen ICC tumors (n = 49) were classified into high- and low-HPV-titer cases using real-time PCR-based HPV genotyping. The mutation spectra were studied using the AmpliSeq Comprehensive Cancer Panel and the expression profiles using total RNA sequencing, and the results were validated using the AmpliSeq Transcriptome assay. HPV DNA genotyping and RNA sequencing showed that 16.6% of ICC tumors contained very low levels of HPV DNA and HPV transcripts. Tumors with low HPV levels had more mutations with a high allele frequency and fewer mutations with low allele frequency relative to tumors with high HPV titer. A number of genes showed significant expression differences between HPV titer groups, including genes with somatic mutations. Gene ontology and pathway analyses implicated the enrichment of genes involved in DNA replication, cell cycle control and extracellular matrix in tumors with low HPV titer. The results indicate that in low titer tumors, HPVs act as trigger of cancer development whereas somatic mutations are clonally selected and become drivers of the tumor development process. In contrast, in tumors with high HPV titer the expression of HPV oncoproteins plays a major role in tumor development and the many low frequency somatic mutations represent passengers. This putative subdivision of invasive cervical tumors may explain the higher radiosensitivity of ICC tumors with high HPV titer and thereby have consequences for clinical management.


Optomechanical properties of GaAs/AlAs micropillar resonators operating in the 18 GHz range.
Recent experiments demonstrated that GaAs/AlAs based micropillar cavities are promising systems for quantum optomechanics, allowing the simultaneous three-dimensional confinement of near-infrared photons and acoustic phonons in the 18-100 GHz range. Here, we investigate through numerical simulations the optomechanical properties of this new platform. We evidence how the Poisson's ratio and semiconductor/vacuum boundary conditions lead to very distinct features in the mechanical and optical three-dimensional confinement. We find a strong dependence of the mechanical quality factor and strain distribution on the micropillar radius, in great contrast to what is predicted and observed in the optical domain. The derived optomechanical coupling constants g0 reach ultra-large values in the 106 rad/s range.


An assessment of the antibacterial activity in larval excretion/secretion of four species of insects recorded in association with corpses, using Lucilia sericata Meigen as the marker species.
The relative antibacterial activities of excretion/secretion (ES) from two carrion-feeding insects, Calliphora vicina Robineau-Desvoidy and Dermestes maculatus DeGeer, and a detritivore, Tenebrio molitor Linnaeus, were compared to that of Lucilia sericata Meigen, a species with ES of known antibacterial capacity, in order to explore the antimicrobial potential of other carrion and detritivore species. Viable counts were used to assess time-kill of ES against five bacterial species, Staphylococcus aureus, Escherichia coli, Bacillus cereus, Pseudomonas aeruginosa and Proteus mirabilis. Antibacterial activity was recorded in all four insect species although T. molitor and D. maculatus were the most effective in controlling growth of P. mirabilis. The blowflies were more effective in controlling a wider range of both Gram-positive and Gram-negative bacteria. The larval ES from all species was shown to reduce bacterial growth rate although differences in antibacterial spectrum were noted and the degree of potency varied between the four species. These differences may be explained ecologically by the different colonisation times of each insect species on the corpse. Overall, this study demonstrates that research into other carrion-feeding insect species has potential to provide an increased source of antimicrobial chemicals to broaden the range of bacterial species beyond that currently controlled using L. sericata.


Design of a Remote Coaching Program to Bridge the Gap From Hospital Discharge to Cardiac Rehabilitation: Intervention Mapping Study.
Remote coaching might be suited for providing information and support to patients with coronary artery disease (CAD) in the vulnerable phase between hospital discharge and the start of cardiac rehabilitation (CR). The goal of the research was to explore and summarize information and support needs of patients with CAD and develop an early remote coaching program providing tailored information and support. We used the intervention mapping approach to develop a remote coaching program. Three steps were completed in this study: (1) identification of information and support needs in patients with CAD, using an exploratory literature study and semistructured interviews, (2) definition of program objectives, and (3) selection of theory-based methods and practical intervention strategies. Our exploratory literature study (n=38) and semistructured interviews (n=17) identified that after hospital discharge, patients with CAD report a need for tailored information and support about CAD itself and the specific treatment procedures, medication and side effects, physical activity, and psychological distress. Based on the preceding steps, we defined the following program objectives: (1) patients gain knowledge on how CAD and revascularization affect their bodies and health, (2) patients gain knowledge about medication and side effects and adhere to their treatment plan, (3) patients know which daily physical activities they can and can't do safely after hospital discharge and are physically active, and (4) patients know the psychosocial consequences of CAD and know how to discriminate between harmful and harmless body signals. Based on the preceding steps, a remote coaching program was developed with the theory of health behavior change as a theoretical framework with behavioral counseling and video modeling as practical strategies for the program. This study shows that after (acute) cardiac hospitalization, patients are in need of information and support about CAD and revascularization, medication and side effects, physical activity, and psychological distress. In this study, we present the design of an early remote coaching program based on the needs of patients with CAD. The development of this program constitutes a step in the process of bridging the gap from hospital discharge to start of CR.


Novel Hybrid Phenotype Revealed in Small Cell Lung Cancer by a Transcription Factor Network Model That Can Explain Tumor Heterogeneity.
Small cell lung cancer (SCLC) is a devastating disease due to its propensity for early invasion and refractory relapse after initial treatment response. Although these aggressive traits have been associated with phenotypic heterogeneity, our understanding of this association remains incomplete. To fill this knowledge gap, we inferred a set of 33 transcription factors (TF) associated with gene signatures of the known neuroendocrine/epithelial (NE) and non-neuroendocrine/mesenchymal-like (ML) SCLC phenotypes. The topology of this SCLC TF network was derived from prior knowledge and was simulated using Boolean modeling. These simulations predicted that the network settles into attractors, or TF expression patterns, that correlate with NE or ML phenotypes, suggesting that TF network dynamics underlie the emergence of heterogeneous SCLC phenotypes. However, several cell lines and patient tumor specimens failed to correlate with either the NE or ML attractors. By flow cytometry, single cells within these cell lines simultaneously expressed surface markers of both NE and ML differentiation, confirming the existence of a "hybrid" phenotype. Upon exposure to standard-of-care cytotoxic drugs or epigenetic modifiers, NE and ML cell populations converged toward the hybrid state, suggesting possible escape from treatment. Our findings indicate that SCLC phenotypic heterogeneity can be specified dynamically by attractor states of a master regulatory TF network. Thus, SCLC heterogeneity may be best understood as states within an epigenetic landscape. Understanding phenotypic transitions within this landscape may provide insights to clinical applications. Cancer Res; 77(5); 1063-74. ©2016 AACR.


CA 15-3 is predictive of response and disease recurrence following treatment in locally advanced breast cancer.
Primary chemotherapy (PC) is used for down-staging locally advanced breast cancer (LABC). CA 15-3 measures the protein product of the MUC1 gene and is the most widely used serum marker in breast cancer. We retrospectively investigated the role of CA 15-3 in conjunction with other clinico-pathological variables as a predictor of response and time to disease recurrence following treatment in LABC. Pre and post primary chemotherapy serum concentrations of CA 15-3 together with other variables were reviewed and related to four outcomes following primary chemotherapy (clinical response, pathological response, time to recurrence and time to progression). Persistently elevated CA 15-3 after PC was considered as consecutively high levels above the cut off point during and after PC. 73 patients were included in this study. Patients received PC (AC or AC-T regimen) for locally advanced breast cancer. 54 patients underwent surgery. The median follow up was 790 days. Patients with high concentrations of CA 15-3 before PC treatment had a poor clinical (p = 0.013) and pathological (p = 0.044) response. Together with Her-2/neu expression (p = 0.009) and tumour lympho-vascular space invasion (LVI) (p = 0.001), a persistently elevated CA 15-3 post PC (p = 0.007) was an independent predictive factor of recurrence following treatment in LABC. Elevated CA 15-3 level is predictive of a poor response to chemotherapy. In addition, persistently elevated CA 15-3 levels post chemotherapy in conjunction with lympho-vascular invasion and HER2 status predict a reduced disease free survival following treatment in locally advanced breast cancer.


Improving detection of mental health problems in community settings in Nepal: development and pilot testing of the community informant detection tool.
Despite increasing efforts to expand availability of mental health services throughout the world, there continues to be limited utilization of these services by persons with mental illness and their families. Community-based detection that facilitates identification and referral of people with mental health problems has been advocated as an effective strategy to increase help-seeking and service utilization. The Community Informant Detection Tool (CIDT) was developed for the community informants to identify people with depression, psychosis, alcohol use problems, epilepsy, and child behavioral problems in community settings. The CIDT has been validated in Nepal and found to be effective in promoting treatment initiation. To facilitate replication in other settings, this paper describes the development process of CIDT and the steps to achieve comprehensibility, utility and feasibility. The CIDT was developed in four steps. First, case vignettes and illustrations were created incorporating local idioms of distress for symptoms of each disorder with an expert panel of 25 Nepali mental health professionals. Second, the utility of a draft tool was assessed through focus group discussions (n = 19) and in-depth interviews (n = 6). Third, a practice run was conducted assessing applicability of the tool through IDI among purposively selected community informants (n = 8). Finally, surveys were administered to 105 community informants to assess feasibility. The first through third steps led to modifications in the format and presentation of the CIDT. The pilot test found CIDT to be comprehensible and feasible for detection and referral of all conditions except child behavioral problems. Female community health volunteers were recommended as the most appropriate persons to utilize the CIDT. Community-based detection using the CIDT for persons in need of mental health care is perceived to be useful and feasible by key community stakeholders who would integrate the tool into their daily activities.


Organization of the myotendinous junction is dependent on the presence of alpha7beta1 integrin.
The laminin receptor alpha7beta1 is enriched at the myotendinous junctions, and mice with a targeted inactivation of the alpha7 gene develop a form of muscular dystrophy that primarily affects this structure. By ultrastructural analysis of alpha7-deficient mice, in comparison with wild-type and mdx mice, we attempted to elucidate the role of alpha7 integrin for the integrity and function of the myotendinous junctions. Ultrastructurally, myotendinous junctions of alpha7-deficient myofibers lose their interdigitations and the myofilaments retract from the sarcolemmal membrane, whereas the lateral side of the myofibers remains morphologically normal. The basement membrane at the myotendinous junctions in alpha7 -/- mice is significantly broadened, and immunogold-histochemistry has demonstrated that the laminin alpha2 chain is not localized here but, instead, in the matrix of the neighboring tendon. In contrast, mdx mice have normal myotendinous junctions, with a matrix protein pattern also found in wild-type mice, however the lateral sides of the myofibers are severely damaged. These results suggest that the alpha7beta1 integrin is a major receptor connecting the muscle cell to the tendon and helps to organize the myotendinous junction, whereas the dystrophin-glycoprotein complex is necessary for the lateral integrity of the muscle cell.


Model Choice, Missing Data, and Taxon Sampling Impact Phylogenomic Inference of Deep Basidiomycota Relationships.
Resolving deep divergences in the tree of life is challenging even for analyses of genome-scale phylogenetic data sets. Relationships between Basidiomycota subphyla, the rusts and allies (Pucciniomycotina), smuts and allies (Ustilaginomycotina), and mushroom-forming fungi and allies (Agaricomycotina) were found particularly recalcitrant both to traditional multigene and genome-scale phylogenetics. Here, we address basal Basidiomycota relationships using concatenated and gene tree-based analyses of various phylogenomic data sets to examine the contribution of several potential sources of bias. We evaluate the contribution of biological causes (hard polytomy, incomplete lineage sorting) versus unmodeled evolutionary processes and factors that exacerbate their effects (e.g., fast-evolving sites and long-branch taxa) to inferences of basal Basidiomycota relationships. Bayesian Markov Chain Monte Carlo and likelihood mapping analyses reject the hard polytomy with confidence. In concatenated analyses, fast-evolving sites and oversimplified models of amino acid substitution favored the grouping of smuts with mushroom-forming fungi, often leading to maximal bootstrap support in both concatenation and coalescent analyses. On the contrary, the most conserved data subsets grouped rusts and allies with mushroom-forming fungi, although this relationship proved labile, sensitive to model choice, to different data subsets and to missing data. Excluding putative long-branch taxa, genes with high proportions of missing data and/or with strong signal failed to reveal a consistent trend toward one or the other topology, suggesting that additional sources of conflict are at play. While concatenated analyses yielded strong but conflicting support, individual gene trees mostly provided poor support for any resolution of rusts, smuts, and mushroom-forming fungi, suggesting that the true Basidiomycota tree might be in a part of tree space that is difficult to access using both concatenation and gene tree-based approaches. Inference-based assessments of absolute model fit strongly reject best-fit models for the vast majority of genes, indicating a poor fit of even the most commonly used models. While this is consistent with previous assessments of site-homogenous models of amino acid evolution, this does not appear to be the sole source of confounding signal. Our analyses suggest that topologies uniting smuts with mushroom-forming fungi can arise as a result of inappropriate modeling of amino acid sites that might be prone to systematic bias. We speculate that improved models of sequence evolution could shed more light on basal splits in the Basidiomycota, which, for now, remain unresolved despite the use of whole genome data.


Soluble thrombomodulin is antithrombotic in the presence of neutralising antibodies to protein C and reduces circulating activated protein C levels in primates.
We studied whether there was a relationship between the anticoagulant effects of recombinant human soluble thrombomodulin (rhsTM) and activation of protein C in a primate model of acute vascular graft thrombosis in 11 baboons (Papio species). Baboons were pretreated with 0.1, 1 and 5 mg/kg of rhsTM, with or without co-injection of a neutralising monoclonal antibody to protein C (HPC4) in the 1 mg/kg rhsTM group. Subsequently, thrombogenic polyester grafts were deployed for 3 h into chronic exteriorised arteriovenous shunts. Thrombus growth in the graft, plasma-activated protein C (APC) levels, coagulation and thrombosis markers were determined. In untreated baboons, baseline circulating APC levels more than doubled and graft thrombi propagated until reaching equilibrium in about 1 h. Treatment with rhsTM reduced thrombus propagation rates, prolonged the clotting and bleeding times, decreased thrombin-antithrombin complex, beta-thromboglobulin and fibrinopeptide A levels, and, surprisingly, also decreased systemic APC levels, in a dose-dependent manner. In the presence of HPC4 antibody to inhibit APC generation, the acute antithrombotic activity of rhsTM on graft thromboses was not attenuated for up to 80 min, but sustained thrombus accumulation was observed over a 180-min period. These findings suggest that, in contrast to the prevailing hypotheses, the primary antithrombotic activity of rhsTM is independent of protein C, at least in this primate model. Direct inhibition of thrombin's prothrombotic activity upon complex formation with rhsTM might explain the molecular mechanism of the observed antithrombotic effect.


Acute oral toxicity of nickel compounds.
Acute oral toxicity studies were conducted on samples of nine unique nickel compounds and two complex materials to comply with the data and classification requirements of the new Registration, Evaluation, and Authorization of Chemicals Regulation (REACH) in Europe. The samples tested in this study confirmed the overall low oral toxicity of nickel substances and demonstrated a wide range of LD(50) values extending from 310 to >11,000 mg/kg. This variation highlights the differences in toxicological properties between various forms of nickel and underscores the importance of Ni(II) ion bioavailability in determining toxicity. The relative acute oral toxicity of the various nickel substances was found to be: nickel fluoride, nickel sulfate, nickel chloride, nickel acetate > nickel sulfamate > nickel hydroxycarbonate > nickel dihydroxide >> nickel subsulfide, nickel oxides, nickel ash, nickel mattes. Based on these data, four nickel compounds would receive a Category 4 acute toxicity classification according to the European Regulation on Classification, Labelling and Packaging of Chemical Substances and Mixtures (CLP), while the rest of the nickel substances tested fit the criterion for no classification. These data also provided the in vivo verification needed to perform read-across for additional oral toxicity endpoints and nickel substances.


A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.
Fanconi anemia is a genetic disease characterized by genomic instability and cancer predisposition. Nine genes involved in Fanconi anemia have been identified; their products participate in a DNA damage-response network involving BRCA1 and BRCA2 (refs. 2,3). We previously purified a Fanconi anemia core complex containing the FANCL ubiquitin ligase and six other Fanconi anemia-associated proteins. Each protein in this complex is essential for monoubiquitination of FANCD2, a key reaction in the Fanconi anemia DNA damage-response pathway. Here we show that another component of this complex, FAAP250, is mutant in individuals with Fanconi anemia of a new complementation group (FA-M). FAAP250 or FANCM has sequence similarity to known DNA-repair proteins, including archaeal Hef, yeast MPH1 and human ERCC4 or XPF. FANCM can dissociate DNA triplex, possibly owing to its ability to translocate on duplex DNA. FANCM is essential for monoubiquitination of FANCD2 and becomes hyperphosphorylated in response to DNA damage. Our data suggest an evolutionary link between Fanconi anemia-associated proteins and DNA repair; FANCM may act as an engine that translocates the Fanconi anemia core complex along DNA.


Internally mediated developmental desynchronization of neocortical network activity.
During neocortical development, neurons exhibit highly synchronized patterns of spontaneous activity, with correlated bursts of action potential firing dominating network activity. This early activity is eventually replaced by more sparse and decorrelated firing of cortical neurons, which modeling studies predict is a network state that is better suited for efficient neural coding. The precise time course and mechanisms of this crucial transition in cortical network activity have not been characterized in vivo. We used in vivo two-photon calcium imaging in combination with whole-cell recordings in both unanesthetized and anesthetized mice to monitor how spontaneous activity patterns in ensembles of layer 2/3 neurons of barrel cortex mature during postnatal development. We find that, as early as postnatal day 4, activity is highly synchronous within local clusters of neurons. At the end of the second postnatal week, neocortical networks undergo a transition to a much more desynchronized state that lacks a clear spatial structure. Strikingly, deprivation of sensory input from the periphery had no effect on the time course of this transition. Therefore, developmental desynchronization of spontaneous neuronal activity is a fundamental network transition in the neocortex that appears to be intrinsically generated.


Patient handling methods taught in occupational therapy curricula.
Sixteen of 100 full-time occupational therapists are injured while performing manual patient handling techniques. We developed a Theory of Planned Behavior self-report questionnaire to determine what educators teach and the behavioral constructs that best predict intention to change curriculum content. Traditional manual patient handling and safe patient handling methods were investigated. The results showed that both methods are taught in most programs; however, only 22% stated that they teach safe patient handling as the standard of practice. Stepwise regression analysis demonstrated that attitude and perceived behavioral control are the best predictors of intention to continue teaching manual transfers as the standard; however, normative belief and attitude best predict intention to teach safe patient handling as the standard. Knowing these predictors will assist in developing strategies to promote a paradigm shift in the way patient transfers are taught.


Comparison of deferral rates using a computerized versus written blood donor questionnaire: a randomized, cross-over study [ISRCTN84429599].
Self-administered computer-assisted blood donor screening strategies may elicit more accurate responses and improve the screening process. Randomized crossover trial comparing responses to questions on a computerized hand-held tool (HealthQuiz, or HQ), to responses on the standard written instrument (Donor Health Assessment Questionnaire, or DHAQ). Randomly selected donors at 133 blood donation clinics in the area of Hamilton, Canada participated from 1995 to 1996. Donors were randomized to complete either the HQ or the DHAQ first, followed by the other instrument. In addition to responses of 'yes' and 'no' on both questionnaires, the HQ provided a response option of 'not sure'. The primary outcome was the number of additional donors deferred by the HQ. A total of 1239 donors participated. Seventy-one potential donors were deferred as a result of responses to the questionnaires; 56.3% (40/71) were deferred by the DHAQ, and an additional 43.7% (31/71) were deferred due to risks identified by the HQ but not by the DHAQ. Fourteen donors self-deferred; 11 indicated on the HQ that they should not donate blood on that day but did not use the confidential self-exclusion option on the DHAQ, and three used the self-exclusion option on the DHAQ but did not indicate that they should not donate blood on the HQ. The HQ identified a blood contact or risk factor for HIV/AIDS or sexually transmitted infection that was not identified by the DHAQ in 0.1% to 2.7% of donors. A self-administered computerized questionnaire may increase risk reporting by blood donors.


A case-control study of wood dust exposure, mutagen sensitivity, and lung cancer risk.
The associations between lung cancer risk, mutagen sensitivity (a marker of cancer susceptibility), and a putative lung carcinogen, wood dust, were assessed in a hospital-based case-control study. There were 113 African -American and 67 Mexican-American cases with newly diagnosed, previously untreated lung cancer and 270 controls, frequency-matched on age, ethnicity, and sex. Mutagen sensitivity ( 1 chromatid break/cell after short-term bleomycin treatment) was associated with statistically significant elevated risk for lung cancer [odds ration (OR) = 4.3; 95% confidence intervals (CI) = 2.3-7.9]. Wood dust exposure was also a significant predictor of risk (overall OR = 3.5; CI = 1.4-8.6) after controlling for smoking and mutagen sensitivity. When stratified by ethnicity, wood dust exposure was s significant risk factor for African-Americans (OR = 5.5; CI = 1.6-18.9) but not for Mexican-Americans (OR = 2.0; CI = 0.5-8.1). The ORs were 3.8 and 4.8 for non-small cell lung cancer in Mexican-Americans (CI = 1.2-18.5). Stratified analysis suggested evidence of strong interactions between wood dust exposure and both mutagen sensitivity and smoking in lung cancer risk.


Atrophy of brown adipocytes in the adult mouse causes transformation into white adipocyte-like cells.
Adipose tissue is an important endocrine regulator of glucose metabolism and energy homeostasis. Researches have focused on this tissue not only as a target for pharmacotherapy of obesity and insulin resistance but also as an endocrine tissue with leptin secretion and high insulin sensitivity. Brown adipose tissue (BAT) additionally plays a unique role in thermoregulation through the mitochondrial uncoupling protein 1 (UCP1), which uncouples oxidative phosphorylation. As a genetic tissue ablation model of BAT, we made transgenic mice expressing herpes simplex virus thymidine kinase (HSV-TK) driven by the brown adipocyte- specific UCP1 minimal regulatory element. The HSV-TK transgene was expressed specifically in BAT and more than 35% increase of apoptosis was induced by ganciclovir (GCV) treatment. Nevertheless, the expression level was not high enough to induce BAT ablation in GCV-treated adult mice. Importantly, however, we found that brown adipocytes in the periphery of interscapular BAT were transformed into white adipocyte-like unilocular cells. These cells express white adipocyte-specific leptin protein but are different in the ultrastructure of mitochondria from classical white adipocytes. Our data indicates that atrophy of BAT causes transformation into white adipocyte-like cells in the adult mouse and also suggests that further molecular understanding of adipocyte plasticity using our transgenic mouse model might be beneficial for the development of anti-obesity/anti-diabetic therapies.


Access to recreational physical activities by car and bus: an assessment of socio-spatial inequalities in mainland Scotland.
Obesity and other chronic conditions linked with low levels of physical activity (PA) are associated with deprivation. One reason for this could be that it is more difficult for low-income groups to access recreational PA facilities such as swimming pools and sports centres than high-income groups. In this paper, we explore the distribution of access to PA facilities by car and bus across mainland Scotland by income deprivation at datazone level. GIS car and bus networks were created to determine the number of PA facilities accessible within travel times of 10, 20 and 30 minutes. Multilevel negative binomial regression models were then used to investigate the distribution of the number of accessible facilities, adjusting for datazone population size and local authority. Access to PA facilities by car was significantly (p<0.01) higher for the most affluent quintile of area-based income deprivation than for most other quintiles in small towns and all other quintiles in rural areas. Accessibility by bus was significantly lower for the most affluent quintile than for other quintiles in urban areas and small towns, but not in rural areas. Overall, we found that the most disadvantaged groups were those without access to a car and living in the most affluent areas or in rural areas.


Social networks, support cliques, and kinship.
Data on the number of adults that an individual contacts at least once a month in a set of British populations yield estimates of network sizes that correspond closely to those of the typical "sympathy group" size in humans. Men and women do not differ in their total network size, but women have more females and more kin in their networks than men do. Kin account for a significantly higher proportion of network members than would be expected by chance. The number of kin in the network increases in proportion to the size of the family; as a result, people from large families have proportionately fewer non-kin in their networks, suggesting that there is either a time constraint or a cognitive constraint on network size. A small inner clique of the network functions as a support group from whom an individual is particularly likely to seek advice or assistance in time of need. Kin do not account for a significantly higher proportion of the support clique than they do for the wider network of regular social contacts for either men or women, but each sex exhibits a strong preference for members of their own sex.


Detection of hypercapnia by normal subjects.
1. To investigate whether changes in PaCO2 can be detected independently of the CO2-induced changes in pulmonary ventilation, we tested five normal subjects for the ability to distinguish different levels of end-tidal PCO2 (PETCO2) while holding minute ventilation constant. 2. Helped by a visual feedback system, the subjects maintained a constant ventilation targeted at a level that was higher than that dictated by the chemical drive at PETCO2 = 50 mmHg (6.7 kPa). End-tidal PCO2 was held at 40 mmHg (5.3 kPa) during the first 2 min of each test trial ('control period'); then, for 4 min ('test period'), PETCO2 was either elevated to 50 mmHg or kept at 40 mmHg. Twelve runs were performed by each subject. 3. In 24 out of the total 30 trials (80%) in which PETCO2 was raised during the test period to 50 mmHg, the subjects detected the changes. There was one false positive result (3%), when PETCO2 kept at 40 mmHg during the test period was reported as different from control. In four out of the five subjects the ability to detect the change in PETCO2 from 40 to 50 mmHg was statistically significant. 4. We conclude that increases in PETCO2 can be detected independently of changes in the absolute level of ventilation.


Which factors predict cognitive decline in Parkinson's disease?
The study assessed cognitive decline in non-demented, non-depressed patients with well defined Parkinson's disease and determined the predictive value for cognitive decline of different motor symptoms. Motor disability was measured with the Unified Parkinson's disease rating scale, impairment in activities of daily living, levodopa test, and long term clinical follow up. Neuropsychological evaluations included modified mini mental state, fluency, Wechsler logical memory, Wisconsin card sorting test, and the Montgomery and Asberg depression rating scale. Fifty three patients fulfilling clinical criteria for idiopathic Parkinson's disease were studied. Cognitive performance on initial testing was significantly correlated with education and disease duration but not with age at disease onset. Cognitive performance on retesting after three years of follow up was significantly reduced. This reduction was significantly greater in the late onset group, in patients with isolated dystonic dyskinesiae, and in patients with a lower percentage of motor improvement on levodopa. Cognitive decline in idiopathic Parkinson's disease may depend on both the prevalence of non-dopaminergic lesions and the topography of dopaminergic denervation. Predictive factors for cognitive decline, especially in executive tasks, relate more to non-dopaminergic than to dopaminergic lesions.


Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells.
The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking of the GLP-1R influence its signalling properties and therapeutic potential in type 2 diabetes. Here, we have evaluated how different factors combine to control the post-endocytic trafficking of GLP-1R to recycling versus degradative pathways. Experiments were performed in primary islet cells, INS-1 832/3 clonal beta cells and HEK293 cells, using biorthogonal labelling of GLP-1R to determine its localisation and degradation after treatment with GLP-1, exendin-4 and several further GLP-1R agonist peptides. We also characterised the effect of a rare GLP1R coding variant, T149M, and the role of endosomal peptidase endothelin-converting enzyme-1 (ECE-1), in GLP1R trafficking. Our data reveal how treatment with GLP-1 versus exendin-4 is associated with preferential GLP-1R targeting towards a recycling pathway. GLP-1, but not exendin-4, is a substrate for ECE-1, and the resultant propensity to intra-endosomal degradation, in conjunction with differences in binding affinity, contributes to alterations in GLP-1R trafficking behaviours and degradation. The T149M GLP-1R variant shows reduced signalling and internalisation responses, which is likely to be due to disruption of the cytoplasmic region that couples to intracellular effectors. These observations provide insights into how ligand- and genotype-specific factors can influence GLP-1R trafficking.


Benefits, risk, and uncertainty: preferences of antiretroviral-naïve African Americans for HIV treatments.
While African Americans in the United States are disproportionately affected by HIV, they are less likely to take antiretroviral therapies. Different first-line antiretroviral therapies are associated with short-term and long-term adverse event (AE) risks. We estimated the willingness of antiretroviral-naïve, HIV-positive African Americans to accept risks of acute AEs with known outcomes and long-term AEs with uncertain outcomes in exchange for virologic suppression. We estimated the relative importance of short-term and long-term AE risks. Two hundred thirty-five subjects were recruited through eight clinics in the United States. One hundred fifty-eight subjects met study inclusion criteria. One hundred fifty-three subjects completed a series of choice-format conjoint trade-off tasks. In each task, subjects were asked to choose between two hypothetical treatments with varying levels of virologic failure, risks of hypersensitivity reaction, decreases in bone mineral density (BMD), and renal impairment, and outcome uncertainty associated with the risks of decreased BMD and renal impairment. Attributes were expressed as probabilities of occurrence. We calculated the relative importance of each AE and the level of risk subjects would accept to reduce the risk of virologic failure. Subjects indicated that short-term AEs with relatively certain outcomes are preferred to long-term AEs with uncertain outcomes. Subjects were strongly averse to the risk of decreased BMD that could not be treated successfully or when the outcome was uncertain and to the risk of renal impairment that could not be treated successfully. Subjects were willing to accept increased risks of AEs in exchange for lower risk of virologic failure.


Predictive Validity of the Cubbin-Jackson and Braden Skin Risk Tools in Critical Care Patients: A Multisite Project.
Patients in intensive care units are 5 times more likely to have skin integrity issues develop than patients in other units. Identifying the most appropriate assessment tool may be critical to preventing pressure injuries in intensive care patients. To validate the Cubbin-Jackson skin risk assessment in the critical care setting and to compare the predictive accuracy of the Cubbin-Jackson and Braden scales for the same patients. In 5 intensive care units, the Cubbin-Jackson and Braden assessments were completed by different clinicians within 61 minutes of each other for 4137 patients between October 2017 and March 2018. Bivariate correlations and the Fisher exact test were used to check for associations between the scores. The Cubbin-Jackson and Braden scores were significantly and positively correlated (r = 0.80, P < .001). Both tools were significant predictors of skin changes and identified as "at risk" 100% of the patients who had a change in skin integrity occur. The specificity was 18.4% for the Cubbin-Jackson scale and 27.9% for the Braden scale, and the area under the curve was 0.75 (P < .001) for the Cubbin-Jackson scale and 0.76 (P < .001) for the Braden scale. These findings show acceptable construct validity for both scales. The predictive validities of the Cubbin-Jackson and Braden scales are similar, but both are sub-optimal because of poor specificity and positive predictive value. Change in practice may not be warranted, because there are no differences between the 2 scales of practical benefit to bedside nurses.


Perturbing phosphoinositide homeostasis oppositely affects vascular differentiation in Arabidopsis thaliana roots.
The plant vascular network consists of specialized phloem and xylem elements that undergo two distinct morphogenetic developmental programs to become transport-functional units. Whereas vacuolar rupture is a determinant step in protoxylem differentiation, protophloem elements never form a big central vacuole. Here, we show that a genetic disturbance of phosphatidylinositol 4,5-bis-phosphate [PtdIns(4,5)P2] homeostasis rewires cell trafficking towards the vacuole in Arabidopsis thaliana roots. Consequently, an enhanced phosphoinositide-mediated vacuolar biogenesis correlates with premature programmed cell death (PCD) and secondary cell wall elaboration in xylem cells. By contrast, vacuolar fusion events in protophloem cells trigger the abnormal formation of big vacuoles, preventing cell clearance and tissue functionality. Removal of the inositol 5' phosphatase COTYLEDON VASCULAR PATTERN 2 from the plasma membrane (PM) by brefeldin A (BFA) treatment increases PtdIns(4,5)P2 content at the PM and disrupts protophloem continuity. Conversely, BFA application abolishes vacuolar fusion events in xylem tissue without preventing PCD, suggesting the existence of additional PtdIns(4,5)P2-dependent cell death mechanisms. Overall, our data indicate that tight PM phosphoinositide homeostasis is required to modulate intracellular trafficking contributing to oppositely regulate vascular differentiation.


Decoding of facial strains via conformable piezoelectric interfaces.
Devices that facilitate nonverbal communication typically require high computational loads or have rigid and bulky form factors that are unsuitable for use on the face or on other curvilinear body surfaces. Here, we report the design and pilot testing of an integrated system for decoding facial strains and for predicting facial kinematics. The system consists of mass-manufacturable, conformable piezoelectric thin films for strain mapping; multiphysics modelling for analysing the nonlinear mechanical interactions between the conformable device and the epidermis; and three-dimensional digital image correlation for reconstructing soft-tissue surfaces under dynamic deformations as well as for informing device design and placement. In healthy individuals and in patients with amyotrophic lateral sclerosis, we show that the piezoelectric thin films, coupled with algorithms for the real-time detection and classification of distinct skin-deformation signatures, enable the reliable decoding of facial movements. The integrated system could be adapted for use in clinical settings as a nonverbal communication technology or for use in the monitoring of neuromuscular conditions.


The effect of action goal hierarchy on the coding of object orientation in imitation tasks: evidence from patients with parietal lobe damage.
In order to explore parietal patients' difficulties in the processing of orientation information, we asked parietal patients (N = 8) and healthy and brain-damaged controls to imitate multicomponent actions where object orientation was one component. In Experiment 1 orientation was not the most relevant aspect of the action to be imitated, and the parietal group showed significant difficulties in processing object orientation. However, in Experiment 2, where orientation was placed at the top end of the goal hierarchy, the parietal group were able to process stimulus orientation sufficiently to place it within the goal hierarchy of the action and to reproduce it accurately. We conclude that patients with parietal lesions might be able to include object orientation in a goal hierarchy, but if their processing of orientation information is impaired they might be disproportionately prone to errors when object orientation is lower in the goal hierarchy and so not prioritized for processing resources.


Drug interactions in at-risk emergency department patients.
Many emergency department (ED) patients are at risk for drug interactions (DIs) because they are elders, and/or they have chronic illnesses requiring treatment with multiple medications. In the ED, medications may be added to complex treatment regimens without the benefit of screening for DIs. Emergency physicians may therefore cause DIs, or miss the opportunity to intervene against a pre-existing DI. Prior studies are contradictory regarding whether DIs are more likely to be due to medications administered or prescribed in the ED or medications prescribed elsewhere. Screening for DIs using computer software, such as that done by retail pharmacies, is now a standard of practice, and is done more frequently than when these other DI studies were reported during the previous decade. The authors monitored DIs among a focused, at-risk outpatient ED population, to test the hypothesis that ED-induced DIs have become the most common DIs in this population-at-risk. A retrospective convenience sample of 200 at-risk patients seen at a tertiary teaching hospital on selected dates of service was analyzed. Eligible patients were ED outpatients aged 60 years or more taking three or more medications, or any age taking five or more medications. Micromedex Drug-Reax software identified DIs. DIs had to represent "major" or "minor" severity, and have "excellent" or "good" literature documentation, to be scored as positive. Pre-existing versus ED-induced DIs were compared by chi-square. DIs were stratified by patient age and by number and type of medications taken. The 200 outpatients (125 female, 75 male) had a mean age (+/-SD) of 64.5 (+/-17.6) years and were taking an average of 7.2 medications. Seventy-nine pre-existing DIs were noted, occurring in 50 of the 200 patients studied. One hundred forty patients received a new medication during their ED visit. Seven new DIs (one in each of seven patients) occurred among these 140 patients. DIs were less frequently caused by medications added during the ED visit (chi(2) = 22.2, p < 0.001). Digoxin and warfarin were the sources of the greatest number of DIs. ED outpatients in the at-risk group frequently present with pre-existing DIs. Medications initiated in the ED are a less frequent cause of DI in this group. Medication screening during an ED visit could complement the role of outpatient pharmacies and potentially improve ED patient safety. DIs are most frequently due to digoxin and warfarin in these patients.


The influence of social factors on help-seeking for people with lung cancer.
While there has been no clear consensus on the potential for earlier diagnosis of lung cancer, recent research has suggested that the time between symptom onset and consultation can be long enough to plausibly affect prognosis. In this article, we present a review of the literature concerning help-seeking delays in lung cancer presentation, and more specifically, the role and influence that social factors may play in determining when and how people decide to seek medical help. We also consider how these factors contribute to patients' understanding of symptoms and illness indicators. We suggest that while there is research highlighting the importance of psychosocial influences on the general help-seeking behaviour of people with concerns about cancer, existing studies are mainly retrospective, and very little work has focused on identifying triggers and barriers specific to lung cancer. Further, we propose that while there have been a number of recent initiatives to raise awareness of the early signs of lung cancer, aimed at both patients and health professionals, little information provision has been targeted specifically at the formal and informal network level. This may be a useful avenue to pursue in future initiatives.


Ultrastructure of primary afferent fibres and terminals expressing alpha-galactose extended oligosaccharides in the spinal cord and brainstem of the rat.
The ultrastructural characteristics of primary afferent fibres, which express alpha-galactose extended oligosaccharides recognized by LD2 and LA4 monoclonal antibodies, and the subcellular localization of these oligosaccharides were studied. LD2 and LA4 antibodies both label intensely the plasma membrane of primary afferent fibres, and with LD2 antibody all immunoreactive profiles also possessed strong intracellular staining. In contrast, intracellular staining with LA4 antibody was observed in only a subpopulation of stained profiles. LD2-immunoreactive fibres were detected in trigeminal and Lissauer tracts and in lamina I (LI) and lamina II (LII), and appeared as a mixture of unmyelinated and myelinated fibres. The highest density of LD2-immunoreactive synaptic boutons was found in lamina II outer (LIIo). Many of the terminals were simple dome-shaped terminals, making single asymmetric synapses over small and medium-sized dendritic shafts and dendritic spines. All LA4-immunoreactive fibres were unmyelinated. In addition, some small scalloped central-glomerular terminals contacting two or three dendrites were found. LA4-immunoreactive fibres were found more frequently than terminals and appeared most heavily immunostained in trigeminal and Lissauer tracts. In the neuropil of LI and LII, LA4 profiles were generally very weakly immunostained, although a small sample of immunostained synaptic boutons was detected. All LA4-immunoreactive terminals were found in lamina II inner (LIIi) and made simple asymmetric axodendritic synapses. In addition to axons and terminals, some dendrites exhibited LD2 immunoreactivity and this was most intense in the region of synaptic vesicles. In addition to neurons, some endothelial cells were immunostained with LD2 antibody and astrocytes were immunostained with LA4 antibody.


Salutary effects of high-intensity interval training in persons with elevated cardiovascular risk.
Although moderate-intensity continuous training (MICT) has been the traditional model for aerobic exercise training for over four decades, a growing body of literature has demonstrated equal if not greater improvement in aerobic capacity and similar beneficial effects on body composition, glucose metabolism, blood pressure, and quality of life from high-intensity interval training (HIIT). An advantage of HIIT over MICT is the shorter time required to perform the same amount of energy expenditure. The current brief review summarizes the effects of HIIT on peak aerobic capacity and cardiovascular risk factors in healthy adults and those with various cardiovascular diseases, including coronary artery disease, chronic heart failure, and post heart transplantation.


Memory modulation in the classroom: selective enhancement of college examination performance by arousal induced after lecture.
Laboratory studies examining moderate physiological or emotional arousal induced after learning indicate that it enhances memory consolidation. Yet, no studies have yet examined this effect in an applied context. As such, arousal was induced after a college lecture and its selective effects were examined on later exam performance. Participants were divided into two groups who either watched a neutral video clip (n=66) or an arousing video clip (n=70) after lecture in a psychology course. The final examination occurred two weeks after the experimental manipulation. Only performance on the group of final exam items that covered material from the manipulated lecture were significantly different between groups. Other metrics, such as the midterm examination and the total final examination score, did not differ between groups. The results indicate that post-lecture arousal selectively increased the later retrieval of lecture material, despite the availability of the material for study before and after the manipulation. The results reinforce the role of post-learning arousal on memory consolidation processes, expanding the literature to include a real-world learning context.