Malignant pleural mesothelioma: diagnostic value of medical thoracoscopy and long-term prognostic analysis.
Malignant pleural mesothelioma (MPM) is marked by its difficult diagnosis and poor prognosis. Medical thoracoscopy (MT) is an effective and safe procedure for the diagnosis of exudative pleural effusions and many factors associated with poor prognosis of MPM. We conducted this study to investigate the value of MT for diagnosing of MPM and to identify prognostic factors for MPM patients. From July 2005 through June 2014, a total of 833 patients with undiagnosed pleural effusions underwent MT and pleural biopsies were taken. Clinical data of all patients with MPM were retrospectively analyzed, and those with complete follow-up data were analyzed for prognostic factors. Eventually, MPM was the final diagnosis in 40 patients. Diagnostic efficiency of MT for MPM was 87.5%, since diagnosis of MPM failed to be established in 5 patients during the initial MT. Median survival was 17.1 mo (95% confidence interval: 13.6-20.7 mo). MT findings of pleural adhesion and plaques were adverse prognostic factors for MPM. In addition, old age, male gender, smoking history, histological type, poor staging, no treatment, low total protein level in pleural fluid, and computed tomographic findings such as pulmonary consolidation or infiltration, mediastinal lymphopathy, pulmonary mass or nodules, and pleural nodularity were also poor prognostic factors for MPM. MT is safe with a high positive rate in the diagnosis of MPM, and pleural adhesion and plaques seen under MT may be the adverse prognostic factors for MPM. Multiple clinical characteristics can affect the survival of MPM patients.


Maize purple plant pigment protects against fluoride-induced oxidative damage of liver and kidney in rats.
Anthocyanins are polyphenols and well known for their biological antioxidative benefits. Maize purple plant pigment (MPPP) extracted and separated from maize purple plant is rich in anthocyanins. In the present study, MPPP was used to alleviate the adverse effects generated by fluoride on liver and kidney in rats. The results showed that the ultrastructure of the liver and kidney in fluoride treated rats displayed shrinkage of nuclear and cell volume, swollen mitochondria and endoplasmic reticulum and vacuols formation in the liver and kidney cells. MPPP significantly attenuated these fluoride-induced pathological changes. The MDA levels in serum and liver tissue of fluoride alone treated group were significantly higher than those of the control group (p < 0.05). The presence of 5 g/kg MPPP in the diet reduced the elevation of MDA levels in blood and liver, and increased the SOD and GSH-Px activities in kidney and GSH level in liver and kidney compared with the fluoride alone treated group (p < 0.05). In addition, MPPP alleviated the decrease of Bcl-2 protein expression and the increase of Bax protein expression induced by fluoride. This study demonstrated the protective role of MPPP against fluoride-induced oxidative stress in liver and kidney of rats.


Complex polarization propagator calculations of magnetic circular dichroism spectra.
It is demonstrated that the employment of the nonlinear complex polarization propagator enables the calculation of the complete magnetic circular dichroism spectra of closed-shell molecules, including at the same time both the so-called Faraday A and B terms. In this approach, the differential absorption of right and left circularly polarized light in the presence of a static magnetic field is determined from the real part of the magnetic field-perturbed electric dipole polarizability. The introduction of the finite lifetimes of the electronically excited states into the theory results in response functions that are well behaved in the entire spectral region, i.e., the divergencies that are found in conventional response theory approaches at the transition energies of the system are not present. The applicability of the approach is demonstrated by calculations of the ultraviolet magnetic circular dichroism spectra of para-benzoquinone, tetrachloro-para-benzoquinone, and cyclopropane. The present results are obtained with the complex polarization propagator approach in conjunction with Kohn-Sham density functional theory and the standard adiabatic density functionals B3LYP, CAM-B3LYP, and BHLYP.


Scaling up of HIV treatment for men who have sex with men in Bangkok: a modelling and costing study.
Despite the high prevalence of HIV in men who have sex with men (MSM) in Bangkok, little investment in HIV prevention for MSM has been made. HIV testing and treatment coverage remains low. Through a pragmatic programme-planning approach, we assess possible service linkage and provision of HIV testing and antiretroviral treatment (ART) to MSM in Bangkok, and the most cost-effective scale-up strategy. We obtained epidemiological and service capacity data from the Thai National Health Security Office database for 2011. We surveyed 13 representative medical facilities for detailed operational costs of HIV-related services for sexually active MSM (defined as having sex with men in the past 12 months) in metropolitan Bangkok. We estimated the costs of various ART scale-up scenarios, accounting for geographical accessibility across Bangkok. We used an HIV transmission population-based model to assess the cost-effectiveness of the scenarios. For present HIV testing (23% [95% CI 17-36] of MSM at high risk in 2011) and ART provision (20% of treatment-eligible MSM at high risk on ART in 2011) to be sustained, a US$73·8 million ($51·0 million to $97·0 million) investment during the next decade would be needed, which would link an extra 43,000 (27,900-58,000) MSM at high risk to HIV testing and 5100 (3500-6700) to ART, achieving an ART coverage of 44% for MSM at high risk in 2022. An additional $55·3 million investment would link an extra 46,700 (30,300-63,200) MSM to HIV testing and 12,600 (8800-16,600) to ART, achieving universal ART coverage of this population by 2022. This increased investment is achievable within present infrastructure capacity. Consequently, an estimated 5100 (3600-6700) HIV-related deaths and 3700 (2600-4900) new infections could be averted in MSM by 2022, corresponding to a 53% reduction in deaths and a 35% reduction in infections from 2012 levels. The expansion would cost an estimated $10,809 (9071-13,274) for each HIV-related death, $14,783 (12,389-17,960) per new infection averted, and $351 (290-424) per disability-adjusted life-year averted. Spare capacity in Bangkok's medical facilities can be used to expand ART access for MSM with large epidemiological benefits. The expansion needs increased funding directed to MSM services, but given the epidemiological trends, is probably cost effective. Our modelling approach and outcomes are likely to be applicable to other settings. World Bank Group and Australian National Health and Medical Research Council.


White Paper AGA: POWER - Practice Guide on Obesity and Weight Management, Education, and Resources.
The epidemic of obesity continues at alarming rates, with a high burden to our economy and society. The American Gastroenterological Association understands the importance of embracing obesity as a chronic, relapsing disease and supports a multidisciplinary approach to the management of obesity. Because gastrointestinal disorders resulting from obesity are more frequent and often present sooner than type 2 diabetes mellitus and cardiovascular disease, gastroenterologists have an opportunity to address obesity and provide an effective therapy early. Patients who are overweight or obese already fill gastroenterology clinics with gastroesophageal reflux disease and its associated risks of Barrett's esophagus and esophageal cancer, gallstone disease, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, and colon cancer. Obesity is a major modifiable cause of diseases of the digestive tract that frequently goes unaddressed. As internists, specialists in digestive disorders, and endoscopists, gastroenterologists are in a unique position to play an important role in the multidisciplinary treatment of obesity. This American Gastroenterological Association paper was developed with content contribution from Society of American Gastrointestinal and Endoscopic Surgeons, The Obesity Society, Academy of Nutrition and Dietetics, and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, endorsed with input by American Society for Gastrointestinal Endoscopy, American Society for Metabolic and Bariatric Surgery, American Association for the Study of Liver Diseases, and Obesity Medicine Association, and describes POWER: Practice Guide on Obesity and Weight Management, Education and Resources. Its objective is to provide physicians with a comprehensive, multidisciplinary process to guide and personalize innovative obesity care for safe and effective weight management.


A simple approach to ranking differentially expressed gene expression time courses through Gaussian process regression.
The analysis of gene expression from time series underpins many biological studies. Two basic forms of analysis recur for data of this type: removing inactive (quiet) genes from the study and determining which genes are differentially expressed. Often these analysis stages are applied disregarding the fact that the data is drawn from a time series. In this paper we propose a simple model for accounting for the underlying temporal nature of the data based on a Gaussian process. We review Gaussian process (GP) regression for estimating the continuous trajectories underlying in gene expression time-series. We present a simple approach which can be used to filter quiet genes, or for the case of time series in the form of expression ratios, quantify differential expression. We assess via ROC curves the rankings produced by our regression framework and compare them to a recently proposed hierarchical Bayesian model for the analysis of gene expression time-series (BATS). We compare on both simulated and experimental data showing that the proposed approach considerably outperforms the current state of the art. Gaussian processes offer an attractive trade-off between efficiency and usability for the analysis of microarray time series. The Gaussian process framework offers a natural way of handling biological replicates and missing values and provides confidence intervals along the estimated curves of gene expression. Therefore, we believe Gaussian processes should be a standard tool in the analysis of gene expression time series.


High-throughput mutation detection underlying adaptive evolution of Escherichia coli-K12.
Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis of base-specific cleavage products is an efficient, highly accurate tool for the detection of single base sequence variations. We describe the first application of this comparative sequencing strategy for automated high-throughput mutation detection in microbial genomes. The method was applied to identify DNA sequence changes that occurred in Escherichia coli K-12 MG1655 during laboratory adaptive evolution to new optimal growth phenotypes. Experiments were based on a genome-scale in silico model of E. coli metabolism and growth. This model computes several phenotypic functions and predicts optimal growth rates. To identify mutations underlying a 40-d adaptive laboratory evolution on glycerol, we resequenced 4.4% of the E. coli-K12 MG1655 genome in several clones picked at the end of the evolutionary process. The 1.54-Mb screen was completed in 13.5 h. This resequencing study is the largest reported by MALDI-TOF mass spectrometry to date. Ten mutations in 40 clones and three deviations from the reference sequence were detected. Mutations were predominantly found within the glycerol kinase gene. Functional characterization of the most prominent mutation shows its metabolic impact on the process of adaptive evolution. All sequence changes were independently confirmed by genotyping and Sanger-sequencing. We demonstrate that comparative sequencing by base-specific cleavage and MALDI-TOF mass spectrometry is an automated, fast, and highly accurate alternative to capillary sequencing.


Relationship between low levels of circulating TRAIL and atheromatosis progression in patients with chronic kidney disease.
Chronic kidney disease (CKD) patients experience a high risk of cardiovascular disease (CV); however, the factors involved in CV-related morbidity and mortality in these patients have not been fully defined. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine, which exhibits pleiotropic activities on endothelial, vascular smooth muscle and inflammatory cells, with relevant effects on atheromatous plaque formation. On this basis, the present study aims to investigate the role of TRAIL in atheromatosis progression in CKD patients. Circulating TRAIL levels were measured in 378 CKD patients belonging to the Spanish National Observatory of Atherosclerosis in Nephrology (NEFRONA) study. All patients were free of previous CV events. Carotid and femoral B-mode ultrasound was performed to detect the presence of plaque at baseline and after 24 months of follow-up. The lowest levels of TRAIL at baseline were significantly (p<0.05) associated with the appearance, after 24 months of follow-up, of at least two new atheromatous plaques in all territories and of one new plaque in the carotid artery, even after adjusting for CV risk factors. In addition, the patients with low levels of TRAIL at baseline were characterized by the presence of at least one hypoechoic plaque in the carotid artery. This association was significant (p<0.05) even after adjusting for CKD stage. Overall, the results of our study suggest TRAIL as an assertable independent prognostic biomarker for atheromatosis plaque formation in CKD patients. This observation further supports the potential role of TRAIL for the prevention/treatment of CV disease.


Deep Volumetric Ambient Occlusion.
We present a novel deep learning based technique for volumetric ambient occlusion in the context of direct volume rendering. Our proposed Deep Volumetric Ambient Occlusion (DVAO) approach can predict per-voxel ambient occlusion in volumetric data sets, while considering global information provided through the transfer function. The proposed neural network only needs to be executed upon change of this global information, and thus supports real-time volume interaction. Accordingly, we demonstrate DVAO's ability to predict volumetric ambient occlusion, such that it can be applied interactively within direct volume rendering. To achieve the best possible results, we propose and analyze a variety of transfer function representations and injection strategies for deep neural networks. Based on the obtained results we also give recommendations applicable in similar volume learning scenarios. Lastly, we show that DVAO generalizes to a variety of modalities, despite being trained on computed tomography data only.


Life and Liesegang: Outcrop-Scale Microbially Induced Diagenetic Structures and Geochemical Self-Organization Phenomena Produced by Oxidation of Reduced Iron.
The Kanab Wonderstone is sandstone (Shinarump Member, Chinle Formation) that is cemented and stained with iron oxide. The iron-oxide cementation and staining in these rocks have been considered examples of the Liesegang phenomenon, but we will show that they comprise a microbially induced structure. The spacing of bands of iron-oxide stain follow the Jablczynski spacing law (wherein the spacing between bands of iron-oxide stain increases as one traverses a series of bands) characteristic of Liesegang. Bands of iron-oxide cement exhibit more variable spacing and exhibit a weak but significant correlation between band thickness and distance between bands of cement. The pore-filling cement contains morphotypes that are similar in size and habit to those exhibited by microaerophilic iron-oxidizing bacteria. Other disseminated iron-oxide mineralization occurs as rhombohedra interpreted to be pseudomorphs after siderite. We interpret the cement to be produced by microbially mediated oxidation of siderite (a typical early diagenetic mineral in fluvial sandstones). Iron-oxidizing bacteria colonized the redox interface between siderite-cemented sand and porous sandstone. Microbes oxidized aqueous Fe(II), generating acid that caused siderite dissolution. The iron-oxide cement is the microbial product of a geochemical drive for organization; whereas the iron-oxide stain is true Liesegang. Together, they comprise a distinctive microbially induced structure with high preservation potential.


Coenzyme Q10 attenuates lung and liver fibrosis via modulation of autophagy in methotrexate treated rat.
The present study was conducted to investigate the potential protective effects of coenzyme Q 10 (CoQ10) administration on methotrexate induced lung and liver fibrosis in rat model, and to explore our hypothesis regarding its possible mechanism of action through reactivation of autophagy pathway. Methotrexate induced fibrosis was achieved by intraperitoneal injections twice a week for 4 weeks. A combined treatment of CoQ10 and methotrexate were used. Blood samples for biochemical analysis, lung and livers tissue for biochemical and histopathological analysis, were investigated. Concomitant treatment of CoQ10 & methotrexate caused improvement in histological picture of the lung and liver tissues, liver function and oxidative stress biomarkers, modulation of autophagy genes [mammalian target of rapamycin (m-TOR), Microtubule-associated proteins 1 A/1B light chain 3 (MAP1LC3B), and Sequestosome 1 ubiquitin-binding protein p62 (p62/SQSTM1)] with simultaneous reduction in High Mobility Group Protein B1 (HMGB1). Based on our results we postulated that CoQ10 up regulates autophagy pathway that could explain its protective properties against lung and liver fibrosis caused by methotrexate treatment in current study rat model.


The evolution of the doctor-patient relationship.
The doctor-patient relationship has undergone a transition throughout the ages. Prior to the last two decades, the relationship was predominantly between a patient seeking help and a doctor whose decisions were silently complied with by the patient. In this paternalistic model of the doctor-patient relationship, the doctor utilises his skills to choose the necessary interventions and treatments most likely to restore the patient's health or ameliorate his pain. Any information given to the patient is selected to encourage them to consent to the doctor's decisions. This description of the asymmetrical or imbalanced interaction between doctor and patient [Parsons T. The social system. Free Press, New York, 1951.](1) has been challenged during the last 20 years. Critics have proposed a more active, autonomous and thus patient-centred role for the patient who advocates greater patient control, reduced physician dominance, and more mutual participation. This patient-centred approach has been described as one where "the physician tries to enter the patient's world, to see the illness through the patient's eyes" [McWhinney I. The need for a transformed clinical method. In: Stewart M, Roter D, Communicating with medical patients. London: Sage, 1989.](2), and has become the predominant model in clinical practice today.


Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human.
Purpose: Mesothelioma has been regarded as a nonimmunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis. Previously, we demonstrated that autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy increased T-cell response toward malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source. The purpose of this study was to investigate whether allogeneic lysate-pulsed DC immunotherapy is effective in mice and safe in humans.Experimental Design: First, in two murine mesothelioma models, mice were treated with autologous DCs pulsed with either autologous or allogeneic tumor lysate or injected with PBS (negative control). Survival and tumor-directed T-cell responses of these mice were monitored. Results were taken forward in a first-in-human clinical trial, in which 9 patients were treated with 10, 25, or 50 million DCs per vaccination. DC vaccination consisted of autologous monocyte-derived DCs pulsed with tumor lysate from five mesothelioma cell lines.Results: In mice, allogeneic lysate-pulsed DC immunotherapy induced tumor-specific T cells and led to an increased survival, to a similar extent as DC immunotherapy with autologous tumor lysate. In the first-in-human clinical trial, no dose-limiting toxicities were established and radiographic responses were observed. Median PFS was 8.8 months [95% confidence interval (CI), 4.1-20.3] and median OS not reached (median follow-up = 22.8 months).Conclusions: DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans. Clin Cancer Res; 24(4); 766-76. ©2017 AACR.


Ultrasonographic evaluation of the thyroid gland in healthy, hypothyroid, and euthyroid Golden Retrievers with nonthyroidal illness.
Ultrasound evaluation of the thyroid gland was performed in healthy, hypothyroid, and euthyroid Golden Retriever dogs with nonthyroidal illness (NTI) to determine the diagnostic usefulness of ultrasound for differentiating between euthyroid and hypothyroid dogs. Thirty-six healthy, 11 hypothyroid, and 35 euthyroid dogs with NTI were evaluated. Each thyroid lobe was examined ultrasonographically for size, shape, echogenicity, and homogeneity. Thyroid lobe volume was estimated by using the equation for an ellipsoid: pi/6(length X height x width). No differences were found between healthy dogs and euthyroid dogs with NTI. In the majority of euthyroid dogs, the thyroid lobes were fusiform and triangular in shape in longitudinal and transverse planes, respectively. The thyroid capsule appeared smooth. The thyroid parenchyma had a homogeneous echogenic pattern and usually was hyperechoic or isoechoic compared with the surrounding musculature. Ultrasound findings in hypothyroid dogs were more variable, including a greater frequency of round to oval-shaped thyroid lobes in the transverse imaging plane (P < .05), hypoechogenicity of the thyroid parenchyma compared with surrounding musculature (P < .001), and a decrease in the size and volume of the thyroid lobes and total volume of the thyroid gland (P < .05) compared with euthyroid dogs. Other findings in hypothyroid dogs included an irregular surface to the thyroid capsule, a heterogeneous pattern to the thyroid parenchyma, and differences in the echogenic pattern between the left and right thyroid lobes. Results suggest that determination of thyroid size and volume by ultrasound may be a useful adjunctive test for differentiating between hypothyroid and euthyroid dogs with NTI.


The Cytotoxicity of Kahweol in HT-29 Human Colorectal Cancer Cells Is Mediated by Apoptosis and Suppression of Heat Shock Protein 70 Expression.
Although coffee is known to have antioxidant, anti-inflammatory, and antitumor properties, there have been few reports about the effect and mechanism of coffee compounds in colorectal cancer. Heat shock proteins (HSPs) are molecular chaperones that prevent cell death. Their expression is significantly elevated in many tumors and is accompanied by increased cell proliferation, metastasis and poor response to chemotherapy. In this study, we investigated the cytotoxicity of four bioactive compounds in coffee, namely, caffeine, caffeic acid, chlorogenic acid, and kahweol, in HT-29 human colon adenocarcinoma cells. Only kahweol showed significant cytotoxicity. Specifically, kahweol increased the expression of caspase-3, a pro-apoptotic factor, and decreased the expression of anti-apoptotic factors, such as Bcl-2 and phosphorylated Akt. In addition, kahweol significantly attenuated the expression of HSP70. Inhibition of HSP70 activity with triptolide increased kahweol-induced cytotoxicity. In contrast, overexpression of HSP70 significantly reduced kahweol-induced cell death. Taken together, these results demonstrate that kahweol inhibits colorectal tumor cell growth by promoting apoptosis and suppressing HSP70 expression.


Paroxysmal nocturnal hemoglobinuria from bench to bedside.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease that presents with protean manifestations. Clinical and laboratory investigation over the past 25 years has uncovered most of the basic science underpinnings of PNH and has led to the development of a highly effective targeted therapy. PNH originates from a multipotent hematopoietic stem cell (HSC) that acquires a somatic mutation in a gene called phosphatidylinositol glycan anchor biosynthesis, class A (PIG-A). The PIG-A gene is required for the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Failure to synthesize GPI anchors leads to an absence of all proteins that utilize GPI to attach to the plasma membrane. Two GPI-anchor proteins, CD55 and CD59, are complement regulatory proteins; their absence on the surface of PNH cells leads to complement-mediated hemolysis. The release of free hemoglobin leads to scavenging of nitric oxide and contributes to many clinical manifestations, including esophageal spasm, fatigue, and possibly thrombosis. Aerolysin is a pore-forming toxin that binds GPI-anchored proteins and kills normal cells, but not PNH cells. A fluorescinated aerolysin variant (FLAER) binds GPI-anchor and serves as a novel reagent diagnosing PNH. Eculizumab, a humanized monoclonal antibody against C5, is the first effective drug therapy for PNH.


The validation of the Edinburgh Post-natal Depression Scale on a community sample.
The Edinburgh Post-natal Depression Scale (EPDS) was validated on a community sample of 702 women at six weeks post-partum using Research Diagnostic Criteria for depression. The estimates of sensitivity, specificity and positive predictive value, being based on a large random sample, offer improved guidelines for the use of the EPDS by the primary care team.


Glutathione depletion during experimental damage to rat skeletal muscle and its relevance to Duchenne muscular dystrophy.
1. The release of glutathione has been studied in comparison with the release of creatine kinase from isolated rat soleus muscles subjected to certain forms of experimental damage. 2. Excessive electrically stimulated contractile activity or treatment of muscles with the mitochondrial inhibitor, 2,4-dinitrophenol, induced a substantial release of both creatine kinase and glutathione and a reduction in the total glutathione content of the muscle. The time course of this release and depletion indicates that the efflux of the two molecules is not directly related and that a reduction in muscle glutathione content does not occur before cytosolic enzyme release. 3. 2,4-Dinitrophenol-stimulated release of creatine kinase was significantly reduced by the omission of external calcium from the incubation media, but glutathione release and depletion was relatively unaffected by this. Deliberate elevation of the muscle intracellular calcium content with the calcium ionophore, A23187, induced a substantial loss of creatine kinase, but had no significant effect on the release of glutathione. 4. Muscle biopsies from patients with Duchenne muscular dystrophy were found to have an elevated content of glutathione and an equivalent protein-thiol content compared with control subjects. 5. We conclude that, although release of glutathione from skeletal muscle occurs after excessive contractile activity or inhibition of mitochondrial metabolism, this is not a key step in the damaging processes leading to cytosolic enzyme release, neither is it relevant to the ongoing damage to skeletal muscle which occurs in patients with Duchenne muscular dystrophy.


Identifying champion nanostructures for solar water-splitting.
Charge transport in nanoparticle-based materials underlies many emerging energy-conversion technologies, yet assessing the impact of nanometre-scale structure on charge transport across micrometre-scale distances remains a challenge. Here we develop an approach for correlating the spatial distribution of crystalline and current-carrying domains in entire nanoparticle aggregates. We apply this approach to nanoparticle-based α-Fe₂O₃ electrodes that are of interest in solar-to-hydrogen energy conversion. In correlating structure and charge transport with nanometre resolution across micrometre-scale distances, we have identified the existence of champion nanoparticle aggregates that are most responsible for the high photoelectrochemical activity of the present electrodes. Indeed, when electrodes are fabricated with a high proportion of these champion nanostructures, the electrodes achieve the highest photocurrent of any metal oxide photoanode for photoelectrochemical water-splitting under 100 mW cm(-2) air mass 1.5 global sunlight.


Graphic methods for interpreting longitudinal dyadic patterns from repeated-measures actor-partner interdependence models.
Researchers commonly use repeated-measures actor-partner interdependence models (RM-APIM) to understand how romantic partners change in relation to one another over time. However, traditional interpretations of the results of these models do not fully or correctly capture the dyadic temporal patterns estimated in RM-APIM. Interpretation of results from these models largely focuses on the meaning of single-parameter estimates in isolation from all the others. However, considering individual coefficients separately impedes the understanding of how these associations combine to produce an interdependent pattern that emerges over time. Additionally, positive within-person, or actor, effects are commonly misinterpreted as indicating growth from one time point to the next when they actually represent decline. We suggest that change-as-outcome RM-APIMs and vector field diagrams (VFDs) can be used to improve the understanding and presentation of dyadic patterns of association described by standard RM-APIMs. The current article briefly reviews the conceptual foundations of RM-APIMs, demonstrates how change-as-outcome RM-APIMs and VFDs can aid interpretation of standard RM-APIMs, and provides a tutorial in making VFDs using multilevel modeling. (PsycINFO Database Record


Religious and Spiritual Coping and Risk of Incident Hypertension in the Black Women's Health Study.
The few studies of the relationship between religion and/or spirituality (R/S) and hypertension are conflicting. We hypothesized that R/S may reduce the risk of hypertension by buffering adverse physiological effects of stress. We prospectively assessed the association of R/S with hypertension within the Black Women's Health Study (BWHS), a cohort study initiated in 1995 that follows participants through biennial questionnaires. The 2005 questionnaire included four R/S questions: (i) extent to which one's R/S is involved in coping with stressful situations, (ii) self-identification as a religious/spiritual person, (iii) frequency of attending religious services, and (iv) frequency of prayer. Incidence rate ratios (IRRs) and 95% confidence intervals were calculated for each R/S variable in relation to incident hypertension using Cox proportional hazards regression models, controlling for demographics, known hypertension risk factors, psychosocial factors, and other R/S variables. During 2005-2013, 5,194 incident cases of hypertension were identified. High involvement of R/S in coping with stressful events compared with no involvement was associated with reduced risk of hypertension (IRR: 0.87; 95% CI: 0.75, 1.00). The association was strongest among women reporting greater levels of perceived stress (IRR: 0.77; 95% CI: 0.61, 0.98; p interaction = .01). More frequent prayer was associated with increased risk of hypertension (IRR: 1.12; 95% CI: 0.99, 1.27). No association was observed for the other R/S measures. R/S coping was associated with decreased risk of hypertension in African American women, especially among those reporting higher levels of stress. Further research is needed to understand the mechanistic pathways through which R/S coping may affect health.


Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies.
A large number of epidemiologic studies have reported on associations between various "inflammatory" factors and coronary heart disease (CHD). To assess the associations of blood levels of fibrinogen, C-reactive protein (CRP), and albumin and leukocyte count with the subsequent risk of CHD. Meta-analyses of any long-term prospective studies of CHD published before 1998 on any of these 4 factors. Studies were identified by MEDLINE searches, scanning of relevant reference lists, hand searching of cardiology, epidemiology, and other relevant journals, and discussions with authors of relevant reports. All relevant studies identified were included. The following information was abstracted from published reports (supplemented, in several cases, by the authors): size and type of cohort, mean age, mean duration of follow-up, assay methods, degree of adjustment for confounders, and relationship of CHD risk to the baseline assay results. For fibrinogen, with 4018 CHD cases in 18 studies, comparison of individuals in the top third with those in the bottom third of the baseline measurements yielded a combined risk ratio of 1.8 (95% confidence interval [CI], 1.6-2.0) associated with a difference in long-term usual mean fibrinogen levels of 2.9 pmol/L (0.1 g/dL) between the top and bottom thirds (10.3 vs 7.4 pmol/L [0.35 vs 0.25 g/dL]). For CRP, with 1053 CHD cases in 7 studies, the combined risk ratio of 1.7 (95% CI, 1.4-2.1) was associated with a difference of 1.4 mg/L (2.4 vs 1.0 mg/L). For albumin, with 3770 CHD cases in 8 studies, the combined risk ratio of 1.5 (95% CI, 1.3-1.7) was associated with a difference of 4 g/L (38 vs 42 g/L, ie, an inverse association). For leukocyte count, with 5337 CHD cases in the 7 largest studies, the combined risk ratio of 1.4 (95% CI, 1.3-1.5) was associated with a difference of 2.8 x 10(9)/L (8.4 vs 5.6 x 10(9)/L). Each of these overall results was highly significant (P<.0001). The published results from these prospective studies are remarkably consistent for each factor, indicating moderate but highly statistically significant associations with CHD. Hence, even though mechanisms that might account for these associations are not clear, further study of the relevance of these factors to the causation of CHD is warranted.


Changes in GFR and Albuminuria in Routine Clinical Practice and the Risk of Kidney Disease Progression.
Changes in urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) have been used separately as alternative kidney disease outcomes in randomized trials. We tested the hypothesis that combined changes in UACR and eGFR predict advanced kidney disease better than either alone. Observational cohort study. 91,319 primary care patients assembled from the Clinical Practice Research Datalink in the United Kingdom between 2000 and 2015. Changes in UACR and eGFR (categorized as ≥30% increase, stable, or ≥30% decrease), alone and in combination, over a 3-year period. The primary outcome was advanced CKD (sustained eGFR <30 mL/min/1.73 m2); secondary outcomes included kidney failure, cardiovascular disease, and all-cause mortality. Multivariable Cox regression with bias from missing values assessed using multiple imputation; discrimination statistics compared across exposure groups. 91,319 individuals were studied, with a mean eGFR of 72.6 mL/min/1.73 m2 and median UACR of 9.7 mg/g; 70,957 (77.7%) had diabetes. During a median follow-up of 2.9 years, 2,541 people progressed to advanced CKD. Compared with stable values, hazard ratios for a ≥30% increase in UACR and ≥30% decrease in eGFR were 1.78 (95% CI, 1.59-1.98) and 7.53 (95% CI, 6.70-8.45), respectively, for the outcome of advanced CKD. Compared with stable values of both, the hazard ratio for the combination of an increase in UACR and a decrease in eGFR was 15.15 (95% CI, 12.43-18.46) for the outcome of advanced CKD. The combination of changes in UACR and eGFR predicted kidney outcomes better than either alone. Selection bias, relatively small proportion of individuals without diabetes, and very few kidney failure events. In a large-scale general population, the combination of an increase in UACR and a decrease in eGFR was strongly associated with the risk of advanced CKD. Further assessment of combined changes in UACR and eGFR as an alternative outcome for kidney failure in trials of CKD progression is warranted.


Metabolic genes in cancer: their roles in tumor progression and clinical implications.
Re-programming of metabolic pathways is a hallmark of physiological changes in cancer cells. The expression of certain genes that directly control the rate of key metabolic pathways including glycolysis, lipogenesis and nucleotide synthesis are drastically altered at different stages of tumor progression. These alterations are generally considered as an adaptation of tumor cells; however, they also contribute to the progression of tumor cells to become more aggressive phenotypes. This review summarizes the recent information about the mechanistic link of these genes to oncogenesis and their potential utility as diagnostic markers as well as for therapeutic targets. We particularly focus on three groups of genes; GLUT1, G6PD, TKTL1 and PGI/AMF in glycolytic pathway, ACLY, ACC1 and FAS in lipogenesis and RRM2, p53R2 and TYMS for nucleotide synthesis. All these genes are highly up-regulated in a variety of tumor cells in cancer patients, and they play active roles in tumor progression rather than expressing merely as a consequence of phenotypic change of the cancer cells. Molecular dissection of their orchestrated networks and understanding the exact mechanism of their expression will provide a window of opportunity to target these genes for specific cancer therapy. We also reviewed existing database of gene microarray to validate the utility of these genes for cancer diagnosis.


Person-Centered Care and the Therapeutic Alliance.
Person-centered care has been gaining prominence in behavioral health care, and service planning has shifted towards "person-centered care planning" (PCCP), where individuals, in partnership with providers, identify life goals and interventions. A strong therapeutic alliance has been identified as key to a person-centered approach, but little is known about how the therapeutic relationship influences person-centered processes and outcomes. Using an explanatory sequential mixed methods design, this study investigated: (1) the association between the therapeutic alliance and PCCP, and (2) how the therapeutic relationship influences the process and outcomes of PCCP. Quantitative analyses found that a strong working alliance predicted greater personcenteredness. Qualitative analyses revealed two central themes: (1) the importance of connection, continuity, and calibration of the relationship to set the right conditions for PCCP, and (2) PCCP as a vehicle for engagement. Findings demonstrated that the therapeutic alliance is inextricably linked to the PCCP process, each influencing the other.


Fate of Bisphenol A in Terrestrial and Aquatic Environments.
Bisphenol A (2,2-bis[4-hydroxyphenyl]propane, BPA), the monomer used to produce polycarbonate plastic and epoxy resins, is weakly estrogenic and therefore of environmental and human health interest. Due to the high production volumes and disposal of products made from BPA, polycarbonate plastic and epoxy resins, BPA has entered terrestrial and aquatic environments. In the presence of oxygen, diverse taxa of bacteria, fungi, algae and even higher plants metabolize BPA, but anaerobic microbial degradation has not been documented. Recent reports demonstrated that abiotic processes mediate BPA transformation and mineralization in the absence of oxygen, indicating that BPA is susceptible to degradation under anoxic conditions. This review summarizes biological and nonbiological processes that lead to BPA transformation and degradation, and identifies research needs to advance predictive understanding of the longevity of BPA and its transformation products in environmental systems.


Reward-modulated Hebbian learning of decision making.
We introduce a framework for decision making in which the learning of decision making is reduced to its simplest and biologically most plausible form: Hebbian learning on a linear neuron. We cast our Bayesian-Hebb learning rule as reinforcement learning in which certain decisions are rewarded and prove that each synaptic weight will on average converge exponentially fast to the log-odd of receiving a reward when its pre- and postsynaptic neurons are active. In our simple architecture, a particular action is selected from the set of candidate actions by a winner-take-all operation. The global reward assigned to this action then modulates the update of each synapse. Apart from this global reward signal, our reward-modulated Bayesian Hebb rule is a pure Hebb update that depends only on the coactivation of the pre- and postsynaptic neurons, not on the weighted sum of all presynaptic inputs to the postsynaptic neuron as in the perceptron learning rule or the Rescorla-Wagner rule. This simple approach to action-selection learning requires that information about sensory inputs be presented to the Bayesian decision stage in a suitably preprocessed form resulting from other adaptive processes (acting on a larger timescale) that detect salient dependencies among input features. Hence our proposed framework for fast learning of decisions also provides interesting new hypotheses regarding neural nodes and computational goals of cortical areas that provide input to the final decision stage.


MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies.
Whether B cells serve as antigen-presenting cells (APCs) for activation of pathogenic T cells in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) is unclear. To evaluate their role as APCs, we engineered mice selectively deficient in MHC II on B cells (B-MHC II(-/-)), and to distinguish this function from antibody production, we created transgenic (Tg) mice that express the myelin oligodendrocyte glycoprotein (MOG)-specific B cell receptor (BCR; IgH(MOG-mem)) but cannot secrete antibodies. B-MHC II(-/-) mice were resistant to EAE induced by recombinant human MOG (rhMOG), a T cell- and B cell-dependent autoantigen, and exhibited diminished Th1 and Th17 responses, suggesting a role for B cell APC function. In comparison, selective B cell IL-6 deficiency reduced EAE susceptibility and Th17 responses alone. Administration of MOG-specific antibodies only partially restored EAE susceptibility in B-MHC II(-/-) mice. In the absence of antibodies, IgH(MOG-mem) mice, but not mice expressing a BCR of irrelevant specificity, were fully susceptible to acute rhMOG-induced EAE, also demonstrating the importance of BCR specificity. Spontaneous opticospinal EAE and meningeal follicle-like structures were observed in IgH(MOG-mem) mice crossed with MOG-specific TCR Tg mice. Thus, B cells provide a critical cellular function in pathogenesis of central nervous system autoimmunity independent of their humoral involvement, findings which may be relevant to B cell-targeted therapies.


Long-term follow-up of pediatric benign cerebellar astrocytomas.
The long-term prognosis of cerebellar astrocytomas needs to be reviewed. To elucidate the factors influencing tumor recurrence or progression and to determine how long these patient with cerebellar astrocytomas require surveillance with neuroimaging. A retrospective review of 101 children surgically treated for a cerebellar astrocytoma and followed up for > 10 years was performed. Mean follow-up was 18.4 years. Total resection confirmed by postoperative imaging was performed in 51 patients (50.5%; group A). Twenty-three patients (22.8%) had surgical total resection; however, equivocal residual tumor was found on postoperative imaging (group B). Subtotal resection leaving a portion of brainstem or cerebellar peduncle was performed in 27 patients (26.7; group C). Of these 50 residual tumors, 16 (32%) showed spontaneous regression and 8 (16%) showed arrested growth. Radiographic recurrence or progression was noted in 29 patients (28.7%). Only 3 of 51 patients (5.9%) of group A with total resection had recurrence, whereas 26 of 50 residual tumors (52%; groups B and C) progressed. The only factor affecting recurrence or progression by multivariate analysis was the extent of surgical resection. All tumor recurrence or progression except for 1 (96.6%) occurred within 8 years from the original surgery (range, 2-132 months). Overall prognosis of cerebellar astrocytomas is good; the 10-year survival rate was 100% and recurrence- or progression-free rate was 71.3% in our cohort. Almost half of residual tumors showed spontaneous regression or arrested growth in the long term. Eight to 10 years is considered to be a reasonable follow-up period by neuroimaging.


Effects of Radiation on Spinal Dura Mater and Surrounding Tissue in Mice.
Spinal surgery in a previously irradiated field carries increased risk of perioperative complications, such as delayed wound healing or wound infection. In addition, adhesion around the dura mater is often observed clinically. Therefore, similar to radiation-induced fibrosis--a major late-stage radiation injury in other tissue--epidural fibrosis is anticipated to occur after spinal radiation. In this study, we performed histopathologic assessment of postirradiation changes in the spinal dura mater and peridural tissue in mice. The thoracolumbar transition of ddY mice was irradiated with a single dose of 10 or 20 Gy. After resection of the irradiated spine, occurrence of epidural fibrosis and expression of transforming growth factor beta 1 in the spinal dura mater were evaluated. In addition, microstructures in the spinal dura mater and peridural tissue were assessed using an electron microscope. In the 20-Gy irradiated mice, epidural fibrosis first occurred around 12 weeks postirradiation, and was observed in all cases from 16 weeks postirradiation. In contrast, epidural fibrosis was not observed in the nonirradiated mice. Compared with the nonirradiated mice, the 10- and 20-Gy irradiated mice had significantly more overexpression of transforming growth factor beta 1 at 1 week postirradiation and in the late stages after irradiation. In microstructural assessment, the arachnoid barrier cell layer was thinned at 12 and 24 weeks postirradiation compared with that in the nonirradiated mice. In mice, spinal epidural fibrosis develops in the late stages after high-dose irradiation, and overexpression of transforming growth factor beta 1 occurs in a manner similar to that seen in radiation-induced fibrosis in other tissue. Additionally, thinning of the arachnoid barrier cell layer was observed in the late stages after irradiation. Thus, consideration should be given to the possibility that these phenomena can occur as radiation-induced injuries of the spine.


Assessment of the safety of injection practices and injection-related procedures in family health units and centers in Alexandria.
The Safe Injection Global Network (SIGN) developed an intervention strategy for reducing overuse of injections and promoting the administration of safe injections. Tool C--Revised is designed to assess the safety of the most common procedures that puncture the skin within health services. The aim of the study was to assess injection safety within the primary healthcare facilities in Alexandria using Tool C--Revised. A total of 45 family health units and centers in Alexandria were selected by proportional allocation from the eight regions of Alexandria. The Tool C--Revised of the WHO was used for observation of the entire facility, injection practices and injection-related procedures, and sterilization practices. Interview of different health providers and immediate supervisor of injections was carried out. Indicators that reflect risk included: deficiency of alcohol-based hand rub for cleansing hands (13.3%), compliance with hand wash before preparing a procedure (56.9% before injection practices, 61.3% before phlebotomy, and 67.6% before lancet puncture), and wearing a new pair of gloves before new procedures (48.6% before injection practices, 9.7% for phlebotomy, 11.8% for lancet puncture, and 80% for both intravenous injections and infusions). Enough disposable equipment in all facilities for at least 2 weeks dependent on the statement of the average numbers of procedures per week was shown. Only 38% of the providers had received training regarding injection safety in the last 2 years and 62.5% had completed their three doses of hepatitis B vaccine. Only 42.2% of staffs who handled healthcare waste had access to heavy gloves. Indicators related to injection and injection-related practices that reflect risk to patients include deficiency of alcohol-based hand rub tools, nonadherence to hand hygiene before preparing an injection, and inadequate adherence to using a clean barrier when opening a glass ampule and use of gloves. Indicators that may reflect risk to patients and providers include inadequate injection safety training and incomplete hepatitis B vaccination of healthcare providers. Indicators that may reflect risk to providers include nonadherence to safety precautions related to injection practices, such as inadequate access to heavy gloves by staff handling healthcare waste.


Kinetic characterization of early intermediates in the folding of E. coli tryptophan-synthase beta 2 subunit.
This report describes the use of fluorescence energy transfer between an intrinsic energy donor (tryptophan 177) and two chemically added acceptors to study intermediates in the folding of the beta 2 subunit of E. coli tryptophan-synthase. Two early folding steps are thus identified and characterized. One is very rapid (its rate constant at 12 degrees C is 0.02 sec-1) and corresponds to the folding of the N-terminal domain into a structure whose overall features approximate well those of the native domain. The second step is somewhat slower (its rate constant at 12 degrees C is 0.008 sec-1) and involves a conformational rearrangement of the N-terminal domain brought about by the interactions between the N- and C-terminal domains within a monomeric beta chain. This brings to five the number of intermediates which have been identified and ordered on the folding pathway of the dimeric beta 2 subunit.


RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland.
RUNX2, a master regulator of osteogenesis, is oncogenic in the lymphoid lineage; however, little is known about its role in epithelial cancers. Upregulation of RUNX2 in cell lines correlates with increased invasiveness and the capacity to form osteolytic disease in models of breast and prostate cancer. However, most studies have analysed the effects of this gene in a limited number of cell lines and its role in primary breast cancer has not been resolved. Using a human tumour tissue microarray, we show that high RUNX2 expression is significantly associated with oestrogen receptor (ER)/progesterone receptor (PR)/HER2-negative breast cancers and that patients with high RUNX2 expression have a poorer survival rate than those with negative or low expression. We confirm RUNX2 as a gene that has a potentially important functional role in triple-negative breast cancer. To investigate the role of this gene in breast cancer, we made a transgenic model in which Runx2 is specifically expressed in murine mammary epithelium under the control of the mouse mammary tumour virus (MMTV) promoter. We show that ectopic Runx2 perturbs normal development in pubertal and lactating animals, delaying ductal elongation and inhibiting lobular alveolar differentiation. We also show that the Runx2 transgene elicits age-related, pre-neoplastic changes in the mammary epithelium of older transgenic animals, suggesting that elevated RUNX2 expression renders such tissue more susceptible to oncogenic changes and providing further evidence that this gene might have an important, context-dependent role in breast cancer.


1,5-anhydroglucitol as a useful marker for assessing short-term glycemic excursions in type 1 diabetes.
Type 1 diabetes is associated with more severe glycemic variability and more frequent hypoglycemia than type 2 diabetes. Glycemic variability is associated with poor glycemic control and diabetic complications. In this study, we demonstrate the clinical usefulness of serum 1,5-anhydroglucitol (1,5-AG) for assessing changes in glycemic excursion in type 1 diabetes. Seventeen patients with type 1 diabetes were enrolled in this study. A continuous glucose monitoring system (CGMS) was applied twice at a 2-week interval to evaluate changes in glycemic variability. The changes in serum glycemic assays, including 1,5-AG, glycated albumin and hemoglobin A1c (HbA1c), were also evaluated. Most subjects showed severe glycemic excursions, including hypoglycemia and hyperglycemia. The change in 1,5-AG level was significantly correlated with changes in the glycemic excursion indices of the standard deviation (SD), mean amplitude of glucose excursion (MAGE), lability index, mean postmeal maximum glucose, and area under the curve for glucose above 180 mg/dL (r=-0.576, -0.613, -0.600, -0.630, and -0.500, respectively; all P<0.05). Changes in glycated albumin were correlated with changes in SD and MAGE (r=0.495 and 0.517, respectively; all P<0.05). However, changes in HbA1c were not correlated with any changes in the CGMS variables. 1,5-AG may be a useful marker for the assessment of short-term changes in glycemic variability. Furthermore, 1,5-AG may have clinical implications for the evaluation and treatment of glycemic excursions in type 1 diabetes.


Intact in situ Preparation of the Drosophila melanogaster Lymph Gland for a Comprehensive Analysis of Larval Hematopoiesis.
Blood cells have a limited lifespan and are replenished by a small number of hematopoietic stem and progenitor cells (HSPCs). Adult vertebrate hematopoiesis occurs in the bone marrow, liver, and spleen, rendering a comprehensive analysis of the entire HSPC pool nearly impossible. The Drosophila blood system is well studied and has developmental, molecular, and functional parallels with that of vertebrates. Unlike vertebrates, post-embryonic hematopoiesis in Drosophila is essentially restricted to the larval lymph gland (LG), a multi-lobed organ that flanks the dorsal vessel. Because the anterior-most or primary lobes of the LG are easy to dissect out, their cellular and molecular characteristics have been studied in considerable detail. The 2-3 pairs of posterior lobes are more delicate and fragile and have largely been ignored. However, posterior lobes harbor a significant blood progenitor pool, and several hematopoietic mutants show differences in phenotype between the anterior and posterior lobes. Hence, a comprehensive analysis of the LG is important for a thorough understanding of Drosophila hematopoiesis. Most studies focus on isolating the primary lobes by methods that generally dislodge and damage other lobes. To obtain preparations of the whole LG, including intact posterior lobes, here we provide a detailed protocol for larval fillet dissection. This allows accessing and analyzing complete LG lobes, along with dorsal vessel and pericardial cells. We demonstrate that tissue architecture and integrity is maintained and provide methods for quantitative analysis. This protocol can be used to quickly and effectively isolate complete LGs from first instar larval to pupal stages and can be implemented with ease.


Light to moderate alcohol consumption is associated with lower frequency of hypertransaminasemia.
The effect of light to moderate alcohol consumption on the liver is controversial. To determine the association between light to moderate alcohol consumption and frequency of hypertransaminasemia, a cross-sectional and a subsequent longitudinal cohort study were conducted using annual health checkup data at a Japanese workplace. We analyzed 1,177 male subjects (age 20-59) without HCV or HBV infection or other chronic liver diseases. To determine the association between alcohol consumption (none or minimal <70 g/wk, light > or =70 g and <140 g/wk, moderate > or =140 g and <280 g/wk, excessive > or =280 g/wk) and hypertransaminasemia, we performed multiple logistic regressions. We then followed 326 subjects without a history of fatty liver or hypertransaminasemia up to 5 years for incidental hypertransaminasemia and performed Cox proportional hazard regressions. Excess alcohol consumption was associated with increased odds of hypertransaminasemia (adjusted odds ratio [AOR]versus none or minimal consumption 1.4[1.1-1.93], P= 0.023). There was significant interaction between age group and alcohol consumption (P < 0.01). In the younger group, moderate consumption was associated with decreased odds (AOR 0.5 [0.3-0.9], P= 0.032), while in the older group, light consumption was associated with decreased odds (AOR 0.6 [0.4-1.0], P= 0.036) and excess consumption was associated with increased odds (AOR 1.6 [1.1-2.3], P= 0.014) of hypertransaminasemia. During follow-up, moderate consumption was associated with decreased incidence of hypertransaminasemia versus none or minimal consumption (adjusted hazard ratio 0.4 [0.1-0.9], P= 0.02). Light to moderate alcohol consumption may protect against the development of hypertransaminasemia among male subjects without other liver conditions. Further studies are required before recommending light to moderate alcohol consumption.


Critical elements determining diversity in agonist binding and desensitization of neuronal nicotinic acetylcholine receptors.
To identify the molecular determinants underlying the pharmacological diversity of neuronal nicotinic acetylcholine receptors, we compared the alpha7 homo-oligomeric and alpha4beta2 hetero-oligomeric receptors. Sets of residues from the regions initially identified within the agonist binding site of the alpha4 subunit were introduced into the alpha7 agonist binding site, carried by the homo-oligomeric alpha7-V201-5HT3 chimera. Introduction of the alpha4 residues 183-191 into alpha7 subunit sequence (chimera C2) selectively increased the apparent affinities for equilibrium binding and for ion channel activation by acetylcholine, resulting in a receptor that no longer displays differences in the responses to acetylcholine and nicotine. Introduction of the alpha4 residues 151-155 (chimera B) produced a approximately 100-fold increase in the apparent affinity for both acetylcholine and nicotine in equilibrium binding measurements. In both cases electrophysiological recordings revealed a much smaller increase (three- to sevenfold) in the apparent affinity for activation, but the concentrations required to desensitize the mutant chimeras parallel the shifts in apparent binding affinity. The data were fitted by a two-state concerted model, and an alteration of the conformational isomerization constant leading to the desensitized state accounts for the chimera B phenotype, whereas alteration of the ligand binding site accounts for the chimera C2 phenotype. Point mutation analysis revealed that several residues in both fragments contribute to the phenotypes, with a critical effect of the G152K and T183N mutations. Transfer of alpha4 amino acids 151-155 and 183-191 into the alpha7-V201-5HT3 chimera thus confers physiological and pharmacological properties typical of the alpha4beta2 receptor.


Ultrafine carbon black particles enhance respiratory syncytial virus-induced airway reactivity, pulmonary inflammation, and chemokine expression.
Exposure to particulate matter (PM) may exacerbate preexisting respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and pneumonia. However, few experimental studies have addressed the effects of PM on lower respiratory tract (LRT) viral infection. Respiratory syncytial virus (RSV) is a major etiological agent for LRT infections in infants, the elderly, and the immunocompromised and may lead to chronic wheezing and the development of asthma in children. In this study, we examined the effects of carbon black (CB) on RSV-induced pulmonary inflammation, chemokine and cytokine expression, and airway hyperresponsiveness in a mouse model of RSV. Female BALB/c mice were instilled via the trachea (i.t.) with 1 x 106 plaque forming units (pfu) RSV or with uninfected culture media. On day 3 of infection, mice were i.t. instilled with either 40 micro g ultrafine CB particles or with saline. End points were examined on days 4, 5, 7, and 14 of RSV infection. Viral titer and clearance in the lung were unaffected by CB exposure. Neutrophil numbers were elevated on days 4 and 7, and lymphocyte numbers were higher on days 4 and 14 of infection in CB-exposed, RSV-infected mice. CB exposure also enhanced RSV-induced airway hyperresponsiveness to methacholine, bronchoalveolar lavage (BAL) total protein, and virus-associated chemokines monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein (MIP-1 alpha), and regulated upon activation, normal T cell expressed and secreted (RANTES). MIP-1 alpha mRNA expression was increased in the alveolar epithelium, where ultrafine particles deposit in the lung. These data demonstrate a synergistic effect of ultrafine CB particles on RSV infection, and suggest a potential mechanism for increased respiratory infections in human populations after PM exposure.


Random modulation cw lidar using new random sequence.
New modulation codes are presented for a random modulation cw lidar. One characteristic of these modulation codes is that for very noisy background conditions, the signal-to-noise ratio is improved by using these new sequences, and is better than for the maximum-length sequence (the M-sequence) which is commonly used as the modulation code. Another characteristic of these modulation codes is that there is no correlation between them. This fact will be useful for the simultaneous multitransmitter of the differential absorption lidar. These two characteristics of the new modulation codes were confirmed experimentally.


Differential impact of unrecognised brain infarction on stroke outcome in non-valvular atrial fibrillation.
There has been little information regarding the impact of unrecognised brain infarctions (UBIs) on stroke outcome in patients with non-valvular atrial fibrillation (NVAF). By using volumetric analysis of ischaemic lesions, we evaluated the potential impact of UBIs on clinical outcome according to their presence and categorised type. This study enrolled 631 patients with NVAF having no clinical stroke history. UBIs were categorised into three types as territorial, lacunar, or subcortical. We collected stroke severity, functional outcome at three months, and the total volume of UBIs and acute infarction lesions. We investigated the association between clinical outcome and the type or volume of UBI, using a linear mixed model and logistic regression analysis. UBIs were detected in 285 (45.2 %) patients; territorial UBIs were observed in 24.4 % of patients (154/631), lacunar UBIs in 25 % (158/631), and subcortical UBIs in 15.7 % (99/631). Although initial stroke severity was not different between patients with UBIs and those without, those with UBIs had less improvement during hospitalisation, leading to poorer outcome at three months. Among the three types of UBIs, only territorial UBIs were associated with poor outcome, especially in patients with relatively smaller acute infarction volume. UBIs, in particular, territorial UBIs, may be considered as predictors for poor outcome after ischaemic stroke in patients with NVAF. Our results suggest that the impact of UBIs on clinical outcome differs according to the type of UBIs and the acute stroke severity.


Shortfall of exome analysis for diagnosis of Shwachman-Diamond syndrome: Mismapping due to the pseudogene SBDSP1.
Shwachman-Diamond syndrome characterized by metaphyseal dysplasia, pancreatic insufficiency, and pancytopenia is caused by biallelic mutations in SBDS. Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. Here, we report two unrelated patients with Shwachman-Diamond syndrome who were shown to be compound heterozygotes for relatively frequent pathogenic alleles (the 258+2T>C allele and another allele composed of 183-184TA>CT and 201A>G) using an established polymerase chain reaction sequencing assay with SBDS-specific primers. Exome analysis of the patients showed discrepant results: 258+2T>C with variant allele frequency around 0.85, and no variants detected for the 183-184TA>CT allele. Parental exome analysis of the two families further supported this notion. Confronted with two patients with an unexpected segregation pattern, we performed a transcriptome analysis of peripheral blood-derived mRNA to demonstrate that the results were compatible with those obtained using SBDS-specific PCR primers. Both alleles could be accounted for by gene conversion events. The diagnostic discrepancy can be accounted for by a decreased efficiency in the computational mapping of the reads with 183-184TA>CT and 201A>G to the reference sequence of the SBDS locus during exome analysis. This report highlights the pitfall of exome analysis for genes with pseudogenes, such as SBDS and the alternative use of RNA-seq is recommended to circumvent this problem.


The synthesis of cardenolide and bufadienolide aglycones, and related steroids bearing a heterocyclic subunit.
Covering: early studies through to March 2016Cardenolides and bufadienolides constitute an attractive class of biologically active steroid derivatives which have been used for the treatment of heart disease in traditional remedies as well as in modern medicinal therapy. Due to their application as therapeutic agents and their unique molecular structures, bearing unsaturated 5- or 6-membered lactones (or other heterocycles) attached to the steroid core, cardio-active steroids have received great attention, which has intensified during the last decade, in the synthetic organic community. Advances in the field of cross-coupling reactions have provided a powerful tool for the attachment of lactone subunits to the steroid core. This current review covers a methodological analysis of synthetic efforts to cardenolide and bufadienolide aglycones. Special emphasis is given to cross-coupling reactions applied for the attachment of lactone subunits at sterically very hindered positions of the steroid core. The carefully selected partial and total syntheses of representative cardio-active steroids will also be presented to exemplify recent achievements (improvements) in the field.


Giant ripples on comet 67P/Churyumov-Gerasimenko sculpted by sunset thermal wind.
Explaining the unexpected presence of dune-like patterns at the surface of the comet 67P/Churyumov-Gerasimenko requires conceptual and quantitative advances in the understanding of surface and outgassing processes. We show here that vapor flow emitted by the comet around its perihelion spreads laterally in a surface layer, due to the strong pressure difference between zones illuminated by sunlight and those in shadow. For such thermal winds to be dense enough to transport grains-10 times greater than previous estimates-outgassing must take place through a surface porous granular layer, and that layer must be composed of grains whose roughness lowers cohesion consistently with contact mechanics. The linear stability analysis of the problem, entirely tested against laboratory experiments, quantitatively predicts the emergence of bedforms in the observed wavelength range and their propagation at the scale of a comet revolution. Although generated by a rarefied atmosphere, they are paradoxically analogous to ripples emerging on granular beds submitted to viscous shear flows. This quantitative agreement shows that our understanding of the coupling between hydrodynamics and sediment transport is able to account for bedform emergence in extreme conditions and provides a reliable tool to predict the erosion and accretion processes controlling the evolution of small solar system bodies.


Recent developments of the in situ wet cell technology for transmission electron microscopies.
In situ wet cells for transmission electron microscopy (TEM) and scanning transmission electron microscopy (STEM) allow studying structures and processes in a liquid environment with high temporal and spatial resolutions, and have been attracting increasing research interests in many fields. In this review, we highlight the structural and functional developments of the wet cells for TEM and STEM. One of the key features of the wet cells is the sealing technique used to isolate the liquid sample from the TEM/STEM vacuum environments, thus the existing in situ wet cells are grouped by different sealing methods. In this study, the advantages and shortcomings of each type of in situ wet cells are discussed, the functional developments of different wet cells are presented, and the future trends of the wet cell technology are addressed. It is suggested that in the future the in situ wet cell TEM/STEM technology will have an increasing impact on frontier nanoscale research.


Melatonin secretion and non-specific immune responses are differentially expressed in corticotropin-dependent and corticotropin-independent Cushing's syndrome.
This study was done to clarify the relation between melatonin secretion and the hypothalamic-pituitary-adrenal axis. In this clinical study using a follow-up approach, we investigated the circadian melatonin secretion and immune parameters of patients with corticotropin-dependent (Cushing's disease) and corticotropin-independent Cushing's syndrome. Plasma hormone concentrations, interleukin 1-beta (IL-1beta) and total immunoglobulin E (IgE) were determined before surgical treatment and during remission of the syndrome 1 year later. Patients with Cushing's disease showed mean nocturnal and diurnal melatonin plasma values similar to those of healthy controls. Only the midday level of patients (taken at 12:00) was significantly higher in comparison to controls (35.44+/-19.5 pg/mL vs 17.14+/-3.58 pg/mL; P<0.05). In contrast, patients with corticotropin-independent Cushing's syndrome had significantly lower mean nocturnal and significantly higher mean diurnal melatonin levels (52.8+/-17.7 pg/mL and 59.2+/-28.7 pg/mL, respectively; P<0.05 and P<0.05) as compared with corresponding values for controls (101.4+/-43.1 pg/mL and 28.9+/-11.7 pg/mL, respectively). In the last group of patients, significantly higher mean IL1beta and plasma IgE concentrations (3.30+/-1.72 pg/mL and 527.8+/-474.0 IU/mL, respectively) were observed compared with controls (1.43+/-0.95 pg/mL and 35.7+/-32.1 IU/mL, respectively) (P<0.05). Remission of the hypercortisolism in these patients resulted in restoration of circadian melatonin secretion and significant reductions in plasma IL1beta and total IgE levels. Our results demonstrate a specific mode of melatonin secretion and different nonspecific immune responses in the 2 investigated forms of hypercortisolism, specifically, corticotropin-dependent and corticotropin-independent Cushing's syndrome.


Long-term outcomes after lower extremity trauma.
Previous studies have shown that over one-quarter of patients who were working before a severe lower extremity fracture had not returned to work by 12 months after injury. Disabilities also persisted in household management, recreation, and social interaction. The objective of this study was to determine whether recovery extended beyond 12 months. Three hundred nineteen patients who were previously working and were treated at three level I trauma centers for a severe lower extremity fracture were prospectively followed at 3, 6, and 12 months after injury. Patients were queried at each follow-up about their work status and completed the Sickness Impact Profile (SIP) at 6 and 12 months. The SIP is a widely used and well validated measure of general health status; it was used in this study to measure functional recovery across several domains of daily living. Patients who had not recovered by 12 months (i.e., 204 who were not working, working with limitations, or had limitations in performing other daily activities as measured by elevated scores on the SIP) were contacted again at 30 months and asked to complete an interview and the SIP. At 30 months, an estimated 82% of the study patients had returned to work (compared to 72% at 12 months). SIP scores improved only slightly from 6.4 at 12 months to 5.7 at 30 months. At 30 months, 64% of the patients had no disability (SIP scores less than 4), 17% had mild disability (SIP scores of 4 to 9), 12% had moderate disability (SIP scores of 10 to 19), and 7% had severe disability (SIP scores of 20 or higher). Although the majority of patients with persistent disabilities at 30 months had residual physical impairments at 12 months, the extent of impairment did not fully explain why some people had and had not recovered at 30 months after injury. The results confirm those of other studies that conclude that overall, outcomes after serious trauma are good when appropriate trauma and rehabilitation care are rendered. However, a minority of patients still report limitations at 30 months after injury, with one-fifth not returning to work.


Impaired Recent, but Preserved Remote, Autobiographical Memory in Pediatric Brain Tumor Patients.
Medulloblastomas, the most common malignant brain tumor in children, are typically treated with radiotherapy. Refinement of this treatment has greatly improved survival rates in this patient population. However, radiotherapy also profoundly affects the developing brain and is associated with reduced hippocampal volume and blunted hippocampal neurogenesis. Such hippocampal (as well as extrahippocampal) abnormalities likely contribute to cognitive impairments in this population. While several aspects of memory have been examined in this population, the impact of radiotherapy on autobiographical memory has not previously been evaluated. Here we evaluated autobiographical memory in male and female patients who received radiotherapy for posterior fossa tumors (PFTs), including medulloblastoma, during childhood. Using the Children's Autobiographical Interview, we retrospectively assessed episodic and nonepisodic details for events that either preceded (i.e., remote) or followed (i.e., recent) treatment. For post-treatment events, PFT patients reported fewer episodic details compared with control subjects. For pretreatment events, PFT patients reported equivalent episodic details compared with control subjects. In a range of conditions associated with reduced hippocampal volume (including medial temporal lobe amnesia, mild cognitive impairment, Alzheimer's disease, temporal lobe epilepsy, transient epileptic amnesia, frontal temporal dementia, traumatic brain injury, encephalitis, and aging), loss of episodic details (even in remote memories) accompanies hippocampal volume loss. It is therefore surprising that pretreatment episodic memories in PFT patients with reduced hippocampal volume are retained. We discuss these findings in light of the anterograde and retrograde impact on memory of experimentally suppressing hippocampal neurogenesis in rodents.SIGNIFICANCE STATEMENT Pediatric medulloblastoma survivors develop cognitive dysfunction following cranial radiotherapy treatment. We report that radiotherapy treatment impairs the ability to form new autobiographical memories, but spares preoperatively acquired autobiographical memories. Reductions in hippocampal volume and cortical volume in regions of the recollection network appear to contribute to this pattern of preserved preoperative, but impaired postoperative, memory. These findings have significant implications for understanding disrupted mnemonic processing in the medial temporal lobe memory system and in the broader recollection network, which are inadvertently affected by standard treatment methods for medulloblastoma tumors in children.


COVID-19 point-of-care testing in care homes: what are the lessons for policy and practice?
COVID-19 has devastated care homes. Point-of-care tests (POCTs), mainly using lateral flow devices (LFDs), have been deployed hurriedly without much consideration of their usability or impact on care workflow. Even after the pandemic, POCTs, particularly multiplex tests, may be an important control against spread of SARS-CoV-2 and other respiratory infections in care homes by enabling identification of cases. They should not, however, replace other infection control measures such as barrier methods and quarantine. Adherence to LFDs as implemented among care home staff is suboptimal. Other tests-such as point-of-care polymerase chain reaction and automated antigen tests-would also need to be accommodated into care home workflows to improve adherence. The up-front costs of POCTs are straightforward but additional costs, including staffing preparation and reporting processes and the impacts of false positive and negative tests on absence rates and infection days, are more complex and as yet unquantified. A detailed appraisal is needed as the future of testing in care homes is considered.


Antihypertensive effect of Nigella sativa seed extract in patients with mild hypertension.
Hypertension (HT) is a lifestyle-related disease and dietary modifications are effective for its management and prevention. We conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of treatment with an oral Nigella sativa (NS) seed extract supplement in patients with mild HT. Subjects were randomized into three groups: a placebo and two test groups that received 100 and 200 mg of NS extract twice a day. After 8 weeks, systolic blood pressure (SBP) values in both case groups were found to be significantly reduced when compared with the baseline values for each group. In addition, the decrease in SBP in the two case groups was statistically significant relative to the placebo group (P < 0.05-0.01). Meanwhile, diastolic blood pressure (DBP) values in the case groups were found to be significantly reduced from the baseline and a significant reduction was also observed in these groups (P < 0.01) when compared with the placebo group. In addition, extract administration reduced both SBP and DBP in a dose-dependent manner. Meanwhile, NS extract caused a significant decline in the level of total and low-density-lipoprotein (LDL)-cholesterol relative to baseline data. No complications caused by NS were observed. The results suggest that the daily use of NS seed extract for 2 months may have a blood pressure-lowering effect in patients with mild HT.


Cardiovascular risk perception in women: true unawareness or risk miscalculation?
Assessing the 'accuracy' of cardiovascular risk perception is a worthy scientific goal that may lead to targeted interventions aimed at improving risk communication and health outcomes. Current cardiovascular risk scores, however, have shown poor calibration when used in populations that differ temporally and/or geographically from the derivation sample, limiting their reliability as the reference standard for absolute risk. In addition, accurately assessing risk awareness is challenging, with few available validated tools for effectively accounting for the outcomes assessed (coronary heart disease vs. cardiovascular disease), the time span of prediction (10-year vs. lifetime risk), and concepts of absolute versus relative risk. In this context, assessing patient awareness of the role of age as the key, non-modifiable driver of absolute risk can be particularly challenging. This commentary will examine each of these issues, providing context for the interpretation of studies on 'discordance' between calculated and perceived cardiovascular risk, such as the one recently published by Oertelt-Prigione et al. Moreover, we explore alternative approaches aimed at overcoming those limitations, enhancing understanding of the factors and true magnitude associated with such discordance.


Polymorphisms in KCNQ1 are associated with gestational diabetes in a Korean population.
Recent genome-wide association studies in East Asians have identified polymorphisms in KCNQ1 as new type 2 diabetes risk variants. The aim of this study was to investigate whether variants in KCNQ1 are associated with development of gestational diabetes mellitus (GDM) and measures of oral glucose tolerance test (OGTT) at the time of diagnosis of GDM. Three candidate single nucleotide polymorphisms (rs2074196, rs2237892, and rs2237895) were genotyped in 869 Korean GDM women and 632 nondiabetic control subjects. Insulin resistance was estimated by homeostasis model assessment and pancreatic β-cell function by the insulinogenic index at 1 h. rs2074196 and rs2237892 were associated with the risk of GDM (OR 1.17, 95% CI 1.01-1.36, p = 0.039; OR 1.24, 95% CI 1.07-1.45, p = 0.0049). Furthermore, rs2237892 and rs2237895 were nominally associated with a decreased insulinogenic index at the time of GDM diagnosis (p = 0.025 and p = 0.037), whereas no association was observed with measures of insulin resistance. The single nucleotide polymorphisms in KCNQ1 showed a significant association with GDM in the Korean population. Although the mechanism is not yet clear, it could be possible that variants in KCNQ1 confer a risk for GDM by altering pancreatic β-cell function.


Anticoagulation: managing adverse events in patients receiving anticoagulation and perioperative care.
When patients present with major or life-threatening bleeding due to warfarin use, rapid reversal with coagulation factors and vitamin K often is warranted. Oral vitamin K should be administered if the international normalized ratio is greater than 10 with no evidence of bleeding, but its use is not recommended if international normalized ratios are between 4.5 and 10. The most important factor in the risk of hemorrhage is the intensity of warfarin therapy. Increasing the time in the therapeutic range results in lower rates of thrombosis and bleeding. There are no available specific reversal agents or pharmacologic antidotes for the new oral anticoagulants. Use of anticoagulation management services (eg, intervention using automated hospital information system-generated triggers from laboratory and pharmacy data) in the outpatient and inpatient settings can be considered to decrease the risk of complications for patients taking anticoagulants. Services that incorporate clear communication, evidence-based drug management, and patient education are important to ensure safe use of anticoagulants. Management of heparin-induced thrombocytopenia should include heparin discontinuation and initiation of a nonheparin anticoagulant.


The challenges of introducing routine G6PD testing into radical cure: a workshop report.
The only currently available drug that effectively removes malaria hypnozoites from the human host is primaquine. The use of 8-aminoquinolines is hampered by haemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Recently a number of qualitative and a quantitative rapid diagnostic test (RDT) format have been developed that provide an alternative to the current standard G6PD activity assays. The WHO has recently recommended routine testing of G6PD status prior to primaquine radical cure whenever possible. A workshop was held in the Philippines in early 2015 to discuss key challenges and knowledge gaps that hinder the introduction of routine G6PD testing. Two point-of-care (PoC) test formats for the measurement of G6PD activity are currently available: qualitative tests comparable to malaria RDT as well as biosensors that provide a quantitative reading. Qualitative G6PD PoC tests provide a binomial test result, are easy to use and some products are comparable in price to the widely used fluorescent spot test. Qualitative test results can accurately classify hemizygous males, heterozygous females, but may misclassify females with intermediate G6PD activity. Biosensors provide a more complex quantitative readout and are better suited to identify heterozygous females. While associated with higher costs per sample tested biosensors have the potential for broader use in other scenarios where knowledge of G6PD activity is relevant as well. The introduction of routine G6PD testing is associated with additional costs on top of routine treatment that will vary by setting and will need to be assessed prior to test introduction. Reliable G6PD PoC tests have the potential to play an essential role in future malaria elimination programmes, however require an improved understanding on how to best integrate routine G6PD testing into different health settings.


Nitrate and nitrite ingestion and risk of ovarian cancer among postmenopausal women in Iowa.
Nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds (NOC), potential human carcinogens. We evaluated the association of nitrate and nitrite ingestion with postmenopausal ovarian cancer risk in the Iowa Women's Health Study. Among 28,555 postmenopausal women, we identified 315 incident epithelial ovarian cancers from 1986 to 2010. Dietary nitrate and nitrite intakes were assessed at baseline using food frequency questionnaire data. Drinking water source at home was obtained in a 1989 follow-up survey. Nitrate-nitrogen (NO3 -N) and total trihalomethane (TTHM) levels for Iowa public water utilities were linked to residences and average levels were computed based on each woman's duration at the residence. We computed multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards regression. We tested interactions of nitrate with TTHMs and dietary factors known to influence NOC formation. Ovarian cancer risk was 2.03 times higher (CI = 1.22-3.38, ptrend = 0.003) in the highest quartile (≥2.98 mg/L) compared with the lowest quartile (≤0.47 mg/L; reference) of NO3 -N in public water, regardless of TTHM levels. Risk among private well users was also elevated (HR = 1.53, CI = 0.93-2.54) compared with the same reference group. Associations were stronger when vitamin C intake was <median (pinteraction = 0.01 and 0.33 for private well and public supplies, respectively). Dietary nitrate was inversely associated with ovarian cancer risk (ptrend = 0.02); whereas, dietary nitrite from processed meats was positively associated with the risk (ptrend = 0.04). Our findings indicate that high nitrate levels in public drinking water and private well use may increase ovarian cancer risk among postmenopausal women.


Explaining Visual Shape-Taste Crossmodal Correspondences.
A growing body of experimental research now demonstrates that neurologically normal individuals associate different taste qualities with design features such as curvature, symmetry, orientation, texture and movement. The form of everything from the food itself through to the curvature of the plateware on which it happens to be served, and from glassware to typeface, not to mention the shapes of/on food product packaging have all been shown to influence people's taste expectations, and, on occasion, also their taste/food experiences. Although the origins of shape-taste and other form-taste crossmodal correspondences have yet to be fully worked out, it would appear that shape qualities are occasionally elicited directly. However, more often, there may be a metaphorical attempt to translate the temporal qualities of taste sensations into a spatial analogue. At the same time, emotional mediation may sometimes also play a role in the affinity people experience between shape properties and taste. And finally, it should be acknowledged that associative learning of the relation between packaging shapes, glassware shapes, logos, labels and iconic food forms that commonly co-occur with specific taste properties (i.e., in the case of branded food products) may also play an important role in determining the nature of shape-taste correspondences. Ultimately, however, any attempt to use such shape-taste correspondences to nudge people's behaviour/perception in the real world is made challenging due to the fact that shape properties are associated with multiple qualities, and not just taste.


Posttraumatic stress and youth violence perpetration: A population-based cross-sectional study.
Exposure to trauma was found to increase later violent behaviours in youth but the underlying psychopathological mechanisms are unclear. This study aimed to test whether posttraumatic stress disorder (PTSD) is related to violent behaviours and whether PTSD symptoms mediate the relationship between the number of trauma experiences and violent behaviours in adolescents. The present study is based on a nationally representative sample of 9th grade students with 3434 boys (mean age=15.5 years) and 3194 girls (mean age=15.5 years) in Switzerland. Lifetime exposure to traumatic events and current PTSD were assessed by the use of the University of California at Los Angeles Posttraumatic Stress Disorder Reaction Index (UCLA-RI). Logistic regression was used to assess associations between PTSD and violent behaviours, and structural equation modelling (SEM) was used to examine the meditation effects of PTSD. PTSD (boys: OR=7.9; girls: OR=5.5) was strongly related to violent behaviours. PTSD symptoms partially mediated the association between trauma exposure and violent behaviours in boys but not in girls. PTSD symptoms of dysphoric arousal were positively related to violent behaviours in both genders. Anxious arousal symptoms were negatively related to violent behaviours in boys but not in girls. In addition to trauma, posttraumatic stress is related to violent outcomes. However, specific symptom clusters of PTSD seem differently related to violent behaviours and they do not fully explain a trauma-violence link. Specific interventions to improve emotion regulation skills may be useful particularly in boys with elevated PTSD dysphoric arousal in order to break up the cycle of violence.


Left ventricular assist device implantation with and without concomitant tricuspid valve surgery: a systematic review and meta-analysis.
Moderate-to-severe tricuspid regurgitation is common in end-stage heart disease and is associated with an impaired survival after left ventricular assist device (LVAD) surgery. Controversy remains whether concomitant tricuspid valve surgery (TVS) during LVAD implantation is beneficial. We aimed to provide a contemporary overview of outcomes in patients who underwent LVAD surgery with or without concomitant TVS. A systematic literature search was performed for articles published between January 2005 and March 2017. Studies comparing patients undergoing isolated LVAD implantation and LVAD + TVS were included. Early outcomes were pooled in risk ratios using random effects models, and late survival was visualized by a pooled Kaplan-Meier curve. Eight publications were included in the meta-analysis, including 562 undergoing isolated LVAD implantation and 303 patients with LVAD + TVS. Patients undergoing LVAD + TVS had a higher tricuspid regurgitation grade, central venous pressure and bilirubin levels at baseline and were more often female. We found no significant differences in early mortality and late mortality, early right ventricular failure and late right ventricular failure, acute kidney failure, early right ventricular assist device implantation or length of hospital stay. Cardiopulmonary bypass time was longer in patients undergoing additional TVS [mean difference +35 min 95% confidence interval (16-55), P = 0.001]. Adding TVS during LVAD implantation is not associated with worse outcome. Adding TVS, nevertheless, may be beneficial, as baseline characteristics of patients undergoing LVAD + TVS were suggestive of a more progressive underlying disease, but with comparable short-term outcome and long-term outcome with patients undergoing isolated LVAD.


Provider costs for prevention and treatment of cardiovascular and related conditions in low- and middle-income countries: a systematic review.
The burden of cardiovascular disease (CVD) and CVD risk conditions is rapidly increasing in low- and middle-income countries, where health systems are generally ill-equipped to manage chronic disease. Policy makers need an understanding of the magnitude and drivers of the costs of cardiovascular disease related conditions to make decisions on how to allocate limited health resources. We undertook a systematic review of the published literature on provider-incurred costs of treatment for cardiovascular diseases and risk conditions in low- and middle-income countries. Total costs of treatment were inflated to 2012 US dollars for comparability across geographic settings and time periods. This systematic review identified 60 articles and 143 unit costs for the following conditions: ischemic heart disease, non-ischemic heart diseases, stroke, heart failure, hypertension, diabetes, and chronic kidney disease. Cost data were most readily available in middle-income countries, especially China, India, Brazil, and South Africa. The most common conditions with cost studies were acute ischemic heart disease, type 2 diabetes mellitus, stroke, and hypertension. Emerging economies are currently providing a base of cost evidence for NCD treatment that may prove useful to policy-makers in low-income countries. Initial steps to publicly finance disease interventions should take account of costs. The gaps and limitations in the current literature include a lack of standardized reporting as well as sparse evidence from low-income countries.


Anastomotic Techniques and Associated Morbidity in Total Minimally Invasive Transthoracic Esophagectomy: Results From the EsoBenchmark Database.
The aim of this study was to describe anastomotic techniques used for total minimally invasive transthoracic esophagectomy (ttMIE) and to analyze the associated morbidity. ttMIE faces increasing application in surgical treatment of esophageal cancer. For esophagogastric reconstruction, different anastomotic techniques are currently used, but their effect on postoperative anastomotic leakage and morbidity has not been investigated. Patients were selected from a basic dataset, collected during a 5-year period from 13 international surgical high-volume centers. Endpoints were anastomotic leakage rate and postoperative morbidity in correlation to anastomotic techniques, measured by the Clavien-Dindo classification and the Comprehensive Complication Index (CCI). Five anastomotic techniques were identified in 966 patients after ttMIE: intrathoracic end-to-side circular-stapled technique in 427 patients (double-stapling n = 90, purse-string n = 337), intrathoracic (n = 109) or cervical (n = 255) side-to-side linear-stapled, and cervical end-to-side hand-sewn (n = 175). Leakage rates were similar in intrathoracic and cervical anastomoses (15.9% vs 17.2%, P = 0.601), but overall complications (56.7%% vs 63.7%, P = 0.029) and median 90-day CCI {21 [interquartile range (IQR) 0-36] vs 29 [IQR 0-40], P = 0.019} favored intrathoracic reconstructions. Leakage rates after intrathoracic end-to-side double-stapling (23.3%) and cervical end-to-side hand-sewn (25.1%) techniques were significantly higher compared with intrathoracic side-to-side linear (15.6%), end-to-side purse-string (13.9%), and cervical side-to-side linear-stapled esophagogastrostomies (11.8%) (P < 0.001). Multivariable analysis confirmed anastomotic technique as independent predictor of leakage after ttMIE. Results of this analysis present the current status of the technical evolution of ttMIE with anastomotic leakage as predominant surgical complication. However, technique-related morbidity requires cautious interpretation considering the long learning curve of this complex surgical procedure.