Structure of the PUB Domain from Ubiquitin Regulatory X Domain Protein 1 (UBXD1) and Its Interaction with the p97 AAA+ ATPase.
AAA+ ATPase p97/valosin-containing protein (VCP)/Cdc48 is a key player in various cellular stress responses in which it unfolds ubiquitinated proteins to facilitate their degradation by the proteasome. P97 works in different cellular processes using alternative sets of cofactors and is implicated in multiple degenerative diseases. Ubiquitin regulatory X domain protein 1 (UBXD1) has been linked to pathogenesis and is unique amongst p97 cofactors because it interacts with both termini of p97. Its N-domain binds to the N-domain and N/D1 interface of p97 and regulates its ATPase activity. The PUB (peptide:N-glycanase and UBA or UBX-containing proteins) domain binds the p97 C-terminus, but how it controls p97 function is still unknown. Here we present the NMR structure of UBXD1-PUB together with binding studies, mutational analysis, and a model of UBXD1-PUB in complex with the p97 C-terminus. While the binding pocket is conserved among PUB domains, UBXD1-PUB features a unique loop and turn regions suggesting a role in coordinating interaction with downstream regulators and substrate processing.


Deciphering key regulators involved in epilepsy-induced cardiac damage through whole transcriptome and proteome analysis in a rat model.
Sudden unexpected death in epilepsy (SUDEP) is a major outcome of cardiac dysfunction in patients with epilepsy. In continuation of our previous work, the present study was envisaged to explore the key regulators responsible for cardiac damage associated with chronic seizures using whole transcriptome and proteome analysis in a rat model of temporal lobe epilepsy. A standard lithium-pilocarpine protocol was used to induce recurrent seizures in rats. The isolated rat heart tissue was subjected to transcriptomic and proteomic analysis. An integrated approach of RNA-Seq, proteomics, and system biology analysis was used to identify key regulators involved in seizure-linked cardiac changes. The analyzed differential expression patterns and network interactions were supported by gene and protein expression studies. Altogether, 1157 differentially expressed genes and 1264 proteins were identified in the cardiac tissue of epileptic animals through RNA-Seq and liquid chromatography with tandem mass spectrometry-based proteomic analysis, respectively. The network analysis revealed seven critical genes-STAT3, Myc, Fos, Erbb2, Erbb3, Notch1, and Mapk8-that could play a role in seizure-mediated cardiac changes. The LC-MS/MS analysis supported the activation of the transforming growth factor β (TGF-β) pathway in the heart of epileptic animals. Furthermore, our gene and protein expression studies established a key role of STAT3, Erbb, and Mapk8 to develop cardiac changes linked with recurrent seizures. The present multi-omics study identified STAT3, Mapk8, and Erbb as key regulators involved in seizure-associated cardiac changes. It provided a deeper understanding of molecular, cellular, and network-level operations of the identified regulators that lead to cardiac changes in epilepsy.


Chromothripsis in healthy individuals affects multiple protein-coding genes and can result in severe congenital abnormalities in offspring.
Chromothripsis represents an extreme class of complex chromosome rearrangements (CCRs) with major effects on chromosomal architecture. Although recent studies have associated chromothripsis with congenital abnormalities, the incidence and pathogenic effects of this phenomenon require further investigation. Here, we analyzed the genomes of three families in which chromothripsis rearrangements were transmitted from a mother to her child. The chromothripsis in the mothers resulted in completely balanced rearrangements involving 8-23 breakpoint junctions across three to five chromosomes. Two mothers did not show any phenotypic abnormalities, although 3-13 protein-coding genes were affected by breakpoints. Unbalanced but stable transmission of a subset of the derivative chromosomes caused apparently de novo complex copy-number changes in two children. This resulted in gene-dosage changes, which are probably responsible for the severe congenital phenotypes of these two children. In contrast, the third child, who has a severe congenital disease, harbored all three chromothripsis chromosomes from his healthy mother, but one of the chromosomes acquired de novo rearrangements leading to copy-number changes. These results show that the human genome can tolerate extreme reshuffling of chromosomal architecture, including breakage of multiple protein-coding genes, without noticeable phenotypic effects. The presence of chromothripsis in healthy individuals affects reproduction and is expected to substantially increase the risk of miscarriages, abortions, and severe congenital disease.


Metal alloys in the oral cavity as a cause of oral discomfort in sensitive patients.
The occurrence of galvanism with its heterogeneous symptomatology is often the source of considerable problems. Abrasion and corrosion not only damage dental alloys but also burden the organism by release of metallic particles. The objective of this study is to evaluate the hypothesis that measurement of galvanic currents could be a useful diagnostic method. PATIENT GROUPS AND METHODOLOGY: Three hundred fifty-seven persons with dental metal restorations were divided into groups according to abnormal values of galvanic currents and by oral discomfort. In all persons a detailed examination of the oral cavity was performed, and galvanic currents were measured. In one hundred fifty-nine patients abnormal galvanic currents were found. Measurement of metallic elements in saliva was performed in these patients and in a group of 21 healthy volunteers without any metals in the oral cavity. Thirty-three patients agreed to treatment which involved removal of the causative alloys and their replacement by non-metallic restorations. No correlation was found between the values of measured currents and the number of teeth treated by metal restorations. However, patients with metal restorations had significantly higher contents not only of mercury, but also of tin, silver, copper, and gold in the saliva than patients without metallic restorations. After removal of the electro-active restorations, both the contents of metals in saliva and galvanic currents decreased in comparison with the levels before the treatment. Galvanic effects as well as metal particles may induce a series of local or systemic pathological phenomena in sensitive individuals. The occurrence of pathologically acting galvanic effects is influenced not only by the composition and combination of different dental alloys, but to a significant degree also by the quality of used materials and processing.


Detecting the unexpected: a research framework for ocean acidification.
The threat that ocean acidification (OA) poses to marine ecosystems is now recognized and U.S. funding agencies have designated specific funding for the study of OA. We present a research framework for studying OA that describes it as a biogeochemical event that impacts individual species and ecosystems in potentially unexpected ways. We draw upon specific lessons learned about ecosystem responses from research on acid rain, carbon dioxide enrichment in terrestrial plant communities, and nitrogen deposition. We further characterize the links between carbon chemistry changes and effects on individuals and ecosystems, and enumerate key hypotheses for testing. Finally, we quantify how U.S. research funding has been distributed among these linkages, concluding that there is an urgent need for research programs designed to anticipate how the effects of OA will reverberate throughout assemblages of species.


Functional random forest with applications in dose-response predictions.
Drug sensitivity prediction for individual tumors is a significant challenge in personalized medicine. Current modeling approaches consider prediction of a single metric of the drug response curve such as AUC or IC50. However, the single summary metric of a dose-response curve fails to provide the entire drug sensitivity profile which can be used to design the optimal dose for a patient. In this article, we assess the problem of predicting the complete dose-response curve based on genetic characterizations. We propose an enhancement to the popular ensemble-based Random Forests approach that can directly predict the entire functional profile of a dose-response curve rather than a single summary metric. We design functional regression trees with node costs modified based on dose/response region dependence methodologies and response distribution based approaches. Our results relative to large pharmacological databases such as CCLE and GDSC show a higher accuracy in predicting dose-response curves of the proposed functional framework in contrast to univariate or multivariate Random Forest predicting sensitivities at different dose levels. Furthermore, we also considered the problem of predicting functional responses from functional predictors i.e., estimating the dose-response curves with a model built on dose-dependent expression data. The superior performance of Functional Random Forest using functional data as compared to existing approaches have been shown using the HMS-LINCS dataset. In summary, Functional Random Forest presents an enhanced predictive modeling framework to predict the entire functional response profile considering both static and functional predictors instead of predicting the summary metrics of the response curves.


[Using the MMSE as a cognitive screener among Turkish and Moroccan migrants].
The Dutch population of first generation Turkish and Moroccan migrants is ageing. Among them hypertension and diabetes mellitus are frequent findings, which will probably cause an increased incidence of dementia. The language barrier, low education and cultural differences make the diagnosis more difficult. To what extent the MMSE can be used as a cognitive screener in this population will be investigated in this retrospective study.Patients received standard diagnostics, a professional translator addressed the language barrier. Correspondence was scored on characteristics of dementia, a procedure was used to diagnose without including the MMSE score. The optimal cut-off was calculated with the Youden Index and Area under the ROC (AUROC).106 patients were included, 61% had no education. Average MMSE-score was 16, with dementia 12, without 19. The AUROC was 0.85, optimal cut-off was 18 with a Youden index of 0.61.By using a professional translator the MMSE can possibly be used as a cognitive screener in this population. However, the cognitive skills addressed by the MMSE require an education and language skills. Developing a test that is independent of education and language barrier will probably be better.


Prognostic significance of molecular upstaging of paraffin-embedded sentinel lymph nodes in melanoma patients.
Detection of micrometastases in sentinel lymph nodes (SLNs) is important for accurate staging and prognosis in melanoma patients. However, a significant number of patients with histopathology-negative SLNs subsequently develop recurrent disease. We hypothesized that a quantitative realtime reverse transcriptase polymerase chain reaction (qRT) assay using multiple specific mRNA markers could detect occult metastasis in paraffin-embedded (PE) SLNs to upstage and predict disease outcome. qRT was performed on retrospectively collected PE SLNs from 215 clinically node-negative patients who underwent lymphatic mapping and sentinel lymphadenectomy for melanoma and were followed up for at least 8 years. PE SLNs (n = 308) from these patients were sectioned and assessed by qRT for mRNA of four melanoma-associated genes: MART-1 (antigen recognized by T cells-1), MAGE-A3 (melanoma antigen gene-A3 family), GalNAc-T (beta1-->4-N-acetylgalactosaminyl-transferase), and Pax3 (paired-box homeotic gene transcription factor 3). Fifty-three (25%) patients had histopathology-positive SLNs by hemotoxylin and eosin and/or immunohistochemistry. Of the 162 patients with histopathology-negative SLNs, 48 (30%) had nodes that expressed at least one of the four qRT markers, and these 48 patients also had a significantly increased risk of disease recurrence by a Cox proportional hazards model analysis (P <.0001; risk ratio, 7.48; 95% CI, 3.70 to 15.15). The presence of > or = one marker in histopathology-negative SLNs was also a significant independent prognostic factor by multivariate analysis for overall survival (P =.0002; risk ratio, 11.42; 95% CI, 3.17 to 41.1). Molecular upstaging of PE histopathology-negative SLNs by multiple-marker qRT assay is a significant independent prognostic factor for long-term disease recurrence and overall survival of patients with early-stage melanoma.


Effects of repeated swine building exposures on normal naive subjects.
Exposure to swine confinement buildings has a negative impact on respiratory health. A short exposure to this environment results in an acute airway inflammatory response. The present study was performed to confirm and further define the acute effects of working in a swine building, and to determine whether these effects are reproducible. Seven previously nonexposed normal subjects underwent evaluations that included hourly measurement of forced expiratory volume in one second (FEV1), methacholine challenge (the provocative concentration producing a 20% fall in FEV1 (PC20)), bronchoalveolar lavage (BAL), nasal lavage (NL), and blood analyses, before (control) and after each of two 5 h exposures to a swine building environment. The exposures were conducted 8 days apart. The levels of total dust, endotoxins, and ammonia (NH3) in the confinement building were measured on each day of exposure. Both exposures resulted in a significant reduction in FEV1 (mean+/-SEM change in FEV1: control = 7+/-2%; exposure 1 = 15+/-3%; exposure 2 = 23+/-3%), decrease in PC20 (median value (25th-75th percentile): 223 (23-256), 20 (15-198) and 20 (11-71), respectively; p=0.05) and increase in BAL cells (129+/-20, 451+/-43 and 511+/-103x10(3) cells x mL(-1), respectively) and NL cells (6+/-4, 126+/-58 and 103+/-26x10(3) cells x mL(-1), respectively), mostly neutrophils. Levels of interleukin-8 (IL-8), but not interleukin-1 (IL-1) or tumour necrosis factors (TNF-alpha), increased both in BAL and nasal fluids with exposure. In normal naive subjects, repeated exposure to the environment of a swine building induced a marked and reproducible reduction in forced expiratory volume in one second, increase in airway responsiveness, and increased neutrophilic inflammatory response. These results could not be accounted for by any of the environmental factors measured.


Sparc: a sparsity-based consensus algorithm for long erroneous sequencing reads.
Motivation. The third generation sequencing (3GS) technology generates long sequences of thousands of bases. However, its current error rates are estimated in the range of 15-40%, significantly higher than those of the prevalent next generation sequencing (NGS) technologies (less than 1%). Fundamental bioinformatics tasks such as de novo genome assembly and variant calling require high-quality sequences that need to be extracted from these long but erroneous 3GS sequences. Results. We describe a versatile and efficient linear complexity consensus algorithm Sparc to facilitate de novo genome assembly. Sparc builds a sparse k-mer graph using a collection of sequences from a targeted genomic region. The heaviest path which approximates the most likely genome sequence is searched through a sparsity-induced reweighted graph as the consensus sequence. Sparc supports using NGS and 3GS data together, which leads to significant improvements in both cost efficiency and computational efficiency. Experiments with Sparc show that our algorithm can efficiently provide high-quality consensus sequences using both PacBio and Oxford Nanopore sequencing technologies. With only 30× PacBio data, Sparc can reach a consensus with error rate <0.5%. With the more challenging Oxford Nanopore data, Sparc can also achieve similar error rate when combined with NGS data. Compared with the existing approaches, Sparc calculates the consensus with higher accuracy, and uses approximately 80% less memory and time. Availability. The source code is available for download at https://github.com/yechengxi/Sparc.


[The Role of Palliative Radiotherapy in Bleeding from Locally Advanced Gastrointestinal Tumors].
Patients with locally advanced gastrointestinal tumors present with typical symptoms including pain, obstructive problems with passage disorders and bleeding. The last of them negatively affects their quality of life and is potentially lethal. Palliative radiotherapy is used in hemostatic indication to control bleeding from locally advanced or recurrent inoperable gastrointestinal tumors for many years. This review summarizes information and available literature about mechanisms, efficiency and toxicity of palliative radiotherapy used in hemostatic indication, separately for each part of the digestive system. Although most of the published studies are retrospective, all of them show fast, effective and technically safe control of bleeding with minimal risk of toxicity and show an improvement of quality of life. Hypofractionated radiotherapy, with a smaller number of high doses, seems to be the appropriate palliative fractionation schedule. The higher daily dose is associated with faster initiation of hemostatic effect, while few radiotherapy treatment sessions are comfortable for patients; both of them meet the basic principles of state-of-the-art palliative care. In addition to external beam radiotherapy, high dose rate brachytherapy represents another possibility in this indication, especially for locally advanced inoperable anal and rectal cancer. Brachytherapy is simple, practical and most importantly a one-time procedure with high local effect without significant toxicity. Radiotherapy is an important treatment possibility for palliative care of bleeding from locally advanced inoperable gastrointestinal cancers. Future prospective studies employing modern radiotherapeutic techniques and procedures are needed to provide consistent and clear evidence in order to weigh risks against benefits of palliative hemostatic radiotherapy in current daily clinical practice.Key words: locally advanced gastrointestinal tumors - bleeding - palliative radiotherapy The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 8. 5. 2017Accepted: 23. 7. 2017.


Functional mapping of SPARC: peptides from two distinct Ca+(+)-binding sites modulate cell shape.
Using synthetic peptides, we have identified two distinct regions of the glycoprotein SPARC (Secreted Protein Acidic and Rich in Cysteine) (osteonectin/BM-40) that inhibit cell spreading. One of these sites also contributes to the affinity of SPARC for extracellular matrix components. Peptides representing subregions of SPARC were synthesized and antipeptide antibodies were produced. Immunoglobulin fractions of sera recognizing an NH2-terminal peptide (designated 1.1) blocked SPARC-mediated anti-spreading activity. Furthermore, when peptides were added to newly plated endothelial cells or fibroblasts, peptide 1.1 and a peptide corresponding to the COOH terminal EF-hand domain (designated 4.2) inhibited cell spreading in a dose-dependent manner. These peptides exhibited anti-spreading activity at concentrations from 0.1 to 1 mM. The ability of peptides 1.1 and 4.2 to modulate cell shape was augmented by an inhibitor of protein synthesis and was blocked by specific antipeptide immunoglobulins. In addition to blocking cell spreading, peptide 4.2 competed for binding of [125I]SPARC and exhibited differential affinity for extracellular matrix molecules in solid-phase binding assays. The binding of peptide 4.2 to matrix components was Ca+(+)-dependent and displayed specificities similar to those of native SPARC. These studies demonstrate that both anti-spreading activity and affinity for collagens are functions of unique regions within the SPARC amino acid sequence. The finding that two separate regions of the SPARC protein contribute to its anti-spreading activity lead us to propose that multiple regions of the protein act in concert to regulate the interactions of cells with their extracellular matrix.


Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, acinar cell damage, and systemic inflammation in acute pancreatitis.
In acute pancreatitis, endoplasmic reticulum (ER) stress prompts an accumulation of malfolded proteins inside the ER, initiating the unfolded protein response (UPR). Because the ER chaperone tauroursodeoxycholic acid (TUDCA) is known to inhibit the UPR in vitro, this study examined the in vivo effects of TUDCA in an acute experimental pancreatitis model. Acute pancreatitis was induced in Wistar rats using caerulein, with or without prior TUDCA treatment. UPR components were analyzed, including chaperone binding protein (BiP), phosphorylated protein kinase-like ER kinase (pPERK), X-box binding protein (XBP)-1, phosphorylated c-Jun NH(2)-terminal kinase (pJNK), CCAAT/enhancer binding protein homologues protein, and caspase 12 and 3 activation. In addition, pancreatitis biomarkers were measured, such as serum amylase, trypsin activation, edema formation, histology, and the inflammatory reaction in pancreatic and lung tissue. TUDCA treatment reduced intracellular trypsin activation, edema formation, and cell damage, while leaving amylase levels unaltered. The activation of myeloperoxidase was clearly reduced in pancreas and lung. Furthermore, TUDCA prevented caerulein-induced BiP upregulation, reduced XBP-1 splicing, and caspase 12 and 3 activation. It accelerated the downregulation of pJNK. In controls without pancreatitis, TUDCA showed cytoprotective effects including pPERK signaling and activation of downstream targets. We concluded that ER stress responses activated in acute pancreatitis are grossly attenuated by TUDCA. The chaperone reduced the UPR and inhibited ER stress-associated proapoptotic pathways. TUDCA has a cytoprotective potential in the exocrine pancreas. These data hint at new perspectives for an employment of chemical chaperones, such as TUDCA, in prevention of acute pancreatitis.


Architecture and fiber type of the pyramidalis muscle.
The paired pyramidalis muscles are small triangular-shaped muscles that lie between the anterior surface of the rectus abdominus and the posterior surface of the rectus sheath. The precise function of pyramidalis muscles is unclear, but together the muscles are thought to tense the linea alba. The muscles are not always present, or are often unilateral, and vary greatly in size. Their wider inferior margins attach to the pubic symphyses and pubic crests, whereas their narrow superior margins attach to the linea alba. The gross anatomy and innervation of the pyramidalis muscles has been described by others, but their architecture and fiber type have not been determined in previous publications. The purpose of the present paper was therefore to investigate these parameters and place the findings into context for the literature available on this muscle. An example of bilateral pyramidalis muscles was recently encountered in a male cadaver that provided ample tissue for an analysis of its architecture and fiber type. The muscle mass, muscle length, fiber length, and pennation angle of muscle fibers were measured to ascertain physiological cross-sectional area and thereby estimate force production. Fiber type composition was also examined using immunofluorescent labeling. The results show that this is a muscle of mixed fiber type composition, similar to the rectus abdominus, and that the estimated forces generated by this muscle are relatively small.


Erythrocyte sodium/lithium countertransport and renal lithium clearance in a random sample of untreated middle-aged men.
1. It has been proposed that the enhanced erythrocyte Na+/Li+ countertransport observed in many patients with essential hypertension could be a marker of abnormal renal proximal tubular function. We thus investigated the relationship of blood pressure and Na+/Li+ countertransport to an index of proximal tubular function such as renal Li+ clearance. 2. The study was carried out in a sample of 299 untreated male subjects (aged 21-59 years) randomly selected from a population at work. Na+/Li+ countertransport was measured in a representative sub-group of 176 men. 3. We did not detect statistically significant correlation of either blood pressure or Na+/Li+ countertransport (Vmax) with fractional excretion of Li+, while confirming the existence of a significant continuous association of blood pressure and body mass index with Na+/Li+ countertransport (P less than 0.01). 4. A sub-sample of 57 participants belonging to the lowest or the highest quintiles of Na+/Li+ countertransport distribution repeated the Li+ clearance study after moderate Na+ restriction. 5. Although fractional excretions of Na+ and Li+ were reduced on the low Na+ diet (both P less than 0.001), they did not differ significantly between groups. 6. Our results are at variance with the findings of a recent case-control study in a young age group and suggest that further studies are necessary before a conclusion can be drawn as to the suitability of Na+/Li+ countertransport as a marker of Na+ reabsorption in the renal proximal tubule.


Plug-and-play inference for disease dynamics: measles in large and small populations as a case study.
Statistical inference for mechanistic models of partially observed dynamic systems is an active area of research. Most existing inference methods place substantial restrictions upon the form of models that can be fitted and hence upon the nature of the scientific hypotheses that can be entertained and the data that can be used to evaluate them. In contrast, the so-called plug-and-play methods require only simulations from a model and are thus free of such restrictions. We show the utility of the plug-and-play approach in the context of an investigation of measles transmission dynamics. Our novel methodology enables us to ask and answer questions that previous analyses have been unable to address. Specifically, we demonstrate that plug-and-play methods permit the development of a modelling and inference framework applicable to data from both large and small populations. We thereby obtain novel insights into the nature of heterogeneity in mixing and comment on the importance of including extra-demographic stochasticity as a means of dealing with environmental stochasticity and model misspecification. Our approach is readily applicable to many other epidemiological and ecological systems.


Test-retest reliability of a lifetime drug use questionnaire.
By adopting the investigational principle of the Lifetime Drinking History (LDH) interview, we developed a Lifetime Drug Use (LDU) Questionnaire to assess the amount and frequency of lifetime drug consumption. The Pearson Correlation Coefficients for test-retest reliability, investigated in a sample of N=47 residents of a drug rehabilitation center and averaged over the investigated seven drug categories, were r=.95 for the abstinence-corrected total duration of regular use, r=.89 for the mean number of consumption days per month of regular use, r=.89 for the mean daily amount, r=.83 for the variability in consumption days per month of regular use, and r=.75 for month variability in daily amount. Applicability and further research needs are discussed.


Evaluation of the Rapidec Carba NP Test for Detection of Carbapenemases in Enterobacteriaceae.
This study evaluated the performance of the Rapidec Carba NP test, which was introduced recently into the market for the detection of carbapenemase production in a broad spectrum of β-lactamase-producing Enterobacteriaceae clinical isolates. In total, 252 clinical Enterobacteriaceae isolates that had been genetically characterized with respect to carbapenemase, extended-spectrum β-lactamase (ESBL), and AmpC genes were analyzed; 51/252 isolates (20.2%) were genetically confirmed to be carbapenemase producers, whereas 201/252 isolates (79.8%) were genetically negative for the presence of carbapenemase genes. The Rapidec Carba NP test was applied according to the manufacturer's instructions, and results were read after 30 and 120 min of incubation. The overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Rapidec Carba NP test were 90.2%, 100%, 100%, and 97.6%, respectively, when the manufacturer's instructions were followed. Four of 5 false-negative results occurred with OXA-48-like enzymes. After an incubation time of 30 min, the sensitivity was 49%. The sensitivity increased to 100% when the recommended bacterial inoculum was doubled and the test was read strictly after 120 min of incubation. The Rapidec Carba NP test is a useful tool for the reliable confirmation of carbapenemase-producing Enterobacteriaceae isolates. The test should be read strictly after 120 min of incubation and the inoculum should be larger than recommended by the manufacturer.


Do Not Divide Count Data with Count Data; A Story from Pollination Ecology with Implications Beyond.
Studies in ecology are often describing observed variations in a certain ecological phenomenon by use of environmental explanatory variables. A common problem is that the numerical nature of the ecological phenomenon does not always fit the assumptions underlying traditional statistical tests. A text book example comes from pollination ecology where flower visits are normally reported as frequencies; number of visits per flower per unit time. Using visitation frequencies in statistical analyses comes with two major caveats: the lack of knowledge on its error distribution and that it does not include all information found in the data; 10 flower visits in 20 flowers is treated the same as recording 100 visits in 200 flowers. We simulated datasets with various "flower visitation distributions" over various numbers of flowers observed (exposure) and with different types of effects inducing variation in the data. The different datasets were then analyzed first with the traditional approach using number of visits per flower and then by using count data models. The analysis of count data gave a much better chance of detecting effects than the traditionally used frequency approach. We conclude that if the data structure, statistical analyses and interpretations of results are mixed up, valuable information can be lost.


Rapid Red Sea Deep Water renewals caused by volcanic eruptions and the North Atlantic Oscillation.
The Red Sea hosts a deep marine environment unique among the world's oceans. It is occupied, almost homogeneously from the subsurface (~137 to 300 m) to depths over 2000 m, by a warm (~21.5°C) and highly saline (~40.5) water mass, referred to as the Red Sea Deep Water (RSDW). Previous studies suggested that the RSDW is mainly ventilated, continuously or intermittently, by dense outflows from the northern Gulfs of Suez and Aqaba with a resulting sluggish renewal time on the order of 36 to 90 years. We use six repeated hydrographic observations spanning the period 1982-2011 and simulations of an ocean general circulation model with realistic atmospheric forcing to show that large portions of the RSDW were episodically replaced during 1982-2001 by new dense waters mainly formed by open-ocean deep convections in the northern Red Sea during anomalously cold winters, pointing to a much shorter renewal time for the RSDW on the order of a decade. We further show that the winter cooling anomaly in the Red Sea region was a part of a large-scale climate variability pattern associated with either large volcanic eruptions or the North Atlantic Oscillation (NAO). Consequently, significant deep water formation events occurred in the Red Sea in the winters following the 1982 El Chichón eruption in Mexico and the 1991 Mount Pinatubo eruption in the Philippines and during the strong positive phase of the NAO in the winter of 1989.


Modulation of endogenous VEGF-A expression under hypoxia by using artificial transcription factors.
The vascular endothelial growth factor A (VEGF-A) gene is an attractive therapeutic target because both activation and repression of the gene are useful for treatment or cure of many diseases related to abnormal angiogenesis. To modulate the endogenous gene expression artificially, we previously designed a six-finger AZP to recognize a 19-bp DNA in the VEGF-A gene, and fused the AZP with a nuclear localization signal and a repressor domain to generate an artificial transcription factor (ATF). Using the ATF, we demonstrated efficient modulation of the VEGF-A expression. In the present study, we evaluate the ability of the ATF to modulate the gene expression under hypoxic conditions. Enzyme-linked immunosorbent assays (ELISA) for VEGF-A protein in the culture medium revealed that the gene-delivered ATF also repressed the expression of the endogenous VEGF-A gene under hypoxia.


Neuropsychological correlates of decision-making in ambiguous and risky situations.
Decision-making situations in real life differ regarding their explicitness of positive and negative consequences as well as regarding the directness of probabilities for reward and punishment. In neuropsychological research, decisions under ambiguity and decisions under risk are differentiated. To assess decisions under ambiguity the Iowa Gambling Task (IGT) is one of the most frequently used tasks. Decisions under risk can be measured by a task that offers explicit rules for gains and losses and stable winning probabilities, as the Game of Dice Task (GDT) does. In this contribution we firstly summarize studies that investigated decision-making in various groups of patients using the IGT or the GDT. We also propose a new model of decision-making in risky situations and describe differences between decisions under ambiguity and decisions under risk from a theoretical and clinical perspective.


Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma.
Cell surface expression levels of GPRC5D, an orphan G protein-coupled receptor, are significantly higher on multiple myeloma (MM) cells, compared with normal plasma cells or other immune cells, which renders it a promising target for immunotherapeutic strategies. The novel GPRC5D-targeting T-cell redirecting bispecific antibody, talquetamab, effectively kills GPRC5D+ MM cell lines in the presence of T cells from both healthy donors or heavily pretreated MM patients. In addition, talquetamab has potent anti-MM activity in bone marrow (BM) samples from 45 patients, including those with high-risk cytogenetic aberrations. There was no difference in talquetamab-mediated killing of MM cells from newly diagnosed, daratumumab-naïve relapsed/refractory (median of 3 prior therapies), and daratumumab-refractory (median of 6 prior therapies) MM patients. Tumor cell lysis was accompanied by T-cell activation and degranulation, as well as production of pro-inflammatory cytokines. High levels of GPRC5D and high effector:target ratio were associated with improved talquetamab-mediated lysis of MM cells, whereas an increased proportion of T cells expressing PD-1 or HLA-DR, and elevated regulatory T-cell (Treg) counts were associated with suboptimal killing. In cell line experiments, addition of Tregs to effector cells decreased MM cell lysis. Direct contact with bone marrow stromal cells also impaired the efficacy of talquetamab. Combination therapy with daratumumab or pomalidomide enhanced talquetamab-mediated lysis of primary MM cells in an additive fashion. In conclusion, we show that the GPRC5D-targeting T-cell redirecting bispecific antibody talquetamab is a promising novel antimyeloma agent. These results provide the preclinical rationale for ongoing studies with talquetamab in relapsed/refractory MM.


Conditional ablation of Pten in osteoprogenitors stimulates FGF signaling.
Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a direct antagonist of phosphatidylinositol 3 kinase. Pten is a well recognized tumor suppressor and is one of the most commonly mutated genes in human malignancies. More recent studies of development and stem cell behavior have shown that PTEN regulates the growth and differentiation of progenitor cells. Significantly, PTEN is found in osteoprogenitor cells that give rise to bone-forming osteoblasts; however, the role of PTEN in bone development is incompletely understood. To define how PTEN functions in osteoprogenitors during bone development, we conditionally deleted Pten in mice using the cre-deleter strain Dermo1cre, which targets undifferentiated mesenchyme destined to form bone. Deletion of Pten in osteoprogenitor cells led to increased numbers of osteoblasts and expanded bone matrix. Significantly, osteoblast development and synthesis of osteoid in the nascent bone collar was uncoupled from the usual tight linkage to chondrocyte differentiation in the epiphyseal growth plate. The expansion of osteoblasts and osteoprogenitors was found to be due to augmented FGF signaling as evidenced by (1) increased expression of FGF18, a potent osteoblast mitogen, and (2) decreased expression of SPRY2, a repressor of FGF signaling. The differentiation of osteoblasts was autonomous from the growth plate chondrocytes and was correlated with an increase in the protein levels of GLI2, a transcription factor that is a major mediator of hedgehog signaling. We provide evidence that increased GLI2 activity is also a consequence of increased FGF signaling through downstream events requiring mitogen-activated protein kinases. To test whether FGF signaling is required for the effects of Pten deletion, we deleted one allele of fibroblast growth factor receptor 2 (FGFR2). Significantly, deletion of FGFR2 caused a partial rescue of the Pten-null phenotype. This study identifies activated FGF signaling as the major mediator of Pten deletion in osteoprogenitors.


Novel CineECG Derived From Standard 12-Lead ECG Enables Right Ventricle Outflow Tract Localization of Electrical Substrate in Patients With Brugada Syndrome.
In Brugada syndrome (BrS), diagnosed in presence of a spontaneous or ajmaline-induced type-1 pattern, ventricular arrhythmias originate from the right ventricle outflow tract (RVOT). We developed a novel CineECG method, obtained by inverse electrocardiogram (ECG) from standard 12-lead ECG, to localize the electrical activity pathway in patients with BrS. The CineECG enabled the temporospatial localization of the ECG waveforms, deriving the mean temporospatial isochrone from standard 12-lead ECG. The study sample included (1) 15 patients with spontaneous type-1 Brugada pattern, and (2) 18 patients with ajmaline-induced BrS (at baseline and after ajmaline), in whom epicardial potential duration maps were available; (3) 17 type-3 BrS pattern patients not showing type-1 BrS pattern after ajmaline (ajmaline-negative); (4) 47 normal subjects; (5) 18 patients with right bundle branch block (RBBB). According to CineECG algorithm, each ECG was classified as Normal, Brugada, RBBB, or Undetermined. In patients with spontaneous or ajmaline-induced BrS, CineECG localized the terminal mean temporospatial isochrone forces in the RVOT, congruent with the arrhythmogenic substrate location detected by epicardial potential duration maps. The RVOT location was never observed in normal, RBBB, or ajmaline-negative patients. In most patients with ajmaline-induced BrS (78%), the RVOT location was already evident at baseline. The CineECG classified all normal subjects and ajmaline-negative patients at baseline as Normal or Undetermined, all patients with RBBB as RBBB, whereas all patients with spontaneous and ajmaline-induced BrS as Brugada. Compared with standard 12-lead ECG, CineECG at baseline had a 100% positive predictive value and 81% negative predictive value in predicting ajmaline test results. In patients with spontaneous and ajmaline-induced BrS, the CineECG localized the late QRS activity in the RVOT, a phenomenon never observed in normal, RBBB, or ajmaline-negative patients. The possibility to identify the RVOT as the location of the arrhythmogenic substrate by the noninvasive CineECG, based on the standard 12-lead ECG, opens new prospective for diagnosing patients with BrS.


Copper-doxorubicin as a nanoparticle cargo retains efficacy with minimal toxicity.
Repeated administration of chemotherapeutics is typically required for the effective treatment of highly aggressive tumors and often results in systemic toxicity. We have created a copper-doxorubicin complex within the core of liposomes and applied the resulting particle in multidose therapy. Copper and doxorubicin concentrations in the blood pool were similar at 24 h (∼40% of the injected dose), indicating stable circulation of the complex. Highly quenched doxorubicin fluorescence remained in the blood pool over tens of hours, with fluorescence increasing only with the combination of liposome disruption and copper trans-chelation. At 48 h after injection, doxorubicin fluorescence within the heart and skin was one-fifth and one-half, respectively, of fluorescence observed with ammonium sulfate-loaded doxorubicin liposomes. After 28 days of twice per week doxorubicin administration of 6 mg/kg, systemic toxicity (cardiac hypertrophy and weight and hair loss) was not detected with the copper-doxorubicin liposomes but was substantial with ammonium sulfate-loaded doxorubicin liposomes. We then incorporated two strategies designed to enhance efficacy, mTOR inhibition (rapamycin) to slow proliferation and therapeutic ultrasound to enhance accumulation and local diffusion. Tumor accumulation was ∼10% ID/g and was enhanced approximately 2-fold with the addition of therapeutic ultrasound. After the 28-day course of therapy, syngeneic tumors regressed to a premalignant phenotype of ∼(1 mm)(3) or could not be detected.


Variety in vegetable and fruit consumption and the risk of gastric and esophageal cancer in the European Prospective Investigation into Cancer and Nutrition.
Diets high in vegetables and fruits have been suggested to be inversely associated with risk of gastric cancer. However, the evidence of the effect of variety of consumption is limited. We therefore investigated whether consumption of a variety of vegetables and fruit is associated with gastric and esophageal cancer in the European Prospective Investigation into Cancer and Nutrition study. Data on food consumption and follow-up on cancer incidence were available for 452,269 participants from 10 European countries. After a mean follow-up of 8.4 years, 475 cases of gastric and esophageal adenocarcinomas (180 noncardia, 185 cardia, gastric esophageal junction and esophagus, 110 not specified) and 98 esophageal squamous cell carcinomas were observed. Diet Diversity Scores were used to quantify the variety in vegetable and fruit consumption. We used multivariable Cox proportional hazard models to calculate risk ratios. Independent from quantity of consumption, variety in the consumption of vegetables and fruit combined and of fruit consumption alone were statistically significantly inversely associated with the risk of esophageal squamous cell carcinoma (continuous hazard ratio per 2 products increment 0.88; 95% CI 0.79-0.97 and 0.76; 95% CI 0.62-0.94, respectively) with the latter particularly seen in ever smokers. Variety in vegetable and/or fruit consumption was not associated with risk of gastric and esophageal adenocarcinomas. Independent from quantity of consumption, more variety in vegetable and fruit consumption combined and in fruit consumption alone may decrease the risk of esophageal squamous cell carcinoma. However, residual confounding by lifestyle factors cannot be excluded.


Primate motor cortex and free arm movements to visual targets in three-dimensional space. I. Relations between single cell discharge and direction of movement.
We describe the relations between the neuronal activity in primate motor cortex and the direction of arm movement in three-dimensional (3-D) space. The electrical signs of discharge of 568 cells were recorded while monkeys made movements of equal amplitude from the same starting position to 8 visual targets in a reaction time task. The layout of the targets in 3-D space was such that the direction of the movement ranged over the whole 3-D directional continuum in approximately equal angular intervals. We found that the discharge rate of 475/568 (83.6%) cells varied in an orderly fashion with the direction of movement: discharge rate was highest with movements in a certain direction (the cell's "preferred direction") and decreased progressively with movements in other directions, as a function of the cosine of the angle formed by the direction of the movement and the cell's preferred direction. The preferred directions of different cells were distributed throughout 3-D space. These findings generalize to 3-D space previous results obtained in 2-D space (Georgopoulos et al., 1982) and suggest that the motor cortex is a nodal point in the construction of patterns of output signals specifying the direction of arm movement in extrapersonal space.


Stress induced obesity: lessons from rodent models of stress.
Stress was once defined as the non-specific result of the body to any demand or challenge to homeostasis. A more current view of stress is the behavioral and physiological responses generated in the face of, or in anticipation of, a perceived threat. The stress response involves activation of the sympathetic nervous system and recruitment of the hypothalamic-pituitary-adrenal (HPA) axis. When an organism encounters a stressor (social, physical, etc.), these endogenous stress systems are stimulated in order to generate a fight-or-flight response, and manage the stressful situation. As such, an organism is forced to liberate energy resources in attempt to meet the energetic demands posed by the stressor. A change in the energy homeostatic balance is thus required to exploit an appropriate resource and deliver useable energy to the target muscles and tissues involved in the stress response. Acutely, this change in energy homeostasis and the liberation of energy is considered advantageous, as it is required for the survival of the organism. However, when an organism is subjected to a prolonged stressor, as is the case during chronic stress, a continuous irregularity in energy homeostasis is considered detrimental and may lead to the development of metabolic disturbances such as cardiovascular disease, type II diabetes mellitus and obesity. This concept has been studied extensively using animal models, and the neurobiological underpinnings of stress induced metabolic disorders are beginning to surface. However, different animal models of stress continue to produce divergent metabolic phenotypes wherein some animals become anorexic and lose body mass while others increase food intake and body mass and become vulnerable to the development of metabolic disturbances. It remains unclear exactly what factors associated with stress models can be used to predict the metabolic outcome of the organism. This review will explore a variety of rodent stress models and discuss the elements that influence the metabolic outcome in order to further extend our understanding of stress-induced obesity.


Molecular mechanisms in down-regulation of tumor necrosis factor expression.
Excessive production of tumor necrosis factor (TNF) after stimulation by lipopolysaccharide (LPS) may result in fever, intravascular coagulation, and lethal shock. An efficient way of preventing the excessive TNF production is desensitization of monocytes/macrophages to LPS. We have analyzed the molecular mechanisms involved in the induction of desensitization and the mechanisms operative in the desensitized, LPS-refractory cells by employing the human monocytic cell line Mono-Mac-6. Similar to human blood monocytes, treatment of Mono-Mac-6 cells with LPS (1 microgram/ml) results in a rapid and transient expression of TNF. When Mono-Mac-6 cells are precultured in medium containing low levels of LPS, they become refractory to subsequent LPS stimulation and show no or little secretion of TNF protein. Desensitization can be blocked by the inhibition of cyclooxygenase and protein kinase C; both prostaglandin E2 (together with a second signal) and phorbol 12-myristate 13-acetate can mimic desensitization. By employing prostaglandin E2 and low concentrations of phorbol 12-myristate 13-acetate, a synergism in the induction of desensitization can be demonstrated. Hence, our studies show that two distinct pathways are involved in the induction of hyporesponsiveness. In both LPS-responsive and LPS-desensitized Mono-Mac-6 cells, LPS was able to induce the transcription factor NF-kappa B in the nucleus. Still, the prevalence of TNF-specific mRNA was dramatically reduced in the desensitized cells. These data indicate that LPS-desensitized Mono-Mac-6 cells are able to activate initial steps of signal transduction up to the level of the NF-kappa B transcription factor. The absence of TNF transcripts, however, indicates that additional nuclear factors may be missing or that silencers may be active such that transcription of the TNF gene is prevented.


Echocardiographic speckle-tracking based strain imaging for rapid cardiovascular phenotyping in mice.
High-sensitivity in vivo phenotyping of cardiac function is essential for evaluating genes of interest and novel therapies in small animal models of cardiovascular disease. Transthoracic echocardiography is the principal method currently used for assessing cardiac structure and function; however, standard echocardiographic techniques are relatively insensitive to early or subtle changes in cardiac performance, particularly in mice. To develop and validate an echocardiographic strain imaging methodology for sensitive and rapid cardiac phenotyping in small animal models. Herein, we describe a modified echocardiographic technique that uses speckle-tracking based strain analysis for the noninvasive evaluation of cardiac performance in adult mice. This method is found to be rapid, reproducible, and highly sensitive in assessing both regional and global left ventricular (LV) function. Compared with conventional echocardiographic measures of LV structure and function, peak longitudinal strain and strain rate were able to detect changes in adult mouse hearts at an earlier time point following myocardial infarction and predicted the later development of adverse LV remodeling. Moreover, speckle-tracking based strain analysis was able to clearly identify subtle improvement in LV function that occurred early in response to standard post-myocardial infarction cardiac therapy. Our results highlight the utility of speckle-tracking based strain imaging for detecting discrete functional alterations in mouse models of cardiovascular disease in an efficient and comprehensive manner. Echocardiography speckle-tracking based strain analysis represents a method for relatively high-throughput and sensitive cardiac phenotyping, particularly in evaluating emerging cardiac agents and therapies in mice.


Food intolerance and the irritable bowel syndrome.
Two hundred patients (156 women) with the irritable bowel syndrome were treated with dietary exclusion for three weeks. Of the 189 who completed this study, 91 (48.2%) showed symptomatic improvement. Subsequent challenge with individual foods showed that 73 of these 91 responders were able to identify one or more food intolerances and 72 remained well on a modified diet during the follow up period (mean (SD), 14.7 (7.98) months). Of the 98 patients who showed no symptomatic improvement after three weeks of strict exclusion only three were symptomatically well at follow up (mean (SD), 12.48 (8.09 months). There was no close correlation between response and symptom complex. There was a wide range of food intolerance. The majority (50%) identified two to five foods which upset them (range 1-14). The foods most commonly incriminated were dairy products (40.7%) and grains (39.4%).


The development of allergic inflammation.
Allergic disorders, such as anaphylaxis, hay fever, eczema and asthma, now afflict roughly 25% of people in the developed world. In allergic subjects, persistent or repetitive exposure to allergens, which typically are intrinsically innocuous substances common in the environment, results in chronic allergic inflammation. This in turn produces long-term changes in the structure of the affected organs and substantial abnormalities in their function. It is therefore important to understand the characteristics and consequences of acute and chronic allergic inflammation, and in particular to explore how mast cells can contribute to several features of this maladaptive pattern of immunological reactivity.


Repeated Chlamydia trachomatis infection of Macaca nemestrina fallopian tubes produces a Th1-like cytokine response associated with fibrosis and scarring.
Chlamydia trachomatis-associated female infertility and ectopic pregnancy are caused by postinflammatory fibrosis and scarring of the upper genital tract. Scarring of the upper genital tract is associated with multiple infectious episodes with C. trachomatis. To study the immune response that occurs with multiple infections of C. trachomatis in the female upper genital tract, a Macaca nemestrina model was used. Subcutaneous pockets containing autologous salpingeal tissue implants were inoculated three times with C. trachomatis. The inflammation after three inoculations was associated with a mononuclear infiltrate dominated by CD8 T-cell lymphocytes. Perforin mRNA was induced in infected pockets, demonstrating that activated cytolytic lymphocytes were present in the lesions. Fibrosis, as evidenced by fibroblast proliferation and connective tissue deposition, was observed by the third infection. Cytokine mRNAs induced by repeated chlamydial infection included gamma interferon, interleukin-2 (IL-2), IL-6, and IL-10 mRNAs, but IL-4 mRNA was not induced. Nearly identical findings were found in macaque fallopian tubes infected in situ repeatedly with C. trachomatis, validating the subcutaneous pocket model of chlamydial salpingitis. However, it was not possible to evaluate if there was an induction of perforin mRNA in infected salpingeal tubes in situ, because there was a high basal level of perforin mRNA in these tissues. These results suggest that repeated chlamydial infection of the female upper genital tract leads to CD8 T-cell predominance, a Th1-like cytokine milieu, and these inflammatory changes are associated with progression to fibrosis associated with female infertility.


Diagnosing and managing psychosis in primary care.
Psychosis is broadly defined as the presence of delusions and hallucinations. It can be organic or functional. The former is secondary to an underlying medical condition, such as delirium or dementia, the latter to a psychiatric disorder, such as schizophrenia or bipolar disorder. The identification and treatment of psychosis is vital as it is associated with a 10% lifetime risk of suicide and significant social exclusion. Psychosis can be recognised by taking a thorough history, examining the patient's mental state and obtaining a collateral history. The history usually enables a distinction to be made between bipolar disorder, schizophrenia and other causes. Early symptoms often include low mood, declining educational or occupational functioning, poor motivation, changes in sleep, perceptual changes, suspiciousness and mistrust. The patient's appearance, e.g. unkempt or inappropriately attired, may reflect their predominant mental state. There may be signs of agitation, hostility or distractibility. Speech may be disorganised and difficult to follow or there may be evidence of decreased speech. Mood may be depressed or elated or change rapidly. Patients may describe abnormal thoughts and enquiry into thoughts of suicide should be routine. Disturbances of thought such as insertion or withdrawal may be present along with perceptual abnormalities i.e. illusions, hallucinations. Insight varies during the course of a psychotic illness but should be explored as it has implications for management. All patients presenting with first episode psychosis for which no organic cause can be found should be referred to the local early intervention service. In patients with a known diagnosis consider referral if there is: poor response or nonadherence to treatment; intolerable side effects; comorbid substance misuse; risk to self or others.


[Complex PTSD following early-childhood trauma: emotion-regulation training as addition to the PTSD guideline].
Posttraumatic stress disorder (PTSD) symptoms in individuals who have experienced repeated trauma (sexual and/or physical) in early childhood can lead to problems associated with emotion regulation, interpersonal functioning and self-image. This so-called complex PTSD is often accompanied by a comorbid personality disorder. Although ptsd is associated with structural and functional abnormalities in emotion-regulation areas in the brain, it is not known whether complex PTSD shows similar abnormalities. Experts take the view that before individuals with complex PTSD are given appropriate therapy they should receive a course of emotion-regulation therapy such as the one tested by Zlotnick e.a. (1997) in a randomised controlled trial (RCT). To replicate Zlotnick's RCT in the Netherlands and to find out whether complex PTSD patients show specific structural and functional brain abnormalities and whether psychological recovery is linked to the 'normalisation' of these abnormalities. In a RCT with complex PTSD patients (n = 71) who had experienced trauma in early childhood, we compared normal individual treatment with treatment supported by 'Before and beyond', which consists of emotion-regulation therapy combined with cognitive group therapy. In a subsample (n= 33) we also performed an mri (repeated, n = 9) in which individuals were required to execute an emotional memory and attention task. In complex PTSD, structural abnormalities in the brain seemed to be more extensive than in PTSD and brain activity in complex PTSD seemed to be strikingly different from the brain activity seen in PTSD patients who had experienced only single trauma. The results of the RCT indicate that 'Before and beyond' is a clinically meaningful treatment (with minimal drop-out) for complex PTSD patients with a variety of personality disorders. The psychological recovery of patients who received the emotion regulation and cognitive group treatment was associated with normalisation of brain function. Treatment guidelines for ptsd patients cannot be applied directly and automatically to complex PTSD because there is no scientific evidence to justify such a step. The neurobiological profile of PTSD differs from that of complex PTSD. Patients with complex PTSD seem to react favourably to emotion regulation therapy. This treatment therefore could be a useful addition to the current PTSD guideline for this specific group. There is a need for further research that focuses on complex PTSD patients.


Programmable bio-nano-chip system: a flexible point-of-care platform for bioscience and clinical measurements.
The development of integrated instrumentation for universal bioassay systems serves as a key goal for the lab-on-a-chip community. The programmable bio-nano-chip (p-BNC) system is a versatile multiplexed and multiclass chemical- and bio-sensing system for bioscience and clinical measurements. The system is comprised of two main components, a disposable cartridge and a portable analyzer. The customizable single-use plastic cartridges, which now can be manufactured in high volumes using injection molding, are designed for analytical performance, ease of use, reproducibility, and low cost. These labcard devices implement high surface area nano-structured biomarker capture elements that enable high performance signaling and are index-matched to real-world biological specimens. This detection modality, along with the convenience of on-chip fluid storage in blisters and self-contained waste, represents a standard process to digitize biological signatures at the point-of-care. A companion portable analyzer prototype has been developed to integrate fluid motivation, optical detection, and automated data analysis, and it serves as the human interface for complete assay automation. In this report, we provide a systems-level perspective of the p-BNC universal biosensing platform with an emphasis on flow control, device integration, and automation. To demonstrate the flexibility of the p-BNC, we distinguish diseased and non-case patients across three significant disease applications: prostate cancer, ovarian cancer, and acute myocardial infarction. Progress towards developing a rapid 7 minute myoglobin assay is presented using the fully automated p-BNC system.


Measuring Trachomatous Inflammation-Intense (TI) When Prevalence Is Low Provides Data on Infection With Chlamydia trachomatis.
Clinical trachoma is the current measure of effectiveness of antibiotic and environmental improvements in trachoma endemic communities. Impact assessments measure only trachomatous inflammation-follicular (TF). Trachomatous inflammation-intense (TI) is not used for decisions on stopping mass drug administration (MDA) or achieving intervention goals. We tested the supposition that TI was not associated with Chlamydia trachomatis when disease prevalence is low. In 35 communities undergoing MDA as part of a larger project, 110 children ages 1 to 9 years were randomly selected in each community for surveys at baseline, 6, and 12 months. Both eyelids were graded for TF and TI, and a swab for detection of C. trachomatis infection was taken. Overall TF prevalence was 5% at baseline. Cases of TI alone constituted 15% of trachoma; 37% of TI cases had infection. At 6 and 12 months, the proportion of trachoma cases that had TI only was 13% and 20%; infection rates were similar to the rates in cases with TF alone. Despite low prevalence of trachoma, infection rates for TF alone and TI alone were similar at each time point. The exclusion of cases of TI alone when reporting trachoma prevalence discards additional information on infection. Trachomatous inflammation-intense could be considered as part of impact surveys.


Online cognitive training in healthy older adults: a preliminary study on the effects of single versus multi-domain training.
It has been argued that cognitive training may be effective in improving cognitive performance in healthy older adults. However, inappropriate active control groups often hinder the validity of these claims. Additionally there are relatively few independent empirical studies on popular commercially available cognitive training programs. The current research extends on previous work to explore cognitive training employing a more robust control group. Twenty-eight healthy older adults (age: M = 64.18, SD = 6.9) completed either a multi-faceted online computerised cognitive training program or trained on a simple reaction time task for 20 minutes a day over a 28 day period. Both groups significantly improved performance in multiple measures of processing speed. Only the treatment group displayed improved performance for measures of memory accuracy. These results suggest improvements in processing speed and visual working memory may be obtained over a short period of computerized cognitive training. However, gains over this time appear only to show near transfer. The use of similar active control groups in future research are needed in order to better understand changes in cognition after cognitive training.


Transformation of primary care during the COVID-19 pandemic: experiences of healthcare professionals in eight European countries.
Primary care has a crucial role in responding to the COVID-19 pandemic as the first point of patient care and gatekeeper to secondary care. Qualitative studies exploring the experiences of healthcare professionals during the COVID-19 pandemic have mainly focused on secondary care. To gain an understanding of the experiences of European primary care professionals (PCPs) working during the first peak of the COVID-19 pandemic. An exploratory qualitative study, using semi-structured interviews in primary care in England, Belgium, the Netherlands, Ireland, Germany, Poland, Greece, and Sweden, between April and July 2020. Interviews were audiorecorded, transcribed, and analysed using a combination of inductive and deductive thematic analysis techniques. Eighty interviews were conducted with PCPs. PCPs had to make their own decisions on how to rapidly transform services in relation to COVID-19 and non-COVID-19 care. Despite being overwhelmed with guidance, they often lacked access to practical training. Consequently, PCPs turned to their colleagues for moral support and information to try to quickly adjust to new ways of working, including remote care, and to deal with uncertainty. PCPs rapidly transformed primary care delivery despite a number of challenges. Representation of primary care at policy level and engagement with local primary care champions are needed to facilitate easy and coordinated access to practical information on how to adapt services, ongoing training, and access to appropriate mental health support services for PCPs. Preservation of autonomy and responsiveness of primary care are critical to preserve the ability for rapid transformation in any future crisis of care delivery.


Gramella aestuariivivens sp. nov., isolated from a tidal flat.
A Gram-stain-negative, aerobic, non-spore-forming, non-flagellated and rod-shaped or ovoid bacterial strain, designated BG-MY13(T), was isolated from a tidal flat sediment on the South Sea, South Korea. Strain BG-MY13(T) grew optimally at 30-35 °C, at pH 7.0-8.0 and in the presence of 2.0-3.0% (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain BG-MY13(T) falls within the cluster comprising the type strains of species of the genus Gramella . Strain BG-MY13(T) exhibited 16S rRNA gene sequ4ence similarity values of 96.9-97.8% to the type strains of Gramella echinicola , Gramella gaetbulicola , Gramella portivictoriae and Gramella marina and of 94.6-96.5% to the type strains of other species of the genus Gramella with validly published names. Strain BG-MY13(T) contained MK-6 as the predominant menaquinone and iso-C(15 : 0) and iso-C(17 : 0) 3-OH as the major fatty acids. The major polar lipids were phosphatidylethanolamine and one unidentified lipid. The DNA G+C content of strain BG-MY13(T) was 38.9 mol% and DNA-DNA relatedness values with the type strains of G. echinicola , G. gaetbulicola , G. portivictoriae and G. marina were 12-23%. The differential phenotypic properties, together with phylogenetic and genetic distinctiveness, revealed that strain BG-MY13(T) is separated from other species of the genus Gramella . On the basis of the data presented, strain BG-MY13(T) is considered to represent a novel species of the genus Gramella , for which the name Gramella aestuariivivens sp. nov. is proposed. The type strain is BG-MY13(T) ( = KCTC 42285(T) = NBRC 110677(T)).


Increasing PET Use in Small Cell Lung Cancer: Survival Improvement and Stage Migration in the VA Central Cancer Registry.
Background: Accurate staging for small cell lung cancer (SCLC) is critical for determining appropriate therapy. The clinical impact of increasing PET adoption and stage migration is well described in non-small cell lung cancer but not in SCLC. The objective of this study was to evaluate temporal trends in PET staging and survival in the Veterans Affairs Central Cancer Registry and the impact of PET on outcomes. Patients and Methods: Patients diagnosed with SCLC from 2001 to 2010 were identified. PET staging, overall survival (OS), and lung cancer-specific survival (LCSS) were assessed over time. The impact of PET staging on OS and LCSS was assessed for limited-stage (LS) and extensive-stage (ES) SCLC. Results: From 2001 to 2010, PET use in a total of 10,135 patients with SCLC increased from 1.1% to 39.2%. Median OS improved for all patients (from 6.2 to 7.9 months), those with LS-SCLC (from 10.9 to 13.2 months), and those with ES-SCLC (from 5.0 to 7.0 months). Among staged patients, the proportion of ES-SCLC increased from 63.9% to 65.7%. Among 1,536 patients with LS-SCLC treated with concurrent chemoradiotherapy, 397 were staged by PET. In these patients, PET was associated with longer OS (median, 19.8 vs 14.3 months; hazard ratio [HR], 0.78; 95% CI, 0.68-0.90; P<.0001) and LCSS (median, 22.9 vs 16.7 months; HR, 0.74; 95% CI, 0.63-0.87; P<.0001) with multivariate adjustment and propensity-matching. In the 6,143 patients with ES-SCLC, PET was also associated with improved OS and LCSS. Conclusions: From 2001 to 2010, PET staging increased in this large cohort, with a corresponding relative increase in ES-SCLC. PET was associated with greater OS and LCSS for LS-SCLC and ES-SCLC, likely reflecting stage migration and stage-appropriate therapy. These findings emphasize the importance of PET in SCLC and support its routine use.


Estimating the regional distribution of men who have sex with men (MSM) based on Internet surveys.
Measurement of prevalence and incidence of infections in a hard to reach population like men who have sex with men (MSM) is hampered by its unknown size and regional distribution. Population-based surveys have recently been used to estimate the total number of MSM, but these surveys are usually not large enough to measure regional differences in the proportion of MSM in the population. We explored the use of the proportional regional distribution of participants of large internet-based surveys among MSM from Germany to estimate the regional distribution of MSM in Germany. We compared participants from two separate MSM behavioural surveys with each other and with the distribution of user profiles of the largest contact and dating website for gay and other MSM in Germany in terms of the representativeness of the regional distribution. In addition, we compared the regional distribution of reportedly HIV positive survey participants with the regional distribution of HIV notifications within the national surveillance system that can be attributed to transmission through homosexual contacts. Regional distribution of survey participants was almost identical in both surveys, despite little overlap between survey participants. Slight discrepancies between surveys and user profiles could be observed. Proportional regional distribution of survey participants with HIV diagnosis resembled national surveillance data. Considering the difficulties to obtain representative data by other sampling methods for "hidden" populations like MSM, internet-based surveys may provide an easy and low cost tool to estimate the regional population distribution -- at least in Western post-industrialized countries. Some uncertainties remain about the exact place of residence of MSM in larger cities or catchment areas of these cities. Slightly different results from different datasets may be due to unequal popularity of MSM websites in different regions. The total population size of the MSM population can be estimated based on e.g. data from representative national population surveys. Both estimates can then be combined to calculate the absolute size of regional MSM populations.


Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.
c-kit-positive, lineage-negative cardiac stem cells (CSCs) improve post-infarction left ventricular (LV) dysfunction when administered to animals. We undertook a phase 1 trial (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy [SCIPIO]) of autologous CSCs for the treatment of heart failure resulting from ischaemic heart disease. In stage A of the SCIPIO trial, patients with post-infarction LV dysfunction (ejection fraction [EF] ≤40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups. In stage B, patients were randomly assigned to the treatment or control group in a 2:3 ratio by use of a computer-generated block randomisation scheme. 1 million autologous CSCs were administered by intracoronary infusion at a mean of 113 days (SE 4) after surgery; controls were not given any treatment. Although the study was open label, the echocardiographic analyses were masked to group assignment. The primary endpoint was short-term safety of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. This study is registered with ClinicalTrials.gov, number NCT00474461. This study is still in progress. 16 patients were assigned to the treatment group and seven to the control group; no CSC-related adverse effects were reported. In 14 CSC-treated patients who were analysed, LVEF increased from 30·3% (SE 1·9) before CSC infusion to 38·5% (2·8) at 4 months after infusion (p=0·001). By contrast, in seven control patients, during the corresponding time interval, LVEF did not change (30·1% [2·4] at 4 months after CABG vs 30·2% [2·5] at 8 months after CABG). Importantly, the salubrious effects of CSCs were even more pronounced at 1 year in eight patients (eg, LVEF increased by 12·3 ejection fraction units [2·1] vs baseline, p=0·0007). In the seven treated patients in whom cardiac MRI could be done, infarct size decreased from 32·6 g (6·3) by 7·8 g (1·7; 24%) at 4 months (p=0·004) and 9·8 g (3·5; 30%) at 1 year (p=0·04). These initial results in patients are very encouraging. They suggest that intracoronary infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure after myocardial infarction, and warrant further, larger, phase 2 studies. University of Louisville Research Foundation and National Institutes of Health.


Value of multicolour fluorescence in situ hybridisation (UroVysion) in the differential diagnosis of flat urothelial lesions.
During the past 10 years, multitarget fluorescence in situ hybridisation has been established as a valuable adjunct in the cytological diagnosis of precancerous and malignant lesions of the urinary tract. The aim of the present study was to define its value in detecting chromosomal imbalances in patients with various flat urothelial lesions in routine paraffin-embedded bladder biopsy samples. In addition, the HER2 gene amplification and HER2 expression pattern were examined, since alterations of the HER2 expression patterns have been demonstrated in invasive bladder cancer. 29 samples of normal urothelium and 86 flat urothelial lesions (hyperplasia, reactive atypia, dysplasia and carcinoma in situ (CIS)) from 73 patients were analysed patients using tissue microarrays and centromeric probes for chromosomes 3, 7 and 17, and gene-specific probes for 9p21/P16 and HER2 (UroVysion, PathVysion). The expression of HER2 was studied by immunohistochemistry. Polysomy of at least one of the chromosomes was found in about half of the dysplastic cells, and in more than 90% of cells in CIS or cells in invasive bladder tumours. Polysomic cells were found in only 17% of urothelial hyperplasia, reactive atypia and normal urothelium of healthy patients, whereas about 30% of non-neoplastic lesions in patients with concomitant urothelial carcinoma showed polysomy of at least one chromosome. These alterations indicate a field effect and are associated with synchronous development of dysplastic lesions of a higher grade. Deletion of the P16 locus was most frequently observed in aneuploid lesions, whereas overexpression of HER2 was found in 10-20% of invasive urothelial carcinomas, and only occasionally in CIS (5%). An altered HER2 expression pattern was present in non-neoplastic lesions (25%). UroVysion fluorescence in situ hybridisation is a valuable tool for the detection of genetically unstable flat urothelial lesions, and can help to resolve difficult cases, particularly the differential diagnosis of reactive atypia and dysplasia.


Lifestyle and precision diabetes medicine: will genomics help optimise the prediction, prevention and treatment of type 2 diabetes through lifestyle therapy?
Precision diabetes medicine, the optimisation of therapy using patient-level biomarker data, has stimulated enormous interest throughout society as it provides hope of more effective, less costly and safer ways of preventing, treating, and perhaps even curing the disease. While precision diabetes medicine is often framed in the context of pharmacotherapy, using biomarkers to personalise lifestyle recommendations, intended to lower type 2 diabetes risk or to slow progression, is also conceivable. There are at least four ways in which this might work: (1) by helping to predict a person's susceptibility to adverse lifestyle exposures; (2) by facilitating the stratification of type 2 diabetes into subclasses, some of which may be prevented or treated optimally with specific lifestyle interventions; (3) by aiding the discovery of prognostic biomarkers that help guide timing and intensity of lifestyle interventions; (4) by predicting treatment response. In this review we overview the rationale for precision diabetes medicine, specifically as it relates to lifestyle; we also scrutinise existing evidence, discuss the barriers germane to research in this field and consider how this work is likely to proceed.


Revisiting hydroxychloroquine and chloroquine for patients with chronic immunity-mediated inflammatory rheumatic diseases.
Hydroxychloroquine and chloroquine, also known as antimalarial drugs, are widely used in the treatment of rheumatic diseases and have recently become the focus of attention because of the ongoing COVID-19 pandemic. Rheumatologists have been using antimalarials to manage patients with chronic immune-mediated inflammatory rheumatic diseases for decades. It is an appropriate time to review their immunomodulatory and anti-inflammatory mechanisms impact on disease activity and survival of systemic lupus erythematosus patient, including antiplatelet effect, metabolic and lipid benefits. We also discuss possible adverse effects, adding a practical and comprehensive approach to monitoring rheumatic patients during treatment with these drugs.


Offender and offense characteristics of sexual sadists: a comparative study.
This paper compares the offender and offense characteristics of 30 sexually sadistic criminals studied by Dietz et al. with those of 29 sexually sadistic criminals and 28 nonsadistic sexual offenders from the Royal Ottawa Hospital. We examined whether the characteristics noted by Dietz et al. would be found among a less violent group of sadistic offenders and also to what extent these characteristics were specific to sexual sadism. Results suggest some offender and offense characteristic are specific to sexual sadism and that others appear to be common to sexually aggressive offenders more generally. In addition, there were a number of characteristics found exclusively among the most violent offenders described by Dietz et al. An explanation of these results in terms of a biopsychosocial understanding of sexual sadistic offenders is provided.


Bayesian networks and information theory for audio-visual perception modeling.
Thanks to their different senses, human observers acquire multiple information coming from their environment. Complex cross-modal interactions occur during this perceptual process. This article proposes a framework to analyze and model these interactions through a rigorous and systematic data-driven process. This requires considering the general relationships between the physical events or factors involved in the process, not only in quantitative terms, but also in term of the influence of one factor on another. We use tools from information theory and probabilistic reasoning to derive relationships between the random variables of interest, where the central notion is that of conditional independence. Using mutual information analysis to guide the model elicitation process, a probabilistic causal model encoded as a Bayesian network is obtained. We exemplify the method by using data collected in an audio-visual localization task for human subjects, and we show that it yields a well-motivated model with good predictive ability. The model elicitation process offers new prospects for the investigation of the cognitive mechanisms of multisensory perception.


Cholesterol Granulomas: A Comparative Meta-Analysis of Endonasal Endoscopic versus Open Approaches to the Petrous Apex.
Petrous apex cholesterol granulomas (PACG) are rare disorders that can lead to patient morbidity and must, occasionally, be drained by either endoscopic endonasal (EN) or open procedures (OP). The objective of our study was to complete a review of the literature to compare the EN and OP approaches on multiple levels, notably on safety and effectiveness. Ovid MEDLINE and Embase were used to perform a thorough literature review of all cases of PACG treated by either EN or OP dating from January 1948 to August 2017. In total, 49 articles were selected including 23 for EN (n=76) and 26 for OP (n=210). Differences were found in the incidence of preoperative hearing loss (HL) (EN 18.4%, OP 57.3%; p<0.001), headache (EN 48.7%, OP 31.2%; p=0.007), and disequilibrium (EN: 14.5%, OP 26.1%; p=0.04). Differences in lesion proximity to the sphenoid sinus (EN 23.6%, OP: 1.0%; p<0.001), clivus (EN 11.8%, OP 4.7%; p=0.03), otic capsule (EN 0.0%, OP 5.2%; p=0.03), internal auditory canal (EN 2.6%, OP 10.9%; p=0.01), and internal carotid artery (ICA) (EN 9.2%, OP 2.8%; p=0.02) were found on preoperative imaging. The EN procedure had better hearing improvement rates (EN 85.7%, OP 23.4%; p<0.001), lower complication rates (EN 7.9%, OP 17.6%; p=0.04), shorter median follow-up (EN:13.5 months, OP:37.2 months; p<0.001), and shorter time to recurrence (EN 3 months, OP 22.6 months; p=0.002) than the known OP. No differences were found in age, preoperative size, recurrence rate, operative time, stent placement, or improvement of other symptoms. Endoscopic nasal approaches, when feasible, should be favored to open procedures for PACG drainage given their better hearing improvement and less complication rates.


Processing of intentional and automatic number magnitudes in children born prematurely: evidence from fMRI.
This study examined the neural correlates of intentional and automatic number processing (indexed by number comparison and physical Stroop task, respectively) in 6- and 7-year-old children born prematurely. Behavioral results revealed significant numerical distance and size congruity effects. Imaging results disclosed (1) largely overlapping fronto-parietal activation for intentional and automatic number processing, (2) a frontal to parietal shift of activation upon considering the risk factors gestational age and birth weight, and (3) a task-specific link between math proficiency and functional magnetic resonance imaging (fMRI) signal within distinct regions of the parietal lobes-indicating commonalities but also specificities of intentional and automatic number processing.


Angiotensin Converting Enzyme Inhibitor Dialyzability and Outcomes in Older Patients Receiving Hemodialysis.
Some angiotensin converting enzyme (ACE) inhibitors are efficiently removed from circulation by hemodialysis ('high dialyzability'), whereas others are not ('low dialyzability'). In patients receiving hemodialysis, this may influence the effectiveness of ACE inhibitors. Using linked healthcare databases we identified older patients receiving chronic hemodialysis who filled new ACE inhibitor prescriptions. The low dialyzability group (n = 3,369) included fosinopril and ramipril. The high dialyzability group (n = 5,974) included enalapril, lisinopril, and perindopril. The primary outcome was all-cause mortality within 180 days of first ACE inhibitor prescription. There were 361 deaths among 5,974 patients (6.0%) prescribed with low dialyzability ACE inhibitors and 179 deaths among 3,369 patients (5.3%) prescribed with high dialyzability ACE inhibitors (relative risk 1.1, 95% CI 0.9-1.3, p = 0.6). In this study of older patients receiving hemodialysis, the dialyzability of ACE inhibitors was not associated with mortality or cardiovascular outcomes.


Lack of major genome instability in tumors of p53 null rats.
Tumorigenesis is often associated with loss of tumor suppressor genes (such as TP53), genomic instability and telomere lengthening. Previously, we generated and characterized a rat p53 knockout model in which the homozygous rats predominantly develop hemangiosarcomas whereas the heterozygous rats mainly develop osteosarcomas. Using genome-wide analyses, we find that the tumors that arise in the heterozygous and homozygous Tp53C273X mutant animals are also different in their genomic instability profiles. While p53 was fully inactivated in both heterozygous and homozygous knockout rats, tumors from homozygous animals show very limited aneuploidy and low degrees of somatic copy number variation as compared to the tumors from heterozygous animals. In addition, complex structural rearrangements such as chromothripsis and breakage-fusion-bridge cycles were never found in tumors from homozygous animals, while these were readily detectable in tumors from heterozygous animals. Finally, we measured telomere length and telomere lengthening pathway activity and found that tumors of homozygous animals have longer telomeres but do not show clear telomerase or alternative lengthening of telomeres (ALT) activity differences as compared to the tumors from heterozygous animals. Taken together, our results demonstrate that host p53 status in this rat p53 knockout model has a large effect on both tumor type and genomic instability characteristics, where full loss of functional p53 is not the main driver of large-scale structural variations. Our results also suggest that chromothripsis primarily occurs under p53 heterozygous rather than p53 null conditions.


Implementing a wound care resource nurse program.
Nurses are leaders in implementing innovations that can create positive outcomes in the prevention and management of pressure ulcers in patients admitted to acute care hospitals. Believing that nurses knowledgeable in best practices could impact prevalence, incidence, and care of pressure ulcers, an educational program was developed in a Canadian healthcare system to inform and empower nurses providing skin and wound care. The program afforded participants the opportunity to acquire the knowledge and skill to recognize patients at risk for developing pressure ulcers and to independently treat Stage I and Stage II pressure ulcers and skin breakdown related to moisture, friction, and shear. The program includes evidence-based practice recommendations and highlights the Best Practice Guidelines developed by the Registered Nurses Association of Ontario, a provincial body taking an active role in the development, implementation, and evaluation of published guidelines derived from global research literature synthesis. Pre- and post participation assessment of 65 nurse participants from three hospitals deemed the program successful in terms of knowledge and fulfillment of their educational expectations. Organizational support to implement the skin and wound care resource nurse role was encouraging and medical directives for Stage I and Stage II pressure ulcers by nurses were implemented. Evaluation and monitoring of program outcomes, including pressure ulcer incidence rates, continue.


Antiplatelet therapy in acute coronary syndrome and atrial fibrillation: aspirin.
Platelets play a critical role in the pathophysiology of acute coronary syndrome and thromboembolic complications associated with atrial fibrillation. Despite the development of newer and more potent antiplatelet agents, aspirin remains the cornerstone of antithrombotic therapy. Clinical trials conducted over the past decades have clearly established the safety and efficacy of aspirin therapy for the acute treatment and secondary prevention of acute myocardial infarction, ischemic stroke, and vascular death among patients at high risk for cardiovascular events. Although the absolute benefit of aspirin for primary prevention is lower than seen in secondary prevention trials, it is nevertheless an accepted preventive. This chapter provides a comprehensive overview of the clinical utility of aspirin in the setting of acute coronary syndrome and atrial fibrillation.


The Relationship of Policymaking and Networking Characteristics among Leaders of Large Urban Health Departments.
The relationship between policy networks and policy development among local health departments (LHDs) is a growing area of interest to public health practitioners and researchers alike. In this study, we examine policy activity and ties between public health leadership across large urban health departments. This study uses data from a national profile of local health departments as well as responses from a survey sent to three staff members (local health official, chief of policy, chief science officer) in each of 16 urban health departments in the United States. Network questions related to frequency of contact with health department personnel in other cities. Using exponential random graph models, network density and centrality were examined, as were patterns of communication among those working on several policy areas using exponential random graph models. All 16 LHDs were active in communicating about chronic disease as well as about use of alcohol, tobacco, and other drugs (ATOD). Connectedness was highest among local health officials (density = .55), and slightly lower for chief science officers (d = .33) and chiefs of policy (d = .29). After accounting for organizational characteristics, policy homophily (i.e., when two network members match on a single characteristic) and tenure were the most significant predictors of formation of network ties. Networking across health departments has the potential for accelerating the adoption of public health policies. This study suggests similar policy interests and formation of connections among senior leadership can potentially drive greater connectedness among other staff.


Preliminary findings of an investigation into the relationship between national culture and EQ-5D value sets.
Despite the growing importance of the EQ-5D descriptive system as a basis for the valuation of QALYs in cost-utility analysis, for most countries, there are no EQ-5D value sets. Researchers and policy makers wishing to use the EQ-5D descriptive system in a country for which there is no value set are advised to use one from a nearby or 'similar' population. Factors other than geographic proximity can affect the relative values of EQ-5D states. This study explores the links between national culture and EQ-5D value sets. Rank correlation analysis is used to explore relationships between the relative values of a set of EQ-5D states and dimensions of national culture. The latter are taken from Hofstede's framework which operationalizes national culture in five dimensions. For the data currently available (countries for which EQ-5D value sets and scores on dimensions of culture both exist), moderate and strong correlations were found between the culture dimension of power distance and individualism and the EQ-5D dimensions of pain/discomfort and anxiety/depression. Moderate correlations were also observed between the cultural dimension of masculinity and the EQ-5D dimensions of self care, usual activities and pain/discomfort. Uncertainty avoidance correlates with the EQ-5D dimension of anxiety/depression. The correlation patterns observed are generally consistent with a priori expectations based on the nature of the dimensions of culture and the EQ-5D model. This analysis demonstrates the potential of national culture in providing insight into the drivers of the relative values of EQ-5D dimensions for different countries and in informing decisions about which EQ-5D value sets to use in situations where one does not exist.


Properties of copper (fluoro-)phthalocyanine layers deposited on epitaxial graphene.
We investigate the atomic structure and electronic properties of monolayers of copper phthalocyanines (CuPc) deposited on epitaxial graphene substrate. We focus in particular on hexadecafluorophthalocyanine (F(16)CuPc), using both theoretical and experimental (scanning tunneling microscopy - STM) studies. For the individual CuPc and F(16)CuPc molecules, we calculated the electronic and optical properties using density functional theory (DFT) and time-dependent DFT and found a red-shift in the absorption peaks of F(16)CuPc relative to those of CuPc. In F(16)CuPc, the electronic wavefunctions are more polarized toward the electronegative fluorine atoms and away from the Cu atom at the center of the molecule. When adsorbed on graphene, the molecules lie flat and form closely packed patterns: F(16)CuPc forms a hexagonal pattern with two well-ordered alternating α and β stripes while CuPc arranges into a square lattice. The competition between molecule-substrate and intermolecular van der Waals interactions plays a crucial role in establishing the molecular patterns leading to tunable electron transfer from graphene to the molecules. This transfer is controlled by the layer thickness of, or the applied voltage on, epitaxial graphene resulting in selective F(16)CuPc adsorption, as observed in STM experiments. In addition, phthalocyanine adsorption modifies the electronic structure of the underlying graphene substrate introducing intensity smoothing in the range of 2-3 eV below the Dirac point (E(D)) and a small peak in the density of states at ∼0.4 eV above E(D).


Multilayer block copolymer meshes by orthogonal self-assembly.
Continued scaling-down of lithographic-pattern feature sizes has brought templated self-assembly of block copolymers (BCPs) into the forefront of nanofabrication research. Technologies now exist that facilitate significant control over otherwise unorganized assembly of BCP microdomains to form both long-range and locally complex monolayer patterns. In contrast, the extension of this control into multilayers or 3D structures of BCP microdomains remains limited, despite the possible technological applications in next-generation devices. Here, we develop and analyse an orthogonal self-assembly method in which multiple layers of distinct-molecular-weight BCPs naturally produce nanomesh structures of cylindrical microdomains without requiring layer-by-layer alignment or high-resolution lithographic templating. The mechanisms for orthogonal self-assembly are investigated with both experiment and simulation, and we determine that the control over height and chemical preference of templates are critical process parameters. The method is employed to produce nanomeshes with the shapes of circles and Y-intersections, and is extended to produce three layers of orthogonally oriented cylinders.


Drug checking as a potential strategic overdose response in the fentanyl era.
Adulteration of illicit drug supplies with synthetic opioids such as fentanyl has contributed to a dramatic rise in overdose morbidity and mortality in North America. One promising response to this crisis is the implementation of "drug checking" services. Drug checking encompasses a range of interventions used to assess the constituents of illicit drug samples, such as colour-spot testing, gas or liquid chromatography, and various methods of spectroscopy. Testing may be performed on-site at events or harm reduction service locales, performed independently by consumers, or sent to a centralized lab for analysis. This information may then serve to inform individual decision-making, enhance harm reduction efforts and strengthen public health surveillance and response strategies to prevent harms associated with illicit drug use. Historical examples of drug checking services that emerged with the 1990s synthetic "party drug" movement in Europe provide a theoretical and practical basis for the adaptation of these services for use in context of the current opioid overdose crisis. Potential harm reduction benefits of drug checking for synthetic opioid adulterants include individuals being more likely to use drugs more safely or to dispose of drugs found to contain harmful adulterants. Public health benefits of drug checking may also include negative feedback on the illicit drug supply with decreased availability or consumption of drugs from sources adulterated with synthetic opioids following public health warning campaigns. As part of the response to the current synthetic opioid epidemic in BC, pilot efforts are being undertaken in Vancouver to determine the feasibility and effectiveness of drug checking as an overdose response strategy. Models of drug checking service delivery and comparison of differing technologies, including unique challenges and potential solutions related to access to these services, legal obstacles, and sensitivity and specificity of testing technologies, are explored, alongside suggestions for future research and directions.