bluuebunny/crossref_metadata_2025 huggingface dataset:
Low Molecular Weight Fibrinogen Degradation Products Stimulate the Release of Growth Factors from Endothelial Cells
Authors: Lorenzet Roberto , Sobel Joan H , Bini Alessandra , Witte Larry D
Published: July 2018

Cultured porcine aortic endothelial cells (PAEC) constitutively produce and secrete in their culture medium mitogens collectively called endothelial cell-derived growth factors (EDGFs). Incubation of PAEC with fibrinogen-degradation products (FDPs) obtained by plasmin digestion of highly purified fibrinogen caused an increased release of EDGFs, as assessed by [3H]-thymidine incorporation in 3T3 mouse fibroblasts. The effect was time-dependent and correlated with the degree of fibrinogenolysis. It was accompanied by elongation of the cells. Neither increase in EDGFs release nor cell damage was observed when non-degraded fibrinogen was incubated with endothelial cells. Low molecular weight fibrinogen degradation products (LMWFDPs) (M
r ≤ 10,000), and the higher molecular weight fibrinogen fragments D and E were tested under the same conditions. Only the LMWFDPs caused elongation and damage to PAEC and a marked stimulation (up to 12 fold) of EDGFs release. A low density growth assay revealed that the released EDGFs were mitogenically active on the same PAEC. The activity of the released EDGFs was time and dose dependent on both 3T3 fibroblasts and PAEC, indicating that LMWFDPs caused enhanced release of EDGFs that can act in paracrine and autocrine fashion. This study suggests an additional role for fibrinogenolysis contributing to wound healing, and possibly to atherosclerosis.
No Association between Thrombin Generation and Intra-Plaque Haemorrhage in Symptomatic Carotid Atherosclerotic Plaques: The Plaque at RISK (PARISK) Study
Authors: Crombag Geneviève , Spronk Henri , Nelemans Patty , Schreuder Floris , Truijman Martine , van Dijk Anouk , de Rotte Alexandra , Liem Madieke , Daemen Mat , van der Steen Anton , Mess Werner , Nederkoorn Paul , Hendrikse Jeroen , van der Lugt Aad , Wildberger Joachim , ten Cate Hugo , van Oostenbrugge Robert , Kooi M.
Published: July 2018

Background Carotid atherosclerosis is an important cause of stroke. Intra-plaque haemorrhage (IPH) on magnetic resonance imaging (MRI) increases stroke risk. Development of IPH is only partly understood. Thrombin is an essential enzyme in haemostasis. Experimental animal studies have shown conflicting results on the relation between thrombin and plaque vulnerability. We hypothesize that decreased thrombin generation (TG) is associated with IPH and plaque vulnerability.

Objective This article investigates whether TG is associated with IPH and other features of plaque vulnerability in stroke patients.

Methods Recently symptomatic stroke patients underwent carotid MRI and blood sampling. MRI plaque features include plaque burden, presence of IPH, amount of lipid-rich necrotic core (LRNC), calcified tissue and fibrous tissue (% of total wall volume). TG was assessed in platelet-poor plasma and expressed as: peak height (PH) and endogenous thrombin potential (ETP). MR images could be analysed in 224 patients. Blood samples were available in 161 of 224 patients. Binary multivariate logistic and linear regression were used to investigate the association between TG and MRI plaque features.

Results IPH and LRNC were present in 65 (40%) and 102 (63%) of plaques. There were no significant associations between TG and IPH; PH odds ratio (OR) = 1, 95% confidence interval (CI): 0.76 to 1.45 and ETP OR = 1, 95% CI: 0.73 to 1.37. After correction for age, sex and hypercholesterolaemia, the association was weak but non-significant; PH: OR = 0.76, 95% CI: 0.52 to 1.10 and ETP: OR = 0.73, 95% CI: 0.53 to 1.37.

Conclusion Features of carotid plaque on MRI show no significant association with TG in stroke patients. Systemic TG does not seem to be an important factor in IPH development.
Predicting Post-Thrombotic Syndrome with Ultrasonographic Follow-Up after Deep Vein Thrombosis: A Systematic Review and Meta-Analysis
Authors: Dronkers C. E. A. , Mol G. C. , Maraziti G. , van de Ree M. A. , Huisman M. V. , Becattini C. , Klok F. A.
Published: July 2018

Background Post-thrombotic syndrome (PTS) is a common and potential severe complication of deep venous thrombosis (DVT). Elastic compression stocking therapy may prevent PTS if worn on a daily basis, but stockings are cumbersome to apply and uncomfortable to wear. Hence, identification of predictors of PTS may help physicians to select patients at high risk of PTS.

Aims This article identifies ultrasonography (US) parameters assessed during or after treatment of DVT of the leg, that predict PTS.

Methods This is a systematic review and meta-analysis study. Databases were searched for prospective studies including consecutive patients with DVT who received standardized treatment, had an US during follow-up assessing findings consistent with vascular damage after DVT and had a follow-up period of at least 6 months for the occurrence of PTS assessed by a standardized protocol.

Results The literature search revealed 1,156 studies of which 1,068 were irrelevant after title and abstract screening by three independent reviewers. After full-text screening, 12 relevant studies were included, with a total of 2,684 analysed patients. Two US parameters proved to be predictive of PTS: residual vein thrombosis, for a pooled odds ratio (OR) of 2.17 (95% confidence interval [CI], 1.79–2.63) and venous reflux at the popliteal level, for a pooled OR of 1.34 (95% CI, 1.03–1.75).

Conclusion The US features reflux and residual thrombosis measured at least 6 weeks after DVT predict PTS. Whether these features may be used to identify patients who may benefit from compression therapy remains to be assessed in further studies.
Fentanyl Delays the Platelet Inhibition Effects of Oral Ticagrelor: Full Report of the PACIFY Randomized Clinical Trial
Authors: Ibrahim Khalil , Shah Rohan , Goli Rakesh , Kickler Thomas , Clarke William , Hasan Rani , Blumenthal Roger , Thiemann David , Resar Jon , Schulman Steven , McEvoy John
Published: July 2018

Morphine delays oral P2Y12 platelet inhibitor absorption and is associated with adverse outcomes after myocardial infarction. Consequently, many physicians and first responders are now considering fentanyl as an alternative. We conducted a single-centre trial randomizing cardiac patients undergoing coronary angiography to intravenous fentanyl or not. All participants received local anaesthetic and intravenous midazolam. Those requiring percutaneous coronary intervention (PCI) with stenting received 180 mg oral ticagrelor intra-procedurally. The primary outcome was area under the ticagrelor plasma concentration–time curve (AUC0–24 hours). The secondary outcomes were platelet function assessed at 2 hours after loading, measured by P2Y12 reaction units (PRUs) and light transmission platelet aggregometry. Troponin-I was measured post-PCI using a high-sensitivity troponin-I assay (hs-TnI). All participants completed a survey of pain and anxiety. Of the 212 randomized, 70 patients required coronary stenting and were loaded with ticagrelor. Two participants in the no-fentanyl arm crossed over to receive fentanyl for pain. In as-treated analyses, ticagrelor concentrations were higher in the no-fentanyl arm (AUC0–24 hours 70% larger, p = 0.03). Platelets were more inhibited by 2 hours in the no-fentanyl arm (71 vs. 113 by PRU, p = 0.03, and 25% vs. 41% for adenosine diphosphate response by platelet aggregation, p < 0.01). Mean hs-TnI was higher with fentanyl at 2 hours post-PCI (11.9 vs. 7.0 ng/L, p = 0.04) with a rate of enzymatic myocardial infarction of 11% for fentanyl and 0% for no-fentanyl (p = 0.08). No statistical differences in self-reported pain or anxiety were found. In conclusion, fentanyl administration can impair ticagrelor absorption and delay platelet inhibition, resulting in mild excess of myocardial damage. This newly described drug interaction should be recognized by physicians and suggests that the interaction between opioids and oral P2Y12 platelet inhibitors is a drug class effect associated with all opioids.

Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02683707 (NCT02683707).
Zielgerichtete Erstdiagnostik bei Typ-1-Diabetes
Authors: Kalscheuer Hannes , Lehnert Hendrik
Published: July 2018

Typ-1-Diabetes mellitus (T1DM) nimmt weltweit zu und ist eine der häufigsten chronischen Erkrankungen im Kindesalter. Allerdings manifestiert sich ein T1DM nicht selten erst im Erwachsenenalter – dann wird die eindeutige klinische Abgrenzung zum Typ-2-Diabetes (T2DM) mitunter schwierig. Andere Diabetesformen und Autoimmunsyndrome müssen ebenfalls berücksichtigt werden. Dieser Beitrag stellt die Möglichkeiten einer zielführenden Diagnostik vor.
Bupropion promotes alterations in the spermatogenesis of mice and congenital malformations in the offspring
Authors: Sanches Eliane S. A. M. , Tsuzuki Felipe , Joinhas Fábio A. , Martins Caio C. N. , Fernandes Glaura S. A. , Salles Maria J. S.
Published: July 2018

Bupropion hydrochloride (BUP) has been associated with male sexual dysfunction. The aim of this study was to evaluate the effects of BUP on the reproductive function of male mice and to evaluate offspring development. The mice were distributed into BUP group (40 mg kg−1) and control group (saline). On Day 35 of treatment the males were placed to mate with females and then killed on Day 46 for evaluation of reproductive function. On Day 18 of pregnancy, pregnant females were killed for evaluation of congenital malformations in the offspring. The BUP group showed a decrease in the Johnsen score (Control, 9.354 ± 0.092; BUP, 7.615 ± 0.147), Sertoli (Control, 5.623 ± 0.184; BUP, 4.215 ± 0.097) and Leydig (Control, 11.430 ± 0.817; BUP, 7.531 ± 0.213) cell counts, testosterone levels (Control, 783.5 ± 154.2 ng dL−1; BUP, 201.4 ± 54.8 ng dL−1) and sperm production (Control, 2.852 ± 0.211; BUP, 1.988 ± 0.116) and increased morphological alterations of the sperm head (Control, 8.134%; BUP, 10.423%) and tail (Control, 4.96%; BUP, 16.211%). The congenital malformations observed in BUP-derived offspring were: kyphosis (Control, 0.00%; BUP, 5.26%), retroverted rear legs (Control, 14.43%; BUP, 53.68%), incomplete ossification of the supraoccipital and exoccipital (Control, 21.82%; BUP, 86.00%) and sternum (Control, 25.45%; BUP, 82.00%). BUP had toxic effects on testicular function and teratogenic potential.
Experimental Evidence on Policy Approaches That Link Agricultural Subsidies to Water Quality Outcomes
Authors: Palm‐Forster Leah H. , Suter Jordan F. , Messer Kent D.
Published: July 2018

Improving water quality in agricultural landscapes is an ongoing challenge, and most agri‐environmental programs in the United States rely on voluntary adoption of conservation practices. Conservation‐compliance initiatives require producers to meet specific conservation standards to qualify for payments from farm programs. However, these requirements do not require actual improvements in observed water quality. In this study, we introduce policies to reduce nonpoint source pollution that link eligibility for agricultural subsidies to compliance with water quality goals. We then use economic laboratory experiments to provide empirical evidence related to the performance of these policies. In the policy treatments, participants risk losing some or all of their subsidies if the ambient pollution level exceeds an announced target. A novel feature of our experiment is that we test a policy treatment that ensures that no subsidies are lost if a producer implements a verifiable conservation technology that reduces emissions. In these experiments, policies that link the receipt of subsidies to ambient water quality nearly achieve the socially optimal level of pollution. The results suggest that water quality policies that rely on the threat of subsidy reductions are a potentially viable option for reducing aggregate water pollution. Although a policy that allows polluters to avoid potential losses by implementing a verifiable conservation technology could increase political support for ambient‐based policies, our results suggest that, depending upon the magnitudes of social damages from emissions and the cost of implementing a conservation technology, such policies may be less cost‐effective for a comparable reduction in pollution.
Recent advances and prospects of computational methods for metabolite identification: a review with emphasis on machine learning approaches
Authors: Nguyen Dai Hai , Nguyen Canh Hao , Mamitsuka Hiroshi
Published: July 2018

Motivation: Metabolomics involves studies of a great number of metabolites, which are small molecules present in biological systems. They play a lot of important functions such as energy transport, signaling, building block of cells and inhibition/catalysis. Understanding biochemical characteristics of the metabolites is an essential and significant part of metabolomics to enlarge the knowledge of biological systems. It is also the key to the development of many applications and areas such as biotechnology, biomedicine or pharmaceuticals. However, the identification of the metabolites remains a challenging task in metabolomics with a huge number of potentially interesting but unknown metabolites. The standard method for identifying metabolites is based on the mass spectrometry (MS) preceded by a separation technique. Over many decades, many techniques with different approaches have been proposed for MS-based metabolite identification task, which can be divided into the following four groups: mass spectra database, in silico fragmentation, fragmentation tree and machine learning. In this review paper, we thoroughly survey currently available tools for metabolite identification with the focus on in silico fragmentation, and machine learning-based approaches. We also give an intensive discussion on advanced machine learning methods, which can lead to further improvement on this task.
Compound–protein interaction prediction with end-to-end learning of neural networks for graphs and sequences
Authors: Tsubaki Masashi , Tomii Kentaro , Sese Jun
Published: July 2018

Motivation

In bioinformatics, machine learning-based methods that predict the compound–protein interactions (CPIs) play an important role in the virtual screening for drug discovery. Recently, end-to-end representation learning for discrete symbolic data (e.g. words in natural language processing) using deep neural networks has demonstrated excellent performance on various difficult problems. For the CPI problem, data are provided as discrete symbolic data, i.e. compounds are represented as graphs where the vertices are atoms, the edges are chemical bonds, and proteins are sequences in which the characters are amino acids. In this study, we investigate the use of end-to-end representation learning for compounds and proteins, integrate the representations, and develop a new CPI prediction approach by combining a graph neural network (GNN) for compounds and a convolutional neural network (CNN) for proteins.

Results

Our experiments using three CPI datasets demonstrated that the proposed end-to-end approach achieves competitive or higher performance as compared to various existing CPI prediction methods. In addition, the proposed approach significantly outperformed existing methods on an unbalanced dataset. This suggests that data-driven representations of compounds and proteins obtained by end-to-end GNNs and CNNs are more robust than traditional chemical and biological features obtained from databases. Although analyzing deep learning models is difficult due to their black-box nature, we address this issue using a neural attention mechanism, which allows us to consider which subsequences in a protein are more important for a drug compound when predicting its interaction. The neural attention mechanism also provides effective visualization, which makes it easier to analyze a model even when modeling is performed using real-valued representations instead of discrete features.

Availability and implementation

https://github.com/masashitsubaki

Supplementary information

Supplementary data are available at Bioinformatics online.
Statistical tests for detecting variance effects in quantitative trait studies
Authors: Dumitrascu Bianca , Darnell Gregory , Ayroles Julien , Engelhardt Barbara E
Published: July 2018

Motivation

Identifying variants, both discrete and continuous, that are associated with quantitative traits, or QTs, is the primary focus of quantitative genetics. Most current methods are limited to identifying mean effects, or associations between genotype or covariates and the mean value of a quantitative trait. It is possible, however, that a variant may affect the variance of the quantitative trait in lieu of, or in addition to, affecting the trait mean. Here, we develop a general methodology to identify covariates with variance effects on a quantitative trait using a Bayesian heteroskedastic linear regression model (BTH). We compare BTH with existing methods to detect variance effects across a large range of simulations drawn from scenarios common to the analysis of quantitative traits.

Results

We find that BTH and a double generalized linear model (dglm) outperform classical tests used for detecting variance effects in recent genomic studies. We show BTH and dglm are less likely to generate spurious discoveries through simulations and application to identifying methylation variance QTs and expression variance QTs. We identify four variance effects of sex in the Cardiovascular and Pharmacogenetics study. Our work is the first to offer a comprehensive view of variance identifying methodology. We identify shortcomings in previously used methodology and provide a more conservative and robust alternative. We extend variance effect analysis to a wide array of covariates that enables a new statistical dimension in the study of sex and age specific quantitative trait effects.

Availability and implementation

https://github.com/b2du/bth.

Supplementary information

Supplementary data are available at Bioinformatics online.
PingPongPro: a tool for the detection of piRNA-mediated transposon-silencing in small RNA-Seq data
Authors: Uhrig Sebastian , Klein Holger
Published: July 2018

Piwi-interacting RNAs (piRNAs) are a class of small non-coding RNAs which guide endonucleases to mRNAs of actively transcribed transposons in order to prevent their translation. The resulting mRNA fragments induce a positive feedback loop (the ‘ping-pong cycle’), which reinforces piRNA production and hence the transposon-silencing effect. PingPongPro is a command-line tool to scan small RNA-Seq data for signs of ping-pong cycle activity. It implements a novel algorithm that combines empirical probabilities in a multi-factor model to accurately identify transposons which are suppressed through the ping-pong cycle.

Availability and implementation

Source code, a user manual, and binaries for Microsoft Windows and Linux are available at https://github.com/suhrig/pingpongpro under the GPLv3 license.

Supplementary information

Supplementary data are available at Bioinformatics online.
GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia
Authors: Eidhof Ilse , Baets Jonathan , Kamsteeg Erik-Jan , Deconinck Tine , van Ninhuijs Lisa , Martin Jean-Jacques , Schüle Rebecca , Züchner Stephan , De Jonghe Peter , Schenck Annette , van de Warrenburg Bart P
Published: July 2018

Autosomal recessive cerebellar ataxias are a group of rare disorders that share progressive degeneration of the cerebellum and associated tracts as the main hallmark. Here, we report two unrelated patients with a new subtype of autosomal recessive cerebellar ataxia caused by biallelic, gene-disruptive mutations inGDAP2, a gene previously not implicated in disease. Both patients had onset of ataxia in the fourth decade. Other features included progressive spasticity and dementia. Neuropathological examination showed degenerative changes in the cerebellum, olive inferior, thalamus, substantia nigra, and pyramidal tracts, as well as tau pathology in the hippocampus and amygdala. To provide further evidence for a causative role ofGDAP2 mutations in autosomal recessive cerebellar ataxia pathophysiology, its orthologous gene was investigated in the fruit flyDrosophila melanogaster. Ubiquitous knockdown ofDrosophila Gdap2 resulted in shortened lifespan and motor behaviour anomalies such as righting defects, reduced and uncoordinated walking behaviour, and compromised flight. Gdap2 expression levels responded to stress treatments in control flies, and Gdap2 knockdown flies showed increased sensitivity to deleterious effects of stressors such as reactive oxygen species and nutrient deprivation. Thus,Gdap2 knockdown inDrosophila andGDAP2 loss-of-function mutations in humans lead to locomotor phenotypes, which may be mediated by altered responses to cellular stress.
Standardized classification and framework for reporting, interpreting, and analysing medication non-adherence in cardiovascular clinical trials: a consensus report from the Non-adherence Academic Research Consortium (NARC)
Authors: Valgimigli Marco , Garcia-Garcia Hector M , Vrijens Bernard , Vranckx Pascal , McFadden Eugène P , Costa Francesco , Pieper Karen , Vock David M , Zhang Min , Van Es Gerrit-Anne , Tricoci Pierluigi , Baber Usman , Steg Gabriel , Montalescot Gilles , Angiolillo Dominick J , Serruys Patrick W , Farb Andrew , Windecker Stephan , Kastrati Adnan , Colombo Antonio , Feres Fausto , Jüni Peter , Stone Gregg W , Bhatt Deepak L , Mehran Roxana , Tijssen Jan G P
Published: July 2018

Non-adherence has been well recognized for years to be a common issue that significantly impacts clinical outcomes and health care costs. Medication adherence is remarkably low even in the controlled environment of clinical trials where it has potentially complex major implications. Collection of non-adherence data diverge markedly among cardiovascular randomized trials and, even where collected, is rarely incorporated in the statistical analysis to test the consistency of the primary endpoint(s). The imprecision introduced by the inconsistent assessment of non-adherence in clinical trials might confound the estimate of the calculated efficacy of the study drug. Hence, clinical trials may not accurately answer the scientific question posed by regulators, who seek an accurate estimate of the true efficacy and safety of treatment, or the question posed by payers, who want a reliable estimate of the effectiveness of treatment in the marketplace after approval. The Non-adherence Academic Research Consortium is a collaboration among leading academic research organizations, representatives from the U.S. Food and Drug Administration and physician-scientists from the USA and Europe. One in-person meeting was held in Madrid, Spain, culminating in a document describing consensus recommendations for reporting, collecting, and analysing adherence endpoints across clinical trials. The adoption of these recommendations will afford robustness and consistency in the comparative safety and effectiveness evaluation of investigational drugs from early development to post-marketing approval studies. These principles may be useful for regulatory assessment, as well as for monitoring local and regional outcomes to guide quality improvement initiatives.
Age and growth rate estimations of the commercially fished gastropod Buccinum undatum
Authors: Hollyman Philip R , Chenery Simon R N , Leng Melanie J , Laptikhovsky Vladimir V , Colvin Charlotte N , Richardson Christopher A
Published: July 2018

Calculating age and growth rate for the commercially important whelk, Buccinum undatum in the aid of fishery management has historically been undertaken using growth rings on the organic operculum. This is difficult due to their poor readability and confusion between two different sets of growth lines present. Recent work presented the calcium carbonate statolith as an alternative for age determination of B. undatum. Here we compare the use of statoliths and opercula, comparing their readability and creating growth curves for three distinct populations across the United Kingdom. Using these data, we also test the most appropriate growth equation to model this species. Lastly, we use oxygen isotope analysis of the shells to assign accurate ages to several individuals from each site. These data were used to test the accuracy of statolith and operculum ages. Statoliths, whilst more time consuming to process have improved clarity and accuracy compared with the opercula. This improved readability has highlighted that a Gompertz growth function should be used for populations of this species, when in past studies, von Bertalanffy is often used. Statoliths are a viable improvement to opercula when assessing B. undatum in the context of fishery monitoring and management.
Marine environmental vulnerability and cumulative risk profiles to support ecosystem-based adaptive maritime spatial planning
Authors: Aps Robert , Herkül Kristjan , Kotta Jonne , Cormier Roland , Kostamo Kirsi , Laamanen Leena , Lappalainen Juho , Lokko Külli , Peterson Anneliis , Varjopuro Riku
Published: July 2018

Human use of marine and coastal areas is increasing worldwide, resulting in conflicts between different interests for marine space, overexploitation of marine resources, and environmental degradation. In this study we developed a methodology that combines assessments of marine environmental vulnerability and cumulative human pressures to support the processes of ecosystem-based adaptive maritime spatial planning. The methodology is built on the spatially explicit marine environmental vulnerability profile (EVP) that is an aggregated product of the distribution of essential nature values (habitat-forming benthic macroalgal and invertebrate species, benthic species richness, birds and seals as top marine predators) and their sensitivities to disturbances. The marine environmental cumulative risk profile (ERP) combines the EVP and the HELCOM Baltic Sea Pressure Index (BSPI), the latter representing the spatial distribution of intensities of cumulative anthropogenic pressures. The ERP identifies areas where environmental risks are the highest due to both long recoveries of the biota and high intensities of human pressures. This methodology can be used in any other sea areas by modifying the list of nature values, their sensitivity to disturbances, and the intensities of human pressure.
Optimal public health intervention in a behavioural vaccination model: the interplay between seasonality, behaviour and latency period
Authors: Buonomo Bruno , Della Marca Rossella , d’Onofrio Alberto
Published: July 2018

Hesitancy and refusal of vaccines preventing childhood diseases are spreading due to ‘pseudo-rational’ behaviours: parents overweigh real and imaginary side effects of vaccines. Nonetheless, the ‘Public Health System’ (PHS) may enact public campaigns to favour vaccine uptake. To determine the optimal time profiles for such campaigns, we apply the optimal control theory to an extension of the susceptible-infectious-removed (SIR)-based behavioural vaccination model by d’Onofrio et al. (2012, PLoS ONE, 7, e45653). The new model is of susceptible-exposed-infectious-removed (SEIR) type under seasonal fluctuations of the transmission rate. Our objective is to minimize the total costs of the disease: the disease burden, the vaccination costs and a less usual cost: the economic burden to enact the PHS campaigns. We apply the Pontryagin minimum principle and numerically explore the impact of seasonality, human behaviour and latency rate on the control and spread of the target disease. We focus on two noteworthy case studies: the low (resp. intermediate) relative perceived risk of vaccine side effects and relatively low (resp. very low) speed of imitation. One general result is that seasonality may produce a remarkable impact on PHS campaigns aimed at controlling, via an increase of the vaccination uptake, the spread of a target infectious disease. In particular, a higher amplitude of the seasonal variation produces a higher effort and this, in turn, beneficially impacts the induced vaccine uptake since the larger is the strength of seasonality, the longer the vaccine propensity remains large. However, such increased effort is not able to fully compensate the action of seasonality on the prevalence.
Sharp Area Bounds for Free Boundary Minimal Surfaces in Conformally Euclidean Balls
Authors: Freidin Brian , McGrath Peter
Published: July 2018

We prove that the area of a free boundary minimal surface $\Sigma ^2 \subset B^n$, where $B^n$ is a geodesic ball contained in a round hemisphere $\mathbb{S}^n_+$, is at least as big as that of a geodesic disk with the same radius as $B^n$; equality is attained only if $\Sigma $ coincides with such a disk. More generally, we prove analogous results for a class of conformally euclidean ambient spaces. This follows works of Brendle and Fraser–Schoen in the euclidean setting.
Rigidity of Linearly Constrained Frameworks
Authors: Cruickshank James , Guler Hakan , Jackson Bill , Nixon Anthony
Published: July 2018

We consider the problem of characterising the generic rigidity of bar-joint frameworks in $\mathbb{R}^d$ in which each vertex is constrained to lie in a given affine subspace. The special case when $d=2$ was previously solved by Streinu and Theran [14] in 2010. We will extend their characterisation to the case when $d\geq 3$ and each vertex is constrained to lie in an affine subspace of dimension $t$, when $t=1,2$ and also when $t\geq 3$ and $d\geq t(t-1)$. We then point out that results on body–bar frameworks obtained by Katoh and Tanigawa [8] in 2013 can be used to characterise when a graph has a rigid realisation as a $d$-dimensional body–bar framework with a given set of linear constraints.
Identification of validated case definitions for medical conditions used in primary care electronic medical record databases: a systematic review
Authors: McBrien Kerry A , Souri Sepideh , Symonds Nicola E , Rouhi Azin , Lethebe Brendan C , Williamson Tyler S , Garies Stephanie , Birtwhistle Richard , Quan Hude , Fabreau Gabriel E , Ronksley Paul E
Published: July 2018

Objectives

Data derived from primary care electronic medical records (EMRs) are being used for research and surveillance. Case definitions are required to identify patients with specific conditions in EMR data with a degree of accuracy. The purpose of this study is to identify and provide a summary of case definitions that have been validated in primary care EMR data.

Materials and Methods

We searched MEDLINE and Embase (from inception to June 2016) to identify studies that describe case definitions for clinical conditions in EMR data and report on the performance metrics of these definitions.

Results

We identified 40 studies reporting on case definitions for 47 unique clinical conditions. The studies used combinations of International Classification of Disease version 9 (ICD-9) codes, Read codes, laboratory values, and medications in their algorithms. The most common validation metric reported was positive predictive value, with inconsistent reporting of sensitivity and specificity.

Discussion

This review describes validated case definitions derived in primary care EMR data, which can be used to understand disease patterns and prevalence among primary care populations. Limitations include incomplete reporting of performance metrics and uncertainty regarding performance of case definitions across different EMR databases and countries.

Conclusion

Our review found a significant number of validated case definitions with good performance for use in primary care EMR data. These could be applied to other EMR databases in similar contexts and may enable better disease surveillance when using clinical EMR data. Consistent reporting across validation studies using EMR data would facilitate comparison across studies.

Systematic review registration

PROSPERO CRD42016040020 (submitted June 8, 2016, and last revised June 14, 2016)
3D deep learning for detecting pulmonary nodules in CT scans
Authors: Gruetzemacher Ross , Gupta Ashish , Paradice David
Published: July 2018

Objective

To demonstrate and test the validity of a novel deep-learning-based system for the automated detection of pulmonary nodules.

Materials and Methods

The proposed system uses 2 3D deep learning models, 1 for each of the essential tasks of computer-aided nodule detection: candidate generation and false positive reduction. A total of 888 scans from the LIDC-IDRI dataset were used for training and evaluation.

Results

Results for candidate generation on the test data indicated a detection rate of 94.77% with 30.39 false positives per scan, while the test results for false positive reduction exhibited a sensitivity of 94.21% with 1.789 false positives per scan. The overall system detection rate on the test data was 89.29% with 1.789 false positives per scan.

Discussion

An extensive and rigorous validation was conducted to assess the performance of the proposed system. The system demonstrated a novel combination of 3D deep neural network architectures and demonstrates the use of deep learning for both candidate generation and false positive reduction to be evaluated with a substantial test dataset. The results strongly support the ability of deep learning pulmonary nodule detection systems to generalize to unseen data. The source code and trained model weights have been made available.

Conclusion

A novel deep-neural-network-based pulmonary nodule detection system is demonstrated and validated. The results provide comparison of the proposed deep-learning-based system over other similar systems based on performance.
Characterization of Serotonin Signaling Components in Patients with Inflammatory Bowel Disease
Authors: Shajib Md Sharif , Chauhan Usha , Adeeb Salman , Chetty Yeshale , Armstrong David , Halder Smita L S , Marshall John K , Khan Waliul I
Published: July 2018

Background

Tryptophan hydroxylase (TPH)1 catalyzes the biosynthesis of serotonin (5-hydroxytrptamine; 5-HT) in enterochromaffin (EC) cells, the predominant source of gut 5-HT. Secreted 5-HT regulates various gut functions through diverse 5-HT receptor (5-HTR) families, and 5-HT transporter (5-HTT) sequesters its activity via uptake into surrounding cells. In inflammatory bowel disease (IBD) mucosal 5-HT signaling is altered, including upregulated EC cell numbers and 5-HT levels. We examined key mucosal 5-HT signaling components and blood 5-HT levels and, as part of a pilot study, investigated the association between 5-HTT gene-linked polymorphic region (5HTTLPR) and Crohn’s disease (CD).

Methods

In the context of inflammation, colonic expressions of TPH1, 5-HTT and 5-HTRs were studied in CD patients (n=15) and healthy controls (HC; n=10) using quantitative polymerase chain reaction (qPCR). We also investigated 5HTTLPR in 40 CD patients and HC utilizing PCR and measured platelet-poor plasma (PPP) and plasma 5-HT concentrations.

Results

Compared with HC, inflammation in CD patients was associated with elevated TPH1, 5-HTR3, 5-HTR4, 5-HTR7 and downregulated 5-HTT expressions. In our second cohort of participants, significantly higher PPP and plasma 5-HT levels and higher S-genotype (L/S+S/S) than L/L genotype were observed in CD patients compared with HC.

Conclusion

Our results suggest that augmented mucosal 5-HT signaling and specific 5-HTTLPR genotype–associated decreased efficiency in 5-HT reuptake, the latter through increased 5-HT availability, may contribute to inflammation in CD patients. These findings revealed important information on various components of 5-HT signaling in intestinal inflammation which may ultimately lead to effective strategies targeting this pathway in IBD.
Procedural Issues in International Investment Arbitration
Authors: Commission Jeffery , Moloo Rahim
Published: July 2018

Procedural issues are an area of increasing complexity and concern in modern investment arbitration, and one in which very little guidance currently exists. There are a number of important points of departure from the procedural rules commonly adopted in the context of international-commercial arbitration. This book is the first of its kind to address this gap, examining the most prevalent and controversial procedural issues that arise in investment arbitration proceedings conducted under the International Centre for Settlement of Investment Disputes (ICSID), UNCITRAL, and other arbitral rules. The book takes the reader through an investment arbitration in chronological order, identifying each key procedural issue in turn and providing details of the relevant precedents. It charts the process of an arbitration from applicable law and first sessions right through to cost submissions and statements of costs and post-award remedies. Fully cross-referenced and tabled, the book is an invaluable and practical guide to issues of increasing importance and relevance in ICSID and other arbitrations today.
The Law Applicable to Procedural Issues
Authors: Commission Jeffery , Moloo Rahim
Published: July 2018

This chapter examines the various sources of procedural law in investment arbitration and articulates a hierarchy among those sources. It first considers the procedural law selected by the parties to the arbitration, emphasizing the fact that some of the laws selected by the parties impose mandatory rules that cannot then be deviated from, while others are binding, unless the parties later decide on a separate course. It then explains how the appropriate governing rules can be determined when the rules selected by the parties are silent. In particular, it describes the arbitral tribunals' role to fill gaps in the rules and suggests that, in doing so, the tribunals and the parties rely on the context of the applicable procedural rules, certain soft law protocols, and prior arbitral practice for guidance.
Provisional Measures
Authors: Commission Jeffery , Moloo Rahim
Published: July 2018

This chapter discusses the provisional measures used to preserve the integrity of an investment arbitration. It first reviews the applicable rules and standards utilized by arbitral tribunals to determine whether to grant a request for provisional measures, including before tribunals applying the International Centre for Settlement of Investment Disputes (ICSID), ICSID Additional Facility, and UNCITRAL rules. In particular, it outlines five criteria that must generally be met to grant a request for provisional measures: prima facie jurisdiction, prima facie establishment of the case, urgency, imminent danger of serious prejudice (necessity), and proportionality. The chapter proceeds by considering case examples of the types of provisional measures requested by parties, namely: security for costs, specific performance, stop parallel domestic proceedings, preservation of documents, preservation of status quo, and non-aggravation of the dispute.
The Splitting of Issues for Separate Determination (Bifurcation/Trifurcation)
Authors: Commission Jeffery , Moloo Rahim
Published: July 2018

This chapter focuses on one of the most important procedural decisions a tribunal can make in an investment arbitration: the bifurcation or trifurcation of issues into separate phases. The rationale behind bifurcation/trifurcation is straightforward: bifurcation may result in the narrowing or even dismissal of claims, but can significantly increase the costs and duration of an arbitration. This has not gone unnoticed by users of the International Centre for Settlement of Investment Disputes (ICSID) and other systems of dispute settlement. After discussing the relevant arbitration rules that govern the decisions of arbitral tribunals on bifurcation, the chapter considers the various procedural aspects of bifurcation requests. It also examines the number of bifurcation requests actually filed in ICSID and UNCITRAL arbitrations, how tribunals decided those requests, and the factors applied by tribunals in those decisions.
Evidentiary Issues
Authors: Commission Jeffery , Moloo Rahim
Published: July 2018

This chapter examines evidentiary issues that arise in investment arbitrations. It first reviews the basic procedures through which the evidentiary record is generally established in international arbitrations before discussing the procedural rules that usually apply in investment arbitration cases. In particular, it considers both the mandatory law and the specific rules that parties are likely to select as applying to an investment dispute. It then explains how tribunals in investment arbitrations have approached key evidentiary issues differently than tribunals in commercial cases, paying attention to issues relating to the collection and presentation of evidence that could apply to any investment dispute. The chapter proceeds by analysing unique evidentiary issues that arise in the context of allegations of corruption and concludes with a brief overview of the unique rules for amicus-curiae submissions that address an additional source that arbitral tribunals may take into account in investment, but generally not commercial, arbitrations.
Hearing Procedures
Authors: Commission Jeffery , Moloo Rahim
Published: July 2018

This chapter examines the components of a typical investment arbitration hearing as well as various procedural issues that arise in the context of the hearing. Hearings often present the best opportunity to test the evidence and arguments presented by the parties over the course of an arbitration. It is therefore important to give both parties an equal and adequate opportunity to present their case at the hearing. Yet, there is a desire to conduct the hearing in an efficient manner. The goal in adopting hearing procedures is to strike a balance between these considerations. The chapter first considers how parties and the tribunal will want to plan for the hearing at the outset. It then discusses the pre-hearing procedures and the hearing itself, taking into account the order of proceedings, cases where witnesses/experts are unavailable to testify in person, transcription of proceedings, and transparency and confidentiality of the hearing.
Post-Award Applications
Authors: Commission Jeffery , Moloo Rahim
Published: July 2018

This chapter focuses on International Centre for Settlement of Investment Disputes (ICSID) and UNCITRAL tribunal practice on post-award applications. It begins with a discussion of certain post-award remedies under the ICSID Convention and ICSID Additional-Facility arbitral rules, including requests for supplementary decision, rectification/correction, interpretation and revision. It then considers annulment under the ICSID Convention, with emphasis on the conduct and procedure for annulment proceedings, the number of annulment applications and rates of success, and the constitution and composition of ad-hoc committees. It also examines the practice of stays of enforcement in annulment proceedings, and in particular the relatively long line of ICSID decisions rendered by ad-hoc committees on such applications. Finally, it outlines the post-award remedies available to parties under the UNCITRAL Arbitration Rules.
General Obligations of States to Take Effective Action to Combat Impunity
Authors: Roht-Arriaza Naomi
Published: July 2018

In general, Principle 1 is the introduction and cornerstone to the Principles. It defines state responsibility for the interrelated obligations spelled out in the Principles, emphasizing the mandatory, interrelated, non-hierarchical nature of these obligations in addition to responsibility for the underlying violations. Principle 1 is based on then-existing jurisprudence of the regional human rights courts and the United Nations human rights bodies, as well as from academic and non-governmental commentary. This chapter first provides a historical background and discusses the contemporary context in which Principle 1 is applied. It then describes the normative (legal/ethical) foundation of the Principle, focusing on how its interpretation is influenced by international law and how it relates to notions of transitional justice. It also analyzes the applications of the Principle in practice before concluding with an assessment of some of its ambiguities and weaknesses.
The Duty to Preserve Memory
Authors: Viebach Julia
Published: July 2018

Principle 3 is concerned with the duty to preserve memory, which falls under the rubric of ‘the right to know’. This principle recognizes the role of collective memory in transitional processes, attests to a people’s right to know ‘the history of its oppression’ as part of its heritage, and calls upon the state’s duty to preserve archives and other evidence. This chapter first provides a historical background and an overview of the contemporary context in which Principle 3 is applied before outlining its normative framework, focusing on case law and truth commissions. It also analyzes the applications of the Principle in practice and argues that the duty to preserve memory has only implicitly been addressed under either symbolic reparations in truth-seeking processes or under satisfaction in jurisprudence. It contends that this approach over-simplifies the collective and societal level and neglects the dangers and complexity of memorialization in transitional contexts.
Guarantees for Persons Implicated
Authors: Bisset Alison
Published: July 2018

Principle 9 provides guarantees of procedural fairness for persons implicated in past violations. An important element of a commission’s historical account is to identify those responsible for past violations, which contributes to the fulfilment of the right to truth. However, the consequences of being named in a final report can have important ramifications, especially for an individual’s reputation, family life and privacy. Before commissions publish findings in relation to specific persons, best practice dictates that information implicating individuals be corroborated and that they be afforded a right to reply to the allegations against them. Such requirements impose administrative burdens on commissions given their often limited resources and short temporal mandates. After giving a contextual and historical background on Principle 9, this chapter discusses its theoretical framework and how commissions operate in practice in terms of verifying the allegations against certain individuals.
Adequate Resources for Commissions
Authors: Varney Howard
Published: July 2018

Principle 11 guarantees adequate resources in support of a commission of inquiry so that it can comply with its legal mandate without compromising its independence and autonomy. A commission with autonomy means that it has control over its own finances and may make its own decisions in respect of the allocation of its resources. The issue of autonomy is inextricably linked to the independence of a commission. This chapter first provides a contextual and historical background on Principle 11 before discussing its theoretical framework, focusing on international law instruments governing the investigation of human rights violations that oblige state parties to adequately resource the responsible investigative agency. In particular, it considers the role of competent authorities, explicit duty, funding principles, and political will. It also examines how commissions of inquiry have been supported in practice and cautions against proceeding with commissions where adequate support is not guaranteed.