bluuebunny/crossref_metadata_2025_split huggingface dataset:
Article 102 TFEU: Introduction and Dominant Position
Authors: Jones Alison , Sufrin Brenda , Dunne Niamh 
Published: September 2019

Abstract
Article 102 TFEU deals with the unilateral conduct of undertakings with substantial market power. It thus prohibits one or more undertakings which hold a dominant position in the internal market or a substantial part of it abusing that position insofar as it may affect inter-Member State trade. This chapter discusses the role of Article 102 and the controversy attending its application, and introduces the elements which must be established before the prohibition applies. The Commission’s review of Article 102 and the publication of its Guidance Paper on enforcement priorities, and the relationship between Article 102 and Article 101, are also considered. The chapter then explores in detail one of the principal limbs of the Article 102 prohibition, namely the concept of an undertaking holding a ‘dominant position’ in a relevant market. The definition of a dominant position in the case law of the Court is discussed, alongside its relation to the concept of substantial market power, including the Commission’s treatment in the Guidance Paper. The chapter then considers how dominance is established, addressing, inter aliai, the definition of the relevant market for the purposes of Article 102; the role of market share in establishing dominance; barriers to entry and other factors indicating dominance; and dominant positions in the digital economy. Article 102
Article 102 TFEU: Conduct Which Can Be an Abuse
Authors: Jones Alison , Sufrin Brenda , Dunne Niamh 
Published: September 2019

Abstract
This chapter discusses the difficult concept of what constitutes an ‘abuse’ of a dominant position for the purposes of Article 102 and whether conduct should be condemned on account of the form it takes or only for its effects. It considers the case law of the EU Courts, the decisional practice of the Commission, and the Commission’s Guidance Paper on enforcement priorities, and the problem of distinguishing competition on the merits from illegimate conduct. The chapter looks at the different classifications of abuse, particularly exclusionary and exploitative abuses; the distinction between form- and effects-based approaches to types of abuse; the leveraging of market power between distinct markets as a theory of harm; the objective justification defence; and general issues in respect of abuses concerning prices, including the ‘as efficient competitor’ test. The chapter then examines the application of Article 102 to various forms of conduct, including: price discrimination; predatory pricing; selective low pricing; margin squeeze; exclusive dealing;; tying and bundling; refusal to supply; self-preferencing; malicious pursuit of legal proceedings; ‘regulatory gaming’; discrimination abuses; unfairly high and low pricing; hindering inter-Member State trade; and more novel claimed abuses within the digital economy.
Mergers
Authors: Jones Alison , Sufrin Brenda , Dunne Niamh 
Published: September 2019

Abstract
This chapter discusses the regime for controlling mergers which have an ‘EU dimension’ under the European Union Merger Regulation (EUMR). The chapter examines: the purposes of merger control; the history of the EUMR; the scheme of the EUMR and the concept of the ‘one-stop shop’; jurisdiction under the EUMR, including the definition of a ‘concentration’ and what amounts to an ‘EU dimension’; procedure, including Phase I and Phase II proceedings; the substantive appraisal of horizontal, and non-horizontal mergers under the EUMR and the test of significantly impeding effective competition (SIEC); EUMR statistics; appeals; and international issues.
Improving the phenotype risk score as a scalable approach to identifying patients with Mendelian disease
Authors: Bastarache Lisa , Hughey Jacob J , Goldstein Jeffrey A , Bastraache Julie A , Das Satya , Zaki Neil Charles , Zeng Chenjie , Tang Leigh Anne , Roden Dan M , Denny Joshua C 
Published: September 2019

Abstract

Objective
The Phenotype Risk Score (PheRS) is a method to detect Mendelian disease patterns using phenotypes from the electronic health record (EHR). We compared the performance of different approaches mapping EHR phenotypes to Mendelian disease features.

Materials and Methods
PheRS utilizes Mendelian diseases descriptions annotated with Human Phenotype Ontology (HPO) terms. In previous work, we presented a map linking phecodes (based on International Classification of Diseases [ICD]-Ninth Revision) to HPO terms. For this study, we integrated ICD-Tenth Revision codes and lab data. We also created a new map between HPO terms using customized groupings of ICD codes. We compared the performance with cases and controls for 16 Mendelian diseases using 2.5 million de-identified medical records.

Results
PheRS effectively distinguished cases from controls for all 15 positive controls and all approaches tested (P &lt; 4 × 1016). Adding lab data led to a statistically significant improvement for 4 of 14 diseases. The custom ICD groupings improved specificity, leading to an average 8% increase for precision at 100 (-2% to 22%). Eight of 10 adults with cystic fibrosis tested had PheRS in the 95th percentile prio to diagnosis.

Discussion
Both phecodes and custom ICD groupings were able to detect differences between affected cases and controls at the population level. The ICD map showed better precision for the highest scoring individuals. Adding lab data improved performance at detecting population-level differences.

Conclusions
PheRS is a scalable method to study Mendelian disease at the population level using electronic health record data and can potentially be used to find patients with undiagnosed Mendelian disease.
Microtubule-dependent transport of arenavirus matrix protein demonstrated using live-cell imaging microscopy
Authors: Takamatsu Yuki , Kajikawa Junichi , Muramoto Yukiko , Nakano Masahiro , Noda Takeshi 
Published: September 2019

AbstractLassa virus (LASV), belonging to the family Arenaviridae, causes severe haemorrhagic manifestations and is associated with a high mortality rate in humans. Thus, it is classified as a biosafety level (BSL)-4 agent. Since countermeasures for LASV diseases are yet to be developed, it is important to elucidate the molecular mechanisms underlying the life cycle of the virus, including its viral and host cellular protein interactions. These underlying molecular mechanisms may serve as the key for developing novel therapeutic options. Lymphocytic choriomeningitis virus (LCMV), a close relative of LASV, is usually asymptomatic and is categorized as a BSL-2 agent. In the present study, we visualized the transport of viral matrix Z protein in LCMV-infected cells using live-cell imaging microscopy. We demonstrated that the transport of Z protein is mediated by polymerized microtubules. Interestingly, the transport of LASV Z protein showed characteristics similar to those of Z protein in LCMV-infected cells. The live-cell imaging system using LCMV provides an attractive surrogate measure for studying arenavirus matrix protein transport in BSL-2 laboratories. In addition, it could be also utilized to analyze the interactions between viral matrix proteins and the cellular cytoskeleton, as well as to evaluate the antiviral compounds that target the transport of viral matrix proteins.
Balamuthia mandrillaris-Related Primary Amoebic Encephalitis in China Diagnosed by Next Generation Sequencing and a Review of the Literature
Authors: Yang Yinan , Hu Xiaobin , Min Li , Dong Xiangyu , Guan Yuanlin 
Published: September 2019

AbstractBackgroundEncephalitis is caused by infection, immune mediated diseases, or primary inflammatory diseases. Of all the causative infectious pathogens, 90% are viruses or bacteria. Granulomatous amoebic encephalitis (GAE), caused by Balamuthia mandrillaris, is a rare but life-threatening disease. Diagnosis and therapy are frequently delayed due to the lack of specific clinical manifestations.MethodA healthy 2 year old Chinese male patient initially presented with a nearly 2 month history of irregular fever. We present this case of granulomatous amoebic encephalitis caused by B. mandrillaris. Next generation sequencing of the patient’s cerebrospinal fluid (CSF) was performed to identify an infectious agent.ResultThe results of next generation sequencing of the CSF showed that most of the mapped reads belonged to Balamuthia mandrillaris.ConclusionNext generation sequencing (NGS) is an unbiased and rapid diagnostic tool. The NGS method can be used for the rapid identification of causative pathogens. The NGS method should be widely applied in clinical practice and help clinicians provide direction for the diagnosis of diseases, especially for rare and difficult cases.
Mobilization of the Vertebral Artery—Surgical Option for C2 Screw Fixation in Cases With “High Riding” Vertebral Artery
Authors: Goel Atul , Rangnekar Ranjit , Shah Abhidha , Rai Survendra , Vutha Ravikiran 
Published: September 2019

Abstract

BACKGROUND
Mobilization of intraosseous course of vertebral artery for safe screw insertion into pedicle of axis in cases with high riding vertebral artery is discussed.

OBJECTIVE
To show drilling, exposure, and mobilization of the “high-riding” vertebral artery loop during its course in relationship with superior facet/pedicle of C2 vertebra can provide safety to techniques of atlantoaxial fixation that involve insertion of screws in the pars/pedicle/facet of C2.

METHODS
During the period June 2016 to April 2018, 15 patients operated for atlantoaxial stabilization underwent vertebral artery exposure and mobilization using the technique discussed. The ages of the patients ranged from 6 to 48 yrs. Four patients had mobile and reducible atlantoaxial dislocation. Seven patients had basilar invagination. Four patients had os-odontoideum. Gentle and precise drilling of bone that covers the “high-riding” vertebral artery can lead to its safe and wide surgical exposure. The arterial loop can then be either completely or partially mobilized out of the vertebral artery groove such that C2 screw insertion can be conducted under direct surgical visualization of the vertebral artery.

RESULTS
During the average follow-up period of 14 mo, there have been no complications related to the surgical procedure, metal implant, or vertebral artery.

CONCLUSION
Vertebral artery exposure and mobilization is rather simple and safe procedure and is remarkably effective in providing a space for C2 screw implantation.
A Multidisciplinary Patient-Specific Opioid Prescribing and Tapering Protocol Is Associated with a Decrease in Total Opioid Dose Prescribed for Six Weeks After Total Hip Arthroplasty
Authors: Tamboli Mallika , Mariano Edward R , Gustafson Kerianne E , Briones Beverly L , Hunter Oluwatobi O , Wang Rachel R , Harrison T Kyle , Kou Alex , Mudumbai Seshadri C , Kim T Edward , Indelli Pier F , Giori Nicholas J 
Published: September 2019

Abstract

Objective
This retrospective cohort study tested the hypothesis that implementing a multidisciplinary patient-specific discharge protocol for prescribing and tapering opioids after total hip arthroplasty (THA) will decrease the morphine milligram equivalent (MME) dose of opioids prescribed.

Methods
With institutional review board approval, we analyzed a Perioperative Surgical Home database and prescription data for all primary THA patients three months before (PRE) and three months after (POST) implementation of this new discharge opioid protocol based on patients’ prior 24-hour inpatient opioid consumption. The primary outcome was total opioid dosage in MME prescribed and opioid refills for six weeks after surgery. Secondary outcomes included the number of tablets and MME prescribed at discharge, in-hospital opioid consumption, length of stay, and postoperative complications.

Results
Forty-nine cases (25 PRE and 24 POST) were included. Total median (10th–90th percentiles) MME for six weeks postoperatively was 900 (57–2082) MME PRE vs 295 (69–741) MME POST (mean difference = 721, 95% confidence interval [CI] = 127–1316, P = 0.007, Mann-Whitney U test). Refill rates did not differ. The median (10th–90th percentiles) initial discharge prescription in MME was 675 (57–1035) PRE vs 180 (18–534) POST (mean difference = 387, 95% CI = 156–618, P = 0.003, Mann-Whitney U test) MME. There were no differences in other outcomes.

Conclusions
Implementation of a patient-specific prescribing and tapering protocol decreases the mean six-week dosage of opioid prescribed by 63% after THA without increasing the refill rate.
Extracting Benefits from Standardization of Digital Forensic Practices
Authors: Cusack Brian 
Published: September 2019

Abstract
Standardization offers consistencies for interoperability between jurisdictions and organizational entities. In some instances, accreditation and certification services are available to assure the reputational transfer of conformance and the compliance with best practice requirements. The impact of these benefits is a more predictable environment in which to deliver sensitive and high-risk services, leading to the reduction in failures and the enhancement of inter-party trust. In this article, the case of international standardization for digital forensic and related services is articulated as an example of structured planning for robust processes and practices that have user trust. Political and economic expediency has always reduced the implementation of standardization to functional attributes and short-term returns. The advocacy is for the long-term investment in standardization and the creation of trusted practices for predictable and robust scientific procedures in the transfer of operational knowledge and the preservation of digital evidences.
30. The paradox
Authors: Saleh Mohammed , Jenkins Charlotte 
Published: September 2019

Abstract

Introduction
Incidental findings on investigations is not uncommon in rheumatology practice. Here such an incidental finding has led to dramatic change in the management of the underlying disease.

Case description
A 38-year-old gentleman known to have ankylosing spondylitis (AS) since 2008, with radiologically evident sacroilitis on X-ray and MRI, was reviewed routinely in clinic and reported pain and restriction of neck movement and subsequent MRI cervical spine in April 2017 has shown incidental finding of apical fibrosis, but no AS activity.
He denied constitutional and respiratory symptoms apart from occasional dry cough. Chest X-ray and high resolution CT scan confirmed the same findings of apical fibrosis in addition to bilateral reticulonodular and fisural changes. Blood tests showed angiotensin converting Eezyme level ACE 65 U/L (normal range 8-65), C-reactive protein <5.
Bronchoscopy/biopsy showed non-caseating epitheliod granuloma. ZN stain and culture showed no TB infection. He was reviewed by the respiratory team and felt findings could conceivably fit with sarcoidosis.
His dry cough has improved after Benepali was discontinued in June 2017 and no steroids were given. However, had a flare of AS symptoms (ribs and lower back pain and stiffness, right SIJ pain) despite regular etoricoxib and required to start on secukinumab.

Discussion
Benepali (Etanercept biosimilar) sounds not different from the originator biologic in causing sarcoid-like reactions commonly present as skin rash and lung lesions. Etanercept is associated with a large majority of reported anti-TNF induced sarcoid-like cases, not effective in treating sarcoidosis and may even exacerbate it.
However, there are few reports of adalimumab induced sarcoid-like reactions that resolved when treated with etanercept. Paradoxical reaction to one TNF alfa inhibitor does not preclude the use of other TNF blocking agents including etanercept.

Key learning points
Lung lesions after exposure to anti-TNF warrants investigating a wide range of differential diagnoses. Paradoxical sarcoid-like reactions can occur with anti-TNF treatment and resolves on discounting it. Alternative biologic in ankylosing spondylitis might be a challenge.

Conflicts of interest
The authors have declared no conflicts of interest.
6. Treatment resistant ulcerating dermatomyositis in metastatic melanoma treated with checkpoint inhibitor therapy
Authors: Parker Lucy , Coull Philippa , Soliotis Fotini 
Published: September 2019

Abstract

Introduction
Paraneoplastic dermatomyositis is a well-recognised clinical entity, and should prompt investigation for an underlying malignancy. Immunosuppressive treatment can be effective in control of both skin and muscle disease. The effect of checkpoint inhibitors for control of solid tumours on autoimmune paraneoplastic phenomena is yet to be fully understood.

Case description
A 49-year-old female with a background of melanoma on the left thigh 2014 (Breslow thickness 1.9mm, treated with wide local excision only) presented with classical features of dermatomyositis; facial erythema, V-sign, Gottron’s papules, muscle weakness and elevated creatine kinase (CK) at 711 IU/L. An MRI of the upper arms was consistent with myositis. Myositis ENA panel was negative. She was initially treated with high dose oral prednisolone and weekly methotrexate. At presentation, there was no clinical or radiographic evidence of recurrent melanoma, but unfortunately after 7 months she developed a lump in the left groin which proved to be metastatic melanoma (stage IV M1a).
She was treated with 3 months palliative pembrolizumab, but this was discontinued due to lack of clinical response, when an interval CT scan showed increasing volume of disease (progressive left pelvic, retroperitoneal and left supra-clavicular fossa lymphadenopathy).
Her skin disease remained painful despite 20mg PO prednisolone and 25mg of subcutaneous methotrexate weekly, so she was treated with intravenous immunoglobulin (IVIG) 2g/kg planned to be given over 5 days. On day 3, she was found to be pyrexial at 38.2 degrees celcius prior to commencement of the infusion. Treatment was delayed by 2 days. On day 6 she was again apyrexial and the IVIG treatment was completed with IV paracetamol and 100mg IV hydrocortisone given alongside.
Following the IVIG, she has developed areas of painful localised ulceration over the dorsi of her feet, limbs and forehead. Her skin disease remains active with facial swelling and erythema, florid Gottron’s papules and periungual erythema. The ulcerated areas are discrete from the areas of known metastasis, and are considered to be secondary to severe dermal inflammation which is being treated with betnovate ointment, with a plan to introduce hydroxychloroquine if there is no clinical improvement.

Discussion
The use of checkpoint inhibitors to treat solid tumours is increasing. The autoimmune side effects of this group are well documented, and pembrolizumab is known to trigger dermatitis as a treatment related adverse event. However, the implications for checkpoint inhibitor use in an existing paraneoplastic autoimmune phenomenon is not yet understood.

Key learning points
Thorough investigation for underlying malignancy is paramount in new dermatomyositis. Patients treated with checkpoint inhibitors should be monitored closely for disease activity.

Conflicts of interest
The authors have declared no conflicts of interest.
The Effects of Genotype × Phenotype Interactions on Transcriptional Response to Silver Nanoparticle Toxicity in Organotypic Cultures of Murine Tracheal Epithelial Cells
Authors: Nicholas Tyler P , Haick Anoria K , Bammler Theo K , Workman Tomomi W , Kavanagh Terrance J , Faustman Elaine M , Gharib Sina A , Altemeier William A 
Published: September 2019

Abstract
The airway epithelium is critical for maintaining innate and adaptive immune responses, and occupational exposures that disrupt its immune homeostasis may initiate and amplify airway inflammation. In our previous study, we demonstrated that silver nanoparticles (AgNP), which are engineered nanomaterials used in multiple applications but primarily in the manufacturing of many antimicrobial products, induce toxicity in organotypic cultures derived from murine tracheal epithelial cells (MTEC), and those differentiated toward a “Type 2 [T2]-Skewed” phenotype experienced an increased sensitivity to AgNP toxicity, suggesting that asthmatics could be a sensitive population to AgNP exposures in occupational settings. However, the mechanistic basis for this genotype × phenotype (G × P) interaction has yet to be defined. In this study, we conducted transcriptional profiling using RNA-sequencing to predict the enrichment of specific canonical pathways and upstream transcriptional regulators to assist in defining a mechanistic basis for G × P effects on AgNP toxicity. Organotypic cultures were derived from MTEC across 2 genetically inbred mouse strains (A/J and C57BL/6J mice), 2 phenotypes (“Normal” and “T2-Skewed”), and 1 AgNP exposure (an acute 24 h exposure) to characterize G × P effects on transcriptional response to AgNP toxicity. The “T2-Skewed” phenotype was marked by increased pro-inflammatory T17 responses to AgNP toxicity, which are significant predictors of neutrophilic/difficult-to-control asthma and suggests that asthmatics could be a sensitive population to AgNP exposures in occupational settings. This study highlights the importance of considering G × P effects when identifying these sensitive populations, whose underlying genetics or diseases could directly modify their response to AgNP exposures.
Neuromelanin Modulates Heterocyclic Aromatic Amine-Induced Dopaminergic Neurotoxicity
Authors: Lawana Vivek , Um Se Young , Rochet Jean-Christophe , Turesky Robert J , Shannahan Jonathan H , Cannon Jason R 
Published: September 2019

Abstract
Heterocyclic aromatic amines (HAAs) are mutagens and potential human carcinogens. Our group and others have demonstrated that HAAs may also produce selective dopaminergic neurotoxicity, potentially relevant to Parkinson’s disease (PD). The goal of this study was to elucidate mechanisms of HAA-induced neurotoxicity through examining a translational biochemical weakness of common PD models. Neuromelanin is a pigmented byproduct of dopamine metabolism that has been debated as being both neurotoxic and neuroprotective in PD. Importantly, neuromelanin is known to bind and potentially release dopaminergic neurotoxicants, including HAAs (eg, β-carbolines such as harmane). Binding of other HAA subclasses (ie, aminoimidazoaazarenes) to neuromelanin has not been investigated, nor has a specific role for neuromelanin in mediating HAA-induced neurotoxicity been examined. Thus, we investigated the role of neuromelanin in modulating HAA-induced neurotoxicity. We characterized melanin from Sepia officinalis and synthetic dopamine melanin, proposed neuromelanin analogs with similar biophysical properties. Using a cell-free assay, we demonstrated strong binding of harmane and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to neuromelanin analogs. To increase cellular neuromelanin, we transfected SH-SY5Y neuroblastoma cells with tyrosinase. Relative to controls, tyrosinase-expressing cells exhibited increased neuromelanin levels, cellular HAA uptake, cell toxicity, and oxidative damage. Given that typical cellular and rodent PD models form far lower neuromelanin levels than humans, there is a critical translational weakness in assessing HAA-neurotoxicity. The primary impacts of these results are identification of a potential mechanism by which HAAs accumulate in catecholaminergic neurons and support for the need to conduct neurotoxicity studies in systems forming neuromelanin.