bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-Governmental Organizations and the ASEAN Charter
Authors: Rüland Jürgen
Published: May 2018

Non-governmental organizations were the main antipode to the Indonesian government in the ASEAN Charter debate. The chapter shows how NGOs proliferated in Indonesia’s post-1998 democratization and became major actors in the country’s domestic politics, including the debate on Indonesia’s ASEAN policies. The chapter examines how civil society activists localized European concepts of regional integration. NGOs promoted bolder reforms than did the government, focusing on popular empowerment in regional decision making, human rights protection, and social benefits for the less advantaged segments of society. NGOs pleaded for an “alternative regionalism” or “regionalism from below,” which critically evaluated ASEAN’s government-driven market-opening reforms. Even more than the government, NGOs also imported ideas on regionalism not only from Europe, but also from Latin America and Africa. Yet NGOs, too, localized these alien concepts of regionalism with extant ideas on welfare, organicism, anticapitalist traditions, and—to a lesser extent—security.
The Press and the ASEAN Charter
Authors: Rüland Jürgen
Published: May 2018

The chapter highlights the changes in Indonesian print media after democratization and their increased role in foreign policy debates and discourses on regionalism. Based on Acharya’s localization theory, the chapter explores the print media’s ideas on the reform of Southeast Asia’s regionalism. The print media contributed strongly to the ASEAN Charter debate, stressing democracy, increased welfare, and security improvements as major motivations for the reforms. While they, too, were receptive of European ideas, in their articles and editorials journalists fused them with the country’s organicist traditions, leadership claims, soft power, and notions of survivalism.
Business and the ASEAN Charter
Authors: Rüland Jürgen
Published: May 2018

Economic interest groups proliferated after the end of the Suharto regime. They, too, became major stakeholders in foreign policy decisions, especially those with implications for the international competitiveness of Indonesian businesses. The chapter investigates how and to what extent business representatives localized EU norms of regional integration. Interestingly, public contributions of business interests to the Charter debate were rare, and the economic implications of the ASEAN Economic Community (AEC) envisaged in the Charter were discussed only much later. Yet responses to the AEC’s common market and production base differed. While EU-style market-opening reforms were supported by large, export-oriented firms, the majority of small- and medium-scale industries producing for the domestic market rejected them. Business representatives localized reforms imitating the EU model, too, thereby relying on ancient prosperity ideas, the vulnerability discourse, leadership, and soft power.
Introduction: Terra Nullius in Zion?
Authors: Kedar Alexandre , Amara Ahmad , Yiftachel Oren
Published: May 2018

The introduction presents the general setting and outlines the book’s main research questions. It does so by reviewing four key events of recent conflictual encounters between Israeli authorities and Bedouin communities, as telling entry points for the book ahead. The chapter than highlights the book's main arguments, mainly dealing with the development of a 'Dead Negev Doctrine' as an Israeli version of a colonial 'terra nullius' approach, through which most of the Bedouin tribes of the Negev (Naqab) have been thoroughly dispossessed. The introduction also outlines the book's main approaches, methods, sources and structure
The Land Regime of the British Mandate Period
Authors: Kedar Alexandre , Amara Ahmad , Yiftachel Oren
Published: May 2018

This chapter continues to cover the history of Southern Palestine and the transformation of the local land system by covering the British Mandate period, 1917–1948. The chapter explores the evolution of British-Bedouin relations and the special Mandate administration of the Beersheba sub-district that granted relative autonomy to Bedouin tribes to run their affairs. The chapter then outlines the significant changes introduced by the British to local the land system in Palestine, particularly the changes to the regime of “dead” (Mewat) lands and the 1928 land Settlement Ordinance. These changes are highly relevant to the Dead Negev Doctrine, and to date form the foundation of Bedouin dispossession. As a key historical legal insight, the chapter analyzes Jewish land purchases from Bedouin land owners, demonstrating the land ownership of the indigenous Bedouins, and British acknowledgement of these rights which were routinely entered into the land registry.
Formulating the Dead Negev Doctrine During the Israeli Period
Authors: Kedar Alexandre , Amara Ahmad , Yiftachel Oren
Published: May 2018

Formulating the Dead Negev Doctrine During the Israeli Period
Chapter abstract: This chapter focuses on the history and impact of the Dead Negev Doctrine—the legal doctrine utilized by the Israeli government and judiciary to dispossess Bedouin Arab communities of their lands. The chapter begins with the land claims lodged by the Bedouins in the early 1970’s and the special governmental committee established in response in 1975 (headed by Pliah Albeck of the State Attorney Office, the mastermind behind the DND). The chapter shows how the DND manipulated Ottoman and British law to determine that all Bedouin lands in the Negev should be classified as mewat and thus “state land,” and how it defined the Bedouin claimants as trespassers on their own lands. First adopted by the Israeli Supreme Court in 1984 in the al-Hawashlah precedent, and applied to hundreds of cases since, the doctrine has led to major evictions, crops’ demolitions, and house demolitions by the Israeli state.
Historical Geography of the Negev: Bedouin Agriculture
Authors: Kedar Alexandre , Amara Ahmad , Yiftachel Oren
Published: May 2018

This chapter begins the task of challenging the geographical components of the DND, by providing a thorough account of the historical geography of the Negev, drawing on various historical accounts of European travelers and Zionists. Relying on these accounts, it challenges the hegemonic history and narrative that depict the Negev as an uncultivated and unsettled desert used by nomadic Bedouins. The chapter demonstrates that the human geography of the northern Negev was characterized, at least from the 19th century, by widespread agriculture, in parallel to traditional pastoralism. There is ample evidence that Bedouin agricultural settlement in general had existed for centuries, including among the al-‘Uqbi tribe in the ‘Araqib area. The chapter shows organized local habitation and economic activities, based on a customary and well developed land system.
The bedouins as an Indigenous Community
Authors: Kedar Alexandre , Amara Ahmad , Yiftachel Oren
Published: May 2018

The chapter seeks to answer the question: are the Bedouins an indigenous people? It first addresses the positions of the Israeli state as well as a group of Israeli scholars who deny the indigeneity of the Bedouins and cling to anachronistic concepts and definitions concerning indigeneity. The chapter then demonstrates that contrary to Israel’s position, the Negev Bedouins correspond to current international standard characterizations and experiences of indigenous peoples. It relates to international debates and discussions over the definition of indigenous peoples with special focus on the various transformations of the internally-accepted definition of indigeneity and its application to the Palestinians in general, and the Negev Bedouins in particular.
International Law, Indigenous Land Rights, and Israel
Authors: Kedar Alexandre , Amara Ahmad , Yiftachel Oren
Published: May 2018

This chapter explores the development of international law on indigeneity. It reviews the legal protections endowed by key documents, such as International Labor Organizations Convention No. 169 and the United Nations Declaration on the Rights of Indigenous Peoples (UNDRIP). The chapter also provides a short comparative legal perspective on land rights of indigenous peoples which helps to situate the Israeli case within other settler colonial situations and to address the status of the relevant international legislation and norms. It concludes that several components of the UNDRIP have gained a status of international customary law, and hence with growing relevance to Israeli jurisprudence and to the Bedouins. The chapter ends by addressing the question of indigenous peoples’ rights in Israeli law and how Israeli basic laws should expand to incorporate the legal protection of the Bedouins.
Unlikely Allies
Authors: Leavitt-Alcántara Brianna
Published: May 2018

Evidence from wills highlight the striking number of non-elite women living outside of marriage who successfully professed as lay Franciscan tertiaries, that is, as members of the powerful Franciscan Third Order. Chapter 2 explores how and why priests in Guatemala’s colonial capital, especially Franciscans and Jesuits, allied with poor single and widowed laywomen and supported active and unenclosed female religiosity. Santiago de Guatemala’s status as a distant provincial capital, removed from the Inquisition’s close oversight and without the institutional resources necessary to enforce female enclosure, led to greater tolerance of lay female religiosity and single women compared to larger cities like Mexico City and Lima. At the same time, global missionary movements forged diverse models of female piety and sustained support for active female ministries. These findings suggest the need to modify interpretations of early modern Catholicism as primarily hostile towards single women and lay female religiosity.
Change within Continuity
Authors: Oi Jean C. , Goldstein Steven M.
Published: May 2018

This chapter introduces the volume and offers an in-depth analyzes of the changes that have taken place in Zouping’s political economy over the last 15 years. It poses the core question of whether China’s political institutions have somehow managed to cope despite remaining basically unreformed, or have there been more subtle and profound changes in the way that the old organizational structures actually operate. Ad hoc bureaucratic adaptations and accommodations change the operation, if not the organizational form, of local government institutions, where existing agencies play new and unexpected roles. It is institutional agility, with on-going political change masked by outward continuity in formal organization. The sections on the county’s economic development include original analysis of the county’s changing economic structure, the shift from public to private enterprise, and the political consequences of economic change. The chapter ends with a summary of the different chapters in the volume.
Nonjudicial Interpreters of “Legality” and the Development of Law in the Local State
Authors: Grob Douglas B.
Published: May 2018

This chapter examines the origins, development, and operations of the Zouping County Legal Affairs Office, and shows how non-judicial actors are charged with “legalizing” the local administrative state. The chapter explicates administrative rulemaking processes in Zouping, and the role that the Office plays in them. The chapter explains how institutional structure empowers the Office to pre-empt, mediate, and resolve administrative conflicts. Over time, the Office has been retooled and assigned tasks beyond its original scope of work. As a non-judicial interpreter of “legality,” it has provided local government officials and departments room and procedures with which to adapt to local demands and changing circumstances.
Reforming and Updating Cadre Training in Zouping’s Communist Party Schools
Authors: Lee Charlotte
Published: May 2018

Institutions of cadre training in Zouping have adjusted to the broad transformations that have swept across the party and Chinese society. Changes in cadre training at the local level demonstrate the responsiveness of traditional Leninist organizations, such as grassroots party schools, to a rapidly changing environment. Cadre training has fragmented, and there now exist myriad providers of services that compete and complement the work of party schools. Party schools have responded to competition by diversifying their portfolio of activities. This indicates that there is adaptive capacity within local party organizations, but these organizations must strike a careful balance between the political imperatives of the party and the economic pressures of the market.
Institutional Agility and Regime Adaptation
Authors: Oi Jean C. , Goldstein Steven M.
Published: May 2018

This chapter concludes the volume, stressing that the barely perceptible changes have permitted an outwardly unchanging government to adapt flexibly in the way that it operates, resulting in institutional agility. It underscores the point that looking closely at the internal operations of local administrative systems reveal significant changes that have taken place within largely unchanged political structures. It acknowledges that one might debate the extent to which the practices described in this volume amount to significant political change, but argues that without these chapters and the fieldwork that went into them the question could not even be considered. It ends by making clear that the goal in this volume is not to argue that governance has become more democratic. The purpose is to provide some insights into how a single party authoritarian system has managed to govern despite fundamental changes in the economy and society.
Rival giant telescopes join to seek U.S. funding
Authors: Hand Eric
Published: May 2018

Projects will offer "public access" in bid for support from astronomy community.
A call to arms against the other retrovirus
Authors: Kupferschmidt Kai
Published: May 2018

HTLV-1, discovered just before HIV but almost forgotten, infects millions and causes cancer.
The war on gluten
Authors: Servick Kelly
Published: May 2018

Wheat sensitivity isn't imaginary, most researchers now agree. But what's really behind it?
From local collective behavior to global migratory patterns in white storks
Authors: Flack Andrea , Nagy Máté , Fiedler Wolfgang , Couzin Iain D. , Wikelski Martin
Published: May 2018

GPS tagging reveals leaders and followers among migrating white storks.
Response to Comment on “Plant diversity increases with the strength of negative density dependence at the global scale”
Authors: LaManna Joseph A. , Mangan Scott A. , Alonso Alfonso , Bourg Norman A. , Brockelman Warren Y. , Bunyavejchewin Sarayudh , Chang Li-Wan , Chiang Jyh-Min , Chuyong George B. , Clay Keith , Cordell Susan , Davies Stuart J. , Furniss Tucker J. , Giardina Christian P. , Gunatilleke I. A. U. Nimal , Gunatilleke C. V. Savitri , He Fangliang , Howe Robert W. , Hubbell Stephen P. , Hsieh Chang-Fu , Inman-Narahari Faith M. , Janík David , Johnson Daniel J. , Kenfack David , Korte Lisa , Král Kamil , Larson Andrew J. , Lutz James A. , McMahon Sean M. , McShea William J. , Memiaghe Hervé R. , Nathalang Anuttara , Novotny Vojtech , Ong Perry S. , Orwig David A. , Ostertag Rebecca , Parker Geoffrey G. , Phillips Richard P. , Sack Lawren , Sun I-Fang , Tello J. Sebastián , Thomas Duncan W. , Turner Benjamin L. , Vela Díaz Dilys M. , Vrška Tomáš , Weiblen George D. , Wolf Amy , Yap Sandra , Myers Jonathan A.
Published: May 2018

Hülsmann and Hartig suggest that ecological mechanisms other than specialized natural enemies or intraspecific competition contribute to our estimates of conspecific negative density dependence (CNDD). To address their concern, we show that our results are not the result of a methodological artifact and present a null-model analysis that demonstrates that our original findings—(i) stronger CNDD at tropical relative to temperate latitudes and (ii) a latitudinal shift in the relationship between CNDD and species abundance—persist even after controlling for other processes that might influence spatial relationships between adults and recruits.
Comment on “Plant diversity increases with the strength of negative density dependence at the global scale”
Authors: Chisholm Ryan A. , Fung Tak
Published: May 2018

LaManna
et al
. (Reports, 30 June 2017, p. 1389) found higher conspecific negative density dependence in tree communities at lower latitudes, yielding a possible mechanistic explanation for the latitudinal diversity gradient. We show that their results are artifacts of a selective data transformation and a forced zero intercept in their fitted model. A corrected analysis shows no latitudinal trend.
An ingestible bacterial-electronic system to monitor gastrointestinal health
Authors: Mimee Mark , Nadeau Phillip , Hayward Alison , Carim Sean , Flanagan Sarah , Jerger Logan , Collins Joy , McDonnell Shane , Swartwout Richard , Citorik Robert J. , Bulović Vladimir , Langer Robert , Traverso Giovanni , Chandrakasan Anantha P. , Lu Timothy K.
Published: May 2018

Using bugs in the gut to detect blood

Bacteria are environmentally resilient and can be engineered to sense various biomolecules. Mimee
et al.
combined biosensor bacteria with a miniaturized wireless readout capsule to produce a minimally invasive device capable of in vivo biosensing in harsh, difficult-to-access environments (see the Perspective by Gibson and Burgell). The device successfully measured gastrointestinal bleeding in pigs.

Science
, this issue p.
915
; see also p.
856
Intervention planning for the REDUCE maintenance intervention: a digital intervention to reduce reulceration risk among patients with a history of diabetic foot ulcers
Authors: Greenwell Kate , Sivyer Katy , Vedhara Kavita , Yardley Lucy , Game Frances , Chalder Trudie , Richards Gayle , Drake Nikki , Gray Katie , Weinman John , Bradbury Katherine
Published: May 2018

Objectives

To develop a comprehensive intervention plan for the REDUCE maintenance intervention to support people who have had diabetic foot ulcers (DFUs) to sustain behaviours that reduce reulceration risk.

Methods

Theory-based, evidence-based and person-based approaches to intervention development were used. In phase I of intervention planning, evidence was collated from a scoping review of the literature and qualitative interviews with patients who have had DFUs (n=20). This was used to identify the psychosocial needs and challenges of this population and barriers and facilitators to the intervention’s target behaviours: regular foot checking, rapid self-referral in the event of changes in foot health, graded and regular physical activity and emotional management. In phase II, this evidence was combined with expert consultation to develop the intervention plan. Brief ‘guiding principles’ for shaping intervention development were created. ‘Behavioural analysis’ and ‘logic modelling’ were used to map intervention content onto behaviour change theory to comprehensively describe the intervention and its hypothesised mechanisms.

Results

Key challenges to the intervention’s target behaviours included patients’ uncertainty regarding when to self-refer, physical limitations affecting foot checking and physical activity and, for some, difficulties managing negative emotions. Important considerations for the intervention design included a need to increase patients’ confidence in making a self-referral and in using the maintenance intervention and a need to acknowledge that some intervention content might be relevant to only some patients (emotional management, physical activity). The behavioural analysis identified the following processes hypothesised to facilitate long-term behaviour maintenance including increasing patients’ skills, self-efficacy, knowledge, positive outcome expectancies, sense of personal control, social support and physical opportunity.

Conclusions

This research provides a transparent description of the intervention planning for the REDUCE maintenance intervention. It provides insights into potential barriers and facilitators to the target behaviours and potentially useful behaviour change techniques to use in clinical practice.
Psychometric properties of the St George’s Respiratory Questionnaire in patients with idiopathic pulmonary fibrosis: insights from the INPULSIS trials
Authors: Swigris Jeffrey J , Wilson Hilary , Esser Dirk , Conoscenti Craig S , Stansen Wibke , Kline Leidy Nancy , Brown Kevin K
Published: May 2018

Introduction

We evaluated the psychometric properties of the St George’s Respiratory Questionnaire (SGRQ) in patients with idiopathic pulmonary fibrosis (IPF) using data from the two INPULSIS trials.

Methods

Data from 1061 patients treated with nintedanib or placebo were pooled. Internal consistency, test–retest reliability, construct validity, known-groups validity, responsiveness and responder thresholds were examined.

Results

Cronbach’s α was 0.93 for SGRQ total score and >0.75 for domain scores. In patients with stable disease based on change in forced vital capacity (FVC) ≤5% predicted or ‘no change’ on Patient’s Global Impression of Change, intraclass correlation coefficients for the SGRQ total score were 0.72 or 0.76, respectively. Moderate to strong correlations were observed between SGRQ total and domain scores and the Cough and Sputum Assessment Questionnaire cough domains (−0.34 to −0.65), University of California San Diego Shortness of Breath Questionnaire (0.56 to 0.83) and EuroQol 5-Dimensional Quality of Life Questionnaire Visual Analogue Scale (−0.41 to −0.55); correlations with FVC % predicted were weak (−0.24 to −0.30). Longitudinal correlations between changes in SGRQ total score and these patient-reported outcomes over 52 weeks were moderate. Changes in SGRQ total, impact and activity scores were sensitive to detecting improvement or deterioration in FVC >10% predicted at week 52. Collectively, distribution-based and anchor-based approaches suggested using a change of 4–5 points in SGRQ total score as a starting point for responder analyses.

Conclusions

The psychometric properties of the SGRQ support its use as a measure of health-related quality of life in patients with IPF.
Italian consensus conference on guidelines for conservative treatment on lower limb muscle injuries in athlete
Authors: Bisciotti Gian Nicola , Volpi Piero , Amato Maurizio , Alberti Giampietro , Allegra Francesco , Aprato Alessandro , Artina Matteo , Auci Alessio , Bait Corrado , Bastieri Gian Matteo , Balzarini Luca , Belli Andrea , Bellini Gianandrea , Bettinsoli Pierfrancesco , Bisciotti Alessandro , Bisciotti Andrea , Bona Stefano , Brambilla Lorenzo , Bresciani Marco , Buffoli Michele , Calanna Filippo , Canata Gian Luigi , Cardinali Davide , Carimati Giulia , Cassaghi Gabriella , Cautero Enrico , Cena Emanuele , Corradini Barbara , Corsini Alessandro , D'Agostino Cristina , De Donato Massimo , Delle Rose Giacomo , Di Marzo Francesco , Di Pietto Francesco , Enrica Drapchind , Eirale Cristiano , Febbrari Luigi , Ferrua Paolo , Foglia Andrea , Galbiati Alberto , Gheza Alberto , Giammattei Carlo , Masia Francesco , Melegati Gianluca , Moretti Biagio , Moretti Lorenzo , Niccolai Roberto , Orgiani Antonio , Orizio Claudio , Pantalone Andrea , Parra Federica , Patroni Paolo , Pereira Ruiz Maria Teresa , Perri Marzio , Petrillo Stefano , Pulici Luca , Quaglia Alessandro , Ricciotti Luca , Rosa Francesco , Sasso Nicola , Sprenger Claudio , Tarantola Chiara , Tenconi Fabio Gianpaolo , Tosi Fabio , Trainini Michele , Tucciarone Agostino , Yekdah Ali , Vuckovic Zarko , Zini Raul , Chamari Karim
Published: May 2018

Provide the state of the art concerning (1) biology and aetiology, (2) classification, (3) clinical assessment and (4) conservative treatment of lower limb muscle injuries (MI) in athletes. Seventy international experts with different medical backgrounds participated in the consensus conference. They discussed and approved a consensus composed of four sections which are presented in these documents. This paper represents a synthesis of the consensus conference, the following four sections are discussed: (i) The biology and aetiology of MIs. A definition of MI was formulated and some key points concerning physiology and pathogenesis of MIs were discussed. (ii) The MI classification. A classification of MIs was proposed. (iii) The MI clinical assessment, in which were discussed anamnesis, inspection and clinical examination and are provided the relative guidelines. (iv) The MI conservative treatment, in which are provided the guidelines for conservative treatment based on the severity of the lesion. Furthermore, instrumental therapy and pharmacological treatment were discussed. Knowledge of the aetiology and biology of MIs is an essential prerequisite in order to plan and conduct a rehabilitation plan. Another important aspect is the use of a rational MI classification on prognostic values. We propose a classification based on radiological investigations performed by ultrasonography and MRI strongly linked to prognostic factors. Furthermore, the consensus conference results will able to provide fundamental guidelines for diagnostic and rehabilitation practice, also considering instrumental therapy and pharmacological treatment of MI. Expert opinion, level IV.
Prehospital emergency anaesthesia: an updated survey of UK practice with emphasis on the role of standardisation and checklists
Authors: Burgess Mark R , Crewdson Kate , Lockey David J , Perkins Zane B
Published: May 2018

Introduction

Prehospital emergency anaesthesia (PHEA or ‘prehospital rapid sequence intubation’) is a high-risk procedure. Standard operating procedures (SOPs) and checklists within healthcare systems have been demonstrated to reduce human error and improve patient safety. We aimed to describe the current practice of PHEA in the UK, determine the use of checklists for PHEA and describe the content, format and layout of any such checklists currently used in the UK.

Method

A survey of UK prehospital teams was conducted to establish the incidence and conduct of PHEA practice. Results were grouped into systems delivering a high volume of PHEA per year (>50 PHEAs) and low volume (≤50 PHEAs per annum). Standard and ‘crash’ (immediate) induction checklists were reviewed for length, content and layout.

Results

59 UK physician-led prehospital services were identified of which 43 (74%) participated. Thirty services (70%) provide PHEA and perform approximately 1629 PHEAs annually. Ten ‘high volume’ services deliver 84% of PHEAs per year with PHEA being performed on a median of 11% of active missions. The most common indication for PHEA was trauma. 25 of the 30 services (83%) used a PHEA checklist prior to induction of anaesthesia and 24 (80%) had an SOP for the procedure. 19 (76%) of the ‘standard’ checklists and 5 (50%) of the ‘crash’ induction checklists used were analysed. On average, standard checklists contained 169 (range: 52–286) words and 41 (range: 28–70) individual checks. The style and language complexity varied significantly between different checklists.

Conclusion

PHEA is now performed commonly in the UK. The use of checklists for PHEA is relatively common among prehospital systems delivering this intervention. Care must be taken to limit checklist length and to use simple, unambiguous language in order to maximise the safety of this high-risk intervention.
A simple technique to construct tissue macroarrays
Authors: Dias Eliane P , Picciani Bruna L S , Santos Vanessa de C B dos , Cunha Karin S
Published: May 2018

Aims

In the diagnostic or research field, there is a need that the histopathological evaluation provides as much information as possible, with the shortest time and lowest cost. The development of the tissue microarray (TMA) technology has significantly facilitated and accelerated studies with tissue analyses using in situ technologies. Nevertheless, one of the most recognised limitations of TMA is that the small cores used to construct a TMA may not accurately represent characteristics of the whole tissue specimen. The aim is to present the technical aspects of a simple system to construct tissue macroarrays (TMaAs), its advantages and limitations, and some results of its use in for research purposes.

Methods

The study presents three possibilities of preparing the specimens with up to 6 mm diameter to be included into the TMaA paraffin block using our method.

Results

With this technique, it was possible to obtain glass slides with multiple whole fragments, which were used in five different studies.

Conclusions

We presented a method for construction of multi-TMaA paraffin blocks, which is very simple for optimising laboratory techniques requiring paraffin-embedded tissue sections and can be easily implemented in any institution with a histology laboratory.
011 Ex-vivo generation of plasmin from patients with acute ischaemic stroke is predictive of successful thrombolysis
Authors: Levi Chris , Lillicrap Thomas , Harman Stevi , Draxler Dominik , Niego Be’Eri , Ho Heidi , McCutcheon Fiona , Kleinig Timothy , Koblar Simon , Hamilton-Bruce Monica Anne , Garcia-Esperon Carlos , Lincz Lisa , Bivard Andrew , Attia John , Maguire Jane , Holliday Elizabeth , Medcalf Robert
Published: May 2018

Introduction

Thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) fails in more than 60% of patients with acute ischaemic stroke (AIS). Simultaneously, there are risks associated with the use of rt-PA, including the risk of symptomatic intracranial haemorrhage (sICH) even in patients who do re-canalise. While thrombus location, aetiology and infarct size can affect the likelihood of successful thrombolysis, other factors distinguishing patients who re-canalise from those who don’t have yet to be fully elucidated. The ability of rt-PA to promote thrombolysis is dependent upon its capacity to generate plasmin, and we set out to test this capacity ex-vivo. We hypothesised that patients with low plasmin generating capacity are less likely to re-canalise following rt-PA treatment.

Methods

Plasma was obtained from 90 AIS patients up to 1 hour before thrombolysis and screened for baseline levels of plasminogen, anti-plasmin, and plasmin-anti-plasmin (PAP) complexes. The degree of inducible plasmin generation was determined using amidolytic assays following ex-vivo addition of rt-PA for 1 hour. ELISA assays were also used to quantitate the fold-increase in PAP complex levels after rt-PA treatment.

Results

rt-PA inducible PAP levels, a surrogate for the capacity to generate plasmin from plasminogen, varied dramatically between patients. The ratio of post-thrombolysis PAP to pre-thrombolysis PAP ranged from 3.4 to 105.9 within the cohort examined for this study. Multivariate regression analyses revealed that each fold increase in PAP levels was associated with a 4.2% increase in the odds of recanalisation (p=0,035) when corrected for blood glucose levels.

Conclusion

This is the first report of ex vivo-inducible plasmin generation as a predictor of thrombolysis. The predictive power of this screening assay for sICH is still under investigation.
014 The diagnostic odyssey for fabry disease: ten years experience in testing
Authors: Dobbins Julia , Fuller Maria , Pyragius Tim , Brion Kristian , Chin Sharon , Gurner Melissa , Pacyna Janina , Stark Samantha , Fletcher Janice M
Published: May 2018

Introduction

Fabry disease is an X-linked disorder of glycosphingolipid metabolism arising from a deficiency of the enzyme, α-galactosidase A (AGA). In the absence of a family history, biochemical diagnosis is conferred by reduced activity in dried filter paper blood spots (DBS), elevations in globotriaosylsphingosine (lyso-Gb3) and/or identification of a mutation within the GLA gene.

Methods

From 2008 to 2012, AGA determinations were performed on leucocytes and in 2012, DBS testing was introduced. A mass spectrometric method to quantify lyso-Gb3 in plasma was added to our repertoire of testing in 2016. Mutation analysis was performed using either Sanger or Next Generation Sequencing, the latter confirmed by sequencing.

Results

Between 2008 and 2012, approximately 1000 samples were screened for Fabry disease using AGA determinations in leucocytes and 29 patients were confirmed positive (diagnosis rate of 2.9%). Since 2012, approximately 4000 samples have been screened from DBS, with 126 patients being confirmed positive (diagnosis rate of 3.2%). There were 24 patients with AGA deficiency and a GLA gene variant which did not have elevated lyso-Gb3 (approximately 20% of positives).

Discussion

Fabry disease is a relatively complicated disease to diagnose and requires significant interpretation of results from all three tests. As an X-linked disease, classically affected males are easier to identify, but females are more difficult to diagnose as their DBS can be normal, even when symptomatic. Further testing via lyso-Gb3 and mutation analysis is required to make a final biochemical diagnosis. The ease of submitting a DBS for testing has contributed to an increase in test requests.
032 Neurological sequelae of immune checkpoint inhibitors: a case series
Authors: Silsby Matthew , Duma Stephen R , Mahant Neil , Vucic Steve , Henderson Andrew
Published: May 2018

Introduction

Monoclonal antibodies directed against co-stimulatory molecules on T cells (checkpoint inhibitors, CIs) are used to treat solid organ malignancies. Neurological complications are an increasingly recognised consequence of their use. We present three patients referred to the Neurology service at Westmead Hospital in 2017 with new neurological complaints following CI therapy.

Cases

Patient 1, a 54 year old woman with stage IV non-small cell lung cancer treated with pembrolizumab (anti-PD-1), presented with cerebral vasculitis causing bilateral ACA territory cerebral infarction. Patient 2, a 59 year old woman with metastatic melanoma treated with ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1), presented with ataxia, diplopia and ptosis consistent with Miller Fisher syndrome. Patient 3, a 77 year old woman with metastatic colorectal adenocarcinoma treated with nivolumab (anti-PD-1), presented with ocular myasthenia manifesting as fatigable ptosis and complex ophthalmoplegia.

The diagnoses were made by clinical assessment with imaging and neurophysiological investigations where possible. Antibodies relevant to the neurological condition were negative, in keeping with previous reports. CIs were discontinued in all patients. Treatment included intravenous pulsed methylprednisolone followed by high dose oral taper in all patients. Additionally, Patient 1 was treated with infliximab and rituximab; Patients 2 and 3 received intravenous immunoglobulin followed by monthly maintenance therapy; Patient 2 underwent plasma exchange. Patients 1 and 2 recovered independent ambulation. Patient 3 died two months after presentation due to underlying malignancy.

Conclusion

Checkpoint inhibitors block co-stimulatory molecules on T-cells, allowing the immune system to mount an anti-tumour response. The resulting immune dysregulation can also lead to organ-specific inflammatory and immune complications, of which neurological sequelae are increasingly recognised. The three reported patients highlight the spectrum of disease that can arise. Their occurrence within one year suggests an increasing incidence, and a need for increased vigilance. Early recognition is paramount as treatment with high dose corticosteroids, even in conditions that would not normally respond, is recommended.
039 Rates of lymphopenia in years 1–4 in patients with relapsing multiple sclerosis treated annually with cladribine tablets
Authors: Cook Stuart , Comi Giancarlo , Giovannoni Gavin , Rieckmann Peter , Sorensen Per Soelberg , Vermersch Patrick , Dangond Fernando , King John , Hicking Christine
Published: May 2018

Introduction

The CLARITY and CLARITY Extension studies demonstrated the efficacy of cladribine tablets in patients with relapsing multiple sclerosis. The most common adverse event was lymphopenia, consistent with the mechanism of action of cladribine tablets. Objective was to evaluate whether lymphopenia persists following annual treatment with cladribine tablets.

Methods

Lymphopenia by grade (NCI CTCAE v3.0) for patients randomised to cladribine tablets 3.5 mg/kg in CLARITY and re-randomised to cladribine tablets 3.5 mg/kg in CLARITY Extension (7 mg/kg cumulative dose over 4 years; n=186) are reported. Patients with Grade 0 lymphopenia (≥1.0×109 cells/L) before the first course of cladribine tablets and Grade 0/1 (≥0.8×109 cells/L) prior to administration in Years 2, 3 and 4 were included in the analysis.

Results

176 patients were Grade 0 at CLARITY baseline and 167 were Grade 0/1 at CLARITY Extension baseline. Grade 3 lymphopenia was observed in 1% of patients at Week 13 in Year 1, and in 7%, 11% and 12% at Week 12 in Years 2, 3 and 4, respectively. By Week 24 in Years 1, 2, 3 and 4, Grade 3 lymphopenia was observed in 1%, 4%, 4% and 4% of patients, respectively. By Week 36 in Years 1, 2, 3 and 4, Grade 3 lymphopenia was observed in 1%, 2%, 2% and 2% of patients, respectively. Grade 3 lymphopenia was only observed in Week 48 of Year 2 (1% of patients). Grade 3 lymphopenia was reported in <18% of patients at any time point. No patients had Grade 4 lymphopenia at the end of any years.

Conclusion

No patients included in this analysis experienced Grade 4 lymphopenia at the end of any treatment year. Grade 3 lymphopenia was uncommon. This study demonstrates the effectiveness of lymphocyte-based treatment criteria in minimising the incidence of severe, sustained lymphopenia during treatment with cladribine tablets.
048 Large pseudo-meningocele causing severe papilledema, retinal haemorrhages and recurrent positional syncope
Authors: Hooi Wai Foong , Waterston John
Published: May 2018

Introduction

Pseudo-meningocele is an abnormal collection of cerebrospinal fluid in the extradural space that occurs due to leakage from the CSF-filled spaces surrounding the brain and spinal cord. Pseudo-meningocele may result after spinal surgery. We report a case of a young woman with pseudo-meningocele post lumbar spinal surgery. She subsequently developed recurrent syncope, headaches and clinical signs of raised intracranial pressure (severe papilledema and retinal haemorrhages).

Case

A 34 year old woman with spina bifida occulta and a large lipoma at the lumbar spinal level of L5 presented with urinary retention, worsening right leg pain, numbness and foot drop. She subsequently underwent L4-S1 laminectomy, debulking of lipoma and detethering of the cord. Her neurological deficits resolved post-surgery. One month later, the patient re-presented with recurrent syncope and intermittent headaches. She was admitted to the hospital for further investigations. Detailed neurological examination revealed grade IV papilledema and retinal haemorrhages. MRI of the brain showed distended optic nerve sheaths and narrowed distal transverse sinuses, in keeping with intracranial hypertension. MRI spine showed a large CSF collection posterior to the spinal canal at the L4-L5 level, measuring 77×53 mm in trans axial plane and 98 mm in craniocaudal dimension. Her symptoms improved with insertion of external ventricular drain. The symptoms resolved completely after a ventriculo-peritoneal shunt was inserted. She was commenced on acetazolamide. She remained well and asymptomatic. Repeat fundus photography a month later showed complete resolution of papilledema.

Conclusion

Postoperative pseudo-meningocele is uncommon and the exact incidence is unknown as most of these patients are asymptomatic. This case illustrates that pseudo-meningocele can cause raised intracranial pressure leading to recurrent syncope. It is important for clinician to recognise the varied clinical presentations of meningocele and pseudo-meningocele.

References

. Marlin A, Epstein F, Rovid R. Positional headache and syncope associated with a pseudomeningocele. Arch Neurol1980;37(11):736–737.

. Bekavac I, Hollaran J. Meningocele-induced positional syncope and retinal haemorrhages. AJNR Am J NeuroradiolMay 2003;24:838–839.

. Arseni C, Maretsis M. Tumours of the lower spinal cord associated with increased intracranial pressure and papilloedema. J Neurosurg1967;27:105–110.
049 Lower stimulus contrast is associated with stronger multifocal visual evoked potential signals
Authors: Barton Joshua L , Barnett Michael H , Klistorner Alexander
Published: May 2018

Introduction

Visual evoked potentials (VEPs) are used to assess the visual system in neuro-ophthalmological diseases such as multiple sclerosis (MS). Axonal damage, and subsequent reduction of VEP amplitude, is considered central to the development of disability. To obtain the strongest signal possible, high contrast (HC) pattern-reversing checkboard stimuli are routinely used to induce cortical electrical potentials. Low contrast (LC) visual acuity assessment is better than HC visual acuity testing in detecting MS-related visual impairment. This study aims to determine if the use of LC stimuli in multifocal VEPs improves detection visual dysfunction in patients with MS.

Methods

14 MS patients (8 with history of optic neuritis) and 12 healthy controls had HC (Michelson 98%) and LC (Michelson 22%) multifocal VEP performed. The VEP signal from the 56 individual sectors was transformed into absolute values and averaged. The area under the curve (AUC) for each individual’s mfVEP was determined for HC and LC stimuli. Subsequently, 5 healthy controls with best-corrected vision ≥20/20 underwent mfVEP assessment at 8 different contrast levels (Michelson contrast 8%, 15%, 22%–31% 41%, 53%, 64%, 98%).

Results

There was no significant difference in the mfVEP AUC between MS patients (including 10 ON eyes only) and controls for HC, LC or the difference between HC and LC stimuli. Part 2 of the study demonstrated the relationship between stimulus contrast and signal strength. All subjects had a roughly parabolic relationship with AUC greatest at mid-level contrast. Averaged data of all subjects showed a parabolic relationship characterised by y=-2834.1x2 – 2127.1x+3144.2, R²=0.911.

Conclusion

Assessing reduction in mfVEP signal strength with LC stimuli requires an appropriate HC comparator stimulus. This study may also provide rationale for clinical mfVEP studies to use lower contrast stimuli to increase the signal strength of the study.
052 Diagnostic accuracy of the CT angiographic ‘spot sign’ for predicting intracerebral haematoma growth
Authors: Krishnadas Natasha , Phan Thanh G , Lai Vivian WY , Batt Michael J , Chandra Ronil V , Srikanth Velandai , Ma Henry
Published: May 2018

Introduction

To study the predictive value of the ‘spot sign’ in predicting spontaneous intracerebral haemorrhage (ICH) expansion.

Method

PubMed, Medline, conference proceedings and manuscript references up to June 2017 were searched for studies reporting “computed tomography angiography” and “spot sign” or “intracerebral haemorrhage” and “spot sign”. The positive (PLR) and negative (NLR) likelihood ratios were calculated using MetaDisc. The PLR needs to be ≥5 and NLR ≤0.1 for a test to be clinically useful.

Results

There were 36 studies describing 6888 patients. This current analysis includes 23 studies that were not used in previous meta-analyses. The frequency of haematoma growth was 21%. The PLR and NLR for the CTA spot sign indicating haematoma growth were 4.25 (95%CI 3.52–5.13) and 0.48 (95%CI 0.41–0.56) respectively. The sensitivity analyses show a plateau in PLR and NLR of 4.3 and 0.48. The heterogeneity chi square was 214.36–250.24 (p<0.001) and inconsistency I2 was 83.7%–86%.

Conclusion

The PLR for the CTA spot sign did not reach the desired threshold of 5 to be clinically useful. The heterogeneity around this estimate adds to uncertainty. The high NLR suggest that the absence of the CTA spot sign does not guarantee a lack of ICH growth.
053 Pregnancy outcomes with delayed-release dimethyl fumarate: interim results from an international registry
Authors: Everage Nicholas J , Liu Shifang , Yun Jang , Prada Claudia , Hanna Jerome
Published: May 2018

Introduction

Clinical trials and post marketing reports show no safety signals with delayed-release dimethyl fumarate (DMF) exposure during pregnancy; however, these data are limited and the product label recommends use during pregnancy only if the potential benefit justifies the potential risk to the foetus. We assessed pregnancy outcomes in an ongoing international registry (NCT01911767) of women with MS exposed to DMF since the first day of their last menstrual period prior to conception or at any time during pregnancy.

Methods

DMF-exposed women were prospectively evaluated for live births and pregnancy loss. Ectopic and molar pregnancies, birth defects, congenital anomalies or infant death occurring at ≤52 weeks of age, and maternal death at ≤12 weeks post-delivery, were reported. Data were collected at baseline (enrolment), 6–7 months of gestation, 4 weeks after the estimated delivery date, and 4, 12, and 52 weeks after birth. Potential birth defects were adjudicated by an external expert.

Results

As of 30, Sept 2016 104 patients were enrolled in the registry; mean (SD) age was 315 years. DMF exposure occurred in the first (95%), second (1%), and third (0%) trimester in the 94 patients with a known exposure date. To date, 58 pregnancy outcomes have been reported, including 52 patients with 54 live births and 4 (7%) spontaneous abortions (<22 weeks). Of the 54 (93%) live births, 47 (87%) were full term (delivered ≥37 weeks) and four (7%) premature. Two (4%) infants had adjudicator-confirmed birth defects; one with pyloric stenosis, and one with transposition of the great vessels/patent ductus arteriosus. No maternal, neonatal, perinatal, or infant deaths were reported.

Conclusion

The results from this ongoing registry did not identify a safety signal for DMF exposure on pregnancy outcomes, are consistent with previous reports, and provide essential information concerning exposure to DMF during pregnancy.
071 Natalizumab extended interval dosing (EID) is associated with a significant reduction in progressive multifocal leukoencephalopathy (PML) risk compared with standard interval dosing (SID) in the touch® prescribing program
Authors: Ryerson Lana Zhovtis , Foley John , Chang Ih , Kister Ilya , Cutter Gary , Metzger Ryan , Goldberg Judith D , Li Xiaochun , Riddle Evan , Smirnakis Karen , Yu Bei , Ren Zheng , Hotermans Christophe , Ho Pei-Ran , Campbell Nolan
Published: May 2018

Introduction

Natalizumab, approved for 300 mg intravenous every-4-weeks dosing, is associated with PML risk. Prior studies have been inconclusive regarding EID’s impact on PML risk. The US REMS program (TOUCH) offers the largest data source that can inform on PML risk in patients on EID. This analysis aimed to determine whether natalizumab EID is associated with reduced PML risk compared with SID.

Methods

Investigators developed SID and EID definitions and finalised the statistical analysis plan while blinded to PML events. Average dosing intervals (ADIs) were ≥3 to<5 weeks for SID and >5 to≤12 weeks for EID. The primary analysis assessed ADI in the last 18 months of infusion history. The secondary analysis identified any prolonged period of EID at any time in the infusion history. The tertiary analysis assessed ADI over the full infusion history. Only anti-JC virus antibody positive (JCV Ab+) patients with dosing intervals≥3 to≤12 weeks were included. PML hazard ratios (HRs) were compared using adjusted Cox regression models and Kaplan-Meier estimates.

Results

Analyses included 13,132 SID and 1988 EID patients (primary), 15,424 SID and 3331 EID patients (secondary), and 23,168 SID and 815 EID patients (tertiary). In primary analyses, ADI (days) was 30 for SID and 37 for EID; median exposure (months) was 44 for SID and 59 for EID. Most EID patients received >2 years SID prior to EID. The PML HR (95% CI) was 0.06 (0.01–0.22; p<0.001) for primary analysis and 0.12 (0.05–0.29; p<0.001) for secondary analysis (both in favour of EID); no EID PML cases were observed in tertiary analyses (Kaplan-Meier log-rank test p=0.02).

Conclusion

In JCV Ab +patients, natalizumab EID is associated with a clinically and statistically significant reduction in PML risk as compared with SID. As TOUCH does not collect effectiveness data, further studies are needed.

Study support

Biogen