bluuebunny/crossref_metadata_2025_split huggingface dataset:
082 The gastrointestinal microbiome in parkinson’s disease: impacts of motor and non-motor features, medications, lifestyle and diet
Authors: Lubomski Michal , Tan Ai Huey , Lim Shen-Yang , Holmes Andrew , Davis Ryan L , Sue Carolyn M 
Published: July 2019

IntroductionThe human gastrointestinal microbiome (GM) has been proposed to be integral in the pathogenesis of Parkinson’s disease (PD). Evidence supports a bidirectional interaction between the brain and the gut that is mediated by the GM. Dysbiosis of the GM is believed to negatively influence vital physiological functions in many diseases.MethodsWe reviewed the literature on changes in human physiological function associated with gut microbial community states in PD. In particular, we evaluated the literature for effects of GM dysbiosis on motor and non-motor features, dietary and lifestyle factors and medication use in PD.ResultsAltered GM profiles in PD have been suggested to disrupt vital signalling pathways within the microbiota-gut-brain axis, integral to regulating physiological digestive function and metabolic homeostasis. Unfavourable variations in the GM have been shown to perturb mood (anxiety/depression), cognition, perception (hallucinations/delusions), gastrointestinal motility, including constipation in PD. Further, varied clinical motor phenotypes, including postural instability and gait disturbance have been attributed to alterations in the GM, in addition to the use of catechol-O-methyltransferase inhibitors, anticholinergics and levodopa. Variations in dietary and lifestyle factors have also been inferred to cause alterations in GM profiles, including caffeine consumption, macronutrient intake, smoking and the effects of ageing and exercise.ConclusionsIt is apparent from the mounting evidence that alterations in the GM are intimately involved in PD pathogenesis. However, the GM can also be modulated by dietary, lifestyle and treatment factors that may influence motor and non-motor features as well as disease progression.
088 Cladribine tablets were associated with rapid onset of improvements in MRI outcomes in the ORACLE-MS trial
Authors: Gillett Alan , Scarberry Susan , Damian Doris , Hyvert Yann , Dangond Fernando , Lebson Lori , Leist Thomas 
Published: July 2019

IntroductionIn ORACLE-MS (616 subjects with a first demyelinating event at high risk of converting to multiple sclerosis), cladribine tablets (CT) 10 mg (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years) significantly delayed the time-to-conversion to clinically definite multiple sclerosis (CDMS), and reduced new/persisting T1 gadolinium-enhancing (T1 Gd+), new/enlarged or active T2 and combined unique active (CUA) lesion number. Here, the timing of CT effect is evaluated.MethodsMRI scans were performed at screening and every 12 weeks, for non-converting CDMS subjects. MRI-based endpoints were analyzed using analysis of covariance (ANCOVA) and negative binomial models. The temporal effects of the first yearly treatment course of CT and placebo on T1 Gd+, active T2, and CUA lesions were evaluated.Results96 weeks: the reduction in mean T1 Gd+, active T2, or CUA lesion number per patient per scan was nominally significantly greater for CT versus placebo (p<0.0001). Early change in Gd+ lesion volume (at Week 13) from baseline was CT, -155.73 mm3; placebo, -14.76 mm3. Comparatively larger reductions in mean active T2 and CUA lesion numbers with CT at Week 13 versus placebo were observed (active T2: CT, -1.25; placebo, -1.43; CUA: CT, -1.56; placebo, -2.41). The mean number of T1 Gd+ lesions at 13 weeks following CT was 0.37 versus 1.0 with placebo.ConclusionsMRI data from ORACLE-MS subjects suggest the first yearly treatment course of CT has a rapid onset of action, with beneficial treatment effects on active lesion number and volume evident by Week 13.
089 Breaking the cycle of chronic daily headache with a low-dose subcutaneous lignocaine and ketamine infusion
Authors: Rofe Christopher JF , Garrick Raymond , Burke David , Brew Bruce J , Tomlinson Susan E 
Published: July 2019

IntroductionManagement of chronic migraine includes correcting analgesic rebound headache and implementing suitable medication for prevention and acute episodes. However, in many cases this management paradigm oversimplifies the complexity of chronic migraine, particularly the entrenched central pathways that perpetuate chronic migraine. Intravenous lignocaine can curtail chronic migraine and analgesic rebound headache (1). Further, ketamine provides short-term analgesia and enables reduction in central sensitisation of pain pathways, particularly in the setting of codeine/opiod overuse (2). This paper describes use of subcutaneous lignocaine and ketamine infusion in chronic migraine.MethodsA prospective observational cohort study was undertaken in patients with chronic migraine. Patients received a prolonged subcutaneous lignocaine and ketamine infusion (mean duration 11 days) and underwent evaluation at four-time points over six months. The effects on the excitability of motor axons in the median nerve were documented using standard procedures.ResultsFourteen patients were recruited. The infusion was well tolerated; no major side effects were seen. There were no significant long-term changes in the excitability of motor axons. At six months, 13/14 patients had sustained benefit. Three of 4 patients remained free of analgesic rebound headache. One patient remained headache-free. Conversion to episodic migraine occurred in 6/14. Improvement in chronic migraine was reported by 6/14. Three of six were able to return to work, with 1 returning to studies. Benefit was greater in those with depression and history of opiod/codeine use.ConclusionSubcutaneous lignocaine and ketamine can help break entrenchment in chronic migraine as part of a structured management plan.
090 The effect of cladribine tablets on delaying the time to conversion to clinically definite multiple sclerosis (MS) or McDonald MS is consistent across subgroups in the ORACLE-MS study
Authors: Bowen James , Gillett Alan , Damian Doris , Hyvert Yann , Dangond Fernando , Grosso Megan , Leist Thomas 
Published: July 2019

IntroductionIn the Phase 3 ORACLE-MS trial in 616 subjects with a first demyelinating event at high risk of converting to multiple sclerosis (MS), treatment with cladribine tablets 10 mg (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years [CT3.5 and CT5.25, respectively]) significantly delayed time to conversion to clinically definite multiple sclerosis (CDMS) according to Poser criteria (67% or 62% risk reduction [RR], respectively) and time to conversion to 2005 McDonald MS (50% or 57% RR, respectively), versus placebo. The objective was to analyze the effect of cladribine tablets vs placebo on converstion to CDMS and McDonald MS across ORACLE-MS patient subgroups based on baseline characteristics.MethodsIn this post-hoc analysis, time-to-conversion to CDMS or McDonald MS over the double-blind period was analyzed for patients treated with CT5.25 (N=204), CT3.5 (N=206) or placebo (N=206) across different subgroups. Subgroups were defined by baseline characteristics which have been investigated as potential predictors of CDMS conversion (age [<30 or ≥30 years], gender, first classification demyelinating event [monofocal or multifocal], presence of T1 Gd+ lesions and number of T2 lesions [<9 or ≥9]).ResultsTreatment with CT3.5 or CT5.25 was consistently efficacious across the subgroups examined on conversion to CDMS versus placebo for most comparisons (RR range: CT3.5, 39%–72%; CT5.25, 36%–79%). Similarly, treatment effect of both doses on conversion to 2005 McDonald MS was consistent across subgroups (CT3.5,40%–59%;CT5.25,42%–79%).ConclusionsThe effect of cladribine tablets on delaying the time-to-conversion to CDMS, or to McDonald MS, is consistent across subgroups.
091 Cerebellar oedema in fulminant adult leigh syndrome
Authors: Edwards Leon S , Halmagyi Gabor M , Barnett Michael H , Blair Christopher A , Kiernan Matthew C 
Published: July 2019

IntroductionWe report a case of adult Leigh syndrome resulting in rapidly fatal cerebellar oedema.CaseA 19-year-old female presented with a five-week history of hyperventilation, generalised weakness, dysarthria and bilateral ptosis. Brain Magnetic resonance imaging (MRI) findings and the presence of a mitochondrial mutation (NC_012920.1(MT-ATP6):m.9176T>C) in blood and urine with approximately 97% heteroplasmy, confirmed a diagnosis of Leigh syndrome.Two-days after a normal lumbar puncture, opening pressure 8cm water, her conscious level rapidly declined. CT revealed marked cerebellar oedema with brainstem compression. Despite immediate decompression, she did not recover consciousness and died six-weeks after symptom onset.ConclusionAdult Leigh syndrome is a progressive untreatable inherited mitochondrial disorder typically of infants and children. Adult cases are rare and described mostly in single case reports. There is marked phenotypic and genotypic variability. Over 83% of Leigh’s syndrome is identified by the age of 2 years, however, there have been cases reported in patients up to 74 years old. There are over 60 mutations described in Leigh syndrome, which are identified in only half of reported cases. Classic MRI changes include bilateral symmetric T2 hyper-intensities in the basal ganglia and brainstem. To our knowledge, this is the first reported case resulting in fulminant cerebellar oedema. A challenge of diagnosis remains the marked heterogeneity in presenting symptoms including cognitive decline, behavioural change and ophthalmoparesis. Typically, this syndrome has been confirmed by histopathology at autopsy. Advances in genetics and imaging have allowed earlier accurate diagnosis, potentially paving the way for improved therapeutics.
104 Silent multilevel vertebral fractures in a severe case of glycine receptor antibody-positive progressive encephalomyelitis with rigidity and myoclonus (PERM)
Authors: Min Myintzu , Liu Han , Silberstein Paul 
Published: July 2019

IntroductionAutoimmune encephalitides are a heterogenous and potentially devastating group of disorders. Antibodies to glycine receptor (GlyR) are rare and increasingly reported in patients with progressive encephalomyelitis with rigidity and myoclonus (PERM). PERM patients develop early brainstem and autonomic dysfunction, and if untreated, can be fatal. We aim to discuss the complications and treatments in this PERM case and review the literature on management of PERM.MethodsWe report a case of PERM currently undergoing treatment in our hospital.ResultsMr GT is a 46-year-old male who presented with a prodromal phase of altered sensation and acute cerebellar signs. He rapidly deteriorated with bulbar dysfunction and developed generalised muscle rigidity and hyperreflexia. Infective work-up, cerebrospinal fluid analysis, magnetic resonance imaging of brain and spine were initially normal. He was started on first line immunosuppressants for a clinical diagnosis of autoimmune encephalitis. Despite sedation in intensive care, generalised myoclonus and truncal extensor spasms were severe and presented on-going management difficulties. A computed tomography scan of his abdomen to exclude malignancy revealed incidental findings of vertebral fractures at multiple thoracic and lumbar levels. He was subsequently administered rituximab and demonstrated some signs of recovery. GlyR antibody positive results from Oxford University Hospital consequently confirmed his diagnosis.ConclusionThis is the fourth reported GlyR antibody-positive PERM case in Australia and the first description to our knowledge with intractable rigidity and myoclonus leading to vertebral fractures. Awareness and screening for this complication may assist in management of patients with PERM.
105 A presentation resembling transient global amnesia with underlying tako-tsubo cardiomyopathy and multifocal ischaemic stroke (with restricted diffusion in the left mesiotemporal lobe)
Authors: Lefever Kristen , Tyson Chloe , Shelley Lisa , Schweitzer Daniel , Swayne Andrew 
Published: July 2019

IntroductionWe present a case of a 65 year-old female with a presentation resembling transient global amnesia (TGA) with investigations revealing a Tako-tsubo cardiomoyopathy and multifocal punctate areas of restricted diffusion consistent with ischaemic stroke.MethodsSingle case report.ResultsA 65 year-old female presented altered behaviour with anterograde amnesia consistent with an episode of TGA. There was no clearly identifiable stressor to provoke this episode. The TGA-like symptoms persistent for 12 hours before the patient made a full recovery.During the presentation the patient complained of chest pain with elevated troponin. Cardiac investigation was notable for mild left ventricular dilation with mid- and apical hypokinesis on transthoracic echocardiogram and a normal coronary angiogram consistent with Tako-tsubo cardiomyopathy. Magnetic resonance imaging of the brain revealed multifocal infarcts including punctate foci of restricted diffusion within the left mesiotemporal lobe.ConclusionThis case is notable as it is rare to have a combined presentation with TGA-type symptoms with Tako-tsubo cardiomyopathy and multifocal ischaemia stroke.1 This is the first clinical case presentation involving the aforementioned triad and mesiotemporal lobe restricted diffusion. We hypothesise that the Tako-tsubo cardiomyopathy acted as the triggering event and the mesiotemporal lobe involvement caused the TGA-like symptoms thereby accounting for the clinical presentation and investigation findings. As mesiotemporal/hippocampal restricted diffusion may be seen with transient global amnesia,2 this case is of special interest mechanistically although we cannot exclude the alternative hypothesis that the episode of TGA resulted in the Tako-tsubo cardiomyopathy which subsequently caused the cardioembolic shower.ReferencesStollberger C, DeCillia N, Finsterer J. ‘Tako-tsubo cardiomyopathy with transient global amnesia and cerebellar embolic stroke triggered by existential fear.’Neurol Neurochir Pol 2018; 52(3):394–396.Enzinger C, Thimary F, Kapeller P, Ropele S, Schmidt R, Ebner F, Fazekas F. ‘Transient global amnesia: diffusion-weighted imaging lesions and cerebrovascular disease.’Stroke 2008;39(8):2219–2225.
108 Endovascular clot retrieval beyond 24 hours for top of the carotid occlusion
Authors: Kopanidis Paul , Zhai Shaun , Lalloo Shivendra , Patel Ronak , Gawarikar Yash 
Published: July 2019

IntroductionSub-clinoid proximal occlusion is defined by internal carotid artery (ICA) occlusion with intact Circle of Willis flow. We hypothesise that such cases of large vessel occlusion provide collateral blood flow to preserve the ischaemic penumbra and may benefit from endovascular clot retrieval (ECR) beyond 24 hours.MethodWe retrospectively searched the stroke database from 2018 at Calvary Hospital, Canberra, Australia for ECR cases performed beyond 24 hours from symptom onset.ResultsTwo patients were identified from the registry data.64-year-old man awoke with left hemiparesis and was last seen well 9.5 hours prior. ECR for ICA occlusion was not initially performed due to rapidly improving National Institute of Health Stroke Scale (NIHSS) of three to zero. ECR was later performed at 38.5 hours for clinical deterioration. Stroke aetiology was atrial fibrillation. At 90-day NIHSS and modified Rankin Scale (mRS) were three.75-year-old man awoke with left hemiparesis and was last seen well 10 hours prior. Baseline NIHSS was four. Off-label thrombolysis was administered based on salvageable penumbra on CTP, however ECR for ICA occlusion was not performed as neurointervention was unavailable. After 24 hours his NIHSS score improved to one but hemispheric hypoperfusion persisted on CTP. At 36 hours he underwent ECR with carotid stenting. Stroke aetiology was large-vessel atherosclerosis. At 90 days his NIHSS and mRS were zero.ConclusionAcute sub-clinoid proximal carotid occlusion requires tissue viability assessment with imaging to guide decision of ECR beyond 24 hours and may be of benefit.
Synthesizing differentially private programs
Authors: Smith Calvin , Albarghouthi Aws 
Published: July 2019

Inspired by the proliferation of data-analysis tasks, recent research in program synthesis has had a strong focus on enabling users to specify data-analysis programs through intuitive specifications, like examples and natural language. However, with the ever-increasing threat to privacy through data analysis, we believe it is imperative to reimagine program synthesis technology in the presence of formal privacy constraints.
In this paper, we study the problem of automatically synthesizing randomized, differentially private programs, where the user can provide the synthesizer with a constraint on the privacy of the desired algorithm. We base our technique on a linear dependent type system that can track the resources consumed by a program, and hence its privacy cost. We develop a novel type-directed synthesis algorithm that constructs randomized differentially private programs. We apply our technique to the problems of synthesizing database-like queries as well as recursive differential privacy mechanisms from the literature.
Call-by-need is clairvoyant call-by-value
Authors: Hackett Jennifer , Hutton Graham 
Published: July 2019

Call-by-need evaluation, also known as lazy evaluation, provides two key benefits: compositional programming and infinite data. The standard semantics for laziness is Launchbury’s natural semantics DBLP:conf/popl/Launchbury93, which uses a heap to memoise the results of delayed evaluations. However, the stateful nature of this heap greatly complicates reasoning about the operational behaviour of lazy programs. In this article, we propose an alternative semantics for laziness,
clairvoyant evaluation
, that replaces the state effect with nondeterminism, and prove this semantics equivalent in a strong sense to the standard semantics. We show how this new semantics greatly simplifies operational reasoning, admitting much simpler proofs of a number of results from the literature, and how it leads to the first
denotational cost semantics
for lazy evaluation.
Intratumoral Fusobacterium Nucleatum Levels Predict Therapeutic Response to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma
Authors: Yamamura Kensuke , Izumi Daisuke , Kandimalla Raju , Sonohara Fuminori , Baba Yoshifumi , Yoshida Naoya , Kodera Yasuhiro , Baba Hideo , Goel Ajay 
Published: July 2019

Abstract

Purpose:
Emerging evidence indicates that gut microbiome plays a crucial role in the cancer pathogenesis. Although Fusobacterium nucleatum (F. nucleatum) is associated with poor prognosis in multiple cancers, its clinical significance in predicting response to chemotherapy in patients with esophageal squamous cell carcinoma (ESCC) remains unclear.

Experimental Design:
The F. nucleatum levels were quantified by qPCR assays in tumor tissues from 551 patients with ESCC from two independent cohorts, including 101 patients who received neoadjuvant chemotherapy prior to curative resection. Associations between F. nucleatum burden and recurrence-free survival (RFS), as well with chemotherapeutic response were evaluated using response evaluation criteria in solid tumors (RECISTs), primary tumor metabolic response defined by maximum standardized uptake value (SUVmax) changes in positron emission tomography-CT (PET/CT), and pathologic tumor regression grade (TRG).

Results:
High burden of F. nucleatum in patients with ESCC associated with poor RFS in both training [log-rank P = 0.02; HR = 1.61; P = 0.03] and validation cohorts (log-rank P = 0.003; HR = 1.96; P = 0.004). Importantly, patients with ESCC with high levels of F. nucleatum displayed poor chemotherapeutic response for all three evaluation methods: RECIST (P = 0.04), SUVmax change in PET/CT (P = 0.0004), and TRG (P = 0.003).

Conclusions:
We conclude that high levels of intratumoral F. nucleatum have a prognostic significance for predicting poor RFS in patients with ESCC. More importantly, our data indicates that higher F. nucleatum burden correlates with poor response to neoadjuvant chemotherapy, suggesting the possibility that an antibiotic intervention against this bacterium may significantly improve therapeutic response in patients with ESCC.
ESM1 as a Marker of Macrotrabecular-Massive Hepatocellular Carcinoma
Authors: Calderaro Julien , Meunier Léa , Nguyen Cong Trung , Boubaya Marouane , Caruso Stefano , Luciani Alain , Amaddeo Giuliana , Regnault Hélène , Nault Jean-Charles , Cohen Justine , Oberti Frédéric , Michalak Sophie , Bouattour Mohamed , Vilgrain Valérie , Pageaux Georges Philippe , Ramos Jeanne , Barget Nathalie , Guiu Boris , Paradis Valérie , Aubé Christophe , Laurent Alexis , Pawlotsky Jean-Michel , Ganne-Carrié Nathalie , Zucman-Rossi Jessica , Seror Olivier , Ziol Marianne 
Published: July 2019

Abstract

Purpose:
Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a novel morphological subtype of HCC associated with early relapse after resection or percutaneous ablation, independently of classical clinical and radiological prognostic factors. The aim of the present study was to identify immunohistochemical markers of MTM-HCC, to ease its diagnosis and implementation into clinical practice.

Experimental Design:
To identify potential biomarkers of MTM-HCC, we first analyzed gene expression profiling data from The Cancer Genome Atlas study and further selected two candidate biomarkers. Performance of both biomarkers for diagnosis of MTM-HCC was further tested by immunohistochemistry in two independent series of 67 and 132 HCC biopsy samples.

Results:
Analysis of RNA sequencing data showed that MTM-HCC was characterized by a high expression of neoangiogenesis-related genes. Two candidate biomarkers, Endothelial-Specific Molecule 1 (ESM1) and Carbonic Anhydrase IX (CAIX), were selected. In the discovery series, sensitivity and specificity of ESM1 expression by stromal endothelial cells for the detection of MTM-HCC were 97% (28/29), and 92% (35/38), respectively. Sensitivity and specificity of CAIX were 48% (14/29) and 89% (34/38). In the validation set, sensitivity and specificity of ESM1 for the identification of MTM-HCC were 93% (14/15) and 91% (107/117), respectively. Interobserver agreement for ESM1 assessment was good in both series (Cohen Kappa 0.77 and 0.76).

Conclusions:
Using a molecular-driven selection of biomarkers, we identified ESM1 as a reliable microenvironment immunohistochemical marker of MTM-HCC. The results represent a step toward the implementation of HCC morpho-molecular subtyping into clinical practice.
How to Enlarge NATO: The Debate inside the Clinton Administration, 1993–95
Authors: Sarotte M.E. 
Published: July 2019

Abstract
Newly available sources show how the 1993–95 debate over the best means of expanding the North Atlantic Treaty Organization unfolded inside the Clinton administration. This evidence comes from documents recently declassified by the Clinton Presidential Library, the Defense Department, and the State Department because of appeals by the author. As President Bill Clinton repeatedly remarked, the two key questions about enlargement were when and how. The sources make apparent that, during a critical decisionmaking period twenty-five years ago, supporters of a relatively swift conferral of full membership to a narrow range of countries outmaneuvered proponents of a slower, phased conferral of limited membership to a wide range of states. Pleas from Central and Eastern European leaders, missteps by Russian President Boris Yeltsin, and victory by the pro-expansion Republican Party in the 1994 U.S. congressional election all helped advocates of full-membership enlargement to win. The documents also reveal the surprising impact of Ukrainian politics on this debate and the complex roles played by both Strobe Talbott, a U.S. ambassador and later deputy secretary of state, and Andrei Kozyrev, the Russian foreign minister. Finally, the sources suggest ways in which the debate's outcome remains significant for transatlantic and U.S.-Russian relations today.