bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychoacoustic measurements of ipsilateral cochlear gain reduction as a function of signal frequency
Authors: DeRoy Milvae Kristina , Strickland Elizabeth A.
Published: May 2018

Forward masking experiments at 4 kHz have demonstrated that preceding sound can elicit changes in masking patterns consistent with a change in cochlear gain. However, the acoustic environment is filled with complex sounds, often dominated by lower frequencies, and ipsilateral cochlear gain reduction at frequencies below 4 kHz is largely unstudied in the forward masking literature. In this experiment, the magnitude of ipsilateral cochlear gain reduction was explored at 1, 2, and 4 kHz using forward masking techniques in an effort to evaluate a range of frequencies in listeners with normal hearing. Gain reduction estimates were not significantly different at 2 and 4 kHz using two forward masking measurements. Although the frequency was a significant factor in the analysis, post hoc testing supported the interpretation that gain reduction estimates measured without a masker were not significantly different at 1, 2, and 4 kHz. A second experiment provided evidence that forward masking in this paradigm at 1 kHz cannot be explained by excitation alone. This study provides evidence of ipsilateral cochlear gain reduction in humans at frequencies below the 4 kHz region.
B612 plans asteroid hunt with fleet of small satellites
Authors: Mann Adam
Published: May 2018

After abandoning plans for a large space telescope, private foundation pins hopes on new technologies.
A 550,000-year record of East Asian monsoon rainfall from
10
Be in loess
Authors: Beck J. Warren , Zhou Weijian , Li Cheng , Wu Zhenkun , White Lara , Xian Feng , Kong Xianghui , An Zhisheng
Published: May 2018

Forcing the East Asian summer monsoon

What factors have controlled the intensity of the East Asian summer monsoon over the recent geological past? To answer this key question requires a robust proxy for rainfall amounts. Beck
et al.
measured the beryllium isotopic content of loess from China, from which they reconstructed a 550,000-year-long record of rainfall. Rainfall correlated with orbital precession and global variations in ice volume. This finding suggests that the monsoon is governed by low-latitude interhemispheric gradients in solar radiation levels, rather than by high-northern-latitude solar radiation levels as previously suggested.

Science
, this issue p.
877
Imaging of pure spin-valley diffusion current in WS
2
-WSe
2
heterostructures
Authors: Jin Chenhao , Kim Jonghwan , Utama M. Iqbal Bakti , Regan Emma C. , Kleemann Hans , Cai Hui , Shen Yuxia , Shinner Matthew James , Sengupta Arjun , Watanabe Kenji , Taniguchi Takashi , Tongay Sefaattin , Zettl Alex , Wang Feng
Published: May 2018

Tracking the spin-valley current

Taking advantage of the electron's spin and valley degrees of freedom requires a method for generating currents of carriers that have a particular spin or come from a particular valley in the electronic structure. Jin
et al.
used a heterostructure made out of adjacent layers of WSe
2
and WS
2
to create a spin-valley diffusion current without applying an external electric field. Instead, they used circularly polarized laser light to initiate the diffusion and a second laser pulse to image the propagation of the carriers. With long lifetimes and diffusion lengths, the method may be of practical use in future valleytronic devices.

Science
, this issue p.
893
Truth with a vengeance
The Ashtray: (Or the Man Who Denied Reality)
Errol Morris
University of Chicago Press, 2018. 223 pp.
Authors: Martin Joseph D.
Published: May 2018

A filmmaker with an ax to grind takes aim at Thomas Kuhn's legacy
Enhancing energy transport in conjugated polymers
Authors: Holmes Russell J.
Published: May 2018

Scalable synthesis enables long-distance exciton transport in crystalline polymer nanofibers
Cold chemistry with two atoms
Authors: Narevicius Edvardas
Published: May 2018

Two atoms react to form a molecule in an optical “beaker”
Following the leader, for better or worse
Authors: Nevitt Gabrielle A.
Published: May 2018

Juvenile white storks use different behavioral strategies for thermal soaring
Antitrypanosomal 8-Hydroxy-Naphthyridines Are Chelators of Divalent Transition Metals
Authors: Wall Richard J. , Moniz Sonia , Thomas Michael G. , Norval Suzanne , Ko Eun-Jung , Marco Maria , Miles Timothy J. , Gilbert Ian H. , Horn David , Fairlamb Alan H. , Wyllie Susan
Published: May 2018

The lack of information regarding the mechanisms of action (MoA) or specific molecular targets of phenotypically active compounds can prove a barrier to their development as chemotherapeutic agents. Here, we report the results of our orthogonal genetic, molecular, and biochemical studies to determine the MoA of a novel 7-substituted 8-hydroxy-1,6-naphthyridine (8-HNT) series that displays promising activity against
Trypanosoma brucei
and
Leishmania donovani
.
Fragments of the Nonlytic Proline-Rich Antimicrobial Peptide Bac5 Kill Escherichia coli Cells by Inhibiting Protein Synthesis
Authors: Mardirossian Mario , Barrière Quentin , Timchenko Tatiana , Müller Claudia , Pacor Sabrina , Mergaert Peter , Scocchi Marco , Wilson Daniel N.
Published: May 2018

Unlike most antimicrobial peptides (AMPs), the main mode of action of the subclass of proline-rich antimicrobial peptides (PrAMPs) is not based on disruption of the bacterial membrane. Instead, PrAMPs exploit the inner membrane transporters SbmA and YjiL/MdtM to pass through the bacterial membrane and enter the cytosol of specific Gram-negative bacteria, where they exert an inhibitory effect on protein synthesis. Despite sharing a high proline and arginine content with other characterized PrAMPs, the PrAMP Bac5 has a low sequence identity with them. Here we investigated the mode of action of three N-terminal Bac5 fragments, Bac5(1-15), Bac5(1-25), and Bac5(1-31). We show that Bac5(1-25) and Bac5(1-31) retained excellent antimicrobial activity toward
Escherichia coli
and low toxicity toward eukaryotic cells, whereas Bac5(1-15) was inactive. Bac5(1-25) and Bac5(1-31) inhibited bacterial protein synthesis
in vitro
and
in vivo
. Competition assays suggested that the binding site of Bac5 is within the ribosomal tunnel, where it prevents the transition from the initiation to the elongation phase of translation, as reported for other PrAMPs, such as the bovine PrAMP Bac7. Surprisingly, unlike Bac7, Bac5(1-25) exhibited species-specific inhibition, being an excellent inhibitor of protein synthesis on
E. coli
ribosomes but a poor inhibitor on
Thermus thermophilus
ribosomes. This indicates that while Bac5 most likely has an overlapping binding site with Bac7, the mode of interaction is distinct, suggesting that Bac5 fragments may be interesting alternative lead compounds for the development of new antimicrobial agents.
Airway clearance physiotherapy improves ventilatory dynamics during exercise in patients with cystic fibrosis: a pilot study
Authors: Vendrusculo Fernanda Maria , Johnstone Zoe , Dhouieb Elaine , Donadio Márcio V F , Cunningham Steven , Urquhart Donald S
Published: May 2018

Background

Airflow limitation and dynamic hyperinflation may limit exercise capacity in patients with cystic fibrosis (CF). The aim was to investigate whether the undertaking of airway clearance physiotherapy (ACT) prior to cardiopulmonary exercise testing (CPET) results in improvements in exercise capacity.

Methods

A prospective randomised, cross-over pilot study was performed in children aged >9 years. Spirometry, plethysmography and CPET were performed on two separate occasions—one test with ACT prior to CPET and the other without.

Results

12 patients with CF were included in the study with a mean (SD) age of 12.83 (1.85) years. No significant difference in peak oxygen uptake (VO2) was found between the tests. However, lower minute ventilation (VE) and ventilatory equivalents (VEVO2 and VEVCO2) at ventilatory threshold (VT) were noted when ACT was undertaken prior to CPET. The mean(SD) VE (L/min) at VT was 26.67 (5.49) vs 28.92 (6.3) (p=0.05), VEVO2 (L/min) at VT was 24.5 (1.75) vs 26.05 (2.5) (p=0.03) and VEVCO2 (L/min) at VT was 26.58 (2.41) vs 27.98 (2.11) (p=0.03).

Conclusions

These pilot data suggest that ACT prior to exercise may lead to improved ventilatory dynamics during exercise in individuals with CF.
Cardiovascular screening of Olympic athletes reported by chief medical officers of the Rio 2016 Olympic Games
Authors: Toresdahl Brett G , Asif Irfan M , Rodeo Scott A , Ling Daphne I , Chang Cindy J
Published: May 2018

Objective

The IOC recommends periodic cardiovascular screening of athletes, but the adoption of these recommendations is unknown. The purpose of this investigation was to evaluate and compare cardiovascular screening practices of countries participating in the Rio 2016 Olympic Games.

Methods

A list of chief medical officers (CMOs) was compiled by the IOC during the 2016 Olympic Games. CMOs were requested to complete an online survey about cardiovascular screening of their countries’ Olympic athletes. Comparisons of screening practices were made by categorising countries by continent, gross domestic product (GDP) per capita and size of athlete delegation.

Results

CMOs for 117/207 (56.5%) countries participating in the 2016 Olympic Games were identified. 94/117 countries (80.3%) completed the survey, representing 45.4% of all countries and 8805/11 358 (77.5%) of all 2016 Olympic athletes. Most of the countries surveyed (70.2%) perform annual cardiovascular screening. Among the survey respondents, all or most athletes from each country were screened at least once with the following components: personal history (86.2% of countries), family history (85.1%), physical examination (87.2%), resting ECG (74.5%), echocardiogram (31.9%) and stress test (30.8%). Athletes were more likely to be screened with ECG in countries with relatively larger athlete delegation (OR 2.05, 95% CI 1.10 to 3.80, p=0.023) and with higher GDP per capita (OR 1.69, 95% CI 1.11 to 2.57, p=0.014).

Conclusion

Most of the responding countries perform annual cardiovascular screening of Olympic athletes, but there are differences in the components used. Athletes from countries with larger athlete delegations and higher GDP per capita were more likely to be screened with ECG.
Linkage to care among adults being investigated for tuberculosis in South Africa: pilot study of a case manager intervention
Authors: Maraba Noriah , Chihota Violet , McCarthy Kerrigan , Churchyard Gavin J , Grant Alison D
Published: May 2018

Objectives

We piloted an intervention to determine if support from a case manager would assist adults being investigated for tuberculosis (TB) to link into TB and HIV care.

Design

Pilot interventional cohort study.

Participants and setting

Patients identified by primary healthcare clinic staff in South Africa as needing TB investigations were enrolled.

Intervention

Participants were supported for 3 months by case managers who facilitated the care pathway by promoting HIV testing, getting laboratory results, calling patients to return for results and facilitating treatment initiation.

Outcomes measured

Linkage to TB care was defined as starting TB treatment within 28 days in those with a positive test result; linkage to HIV care, for HIV-positive people, was defined as having blood taken for CD4 count and, for those eligible, starting antiretroviral therapy within 3 months. Intervention implementation was measured by number of attempts to contact participants.

Results

Among 562 participants (307 (54.6%) female, median age: 36 years (IQR 29–44)), most 477 (84.8%) had previously tested for HIV; of these, 328/475 (69.1%) self-reported being HIV-positive. Overall, 189/562 (33.6%) participants needed linkage to care (132 HIV care linkage only; 35 TB treatment linkage only; 22 both). Of 555 attempts to contact these 189 participants, 407 were to facilitate HIV care linkage, 78 for TB treatment linkage and 70 for both. At the end of 3-month follow-up, 40 participants had not linked to care (29 of the 132 (22.0%) participants needing linkage to HIV care only, 4 of the 35 (11.4%) needing to start on TB treatment only and 7 of the 22 (31.8%) needing both).

Conclusion

Many people testing for TB need linkage to care. Despite case manager support, non-linkage into HIV care remained higher than desirable, suggesting a need to modify this intervention before implementation. Innovative strategies to enable linkage to care are needed.
Idylla assay and next generation sequencing: an integrated EGFR mutational testing algorithm
Authors: De Luca Caterina , Rappa Alessandra G , Gragnano Gianluca , Malapelle Umberto , Troncone Giancarlo , Barberis Massimo
Published: May 2018

Aims

Any reference laboratory testing non-small cell lung cancer samples for predictive biomarkers needs to develop and validate a wide range of different molecular techniques, each with a specific time requirement and application. Updated international guidelines suggest that next generation sequencing (NGS) to be the initial procedure. However, in a non-negligible subset of cases, library generation may fail or amplicon coverage may be insufficient. In these NGS ‘invalid’ cases, the Idylla system may represent a viable option for rapid epidermal growth factor receptor (EGFR) genotyping.

Methods

This retrospective study included 68 archival DNA samples previously processed by Ion Torrent NGS assay. Out of these, 43 cases, including 24EGFRmutant samples, had a valid NGS result, whereas 25/68 (37%) were invalid. All samples were retested by directly pipetting the DNA inside theEGFRIdylla assay cartridge.

Results

In all 43 cases with a valid NGS result, Idylla confirmed theEGFRmutational status. In particular, 24/24 (100%) ofEGFRmutant samples as detected by NGS were confirmed by Idylla. Moreover, a large portion of cases (20/25; 80%) whose assessment by NGS was invalid were adequately processed by Idylla. Noteworthy, in 4/25 (16%) of cases, Idylla detected actionableEGFRmutations.

Conclusions

Idylla assay could be very useful to quickly process cases for which NGS does not allow genotyping.
102 Alemtuzumab associated thrombocytopenia: a case series
Authors: Gaekwad Aaron , Lee Andrew
Published: May 2018

Introduction

Alemtuzumab is a humanised anti-CD52 monoclonal antibody for the early treatment of relapsing remitting multiple sclerosis (RRMS) that works by inducing T-cell depletion.1 Alemtuzumab has shown benefit in reducing disease activity, relapse, and MRI lesion activity in clinical trials.2 There is emerging evidence of autoimmune related adverse effects that include thyroid disease, nephropathy, and thrombocytopenia.3 Thrombocytopenia secondary to alemtuzumab has been associated with mortality. The pathophysiological mechanism of alemtuzumab-associated thrombocytopenia is yet to be elucidated and treatment efficacy for patients with thrombocytopenia is unclear, ranging from watchful waiting to intravenous immunoglobulin (IVIG). We discuss a four patient case series in regards to alemtuzumab-associated thrombocytopenia.

Methods

A retrospective review of a random sample of four patients at one institution with RRMS who had been treated with alemtuzumab and developed thrombocytopenia requiring intervention with either prednisolone, IVIG or romiplostim.

Results

We describe four patients with varying degrees of alemtuzumab-associated thrombocytopenia. Patient 1 developed mild thrombocytopenia with response to prednisolone. Patient 2 developed moderate thrombocytopenia and responded to methylprednisolone and prednisolone. Patient 3 developed fluctuating thrombocytopenia that required prednisolone. This patient then developed severe thrombocytopenia with clinical evidence of purpura. A bone marrow biopsy was undertaken and romiplostim was started with platelet recovery. Patient 4 developed severe thrombocytopenia refractory to prednisolone and IVIG. Romiplostim was initiated with platelet recovery.

Conclusion

The pathophysiology of alemtuzumab-associated thrombocytopenia is incompletely understood and may include both a central immune tolerance checkpoint failure of platelet self-antigens and potentially peripheral immune mechanisms.4 Treatment of alemtuzumab-associated thrombocytopenia under the assumption that the mechanism is primarily similar to immune thrombocytopenic purpura may be incorrect, and thrombopoietin receptor agonists may have a role.

References

. Sprenger, et al. Alemtuzumab: who and when to treat?Comment in the Lancet 2012;380:1795–1797.

. Cohen, et al. Alemtuzumab versus interferon beta 1a as first line treatment for patients with relapsing-remitting multiple scleorsis: A randomised controlled phase 3 trial.The Lancet 2012;380:1819–28.

. Havroda, et al. Understanding the positive benefit: risk profile of alemtuzumab in relapsing multiple sclerosis: perspectives from the Alemtuzumab Clinical development program. Therapeutics and Clinical Risk management 2017:13:1423–1437.

. Fogarty, et al. ITP: Tolerance Lost. Blood 2011;118(24):6232–6233.
104 Severe unilateral optic neuritis in multiple sclerosis
Authors: Gerbis Natasha , Parratt John
Published: May 2018

Introduction

Optic neuritis (ON) results in acute loss of vision with pain on eye movement. It may be the first manifestation of multiple sclerosis (MS) and usually follows a resolving course. Here we describe five patients with MS who developed severe unilateral ON resulting in persistent visual loss without significant resolution.

Methods

A retrospective clinical review of five cases identified from a database of 550 patients with MS.

Results

All patients were female and the mean age was 30 years at onset (range 25–40). All patients had no light perception at diagnosis, and received treatment with high dose intravenous methylprednisolone. Two patients also had plasma exchange. All of the patients were subsequently treated with immunomodulatory therapy. The patients were followed for a mean period of 13.3 years (range 2 months to 31 years). None of the patients had significant improvement in their visual acuity, with most achieving vision of 6/60. The mean retinal nerve fibre layer thickness was 66.33 microns (range 46–98 microns) in the affected eye, compared to 86.7 microns (69–105 microns) in the unaffected eye. All patients were aquaporin-4 antibody negative and oligoclonal band positive, with the MRI brain and spine being diagnostic for MS. Interestingly, none of the patients developed significant symptoms in the contralateral eye with vision of 6/5. All patients had an EDSS score of 4.0 predominantly due to visual impairment.

Conclusion

Severe unilateral ON is rarely seen in MS. This case series highlights a phenotypically distinct group of female MS patients with severe unilateral ON, and no improvement in visual acuity after prolonged follow-up and despite treatment with steroids and potent immune therapies. In such patients, where the diagnosis of MS is confirmed by MRI and CSF analysis, the patient might be reassured that visual loss in the fellow eye is unlikely.

References

. Wilhelm H, Schabet M. The diagnosis and treatment of optic neuritis. Deutsches Arzteblatt International2015;112(37):616–626.

. Dachsel RM, et al. Optic neuropathy after retrobulbar neuritis in multiple sclerosis: Are optical coherence tomography and magnetic resonance imaging useful and necessary follow-up parameters?Der Nervenarzt2015;86(2):187–96.
108 Longitudinally extensive transverse myelitis as the sole manifestation of sarcoidosis
Authors: Fontes-Villalba Ariadna , Parratt John
Published: May 2018

Introduction

Neurosarcoidosis is a rare disease with variable clinical and radiological manifestations. We report a case of longitudinally extensive transverse myelitis mimicking NMO that was pathologically confirmed to be sarcoidosis.

Case a 50 year old Caucasian man presented with left arm paraesthesia, sensory and gait disturbance. Spinal MRI showed a swollen longitudinally extensive cord lesion (6 spinal segments) with peripheral enhancement. Brain MRI was normal. The CSF protein was 0.51 g/L and oligoclonal bands were restricted to the CSF. AQP-4 and MOG antibodies were negative. Serum ACE, vasculitis, and infectious screens were negative. The patient was administered a four day course of 1 g of iv methylprednisolone once daily, and improved clinically and radiologically. However, subsequent deterioration prompted treatment with plasma exchange (6 courses) and rituximab, which was ineffective. The peripheral nature of the enhancement pattern and steroid responsiveness prompted a whole body PET, showing FDG avid mediastinal lymph nodes, and a biopsy demonstrated non-necrotizing granulomas. Mycobacteria were absent. The diagnosis of sarcoidosis was made and the patient was initiated on intravenous infliximab (500 mg at 0, 2, 6 and 8 weeks). The patients gait and sensation improved.

Conclusion

Neurosarcoidosis should be included in the differential of longitudinally extensive transverse myelitis, particularly in AQP4-IgG seronegative patients.

References

1. Tavee JO, Stern BJ. Neurosarcoidosis. Continuum (Minneap Minn)2014Jun;20(3 Neurology of Systemic Disease):545–59.

2. Sohn M, Culver DA, Judson MA, Scott TF, Tavee J, Nozaki K. Spinal cord neurosarcoidosis. Am J Med Sci2014Mar;347(3):195–8.

3. Flanagan EP, Kaufmann TJ, Krecke KN, Aksamit AJ, Pittock SJ, Keegan BM, Giannini C, Weinshenker BG. Discriminating long myelitis of neuromyelitis optica from sarcoidosis. Ann Neurol2016Mar;79(3):437–47.
113 Rituximab and maintenance mycophenolate mofetil for treatment of refractory ANTI-N-METHYL-D-ASPARTATE-receptor (NMDAR) encephalitis
Authors: Edwards Leon S , Barnett Michael H , Kiernan Matthew C
Published: May 2018

Introduction

NMDAR encephalitis is an autoimmune condition with antibodies to the NR1 subunit of the NMDAR. It has a variable clinical presentation with behavioural and psychiatric symptoms. There is frequently a relapsing course. A known association exists with tumours, particularly ovarian teratoma. Cases which are not associated with tumour often fail first line therapy. As such, therapy for this disease can be challenging and involves a spectrum of immunotherapy. Rituximab is widely considered to be second line treatment for this illness. We present two cases of refractory anti-NMDAR encephalitis.

Cases

Both patients were confirmed antibody positive in the serum and cerebral spinal fluid. There was no tumour identified on whole body positron emission tomography and transvaginal pelvic ultrasound. Each patient was initially treated with first line therapy of intravenous immunoglobulin, plasmapheresis and methylprednisolone with limited symptomatic improvement. Second line therapy of two doses of rituximab was administered intravenously two weeks apart at a dose of 1000 mg. Mycophenolate mofetil was used at a dose of 1000 mg twice daily to minimise B-cell reconstitution. Response to treatment was monitored with measurement of CD 19+ Pan B cells in peripheral blood and clinical assessment by the consultant liaison psychiatry service. Both patients demonstrated significant response with undetectable CD 19+ Pan B cells on serial testing and sustained clinical improvement in initial behavioural symptoms.

Conclusion

In patients with anti-NMDAR encephalitis, rituximab combined with maintenance mycophenolate mofetil may be an effective treatment.
013 Lipid metabolism and body composition in frontotemporal dementia-amyotrophic lateral sclerosis spectrum: effect on survival and disease progression
Authors: Ahmed Rebekah M , Highton-Williamson Elizabeth , Caga Jashelle , Thornton Nicollette , Ramsey Eleanor , Zoing Margaret , Piguet Olivier , Hodges John , Halliday Glenda , Farooqi Sadaf , Kiernan Matthew C
Published: May 2018

Introduction

Patients with Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exhibit changes in eating behaviour that could potentially affect lipid levels and body composition. This study aimed to document changes in lipid metabolism and body composition across the ALS-FTD spectrum to identify potential relationships to eating behaviour (including fat intake), cognitive change, body mass index (BMI) and effect on survival.

Methods

One hundred and twenty eight participants were recruited: 37 ALS patients, 15 ALS patients with cognitive and behavioural change (ALS-Plus), and 13 ALS-FTD, 31 behavioural variant FTD, and 32 healthy controls. Fasting total cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglyceride levels were measured and correlated to eating behaviour (caloric, fat intake), cognitive change, and BMI; effect on survival was examined using cox regression analyses. In a cohort of 60 patients, changes in body composition and fat deposition was examined using Dual energy X-ray absorptiometry scans (DEXA), a technique used in obesity research.

Results

There was a spectrum of lipid changes from ALS to FTD with increased triglyceride (p<0.001), total cholesterol/HDL ratio (p<0.001), and lower HDL levels (p=0.001) in all patient groups compared to controls. Whilst there was no increase in total cholesterol levels, a higher cholesterol level was found to correlate with 3.25 times improved survival (p=0.031). Triglyceride and HDL cholesterol correlated to fat intake, BMI, and measures of cognition and

Conclusion

A spectrum of changes in lipid metabolism and body composition has been identified in ALS-FTD, with total cholesterol levels found to potentially impact on survival. These changes were mediated by changes in fat intake, and BMI, and may also be mediated by the neurodegenerative process, offering the potential to modify these factors to slow disease progression and improve survival.
019 Correlation of visual field loss with mri findings in patients with pituitary tumours
Authors: Lueck Christian J , Kane Emily , Ashton David , Mews Peter , Reid Kate , Neely Andrew J
Published: May 2018

Introduction

The exact mechanism that gives rise to bi-temporal hemianopia in chiasmal compression by pituitary tumours is currently unknown. One theory suggests that, because crossing fibres cross each other and therefore have less contact area, they experience greater stress from compressive forces than those experienced by uncrossed fibres (which have a larger contact area). Finite element modelling has been used has been used to investigate this in silico but the hypothesis needs testing in vivo. This study aimed to determine whether extrinsic chiasmal compression was associated with patterns of visual field loss which supported the ‘crossing hypothesis’ or not.

Methods

Subjects with chiasmal compression secondary to pituitary tumours who also had clear visual field abnormalities were identified from the Canberra Hospital database. Visual fields were analysed to derive ‘temporality’ and ‘bi-temporality’ indices. MRI scans were analysed to determine the relative elevations of centre and peripheral portions of the optic chiasm and, in turn, the eccentricity of compression. Temporality indices were plotted against central chiasmal elevation, and both temporal and nasal hemi-field abnormalities were plotted against eccentricity.

Results

122 patients were identified but only 12 were suitable for analysis. Both temporality and bi-temporality indices were significantly correlated with central chiasmal elevation (p=0.004). Hemi-field studies demonstrated patterns of visual loss with increasing eccentricity that were more consistent with the ‘crossing hypothesis’ though the correlations failed to reach significance.

Conclusion

This study provides tentative support for the ‘crossing hypothesis’. The information will be used to inform further finite element models of chiasmal compression. A larger, prospective study is warranted.
002 Persistent improvement in door-to-needle times after implementation of the helsinki protocol for routine acute stroke care
Authors: Silsby Matthew , Duma Stephen R , Fois Alessandro F , Koryzna Joanna , Mahant Neil , Evans Andrew , Fung Victor SC
Published: May 2018

Introduction

Intravenous thrombolysis for acute ischaemic stroke is a time-critical intervention. Time to treatment may be reduced by implementing measures known as the Helsinki protocol. We aimed to investigate the effectiveness of implementing the Helsinki protocol at a large tertiary teaching hospital.

Methods

The protocol for treatment of acute stroke at Westmead hospital was modified to mirror the Helsinki protocol. Focus was placed on reducing time factors after patient arrival to hospital, without changes to the existing infrastructure. This included:

education of triage staff to improve stroke recognition;

transferring patients directly from the ambulance to CT;

intravenous contrast administration as standard CT imaging; and

tissue plasminogen activator preparation in CT.

The primary endpoints were ‘door-to-CT’ time (DCT) and ‘door-to-needle’ time (DNT).

Results

Data from stroke calls made in-hours were compared from 2016–2017. In the 12 months prior to implementation, 156 stroke calls occurred and 26 patients received thrombolysis. In the initial ten-week study, 49 stroke calls occurred and seven patients received thrombolysis. Median DNT was significantly reduced (77.5 vs 28 min, p=0.0477). In the following six months, 93 stroke calls occurred and eight patients received thrombolysis. Median DNT remained significantly reduced (77.5 vs 39 min, p=0.012). DCT was unchanged across the eight-month period (26 vs 23 min, p=0.646). Post-implementation, fewer patients received thrombolysis (17% vs 11%), but the number of calls increased (13 vs 18 per month).

Conclusion

Introduction of the Helsinki protocol for acute stroke calls resulted in a significant reduction in DNT. The changes persisted notwithstanding routine changes in junior staff. Fewer patients received thrombolysis, despite the focus on minimising delays. This might be because there were more calls, reflecting the preference for sensitivity over specificity. Reduction in DNT has significant implications for patient recovery and the effects of simple process changes persist beyond a dedicated study period.
029 Multiple-acyl-coa dehydrogenase deficiency (MADD): a rare but treatable genetic metabolic myopathy
Authors: Hooi Wai Foong , Kyndt Christopher , Faragher Mark , Day Bruce
Published: May 2018

Introduction

Multiple-acyl-CoA dehydrogenase deficiency or MADD is a rare autosomal recessive disorder caused by deficiency of electron transfer flavoprotein. Late onset form of MADD typically present with slowly progressive proximal weakness, myalgia, lethargy, vomiting, hypoglycaemia and metabolic acidosis. This condition is highly variable in age and symptoms at onset. The mean delay between onset of symptoms and diagnosis was 3.9 years. Confirmation of the diagnosis requires relatively complicated tests including muscle biopsy, Acylcarnitine profiling, urinary organic acid analysis and molecular gene testing. MADD responds dramatically to riboflavin supplementation and dietary treatment i.e. high carbohydrate, low fat and low protein diet. We report of a case of Multiple-Acyl-CoA Dehydrogenase Deficiency (MADD) and a review of the literature.

Case

A 22 year old female presented with 3 year history of slowly progressive muscle weakness, fatigue and dyspnea on minimal exertion. Clinical examination revealed profound neck extension weakness (‘dropped head syndrome’), proximal muscle weakness (winged scapula and positive Gower’s sign), mild dysphagia and dysarthria. There was no obvious facial weakness, ptosis or ophthalmoplegia. Muscle biopsy showed prominent lipid and generalised hypotrophy of type I fibres. The diagnosis of MADD was suspected on the basis of clinical presentation. The patient was commenced on riboflavin, carnitine supplementation and low protein, low fat diet. Her symptoms improved significantly over 2 months (improvement in muscle strength and respiratory function, FVC improved from 42% to 89%). Acylcarnitine and amino acid screen results came back later showing elevated levels of C6, C8, C10 and C12 in keeping with the diagnosis of MADD.

Conclusion

Multiple-acyl-CoA dehydrogenase deficiency is a rare genetic metabolic myopathy. It is under-recognised and diagnosis of the adult onset form is often challenging. The majority of patients respond well to riboflavin and dietary modifications with excellent clinical outcome.

References

. Sharp LJ, Haller RG. Metabolic and mitochondrial myopathies. Neurol Clin2014Aug;32:777–99.

. Grunert SC. Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme: A dehydrogenase deficiency. Orphanet J Rare Dis2014Jul 22;9:117.

. Angelini C. Spectrum of metabolic myopathies. Biochem Biophys Acta2015Apr;1852(4):615–21.

. Yee WC. Two eminently treatable genetic metabolic myopathies. Neurol India2008Jul–Sep;56(3):333–8.
031 Investigating motor evoked potentials as a biomarker for disease severity in hereditary spastic paraplegia
Authors: Siow Sue-Faye , Sue Carolyn , Kumar Kishore , Coward Sharon , Lofts Amy , Ng Karl
Published: May 2018

Introduction

Hereditary spastic paraplegia (HSP) encompasses a diverse group of neurodegenerative disorders that results in significant disability with no curative or disease-modifying treatment. The lack of standardised biomarkers of disease severity has limited the evaluation of potential therapeutic agents. Our aim is to investigate motor evoked potentials (MEPs) as a marker of HSP disease severity.

Methods

We studied 21 subjects (10 male, 11 female; mean age 54.3±13.8 years) with a clinical diagnosis of HSP (10 SPG4, 4 SPG7, 1 SPG3A, 1 SPG 30, 5 genetically undetermined). All patients underwent transcranial magnetic stimulation to measure central motor conduction time (CMCT), resting motor threshold (rMT) and MEP amplitude from the tibialis anterior (TA), abductor hallucis (AH) and abductor digiti minimi (ADM). Clinical disease severity was assessed with the Spastic Paraplegia Rating Scale (SPRS). Pearson correlation coefficient was used to assess correlation between variables, significance was defined as P value<0.05.

Results

TA CMCT was prolonged in 16/21 subjects (76%). AH CMCT was absent in 3/18 subjects (16.7%) and prolonged in 9/18 subjects (50%). ADM CMCT was measured in 19 subjects; all were normal. There was no significant correlation between SPRS scores and MEP amplitude, rMT or CMCT for TA or AH. There was also no significant correlation between these MEP measures and disease duration or patient age. Subgroup analysis of SPG4 HSP (10 subjects) revealed significant correlation between TA and AH CMCT with disease duration (r=0.841, p=0.001; r=0.930, p=0.001) but not SPRS scores.

Conclusion

Lower limb CMCT was absent or prolonged in the majority of subjects. Despite being potentially useful as a diagnostic biomarker for HSP, this study only showed a correlation between lower limb CMCT and disease duration in the SPG4 subgroup. Further genotype-specific studies utilising larger numbers may clarify the relationship between MEP markers and clinical features.
004 Mechanisms of nerve dysfunction in inflammatory neuropathies
Authors: Garg Nidhi , Park Susanna B , Howells James , Yiannikas Con , Vucic Steve , Noto Yu-ichi , Krishnan Arun V , Spies Judith , Mathey Emily K , Pollard John D , Kiernan Matthew C
Published: May 2018

Introduction

Immune-mediated neuropathies are a cause of disability and an immense cost to the healthcare system. They include chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN) and the neuropathy associated with IgM antibodies against myelin-associated glycoprotein (MAG). CIDP is extremely heterogeneous with marked variability in treatment responsiveness. Patients with MMN often respond to treatment but progressive weakness and wasting typically ensues over time. No therapy has consistently proven effective in anti-MAG neuropathy. The present series of studies were undertaken to improve understanding of disease mechanisms in these neuropathies, a critical step before targeted treatment approaches can be developed.

Methods

Patients fulfilling Peripheral Nerve Society criteria for CIDP or MMN and patients positive for anti-MAG IgM underwent comprehensive clinical assessments, neurophysiology, serological testing and structural assessments.

Results

The patient cohort consisted of 80 patients (51 CIDP, 14 MMN, 15 MAG). 6% of CIDP patients tested positive for anti-neurofascin 155 (NF155) and 4% for anti-contactin 1 IgG4. Anti-NF155 neuropathy was characterised by diffuse nerve enlargement and an axonal excitability profile consistent with severe disruption of the paranodal seal. CIDP patients testing negative for IgG4 antibodies also demonstrated significant nerve enlargement compared with healthy subjects. Axonal excitability profiles differed in those with and without median nerve conduction block. MMN was characterised by patchy nerve enlargement, marked increases in super-excitability and enlarged motor unit size. In contrast, anti-MAG neuropathy patients demonstrated a proximal pattern of nerve enlargement and an axonal excitability profile characterised by reduced super-excitability consistent with increased juxta-paranodal fast potassium channel conductance.

Conclusion

Patterns of nerve enlargement and neurophysiological profiles differ in the immune-mediated neuropathies providing insights into molecular mechanisms. These results provide templates that can guide treatment approaches. The combination of directed autoantibody assays and measures of axonal function can be used to monitor disease progression and therapeutic response.
042 Chronic inflammatory demyelinating polyneuropathy presenting as focal amyotrophy
Authors: El-Wahsh Shadi , Cordato Dennis , Yiannikas Con
Published: May 2018

Introduction

We aimed to report a rare case of chronic inflammatory demyelinating polyneuropathy (CIDP) presenting as focal lower limb amyotrophy.

Case

A 65 year old man presented with a 12 month history of painless, left anterior thigh wasting. Examination revealed marked left quadriceps and mild left hamstring and tibial wasting (Image 1). He had MRC grade 4/5 left hip flexion and 3/5 knee extension weakness, with normal power elsewhere. His left knee jerk was absent. Remaining reflexes were retained. There was reduced left L5 pinprick and light touch sensation. His neurological exam was otherwise normal. Blood tests, including creatine kinase, blood glucose, and autoimmune panel, were normal. Anti-neuronal, anti-ganglioside and anti-MAG antibodies were negative. Trace IgM lambda para-proteinaemia was detected. Cerebrospinal fluid was unremarkable [protein 0.37 g/L (n<0.45), glucose 4.1 mmol/L (2.5–4.5), leukocytes 0×106/L]. Nerve conduction studies showed normal lower limb motor velocities with reduced left peroneal motor amplitudes and mildly prolonged sural sensory latencies bilaterally. Electromyography showed chronic denervation of bilateral L3-S1 innervated muscles without fibrillation potentials. Posterior tibial somatosensory evoked potential studies demonstrated absent lumbar responses and prolonged cortical latencies. Muscle biopsy confirmed chronic denervation without evidence of myopathy or vasculitis. The patient declined sural nerve biopsy. MRI revealed bilateral multifocal lumbosacral plexopathy with increased T2 signal and thickening of multiple nerves, including femoral, lateral femoral cutaneous and L5 nerve roots (Image 2). CT chest, abdomen and pelvis, and whole body PET scan were normal. High-dose oral prednisone and induction intravenous immunoglobulin (IVIG) therapy followed by 4-weekly maintenance IVIG and low-dose prednisolone were commenced for a presumed diagnosis of CIDP.

Conclusion

In this patient, the presence of multifocal nerve thickening on MRI was consistent with an inflammatory neuropathy. The normal PET scan and CSF studies made other diagnoses, such as neuro-lymphoma, less likely. CIDP should be considered in atypical presentations such as focal amyotrophy.
043 Rheumatoid leptomeningitis: an acute presentation of neuropsychiatric disturbance
Authors: Lubomski Michal , Sy Joanne , Buckland Michael , Lee Andie S , Richards Bethan , Thompson Elizabeth , Fulham Michael , Halmagyi Michael
Published: May 2018

Introduction

We report a case of an isolated acute neuropsychiatric presentation due to rheumatoid meningitis (RM), successfully treated with steroids and rituximab.

Case

A 41 year old man with a chronic headache and acute neuropsychiatric disturbance including impulsivity, grandiose delusions and agitation on a background of no known psychiatric history. Incidentally, he reported migratory palindromic, large and small joint polyarthritis over the preceding 18 months accompanied by headache, symptomatically treated with indomethacin. He had no prior diagnosis of rheumatoid arthritis (RA) or other connective tissue disorder. Serum and cerebrospinal fluid (CSF) cyclic citrullinated peptide antibodies were strongly positive, with a normal serum rheumatoid factor. An interferon-gamma release assay was positive, suggestive of prior tuberculosis (TB) exposure. CSF examination was unremarkable with an MRI brain demonstrating asymmetric features of leptomeningeal thickening and enhancement over both cerebral cortices, suggesting an inflammatory or infiltrative leptomeningitis. Lymphoma, IgG4–related disease, granulomatous diseases such as TB, granulomatosis with polyangiitis, neurosarcoidosis, neurosyphilis and meningeal metastasis were considered as differential diagnoses. A leptomeningeal and brain biopsy showed necrotising inflammation with ill-defined granulomas and a dense lymphoplasmacytic infiltrate. No organisms were identified. Mycobacterial polymerase chain reaction and cultures over three months were negative. RM was the favoured histological diagnosis. Empirical treatment for prior TB exposure was commenced in conjunction with steroids. Subsequent addition of iv rituximab resulted in sustained improvement of neuropsychiatric and joint symptoms.

Conclusion

This report illustrates for the first time isolated acute neuropsychiatric disturbances attributable to RM without a prior history of RA that was responsive to rituximab. Clinicians should consider infiltrative and inflammatory leptomeningeal causes, particularly with asymmetric meningeal thickening and enchantment on MRI and should commit to a tissue biopsy when no other systemic connective tissue, infective or neoplastic causes are identified.
044 Durable clinical efficacy of alemtuzumab in patients with active rrms in the absence of continuous treatment: 7-year follow-up of CARE-MS I patients (Topaz Study)
Authors: McCombe Pamela , Boyko Alexey N , DeSeze Jérôme , Hartung Hans-Peter , Havrdova Eva , Inshasi Jihad Said , Montalban Xavier , Pozzilli Carlo , Selmaj Krzysztof W , Vermersch Patrick , Melanson Maria , Daizadeh Nadia , Rodriguez Claudio E , Wijmeersch Bart Van ,   on behalf of the CARE-MS I, CAMMS03409, and TOPAZ Investigators
Published: May 2018

Introduction

In CARE-MS I (NCT00530348), alemtuzumab 12 mg/day (baseline: 5 days; 12 months later: 3 days) improved clinical/MRI outcomes versus SC IFNB-1a over 2 years (y) in treatment-naive relapsing-remitting MS (RRMS) patients. Efficacy was durable in a 4-y extension (NCT00930553; 95% enrolled, 92% completed), wherein patients could receive as-needed alemtuzumab retreatment for relapse/MRI activity or other disease-modifying therapies (DMTs) per investigator’s discretion. Patients completing the extension could enrol in the 5-y TOPAZ study (NCT02255656) for further evaluation. Here we examine efficacy/safety through Y7 in alemtuzumab-treated patients from CARE-MS I.

Methods

In TOPAZ, patients can receive alemtuzumab retreatment (≥12 months apart) or other DMTs (both per investigator’s discretion). MRI scans are performed annually. Assessments: annualised relapse rate (ARR); stable/improved Expanded Disability Status Scale (EDSS) from core study baseline; 6 month confirmed disability worsening (CDW); 6 month confirmed disability improvement (CDI); no evidence of disease activity (NEDA); adverse events (AEs).

Results

299/321 patients (93%) completed TOPAZ Y1 (Y7 after initiating alemtuzumab). ARR remained low (Y7: 0.13); 60% were relapse-free in Y3–7. The percentage of patients with stable/improved EDSS remained high (Y7: 78%). Through Y7, 74% were free from 6 month CDW, 37% achieved 6 month CDI, and the majority achieved NEDA each year (Y7: 61%). 59% received no additional treatment (alemtuzumab or other DMT) after the initial 2 courses. Overall AE incidence, infusion-associated reactions, and infections decreased over time. Thyroid AE incidence peaked in Y3 (15%) and then declined.

Conclusion

Alemtuzumab efficacy was maintained for 7 years in treatment-naive patients, despite 59% receiving no additional treatment since the initial 2 courses. 37% of patients also showed disability improvement. The alemtuzumab safety profile remained consistent; overall AE incidence decreased over time. Alemtuzumab may provide a unique treatment approach for RRMS patients, offering durable efficacy in the absence of continuous treatment.

Study support

Sanofi and Bayer HealthCare Pharmaceuticals.
051 Systematic review of CT angiographic ‘spot sign’ for predicting mortality
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 whether presence of the CT angiographic ‘spot sign’ for spontaneous intracerebral haemorrhage (ICH) expansion is predictive of mortality.

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”. 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 have not been previous systematic reviews correlating the spot sign to clinical outcome. There were 36 studies describing 6888 patients and 32 clinical outcome measures. However, there were only three outcome measures with sufficient comparability across the studies. PLR, and NLR for in-hospital mortality by spot sign were 2.47 (95% CI 1.59–3.82) and 0.62 (95%CI 0.46–0.82) with a plateau of 2.7 and 0.6 respectively across 10 studies. PLR and NLR for 3 month mortality by haematoma expansion were 0.41 (95%CI 0.35–0.47) and 0.8 (95%CI 0.78–0.83) with a plateau of 2.0 and 0.8 respectively across 8 studies.

Conclusion

Overall, there is limited data available on clinical outcomes stratified by the ‘spot sign’. Based on the available information, the PLR and NLR did not meet respective thresholds of 5 and 0.1 required to have clinical utility.