bluuebunny/crossref_metadata_2025 huggingface dataset:
“They Couldn’t Win and Didn’t Want to Lose”: The 1982 Inter-District Championship Final (Fiji Soccer)
Authors: James Kieran Edmond , Nadan Yogesh
Published: May 2022

In this article, we review one iconic match in Fiji soccer history, the 1982 Inter-District Championship Final, when bad light stopped play after ten kicks each in the penalty shootout with penalty goals tied at 6–6. In interviews with ex-administrators and players from the match, we learn that Ba reneged upon a “gentlemen’s agreement,” between the two team presidents, not to turn up for any replay match scheduled for outside of Nadi, the original venue. Ba turned up at the replay venue and claimed the trophy much to the disgust of Nadi supporters and officials. Because the Indo-Fijian community “controls” coaching and administrative positions in soccer, it is able to fashion and refashion how Indigenous Fijian men’s bodies are presented and administered within the sport. Significantly, race and class combine to make it difficult for Indigenous ex-players to move into coaching and administrative positions in soccer postretirement.
The requirement of phosphoenolpyruvate carboxykinase 1 for angiogenesis in vitro and in vivo
Authors: Yao Jin , Wu Xin-yuan , Yu Qing , Yang Shuo-fei , Yuan Jin , Zhang Zhi-qing , Xue Jin-song , Jiang Qin , Chen Min-bin , Xue Guan-hua , Cao Cong
Published: May 2022

We here examined the potential biological function of phosphoenolpyruvate carboxykinase 1 (PCK1) in angiogenesis. shRNA- or CRISPR-Cas9–induced PCK1 depletion potently inhibited endothelial cell proliferation, migration, sprouting, and tube formation, whereas ectopic PCK1 overexpression exerted opposite activity. In HUVECs, Gα
i3
expression and Akt activation were decreased following PCK1 depletion, but were augmented by ectopic PCK1 overexpression. In vivo, retinal expression of PCK1 gradually increased from postnatal day 1 (P1) to P5. The intravitreous injection of endothelial-specific PCK1 shRNA adenovirus at P1 potently inhibited the radial extension of vascular plexus at P5. Conditional endothelial knockdown of PCK1 in adult mouse retina increased vascular leakage and the number of acellular capillaries while decreasing the number of RGCs in murine retinas. In diabetic retinopathy patients,
PCK1
mRNA and protein levels were up-regulated in retinal tissues. Together, PCK1 is essential for angiogenesis possibly by mediating Gα
i3
expression and Akt activation.
Mapping microglia and astrocyte activation in vivo using diffusion MRI
Authors: Garcia-Hernandez Raquel , Cerdán Cerdá Antonio , Trouve Carpena Alejandro , Drakesmith Mark , Koller Kristin , Jones Derek K. , Canals Santiago , De Santis Silvia
Published: May 2022

While glia are increasingly implicated in the pathophysiology of psychiatric and neurodegenerative disorders, available methods for imaging these cells in vivo involve either invasive procedures or positron emission tomography radiotracers, which afford low resolution and specificity. Here, we present a noninvasive diffusion-weighted magnetic resonance imaging (MRI) method to image changes in glia morphology. Using rat models of neuroinflammation, degeneration, and demyelination, we demonstrate that diffusion-weighted MRI carries a fingerprint of microglia and astrocyte activation and that specific signatures from each population can be quantified noninvasively. The method is sensitive to changes in glia morphology and proliferation, providing a quantitative account of neuroinflammation, regardless of the existence of a concomitant neuronal loss or demyelinating injury. We prove the translational value of the approach showing significant associations between MRI and histological microglia markers in humans. This framework holds the potential to transform basic and clinical research by clarifying the role of inflammation in health and disease.
Explosive-effusive-explosive: The role of magma ascent rates and paths in modulating caldera eruptions
Authors: Bernard Olivier , Li Weiran , Costa Fidel , Saunders Steve , Itikarai Ima , Sindang Mikhail , Bouvet de Maisonneuve Caroline
Published: May 2022

One of the biggest challenges in volcanology is assessing the role of magma properties (volatile budgets, storage depths, and ascent rates) in controlling eruption explosivity. We use a new approach based on apatite to estimate volatile contents and magma ascent rates from a sequence of sub-Plinian, effusive, and Vulcanian eruption deposits at Rabaul caldera (Papua New Guinea) emplaced in 2006 CE to probe the mechanisms responsible for the sudden transitions in eruption styles. Our findings show that all magmas were originally stored at similar conditions (2–4 km depth and 1.8–2.5 wt% H2O in the melt); only the magma that formed the lava flow stalled and degassed at a shallower level (0.2–1.5 km) for several months. A more energetic batch of magma rose from depth, bypassed the transient reservoir, and ascended within ≤8 h to Earth's surface (mean velocity ≥0.2 m/s), yielding the initial sub-Plinian phase of the eruption. The shallowly degassed magma was then able to reach the surface as a lava flow, likely through the path opened by the sub-Plinian magma. The magma of the last Vulcanian phase ascended without storage at a shallow depth, albeit more slowly (ascent rate 0.03–0.1 m/s) than the sub-Plinian magma. Our study illustrates how the complexity of plumbing systems may affect eruption styles, including at other volcanic systems, and have implications for interpreting volcano monitoring data.
Mayflies as resource pulses in Jurassic lacustrine ecosystems
Authors: Zhang Qianqi , Wang Bo , Zheng Daran , Li Jiahao , Wang Xueheng , Jarzembowski Edmund A. , Xu Chunpeng , Li Ting , Zhang Haichun , Engel Michael S.
Published: May 2022

Resource pulses, occasional events of ephemeral resource superabundance, represent a fundamental mechanism by which energy, nutrients, and biomass are transported across ecotones. They are widespread in extant ecosystems; however, little is known about their deep-time record. We report the earliest-known mayfly swarm from the Early Jurassic Xiwan biota of southern China. Our taphonomic and sedimentological analyses show that these mayflies were buried on the bottom of a calm lake after post-mating death. Our suite of analyses suggests that the complex mating-swarm behavior was already well established in mayflies by the Early Jurassic. More importantly, our find represents the earliest-known resource pulse of insects, a mechanism that can play a substantial role in nutrient transport from aquatic ecosystems to surrounding terrestrial ecosystems. Such an aquatic-terrestrial ecosystem linkage may be a key novelty in Mesozoic lacustrine ecosystems. Our results high-light the underappreciated ecological significance of insects in deep-time terrestrial ecology.
Case of cryoglobulinaemia associated with chronic hepatitis B
Authors: Kolli Himabindu , Ali Mukarram Jamat , Campoverde Reyes Karen J , Lau Daryl T-Y
Published: May 2022

We present a case of a woman in her 50s with chronic hepatitis B (CHB) who had a longstanding history of arthralgia and swollen joints associated with severe fatigue. Investigations were consistent with a diagnosis of hepatitis B virus (HBV)-related cryoglobulinaemia. Two months after treatment with tenofovir alafenamide, an antiviral therapy for HBV, there was a significant improvement of her symptoms and undetectable serum cryoglobulins. Cryoglobulinaemia is a relatively rare extrahepatic manifestation of HBV infection and only presents in about 2%–4% of the patients with CHB. Its clinical manifestations include purpura, renal dysfunction, arthralgias and neuropathy. Since the presentation of cryoglobulinaemia in CHB can be non-specific, one needs to have a high index of suspicion to avoid delay in diagnosis and treatment.
Knowledge and practices related to COVID-19 among mothers of under-2 children and adult males: a cross-sectional study in Bangladesh
Authors: Talukder Animesh , Islam Muhammed Nazmul , Sarker Malabika , Goswami Indranil , Siddiqua Rubaiya Riya , Akter Fahmida , Chowdhury Srizan , Chowdhury Imran Ahmed , Rahman Albaab-Ur , Latif Mahbub
Published: May 2022

Objectives

To assess the knowledge and practices related to COVID-19 among Bangladeshi mothers with children aged 2 years or less and adult males.

Design

We conducted a cross-sectional study to assess the knowledge and practices using a multistage cluster sampling technique.

Settings

Six districts with high COVID-19 infection rates in Bangladesh.

Participants

2185 mothers of under-2 children and 657 adult males were surveyed in December 2020.

Main outcome measures

We constructed weighted composite knowledge and practice scores and examined associations between composite scores and background characteristics using linear regression models.

Results

Knowledge on possible routes of transmission of the novel coronavirus and the critical handwashing and mask-wearing etiquettes was poor. On a scale of 100, the mean composite knowledge scores of mothers and adult males were respectively 33.5 (SD=15; 95% CI 32.9 to 34.1) and 38.2 (SD=14.8; 95% CI 37.1 to 39.4). In contrast to knowledge, adult males obtained lower practice scores than mothers, primarily due to poor physical distancing practices. The mean practice scores of mothers and adult males were 63.0 (SD=18.1; 95% CI 62.3 to 63.8) and 53.4 (SD=17.5; 95% CI 52.0 to 54.7). Moreover, education, household income and access to television and the internet are significantly associated with knowledge. People residing proximal to a city revealed higher knowledge than the relatively distant ones. This was also the case for practice scores; however, the other factors associated with knowledge did not have a significant association with practices.

Conclusions

In general, both mothers and adult males presented with poor knowledge and practices related to COVID-19. While local, national and international institutions should design and implement educational interventions to help improve knowledge, our research shows that mere knowledge may not be enough to ensure practice. Hence, authorities could reinforce positive social norms by setting benchmarks and introducing rewards or sanctions to improve practices.
Intratumoral administration of STING-activating nanovaccine enhances T cell immunotherapy
Authors: Jiang Xiaoyi , Wang Jian , Zheng Xichen , Liu Zhida , Zhang Xinyu , Li Yuwei , Wilhelm Jonathan , Cao Jun , Huang Gang , Zhang Jinlan , Sumer Baran , Lea Jayanthi , Lu Zhigang , Gao Jinming , Luo Min
Published: May 2022

Background

Cancer vaccines are able to achieve tumor-specific immune editing in early-phase clinical trials. However, the infiltration of cytotoxic T cells into immune-deserted tumors is still a major limiting factor. An optimized vaccine approach to induce antigen-specific T cells that can perform robust tumor infiltration is important to accelerate their clinical translation. We previously developed a STING-activating PC7A nanovaccine that produces a strong anti-tumor T cell response on subcutaneous injection. This study systematically investigated the impact of administration methods on the performance of nanovaccines.

Methods

Tumor growth inhibition by intratumoral delivery and subcutaneous delivery of nanovaccine was investigated in TC-1 human papillomavirus-induced cancer model and B16-OVA melanoma model. Nanovaccine distribution in vivo was detected by clinical camera imaging, systemic T cell activation and tumor infiltration were tested by in vivo cytotoxicity killing assay and flow cytometry. For mechanism analysis, T cell recruitment was investigated by in vivo migration blocking assay, multiplex chemokine array, flow cytometry, RT-qPCR, chemotaxis assay and gene knockout mice.

Results

Nanovaccine administration was found to alter T cell production and infiltration in tumors. Intratumoral delivery of nanovaccines displayed superior antitumor effects in multiple tumor models compared with subcutaneous delivery. Mechanistic investigation revealed that intratumoral administration of the nanovaccine significantly increased the infiltration of antigen-specific T cells in TC-1 tumors, despite the lower systemic levels of T cells compared with subcutaneous injection. The inhibition of tumor growth by nanovaccines is primarily dependent on CD8+cytotoxic T cells. Nanovaccine accumulation in tumors upregulates CXCL9 expression in myeloid cells in a STING dependent manner, leading to increased recruitment of IFNγ-expressing CD8+T cells from the periphery, and IFNγ reciprocally stimulates CXCL9 expression in myeloid cells, resulting in positive feedback between myeloid-CXCL9 and T cell-IFNγ to promote T cell recruitment. However, the STING agonist alone could not sustain this effect in the presence of a systemic deficiency in antigen-specific T cells.

Conclusions

Our results demonstrate that intratumoral administration of PC7A nanovaccine achieved stronger antitumor immunity and efficacy over subcutaneous injection. These data suggest intratumoral administration should be included in the therapeutic design in the clinical use of nanovaccine.
Variation at the LRRK2 locus determines the rate of disease progression in pro- gressive supranuclear palsy
Authors: Jabbari Edwin , Tan Manuela , Jaunmuktane Zane , Holton Janice , Revesz Tamas , Warner Thomas , Lees Andrew , Ryten Mina , Hardy John , Morris Huw ,   et al
Published: May 2022

Background

The genetic basis of variation in the rate of disease progression in primary tauopathies is poorly understood. Here, we have conducted a genome-wide association study (GWAS) of Progressive Supranuclear Palsy cases using survival as a marker of disease progression.

Methods

Two independent, deeply-phenotyped, PSP cohorts of European ancestry underwent genotyp- ing and SNP imputation. Standard data quality control steps were used, including a MAF threshold of 1%. We used a cox-proportional hazards survival model GWAS that adjusted for sex, age at motor symptom onset, PSP phenotype and ethnicity (first three principal components).

Results

1,001 PSP cases (2011 case-control GWAS, n=424; UCL PSP cohort, n=577) and 4,817,946 SNPs passed quality control steps and were available for analysis. We found a genome-wide significant signal on chromosome 12 with the lead SNP identified as rs2242367 (hazard ratio = 2.24, p-value = 7.5x10-10). This signal replicated when each independent cohort was analysed separately. The risk allele at this SNP was associated with a 1 year reduction in survival. eQTL analyses revealed that rs2242367 and its tagging SNPs are eQTLs for LRRK2 expression in whole blood and brain.

Conclusions

We hypothesise that the whole blood eQTL signal may impact on monocyte-derived micro- glia-like cells and that increased LRRK2 expression may result in a reactive microglia-induced pro-inflam- matory state which drives ongoing accumulation of misfolded tau protein and clinical disease progression.

e.jabbari@ucl.ac.uk
Pure tone audiometry and cerebral pathology in healthy older adults
Authors: Parker Thomas , Keshavan Ashvini , Buchannan Sarah , Keuss Sarah , Bamiou Doris-Eva , Warren Jason , Fox Nick , Richards Marcus , Schott Jonathan ,   et al
Published: May 2022

Background

Hearing impairment may be a modifiable risk factor for dementia. However, it is unclear how hearing associates with pathologies relevant to dementia in preclinical populations.

Methods

Data from 368 cognitively healthy individuals born during 1 week in 1946 (age range 69.2–71.9 years), who underwent structural MRI, 18F-florbetapir positron emission tomography, pure tone audiom- etry and cognitive testing as part of a neuroscience substudy the MRC National Survey of Health and Development were analysed. The aim of the analysis was to investigate whether pure tone audiometry performance predicted a range of cognitive and imaging outcomes relevant to dementia in older adults.

Results

There was some evidence that poorer pure tone audiometry performance was associated with lower primary auditory cortex thickness, but no evidence that it predicted in vivo β-amyloid deposition, white matter hyperintensity volume, hippocampal volume or Alzheimer’s disease-pattern cortical thickness. A negative association between pure tone audiometry and mini-mental state examination score was observed, but this was no longer evident after excluding a test item assessing repetition of a single phrase.

Conclusion

Pure tone audiometry performance did not predict concurrent β-amyloid deposition, small vessel disease or Alzheimer’s disease-pattern neurodegeneration, and had limited impact on cognitive function, in healthy adults aged approximately 70 years.

thomasparker@nhs.net
253  Economic burden of care and treatment options for Rett syndrome: two systematic literature reviews
Authors: Dabbous Omar , Taieb Vanessa , Abdennadher Emna , Bouchemi Meryem , Chorąży Justyna , Borkowska Katarzyna , Georgieva Veneta , Loukes Jonathan , Maru Benit , Arjunji Ramesh ,   et al
Published: May 2022

Rett syndrome, a rare disorder caused by MECP2 mutation, causes severe developmental impairment in afflicted girls. We performed two literature reviews in June 2018 to assess Rett syndrome clinical trials (MEDLINE/Embase/ClinicalTrials.gov/Cochrane Library) and the economic burden of care (Medline/Embase/Cochrane Library/Database of Abstracts of Reviews and Effects). The economic burden search yielded 133 articles; intervention type/costs were extracted from 9, representing 4 studies. Enteral feeding/assisted walking increased the risk of respiratory-related hospital admissions, while length-of-stay was lower in younger patients. Mean recovery-stay after scoliosis-correcting surgery was 18.2/12.3 days in each of two studies. Care integration improved outcomes and reduced costs. The clinical trials search yielded 652 articles; efficacy/safety were extracted from 28, representing 20 studies (15 randomized controlled trials, 5 single-arm; N=8–82; follow-up 1–26 months). Nineteen focused on pharmacological symptom treatment; 1 examined environmental enrichment effects; most common primary endpoints: Rett syndrome Gross Motor Scale, Clinical Severity Score, Motor and Behavioral Assessment, and the Anxiety Depression and Mood Scale. Naltrexone, trofinetide, and mecasermin demonstrated clinical benefits, but most treat- ments yielded no significant improvement. Clinical practice guidelines and treatment patterns data were limited. There is demand for treatments targeting the underlying cause, such as gene therapy. Previously presented after 08/2019.

jloukes879@avexis.com

158
Population-based blood screening for pre-clinical Alzheimer’s disease: a British birth cohort at age 70
Authors: Keshavan Ashvini , Pannee Josef , Karikari Thomas K , Rodriguez Juan Lantero , Ashton Nicholas J , Nicholas Jennifer M , Cash David M , Coath William , Lane Christopher A ,   et al
Published: May 2022

In pre-clinical Alzheimer’s disease, cerebral amyloid-β (Aβ) deposition precedes symptoms; Aβ-targeted therapies may have maximum benefits at this stage. Existing Aβ status measurement techniques, including amyloid PET and CSF testing, are difficult to upscale. We therefore compared the concordance of three different blood-based techniques (liquid chromatography-mass spectrometry (LC¬-MS) measures of plasma Aβ, and single molecule array (Simoa) measures of plasma Aβ and phospho-tau181 (p-tau181)) with amyloid PET-positivity in dementia-free members of Insight 46, a sub-study of the British 1946 birth cohort.

Of 441 dementia-free individuals with complete data, 82 (18.6%) were amyloid PET-positive. The area under the receiver operating characteristics curve for amyloid PET status using a base model comprising age, sex and APOE ε4 carrier status was 0.695 (95% confidence interval: 0.628–0.762). The best perform- ing Simoa biomarker was p-tau181 (0.707; 0.646–0.768). LC-MS Aβ1–42/1–40 performed significantly better (0.817; 0.770–0.864), with a Youden’s index cut-point of 0.095 detecting amyloid PET-positivity with 86.6% sensitivity and 71.9% specificity. Without screening, 543 individuals would need PET scans, to obtain 100 PET-positive individuals. Screening using the base model would require 940 individuals, with 266 proceeding to scan. Using LC-MS Aβ1–42/1–40 alone would reduce these numbers to 623 and 243 respectively. Across a theoretical range of amyloid PET-positivity prevalence of 10–50%, LC-MS Aβ1–42/1–40 would consistently reduce scan numbers, with greater cost savings at lower prevalence.

ashvini.keshavan@nhs.net
Retinoid-X receptor agonism promotes remyelination in relapsing-remitting multiple sclerosis: a phase 2 clinical trial
Authors: L Brown J William , Cunniffe Nicholas G , Prados Ferran , Kanber Baris , Connick Peter , lin Robin Frank- , Chandran Siddharthan , Altmann Daniel , Chard Declan T , Coles Alasdair J
Published: May 2022

Background

In rodents, retinoid acid X receptor [RXR]-gamma agonists promote CNS remyelination.

Methods

In this double-blind phase 2a trial, participants with relapsing remitting multiple sclerosis (RRMS), stable on dimethyl fumarate, were randomised to bexarotene 300mg/m2 (a non-specific RXR agonist) or placebo for 6 months. The primary efficacy outcome was change in mean lesional magnetisation transfer ratio (MTR) for lesions below the within-patient median MTR. The secondary efficacy outcome was change in visual evoked potential (VEP) latency in eyes with electrophysiological evidence of optic neuropathy.

Results

52 patients were randomised to bexarotene or placebo. All bexarotene patients experienced adverse effects, notably central hypothyroidism (26 [100%]), hypertriglyceridaemia (24 [92%]), rash (13 [50%]) and neutropenia (10 [38%]). Two discontinued placebo and five discontinued bexarotene through adverse events.

The primary efficacy outcome was negative (mean submedian lesion MTR change 0.25pu (bexarotene) vs 0.09pu (placebo), p=0.54), but significant effects were seen in grey matter lesions (p=0.008). Bexarotene reduced VEP latency in those with optic neuropathy (group difference 4·66 ms/eye, p=0·014).

Conclusions

Despite a negative primary outcome, we found imaging and electrophysiological evidence of remyelination following RXR agonism in people with RRMS. Bexarotene’s safety profile precludes it’s use, but these data support selective RXR-gamma agonist development.

william.brown@doctors.org.uk
Advanced blood and neuroimaging biomarkers of axonal injury after TBI in the prospective multi-centre BIO-AX-TBI study
Authors: Graham Neil , Zimmerman Karl , Moro Federico , Gradisek Primoz , Magnoni Sandra , Oddo Mauro , Zetterberg Henrik , Bertolini Guido , Sharp David ,   et al
Published: May 2022

Background

Outcomes after traumatic brain injury (TBI) are variable and frequently poor. Axonal injury is considered a significant determinant of outcome, which may be quantified using novel fluid biomark- ers and advanced MRI.

Methods

BIO-AX-TBI is a multi-centre cohort study of acute moderate-severe TBI. Patients underwent clinical and blood biomarker/MRI assessment over one year. Blood levels of neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), glial fibrillary acidic protein (GFAP), total tau and S100B were quantified, with cerebral microdialysis facilitating measures in brain extracellular fluid.

Results

197 patients were assessed post-TBI. Compared with controls, TBI patients had significant acute elevations in GFAP, S100B, tau and UCH-L1, with NfL peaking subacutely and remaining elevated. NfL in plasma and brain interstitial fluid were highly correlated in the microdialysis subgroup. Diffusion tensor imaging (DTI) showed reduced fractional anisotropy, remaining chronically abnormal post-injury. Early cortical atrophy was predicted by acute plasma tau and chronic white matter atrophy was predicted by NfL. Clinical outcomes were accurately predicted by acute blood biomarker levels and DTI MRI.

Conclusions

Neuronal/glial markers in blood provided a reliable readout of TBI severity and predicted clinical outcomes. NfL and DTI MRI were highly sensitive to white matter injury and predicted chronic atrophy.

neil.graham@imperial.ac.uk
059  Switching CGRP monoclonal antibodies for chronic migraine: real-world outcomes of 37 episodes
Authors: Weatherall Mark , Matharu Manjit
Published: May 2022

CGRP monoclonal antibodies (mAbs) have been shown in clinical trials to be effective therapies for episodic and chronic migraine. Three CGRP mAbs are licensed for use in the UK: erenumab, freman- ezumab, and galcanezumab. The overall efficacy of these three drugs is similar in published trials, but no head-to-head comparisons have been undertaken. Very little real world data on this question has been published. It is unknown, therefore, whether some patients may respond better to one member of this novel class of migraine therapeutics than others.

The authors conducted a retrospective review of patients prescribed CGRP mAbs between 2018–2020, identifying 37 occasions on which a patient was switched from one CGRP mAb to another. In 24 cases, the switch was made because of lack of efficacy; in 13 cases, the switch was made because of side effects, cost, or other logistical factors.

Where the switch was made because of lack of efficacy, 11/24 patients found the second CGRP mAb effective in significantly reducing the frequency of migraine days; in all but two of these cases patients moved from chronic migraine to episodic migraine. Where a switch was made for reasons other than efficacy, all patients found both CGRP mAbs were effective.

In conclusion, patients with chronic migraine who fail to respond to, or do not tolerate, a first CGRP mAb should be offered treatment with another member of the class.

mark.weatherall1@nhs.net
070  A pilot study assessing choroidal thickness in frontotemporal dementia and motor neuron disease
Authors: Chen Yingdi , Larraz Juan , Wong Michael , Pearson Tom , Kalam Sabrina , Glasmacher Stella , Davenport Richard , Newton Judy , Pal Suvankar ,   et al
Published: May 2022

Background

Frontotemporal dementia and motor neurone disease are neurodegenerative disorders known to occur on a clinical continuum and to share underlying genetic and neuropathological char- acteristics. Retinal choroidal thickness (RCT) has been reported as a marker for inflammatory diseases. By comparing RCT between these disorders, this study aims to investigate the value of RCT in subclinical inflammation.

Methods

Spectral domain optic coherence tomography (SD-OCT) images were analysed to evaluate RCT in 38 people with FTD(pwFTD) (median age 65(9)), 29 with MND (pwMND) (median age 66(15)) and 31 healthy controls (median age 54(20)). The regression of RCT with age was compared amongst the three groups.

Results

1) Accelerated choroidal thinning was found in pwMND in all choroidal locations, but only identified in the sub-fovea area of the pwFTD group. 2) Compared to age matched pwMND and healthy controls, choroidal thickness was significantly lower in the temporal region of pwFTD patient aged under 65 year.

Conclusion

This study demonstrates an increase in rate of choroidal thinning in MND and FTD. Measurement of RCT using OCT may be a useful non-invasive surrogate biomarker to monitor subclinical inflammation and has potential for use as a secondary outcome measure in clinical trials of disease modifying treatments.

ychen112@ed.ac.uk

60
085  Ten year follow-up surveillance of paediatric acquired demyelinating syndromes (ADS) in the UK
Authors: Abdel-Mannan Omar , Absoud Michael , Benetou Christina , Hickson Helga , Chong WK , Hemingway Cheryl , Lim Ming , Wright Sukhvir , Hacohen Yael ,   et al
Published: May 2022

Objective

To describe 10-year follow-up of children <16 years with acquired demyelinating syndromes (ADS) from a UK-wide prospective surveillance study.

Methods

Diagnoses were retrieved from the patients’ records via the patients’ paediatric or adult neurolo- gist using a questionnaire. Demyelinating phenotypes, at follow-up, were classified by expert review panel.

Results

24/125 (19.2%) children, identified in the original study, were diagnosed with multiple sclerosis (MS, incidence of 2.04/million children/year); 23/24 fulfilled 2017 McDonald criteria at onset. AQP4-Ab neuromy- elitis optica spectrum disorders were diagnosed in 2/125 (1.6%, 0.26/million children/year), and relapsing MOG-Ab associated disease in 5/125 (4%, 0.43/million children/year). 4/125 seronegative non-MS patients relapsed and 85/125 (68%) remained monophasic over 10 years. 5/125 (4%) originally diagnosed with ADS were reclassified during follow-up: three children diagnosed initially with acute disseminated encepha- lomyelitis were subsequently diagnosed with acute necrotising encephalopathy (RANBP2 mutation), primary hemophagocytic lymphohistiocytosis (Munc 13–4 gene inversion) and anti-NMDA-R encephalitis. One child initially diagnosed with optic neuritis was later diagnosed with vitamin B12 deficiency, and one presenting with transverse myelitis was subsequently diagnosed with Sjögren’s syndrome.

Conclusions

The majority of ADS presentations in children are monophasic even at 10-year follow. Given the implications for treatment strategies, MS and CNS autoantibody mimics warrant extensive investigations.

o.abdel-mannan@ucl.ac.uk|NIHR Bursary
089  COVID-19 vaccinations in multiple sclerosis: UK MS register participant survey
Authors: Huang Yun , Baheerathan Aravindhan , Middleton Rodden , Rodgers William , Dalton Katherine Tuite , Nicholas Richard ,   MS Register Research Group
Published: May 2022

Introduction

Global efforts in vaccine development against SARS-CoV-2 saw the Pfizer-BioNTech vaccine approved for use in the United Kingdom (UK) on 2nd December 2020. There have long been discussions around vaccination in patients with multiple sclerosis (pwMS). We conducted a patient survey as part of the UK MS Register (UKMSR), to understand pwMS views on COVID vaccination.

Method

PwMS were invited by email to complete a COVID-19 vaccine online questionnaire as part of the UKMSR on 7th December 2020.

Results

A total of 3092 pwMS completed the survey by 7th January 2021. 69.1% of patients indicated they are definitely going to get a COVID-19 vaccine, 16.1% probably, 9.1% possibly, 3.4% probably not and 2.3% definitely not. Factors examined includes gender, age, highest educational attainment and type of MS. Additionally, we explored whether previous experiences of vaccinations affected attitudes towards COVID vaccination. The top reasons for not taking a COVID vaccine included safety concerns and insufficient information.

Conclusion

This UKMSR patient survey showed 85.2% of pwMS intend to get vaccinated against SARS- CoV-2, which is higher than the UK general public of 67% (1). More information on vaccine safety in pwMS would be helpful in making informed decisions.

References

YouGov Research: How many Britons are willing to take a coronavirus vaccine? 11–12 November 2020

yun.huang@nhs.net
110  UK multiple sclerosis service audit of 70 centres: MS-MDTs
Authors: Rog David , Hobart Jeremy , Mathews Joela ,   Raising the Bar 4 MS UK MS Study Group
Published: May 2022

Introduction

The UK MS service audit builds upon GIRFT’s recommendation for disease-specific data. Here, we address MS-specific Multidisciplinary Team (MS-MDT) meetings, an NHSE requirement for services prescribing disease modifying treatments (DMTs), although the wider MS-MDT parameters are less clear.

Aim

To document the characteristics and variability in UK MS-MDTs.

Methods

We asked all MS services to complete service questionnaires, supplemented with individual clinician interviews. Specifically, we asked about occurrence, frequency, who attends, and numbers and types of patients discussed at, MS-MDTs.

Results

Forty-six of the 70 centres (68%) had an MS-MDT, 63% were weekly. Neuroradiologists attended only 49%, MS Coordinators 79% and Neuropharmacists 50%, of meetings. Neurology SpRs (73%) and Research Registrars (62%), attended the majority of MS-MDTs. A mean of 9 patients (range 1–40, SD 7) were discussed, predominantly complex patients and/or those considered for high efficacy DMTs.

Conclusions

There was considerable variation in the occurrence, frequency, composition and types of patients discussed at UK MS MDTs. Neuroradiologists absence is concerning, given the central role of MRI in MS clinical decision-making. Neuropharmacists and MS coordinators absence, limits the wider benefits from MS Team members. The MS-MDT is a regular touch point and a significant educational opportunity for the whole team, including trainees. We recommend that the UK MS community defines the param- eters of an MS-MDT so that these can be consistently implemented, through job-planning, across services.

david

rog@srft.nhs.uk

80
115  Impact of siponimod on myelination across SPMS subgroups: post-hoc analysis from EXPAND MRI substudy
Authors: Arnold DL , Bar-Or A , Cree BAC , Giovannoni G , Gold R , Vermersch P , Piani-Meier D , Arnould S , Kappos L ,   et al
Published: May 2022

Background

Changes in magnetization transfer ratio (MTR) are a marker of changes in myelin density and brain tissue integrity. Siponimod improved lesional MTR recovery in the overall EXPAND secondary progressive multiple sclerosis (SPMS) population.

Objectives

Investigate the effect of siponimod on MTR changes in SPMS subgroups.

Methods

This prospective sub-study assessed the effect of siponimod versus placebo on median nor- malized MTR (nMTR) in normal appearing brain tissue (NABT), cortical Grey Matter (cGM) and normal appearing white matter (NAWM). Subgroups were defined by: disease history, severity and duration, EDSS score, Symbol Digit Modalities Test score, and inflammatory disease activity.

Results

There was an attenuation in median nMTR decrease versus placebo across all subgroups (all p<0.05 except EDSS≥6 subgroup, p=0.064). In the active SPMS subgroup, siponimod attenuated median nMTR decrease across NABT, cGM and NAWM by 91–109% (p<0.01 all); and in the non-active SPMS subgroup by 170– 198% (p=0.0151 for NAWM, p>0.05 for NABT, cGM).

Conclusions

Over 24 months, siponimod attenuated the decrease in median nMTR in brain tissues across patient subgroups characterized by disease activity and severity, with most pronounced effects in NAWM. This supports preclinical studies, showing beneficial CNS effects on myelination.

teresa.sawtell@novartis.com
118  Sustained reduction of disability and cognitive decline with long-term siponimod in EXPAND active SPMS patients
Authors: Giovannoni G , Kappos L , Fox RJ , Vermersch P , Cree BAC , Benedict RHB , Bar-Or A , Piani-Meier D , Ritter S ,   et al
Published: May 2022

Background

In the EXPAND study, patients with active SPMS (aSPMS) demonstrated a reduced risk of 3/6-month confirmed disability progression (3m/6m CDP) and risk of decline in cognitive processing speed (CPS, 6-month confirmed cognition worsening of ≥4-point on Symbol Digit Modalities Test [6mCCW]) versus placebo.

Objectives

Assess long-term efficacy and safety of siponimod in patients with aSPMS.

Methods

In aSPMS patients who entered the EXPAND Extension, time to 3m/6mCDP, 6mCCW, and annu- alized relapse rate (ARR) were assessed for the Continuous (siponimod in Core and Extension) and Switch (placebo in Core and open-label siponimod in Core/Extension) groups.

Results

Risk of 6mCDP was reduced by 29% (0.71 [0.57–0.90]; p=0.0044) for Continuous versus Switch group, corresponding to approximately 70% delay in time to 6mCDP. The risk of 6mCCW for Continuous versus Switch group was reduced by 33% (0.67 [0.53–0.86]); p=0.0018), corresponding to approximately 70% delay in time to 6mCCW. A significant reduction in ARR for the Continuous versus Switch groups was observed in patients with or without active disease.

Conclusions

Long-term data analyses showed that siponimod effects on disability, cognitive processing speed, and relapse outcomes in patients with active SPMS are sustained up to 5 years, and highlight the value of early treatment initiation.

teresa.sawtell@novartis.com
025  Baseline data from OPTIMISE: MS – a prospective, real word pharmacovigilance study in MS
Authors: Dobson Ruth , Craner Matthew , Waddingham Ed , Cavey Ana , Miller Aleisha , Matthews Paul M ,   on behalf of all OPTIMISE:MS investigators
Published: May 2022

Background

Therapeutic options in MS have increased rapidly, but real-world safety data is limited. Safety signals have emerged from clinical trials and early clinical experience with newer MS therapies, however the rates at which these occur in a real-world, UK MS population is unknown.

Methods

OPTIMISE: MS is a longitudinal observational study that will recruit at least 4000 people with MS eligible for DMT from centres across the UK. It will follow them up for at least 5 years in the first instance using electronic case records. Serious adverse events (SAEs), DMT use and disease outcomes will be captured. The study design has been informed by rheumatological biologic registries and is anticipated to expand in scope, as participants consent to be re-contacted regarding sub-studies.

Results

Since its initiation in June 2019, 906 people with MS have enrolled. 72% are female (mean age

44.5 (SD 11.1); mean disease duration 8.9 years (SD 7.3)) 95% study population have RRMS and 35% were receiving DMT prior to consent. Data from a larger cohort will be presented.

Conclusions

This study has the potential to deliver clinically meaningful data on the association of MS DMT with serious adverse events in a real-world population. The association of SAEs with lymphopaenia, and prior DMT/DMT switching will be studied. Rates of malignancies will be examined with particular reference to immunosuppressive therapies.

ruth.dobson@qmul.ac.uk
051  The capture of a UK minimum data set for MS
Authors: Nicholas Richard , Craig Elaine , Middleton Rod , Ford David , Tuite-Dalton Katie ,   UK MS Register Group
Published: May 2022

Background

The UK Multiple Sclerosis Register (UKMSR) was established in 2011 to capture ‘real world’ data from people with MS (pwMS) and the NHS. Capturing clinical data from the NHS for research is time consuming for clinical staff, can involve complicated governance, security and data quality issues. UKMSR has implemented quality controls, validation rules, new capture systems and site reporting to improve this.

Method

Compare the Minimum Data Set (MDS) consisting of 7 items including demographics and EDSS for quality and quantity in the first 3 years (pilot phase) to the most recent 3 years of data capture

Results

Completion of MDS (100% valid and completed values) (2011–2014) 4 sites, n=884. MDS received= 159 (17.9%), Time to add site ~3 Months (2017–2020) 48 Sites, n= 8836. MDS received = 5791 (65.5%), Time to add site ~6 Weeks

Conclusion

The UKMSR has improved the clinical capture of MDS from a vastly increased number of patients and clinical sites. Improved validation standards and systems have increased data quality. Sites are added more quickly and rapidly notified of data quality issues for correction, making the data more useful to the site and ultimately of more utility to researchers.

richard.nicholas@btinternet.com
Hoxa5 inhibits adipocyte proliferation through transcriptional regulation of Ccne1 and blocking JAK2/STAT3 signaling pathway in mice
Authors: Pan Miao , Sun Qian , Li Chaowei , Tai Ruiqing , Shi Xin’e , Sun Chao
Published: May 2022

The highly regulated proliferation of adipocytes plays a momentous role in fat development and obesity. Hoxa5 is an important member of the Hox family, its encoded protein is an important transcription factor related to development, and its differential expression in different adipose tissues seems to indicate that Hoxa5 may be involved in the regulation of adipocyte proliferation. To evaluate the regulatory mechanism of Hoxa5 on adipocyte proliferation, we constructed a variety of Hoxa5 expression vectors in vivo and in vitro to explore its mechanism on adipocyte proliferation and its potential impact on obesity. We observed that the overexpression of Hoxa5 strongly reduces cell counts and Hoxa5 can inhibit cell proliferation and block cell cycle progression by regulating the expression of genes such as Cyclin E, Cyclin D1, and p53. Most importantly, we demonstrated that Hoxa5 exerts its effect by regulating the signaling pathway of Janus kinase 2 (JAK2) signal transduction and transcription 3 (STAT3) activator, as well as binding to the promoter region of Ccne1 and inhibiting the transcription of Ccne1. This study provides an in-depth understanding of the potential molecular mechanism of Hoxa5 inhibiting adipocyte proliferation. Our results suggest the importance of Hoxa5 in the treatment of obesity.
Patterns of pollen dispersal and pollen capture in the hybridizing cattails,Typha latifoliaandTypha angustifolia
Authors: Pieper Sara J. , Freeland Joanna R. , Dorken Marcel E.
Published: May 2022

Pollen dispersal regulates the formation of the invasive, wind-pollinated hybrid cattail Typha × glauca Godron, the F1offspring of the broadleaf ( Typha latifolia L.) and narrowleaf ( Typha angustifolia L.) cattail. An earlier study suggested that pollen dispersal by T. latifolia might be spatially restricted, with most dispersal occurring over distances less than 2 m. Restricted pollen dispersal would imply that hybrid formation primarily occurs within mixed stands of cattails. Hybrid formation might also be affected by preferential receipt of conspecific pollen, but this has not been investigated for cattails. We compared patterns of pollen dispersal for T. latifolia and T. angustifolia using a wind tunnel. We then tested whether patterns of pollen receipt were biased toward the capture of conspecific versus heterospecific pollen using monospecific cattail stands with a single local pollen source. Results from the wind tunnel partially supported the previous finding of spatially restricted pollen dispersal for T. latifolia, the paternal parent of F1hybrids. Pollen receipt by T. angustifolia was biased toward the capture of conspecific pollen. Localized pollen dispersal by T. latifolia and preferential conspecific pollen capture by T. angustifolia should reduce rates of hybrid formation below that expected under random mating.
Destroying general family of rotating and accelerating charged Plebanski–Demianski black holes
Authors: Molla Niyaz Uddin , Debnath Ujjal
Published: May 2022

Neglecting the self-energy, self-force and radiative effects, we apply Wald’s Gedanken experiment to destroy the general family of rotating and accelerating charged Plebanski–Demianski (PD) black hole (BH) by capturing a test-charged particle. We investigate that an extremal or a near-extremal PD BH can turn into a naked singularity by capturing the test particle. We also discuss the overspinning of PD BHs with a neutral test scalar field. Furthermore, we discuss the destruction of the near-extremal PD BH with the neutrino fields.
A general framework for gravitational charges and holographic renormalization
Authors: Chandrasekaran Venkatesa , Flanagan Éanna É. , Shehzad Ibrahim , Speranza Antony J.
Published: May 2022

We develop a general framework for constructing charges associated with diffeomorphisms in gravitational theories using covariant phase space techniques. This framework encompasses both localized charges associated with space–time subregions, as well as global conserved charges of the full space–time. Expressions for the charges include contributions from the boundary and corner terms in the subregion action, and are rendered unambiguous by appealing to the variational principle for the subregion, which selects a preferred form of the symplectic flux through the boundaries. The Poisson brackets of the charges on the subregion phase space are shown to reproduce the bracket of Barnich and Troessaert for open subsystems, thereby giving a novel derivation of this bracket from first principles. In the context of asymptotic boundaries, we show that the procedure of holographic renormalization can be always applied to obtain finite charges and fluxes once suitable counterterms have been found to ensure a finite action. This enables the study of larger asymptotic symmetry groups by loosening the boundary conditions imposed at infinity. We further present an algorithm for explicitly computing the counterterms that renormalize the action and symplectic potential, and, as an application of our framework, demonstrate that it reproduces known expressions for the charges of the generalized Bondi–Metzner–Sachs algebra.
Limit Cycle Bifurcations Near a Heteroclinic Loop with Two Nilpotent Cusps of General Order
Authors: Yang Junmin , Hu Xing
Published: May 2022

In this paper, we study the expansion of the first order Melnikov function near a heteroclinic loop with two nilpotent cusps of general order. More precisely, the order of the two cusps is [Formula: see text] and [Formula: see text] respectively, where [Formula: see text] [Formula: see text]. For general [Formula: see text] and [Formula: see text], we give the expansion of the first order Melnikov function and the formulas for the first few coefficients. We further give a general theorem on the number of limit cycles bifurcated from the heteroclinic loop. These results extend the existing results for [Formula: see text], [Formula: see text] and [Formula: see text] [Formula: see text]. As an application, these results are applied to study the number of limit cycles near a heteroclinic loop with two cusps of different order.
Observables from spherically symmetric modified dispersion relations
Authors: Läänemets Dagmar , Hohmann Manuel , Pfeifer Christian
Published: May 2022

In this work, we continue the systematic study of observable effects emerging from modified dispersion relations. We study the motion of test particles subject to a general first-order modification of the general relativistic dispersion relation as well as subject to the [Formula: see text]-Poincaré dispersion relation in spherical symmetry. We derive the corrections to the photon sphere, the black hole shadow, the and the light deflection and identify the additional dependence of these observables on the photons’ four momentum, which leads to measurable effects that can be compared to experimental data. The results presented here can be interpreted in two ways, depending on the origin of the modified dispersion relation: on the one hand as prediction for traces of quantum gravity, when the modified dispersion relation is induced by phenomenological approaches to quantum gravity, on the other hand as predictions of observables due to the presence of a medium, like a plasma, which modifies the dispersion relation of light on curved spacetimes.
Gravitational radiation in higher order non-local gravity
Authors: Capriolo Maurizio
Published: May 2022

In this paper, we examine gravitational radiation in higher order non-local gravity described by the non-local gravitational Lagrangian density [Formula: see text]. This non-local theory of gravitation always exhibits the tensor transverse gravitational radiation for [Formula: see text], corresponding to the angular frequency [Formula: see text], composed of two standard [Formula: see text] and [Formula: see text] polarization modes, massless and of helicity 2. Furthermore, it shows, under suitable constraint and [Formula: see text], an additional massive transverse scalar gravitational radiation with helicity 0. It is composed of [Formula: see text] modes associated to [Formula: see text] angular frequencies [Formula: see text], each of which is of breathing polarization [Formula: see text] to lowest order in [Formula: see text], a parameter that takes into account the difference in speed between the slightly massive wave and the massless one. Thanks to NP formalism, we find that the [Formula: see text] class of non-local gravitational waves is [Formula: see text], according to Petrov classification, where the presence or absence of all modes are observer independent. Also, the scalar radiation is forbidden for [Formula: see text] and [Formula: see text] cases, when some conditions are satisfied. Finally, in [Formula: see text] gravity where [Formula: see text], a possible degenerate case with a continuous infinity of transverse massive scalar breathing modes appears under a particular constraint, which reproduces in two-dimensional spacetime the Polyakov–effective action.