bluuebunny/crossref_metadata_2025 huggingface dataset:
Amelioration of systemic antitumor immune responses in cocktail therapy by immunomodulatory nanozymes
Authors: Wang Shuren , Wang Zhiyi , Li Ziyuan , Zhang Xiaoguang , Zhang Hongtao , Zhang Teng , Meng Xiangxi , Sheng Fugeng , Hou Yanglong
Published: May 2022

Nanozymes that mimic natural enzyme–like activities have gradually emerged in cancer therapy. To overcome the bottlenecks of single-mode nanozymes, including “off-target” toxicity and ineffectiveness toward metastatic cancers, we designed magnetic nanoparticle–based multifunctional visualized immunomodulatory nanozymes. Besides the partial initiation of the prime immune response by intrinsic immunogenicity, as a smart drug delivery system with a temperature- and pH-sensitive dual response to the tumor microenvironment, these nanozymes released immune agonists to boost enhanced systemic immune response, eventually ameliorating the cancer immune microenvironment through many aspects: activating dendritic cells, improving the function of CD8
+
T cells, and decreasing the population of myeloid-derived suppressor cells, which inhibited both primary and metastatic cancers. Mechanistically, these nanozymes regulated the reactive oxygen species–related Akt signaling pathway and consequently activated cell apoptosis–related signaling pathways, which provided a deeper understanding of the synergistic mechanism of multifunctional nanozymes. Our findings offer a promising imaging-guided cocktail therapy strategy through immunomodulatory nanozymes.
Rgs16 promotes antitumor CD8
+
T cell exhaustion
Authors: Weisshaar Nina , Wu Jingxia , Ming Yanan , Madi Alaa , Hotz-Wagenblatt Agnes , Ma Sicong , Mieg Alessa , Hering Marvin , Zettl Ferdinand , Mohr Kerstin , Schlimbach Tilo , Ten Bosch Nora , Hertel Franziska , Müller Lisann , Byren Hannah , Wang Mona , Borgers Helena , Munz Mareike , Schmitt Lukas , van der Hoeven Franciscus , Kloz Ulrich , Carretero Rafael , Schleußner Nikolai , Jackstadt Rene-Filip , Hofmann Ilse , Cui Guoliang
Published: May 2022

T cells become functionally exhausted in tumors, limiting T cell–based immunotherapies. Although several transcription factors regulating the exhausted T (T
ex
) cell differentiation are known, comparatively little is known about the regulators of T
ex
cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed T
ex
cell survival in tumors. By performing lineage tracing using reporter mice in which mCherry marked Rgs16-expressing cells, we identified that Rgs16
+
CD8
+
tumor-infiltrating lymphocytes (TILs) were terminally differentiated, expressed low levels of T cell factor 1 (Tcf1), and underwent apoptosis as early as 6 days after the onset of Rgs16 expression.
Rgs16
deficiency inhibited CD8
+
T cell apoptosis and promoted antitumor effector functions of CD8
+
T cells. Furthermore,
Rgs16
deficiency synergized with programmed cell death protein 1 (PD-1) blockade to enhance antitumor CD8
+
T cell responses. Proteomics revealed that Rgs16 interacted with the scaffold protein IQGAP1, suppressed the recruitment of Ras and B-Raf, and inhibited Erk1 activation.
Rgs16
deficiency enhanced antitumor CD8
+
TIL survival in an Erk1-dependent manner. Loss of function of Erk1 decreased antitumor functions of
Rgs16
-deficient CD8
+
T cells.
RGS16
mRNA expression levels in CD8
+
TILs of patients with melanoma negatively correlated with genes associated with T cell stemness, such as
SELL
,
TCF7
, and
IL7R
, and predicted low responses to PD-1 blockade. This study uncovers Rgs16 as an inhibitor of T
ex
cell survival in tumors and has implications for improving T cell–based immunotherapies.
Intratumoral immunotherapy relies on B and T cell collaboration
Authors: Sagiv-Barfi Idit , Czerwinski Debra K. , Shree Tanaya , Lohmeyer Julian J. K. , Levy Ronald
Published: May 2022

Antitumor T cell responses are the primary mediators of cancer immunotherapy. However, many other components of the immune system are needed for efficient T cell responses to be generated. Here, we developed a combinatorial approach where a Toll-like receptor 9 agonist (CpG) and Fc-fused IL-12 protein were injected together into just one of several tumor sites in a mouse. This combination led to body-wide (abscopal) therapeutic responses in multiple cancer models. These systemic responses were dependent not only on T cells but also on B cells. B cells were activated by the treatment and were required for optimal T cell activation. This cross-talk was dependent on MHC and was tumor antigen specific. The addition of an agonistic antibody against OX40 further enhanced T cell activation and therapeutic responses. Our data suggest that the combination of CpG, anti-OX40, and IL-12Fc may have success in patients with cancer and that B and T cell collaboration is crucial for the efficacy of this combination immunotherapy.
Applicability of five nutritional screening tools in Chinese patients undergoing colorectal cancer surgery: a cross-sectional study
Authors: Xie Bingxin , Sun Yefei , Sun Jian , Deng Tingting , Jin Baodi , Gao Jia
Published: May 2022

Objectives

To identify the most appropriate nutritional risk screening tool for patients undergoing colorectal cancer surgery, five nutritional screening tools, including the Nutritional Risk Screening 2002 (NRS 2002), Short Form of Mini Nutritional Assessment (MNA-SF), Malnutrition Universal Screening Tool (MUST), Malnutrition Screening Tool (MST) and Nutritional Risk Index (NRI), were employed to evaluate the nutritional risk at admission and short-term clinical outcome prediction.

Design

A cross-sectional study.

Setting

A comprehensive affiliated hospital of a university in Shenyang, Liaoning Province, China.

Participants

301 patients diagnosed with colorectal cancer were continuously recruited to complete the study from October 2020 to May 2021.

Primary and secondary outcome measures

Within 48 hours of hospital admission, five nutritional screening tools were used to measure the nutritional risk and to determine their relationship with postoperative short-term clinical outcomes.

Results

The nutritional risk assesed by the five tools ranged from 25.2% to 46.2%. Taking the Subject Global Assessment as the diagnostic standard, MNA-SF had the best consistency (κ=0.570, p<0.001) and MST had the highest sensitivity (82.61%). Multivariate Logistic regression analysis after adjusting confounding factors showed that the NRS 2002 score ≥3 (OR 2.400, 95% CI 1.043 to 5.522) was an independent risk factor for postoperative complications and was the strongest predictor of postoperative complications (area under the curve 0.621, 95% CI 0.549 to 0.692). The scores of NRS 2002 (r=0.131, p<0.001), MNA-SF (r=0.115, p<0.05) and NRI (r=0.187, p<0.05) were poorly correlated with the length of stay. There was no correlation between the five nutritional screening tools and hospitalisation costs (p>0.05).

Conclusions

Compared with the other four nutritional screening tools, we found that NRS 2002 is the most appropriate nutritional screening tool for Chinese patients with colorectal cancer.
Influence of social support on return to work after total hip or total knee arthroplasty: a prospective multicentre cohort study
Authors: Kamp Tamara , Stevens Martin , Van Beveren Jan , Rijk Paul C , Brouwer Reinoud , Bulstra Sjoerd , Brouwer Sandra
Published: May 2022

Objectives

There is strong evidence that social support is an important determinant of return to work (RTW). Little is known about the role of social support in RTW after total hip or knee arthroplasty (THA/TKA). Objective was to examine the influence of preoperative and postoperative perceived social support on RTW status 6 months postoperatively.

Design

A prospective multicentre cohort study was conducted.

Setting

Orthopaedic departments of four Dutch medical centres; a tertiary university hospital, two large teaching hospitals and a general hospital.

Participants

Patients planned to undergo THA/TKA, aged 18–63 and employed preoperatively were included.

Main outcome measures

Questionnaires were filled out preoperatively and 3 and 6 months postoperatively and included questions to assess patients’ perceived social support targeting three sources of social support: from home (friends, family), from work (coworkers, supervisors) and from healthcare (occupational physician, general practitioner, other caregivers). Control variables included age, gender, education, type of arthroplasty and comorbidities. RTW was defined as having fully returned to work 6 months postoperatively. Univariate and multivariate logistic regression analyses were conducted.

Results

Enrolled were 190 patients (n=77 THA, n=113 TKA, median age was 56 years, 56% women). The majority returned to work (64%). Preoperatively, social support from the occupational physician was associated with RTW (OR 2.53, 95% CI 1.15 to 5.54). Postoperatively, social support from the occupational physician (OR 3.04, 95% CI 1.43 to 6.47) and the supervisor (OR 2.56, 95% CI 1.08 to 6.06) was associated with RTW.

Conclusions

This study underscores the importance of work-related social support originating from the occupational physician and supervisor in facilitating RTW after primary THA/TKA, both preoperatively and postoperatively. Further research is needed to confirm our results and to understand the facilitating role of social support in RTW, as arthroplasty is being performed on a younger population for whom work participation is critical.
Assessing knowledge, acceptability and social implications of a peer-to-peer HIV self-testing kit distribution model among adolescents aged 15–24 in Zambia and Uganda—HISTAZU: a mixed-method study protocol
Authors: Ssemata Andrew Sentoogo , Bwalya Chiti , Muhumuza Richard , Ndekezi Denis , Mbewe Madalitso , Simwinga Musonda , Bond Virginia , Seeley Janet
Published: May 2022

Introduction

HIV self-testing (HIVST) across sub-Saharan African countries may be acceptable as it overcomes significant barriers to clinic-based HIV testing services such as privacy and confidentiality. There are a number of suggested HIVST distribution models. However, they may not be responsive to the testing service needs of adolescents and young people (AYP). We will investigate the knowledge, acceptability and social implications of a peer-to-peer distribution model of HIVST kits on uptake of HIV prevention including pre-exposure prophylaxis, condoms, and voluntary medical male circumcision and testing services and linkage to anti-retroviral therapy among AYP aged 15–24 in Zambia and Uganda.

Methods and analysis

We will conduct an exploratory mixed methods study among AYP aged 15–24 in Uganda and Zambia. Qualitative data will be collected using audio-recorded in-depth interviews (IDIs), focus group discussions (FGDs), and participant observations. All IDIs and FGDs will be transcribed verbatim, coded and analysed through a thematic-content analysis. The quantitative data will be collected through a structured survey questionnaire derived from the preliminary findings of the qualitative work and programme evaluation quantitative data collected on uptake of services from a Zambian trial. The quantitative phase will evaluate the number of AYP reached and interested in HIVST and the implication of this on household social relations and social harms. The quantitative data will be analysed through bivariate analyses. The study will explore any social–cultural and study design barriers or facilitators to uptake of HIVST.

Ethics and dissemination

This study is approved by the Uganda Virus Research Institute Research and Ethics committee, Uganda National Council for Science and Technology, University of Zambia Biomedical Ethics Committee, Zambia National Health Research Authority and the London School of Hygiene and Tropical Medicine. Dissemination activities will involve publications in peer-reviewed journals, presentations at conferences and stakeholder meetings in the communities.
063  Anti-MOG and anti AQP4 antibodies in pediatric acquired memyelinating syndromes (ADS): an Indian cohort
Authors: Sankhyan Naveen , Rawat Amit , Vyas Sameer , Sahu Jitendra , Priyanka Chandana , Saini Lokesh , Saini Arushi , Suthar Renu , Sukhija Jaspreet , Murlidharan Jayashree
Published: May 2022

Aim

To determine positivity to myelin oligodendrocyte glycoprotein (MOG-Ab) and aquaporin-4 antibod- ies (AQP4-Ab) in children with Pediatric Acquired Demyelinating Syndromes (ADS).

Method

Prospectively, in one centre, between May 2018 and Sep 2019, children (6 mo- 15 yrs) with suspected ADS were enrolled and tested for MOG-Ab and AQP4-Ab. Children with a proven non-immune mediated neurological disease were enrolled as controls.

Results

Seventy-nine children with suspected ADS were screened and 72 enrolled. There were 29 with acute disseminated encephalomyelitis (ADEM), 22 with optic neuritis and 19 with myelitis. Fourteen (19.4%, 95% CI 11–30.5) tested positive for one antibody [12 ( 17%, 95% CI 9–27) tested positive for MOG-Ab and two ( 3%, 95% CI 0.3–10) for AQP4-Ab]. None of the 62 controls tested positive for any antibody. Among those with first event, 7/58 (9%, 95% CI 3–19%) were MOG-Ab positive and two AQP4-Ab positive, whereas, 7/14 (50%, 23–77%) with recurrent events were MOG-Ab positive. All four with multiphasic ADEM were MOG Ab (4/4) positive. One of the 19 with myelitis was MOG-Ab positive.

Conclusions

Detected in one in five children, MOG-Ab are the most common antibodies detected in Pediatric ADS, especially in relapsing disease. AQP4-Ab are rare in children with ADS.

drnsankhyan@yahoo.co.in
065  Paraneoplastic glycine receptor antibody positive progressive encephalomyeli- tis with rigidity and myoclonus with breast cancer
Authors: Sumangala Salini , Bose Smriti , Marie-Watts Lisa , Jacob Saiju
Published: May 2022

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is an autoimmune condition character- ised by various neurological symptoms associated with the dysfunction of the brain stem and spinal cord. PERM has been recognised as a paraneoplastic syndrome, its effects due mainly to the cross reaction of onconeural antibodies against the tumour also affecting neuronal cells.

Interestingly, PERM can also present as an isolated syndrome not linked to malignancy. It must be noted however, that tumours may present much later than the syndrome and the aggressive nature of PERM may lead to patient mortality before the tumour can be identified clinically. Paradoxically, the treatment of malignancy can induce remission of PERM as will be illustrated in this case report.

A 45-year-old lady initially presented with paraesthesia in both lower limbs followed by leg spasms. There was also difficulty with voiding and constipation. All the initial investigations were negative and the pos- sibility of functional neurological syndrome was made. Few weeks later, patient was readmitted and on this occasion transferred to the neuroscience centre. The patient had features of increased reflexes (including clonus) and also exhibited features of autonomic dysfunction such as heat intolerance, tachy- cardia, hypertension and bowel and urinary dysfunction.

Glycine receptor positive progressive encephalomyelitis with rigidity and myoclonus (PERM) was diagnosed and investigations including PET scan confirmed an underlying breast cancer. Initial improvement with immunotherapy was sustained after cancer chemotherapy and surgery.

saiju.jacob@uhb.nhs.uk
070  What is seronegative neuromyelitis optica spectrum disorder?
Authors: Gibbons Emily , Campgana Giovanna , O’Connell Karen , Yeo Tianrong , Whittam Daniel , Karthikeayan Venkatra- man , Leite Maria Isabel , Palace Jacqueline , Jacob Anu , Huda Saif
Published: May 2022

Background

Most but not all cases of Neuromyelitis Optica Spectrum Disorder (NMOSD) are associated with Aquaporin-4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG) antibodies.

Objective

To determine the clinical characteristics of seronegative NMOSD

Method

Retrospective review of seronegative NMOSD in Liverpool and Oxford between January 2010–2020

Results

Of NMOSD=727, 49(7%) were seronegative. The male to female ratio was 1:2.5 and median age at onset was 36(5–57) years. In 2/3 of patients the index presentation was myelitis=22 or myelitis+optic neuritis=11. In 26/33 (79%), longitudinally extensive myelitis was present. Optic neuritis=9 (4 bilateral) and brain involvement=7 were also seen. Relapsing disease was observed in 39/49(80%) of patients. The median annualised attack rate was 0.58 over a median disease duration of 78 (3–258) months. Unmatched CSF oligoclonal bands (CSF-OCBs) were detected in 4/38(11%) and 31/49(63%) fulfilled multiple sclerosis (MS) diagnostic criteria. Immunosuppression (typically Mycophenolate and Rituximab) was used in 34/49(69%). Median last EDSS was 4 (1–10) with death recorded in 5/49 (10%) patients.

Conclusion

Seronegative NMOSD is uncommon. Longitudinal myelitis with/without optic neuritis is a common initial presentation. Similar to AQP4-IgG, NMOSD disability and mortality rates are high. Absence of unmatched CSF-OCB and typical brain lesions help to distinguish this disease from MS.

emily.gibbons@doctors.org.uk
Somatic copy number variant mutations in alpha-synuclein and genome-wide in brains of synucleinopathy cases
Authors: Perez-Rodriguez Diego , Kayla Maria , Leija-Salazar Melissa , Lashley Tammaryn , Warner Thomas , Gentleman Steve , Schapira Anthony , Holton Janice , Jaunmuktane Zane , Proukakis Christos
Published: May 2022

Synucleinopathies are mostly sporadic neurodegenerative disorders, and include Parkinson’s disease (PD), and multiple system atrophy (MSA). Inherited copy number variants (CNVs) ofSNCA(α-synuclein) are rare causes of familial disease. There is increasing evidence for somatic mutations in the human brain, and we have hypothesized a role for these in synucleinopathies.

We further investigated somatic CNVs in brains from synucleinopathy cases, using Fluorescent in-situ Hybri- disation forSNCAgains, and single-cell whole genome sequencing for the first time in a synucleinopathy. In the cingulate cortex, mosaicism forSNCAgains was higher in MSA and PD than controls in neurons (> 2% in both diseases), and for MSA also in non-neurons. In MSA substantia nigra (SN), we notedSNCAgains in

> 3% of cells. Cells with CNVs were more likely to have α-synuclein inclusions, in a pattern corresponding to cell categories mostly relevant to the disease: dopaminergic neurons in Lewy-body cases, and other cells in striatonigral degeneration-dominant MSA (MSA-SND). HigherSNCACNV mosaicism in typical MSA-SND SN non-dopaminergic cells may correlate with younger onset, and in PD cingulate neurons with younger death. Whole genome sequencing of 169 single cells from two MSA cases showed somatic CNVs in ~ 30%. Neurons had gains and losses, and other cells almost exclusively gains.

We propose that somaticSNCACNVs contribute to the aetiology and pathogenesis of synucleinopathies, and that genome-wide somatic CNVs merit further study

c.proukakis@ucl.ac.uk
074  Long-term effect of idebenone in reducing respiratory function decline in patients with Duchenne muscular dystrophy
Authors: Servais L , Mayer OH , McDonald CM , Voit T , Mercuri E , Buyse GM
Published: May 2022

Two placebo-controlled trials of 52-week duration showed that idebenone consistently reduced respira- tory function decline rate in patients with DMD. Long-term data from the DELPHI-Extension (DELPHI-E) study and SYROS (DELOS patients who transitioned to idebenone under an Expanded Access Program) are now presented. The aim was to assess the consistency of the long-term effect of idebenone.

11 DELPHI-E and 18 SYROS patients with abnormal (<80%) forced vital capacity (as percent predicted, FVC%p) were treated with idebenone for an average of 2.0 and 4.2 years respectively. Annualized FVC%p decline rates were compared to untreated patients from SYROS or matched external controls.

Mean (SD) baseline age was 13.6 (2.3) and 13.3 (2.7) years in DELPHI (N=11) and DELOS (N=18), respec- tively, and FVC%p was 47.2% (19.7%) and 58.7% (17.6%). For the first 2-year period, the average annual decline rate was comparable in treated patients (4.5% and 5.4% in DELPHI-E and SYROS) and lower than in untreated SYROS patients and external controls (7.9% untreated and 8.1% in CINRG-DNHS). During years 3–6, the annual decline rate was consistently lower than for matched controls.

Treatment with idebenone resulted in a sustained reduction in the rate of decline in respiratory function. laurent.servais@paediatrics.ox.ac.uk
078  Myotonic dystrophy service redesign: report on a patient engagement event
Authors: Dent James , Akintade Sola , Kelly Phillip , Roberts Mark , Lilleker James
Published: May 2022

Introduction

International consensus-based care recommendations for Myotonic Dystrophy Type 1 (DM1) have been published recently. Audit of the DM1 service at the Manchester Centre for Clinical Neurosciences (MCCN) against these was presented at the 2019 ABN. Significant scope for improve- ment was identified.

Methods

As part of DM1 service redesign at MCCN an engagement event was organised. Opinions of patients, carers and relatives on service provision and areas for improvement were explored. With reference to published care recommendations, attendees participated in structured small group discus- sions. Responses were recorded by a facilitator and thematic analysis performed.

Results

In total, 69 service-users attended. Themes emerging included a perceived lack of support between consultant appointments, inadequate access to specialist therapy services, a lack of awareness of available support services, and an inadequate understanding of DM1 by healthcare professionals. Suggestions for improvement included setting up joint appointments and patient forums for group discus- sion, increased use of telephone/online appointments, and setup of a more responsive service facilitated by a specialist nurse.

Conclusion

These findings have been incorporated in to the DM1 service redesign programme at MCCN, which has included the recent appointment of a neuromuscular specialist nurse. Re-audit of the service is planned.

james.dent@doctors.org.uk
081  Ultrasound-guided muscle biopsy: a practical alternative for investigation of myopathy
Authors: Ashraghi Mohammad , Raithatha Anish , Lord Christopher , Limback-Stanic Clara , Viegas Stuart , Amiras Dimitri
Published: May 2022

Objective

We propose the use of ultrasound-guided muscle biopsy as a viable method of obtaining muscle specimen to aid the diagnosis of myopathy. We retrospectively review the diagnostic accuracy and patient feedback of ultrasound-guided muscle biopsies in our neuromuscular service.

Method

Mul- tidisciplinary team meeting reviewed select patients and agreed on those suitable for ultrasound-guided muscle biopsy. They underwent biopsy using direct ultrasound guidance and a modified Bergström needle. The specimens were sent for histopathological analysis and patients were given a feedback form.

Results

10 patients underwent 11 ultrasound-guided muscle biopsies. Of these 11, 1 was processed incorrectly, but all others were suitable for analysis. All of those processed correctly aided diagnosis. All patient feedback was rated good or excellent. In 4 patients with a previous unsuccessful surgical biopsy, ultrasound-guided biopsy was successful in obtaining suitable muscle. Of those 4 patients, 2 preferred ultrasound-guided biopsy and 2 did not state a preference.

Discussion

Our ultrasound-guided muscle biopsy technique offers an alternative to surgical biopsy. It yields high quality specimens that aids diagnosis and receives good patient feedback. It can be performed as a day-case and does not require theatre space. Fur- thermore, direct visualization of structures minimizes complications and allows biopsy of otherwise difficult targets.

Conclusion

Utilisation of ultrasound-guided modified Bergström needle technique for muscle biopsy provides comparable success rates to other techniques, and has several benefits compared to alternative techniques.

m.ashraghi@nhs.net
Rare genetic modifiers of Huntington’s disease reveal novel pathological mechanisms
Authors: Massey Tom , McAllister Branduff , Binda Caroline , Donaldson Jasmine , Chughtai Uroosa , Holmans Peter , Jones Lesley
Published: May 2022

Huntington’s disease (HD) is a progressive, untreatable neurodegenerative disorder that presents with a variable array of motor, psychiatric, cognitive and behavioural symptoms. HD is caused by a CAG repeat expansion in theHTTgene over a threshold length of 35 repeats, with longer repeats associated with earlier onset disease. Other genes, often associated with DNA repair, are known to modify HD onset. By exome sequencing 500 individuals with very early or late onset HD we identifiedcisandtransmodifiers of HD onset.Cismodifiers involved the DNA sequence just 3’ to the CAG repeat: alteration of the canonical 5’-CAACAG-3’ to pure CAG was always associated with early onset HD (p = 2.77 x 10-7) whereas extra CAA trinucleotides were associated with late onset HD (p = 3.48 x 10-6). Significanttransmodifiers included non-synonymous damaging variants in FAN1, a DNA repair nuclease. These variants were mostly associated with early onset HD and increased repeat expansion in a stem cell model of HD. Purified variant proteins showed significantly reduced DNA binding and nuclease activitiesin vitro. Overall these results link genetic modifiers in humans to a molecular mechanism of repeat expansion that represents an exciting novel therapeutic target.

thomas.massey78@gmail.com
085  Durvalumab-induced fatal myasthenia gravis
Authors: Dodd Katherine , Sussman Jonathan
Published: May 2022

In recent years a number of immune checkpoint inhibitors (ICIs) have been developed for use in oncology, as treatment strategies increasingly focus on targeted therapies and immunotherapies. These include monoclonal antibodies against programmed cell death receptor-1 (PD-1), it’s ligand programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4). ICIs aim to prevent tumour cells from evading immune attack by downregulating T cell responses, and are proving to be clinically beneficial compared with standard chemotherapy in various advanced solid tumours. The main side effect is of immune dysregulation, causing or exacerbating pre-existing autoimmune conditions, such as myasthe- nia gravis (MG).

We report a case of a 77 year old gentleman, treated with durvalumab (a PD-L1 inhibitor), for clear cell renal carcinoma, who developed severede novoMG, refractory to treatment, and died. We summarise the literature onde novoand exacerbations of pre-existing or subclinical MG with ICI use, and the high mortality rates seen with these. We believe that this is the first reported case of MG presenting in a patient with sole durvalumab use; without an additional ICI. It adds to the growing literature on the risks of severe ICI-related MG.

katherine.dodd@srft.nhs.uk
086  Thymectomy in myasthenia gravis – a review of 36 patients
Authors: Sumangala Salini , Sehmbi Gurpreet , Payyappilly Sherin Jos , Kalkat Maninder , Jacob Saiju
Published: May 2022

Guidelines set by the Association of British Neurologists recommend thymectomy for patients under the age of 45 with positive AChR antibodies or thymoma. Previous literature supports this, as thymectomy had been shown to improve clinical outcomes and reduce the need for immunosuppressive therapy. However, given the advancement of more successful immunosuppressive medicine the need for thymec- tomy can be questioned.

Aim- to identify whether thymectomy aids Myasthenia Gravis (MG) management by reducing the need for immunosuppressive medication.

Method- A retrospective evaluation identified 173 patients who had thymectomy in the UHB trust in the past 10 years, from which patients who had a primary indication of MG were extracted. Patient records were reviewed to collate data. Relevant trusts departments were contacted to fill the missing data.

Results- 36 patients filled the criteria for inclusion. The average dose of prednisolone had an insignificant reduction by 22mg (STD- 10mg). 16 patients (44%) had a lower dose of prednisolone than prior to surgery. The average dose of Azathioprine had an insignificant increase since surgery by 18mg. There was also a reduction in the use of IVIG and plasma exchange.

Conclusion- Thymectomy is unlikely to cause a significant reduction in the need for immunosuppressive therapy. Further research may be required to secure a larger sample size over a longer time period.

saiju.jacob@uhb.nhs.uk
090  Clinical trials in amyotrophic lateral sclerosis: a systematic review
Authors: Wong Charis , Dakin Rachel , Chataway Jeremy , Swingler Robert , Weir Christopher , Stallard Nigel , Parmar Mahesh , Macleod Malcolm , Pal Suvankar , Chandran Siddharthan
Published: May 2022

Background

Amyotrophic lateral sclerosis (ALS) is a rapidly fatal neurodegenerative disease. Despite decades of clinical trials, there remains a pressing unmet need for effective treatments. We reviewed past and present ALS clinical trials to understand the methodological challenges in trial design and delivery.

Methods

Trial registry databases including clinicaltrials. gov, International Clinical Trials Registry Platform, European Union Clinical Trials Register, and PubMed were systematically searched to identify Phase II, Phase II/III and Phase III Clinical Trials of Investigational Medicinal Products (CTIMPs) assessing potential disease modifying treatments in ALS. Trials registered, completed or published during 2008–2019 were included.

Results

125 CTIMPs, evaluating 76 drugs, involving 15647 people with ALS (pwALS) were reviewed. Ten drugs were tested in three or more trials. Trials employed predominantly traditional two-arm designs; only 12 used novel designs. Median number of participants was 86. 40% of trials had an attrition rate ≥ 20%. There was a wide variation of primary outcome measures and primary endpoints used.

Conclusion

Historically, limited participation of pwALS in trials, resources and outcome measures hindered definitive and timely evaluation of drugs in two-arm trials. We propose that future trials will need to be more flexible, scalable and acceptable to all stakeholders.

charis.wong@ed.ac.uk
093  Tracheostomy in plw motor neuron disease – prolonged survival with continuous ventilation via a cuffed tube
Authors: Ramsay Michelle , Kaltsakas George , Howard Leo , Sheridan Shauna , Marino Phillip , Murphy Patrick , Hart Nick , Howard Robin
Published: May 2022

The role of tracheostomy in the management of ventilatory failure due to motor neuron disease (MND) remains controversial. Although it is an effective alternative to non-invasive ventilation (NIV) in supporting ventilation, the risk of prolonged survival in the face of reduced quality of life is a concern.

We present 25 patients living with (plw) MND who underwent tracheostomy. There were 16 males, the mean age was 64.0 yrs (36–83), 13 patients underwent tracheostomy prior to the diagnosis and could not be weaned, the mean duration of tracheostomy to death or December 2019 was 3.4 yrs (0.2–8.7). 19 patients required continuous ventilation using a permanently cuffed tube. All the patients became entirely dependant, and 8 had limited or no communication despite eye gaze or environmental control systems. 14 patients were in care homes and 11 required 24 hr support at home.

Several patients expressed their desire to maintain invasive ventilatory support despite inevitable and progressively increasing dependence.

Many plw MND become dependent on invasive ventilatory support before the diagnosis is established and may live for prolonged periods following tracheostomy despite total dependence. The use of tra- cheostomy in MND raises issues about the balance of patient autonomy, resource allocation and the role of medical professionals.

robinhoward@nhs.net
097  An undisputed case of left hand weakness
Authors: Morrison Hamish , Walton Edward , Fox Mike , Stevens James
Published: May 2022

Introduction

Neurogenic thoracic outlet syndrome (NTOS) is a rare and sometimes overlooked cause of upper limb pain, weakness and disability and presents to a range of different healthcare professionals. Here we present a case of severe NTOS with characteristic clinical, radiological and electroclinical findings.

History

A 16 year old right-handed female presented with a two year history of progressive symptoms affecting her left hand. Initially she noticed weakness affecting initially the 4thand 5thleft digits which progressed to involve the whole hand. She described a burning sensation affecting the medial aspect of her left forearm at night.

Examination

Examination of the left arm revealed decreased bulk of the thenar, hypothenar and inter- ossei intrinsic muscles of the hand, power diminished to grade 4 in the left ADM, APB, FDIO and to grade 4+ in left EDC, and altered sensation in the T1 dermatome.

Investigations

A lordotic chest radiograph revealed bilaterally elongated C7 transverse processes, a finding confirmed on retrospective review of the brachial plexus MRI, which also revealed bilateral grade 1 cervical ribs and increased signal on STIR sequence of the left C8 and T1 nerve roots. Nerve conduction studies revealed electroclinical evidence of a left lower trunk brachial plexopathy.

Outcome

The patients neuropathic pain responded to low dose gabapentin. She was assessed at the Peripheral Nerve Injuries Unit at RNOH Stanmore and recently underwent successful left thoracic outlet decompression.

hamish.morrison@nhs.net
099  High relapse rate with steroid monotherapy in non-systemic vasculitic neuropathy
Authors: Bunting Eva , Cooper Rebecca , Seral M , Manji H , Rossor A , Reilly MM , Lunn MP , Bennett D , Hadden R , Carr AS
Published: May 2022

Introduction

Historically, single tissue vasculitis has been managed with steroid monotherapy. Recent data from large longitudinal databases on systemic vasculitis suggest Non-Systemic Vasculitic Neuropathy (NSVN) has higher rates of relapse, recommending that more aggressive immunotherapy is employed.

Aim

To investigate the relapse rate in NSVN in response to steroid monotherapy.

Methods

A retrospective case note review of clinically and/or pathologically defined cases of (Systemic Vasculitic Neuropathy) SVN and NSVN in two London specialist peripheral nerve centres, between 2005

- 2012 and 2015 - 2019.

Results

32 cases of SVN and 34 cases of NSVN were identified. In each group 14 individuals were treated first-line with steroid monotherapy, and 8 with cyclophosphamide. 8 SVN and 9 NSVN cases received steroids plus azathioprine. 15/32 SVN and 13/34 NSVN relapsed after first-line therapy (10/14 and 9/14 on steroid monotherapy, 3/8 and 3/9 on steroids and azathioprine, 2/8 and 1/8 on cyclophosphamide). 10 individuals stabilised with the addition of azathioprine, 13 with cyclophosphamide and 4 with Rituximab.

Conclusion

This representative case series suggests that steroid monotherapy is inadequate in the treatment of NSVN and supports an approach akin to that recommended in SVN, even if nerve is the only tissue clinically involved.

e.bunting@nhs.net
Pregnancy outcomes in a dimethyl fumarate exposure registry
Authors: Hellwig Kerstin , Rog David , McGuigan Christopher , Chen Kun , Parks Becky , Jones Cynthia C
Published: May 2022

Introduction

The delayed-release dimethyl fumarate (DMF) label recommends use during pregnancy only if potential benefit justifies the potential risk. Given limited pregnancy data, United Kingdom (UK) and Ireland are enrolling DMF-exposed pregnant women into an ongoing international registry assessing pregnancy outcomes. Pregnancies end in live birth (62%), abortion (22%), and fetal loss (16%) in general, with similar rates in MS patients.

Methods

Pregnant women with MS exposed to DMF since the first day of their last menstrual period prior to conception/during pregnancy were included. The UK/Ireland Coordinating Centres liaise directly with patients and HCPs.

Results

As of April 2019, 263 patients (14 patients from UK/Ireland) were enrolled. Of the 214 pregnancy outcomes (12 UK/Ireland) reported to date, 197(92%) were live births (12 UK/Ireland) and 17(8%) foetal loss. Of infants with known gestational age (n=197), 176(89%) births were full-term (12 UK/Ireland) and 18(9%) premature (<37 weeks). There were 16 spontaneous abortions (1 ectopic pregnancy), and 1 foetal death at ≥28 weeks of gestation. No molar pregnancies or infant or maternal deaths were reported. Seven(4%) infants (1 UK/Ireland) had confirmed birth defects.

Conclusion

No safety signal was observed, consistent with MS and general populations. Support: Biogen; disclosures detailed on poster.

david.rog@srft.nhs.uk
104  Acute mononeuritis multiplex in a patient with plasma cell leukaemia
Authors: Poole Olivia , Midgley Laura , Siddiqui Sarah , Flores Lorena , Delaj Laura , Hadden Robert , Alkufri Fadi
Published: May 2022

A 74 year old male with a history of plasma cell leukaemia, treated with VMP (bortezomib, melphalan, prednisolone) presented with a 2 week history of lumbar back pain and weakness of the hands and ankles.

Clinical examination confirmed asymmetric weakness in the hands and ankles. Sensory examination was initially normal, reflexes preserved and plantars mute. Other than the known IgG paraproteinaemia and longstanding hyponatraemia, bloods, including a vasculitis screen, were unremarkable. MRI brain and spine were non-contributary. CSF examination revealed paired bands consistent with the presence of an IgG paraprotein, but was otherwise bland. Nerve conduction studies showed a severe sensorimotor axonal neuropathy.

The patient was treated with plasma exchange followed by IV methylprednisolone but continued to progress developing more proximal weakness and sensory loss to the knees and elbows, with loss of deep tendon reflexes within 2 weeks. Sural nerve biopsy showed axonal degeneration but no vasculitis or malignant infiltration. The patient became increasingly fatigued and cachectic and the decision was made jointly with the haematologists to palliate.

Plasma cell leukaemia is a rare and aggressive subtype of multiple myeloma with a poor prognosis which has been associated with malignant nerve infiltration. Bortezomib may also cause a peripheral neuropathy.

o.poole@nhs.net
105  Broadening the clinical spectrum of bortezimib induced peripheral neuropathy: 4 illustrative cases
Authors: Grundy Kristina , Keh Ryan , Power Rachael , Gosal David , Lavin Tim
Published: May 2022

Bortezomib is a proteasome inhibitor, used in the treatment of multiple myeloma. Bortezimib induced peripheral neuropathy (BIPN) is classically a painful, sensory predominant, length dependent axonal neuropathy [1]. Atypical presentations including demyelinating neuropathies can occur, though rarely (2].

We identified 4 patients from the Manchester Centre for Clinical Neuroscience with atypical BIPN. All 4 had multiple myeloma and developed symptoms within 2 cycles of intravenous treatment.

Case 1 and 2 developed proximal and distal motor weakness and neuropathic pain. Neurophysiology confirmed mixed demyelinating/axonal neuropathy in both. Cerebral Spinal Fluid analysis confirmed albuminocytological dissociation. Immunomodulatory treatment with IVIg and steroids had minimal effect.

Case 3 developed left hand weakness, predominantly affecting the radial musculature with motor conduction block on neurophysiology.

Case 4 developed whole body paraesthesias, ataxia and thoracic radicular pain after 2 cycles, neurophysiology confirmed a sensory neuronopathy.

Case 2 died due to disease progression, the other 3 cases improved on withdrawal of Bortezimib.

Conclusion

BIPN can cause neuropathy phenotypes including sensory neuronopathy, motor neuropathy with conduction block and severe demyelinating polyradiculoneuritis. Immunogenic, as well as toxic mechanisms may have a role in the pathogenesis of BIPN.

1. Chaudhry V, Cornblath D, Polydefkis M, Ferguson A, Borrello I. Characteristics of bortezomib- and thalidomide-induced peripheral neuropathy. Journal of the Peripheral Nervous System. 2008;13(4):275–282

2. Thawani S, Tanji K, De Sousa E, Weimer L, Brannagan T. Bortezomib-Associated Demyelinating Neuropathy—Clinical and Pathologic Features. Journal of Clinical Neuromuscular Disease. 2015;16(4):202–209

tim.lavin@srft.nhs.uk
126  Headache recognition and management in acute traumatic brain injury patients – a service audit
Authors: Lichtblau Nicole , Griffin Colette
Published: May 2022

Background

Headache is one of the most frequent immediate and long-term consequences following head injury. No standardised guidelines on management of post-traumatic headache exist and for non- neurologists treatment can be challenging. Inappropriate analgesia prescription can cause medication- overuse headache.

Methods

We audited all head injury related admissions to St. George’s Hospital within a two-month period. We assessed documentation of post-traumatic headache, immediate management and long-term advice to patients and General Practitioners.

Results

We audited 91 head injury related admissions to surgical and medical wards. 65% of patients suffered traumatic brain injury (TBI) (26.7% mild; 73.7% moderate-severe). Even though 60% of all patients received regular analgesia in hospital, a clear documentation of headache was found in only 5% of them. Only 7.7% of patients discharged with regular analgesia received written advice about headache management in the discharge summary.

22% of patients with a TBI were reviewed by the TBI specialty team which diagnosed post-traumatic headache in 50% of reviewed cases and initiated change of headache management in 90% of reviewed cases.

Conclusions

Our data shows that post-traumatic headache is not well documented and managed. Wider awareness and education on headache management among all specialities needs to be raised.

nicole.lichtblau@nhs.net
129  Network controllability and regional gene expression explain visual hallucinations in Parkinson’s
Authors: Zarkali Angeliki , McColgan Peter , Ryten Mina , Reynolds Regina , Leyland Louise-Ann , Lees Andrew J , Rees Geraint , Weil Rimona S
Published: May 2022

Visual hallucinations are common in Parkinson’s (PD) and associated with poorer prognosis. Imaging studies have shown white matter and functional changes in PD-hallucinations1 2but the biological factors underlying selective vulnerability of brain regions are unknown.

We performed diffusion-weighted imaging in 100 PD patients (81 without hallucinations [PD-non-VH], 19 with hallucinations [PD-VH]) and 34 controls. We used network-based statistics to identify structural con- nectivity changes in PD-VH and performed an analysis of controllability, an emerging technique that allows quantification of influence across the rest of the network. We used the Allen brain atlas to identify regional gene expression patterns associated with affected areas of the network.

We identified a subnetwork of reduced connectivity in PD-VH. Within this network, PD-VH showed reduced controllability (influence over other brain regions), than PD-non-VH (U=526, p=0.014) and controls (U=176.5, p=0.003). This subnetwork appears to be critical for brain integration, as even in controls, nodes with high controllability were more likely to be within the subnetwork (U=572.5, p<0.001). Gene expression analysis revealed downregulated genes related to mRNA metabolism and upregulated genes related to membrane localisation.

Our findings provide insights into how hallucinations are generated, with breakdown of a key structural subnetwork that exerts control across distributed brain regions.

Reference

Shine,et al. The role of dysfunctional attentional control networks in visual misperceptions in Parkinson’s disease. HumBrainMapp;2014.

a.zarkali@ucl.ac.uk
138  Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane systematic review and meta-analysis
Authors: Mbizvo Gashirai , Chandrasekar Bharath , Nevitt Sarah , Dixon Pete , Hutton Jane , Marson Anthony
Published: May 2022

Objective

To evaluate the effectiveness of adjuvant levetiracetam in drug-resistant focal epilepsy. This is an update to the 2001 and 2012 reviews.

Methods

The search included the Cochrane Register of Studies and MEDLINE to 09/2018 for randomised, placebo-controlled trials of add-on levetiracetam in drug-resistant focal epilepsy. Two authors indepen- dently performed study selection, data extraction, and risk of bias assessments. Outcomes included

≥50% reduction in seizure frequency (response) and adverse effects. We performed Mantel-Haenszel meta-analyses for risk ratios (RR), with 95% CI (99% for adverse effects). We assessed heterogeneity using I².

Results

This update includes 14 trials (three more than the previous update), assessing 2,452 participants (296 children). Risks of bias were predominantly low. There were important levels of heterogeneity across multiple comparisons. There were two new findings: 1) Levetiracetam at either 500 mg/day or 4000 mg/day did not perform better than placebo for response (500 mg: RR 1.60, CI 0.71–3.62; 4000 mg: RR 1.64, CI 0.59–4.57). Levetiracetam was significantly better than placebo at all other individual doses (1000–3000 mg). 2) Odds of achieving response were increased by nearly 40% (odds ratio 1.39, CI 1.23–1.58) for each 1000 mg increase in dose of levetiracetam. Somnolence remained the most common adverse effect, and changes in behaviour were negligible overall.

Conclusions

It seems reasonable to continue using levetiracetam in drug-resistant focal epilepsy,

10a2lthough a 500-mg dose may be no more effective than placebo.

mbizvogkm@gmail.com
139  Can processed EEG improve our ability to monitor status epilepticus?
Authors: Gimson Amy , Smith Matthew
Published: May 2022

Processed electroencephalogram (EEG) is being increasingly used in operative anaesthetic practice for monitoring depth of anaesthesia. This potentially provides a frequently available, cost effective and simple to interpret method for monitoring status-epilepticus. This is important as continuous formal EEG monitoring (the NICE gold standard) is not available in most critical care environments. We undertook a systematic review of the evidence for using processed EEG for this indication.

Literature was available for many of the processed EEG systems now available, with most concerning the Bispectral Index (BIS) device. This equipment provides a numerical value indicative of extent of burst suppression, which correlates to burst suppression observed on standard EEG recordings. Multiple case reports and eight prospective studies report the use of BIS for optimisation of burst suppression in patients with status-epilepticus at the bedside. Further reports suggest the ability of processed EEG to detect the presence of non-convulsive status-epilepticus. Evidence also exists from prospective studies performed during electro-convulsive therapy, providing a predictable model for examining the utility of processed EEG interpretation. We conclude that processed EEG may be helpful in monitoring clinical response in the treatment of status epilepticus, however additional prospective studies are required to provide a robust evidence base.

a.gimson@nhs.net