10 research outputs found
Correction: Uncovering drug targets for cluster headache through proteome-wide Mendelian randomization analysis
No full textCluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor
Get PDFOBJECTIVE: Aggregating data for the first genome-wide association study meta-analysis of cluster headache, to identify genetic risk variants and gain biological insights. METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from ten European and one East Asian cohorts. We first performed an inverse-variance genome-wide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by five complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis and Mendelian randomization were part of the downstream analyses. RESULTS: The estimated SNP-based heritability of cluster headache was 14.5%. We identified nine independent signals in seven genome-wide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, ADHD, depression and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. INTERPRETATION: This first genome-wide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. This article is protected by copyright. All rights reserved
Cluster headache : focus on sleep, treatment, and genetics
No full textThe main hypothesis of this thesis is that cluster headache (CH) has a genetic component and by investigating this genetic component we can get insights into pathophysiological mechanisms behind CH. Clinical data can help indicate which genes can be contributing to the disease. The genetic variants can in turn help us better understand the biological mechanisms which give rise to CH. In that way we lay a foundation for developing treatment which can alleviate the suffering of millions of people around the world. This thesis focused on three major areas within CH research: sleep, treatment usage/response, and genetic links to CH pathophysiology.Sleep has long been studied in connection to CH due to the strikingly rhythmic nature of CH attacks which regularly disrupt sleep. In Paper I, we studied sleep patterns of CH participants using actigraph units to record sleep and wake times, complemented with sleep diaries. Actigraphy data showed that, although sleep time did not differ between CH participants and controls, sleep latency and time in bed was increased in CH participants. Participants with CH scored worse in almost all subjective sleep scores. Interestingly, in objective sleep measurements, CH participants in an active bout did not significantly differ to participants in remission.In Paper II, a survey investigating sleep quality, dysfunctional beliefs regarding sleep, and insomnia symptoms was sent to >700 CH participants. The survey results further established that sleep is disturbed during an active bout as compared to participants in remission and even more so to the general population. The sleep scores were additionally correlated to years since last active bout, again indicating participants in remission are still disrupted by the disease. Paper III used a similar method to investigate extent of burnout in the CH cohort. As high as 67.6% of participants in an active bout were in the risk zone for burnout. Burnout symptoms were also present in remission, but to a lesser degree and correlated to the length of time since the last active bout.To study possible biological links to the observed sleep patterns and circadian rhythm of attacks we studied genetic variants in biological clock genes. PER, CRY, BMAL1, and CLOCK are the core clock genes which drives the 24-hour rhythm. In Paper IV six genetic variants were genotyped in PER1, PER2, and PER3 which had previous links to diurnal preference or sleep. No significant difference between CH participants and controls was found. In Paper V, genetic variants in BMAL1, and NPAS2, a paralog to CLOCK, were investigated. Variants in BMAL1 (rs3789327) and NPAS2 (rs3768984) were associated with CH. Significant or trending genetic variants in the core clock genes from this study and previous studies were combined in a multi allele risk analysis. This analysis showed that CH participants carried more risk alleles than controls further strengthening the possible role of the biological clock in CH.Treatment response can vary greatly between different individuals and treatment options, and is not fully understood. In Paper VI a survey was sent out to investigate treatment response in a Swedish CH cohort. It confirmed the previously reported wide range of treatment responses observed for CH. Surprisingly, a considerable number of CH participants didn’t take any preventative medication. Side effects were common and prevented some participants with continuing their otherwise effective treatment.Since treatment response varied between participants, Paper VII investigated if genetics could partially explain this variation in the first line treatment, triptans. Five genetic variants which had previously been linked to triptan response in other diseases were genotyped and the allelic distribution was compared between triptan users and non-users. One single nucleotide polymorphism (SNP) previously linked to triptan response in migraine was significantly associated with CH triptan usage, meaning the mechanisms of action behind triptan non-response could be similar.Anecdotally, some CH patients have reported taking vitamin D supplements to improve their CH. To investigate if this was reflected in genetics, a SNP in the VDR gene was genotyped in Paper VIII. We pooled the data from the genotyped SNP and two other VDR SNPs from our previous genome-wide association study (GWAS) with data from a Greek CH cohort into a meta-analysis. No significant associations were found to CH for any of the SNPs.In the last few years genetics have increasingly shown to play an important role in CH pathology. In Paper IX, a meta-GWAS was performed on genetic material from 11 cohorts comparing CH participants to controls. When only including the 10 European cohorts, the four significant loci from previous CH GWAS were replicated, in proximity to the genes MERTK, DUSP10, FTCDNL1, and FHL5. Three new loci reached genome wide significance: WNT2, PLCE1, and LRP1.The next step was to translate the genetic findings to possible biological pathways which can contribute to the disease. MERTK is a cell-surface receptor mostly present on immune cells which plays a role in immune suppression, efferocytosis, and a range of other functions. Paper X investigated its potential role in CH. Trigeminal nerves from rats were stained with MERTK antibodies. MERTK was found to be present in Satellite cells and in Schwann cells close to the nodes of Ranvier which would allow MERTK to bind to its ligands if they were released during neuronal activation. Additionally, the protein expression levels of three of MERTK’s ligands were measured in serum. Protein levels of Galectin-3 were significantly higher in CH participants compared to controls.To further investigate a possible immunological mechanism in CH, in Paper XI cerebral spinal fluid (CSF) and serum samples were sent for an immunoassay which allowed us to look at concentrations of dozens of proteins. Eleven immune system related proteins were elevated in the CSF of CH participants compared to controls. Only two cytokines showed differentiated protein expression in the serum. These data indicate increased inflammatory markers in CH participants both in an active bout and in remission, mostly isolated to the central nervous system.List of scientific papersI. Ran C, Jennysdotter Olofsgård F, Steinberg A, Sjöstrand C, Waldenlind E, Dahlgren A, Belin AC. Patients with cluster headache show signs of insomnia and sleep related stress: results from an actigraphy and self-assessed sleep study. J Headache Pain. 2023 Aug 18;24(1):114.https://doi.org/10.1186/s10194-023-01650-wII. Jennysdotter Olofsgård F, Ran C, Steinberg A, Sjöstrand C, Waldenlind E, Lantz M, Sundholm A, Söderström M, Dahlgren A, Belin AC. Characterization of insomnia and sleep quality in a cluster headache population. [Manuscript]III. Jennysdotter Olofsgård F, Ran C, Steinberg A, Sjöstrand C, Waldenlind E, Lantz M, Sundholm A, Söderström M, Dahlgren A, Belin AC. Evidence of High Rates of Burnout in a Cluster Headache Cohort. [Manuscript]IV. Jennysdotter Olofsgård F, Ran C, Fourier C, Wirth C, Sjöstrand C, Waldenlind E, Steinberg A, Belin AC. PER gene family polymorphisms in relation to cluster headache and circadian rhythm in Sweden. Brain Sci. 2021 Aug 23;11(8):1108.https://doi.org/10.3390/brainsci11081108V. Deborgies Sanches C, Jennysdotter Olofsgård F, Fourier C, Sundholm A, Lantz M, Sjöstrand C, Waldenlind E, Steinberg A, Ran C, Belin AC. Genetic variability within molecular core clock genes in cluster headache. [Manuscript]VI. Smedfors G, Jennysdotter Olofsgård F, Steinberg A, Waldenlind E, Ran C, Belin AC. Use of prescribed and non-prescribed treatments for cluster headache in a Swedish cohort. Brain Sci. 2024 Mar 31;14(4):348.https://doi.org/10.3390/brainsci14040348VII. Jennysdotter Olofsgård F, Ran C, Qin Y, Fourier C, Waldenlind E, Steinberg A, Sjöstrand C, Belin AC. Genetic and phenotypic profiling of triptan users in a Swedish cluster headache cohort. J Mol Neurosci. 2024 Apr 18;74(2):45.https://doi.org/10.1007/s12031-024-02219-1VIII. Jennysdotter Olofsgård F, Ran C, Qin Y, Fourier C, Sjöstrand C, Waldenlind E, Steinberg A, Belin AC. Investigating vitamin D receptor genetic markers in a cluster headache meta-analysis. Int J Mol Sci. 2023 Mar 21;24(6):5950.https://doi.org/10.3390/ijms24065950IX. Winsvold BS, Harder AVE, Ran C, Chalmer MA, Dalmasso MC, Ferkingstad E, Tripathi KP, Bacchelli E, Børte S, Fourier C, Petersen AS, Vijfhuizen LS, Magnusson SH, O'Connor E, Bjornsdottir G, Häppölä P, Wang YF, Callesen I, Kelderman T, Gallardo VJ, de Boer I, Jennysdotter Olofsgård F, Heinze K, Lund N, Thomas LF, Hsu CL, Pirinen M, Hautakangas H, Ribasés M, Guerzoni S, Sivakumar P, Yip J, Heinze A, Küçükali F, Ostrowski SR, Pedersen OB, Kristoffersen ES, Martinsen AE, Artigas MS, Lagrata S, Cainazzo MM, Adebimpe J, Quinn O, Göbel C, Cirkel A, Volk AE, Heilmann-Heimbach S, Skogholt AH, Gabrielsen ME, Wilbrink LA, Danno D, Mehta D, Guðbjartsson DF; HUNT All-In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium; Rosendaal FR, Willems van Dijk K, Fronczek R, Wagner M, Scherer M, Göbel H, Sleegers K, Sveinsson OA, Pani L, Zoli M, Ramos-Quiroga JA, Dardiotis E, Steinberg A, Riedel-Heller S, Sjöstrand C, Thorgeirsson TE, Stefansson H, Southgate L, Trembath RC, Vandrovcova J, Noordam R, Paemeleire K, Stefansson K, Fann CS, Waldenlind E, Tronvik E, Jensen RH, Chen SP, Houlden H, Terwindt GM, Kubisch C, Maestrini E, Vikelis M, Pozo-Rosich P, Belin AC, Matharu M, van den Maagdenberg AMJM, Hansen TF, Ramirez A, Zwart JA; International Consortium for Cluster Headache Genetics. Cluster headache genomewide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor. Ann Neurol. 2023 Oct;94(4):713-726.https://doi.org/10.1002/ana.26743X. Edvinsson JCA, Ran C, Jennysdotter Olofsgård F, Steinberg A, Edvinsson L, Belin AC. MERTK in the rat trigeminal system: a potential novel target for cluster headache? J Headache Pain. 2024 May 23;25(1):85.https://doi.org/10.1186/s10194-024-01791-6XI. Ran C, Jennysdotter Olofsgård F, Wellfelt K, Steinberg A, Belin AC. Elevated cytokine levels in the central nervous system of cluster headache patients in bout and in remission. J Headache Pain. 2024 Jul 23;25(1):121.https://doi.org/10.1186/s10194-024-01829-9</p
Cluster Headache Genomewide Association Study and Meta‐Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor
Get PDFObjectiveThe objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights.MethodsA total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses.ResultsThe estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine.InterpretationThis first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023Objective: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. Methods: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. Results: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. Interpretation: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023.</p
Involvement of astrocyte and oligodendrocyte gene sets in migraine
Get PDFBACKGROUND: Migraine is a common episodic brain disorder characterized by recurrent attacks of severe unilateral headache and additional neurological symptoms. Two main migraine types can be distinguished based on the presence of aura symptoms that can accompany the headache: migraine with aura and migraine without aura. Multiple genetic and environmental factors confer disease susceptibility. Recent genome-wide association studies (GWAS) indicate that migraine susceptibility genes are involved in various pathways, including neurotransmission, which have already been implicated in genetic studies of monogenic familial hemiplegic migraine, a subtype of migraine with aura.METHODS: To further explore the genetic background of migraine, we performed a gene set analysis of migraine GWAS data of 4954 clinic-based patients with migraine, as well as 13,390 controls. Curated sets of synaptic genes and sets of genes predominantly expressed in three glial cell types (astrocytes, microglia and oligodendrocytes) were investigated.DISCUSSION: Our results show that gene sets containing astrocyte- and oligodendrocyte-related genes are associated with migraine, which is especially true for gene sets involved in protein modification and signal transduction. Observed differences between migraine with aura and migraine without aura indicate that both migraine types, at least in part, seem to have a different genetic background.</p
Clinical characteristics of children and young people hospitalised with covid-19 in the United Kingdom: Prospective multicentre observational cohort study
No full textObjective To characterise the clinical features of children and young people admitted to hospital with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the UK, and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to covid-19 (MIS-C). Design Prospective observational cohort study with rapid data gathering and near real time analysis. Setting 260 acute care hospitals in England, Wales, and Scotland between 17th January and 5th June 2020, with a minimal follow-up time of two weeks (to 19th June 2020). Participants 451 children and young people aged less than 19 years admitted to 116 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory-confirmed SARS-CoV-2. Main Outcome Measures Admission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C. Results Median age was 3.9 years [interquartile range (IQR) 0.3-12.9 years], 36% (162/451) were under 12 months old, and 57% (256/450) were male. 56% (224/401) were White, 12% (49/401) South Asian and 10% (40/401) Black. 43% (195/451) had at least one recorded comorbidity. A muco-enteric cluster of symptoms was identified, closely mirroring the WHO MIS-C criteria. 17% of children (72/431) were admitted to critical care. On multivariable analysis this was associated with age under one month odds ratio 5.05 (95% confidence interval 1.69 to 15.72, p=0.004), age 10 to 14 years OR 3.11 (1.21 to 8.55, p=0.022) and Black ethnicity OR 3.02 (1.30 to 6.84, p=0.008). Three young people died (0.7 %, 3/451) aged 16 to 19 years, all of whom had profound comorbidity. Twelve percent of children (36/303) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Those meeting MIS-C criteria were older, (median age 10.8 years ([IQR 8.4-14.1] vs 2.0 [0.2-12.6]), p&lt;0.001) and more likely to be of non-White ethnicity (70% (23/33) vs 43% (101/237), p=0.005). Children with MIS-C were four times more likely to be admitted to critical care (61% (22/36) vs 15% (40/267, p&lt;0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with headache (45% (13/29) vs 11% (19/171), p&lt;0.001), myalgia (39% (11/28) vs 7% (12/170), p&lt;0.001), sore throat (37% (10/27) vs (13% (24/183, p = 0.004) and fatigue (57% (17/30) vs 31% (60/192), p =0.012) than children who did not and to have a platelet count of less than 150 x109/L (30% (10/33) vs 10% (24/232), p=0.004). Conclusions Our data confirms less severe covid-19 in children and young people than in adults and we provide additional evidence for refining the MIS-C case definition. The identification of a muco-enteric symptom cluster also raises the suggestion that MIS-C is the severe end of a spectrum of disease. Study registration ISRCTN66726260Competing Interest StatementAll authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: JSN-V-T reports grants from Department of Health and Social Care, England, during the conduct of the study; PWH reports grants from Wellcome Trust / Department for International Development / Bill and Melinda Gates Foundation, grants from NIHR , during the conduct of the study; PJMO reports personal fees from Consultancy, grants from MRC, grants from EU Grant, grants from NIHR Biomedical Research Centre, grants from MRC/GSK, grants from Wellcome Trust, grants from NIHR (HPRU), grants from NIHR Senior Investigator, personal fees from European Respiratory Society, grants from MRC Global Challenge Research Fund, outside the submitted work; and The role of President of the British Society for Immunology was an unpaid appointment but my travel and accommodation at some meetings is provided by the Society; AMD reports grants from Department of Health nd Social Care, during the conduct of the study; grants from Wellcome Trust, outside the submitted work; JKB reports grants from DHSC National Institute of Health Research UK, grants from Medical Research Council UK, grants from Wellcome Trust, grants from Fiona Elizabeth Agnew Trust, grants from Intensive Care Society, grants from Chief Scientist Office, during the conduct of the study; MGS reports grants from DHSC National Institute of Health Research UK, grants from Medical Research Council UK, grants from Health Protection Research Unit in Emerging &amp; Zoonotic Infections, University of Liverpool, during the conduct of the study; other from Integrum Scientific LLC, Greensboro, NC, USA, outside the submitted work; the remaining authors declare no competing interests; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.Clinical TrialISRCTN66726260Clinical Protocolshttps://isaric4c.net/protocols/Funding StatementThis work is supported by grants from: the National Institute for Health Research [award CO-CIN-01], the Medical Research Council [grant MC_PC_19059] and by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford [NIHR award 200907], Wellcome Trust and Department for International Development [215091/Z/18/Z], and the Bill and Melinda Gates Foundation [OPP1209135], and Liverpool Experimental Cancer Medicine Centre for providing infrastructure support for this research (Grant Reference: C18616/A25153). JSN-V-T is seconded to the Department of Health and Social Care, England (DHSC). The views expressed are those of the authors and not necessarily those of the DHSC, DID, NIHR, MRC, Wellcome Trust or PHE.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval was given by the South Central - Oxford C Research Ethics Committee in England (Ref 13/SC/0149), the Scotland A Research Ethics Committee (Ref 20/SS/0028), and the WHO Ethics Review Committee (RPC571 and RPC572, 25 April 2013).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesWe welcome applications for data and material access through our Independent Data and Material Access Committee (https://isaric4c.net). The lead author (the manuscript's guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. https://isaric4c.nethttps://isaric4c.net/sample_acces
Clinical characteristics of children and young people hospitalised with covid-19 in the United Kingdom: Prospective multicentre observational cohort study
No full textObjective To characterise the clinical features of children and young people admitted to hospital with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the UK, and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to covid-19 (MIS-C). Design Prospective observational cohort study with rapid data gathering and near real time analysis. Setting 260 acute care hospitals in England, Wales, and Scotland between 17th January and 5th June 2020, with a minimal follow-up time of two weeks (to 19th June 2020). Participants 451 children and young people aged less than 19 years admitted to 116 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory-confirmed SARS-CoV-2. Main Outcome Measures Admission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C. Results Median age was 3.9 years [interquartile range (IQR) 0.3-12.9 years], 36% (162/451) were under 12 months old, and 57% (256/450) were male. 56% (224/401) were White, 12% (49/401) South Asian and 10% (40/401) Black. 43% (195/451) had at least one recorded comorbidity. A muco-enteric cluster of symptoms was identified, closely mirroring the WHO MIS-C criteria. 17% of children (72/431) were admitted to critical care. On multivariable analysis this was associated with age under one month odds ratio 5.05 (95% confidence interval 1.69 to 15.72, p=0.004), age 10 to 14 years OR 3.11 (1.21 to 8.55, p=0.022) and Black ethnicity OR 3.02 (1.30 to 6.84, p=0.008). Three young people died (0.7 %, 3/451) aged 16 to 19 years, all of whom had profound comorbidity. Twelve percent of children (36/303) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Those meeting MIS-C criteria were older, (median age 10.8 years ([IQR 8.4-14.1] vs 2.0 [0.2-12.6]), p&lt;0.001) and more likely to be of non-White ethnicity (70% (23/33) vs 43% (101/237), p=0.005). Children with MIS-C were four times more likely to be admitted to critical care (61% (22/36) vs 15% (40/267, p&lt;0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with headache (45% (13/29) vs 11% (19/171), p&lt;0.001), myalgia (39% (11/28) vs 7% (12/170), p&lt;0.001), sore throat (37% (10/27) vs (13% (24/183, p = 0.004) and fatigue (57% (17/30) vs 31% (60/192), p =0.012) than children who did not and to have a platelet count of less than 150 x109/L (30% (10/33) vs 10% (24/232), p=0.004). Conclusions Our data confirms less severe covid-19 in children and young people than in adults and we provide additional evidence for refining the MIS-C case definition. The identification of a muco-enteric symptom cluster also raises the suggestion that MIS-C is the severe end of a spectrum of disease. Study registration ISRCTN66726260Competing Interest StatementAll authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: JSN-V-T reports grants from Department of Health and Social Care, England, during the conduct of the study; PWH reports grants from Wellcome Trust / Department for International Development / Bill and Melinda Gates Foundation, grants from NIHR , during the conduct of the study; PJMO reports personal fees from Consultancy, grants from MRC, grants from EU Grant, grants from NIHR Biomedical Research Centre, grants from MRC/GSK, grants from Wellcome Trust, grants from NIHR (HPRU), grants from NIHR Senior Investigator, personal fees from European Respiratory Society, grants from MRC Global Challenge Research Fund, outside the submitted work; and The role of President of the British Society for Immunology was an unpaid appointment but my travel and accommodation at some meetings is provided by the Society; AMD reports grants from Department of Health nd Social Care, during the conduct of the study; grants from Wellcome Trust, outside the submitted work; JKB reports grants from DHSC National Institute of Health Research UK, grants from Medical Research Council UK, grants from Wellcome Trust, grants from Fiona Elizabeth Agnew Trust, grants from Intensive Care Society, grants from Chief Scientist Office, during the conduct of the study; MGS reports grants from DHSC National Institute of Health Research UK, grants from Medical Research Council UK, grants from Health Protection Research Unit in Emerging &amp; Zoonotic Infections, University of Liverpool, during the conduct of the study; other from Integrum Scientific LLC, Greensboro, NC, USA, outside the submitted work; the remaining authors declare no competing interests; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.Clinical TrialISRCTN66726260Clinical Protocolshttps://isaric4c.net/protocols/Funding StatementThis work is supported by grants from: the National Institute for Health Research [award CO-CIN-01], the Medical Research Council [grant MC_PC_19059] and by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford [NIHR award 200907], Wellcome Trust and Department for International Development [215091/Z/18/Z], and the Bill and Melinda Gates Foundation [OPP1209135], and Liverpool Experimental Cancer Medicine Centre for providing infrastructure support for this research (Grant Reference: C18616/A25153). JSN-V-T is seconded to the Department of Health and Social Care, England (DHSC). The views expressed are those of the authors and not necessarily those of the DHSC, DID, NIHR, MRC, Wellcome Trust or PHE.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval was given by the South Central - Oxford C Research Ethics Committee in England (Ref 13/SC/0149), the Scotland A Research Ethics Committee (Ref 20/SS/0028), and the WHO Ethics Review Committee (RPC571 and RPC572, 25 April 2013).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesWe welcome applications for data and material access through our Independent Data and Material Access Committee (https://isaric4c.net). The lead author (the manuscript's guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. https://isaric4c.nethttps://isaric4c.net/sample_acces
Clinical and functional studies of autoimmune disorders of neuromuscular transmission
No full textInherited and acquired disorders of the neuromuscular junction are an important cause of muscle weakness and fatigability. In this thesis I focus on the autoimmune disorders of neuromuscular transmission. Myasthenia Gravis (MG) is the most common of these diseases and is typically caused by antibodies against the post-synaptic acetylcholine receptor. Lambert Eaton Myasthenic Syndrome (LEMS) is a pre-synaptic disorder typically caused by antibodies against voltage gated calcium channels (VGCC). With regard to LEMS, my main aim was to gain a more complete understanding of the pathomechanisms of the disease. To date, the direct effect of LEMS IgG on presynaptic neurotransmitter release had not been investigated in detail. I examined how LEMS IgG affects neurotransmitter release by imaging action potential dependent vesicle exocytosis using a fluorescent dye. I found that LEMS IgG significantly inhibited the rate of synaptic vesicle release but this effect was lost in synapses from a Cacna1a knockout mouse. These data provide direct evidence that LEMS is caused by impaired neurotransmitter release due to an effect on P/Q-type VGCCs. With regard to MG, I studied the long-term outcome of patients with thymomatous and non-thymomatous MG after thymectomy and found that in general the outcome was favourable in the majority of patients with 34% of patients achieving complete stable remission. I also reviewed the long-term outcome of patients after a severe exacerbation of MG requiring ITU admission. Despite the significant mortality associated with severe exacerbations of MG, it was found that specialised neuro-intensive care was associated with a good long-term prognosis in the majority of patients. There were no significant differences in outcome in those with early or late onset MG. Overall the data presented in this thesis provide new insights into the pathomechanisms of LEMS IgG and provide new information regarding the long-term outcome of patients with MG
An investigation of genetic risk factors in primary open-angle glaucoma
No full textPrimary open-angle glaucoma (POAG) is a multifactorial disease with a strong genetic
component. Notably however, few genes have been robustly associated with POAG in
the general population. Genes in which mutation causes anterior segment angle
anomalies, including LMX1B and FOXC1 are associated with a high incidence of
glaucoma to about 33-75% and are strong candidates for glaucoma susceptibility. In
addition, growth factors including TGFβ2 and BMP4 act in concert to maintain a
balance between extracellular matrix (ECM) deposition and degradation and may play a
role in glaucoma pathogenesis through misregulation of ECM synthesis of the
trabecular meshwork (TM). Furthermore, OPTN E50K mutation, a known genetic locus
for POAG, has been shown to account for a high percentage of 13.5% of familial
normal-tension glaucoma (NTG) in individuals of white British origin. In this study, the
contribution of variation at the LMX1B, FOXC1, TGFβ2 and BMP4 loci to risk of
glaucoma was investigated in a case-control genetic association study in a cohort of
white British descent recruited in the North-East of England comprised of 272 patients
with high-tension glaucoma (HTG), 37 patients with NTG, 58 patients with ocular
hypertension (OHT), and 276 normal controls. The role of OPTN E50K mutation in
these unrelated white British individuals with POAG was also examined. No significant
associations were identified for FOXC1, TGFβ2 and BMP4. The OPTN E50K mutation
was also absent in this cohort. The study identified a significant under representation of
two LMX1B haplotypes [ATG; P = 5.0E-4 (permutation P = 0.01), GCAGAC; P =
5.0E-4 (permutation P = 0.0150)] among the POAG individuals compared to the control
population, consistent with a 0.3 fold decreased risk of developing POAG. A replication
study involving a second cohort of 222 NTGs and 108 HTGs recruited in London
showed a similar distribution of the ATG haplotype (P = 0.0047) but did not withstand
permutation testing.
In conclusion, LMX1B haplotypes may influence susceptibility to develop POAG in the
white British population, suggesting altered LMX1B function predisposes to
glaucomatous damage
Depression: Can we predict who will relapse?
No full textThis thesis addresses risk factors and proposed mechanisms to explain relapse to depression. Volume 1 comprises three parts: Part 1 is a literature review consisting of meta-reviews of systematic and non-systematic reviews of studies reporting on risk factors for relapse to depression, and a systematic-review of neuroimaging and experimental studies investigating risk factors for relapse and potential mechanisms of action of these risk factors. The reviews found that only residual symptoms of depression at the end of treatment and childhood maltreatment were sufficiently evidenced as predictors of relapse and neither have great clinical utility. A number of psychological and neuropsychological factors were suggested to play a role in conferring risk for relapse. Considering the inter-relationships between these factors the reviews were used to propose a conceptual framework which may be used to help guide future research into relapse to depression in adults. Part 2 is an empirical paper in which data were analysed from service users of a primary care mental health service to identify risk factors for relapse and for the presence of residual symptoms, and survival analysis methods were used to determine when relapses occur most often and what factors impact survival. In addition, a prospective cohort study was formed to investigate the relationship between cognitive control and depressive symptoms. The findings confirmed that cognitive control can be used to predict residual symptoms of depression post-treatment and therefore potentially to predict relapse. Part 3 is a critical appraisal focussing on the theoretical reasons as to why studying relapse in a manner as used in the prospective study is so important and discusses the logistical difficulties conducting such research in the current context of NHS services and of the D.Clin.Psy research project. Methodological decisions made that impacted upon the research process are discussed and reflective conclusions are offered
