Abstract Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME ( n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 ( P = 7.5 × 10 −9 ) and 10p11.21 ( P = 3.6 × 10 −8 ). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex ( P = 9.5 × 10 −3 ). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes ( P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes ( P = 0.0005) including NLGN1 and PTPRD . RNAi knockdown of Oatp30B , the Drosophila polypeptide with the highest homology to SLCO5A1 , causes over-reactive startling behaviour ( P = 8.7 × 10 −3 ) and increased seizure-like events ( P = 6.8 × 10 −7 ). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME ( P = 1.60 × 10 −3 ). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.
Background: The threshold of protection for anti-SARS-CoV-2 spike glycoprotein antibodies and their longevity are not known. Interpretation of serological results in with respect to international reference material can inform this essential question.Methods: 1,507 West Midlands dental care professionals were recruited into this study in June 2020. Baseline seroprevalence of antibodies directed against the SARS-CoV-2 spike glycoprotein was determined and the cohort was followed longitudinally for 6 months until January/February 2021 through the second wave of the COVID-19 pandemic in the United Kingdom, and commencement of vaccination.Findings: Baseline seroprevalence was 16.3% in this cohort, compared to estimates in the general population of between 6-7%. Seropositivity was retained in over 70% of participants at 3 and 6-month follow up and conferred a 74% reduced risk of infection. During follow-up, no PCR-proven infections occurred in individuals with a baseline anti-SARS-CoV-2 IgG level greater than 3.69 IU/ml with respect to the World Health Organization international standard 20-136. Post-vaccination, antibody responses were more rapid and of higher magnitude in individuals with who were seropositive at baseline.Interpretation: Natural infection leads to a serological response that remains detectable in over 70% of individuals 6 months after initial sampling and 9 months from the peak of the first wave of the pandemic. This response is associated with protection from future infection. Even if serological responses wane, a single dose of the Pfizer-BioNTech vaccine is associated with an antibody response indicative of immunological memory.Funding: The Association of Clinical Biochemistry and Laboratory Medicine and The Institute for Global Innovation (IGI) of the University of Birmingham.Conflict of Interest: MTD reports personal fees from Abingdon Health, outside the submitted work. AMC isan employee of the Binding Site Group. All other authors declare no competing interests.Ethical Approval: The study was approved by the London - Camden and Kings Cross Research EthicsCommittee (reference 20/HRA/1817). All participants provided written informed consent prior to enrolment in the study.
Abnormal EEG features are a hallmark of epilepsy, and abnormal frequency and network features are apparent in EEGs from people with idiopathic generalized epilepsy in both ictal and interictal states. Here, we characterize differences in the resting-state EEG of individuals with juvenile myoclonic epilepsy and assess factors influencing the heterogeneity of EEG features. We collected EEG data from 147 participants with juvenile myoclonic epilepsy through the Biology of Juvenile Myoclonic Epilepsy study. Ninety-five control EEGs were acquired from two independent studies [Chowdhury et al. (2014) and EU-AIMS Longitudinal European Autism Project]. We extracted frequency and functional network-based features from 10 to 20 s epochs of resting-state EEG, including relative power spectral density, peak alpha frequency, network topology measures and brain network ictogenicity: a computational measure of the propensity of networks to generate seizure dynamics. We tested for differences between epilepsy and control EEGs using univariate, multivariable and receiver operating curve analysis. In addition, we explored the heterogeneity of EEG features within and between cohorts by testing for associations with potentially influential factors such as age, sex, epoch length and time, as well as testing for associations with clinical phenotypes including anti-seizure medication, and seizure characteristics in the epilepsy cohort. P-values were corrected for multiple comparisons. Univariate analysis showed significant differences in power spectral density in delta (2-5 Hz) (P = 0.0007, hedges' g = 0.55) and low-alpha (6-9 Hz) (P = 2.9 × 10-8, g = 0.80) frequency bands, peak alpha frequency (P = 0.000007, g = 0.66), functional network mean degree (P = 0.0006, g = 0.48) and brain network ictogenicity (P = 0.00006, g = 0.56) between epilepsy and controls. Since age (P = 0.009) and epoch length (P = 1.7 × 10-8) differed between the two groups and were potential confounders, we controlled for these covariates in multivariable analysis where disparities in EEG features between epilepsy and controls remained. Receiver operating curve analysis showed low-alpha power spectral density was optimal at distinguishing epilepsy from controls, with an area under the curve of 0.72. Lower average normalized clustering coefficient and shorter average normalized path length were associated with poorer seizure control in epilepsy patients. To conclude, individuals with juvenile myoclonic epilepsy have increased power of neural oscillatory activity at low-alpha frequencies, and increased brain network ictogenicity compared with controls, supporting evidence from studies in other epilepsies with considerable external validity. In addition, the impact of confounders on different frequency-based and network-based EEG features observed in this study highlights the need for careful consideration and control of these factors in future EEG research in idiopathic generalized epilepsy particularly for their use as biomarkers.
Abstract Background The threshold of protection for anti-SARS-CoV-2 spike glycoprotein antibodies and their longevity are not known. Interpretation of serological results in with respect to international reference material can inform this essential question. Methods 1,507 West Midlands dental care professionals were recruited into this study in June 2020. Baseline seroprevalence of antibodies directed against the SARS-CoV-2 spike glycoprotein was determined and the cohort was followed longitudinally for 6 months until January/February 2021 through the second wave of the COVID-19 pandemic in the United Kingdom, and commencement of vaccination. Results Baseline seroprevalence was 16.3% in this cohort, compared to estimates in the general population of between 6-7%. Seropositivity was retained in over 70% of participants at 3 and 6-month follow up and conferred a 74% reduced risk of infection. During follow-up, no PCR-proven infections occurred in individuals with a baseline anti-SARS-CoV-2 IgG level greater than 147.6 IU/ml with respect to the World Health Organization international standard 20-136. Post-vaccination, antibody responses were more rapid and of higher magnitude in individuals with who were seropositive at baseline. Conclusion Natural infection leads to a serological response that remains detectable in over 70% of individuals 6 months after initial sampling and 9 months from the peak of the first wave of the pandemic. This response is associated with protection from future infection. Even if serological responses wane, a single dose of the Pfizer-BioNTech vaccine is associated with an antibody response indicative of immunological memory. Funding The Association of Clinical Biochemistry and Laboratory Medicine and The Institute for Global Innovation (IGI) of the University of Birmingham.
Older adults are less likely to produce robust antibody responses to vaccines, partly due to immunosenescence. We have previously shown morning vaccination induced robust antibody responses for annual influenza vaccination (T-cell antigenic response), but were uncertain if this effect could be applied to T-cell independent vaccines such as Pneumovax® (PPV-23). The aim of this study was to determine whether diurnal timing of a single dose of PPV-23 and annual influenza vaccine affects innate and adaptive immune responses in healthy older adults. 140 healthy older adults received PPV-23 and annual influenza vaccines in 2018-20. Serum was taken at baseline (pre-vaccination), 24 hours and 1-, 4- and 52-weeks post-vaccination and Pneumococcal serotype-specific (PnPS) IgG, IgA and IgM were measured by in-house Luminex assay. PnPs-IgG antibody concentrations were assessed according to the WHO threshold (0.35 µg/ml) for at least two thirds of the PnPS tested (WHO≥8/12PnPS). Haemagluttination Inhibition Assays (HAIs) were run for A/H1N1, A/H3N2 and B Victoria strains included in the annual influenza vaccines. Over half of the participants exhibited WHO≥8/12PnPS at baseline (57.1% AM/ 50.0% PM), which increased rapidly at week 1 (75.0% AM/72.1% PM), and was maintained at 4 (85.5 AM/ 81.4% PM) and 52 weeks (85.0% AM/85.7% PM). Pn-specific antibodies and HAI titres did not vary between AM and PM cohorts. The poorest serotype coverage was for the B/Victoria strain at both baseline and vaccination with less than 50% of the cohort protected at 1-year. Time of day of PPV-23 and influenza vaccines did not influence antigen-specific antibody responses in this cohort. In this older, but not severely immunosenescent population, we show robust cohort-wide antibody responses that are sustained at 52-weeks post-vaccination. However, identifying that 18% of the total cohort exhibited suboptimal responses to pneumococcal or flu vaccines underscores the imperative for enhancing vaccine efficacy within this age group.
Abstract Reliable definitions, classifications and prognostic models are the cornerstones of stratified medicine, but none of the current classifications systems in epilepsy address prognostic or outcome issues. Although heterogeneity is widely acknowledged within epilepsy syndromes, the significance of variation in electroclinical features, comorbidities and treatment response, as they relate to diagnostic and prognostic purposes, has not been explored. In this paper, we aim to provide an evidence-based definition of juvenile myoclonic epilepsy showing that with a predefined and limited set of mandatory features, variation in juvenile myoclonic epilepsy phenotype can be exploited for prognostic purposes. Our study is based on clinical data collected by the Biology of Juvenile Myoclonic Epilepsy Consortium augmented by literature data. We review prognosis research on mortality and seizure remission, predictors of antiseizure medication resistance and selected adverse drug events to valproate, levetiracetam and lamotrigine. Based on our analysis, a simplified set of diagnostic criteria for juvenile myoclonic epilepsy includes the following: (i) myoclonic jerks as mandatory seizure type; (ii) a circadian timing for myoclonia not mandatory for the diagnosis of juvenile myoclonic epilepsy; (iii) age of onset ranging from 6 to 40 years; (iv) generalized EEG abnormalities; and (v) intelligence conforming to population distribution. We find sufficient evidence to propose a predictive model of antiseizure medication resistance that emphasises (i) absence seizures as the strongest stratifying factor with regard to antiseizure medication resistance or seizure freedom for both sexes and (ii) sex as a major stratifying factor, revealing elevated odds of antiseizure medication resistance that correlates to self-report of catamenial and stress-related factors including sleep deprivation. In women, there are reduced odds of antiseizure medication resistance associated with EEG-measured or self-reported photosensitivity. In conclusion, by applying a simplified set of criteria to define phenotypic variations of juvenile myoclonic epilepsy, our paper proposes an evidence-based definition and prognostic stratification of juvenile myoclonic epilepsy. Further studies in existing data sets of individual patient data would be helpful to replicate our findings, and prospective studies in inception cohorts will contribute to validate them in real-world practice for juvenile myoclonic epilepsy management.
Background The correlates of protection against SARS-CoV-2 and their longevity remain unclear. Studies in severely ill individuals have identified robust cellular and humoral immune responses against the virus. Asymptomatic infection with SARS-CoV-2 has also been described, but it is unknown whether this is sufficient to produce antibody responses. Methods We performed a cross-sectional study recruiting 554 health care workers from University Hospitals Birmingham NHS Foundation Trust who were at work and asymptomatic. Participants were tested for current infection with SARS-CoV-2 by nasopharyngeal swab for real-time polymerase chain reaction and for seroconversion by the measurement of anti-SARS-CoV-2 spike glycoprotein antibodies by enzyme linked immunosorbent assay. Results were interpreted in the context of previous, self-reported symptoms of illness consistent with COVID-19. Results The point prevalence of infection with SARS-CoV-2, determined by the detection of SARS-CoV-2 RNA on nasopharnygeal swab was 2.39% (n=13/544). Serum was available on 516 participants. The overall rate of seroconversion in the cohort was 24.4% (n=126/516). Individuals who had previously experienced a symptomatic illness consistent with COVID-19 had significantly greater seroconversion rates than those who had remained asymptomatic (37.5% vs 17.1%, χ2 =21.1034, p<0.0001). In the week preceding peak COVID-19-related mortality at UHBFT, seroconversion rates amongst those who were suffering from symptomatic illnesses peaked at 77.8%. Prior symptomatic illness generated quantitatively higher antibody responses than asymptomatic seroconversion. Seroconversion rates were highest amongst those working in housekeeping (34.5%), acute medicine (33.3%) and general internal medicine (30.3%) with lower rates observed in participants working in intensive care (14.8%) and emergency medicine (13.3%). Conclusions In a large cross-sectional seroprevalence study of health-care workers, we demonstrate that asymptomatic seroconversion occurs, however prior symptomatic illness is associated with quantitatively higher antibody responses. The identification that the potential for seroconversion in health-care workers can associate differentially with certain hospital departments may inform future infection control and occupational health practices.
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