A retrospective observational study on characteristics, treatment patterns, and healthcare resource use of patients with myasthenia gravis in England.

Background: There are limited data on the real-world healthcare resource use (HCRU) and management costs of myasthenia gravis (MG) in England. Objective: This study aims to assess the burden of disease for patients with MG in England. Design: A retrospective, observational cohort study of adult patients diagnosed with MG, using data from the Hospital Episode Statistics data warehouse. Methods: Patients with a first-ever recorded diagnosis of MG between 30 June 2015 and 30 June 2020 were followed up until 30 June 2021 or death, whichever occurred first. Post-diagnosis patient characteristics, treatment patterns, HCRU, and costs were described. Costs were evaluated using National Health Service reference costs. Results: A total of 9087 patients with a median follow-up time of 2.9 years (range, 1.7-4.3 years) were included. The mean age at diagnosis was 66.5 years and 53% of the patients were male. A large proportion of patients (72.8%) were admitted as inpatients during follow-up with a mean number of 1.3 admissions. Patients hospitalized for MG-related complications spent a mean of 9.7 days per patient-year in the hospital. During follow-up, 599 (6.6% of the total cohort) and 163 (1.8%) patients had a record of rescue therapy with intravenous immunoglobulin (IVIg) and plasma exchange (PLEX), respectively. Rituximab was administered to 81 (0.9%) patients and 268 (2.9%) patients underwent thymectomy. In those patients receiving rescue therapy or rituximab, >10% received at least three cycles of the same treatment. The average annual cost of hospital admissions across all patients treated with IVIg, PLEX, and rituximab were £907,072, £689,979, and £146,726, respectively. Conclusion: A majority of MG patients required hospitalization or accident and emergency attendance, resulting in high HCRU and costs. A subset of patients required rescue therapy (including IVIg and PLEX), rituximab administration, ventilation, or thymectomy.

Testing for pharmacogenomic predictors of ppRNFL thinning in individuals exposed to vigabatrin.

Background: The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug. Methods: Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants. Results: The GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing. Conclusion: We set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.

Autistic Traits of People Who Engage in Pup Play: Occurrence, Characteristics and Social Connections.

Pup play is a kink or BDSM activity and subculture that provides opportunities for social and sexual play and exploration. While growing scholarly attention has focused on the diverse dynamics of pup play cultures, and reasons for participation within them, no research has considered how pup play may be attractive for neurodivergent people. This study sample consisted of 413 pup play practitioners from an international internet survey to examine the occurrence of autistic traits and explore characteristics and social connections of people with autistic traits who engage in pup play. Autistic traits were assessed using the Autism-Spectrum Quotient-Short Form (AQ-S), with 1 in 2 participants reporting a score that is indicative of an autism diagnosis, substantially higher than the prevalence of autism in the general population (1 in 44). Using linear and multinomial regression analyses, we found that people with high autistic traits preferred non-flexible roles in pup play, had lower identity resilience, and more restricted sociosexuality. People with high autistic traits were also less likely to belong to pup play social communities or to closer-knit family/pack units despite wishing to and were also less likely to have a strong identification with pup play communities than people with low AQ-S scores. While these findings need to be treated as preliminary based on methodological and sample limitations, this research demonstrates the importance of considering intersections between autistic traits and sexual subcultures and provides evidence that sexuality research would be enhanced by a more inclusive approach to considering neurodivergence more broadly.

Issues in bisexual men's lives: Identity, health and relationships.

This article provides a critical review of recent research about bisexual men. It foregrounds research dedicated to this group, rather than when bisexual men are included in a broader study, providing a rationale for the importance of doing this. The review finds that there is still a preponderance of research on bisexual men focused on experiences of stigma and discrimination, often from a public health perspective or with a focus on negative health outcomes. Social science research explores disclosure of bisexual identity, with evidence of widespread stigma but also positive experiences of disclosure. Bisexual men have diverse experiences of romantic relationship, with the gender and sexuality of the partner influencing relationship dynamics. Research also highlights sexual health issues, including difficulties in accessing healthcare. The review shows that further research is needed into this understudied population.

Kink in an English Field: The Drinking, Drug use and Sexual Practices of English Festival-Goers Who Engage in Kink.

Little is known about the other leisure activities of people who engage in kink, including sexual practices and the use of alcohol and other drugs. This article examines the drinking, illicit drug use and sexual practices of people who engage in kink from a novel sample of attendees at an English festival. Of 966 respondents, 64 reported having engaged in kink within the past 12 months. We provide evidence of these respondents' self-reported demographic characteristics, alcohol and other drug use in their lifetime and within the past 12 months, as well as other sexual practices they engaged in. This study illustrates the value of accessing participants through in situ festival fieldwork to understand kink practices, and helps us move beyond notions of clustered risky activities toward a leisure studies approach to understanding the practices of people who engage in kink.

Findings From a Community Survey of Individuals Who Engage in Pup Play.

This study presents findings from a community survey on pup play. Pup play is a kink activity and a form of role play that is growing in popularity internationally, and gaining increasing attention in sexology, yet prior research on pup play has almost entirely employed qualitative methods and primarily involved gay and bisexual men. Using survey data of 733 pup play participants primarily from the US, but also internationally, this study reports on the demographics of participants, how they engage in pup play, its social and sexual elements, and how it relates to social identity and mental health. Unique pup names and identifying with breeds of dogs were used to foster a sense of individuality within pup play, while the majority of participants owned and wore gear when engaging in pup play. We also found significant associations between being younger and identifying as a pup. Most participants reported that pup play improved their mental health. Binary logistic regression analyses indicated that having a mental health diagnosis was associated with identifying with a more social style of pup play and self-reporting the mental health benefits of pup play. We find that the conceptualization of pup play in the existing literature to be accurate to this international sample and highlight areas where further research is needed, alongside limitations of the study.

A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam.

OBJECTIVE: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). RESULTS: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. SIGNIFICANCE: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.

Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications.

Objective: Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation. Methods: A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance. Results: We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs. Significance: This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale.

Changes in Sexual Fantasy and Solitary Sexual Practice During Social Lockdown Among Young Adults in the UK.

INTRODUCTION: Pandemic-related social lockdown limited many sexual behaviors, but to date, no study has examined the perceived impact of social lockdown due to COVID-19 on sexual fantasy and solitary sexual behavior. AIMS: The present study sought to examine the perceived impact of social lockdown on sexual fantasy and solitary sexual behavior among UK young adults in various living situations. METHODS: A convenience sample of 565 adults aged 18-32 and living in the UK completed anonymous, web-based, study-specific questionnaires between May 14 and 18, 2020, 7 weeks after social lockdown was initiated. Mixed-method analyses were conducted. MAIN OUTCOME MEASURES: The study presents qualitative and quantitative data. Criterion variables were measured dichotomously as increases (vs no change) in sexual fantasy and increases (vs no change) in pornography consumption. Predictor variables were living arrangement, relationship status, and postlockdown changes in masturbation and pornography consumption. RESULTS: Of all, 34.3% engaged in more sexual fantasizing during lockdown; women were more likely than men to report this increase. Living context and relationship status were predictors of increased fantasizing. Of all, 30.44% reported an increase in at least one solitary sexual practice. This increase was associated with an increase in sexual fantasizing and also with increased pornography consumption. Nineteen percent of participants reported an increase in pornography use, with men being more likely than women to report this increase. Participants mostly attributed their increases to boredom, increased free time, and replacing partnered sex. CONCLUSION: Shifts in sexual fantasizing and solitary sexual practices were predicted by living arrangements, relationship status, and gender. The present findings suggest that the assessment of sexual fantasy and solitary sexual activities may benefit patients presenting with pandemic-related stress. Although mostly exploratory, significant changes in sexual fantasy and solitary sexual practices were observed. A cross-sectional design, convenience sampling, and study-specific measures are limitations. Cascalheira CJ, McCormack M, Portch E, et al. Changes in Sexual Fantasy and Solitary Sexual Practice During Social Lockdown Among Young Adults in the UK. J Sex Med 2021;9:100342.

Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy.

OBJECTIVE: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug-resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. METHODS: We performed exome sequencing of 1,128 individuals with non-familial non-acquired focal epilepsy (NAFE) (762 non-responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non-responders, 185 responders). We performed gene-based and gene-set-based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. RESULTS: We found no gene or gene set that reached genome-wide significance. Yet, we identified several prospective candidate genes - among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non-familial NAFE and in association with drug-resistant NAFE. INTERPRETATION: Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non-familial NAFE and imply their involvement in drug-resistant epilepsy. Future large-scale genetic research studies are needed to substantiate these findings.

Changes in Sexual Desire and Behaviors among UK Young Adults During Social Lockdown Due to COVID-19.

This study examined self-reported changes in young adults' sexual desire and behaviors during the most significant social restrictions imposed to deal with COVID-19. Drawing on a survey of 565 British adults aged 18-32 collected at the peak of social lockdown restrictions, we document an overall decrease in sexual behaviors consistent with abiding by social restrictions. We found that the levels of sexual desire reported by women (but not men) decreased compared with reports of pre-lockdown levels. Participants in serious relationships reported more increases in sexual activity than people who were single or dating casually, and there were significant differences according to gender and sexual orientation. The perceived impact of subjective wellbeing of people with high sociosexuality scores was disproportionately associated with social lockdown but there was no effect for general health. Thus, the impact on sexuality and general wellbeing should be considered by policymakers when considering future social restrictions related to COVID-19 or other public health emergencies.

Symptomatology of carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy.

OBJECTIVE: To ascertain whether adverse effects experienced by people taking carbamazepine or oxcarbazepine could be attributed to carbamazepine- or oxcarbazepine-induced hyponatremia (COIH). METHODS: We performed an observational study, collecting data between 2017 and 2019 on serum sodium levels and adverse effects retrospectively in people with epilepsy while receiving treatment with either carbamazepine (CBZ) or oxcarbazepine (OXC). We defined hyponatremia as sodium level ≤134 mEq/L and severe hyponatremia as sodium level ≤128 mEq/L. Adverse effects experienced were compared between groups of individuals with and without hyponatremia. RESULTS: A total of 1370 people using CBZ or OXC were identified, of whom 410 had at least one episode of hyponatremia. We checked for symptoms related to the use of CBZ and OXC in 710 people (410 with and 300 without hyponatremia) and found relevant information in 688. Adverse effects occurred in 65% of people with hyponatremia compared to 21% with normal sodium levels (odds ratio [OR] 7.5, P ≤ .001) and in 83% of people with severe hyponatremia compared to 55% in those with mild hyponatremia (P ≤ .001). Significant predictors of adverse effects were the drug (OXC vs CBZ), and the number of concomitant anti-seizure medications. Dizziness (28% vs 6%), tiredness (22% vs 7%), instability (19% vs 3%), and diplopia (16% vs 4%) were reported more often in the hyponatremia group than in patients with normal levels. SIGNIFICANCE: People with COIH had a 7-fold increased risk of developing adverse effects during treatment. Clinicians should consider ascertainment of sodium levels in patients taking CBZ and OXC and act upon findings.

Older Iranian Muslim women's experiences of sex and sexuality: A biographical approach.

Muslim women in Iran live in a patriarchal society which significantly restricts their freedom and agency. While there is a growing understanding of social change as it relates to younger Muslim women in Iran, the perspectives and experiences of older women are marginalized; mirroring problems with the intersections of age, gender, and sexuality in the West. In order to address this occlusion, this article draws on life history interviews with 30 older Muslim women living in Tehran and Karaj. Adopting a biographical life course approach, and examining pivotal moments related to sexuality in their lives, we discuss how cultural meanings and symbols of sexuality have emerged and been negotiated by these women at the life stages of puberty, first sex at marriage, and menopause. The patriarchal and religious gender order of Iran transgresses these women's human rights so that sexuality is experienced as a source of shame, stigma, and pollution, yet the women also exert forms of agency in their lives as they adopt and challenge these norms.

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy.

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins.

A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability.

Next generation sequencing provides an important opportunity for improved diagnosis in epilepsy. To date, the majority of diagnostic genetic testing is conducted in the paediatric arena, while the utility of such testing is less well understood in adults with epilepsy. We conducted whole exome sequencing (WES) and copy number variant analyses in an Irish cohort of 101 people with epilepsy and co-morbid intellectual disability to compare the diagnostic yield of genomic testing between adult and paediatric patients. Variant interpretation followed American College of Medical Genetics and Genomics (ACMG) guidelines. We demonstrate that WES, in combination with array-comparative genomic hybridisation, provides a diagnostic rate of 27% in unrelated adult epilepsy patients and 42% in unrelated paediatric patients. We observe a 2.7% rate of ACMG-defined incidental findings. Our findings indicate that WES has similar utility in both adult and paediatric cohorts and is appropriate for diagnostic testing in both epilepsy patient groups.

Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study.

Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE - responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10-5) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.

Testing association of rare genetic variants with resistance to three common antiseizure medications.

OBJECTIVE: Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). METHODS: A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set-based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. RESULTS: We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. SIGNIFICANCE: In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.

De-novo mutations in patients with chronic ultra-refractory epilepsy with onset after age five years.

We set out to investigate whether a de-novo paradigm could explain genetic causes of chronic ultra-refractory epilepsy, with onset later than the typical age for the epileptic encephalopathies. We performed exome sequencing on nine adult patients with MRI-negative epilepsy and no preceding intellectual disability. All had an onset of seizures after five years old and had chronic ultra-refractory epilepsy defined here as having failed more than six anti-epileptic drugs and currently experiencing ≥4 disabling seizures per month. Parents were sequenced to identify de-novo mutations and these were assessed for likelihood of pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) criteria. We confirmed the presence of functional and predicted-damaging de-novo mutations in 3/9 patients. One of these pathogenic de-novo mutations, in DNM1L, was previously reported in a patient with severe epilepsy and chronic pharmacoresistance adding to the evidence for DNM1L as an epilepsy gene. Exome sequencing is a successful strategy for identifying de-novo mutations in paediatric epileptic encephalopathies and rare neurological disorders. Our study demonstrates the potential benefit of considering ultra-refractory epilepsy patients with later onset for genetic testing. Identifying genetic mutations underpinning severe epilepsy of unknown aetiology may provide new insight into the underlying biology and offers the potential for therapeutic intervention in the form of precision medicine in older patients.

Genomic and clinical predictors of lacosamide response in refractory epilepsies.

OBJECTIVE: Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting. METHODS: We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes. RESULTS: Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (<25% seizure reduction). No variants reached the genome-wide significance threshold in our case-control analysis. SIGNIFICANCE: No genetic predictor of lacosamide response was identified. Patients with refractory GGE might benefit from treatment with lacosamide.

Development of a genomics module within an epilepsy-specific electronic health record: Toward genomic medicine in epilepsy care.

OBJECTIVES: Both clinical genomics and e-Health technology are changing the way medicine is being practiced. Although the basic clinical methodology of good medical care will remain unchanged, the combined power of genomics and electronic health records has the capability of enhancing, and in some cases transforming, the practice of medicine. This is particularly true in the care of patients with complex long-term medical conditions such as chronic refractory epilepsy, especially in those with related complex comorbidities including intellectual disability and psychiatric disease. METHODS: Herein we outline the development and integration of an epilepsy genomics module into a preexisting epilepsy electronic patient record (EPR) system. RESULTS: We describe how this EPR infrastructure is used to facilitate discussion at multidisciplinary clinical meetings around molecular diagnosis and resulting changes in management. SIGNIFICANCE: This work illustrates the role of eHealth technology in embedding genomics into the clinical pathway.