Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes.

In animal models, brain neurodegeneration biomarkers drain into cervical lymph nodes (CLNs), and this drainage function is reduced with ageing. If this occurred in humans, CLNs may provide a readily accessible measure of this aspect of protein clearance. We tested this hypothesis in people using ultrasound-guided fine needle aspiration (FNA). We measured amyloid-beta 40 and 42, phospho-Tau-181, glial-fibrillary-acidic-protein, and neurofilament-light using single molecule array in CLN aspirates and plasma from: i) a discovery cohort of 25 autoimmune patients, and from ii) plasma, CLNs and capillary blood in four healthy volunteers, an optimisation cohort. FNA was well-tolerated by all participants. In both cohorts, all biomarkers were detected in all plasma and CLN samples, other than neurofilament-light (8/17 of discovery cohort). CLN biomarker concentrations were significantly greater than plasma concentrations for all except neurofilament-light, most markedly for phospho-Tau-181 (266-fold; P<0.02), whose CLN concentrations decreased with age (Spearman r=-0.66, P=0.001). This study presents the first evidence that neurodegenerative biomarkers are detectable in human CLNs. Raised CLN:plasma biomarker ratios suggest their concentration in CLNs may offer a distinct compartment for minimally-invasive measurement of brain clearance and lymphatic drainage, with potential applicability to study of ageing and future clinical trials.

Learning for life, friendships and relationships from the perspective of children and young people with intellectual disabilities: findings from a UK wide qualitative study.

BACKGROUND: Relationships and sexuality education (RSE) programmes are widely taught in schools, however for children and young people with intellectual disabilities, these programmes appear to be limited regarding information on relationships, informed choices and decision making. The purpose of this study was to seek the views and understanding of children and young people with intellectual disabilities, and those involved in their care and education, to identify best practice and approaches to the delivery on relationships and sexuality education. METHODS: This study used a qualitative design with 37 pupils from five special schools from across the United Kingdom (UK) participating. In-depth semi-structured interviews were held online, or in person. All interviews were recorded and transcribed verbatim. Transcripts were anonymised, assigned a pseudonym and subjected to inductive thematic analysis. FINDINGS: Four themes emerged from the data: (i) enthusiasm and inquisitiveness to acquire knowledge; (ii) dynamics of positive friendships; (iii) experiences and understanding of supportive relationships and sexuality; and (iv) valuing the exchange of knowledge and information. The findings highlight that children and young people with intellectual disabilities want education, support and information on matters relating to their relationships and sexuality. CONCLUSIONS: This is the largest study to date providing a voice to children and young people with intellectual disabilities regarding their relationships and sexuality. While special schools provide relationships and sexuality education, there is a requirement for a programme and resources specific to the needs of pupils with intellectual disabilities to be developed and evaluated. Such education should continue beyond school and be embedded in adult services.

The Experiences of Young People with Intellectual Disability, Parents and Professionals in Relationships and Sexuality Education Programmes: Findings from a Qualitative Study.

People with intellectual disability want friendships and meaningful relationships, and some want intimacy. However, the expression of sexuality is an area where potential freedoms are often limited and restricted compared to their peers. While some relationships and sexuality education programmes do exist for this population, most focus on knowledge acquisition regarding sexuality and sex but lack in their focus on relationships, informed choices and decision-making. The aim of this study was to identify good practices and methods of delivery in relationships and sexuality education for children and young people with intellectual disability. A qualitative design was undertaken. Information about our study was distributed to eight special schools in the UK. Semi-structured interviews and focus groups were employed for data collection. Data from 37 pupils with intellectual disability, 11 parents and 16 healthcare and other professionals were thematically analysed. Following data analysis, three themes emerged: (i) seeking and sharing information; (ii) protecting and keeping safe; and (iii) learning for the future. The findings highlight that pupils are keen to learn about life changes and societal influences and want reliable information. Parents and professionals recognise that children and young people with intellectual disability will develop into adults and may be vulnerable when they leave the security of the school setting. They recognise that children and young people need to know about socialising, puberty, consent and contraception. Evidence-based programmes should be designed with these stakeholders to ensure children and young people with intellectual disability receive developmentally appropriate information to make happy and safe decisions about their relationships.

Embracing authenticity and challenging norms: Including people with an intellectual disability as lecturers in third level intellectual disability nursing programmes.

UNDERREPRESENTATION OF VOICES FROM PEOPLE WITH INTELLECTUAL DISABILITY IN NURSE EDUCATION: In the Republic of Ireland and the United Kingdom, university level programmes for intellectual disability nurses have traditionally incorporated the perspectives of people with intellectual disabilities but have been delivered by non-disabled educators. Perspectives are interpreted through the lens of the non-disabled person, with the voices of people with intellectual disabilities rarely heard. AN ALTERNATIVE APPROACH: INCLUDING PEOPLE WITH INTELLECTUAL DISABILITY AS EDUCATORS: In this article, an alternative approach is proposed that addresses this problem by including individuals with intellectual disabilities as educators within university programmes. Such inclusion will benefit students, academics, and ultimately the individuals who will receive health and social care from these nurses. Many countries have seen legislative and policy changes promoting inclusion for people with an intellectual disability. These are welcomed, but if they are to have a meaningful impact, societal attitudes and perceptions towards people with intellectual disabilities must be challenged. Drawing upon the concepts of social reconstruction and the ideologies of Paulo Freire and John Dewey, we argue that education can catalyze societal transformation. By including individuals with intellectual disabilities as educators in undergraduate programmes, such as nursing, traditional hierarchies of educators can be challenged, and students can learn from experts with lived experiences. This approach fosters critical thinking, reflection, and the development of authentic and informed healthcare professionals. The experiences of a co-author with a lived experience of intellectual disability as an educator, highlights the positive impact of such inclusion on students' perspectives, understanding, and empathy.

Magnetic Resonance Imaging Characteristics of LGI1-Antibody and CASPR2-Antibody Encephalitis.

Importance: Rapid and accurate diagnosis of autoimmune encephalitis encourages prompt initiation of immunotherapy toward improved patient outcomes. However, clinical features alone may not sufficiently narrow the differential diagnosis, and awaiting autoantibody results can delay immunotherapy. Objective: To identify simple magnetic resonance imaging (MRI) characteristics that accurately distinguish 2 common forms of autoimmune encephalitis, LGI1- and CASPR2-antibody encephalitis (LGI1/CASPR2-Ab-E), from 2 major differential diagnoses, viral encephalitis (VE) and Creutzfeldt-Jakob disease (CJD). Design, Setting, and Participants: This cross-sectional study involved a retrospective, blinded analysis of the first available brain MRIs (taken 2000-2022) from 192 patients at Oxford University Hospitals in the UK and Mayo Clinic in the US. These patients had LGI1/CASPR2-Ab-E, VE, or CJD as evaluated by 2 neuroradiologists (discovery cohort; n = 87); findings were validated in an independent cohort by 3 neurologists (n = 105). Groups were statistically compared with contingency tables. Data were analyzed in 2023. Main Outcomes and Measures: MRI findings including T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensities, swelling or volume loss, presence of gadolinium contrast enhancement, and diffusion-weighted imaging changes. Correlations with clinical features. Results: Among 192 participants with MRIs reviewed, 71 were female (37%) and 121 were male (63%); the median age was 66 years (range, 19-92 years). By comparison with VE and CJD, in LGI1/CASPR2-Ab-E, T2 and/or FLAIR hyperintensities were less likely to extend outside the temporal lobe (3/42 patients [7%] vs 17/18 patients [94%] with VE; P < .001, and 3/4 patients [75%] with CJD; P = .005), less frequently exhibited swelling (12/55 [22%] with LGI1/CASPR2-Ab-E vs 13/22 [59%] with VE; P = .003), and showed no diffusion restriction (0 patients vs 16/22 [73%] with VE and 8/10 [80%] with CJD; both P < .001) and rare contrast enhancement (1/20 [5%] vs 7/17 [41%] with VE; P = .01). These findings were validated in an independent cohort and generated an area under the curve of 0.97, sensitivity of 90%, and specificity of 95% among cases with T2/FLAIR hyperintensity in the hippocampus and/or amygdala. Conclusions and Relevance: In this study, T2 and/or FLAIR hyperintensities confined to the temporal lobes, without diffusion restriction or contrast enhancement, robustly distinguished LGI1/CASPR2-Ab-E from key differential diagnoses. These observations should assist clinical decision-making toward expediting immunotherapy. Their generalizability to other forms of autoimmune encephalitis and VE should be examined in future studies.

Fine needle aspiration of human lymph nodes reveals cell populations and soluble interactors pivotal to immunological priming.

Lymph node (LN) fine needle aspiration (LN FNA) represents a powerful technique for minimally invasive sampling of human LNs in vivo and has been used effectively to directly study aspects of the human germinal center response. However, systematic deep phenotyping of the cellular populations and cell-free proteins recovered by LN FNA has not been performed. Thus, we studied human cervical LN FNAs as a proof-of-concept and used single-cell RNA-sequencing and proteomic analysis to benchmark this compartment, define the purity of LN FNA material, and facilitate future studies in this immunologically pivotal environment. Our data provide evidence that LN FNAs contain bone-fide LN-resident innate immune populations, with minimal contamination of blood material. Examination of these populations reveals unique biology not predictable from equivalent blood-derived populations. LN FNA supernatants represent a specific source of lymph- and lymph node-derived proteins, and can, aided by transcriptomics, identify likely receptor-ligand interactions. This represents the first description of the types and abundance of immune cell populations and cell-free proteins that can be efficiently studied by LN FNA. These findings are of broad utility for understanding LN physiology in health and disease, including infectious or autoimmune perturbations, and in the case of cervical nodes, neuroscience.

An exploration of mental distress in transgender people in Ireland with reference to minority stress and dissonance theory.

Introduction: Internationally mental distress is more prominent in the LGBTI community than the general population. The LGBTIreland study was set up to take stock of this in the Republic of Ireland. This paper reports on the analysis of the transgender group with reference to minority stress theory and cognitive dissonance theory. Method: An online survey was conducted addressing several aspects of mental health and distress that received responses from all groupings (n = 2,264) among which 12.3% (n = 279) identified as transgender. The survey consisted of several validated tools to measure depression, anxiety, stress (DASS-21), coping (CSES), self-esteem (RSES), alcohol and drugs misuse (AUDIT) and a variety of questions addressing demographics, experiential aspects, coping and self-related factors. Data analysis focused on predicting mental distress using DASS-general (composite of depression, anxiety and stress). Results: Transgender participants reported higher levels of mental distress, self-harm, suicidal ideation and attempts, and lower levels of self-esteem in comparison with the LGB groups, as well as the general population. Hierarchical multiple regression showed that 53% of variance in mental distress could be predicted from reduced self-esteem, the experience of harassment and not belonging in school. Furthermore, mental distress was highest among younger participants, those who were 'not out', those who had self-harmed and used avoidant coping. There was no significant difference in distress levels among those who had sought mental health support and those who had not. Conclusions: To understand mental distress in transgender people, the minority stress model is useful when taking into account both adverse external (environmental) and internal (cognitive/emotional) factors. The cognitive dissonance mechanism is essential in outlining the mechanism whereby gender incongruence is associated with psychological discomfort, low self-esteem and high mental distress.

A national cohort study of spiritual and religious practices of older people with intellectual disability.

Background: Spirituality and spiritual support for older people with intellectual disability are deemed important, however little is known about their specific needs. This paper reports for the first time on the religious and spiritual practices of older adults with intellectual disability. Methods: A national longitudinal study examined the prevalence of spiritual practices among older people with intellectual disability in the Republic of Ireland. Results: Older people with intellectual disability seek and receive solace from religious and spiritual practices, especially if they are lonely, in poor health, distressed or bereaved. There is likely a social benefit to spiritual and religious aspects of life that would be beneficial to explore further. Conclusions: Globally more research is required and efforts should be made to ensure greater opportunities for inclusion in societal spiritual and religious activities and to more clearly determine the spiritual needs of this population.

Active older adults goal setting outcomes for engaging in a physical activity app and the motivation characteristics of these goals (MOVEAGE-ACT).

Approximately 70% of older adults do not meet physical activity (PA) guidelines. While many interventions, are used in promoting PA, few target older adults or include substantial behavioural change techniques. Setting PA goals is often used but there is less research on goal setting outcomes, like improving health, preventing age effects, improving flexibility, goals that have been associated with increased likelihood of maintenance of PA. To understand the concept more fully in this cohort, the aim of this study was to identify older adults' goal setting outcomes - the purpose of engaging in a PA app and through analysis determine the motivation characteristics of these. A cross-sectional, qualitative online survey was completed by 24, 60+, community dwelling, mostly active, French and Irish older adults. Thematic template analysis was used, and the motivation of these outcomes was assessed using the Self-Determination Theory of Motivation. The themes were: improving/staying healthy or physically active, maintaining functional aspects of physical health, continuing to do the things I want, sustaining mental wellbeing, and preventing disease and aging. Individuals cited goal setting outcomes that were generic, specific or both, and goals related to maintenance of PA and prevention of aging decline, were cited most. The motivation characteristics of these goals in mostly active older adults were autonomous and internally driven. Interventions, including apps, for older adults that encourage them to set specific goal setting outcomes/purposes for PA, are likely to generate stronger internally driven motivation, enhance ownership and participation, and may therefore increase effectiveness.

Epilepsy severity mediates association between mutation type and ADHD symptoms in tuberous sclerosis complex.

The association between attention-deficit/hyperactivity disorder (ADHD) and tuberous sclerosis complex (TSC) is widely reported, with support for the role of epilepsy, yet the mechanisms underlying the association across development are unclear. The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of TSC. In Phase 1 of the study, baseline measures of epilepsy, cortical tuber load, and mutation were obtained with 125 children ages 0-16 years. In Phase 2, at an average of 8 years later, ADHD symptoms were measured for 81 of the participants. Structural equation modeling revealed an indirect pathway from genetic mutation, to cortical tuber load, to epileptic spasm severity in infancy, to ADHD symptoms in middle childhood and adolescence, in addition to a pathway linking current seizure severity to ADHD symptoms. Findings were retained when intelligence quotient (IQ) was entered as a correlated factor. The findings support a cascading developmental pathway to ADHD symptoms mediated by early-onset and severe epilepsy in the first 2 years of life. This warrants detailed investigation of seizure characteristics and cognitive and behavioral sequelae associated with ADHD from early in life, to further the understanding of the association between ADHD and early-onset epilepsy across syndromic and non-syndromic populations.

The challenges of mental health of staff working with people with intellectual disabilities during COVID-19--A systematic review.

BACKGROUND: The COVID-19 pandemic has posed a great risk to the mental health of health workers (HWs). There are likely to be particular concerns for staff working with adults with an intellectual disability, where infection control may be more challenging. METHOD: We conducted a systematic review of original research examining the mental health of HWs working with people with intellectual disability, published between March 2020 and July 2021. RESULTS: Five original research studies were included. A high proportion of HWs working with people with intellectual disability reported having had poor mental health including stress, anxiety, and depression. This manifested in similar patterns as for other HWs and also some specific patterns seen as the need to manage increased rates of mental health issues of the people they support. Sources of support and resilience were also identified. CONCLUSION: The support system should target risk factors, answer unmet needs, and build resilience. More research is also required on the ongoing and long-term effects.

Transcranial ultrasound stimulation to human middle temporal complex improves visual motion detection and modulates electrophysiological responses.

BACKGROUND: Transcranial ultrasound stimulation (TUS) holds promise as a novel technology for non-invasive neuromodulation, with greater spatial precision than other available methods and the ability to target deep brain structures. However, its safety and efficacy for behavioural and electrophysiological modulation remains controversial and it is not yet clear whether it can be used to manipulate the neural mechanisms supporting higher cognitive function in humans. Moreover, concerns have been raised about a potential TUS-induced auditory confound. OBJECTIVES: We aimed to investigate whether TUS can be used to modulate higher-order visual function in humans in an anatomically-specific way whilst controlling for auditory confounds. METHODS: We used participant-specific skull maps, functional localisation of brain targets, acoustic modelling and neuronavigation to guide TUS delivery to human visual motion processing cortex (hMT+) whilst participants performed a visual motion detection task. We compared the effects of hMT+ stimulation with sham and control site stimulation and examined EEG data for modulation of task-specific event-related potentials. An auditory mask was applied which prevented participants from distinguishing between stimulation and sham trials. RESULTS: Compared with sham and control site stimulation, TUS to hMT+ improved accuracy and reduced response times of visual motion detection. TUS also led to modulation of the task-specific event-related EEG potential. The amplitude of this modulation correlated with the performance benefit induced by TUS. No pathological changes were observed comparing structural MRI obtained before and after stimulation. CONCLUSIONS: The results demonstrate for the first time the precision, efficacy and safety of TUS for stimulation of higher-order cortex and cognitive function in humans whilst controlling for auditory confounds.

A Case for Genetic Testing in Isolated Tympanic Paragangliomas.

OBJECTIVE: The aim of this study is to describe two clinical cases, which we believe highlight the need to consider routine genetic testing of all patients with new diagnosis of a tympanic paraganglioma (PGL). PATIENTS: Two patients seen in the ENT clinic at a tertiary center with a diagnosis of isolated tympanic PGL, without family history. INTERVENTION: Since 2016, all patients with newly diagnosed isolated tympanic PGL (glomus tympanicum) are offered review by the clinical genetic team and genetic testing of a panel of paraganglioma/phaeochromocytoma predisposition genes. Previously only those with multiple PGL or a family history were tested. MAIN OUTCOME MEASURES: We describe the results of genetic testing, the clinical course and discuss the ongoing implications for management. RESULTS: Both cases were identified to have a pathogenic variant in the SDHB gene after initial surgery. The clinical course for both cases was complicated by disease recurrence, as well as metastatic and secretory disease in one case. Knowledge of genetic status has influenced ongoing management, with annual MRI surveillance for other SDH-related tumors. CONCLUSION: These two cases reinforce the importance of offering genetic testing for all cases of isolated tympanic PGL. The discovery of a significant underlying genetic variant may affect management decisions and subsequent follow-up.

Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSDs) are caused by immunoglobulin G (IgG) autoantibodies directed against the water channel aquaporin-4 (AQP4). In NMOSDs, discrete clinical relapses lead to disability and are robustly prevented by the anti-CD20 therapeutic rituximab; however, its mechanism of action in autoantibody-mediated disorders remains poorly understood. We hypothesized that AQP4-IgG production in germinal centers (GCs) was a core feature of NMOSDs and could be terminated by rituximab. To investigate this directly, deep cervical lymph node (dCLN) aspirates (n = 36) and blood (n = 406) were studied in a total of 63 NMOSD patients. Clinical relapses were associated with AQP4-IgM generation or shifts in AQP4-IgG subclasses (odds ratio = 6.0; range of 3.3 to 10.8; P < 0.0001), features consistent with GC activity. From seven dCLN aspirates of patients not administered rituximab, AQP4-IgGs were detected alongside specific intranodal synthesis of AQP4-IgG. AQP4-reactive B cells were isolated from unmutated naive and mutated memory populations in both blood and dCLNs. After rituximab administration, fewer clinical relapses (annual relapse rate of 0.79 to 0; P < 0.001) were accompanied by marked reductions in both AQP4-IgG (fourfold; P = 0.004) and intranodal B cells (430-fold; P < 0.0001) from 11 dCLNs. Our findings implicate ongoing GC activity as a rituximab-sensitive driver of AQP4 antibody production. They may explain rituximab's clinical efficacy in several autoantibody-mediated diseases and highlight the potential value of direct GC measurements across autoimmune conditions.

Cervical lymph nodes and ovarian teratomas as germinal centres in NMDA receptor-antibody encephalitis.

Autoantibodies against the extracellular domain of the N-methyl-d-aspartate receptor (NMDAR) NR1 subunit cause a severe and common form of encephalitis. To better understand their generation, we aimed to characterize and identify human germinal centres actively participating in NMDAR-specific autoimmunization by sampling patient blood, CSF, ovarian teratoma tissue and, directly from the putative site of human CNS lymphatic drainage, cervical lymph nodes. From serum, both NR1-IgA and NR1-IgM were detected more frequently in NMDAR-antibody encephalitis patients versus controls (both P < 0.0001). Within patients, ovarian teratoma status was associated with a higher frequency of NR1-IgA positivity in serum (OR = 3.1; P < 0.0001) and CSF (OR = 3.8, P = 0.047), particularly early in disease and before ovarian teratoma resection. Consistent with this immunoglobulin class bias, ovarian teratoma samples showed intratumoral production of both NR1-IgG and NR1-IgA and, by single cell RNA sequencing, contained expanded highly-mutated IgA clones with an ovarian teratoma-restricted B cell population. Multiplex histology suggested tertiary lymphoid architectures in ovarian teratomas with dense B cell foci expressing the germinal centre marker BCL6, CD21+ follicular dendritic cells, and the NR1 subunit, alongside lymphatic vessels and high endothelial vasculature. Cultured teratoma explants and dissociated intratumoral B cells secreted NR1-IgGs in culture. Hence, ovarian teratomas showed structural and functional evidence of NR1-specific germinal centres. On exploring classical secondary lymphoid organs, B cells cultured from cervical lymph nodes of patients with NMDAR-antibody encephalitis produced NR1-IgG in 3/7 cultures, from patients with the highest serum NR1-IgG levels (P < 0.05). By contrast, NR1-IgG secretion was observed neither from cervical lymph nodes in disease controls nor in patients with adequately resected ovarian teratomas. Our multimodal evaluations provide convergent anatomical and functional evidence of NMDAR-autoantibody production from active germinal centres within both intratumoral tertiary lymphoid structures and traditional secondary lymphoid organs, the cervical lymph nodes. Furthermore, we develop a cervical lymph node sampling protocol that can be used to directly explore immune activity in health and disease at this emerging neuroimmune interface.

Staff mental health while providing care to people with intellectual disability during the COVID-19 pandemic.

Background: The COVID-19 pandemic has placed enormous strain on health systems around the world, undermining the mental health and wellbeing of healthcare workers. Supporting people with intellectual disabilities may be particularly challenging for workers, as some people with intellectual disabilities may have a limited understanding of the pandemic, and find it challenging to adhere to the restrictions imposed by public health guidelines such as social distancing, lockdowns and change in usual routine and activities. In addition, many people with intellectual disabilities have increased vulnerability to more negative effects of COVID-19, with significantly higher mortality rates. Although there is emerging research on the mental health of healthcare staff during this time, there has been little specific work on the mental health of staff working with people with intellectual disability, particularly a lack of qualitative research. Methods: The current study employed semi-structured interviews with 13 healthcare workers (12 women and 1 man) who were working with people with intellectual disability during the COVID-19 pandemic. The interview data were analysed using thematic content analysis. Findings: The participants spoke in depth about the challenges of the working environment, the impact of providing care during the pandemic on staff mental health, supporting staff mental health and wellbeing and learning for the future. Conclusions: Systematic efforts are required to protect the mental health of this staff cohort, as well as encouraging resilience and successful coping among staff themselves.