Search results
Found 22862 matches for
Stephen Hicks, Research Fellow in Neuroscience and Visual Prosthetics, has won the 2014 SET for BRITAIN Gold Award and Engineering Medal
Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis
Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.
Neuronal pSTAT1 hallmarks synaptic pathology in autoimmune encephalitis against intracellular antigens.
Autoimmune encephalitis (AE) is an inflammatory syndrome of the central nervous system (CNS) triggered by aberrant immune responses against neuronal intracellular (IC-AE) or surface (NS-AE) autoantigens. The resulting neuronal alterations and clinical trajectories differ, with IC-AE often leading to fatal outcomes. Unfortunately, the scarce availability of tissue from AE cases has hampered systematic analyses that would allow an understanding of the pathogenesis underlying neuronal alterations in T cell-mediated AE syndromes. Here, we assembled a cohort comprising both NS-AE (n = 8) and IC-AE (n = 12) from multiple institutions to delineate key histopathological features that distinguish neuronal pathology between IC-AE and NS-AE. In contrast to NS-AE, IC-AE lesions present a prominent neuronal pSTAT1 signature, accompanied by a high proportion of brain-resident memory CD8 + T cells and neurodegenerative GPNMB + phagocytes which show synaptic engulfment with little C3-complement deposition. Our findings highlight distinct histopathological features of IC-AE compared to NS-AE, providing actionable biomarkers for diagnostics and treatment strategies.
Distinctive seizure signature in the first video case-control study of a naturally-occurring feline autoimmune encephalitis model.
BACKGROUND AND OBJECTIVE: Autoimmune encephalitis (AE) is a form of brain inflammation where pathogenic autoantibodies bind surface proteins. In humans, AE is at least as common as infective encephalitis, and seizures are a prominent manifestation. The most common adult human AE is associated with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E). AE in non-human mammals is also recognised, notably the polar bear 'Knut', diagnosed with N-methyl D-aspartate receptor antibody encephalitis. LGI1-Ab-E is an emerging cause of spontaneously-arising AE in domestic cats. Our objective was to phenotype the seizure profile of feline LGI1-Ab-E and probe parallels to its human counterpart. METHODS: We characterised seizures in naturally-occurring feline LGI1-Ab-E. Three veterinary and two human neurologists independently blind-rated 35 LGI1-antibody positive and negative feline seizure videos from 24 cats (16 LGI1-Ab-E positive, 8 negative). Data analysed included seizure frequency, semiologies and their co-occurrence, localisation, inter-rater agreement, and predictive factors. RESULTS: The mean number of daily seizures at peak was significantly higher in LGI1-antibody positive compared to LGI1-antibody-negative cats (12.6 vs. 1.9/day, pcorr = 0.011). Semiologies statistically significantly enriched in LGI1-Ab-E observations included orofacial automatisms (88/120, 73 % vs. 26/55, 47 %, pcorr = 0.024), salivation (87/120, 73 % vs. 23/55, 42 %, pcorr = 0.004); and mydriasis (79/120, 66 % vs 19/55, 35 %, pcorr = 0.004), and almost exclusively seen in LGI1-Ab-E were circling (39/120, 33 % vs. 1/55, 2 %, pcorr=<0.001) and aggression (14/120, 12 % vs. 0/55, 0 %, non significant after correction). A temporal lobe onset was proposed in 67 % (80/120) of seropositive ratings, compared to 28 % (15/55) LGI1-Ab-E negative (p
Evaluating the perceived impact and legacy of master’s degree level research in the allied health professions: a UK-wide cross-sectional survey
Abstract Background Post graduate master’s degree qualifications are increasingly required to advance allied health profession careers in education, clinical practice, leadership, and research. Successful awards are dependent on completion of a research dissertation project. Despite the high volume of experience gained and research undertaken at this level, the benefits and impact are not well understood. Our study aimed to evaluate the perceived impact and legacy of master’s degree training and research on allied health profession practice and research activity. Methods A cross-sectional online survey design was used to collect data from allied health professionals working in the United Kingdom who had completed a postgraduate master’s degree. Participants were recruited voluntarily using social media and clinical interest group advertisement. Data was collected between October and December 2022 and was analysed using descriptive statistics and narrative content analysis. Informed consent was gained, and the study was approved by the university research ethics committee. Results Eighty-four responses were received from nine allied health professions with paramedics and physiotherapists forming the majority (57%) of respondents. Primary motivation for completion of the master’s degree was for clinical career progression (n = 44, 52.4%) and formation of the research dissertation question was predominantly sourced from individual ideas (n = 58, 69%). Formal research output was low with 27.4% (n = 23) of projects published in peer reviewed journal and a third of projects reporting no output or dissemination at all. Perceived impact was rated highest in individual learning outcomes, such as improving confidence and capability in clinical practice and research skills. Ongoing research engagement and activity was high with over two thirds (n = 57, 67.9%) involved in formal research projects. Conclusion The focus of master's degree level research was largely self-generated with the highest perceived impact on individual outcomes rather than broader clinical service and organisation influence. Formal output from master’s research was low, but ongoing research engagement and activity was high suggesting master’s degree training is an under-recognised source for AHP research capacity building. Future research should investigate the potential benefits of better coordinated and prioritised research at master’s degree level on professional and organisational impact.
Mobility and Function
Patients experiencing critical illness often have extreme derangement of physiological function requiring admission to an intensive care unit (ICU). Within the ICU, there is an initial focus on aggressive life support, coupled with continuous monitoring and treatment for organ failure. While providing this care, management of the critically ill patient has traditionally involved supine or semi-recumbent positioning and bed rest, mechanical ventilation, analgesia and sedation but with historically little attention placed on long-term outcomes and in particular neuromuscular function. Consequently, survivors of critical illness often experience significant physical, psychological and cognitive morbidity, the effects of which can last for months to years after hospital (Herridge et al., N Engl J Med 364:1293-1304, 2011). Preventing or minimising the physical consequences of critical illness and supporting recovery from intensive care are, therefore, essential to improve patient outcomes. This has placed an increased focus on the importance of early rehabilitation during intensive care, followed by structured and comprehensive programmes of rehabilitation throughout the recovery period.
Exploring individual character traits and behaviours of clinical academic allied health professionals: a qualitative study
Abstract Background Clinical academic allied health professionals can positively impact patient care, organisational performance, and local research culture. Despite a previous national drive to increase these roles, they remain low in number with no clear strategy for growth. Reported barriers to this growth cite organisational and economic factors with little recognition of the challenges posed to individuals. There is a lack of research to help allied health professionals understand the personal challenges of clinical academic training and practice. The aim of this study is to explore the character traits and behaviours of clinical academic allied health professionals to understand the individual attributes and strategies taken to pursue a career in this field. Methods A semi-structured interview study design was used to collect data from aspiring and established clinical academic allied health professionals. Participants were recruited voluntarily through social media advertisement (aspiring) and purposively through direct email invitation (established). Participants were asked about their experience of pursuing a clinical academic career. The interviews were conducted virtually using Zoom and were audio recorded. The data were transcribed verbatim prior to reflexive thematic analysis. Informed consent was gained prior to data collection and the study was approved by the university’s research ethics committee. Results Twenty participants from six allied health professions were interviewed. We developed five themes: risk and reward, don’t wait to be invited, shifting motivations, research is a team sport, and staying the course. Clinical academic allied health professionals demonstrated traits including inquisitiveness, intuition, motivation, and resilience. The source of their motivation was rooted in improving clinical services, conducting research, and personal achievement. Conclusion Clinical academic allied health professionals describe personal traits of high inquisitiveness, opportunism, motivation, and determination in pursuing their career ambitions. The tolerance of rejection, failure, and risk was considered important and viewed as an essential source for learning and professional development. Future research should concentrate on ways to reduce the over-reliance on individual strength of character to succeed in this field and explore programmes to increase the preparedness and support for clinical academics from these professions.