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Staff at our Oxford Simulation,Teaching & Research centre (OxSTaR) helped to develop this new type of aerosol shield designed by Formula One motor racing engineers
Epilepsy Research Institute UK Sudden Unexpected Death in Epilepsy (SUDEP) workshop: Identifying the pre-clinical and clinical priorities for SUDEP research.
The Epilepsy Research Institute's Mortality, Morbidity and Risk Theme workshop on Sudden Unexpected Death in Epilepsy (SUDEP) brought together a diverse group of stakeholders, including basic science researchers, clinicians and clinical researchers, charity partners, bereaved individuals and people with epilepsy to identify important gaps in pre-clinical and clinical SUDEP research. Collectively, the SUDEP workshop highlighted recommendations for future research to address several identified gaps and the need to develop infrastructures that utilise data-driven approaches to reduce SUDEP risk. National and global cross-institution collaborations will be fundamental in driving these research efforts forward.
Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches
AbstractExtracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year‐on‐year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non‐vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its ‘Minimal Information for Studies of Extracellular Vesicles’, which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.
The effects of fasting on acute ischemic infarcts in the rat
Inflammation is largely detrimental early in the acute phase of stroke but beneficial at more chronic stages. Fasting has been shown to reduce inflammation acutely. This preliminary study aimed to determine whether post-ischemic fasting improves stroke outcomes through attenuated inflammation. After an endothelin-1 lesion was created in the striatum, Wistar rats were subjected to either regular feeding or water-only fasting for 24 hours. Brain damage and central inflammation were measured histologically, while systemic inflammation was assessed through blood analysis. After 24 hours, fasting was found to reduce infarct volume and BBB breakdown, and lower both circulating and brain neutrophils. These findings suggest that fasting may be a beneficial non-pharmacological additive therapeutic option for cerebral ischemia, potentially by reducing inflammation in the acute stage of the disease.
Rapamycin Treatment Reduces Brain Pericyte Constriction in Ischemic Stroke
AbstractThe contraction and subsequent death of brain pericytes may play a role in microvascular no-reflow following the reopening of an occluded artery during ischemic stroke. Mammalian target of rapamycin (mTOR) inhibition has been shown to reduce motility/contractility of various cancer cell lines and reduce neuronal cell death in stroke. However, the effects of mTOR inhibition on brain pericyte contraction and death during ischemia have not yet been investigated. Cultured pericytes exposed to simulated ischemia for 12 h in vitro contracted after less than 1 h, which was about 7 h prior to cell death. Rapamycin significantly reduced the rate of pericyte contraction during ischemia; however, it did not have a significant effect on pericyte viability at any time point. Rapamycin appeared to reduce pericyte contraction through a mechanism that is independent of changes in intracellular calcium. Using a mouse model of middle cerebral artery occlusion, we showed that rapamycin significantly increased the diameter of capillaries underneath pericytes and increased the number of open capillaries 30 min following recanalisation. Our findings suggest that rapamycin may be a useful adjuvant therapeutic to reduce pericyte contraction and improve cerebral reperfusion post-stroke.
Prevalence of common autosomal recessive and X-linked conditions in pregnant women in Vietnam: a cross-sectional study.
The prevalence of recessive disorder carriers among Vietnamese women is still indistinct. This study aims to assess the prevalence of carriers for common autosomal recessive and X-linked conditions among Vietnamese pregnant women and to identify common mutations within these genes. A cross-sectional study was conducted with 8,464 Vietnamese pregnant women with indications for carrier screening tests for recessive disorders from November 2022 to August 2023 at the Institute of DNA Technology and Genetic Analysis. The survey includes demographic information, and the genetic screening was conducted using next-generation sequencing (NGS) techniques, focusing on 13 specific recessive conditions. 8,464 Vietnamese pregnant women's records were involved in this study. 1,928 of them carried at least one genetic recessive condition, representing the frequency of a recessive disorder was 22.8%. The highest recessive disorders rate among pregnant women was found for the G6PD gene mutation (G6PD deficiency) at a rate of about 1 in 20 individuals, followed by the HBA1 and HBA2 gene mutations (Alpha Thalassemia) at a rate of about 1 in 25. Other common recessive carrier genes included SRD5A2 (5-alpha reductase deficiency) at a rate of about 1 in 27, HBB (Beta Thalassemia) at a rate of about 1 in 28, ATP7B (Wilson's disease) at a rate of about 1 in 40, PAH (Phenylketonuria) at a rate of about 1 in 40, and SLC25A13 (Citrin deficiency) at a rate of about 1 in 45. The prevalence of recessive carriers among Vietnamese pregnant women is high, and at least 1 in 5 pregnant women carries one recessive gene. It is essential to encourage Vietnamese pregnant women to conduct recessive carrier screening tests to reduce mortality rates among children and to implement effective pregnancy planning and childbirth.
Can we identify stroke sub-type without imaging? A multidimensional analysis
Stroke is a major cause of mortality and disability worldwide, with ischemic stroke (AIS) and intracerebral haemorrhage (ICH) requiring distinct management approaches. Accurate early detection and differentiation of these subtypes is crucial for targeted treatment and improved patient outcomes. Traditionally, imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) are required to distinguish between AIS and ICH. However, this study explores a non-imaging approach to differentiate between stroke subtypes. Using a retrospective dataset of 80 mild-to-moderate patients suffering stroke (68 AIS and 12 ICH), we employed principal component analysis (PCA) combined with logistic regression (LR) to evaluate 67 parameters. These parameters include baroreceptor sensitivity, and cerebral and peripheral hemodynamic variables. The PCA-LR model, validated through two-fold and six-fold cross-validation methods, effectively differentiated between AIS and ICH. BRS parameters and cerebral hemodynamic factors contributed significantly to the model's accuracy. The two-fold cross-validation approach achieved an area under the curve (AUC) of ≥0.92, while the six-fold method maintained a consistent variance explanation (AUC ≥0.79). Results suggest that this multidimensional approach may facilitate early stroke subtype identification (AIS vs ICH) without reliance on imaging, offering a promising tool for ultra-acute stroke care in prehospital settings. However, it is important to note that the model has been tested in confirmed stroke cases, and its ability to distinguish between stroke and stroke mimics remains an important limitation for broader clinical application. Future research with larger datasets is warranted to refine the model and validate its clinical applicability.
Associations of sarcopenia, sarcopenia components and sarcopenic obesity with cancer incidence: A prospective cohort study of 414,094 participants in UK Biobank
AbstractSarcopenia is characterised by low grip strength, muscle quantity or quality, and physical performance. This study investigated the associations of sarcopenia and its components with cancer incidence. A prospective cohort study was conducted utilising data from the UK Biobank. Sarcopenia and its components were defined according to the European Working Group on Sarcopenia in Older People criteria (EWGSOP2 2019). Cox proportional hazard models adjusted for sociodemographic, lifestyle, and health‐related factors were performed. Overall, 63,379 out of 414,094 study participants had an incident diagnosis of cancer during a median follow‐up of 11.7 years. In total, 32,286 participants had probable sarcopenia and 934 confirmed/severe sarcopenia at recruitment. Combined probable, confirmed, and severe sarcopenia was associated with a higher risk of liver (hazard ratio [HR] = 1.65, 95% confidence interval [CI]: 1.17–2.33), haematological (HR = 1.22, 95% CI: 1.01–1.46), and colorectal cancer (HR = 1.21, 95% CI: 1.04–1.41) in males, but not in females. The components of sarcopenia were associated with a higher risk of several cancers, including low grip strength (with liver, haematological and colorectal cancer in males), low muscle mass index (oesophageal in females and oral cancer in males), and slow walking pace (liver and lung in males, lung and overall cancer in females). Compared to participants with non‐sarcopenic obesity, those with sarcopenic obesity had a higher risk of colorectal cancer in males (HR = 1.31, 95% CI: 1.03–1.68). Our study suggests that sarcopenia, sarcopenia components, and sarcopenic obesity can be associated with risk for several cancers, mainly of the gastrointestinal tract and in males. Thus, early identification of sarcopenia components may benefit cancer prevention.
Neurosurgery
The nervous system is the principal means with which we negotiate the outside world. Injury to the nervous system (brain, spinal cord and nerves) therefore may result not simply in physical impairments, but psychological, social and economic impairments too. Legal proceedings therefore may focus upon the effect of medical errors on claimants’ psychological, economic or social capacities, not simply on physical harm. The role of neurosurgery in many disorders of the nervous system concerns prevention of secondary injury: despite the sophistication of modern medicine, damage to the nervous system caused by a primary event (for example, head injury, spontaneous bleed, acutely prolapsed disc) is often irreversible and may set a spiral of deterioration in motion that may be beyond the abilities of physicians to halt.The scope of this chapter is to describe current management strategies of nervous system disorders in which a neurosurgeon would be reasonably expected to play a lead role, although not necessarily an exclusive role. Neurosurgery is a ‘tertiary service’ in the NHS, meaning a patient may have been managed by another hospital-based specialist, or even pre-hospital specialist, prior to transfer to the care of a neurosurgeon. Neurosurgeons may therefore become involved in complaints arising from problems with delayed diagnosis or timely transfer to neurosurgical care, in addition to surgical and post-surgical care.
Genetic testing for monogenic forms of motor neuron disease/amyotrophic lateral sclerosis in unaffected family members
AbstractMotor neuron disease (MND), also referred to as amyotrophic lateral sclerosis (ALS), is a monogenic disease in a minority of cases, with autosomal dominant inheritance. Increasing numbers of people with MND are requesting genetic testing, and indeed receiving a genetic diagnosis. Consequently, requests for genetic counselling and predictive testing (i.e. of unaffected family members) are similarly expected to rise, alongside pre-symptomatic clinical trials. Despite this, there is no evidence-based guideline for predictive genetic testing in MND. This paper provides an overview of the genomic basis of MND, focusing specifically on the most common monogenic causes of MND. It then lays out the complexities of MND predictive testing, including the genetic landscape characterised by incomplete penetrance, clinical and genetic heterogeneity, and an oligogenic mechanism of pathogenesis in some cases. Additionally, there is limited research on the psychosocial impact of predictive genetic testing for MND, with studies suggesting potential difficulty in adjusting to the news, in part due to a lack of support and follow-up. This underscores a case for evidence-based, disease-specific guidance for predictive testing in MND.
Identification of diagnostic candidates in Mendelian disorders using an RNA sequencing-centric approach
Abstract Background RNA sequencing (RNA-seq) is increasingly being used as a complementary tool to DNA sequencing in diagnostics where DNA analysis has been uninformative. RNA-seq enables the identification of aberrant splicing and aberrant gene expression, improving the interpretation of variants of unknown significance (VUSs), and provides the opportunity to scan the transcriptome for aberrant splicing and expression in relevant genes that may be the cause of a patient’s phenotype. This work aims to investigate the feasibility of generating new diagnostic candidates in patients without a previously reported VUS using an RNA-seq-centric approach. Methods We systematically assessed the transcriptomic profiles of 86 patients with suspected Mendelian disorders, 38 of whom had no candidate sequence variant, using RNA from blood samples. Each VUS was visually inspected to search for splicing abnormalities. Once aberrant splicing was identified in cases with VUS, multiple open-source alternative splicing tools were used to investigate if they would identify what was observed in IGV. Expression outliers were detected using OUTRIDER. Diagnoses in cases without a VUS were explored using two separate strategies. Results RNA-seq allowed us to assess 71% of VUSs, detecting aberrant splicing in 14/48 patients with a VUS. We identified four new diagnoses by detecting novel aberrant splicing events in patients with no candidate sequence variants from prior DNA testing (n = 32) or where the candidate VUS did not affect splicing (n = 23). An additional diagnosis was made through the detection of skewed X-inactivation. Conclusion This work demonstrates the utility of an RNA-centric approach in identifying novel diagnoses in patients without candidate VUSs. It underscores the utility of blood-based RNA analysis in improving diagnostic yields and highlights optimal approaches for such analyses.